独立行政法人国立病院機構
水戸医療センター
研 究 業 績 集
令和4年度

巻頭言

病院長 米野琢哉
水戸医療センターの基本方針として、「臨床研究を積極的に推進します」を掲げています。
令和４年度は、COVID-19 に継続的に対応しながらも、日常診療を黙々とこなし、臨床研究にも真撃に取り組んでいただきました。職員の皆様のご努力に敬意をはらいたいと思います。
臨床研究の推進は、診療の質向上のためにも必須です。様々な職種の方々が研究に取り組
むことによって、診療の活性化にもつながると期待しております。病院としても、臨床研究部を中心に、資金提供、研究に必要な文書作成のアドバイスなど研究実施のサポートを継続
していきます。今後も是非臨床研究にチャレンジしてみてください。

2022年度

受託研究実績金額

9,010万円

契約種類別グラフ

各種調査¥14,608,418

製造販売後臨床試験¥1,073,864

治験¥74,426,160

診療科別グラフ

呼吸器科

その他診療科

血液内科
循環器科

消化器科

泌尿器科

受託研究実績報告①

受託研究実績金額 （治験・製造販売後臨床試験・製造販売後調査）
実績金額
120,000,000

100,000,000

98,114,743
81,660,560

80,000,000

76,600,888

83,739,626

90,108,442

60,000,000

40,000,000

20,000,000

0

2018年度②

2019年度

2020年度

2021年度

2022年度

治験・製造販売後臨床試験 新規登録症例数
新規登録症例数
45

41

39

40
35

28

30
25
20

20

21

2020年度

2021年度15
10
50

2018年度

2019年度

2022年度NHOネットワーク共同研究
研究責任者

研究課題名(採択番号)

新規症例登録数研究代表者(施設名)

未治療濾胞性リンパ腫における堤 育代

Obinutuzumabの治療成績、
QOL、費用対効果、予後に関する

当該施設
文書同意
新規症例
有・無
登録数

堤育代
（水戸医療センター）

有

4

末永 雅也
完する新規バイオマーカーの確立に関（名古屋医療センター）
する研究

有

8

多施設前向きコホート研究 （採択番号：H31-NHO(血液)-01）

稲毛 芳永

膵癌における腹腔洗浄細胞診を補競争的研究費
主任
分担

研究費
受領日

(単位：円)悠介

水戸医療センター(堤 悠介)

主任

R4.4.81,885,000

湯沢賢治

水戸医療センター(湯沢賢治)

主任

R4.6.30

3,000,000

安田

貢

国立病院機
構三重病院
(谷口清洲)

分担

R4.8.3500,000

科学研究費助成 臓器移植法制・法政策の包括的再事業（科学研究 検証―改正法施行10年目の現況を費補助金）踏まえた提言 (20H01430)

湯沢賢治

分担

R4.8.4520,000

科学研究費助成
包括的外傷長期予後データベースを事業（学術研究用いたテーラーメイド型社会復帰支援
助成基金助成システムの確立(22K10476)
金）

北海道大学
大学院法学
研究科(城下祐二)

堤東海大学(土谷飛鳥)

分担

R4.8.565,000

HAMならびに類縁疾患の患者レジス
厚生労働科学研
トリによる相談機能の強化と診療ガ
究費
イドラインの改訂(22FC1013)

湯沢賢治

分担

R4.8.16200,000

HAM・HTLV-1陽性難治性疾患の日本医療研究開患者レジストリ活用によるエビデンス
発機構研究費創出 (22ek0109529h0002)

湯沢賢治

分担

R4.8.16

325,000

新規HTLV-1感染モデルを用いた
日本医療研究開
HAMの発症予防法・治療法の開発
発機構研究費(22ek0109441h0003)

湯沢賢治

分担

R4.8.16

910,000

項目

研究課題名

科学研究費助成
医師の病院前診察における網羅的事業（学術研究
文献データベース構築とエビデンス診助成基金助成療ギャップの解明 (21K10386)金）
心停止後臓器提供数の減少への効
厚生労働科学研
果的な対策に資する研究究費(21FF2001)
新型インフルエンザ等の感染症発症
厚生労働科学研 時のリスクマネジメントに資する感染究費
症のリスク評価及び公衆衛生的対策の強化のための研究 (20HA1005)

科学研究費助成
文献レジストリ構築とリアルワールド
事業（学術研究
データによる膠原病予後因子の網羅
助成基金助成的負荷推計 (22K10423)
金）
民間セクターからの 腹水濾過濃縮再静注法の臨床応寄附金用への適応拡大

研究者名

堤

悠介

研究事業名
(依頼者名)

聖マリアンナ医科大学医学研究科(山野嘉久)
聖マリアンナ医科大学医学研究科(山野嘉久)
聖マリアンナ医科大学医学研究科(山野
嘉久)

研究費

悠介

昭和大学
(辻本 康)

分担

R4.8.1765,000

矢田部芳治

中外製薬株
式会社

主任

R4.11.21

200,000

堤

英文論文
No
1

タイトル
Real-world treatment patterns and clinical outcomes inpatients with AML in Japan who were ineligible for firstline intensive chemotherapy
Methodological Quality of Physical Therapy-Related

著者

ポイント

吉田近思

12.200

Trials Published in Open Access and Subscription

堤

悠介

6.000

3

Analyzing Chronological Change in Postoperative
Magnetic Resonance Imaging Results in Patients With

小川健

10.4004

Prognostic Implication of PD-L1 Expression on
Osimertinib Treatment for EGFR-mutated Non-small Cell

沼田岳士

5.000

小泉智三

1.450

湯沢賢治

5.600

石田博保

5.800

中村亮太

12.000

石田博保

5.400

堤

悠介

19.600

小川健

6.600

稲留征典

2.300

堤

2.050

2

5
6
7
8

9

10

11

12
13

Journal A Cross-sectional Meta-Epidemiological Study

Kienbock's Disease by Using an Original Grading System

Lung Cancer
Macrophage behaviour 72 hours after implantation of
biodegradable polymer-based sirolimus-eluting stent ina case of ST elevation myocardial infarction
Impact of COVID-19 on living donor liver and kidneytransplantation programs in Japan in 2020
Prospective analysis of the expression status of FGFR2
and HER2 in colorectal and gastric cancer populations:
DS-Screen Study
Effect of Postoperative Muscle Loss After Resection of
Non-small Cell Lung Cancer on Surgical Outcomes
Impact of chronological age on efficacy and safety offluoropyrimidine plus bevacizumab in older non-frail
patients with metastatic colorectal cancer: a combined

analysis of individual data from two phase II studies ofpatients aged > 75 years
Proportion attributable to contextual effects in general
medicine: a meta-epidemiological study based on
Cochrane reviews
Individual Evaluation of the Common Extensor Tendon
and Lateral Collateral Ligament Improves the Severity

Diagnostic Accuracy of Magnetic Resonance Imaging for
Lateral Epicondylitis
Novel translocation of POGZ/STK11 in de novo mast cellleukemia with KIT D816H mutation
The effectiveness of exercise with behavior change
techniques in people with knee osteoarthritis: A
systematic review with meta-analysis

悠介

No
14

15

16

17

18

19

20

21

22

23
24
25

26

27

タイトル
'Hook' Shape Lister Tubercle Is Associated with a Greater
Incidence of Extensor Pollicis Longus Tendon Rupture
after Distal Radius Fracture
Use of a Small Car-Mounted Magnetic Resonance

著者

ポイント

小川健

3.000

Imaging System for On-Field Screening for

小川健

6.600

optica spectrum disorder following the COVID-19 mRNA

田代裕一

2.650

kidney transplantation by quantifying the "nephron

湯沢賢治

6.900

小川健

6.600

小川健

15.200吉田近思

12.200

小泉智三

1.450

遠藤健夫

9.800

中村亮太

1.000

中村亮太

1.800

小川健

1.000

小川健

6.900

岡田脩平

2.000

Osteochondritis Dissecans of the Humeral CapitellumFirst manifestation of AQP4-IgG-positive neuromyelitis
vaccine BNT162b2
Prediction of early graft function after living donor

mass" using CT-volumetric software
Clinical Relevance of Ultrasonographic andElectrophysiological Findings of the Median Nerve in

Unilateral Carpal Tunnel Syndrome Patients
Clinical Significance of Maximum Intensity Projection
Method for Diagnostic Imaging of Thoracic Outlet
Syndrome
Importance of TKI treatment duration in treatment-freeremission of chronic myeloid leukemia: results of the DFREE study
Sustained Lumen Area by Paclitaxel-Coated Balloon
Following Rotational Atherectomy for Napkin-Ring Left
Main Trunk Ostial Lesion
Classifications of moderate to severe asthma
phenotypes in Japan and analysis of serum biomarkers:
A Nationwide Cohort Study in Japan (NHOM Asthma
Study)
Prognostic factors for recurrence in patients withsurgically resected non-small cell lung cancer
Surgical treatment of pulmonary bullous diseases
Flexor Pollicis Longus Tendon Rupture and Carpal

Tunnel Syndrome due to Scaphoid Nonunion Advanced
Collapse: A Case Report.
Potential Relationships between the Median Nerve
Cross-Sectional Area and Physical Characteristics in
Unilateral Symptomatic Carpal Tunnel Syndrome
Patients.
Abdominal compartment syndrome after endscopic
combined intrarenal surgery

No
28

タイトル
Elevation of C-reactive protein during concurrent

chemoradiotherapy is a poor predictive factor for headand neck cancer

著者
瀬成田雅光

ポイント
4.700

和文論文
No

論文名

著者

1

NUP98::DDX10融合遺伝子を有した急性骨髄性白血病

吉田近思

1.000

吉田近思

1.000

安田

貢

1.500

安田

貢

1.500

山名英俊

1.500

福富俊明

1.500

加藤丈人

1.500

森 千子

1.500

湯沢賢治

1.500

2
3

急性骨髄性白血病に対するベネトクラクス治療マネジ
メント
茨城県における新型コロナウイルス感染症医療体制の
構築

ポイント

茨城県における新型コロナウイルス感染症医療体制と4

連携機能強化-行政と医療の連携、県調整本部活動と統括医療連携システム（I-HOPE）-

5
6
7
8
9

二次医療機関での時間外の外傷用CT撮像プロトコル作
成
食道再建術における縫合不全回避のための工夫
組織オキシメータを用いた腸管血流評価法についての検討
当院のBRCA1/2遺伝子検査の現状と課題について
パンデミックは移植医療にどんな影響を与えていますか？

10

ドナー②術前検査

1)生体腎移植

湯沢賢治

1.500

11

ドナー②術前検査

2)死体(献)腎移植

湯沢賢治

1.500

湯沢賢治

1.500

12

新型コロナウイルス感染症（COVID-19）の腎移植への影響

13

心停止後臓器提供

湯沢賢治

1.500

14

移植医からみた子宮移植の論点

湯沢賢治

1.500

湯沢賢治

1.000

湯沢賢治

1.500

湯沢賢治

1.500

湯沢賢治

1.000

湯沢賢治

1.000

15
16
17
18
19

COVID-19感染流行期における摘出医の負担軽減を目指した臓器摘出機材貸出シミュレーション
日本移植学会2021年症例登録 統計報告
わが国における臓器移植のための臓器摘出の現状と実績 (2022)
腎移植臨床登録集計報告（2022） 2021年実施症例の集計報告と追跡調査結果
本邦における腎移植後管理の現状調査と今後の課題

No

論文名

著者

20

腎移植登録事業の現況―ドナーのフォローの必要性ー

湯沢賢治

1.000

湯沢賢治

1.000

湯沢賢治

1.000

森田純一郎

1.000

小川 健

1.500

小川 健

1.000

小川 健

1.500

小川 健

1.500

小川 健

1.000

小川 健

1.500

田中善啓

1.500

21
22
23
24
25
26
27
28
29
30

固形臓器移植患者におけるSARS-CoV-2ワクチン接種
後抗体獲得率に関する実態調査
CT-volumetricソフトウェアを用いたnephron mass定量による生体腎移植後早期グラフト機能の予測
三次救命救急センターにおけるびまん性特発性骨増殖症の有病率と骨折椎体高位の関係
胸郭出口症候群の診断におけるMRIの有用性の検討
手根管症候群で片側に症状を呈した症例における正中神経の電気生理学的特徴
肘関節terrible triad injuryの治療戦略

前方要素の修復は必須か?
【四肢骨折プレート固定術の創意工夫】鎖骨骨幹部骨折(1)(解説)
創外固定で加療した小児上腕骨顆上骨折の治療成績(原著論文)【上肢の麻痺と痛み】複合性局所疼痛症候群(CRPS)に伴う上肢麻痺と痛み(解説)．
救急CT画像活用法-診断・治療・予後-

ポイント

国際学会
学会名

演題名

Different Distribution of CD
163 Positive Macrophages in
American Heart Association
Scientific Session 2022

Thrombus Retrieved frominfarct-related Artery:Atherothrombosis
vs.Cardiogenic

Thrombosis,Pathlolgical
Analyses From MITO study

演者名

発表年月日

TomomiKoizumi ,NoriyukiInamoto, Koji
Nakano, Yu

Yamada, Yuto
Abe, Fumimasa

2022/11/5-7

tabata,Tomosato
Yamazaki,

Masao Ono

Ecessity of remote 3D
imaging creation in

Emergency Radiology: An
European Congress of Radiology
optimal way to enhance
2023, Vienna, Austria
patient satisfaction for qualityof emergency care delivery by
improving availability.

田中善啓

2023/3/1

国内学会
学会名

演題名

演者名

A case of cardiac tamponade
第62回日本リンパ網内系学会 diagnosed as recurrence of AITL by
坪井宥璃
学術集会・総会
detection of the p.Gly17ValRHOA
mutation in pericardial effusions
第41回茨城造血器疾患研究 骨髄異形成症候群に合併した TRALI
橋川 諒
会
type Ⅰ
A real-world multicenter prospective
第83回日本血液学会学術集
堤 育代
cohort study in localized diffuse large
会
B-cell lymphoma
輸血製剤中の抗HLA抗体に起因する輸
日本内科学会第684回関東地
橋川 諒
血関連急性肺方会
傷害(TRALI)type １
骨髄腫に対するVRD 療法と低用量シクロ
第44回日本造血・免疫細胞療
堤 育代
フォスファミド＋ボルテゾミブによる幹細胞動法学会総会
員・自家移植の有効性【ポスターセッションA】(PE04-1)
Impact of Onset-to-balln Time on In
第87回 日本循環器学会学術
hosptal Mortality in Nonagenarian
Tomomi Koizumi（FJCS)
集会
JCS2023
with ST-elevation My-ocardial
FUKUOKA
infarction(Report fromMie ACS Registry)(OE26-8)
Yoshinobu
Murasato,Hitoshi
Nakashima,Hiroshi
Suigino,Masaya
Arakawa,Fumuaki
Mori,Yasunori
Ueda,Kerisuke
第87回 日本循環器学会学術
Oral Presentation26
Matumura,Mitsuura Abe,集会
JCS2023PCI Imaging / Physiology
Tomomi Koizumi,Mitsuhiro
FUKUOKA
Shimomura,Kazuteru Fujimoto,Takahiro Saeki,shogo
ImagawaTakashi
Takenaka,Yukiko
Morita,Katsuro
Kashima,Akira
Takami,Yujiro Ono,Atsuki
第87回 日本循環器学会学術(OJ24-3)Heart Failure Diagnosis
集会
JCS2023FUKUOKA

CROJ12-5
第87回 日本循環器学会学術
Ivabradine Effective Inappropriate
集会
JCS2023
Sinus Tachycar-dia Induced
FUKUOKA
Cardiomyopathy

小泉智三

川邉 優希、小泉 智三、田畑
文昌、丸田 俊介、宇佐美 恭
平、貝塚 奈穂

発表年月日

2022/6/24

2022/6/5
2022/10/14

2023/2/12

2022/5/13

2023/3/10

2023/3/10

2023/3/11

2023/3/11

学会名

演題名

典型的な画像所見を呈さず経食道的気管支鏡下穿刺吸引生検法により診断した
播種性クリプトコッカス症の一剖検例
急性期病院での抗菌薬適正支援チーム
第37回日本環境感染学会（AST）活動の効果
肺小細胞癌に対してデュルバルマブ投与後
第251回日本呼吸器学会関東に irAE による自己免疫性脳炎を呈した一地方会例
肺扁平上皮癌に対する免疫チェックポイン
第253回日本呼吸器学会関東
ト阻害薬（ICI）使用後に肺結核を発症
地方会した一例
尿中抗原が陰性であったが、気管支肺胞
第684回日本内科学会関東地洗浄液のPCR・培養検査で診断に至ったレ方会
ジオネラ肺炎の１例
十二指腸転移を認めた小細胞肺がんの第220回茨城内科学会
１例
両肺に多発する浸潤影、左胸水を呈した
第221回茨城内科学会
肺原発T細胞性リンパ腫の１例
非典型的な画像を呈した肺腺癌・癌性リ
第222回茨城内科学会
ンパ管症の１例
忘れ去られたインフルエンザ〜今冬、捲土
第53回抗酸菌症治療研究会
重来なるか〜
茨城県Respiratory
気管支喘息治療―現状と課題―
Conference
第7回桜の郷チェストカンファレン
呼吸器領域における興味深い症例の提示ス
茨城県中央保健所感染症対 忘れ去られたインフルエンザ〜今冬、復活
策研修会
なるか〜
Lung Cancer Webinar For
肺癌の薬物療法について Part1〜薬物
Pharmacist
療法を知る〜
Lung Cancer Webinar For
肺癌の薬物療法における副作用について
Pharmacist
Part2〜副作用を知る〜
水戸エリア 肺扁平上皮癌
ネシツムマブによる副作用への対応について
WEBセミナー
茨城県内における肺NTM症への取り組み
北関東 NTM誌上座談会と今後の展望完全切除後の非小細胞肺癌
Lung Cancer Online Meeting（NSCLC）治療におけるアンメットメディカ
令和4年度肺がん検診従事者
令和4年度肺がん検診従事者講演会
講演会
第62回日本呼吸器学会学術講演会

呼吸器DICフォーラムin 水戸

呼吸器疾患とDIC

日本消化器病学会関東支部 合併症のない40代男性が出血性胆嚢炎
第３７２回例会を来した一例
日本内科学会第685回関東地 胃癌に対するニボルマブ投与後に発症した
方会
irAE腸炎の１例
小細胞肺癌に対してデュルバルマブ投与後
日本内科学会 第677回関東に発症した抗NMDA受容体抗体陽性自地方会
己免疫性脳炎のirAE例
日本内科学会 第680回関東 骨転移による背部痛で発症した胃悪性黒
地方会
色腫の1例

演者名

発表年月日

羽鳥貴士

2022/4/24

箭内英俊

2022/6/17

山崎健斗

2022/9/10

武石 岳大（退職）2023/2/25

山崎健斗

2023/2/12

米野友一朗

2022/6/18

和田亮一郎

2022/10/16

寺門正尊

2023/3/18

遠藤健夫

2022/12/4

遠藤健夫

2022/10/5

太田恭子

2022/11/16

遠藤健夫

2022/11/18

遠藤健夫

2022/5/18

太田恭子

2022/5/18

箭内英俊

2022/6/8

遠藤健夫

2022/6/11

遠藤健夫

2022/12/12

遠藤健夫

2023/1/25

遠藤健夫

2023/1/26

辻実季

2022/12/10

藤川健太郎

2023/3/11

相澤哲史

2022/5/8

李2022/9/4

礼真

学会名

演題名

演者名

第24回 茨城県脊髄・脊椎研 背部痛で発症し原発巣検索に難渋した転相澤哲史
究会
移性椎体腫瘍の1例
第242回日本神経学会関東甲 関節症状を認めず発症した抗MOG抗体
井岡桂
信越地方会
陽性のリウマチ性髄膜炎の一例
第25回日本臨床救急医学会 茨城県におけるCOVID-19臨時医療施設
安田 貢
総会・学術集会体制整備と運用
新型コロナウイルス感染症・茨城県におけ
第46回茨城県救急医学会
安田 貢
る有事医療体制構築の実際と課題
県内における新型コロナウイルス感染疑い
第46回茨城県救急医学会
安田 貢
傷病者に対する救急車搬送困難対策の早期立案と効果
茨城県における新型コロナウイルス感染症
医療体制構築-行政と医療の連携、県庁 安田貢、石上耕司、塚田紀
第76回国立病院総合医学会
調整本部活動と医療連携システム（i- 明

第50回日本集中治療医学会
第75回日本胸部外科学会定
期学術集会
第84回
総会

日本臨床外科学会

第59回
会総会

日本腹部救急医学

第250回

茨城外科学会

第11回 茨城消化器鏡視下治療研究会（IDES文科会）
第59回 日本腹部救急医学会総会
第37回 日本環境感染学会
総会・学術集会
第30回 日本乳癌学会学術総会
第67回 日本透析医学会学術集会・総会
第77回
会総会

日本消化器外科学

第46回

茨城県救急医学会

第58回

日本移植学会総会

第30回 日本消化器関連学会週間（JDDW 2022）

HOPE)
集中治療領域におけるランダム化比較試
験と系統的レビューの出版数の傾向：メタ
疫学研究
術前体組成計を用いて筋量を評価した肺癌手術症例の検討
腹部主要3動脈の慢性狭窄を背景に生じた右側結腸虚血に対し血管内治療が奏功した1例
適切に診断・治療し重篤化重篤化を回避できた胆嚢出血の１例
上部消化管造影検査後にバリウム塊によるS状結腸穿孔を来たし治療に難渋した肥満男性の１例
LAR～助手との協調～

腹腔鏡手術を施行した結腸脾弯曲部捻転の1例
当院のサイトメガロウイルス(CMV)抗体陽
性 ドナーから抗体陰性レシピエント腎移植の対策
乳癌患者の難治性大量腹水に対する腹水濾過濃縮再静注法（CART）
腎移植患者の自己腎腎癌の検討
Result of 10 years of surveillance forsurgical site infection in lower
gastrointestinal surgery
同一ドナーから提供された 同日2腎献腎移植の経験
わが県の腎移植に現状からみた地域の移植医療の未来～働き方改革で問題は解決するのか？～
消化器悪性腫瘍難治性腹水に対する低温保存腹水濾過濃縮再静注法

堤

発表年月日
2022/12/5
2022/9/5
2022/5/26
2022/9/10
2022/9/10

2022/10/7

悠介

2023/3/2

飛田理香

2022/10/8

小林仁存

2022/11/25

和田亮一郎

2023/3/10

山本恭彰

2022/5/21

山本恭彰

2023/3/23

成田保和

2023/3/9

小﨑浩一

2022/6/16

小﨑浩一

2022/6/30

小﨑浩一

2022/7/1

小﨑浩一

2022/7/20

小﨑浩一

2022/9/10

小﨑浩一

2022/10/13

小﨑浩一

2022/10/28

学会名

演題名

ワークショップ：「移植関連（移植患者の外科感染症対策）」
腎移植患者における尿路感染症発症のrisk factorの検討
S状結腸癌腹膜播種による難治性腹水に第43回 日本アフェレシス学会
対し繰り返し腹水濾過濃縮再静注法を学術大会行った高齢者患者の一例
第56回 茨城人工透析談話
抗ドナー抗体陽性腎移植の3例
会
ワークショップ：低温保存腹水CART（腹第19回 CART研究会学術集 水濾過濃縮再静注法）の安全性に関す
会
る検討～CART研究会・多施設共同研究～
第56回 日本臨床腎移植学 ABO血液型不適合・抗ドナー抗体陽性腎会
再移植の2例
第39回日本呼吸器外科学会 当院における病理病期Ⅰ期肺腺癌症例
学術集会の検討
第59回 日本腹部救急医学 診断に苦慮した膿瘍形成下行結腸粘液会総会
癌の1例
第30回 日本乳癌学会学術 進行・再発乳癌の腫瘍マーカーの推移につ総会
いての検討
第18回 日本乳癌学会関東
腎細胞癌術後乳腺転移の1例
地方会
第日本外科代謝栄養学会
胃切除術後再建方法と骨格筋量減少の第59回学術集会
関連
第77回 日本消化器外科学 異なるアプローチ法を行った腰ヘルニアの2
会総会
例
第35回 日本内視鏡外科学 右側肝円索に伴う左側胆嚢に対して腹腔会総会
鏡下胆嚢摘出術を行った1例
第59回 日本腹部救急医学
当院における閉鎖孔ヘルニアの治療成績
会総会
県央地区の脳卒中急性期治療に対する
我が街脳卒中を考える会
取り組みについて茨城県央県北ブレインアタック 水戸・ひたちなか医療圏の脳卒中連携にフォーラム
ついて再考する
脳出血に対する磁場式ナビゲーション下血第81回 日本脳神経外科学
腫吸引術+ウロキナーゼ注入療法の安全会学術総会
性と効果の検討
第81回 日本脳神経外科学 血流改変 (Flow diverter stent)ステント会学術総会
留置術後に広範白質浮腫を呈した1例
第107回茨城脳神経外科集談 血流改変 (Flow diverter stent)ステント会
留置術後に広範白質浮腫を呈した1例
当院でのFD使用経験
PIPELINE STEP UP SEMINAR
第35回 日本外科感染症学
会総会学術集会

茨城脊椎・脊髄カンファレンス

嚥下障害で発症したびまん性特発性骨増殖症(DISH)の1例

第5回関東HLA研究会学術集
臓器移植とHLA会
第６７回日本透析医学会学
腎移植up to date，腎移植登録事業の
術集会
現況，
・総会

演者名

発表年月日

小﨑浩一

2022/11/8

小﨑浩一

2022/11/10

小﨑浩一

2022/11/13

小﨑浩一

2022/12/3

小﨑浩一

2022/2/11

栗原秀輔

2022/5/20

栗原秀輔

2023/3/10

森千子

2022/6/30

森千子

2022/12/3

米山

智

2022/7/7

米山

智

2022/7/21

米山

智

2022/12/9

米山

智

2023/3/10

山崎友郷

2022/4/19

加藤徳之

2022/6/4

山崎友郷

2022/9/28

加藤徳之

2022/9/28

加藤徳之

2022/10/16

加藤徳之

2022/10/21

加藤徳之

2022/12/5

湯沢賢治

2022/6/4

湯沢賢治

2022/7/1

学会名

演題名

演者名

発表年月日

湯沢賢治

2022/11/4

森田純一郎

2022/6/25

森田純一郎

2022/6/25

小林賢司

2022/7/8

森田純一郎

2022/10/14

森田純一郎

2022/10/13

小川健

2022/3/5

小川健

2022/4/23

小川健

2022/5/21

小川健

2023/2/4

小川健

2023/2/4

小川健

2023/2/4

思春期前のリトルリーガーにおける肘関節
内側障害に関する高分解能MRI
母指CM関節症患者における牽引MRIによる関節軟骨評価
野球選手における超音波検査での肘関節
外反弛緩性評価時の至適肢位小川健2023/2/3

小川健

2022/5/21

小川健

2022/5/21

大学野球選手における肩関節外転外旋位での回旋筋力の特徴

小川健2022/5/21

車載型ポータブルMRIによる上腕骨離断性骨軟骨炎検診の有用性

小川

健2022/5/21

野球選手の尺骨神経脱臼は投球側で多
いか?

小川

健

2022/11/12

胸郭出口症候群の補助診断としてMRI最大値投射法は有効か小川

健

2022/5/21

上腕骨外側上顆炎に対するMRI検査
治療指標としての有用性の検討

小川健

2022/5/20

第48回日本臓器保存生物医 臓器移植患者のCOVID-19－日本移植学会学術集会
学会COVID-19対策委員会の活動－
第48回日本骨折治療学会学 上方アプローチによる人工骨頭置換術は第術集会
一助手の経験が重要である
第48回日本骨折治療学会学 2方向透視法による経皮的椎弓根スク
術集会
リュー固定の逸脱率と関連因子の検討
第45回日本骨・関節感染症学 BCG膀胱内注入療法後に感染性大動脈会学術集会
瘤を経て結核性脊椎炎を発症した1例
第37回日本整形外科学会基 Transiliac-transsacral screw挿入のため
礎学術集会の術中透視仙骨側面像の検討
ゲームエンジンを用いた骨折手術VRプレート
第37回日本整形外科学会基
術前計画の試み 模擬骨を使用した基
礎学術集会
礎実験
キーンベック病に対する骨髄血移植・創外第36回東日本手外科研究会
固定・低出力超音波併用治療
第65回日本手外科学会学術
キーンベック病の病態に迫る
集会
Chronological change inpostoperative magnetic resonance
第95回日本整形外科学会学
imaging results in patients with Kienb
術総会
öck’s disease using an original
grading system
第35回日本肘関節学会学術 スポーツ選手における特発性肘部管症候
集会群手術例の特徴
第35回日本肘関節学会学術 スポーツ選手の特発性肘部管症候群手術
集会例における神経伝導速度検査の有用性
上腕骨遠位端骨折に対する第35回日本肘関節学会学術
A.L.P.S.Elbow Plating Systemの治療成集会
績
第35回日本肘関節学会学術集会
第95回日本整形外科学会学術総会
第95回日本整形外科学会学術総会
第95回日本整形外科学会学術総会
第95回日本整形外科学会学術総会
第33回日本臨床スポーツ医学会学術集会
第95回日本整形外科学会学術総会
第95回日本整形外科学会学
術総会

学会名

演題名

演者名

発表年月日

第19 回茨城形成外科研究会

遊離DIEP皮弁による再建乳房・採取部に低温熱傷を生じた1例

手口円花

2022/6/10

左脛腓骨開放骨折Gastilo3Bの1例

笠井丈博

2022/8/14

笠井丈博

2022/11/12

手口円花

2023/3/11

岡田脩平

2022/11/11

岡田脩平

2022/12/4

飯沼昌宏

2022/11/11

飯沼昌宏

2022/10/29

飯沼昌宏

2022/6/4

齋藤拓郎

2022/6/18

栃木・茨城（第6回形成外科）Peer Review Meeting

Local flapとcomposite graftを併用した
鼻翼再建の2例
第16回筑波大学形成外科同 汚染が疑われる眼窩部複合組織損傷に
門会
対して、一期的に再建した1例
悪性を否定しえない前立腺間質腫瘍に対
第36回日本泌尿器内視鏡・ロ
しロボット支援腹腔鏡下前立腺全摘術をボティクス学会総会
施行した1例
腸管利用膀胱拡大術後30年目に腎後
第26回秋田腎不全研究会
性腎不全のため透析導入に至った1例
第36回日本泌尿器内視鏡・ロ 当院におけるロボット支援下体外尿路変ボティクス学会総会
更膀胱全摘術の初期経験
第87回日本泌尿器科学会東 腎癌術後12年目に乳腺転移をきたした1部総会
例
右腎尿管膀胱全摘回腸導管術後の骨第19回泌尿器再建再生研究
盤再発による左水腎症に対して腹腔鏡下会
尿管皮膚廔作成術を行った1例
同一腎に腎血管金脂肪腫と腎細胞癌が第123回茨城地方会
同時発生した1例
第20回茨城形成外科研究会

第124回茨城地方会

後腹膜に発生した骨髄脂肪腫の1例

齋藤拓郎

2022/10/16

第125回茨城地方会

新型コロナウイルス感染症に関連した虚血性持続勃起症の1例

齋藤拓郎

2023/2/18

日本サイコネフロロジ―学会

移植腎廃絶後の透析回避

仲宮優子

2022/7/23

第46回茨城県救急医学会

COVID-19禍の献腎移植仲宮優子

2022/9/10

木村梨奈

2022/10/8

仲宮優子

2022/10/15

仲宮優子

2023/2/12

田所あき穂

2022/10/7

田中善啓

2022/4/16

田中善啓

2022/5/26

田中善啓

2022/7/1

新井杏奈

2022/10/8

幡谷夏海

2022/6/12

第76回国立病院総合医学会
日本移植学会
日本臨床腎移植学会
第76回国立病院総合医学会

当院におけるOICに対する治療の現状
ナルデメジントシル塩酸錠の使用状況と効果
RTCが考える腎代替療法選択におけるSDM
RTCの育成～私がRTCを目指し、継続できた理由～
カルバペネム系抗菌薬の使用実態と薬剤師の関わり方

第78回日本放射線技術学会
CT撮影における標準化改訂 救急領域
総会学術大会
第25回日本臨床救急医学会 COVID-19における放射線部門の感染対
総会・学術集会
策：ハイブリットチーム化の有用性
第36回日本外傷学会総会・学 外傷における潜伏性股関節骨折の早期術集会
診断MRIとCTスキャンの比較
腎細胞癌術後13年で発見された転移性
第76回国立病院総合医学会
乳腺腫瘍の１例
高齢心不全患者における退院時身体機第２８回日本心臓リハビリテー
能と再入院までの期間の検討(県内２施ション学会学術集会
設前向き観察研究⁾

学会名
第７６回国立病院総合医学会

演題名

橋損傷患者における前頭葉由来の高次脳機能障害の調査
運動恐怖症がTKA術後患者の身体機能
第７6回国立病院総合医学会に及ぼす影響について
高齢HFpEF患者における入院中の心臓リ
第76回国立病院総合医学会 ハビリテーションが身体機能に与える効果の検討
サルコペニアを有する周術期肺がん患者の第76回国立病院総合医学会
リハビリテーションの必要性
感染管理体制下における、治験実施体制
整備の取り組みについて
第22回 CRCと臨床試験のあ～COVID-19対象患者の治験からCRCのり方を考える会議
役割について考える～

演者名

発表年月日

中津川泰生

2022/10/8

村島昂瑛

2022/10/7

柳澤宏昭

2022/10/8

木村匠吾

2022/10/7

小野直美

2022/9/17

令和4年度院内臨床研究課題
研究代表者
相澤哲史

課題名
免疫チェックポイント阻害薬を使用した担癌患者における免疫関連有配分額

害事象（irAE）発現に影響を与える因子を探索する後ろ向き症例集

690,000

小川 健

手関節周辺疾患に対する造影ダイナミックMRIの有用性に関する研究

800,000

佐藤真剛

亜急性期大動脈解離に対するステントグラフト治療の中期成績

450,000

田中善啓

放射線診断における遠隔３D画像作成運用の可能性と検証

1,000,000

堤 悠介

外傷診療中のCTにおける偶発的所見の発見率：系統的レビュー・メタ
アナリシス

630,000中村亮太

肺癌術前の筋量・筋力が術後に与える影響について明らかにする

600,000

森田純一郎
山崎友郷
山本恭彰
米山 智

積研究

寛骨臼骨折に対する骨盤模型を用いたプレート成形の有効性を検討
する観察研究茨城県のELVOスクリーンによる主幹動脈閉塞症例搬送システム導入による臨床転帰に与える影響について
横行結腸癌の発生部位の差における至適術式についての後ろ向き観察研究
胃切除術後の再建形成と骨格筋量・体脂肪量変化の関連および臨床経過との関連についての研究

500,000
500,000
500,000
600,000

水戸医療センター
令和4年度

代表的論文

International Journal of Hematology
https://doi.org/10.1007/s12185-022-03334-8

ORIGINAL ARTICLE

Real‑world treatment patterns and clinical outcomes in patientswith AML in Japan who were ineligible for first‑line intensive
chemotherapy
Chikashi Yoshida1 · Takeshi Kondo2 · Tomoki Ito3 · Masahiro Kizaki4 · Kazuhiko Yamamoto5 · Toshihiro Miyamoto6 ·Yasuyoshi Morita7 · Tetsuya Eto8 · Yuna Katsuoka9 · Naoki Takezako10 · Nobuhiko Uoshima11 · Kazunori Imada12 ·Jun Ando13 · Takuya Komeno1 · Akio Mori2 · Yuichi Ishikawa14 · Atsushi Satake3 · Junichi Watanabe4 ·Yoshiko Kawakami15 · Tetsuo Morita15 · Ikue Taneike15 · Masahiko Nakayama15 · Yinghui Duan16 ·Belen Garbayo Guijarro17 · Alexander Delgado18 · Cynthia Llamas16 · Hitoshi Kiyoi14
Received: 16 November 2021 / Revised: 15 March 2022 / Accepted: 15 March 2022
© Japanese Society of Hematology 2022

Abstract
Acute myeloid leukemia (AML) predominantly affects elderly adults, and its prognosis worsens with age. Treatment options
for patients in Japan ineligible for intensive chemotherapy include cytarabine/aclarubicin ± granulocyte colony-stimulating
factor (CA ± G), azacitidine (AZA), low-dose cytarabine (LDAC), targeted therapy, and best supportive care (BSC). The
country’s aging population and the evolving treatment landscape are contributing to a need to understand treatment pathways
and associated outcomes. This retrospective chart review evaluated outcomes in patients across Japan with primary/secondary AML who were ineligible for intensive chemotherapy and began first-line treatment or BSC between 01/01/2015 and12/31/2018. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS)and healthcare resource utilization (HRU). Of 199 patients (58% > 75 years), 121 received systemic therapy (38 CA ± G, 37
AZA, 7 LDAC, 39 other) and 78 received BSC. Median OS was 5.4, 9.2, 2.2, 3.8, and 2.2 months for CA ± G, AZA, LDAC,
other systemic therapy, and BSC, respectively; median PFS was 3.4, 7.7, 1.6, 2.3, and 2.1 months, respectively. HRU rates
were uniformly high, with > 80% patients hospitalized in each cohort. The poor clinical outcomes and high HRU among
Japanese AML patients who are ineligible for intensive chemotherapy highlight an unmet need for novel therapies.
Keywords Acute myeloid leukemia · Azacitidine · Aclarubicin ± granulocyte colony-stimulating factor · Low-dose
cytarabine
Department and institution in which the work was done: Kyushu
University Hospital, Department of Hematology, Oncology &Cardiovascular Medicine. Hamanomachi Hospital, Department
of Hematology. Okayama City General Medical Center,
Department of Hematology. Osaka Red Cross Hospital,
Department of Hematology. Kindai University Hospital,
Department of Hematology and Rheumatology. Kansai Medical
University Hospital, Department of Hematology-Oncology.
Japanese Red Cross Kyoto Daini Hospital, Department of
Hematology. Nagoya University Hospital, Department of
Hematology. Juntendo University Hospital, Department of
Hematology. National Hospital Organization Disaster Medical
Center, Department of Hematology. Saitama Medical Center,
Saitama Medical University, Department of Hematology.
National Hospital Organization Mito Medical Center,
Department of Hematology. Sendai Medical Center, Department
of Hematology. Aiiku Hospital, Department of Hematology andBlood Disorders Center.
Extended author information available on the last page of the article

Introduction
Acute myeloid leukemia (AML) is a clonal hematopoietic
malignancy characterized by high molecular and pathogenic
heterogeneity [1, 2]. Although AML accounts for only about
1% of cancers, it is the most common form of acute leukemia in adults (approximately a quarter of total leukemia
cases) and is the leading cause of leukemia-related death[1, 3]. AML primarily affects older adults, and the medianage at diagnosis is 68 years [3]. In Japan, approximately
40–50% of patients with leukemia are diagnosed at the ageof 75 years or older [4]. The global incidence of AML is rising with an aging population, almost doubling between 1990
and 2017 [5, 6]. In Japan, the annual incidence of AML is
5.6/100,000 and this rises to 10–17/100,000 for those older
than age 69 years [7].

13Vol.:(0123456789)

C. Yoshida et al.

Patients with AML have a poor prognosis, particularly
those with advanced age [8]. Older patients have a long-term
survival rate of < 10%, compared with 30–50% for patients
younger than age 60 years [1]. For patients aged 75 years orolder, the estimated 5-year survival rate is as low as 1.5%
[6].
Historically, the standard of care for AML has been
induction therapy with 7 days of standard-dose cytarabineand 3 days of an anthracycline (‘7 + 3’ regimen) followedby consolidation therapy, with hematopoietic stem celltransplantation an option for eligible patients [1, 2, 9, 10].
However, older patients and those with comorbidities or apoor performance status are often unable to tolerate suchintensive therapy [9, 10]. For patients considered ineligible
for intensive treatment, low-dose cytarabine (LDAC) andbest supportive care (BSC) are among the few options recommended by Japanese guidelines [11, 12]. In Japan, cytarabine, aclarubicin ± granulocyte colony-stimulating factor(CA ± G) [11, 13–15], and the recently approved hypomethylating agent, azacitidine (AZA) [16], have also been practical treatment options for patients with AML ineligible forintensive treatment.
Despite complete remission (CR) rates of up to 58%
reported following treatment with CA ± G [13], outcomesin patients with AML deemed ineligible for intensive
chemotherapy typically remain poor [17–21], and overall survival (OS) estimates range from 7.5–12.1 months
for CA ± G, 7.7–10.4 months for hypomethylating agents,
4.1–6.4 months for LDAC, and 3.6–3.7 months for BSC [15,17, 18, 22–27].
Increased understanding of the heterogeneity of AML
has led to the development of targeted, chemotherapy-freetherapies including B-cell lymphoma-2 (BCL-2), FMS-liketyrosine kinase-3 (FLT3), and hedgehog inhibitors [1, 2,
8, 9]. Although the use of targeted therapies as first-line
therapy for AML is currently limited in Japan, the recent
approval of venetoclax, a BCL-2 inhibitor, has expanded
the available options for patients with AML ineligible forintensive chemotherapy [28].
As novel agents and management strategies become
increasingly, but not uniformly, available, there is an unmet
need to understand current treatment pathways and theirassociated clinical outcomes. Furthermore, patients with
AML place a high burden on healthcare systems, with hospitalizations more frequent among older patients than their
younger counterparts [29]. There is also a need to understand the healthcare resource utilization (HRU) affiliatedwith different treatment pathways.
CURRENT (Real-World Treatment Patterns and Clinical Outcomes in Unfit AML Patients Receiving First Line
Systemic Treatment or Best Supportive Care) was a retrospective chart review designed to examine real-world treatment patterns and HRU in patients who were ineligible for

13

intensive chemotherapy and received first-line systemic
therapy or BSC [30]. Here, we report a subanalysis of the
CURRENT study population that evaluated the clinical outcomes, patient characteristics, treatment patterns, and HRU
of patients with AML in Japan. This study collated data frompatients who initiated treatment between 2015 and 2018,
therefore, prior to the approval of venetoclax and AZA for
AML in Japan.

Methods
Study design
This noninterventional retrospective chart review was carried out in patients diagnosed with AML who were considered ineligible for intensive induction chemotherapy andwho initiated first-line treatment or BSC between January
1, 2015 and December 31, 2018. Sites with eligible patientsthat exceeded the site enrolment limit (10–27 patientsdepending on the site) used a random sampling method toselect patients for inclusion; the total number of eligible
patients was divided by the maximum number allowed toenrol to determine the selection factor (i.e., every 3rd or 4th
patient). The study was carried out in accordance with theguidelines for good pharmacoepidemiology practices in noninterventional studies and the ethical guidelines for medical
and health research involving human subjects. Treatment
was determined by each treating investigator. Data collection
was carried out anonymously following ethics committee
approval. CURRENT was conducted across 112 centers in
22 countries. This subanalysis focused on the patients who
received treatment at 14 centers across Japan.

Patient selection and data collection
Patients were ≥ 18 years old, diagnosed with primary or
secondary AML, and were deemed ineligible for intensive
chemotherapy. Ineligibility for intensive induction therapy
was defined on the basis of treating physician’s assessmentof age, Eastern Cooperative Oncology Group (ECOG)
performance status, comorbidities, regional guidelines,
and institutional practice [31]. Patients with unconfirmed
AML diagnosis, acute promyelocytic leukemia, and those
who received first-line treatment within a clinical trial were
excluded. Patients had to have received first-line systemictreatment with CA ± G, AZA, LDAC, targeted therapy, or
BSC, and had ≥ 2 practice visits during the treatment period,in addition to the initial treatment visit (defined as start ofsystemic treatment or BSC). Patients were followed until thelast recorded contact or death, whichever was applicable atthe time of data collection. Anonymized patient data wereextracted from patient charts and/or site documentation andReal‑world treatment patterns and clinical outcomes in patients with AML in Japan who were…

recorded via electronic case report forms (CRFs) completed
by each center.

Endpoints
The primary endpoint was overall survival (OS), measured from diagnosis of AML. Secondary clinical endpoints
included progression-free survival (PFS, measured fromdiagnosis of AML to physician-assessed disease progression or death), time to treatment failure (TTF; defined as thetime from start of first-line systemic therapy or BSC until
treatment discontinuation for any reason), and response rates(complete remission [CR] + CR with incomplete hematologic recovery [CRi]) according to the treating physician’s
assessment. Additional secondary endpoints were minimal
residual disease (MRD) testing rates, and HRU determinedby hospitalizations, outpatient consultations, transfusions(red blood cell [RBC] and/or platelet), supportive care(including growth factors) and other medications (including antibiotics, antivirals, and antifungals) from the initiation of first-line systemic therapy or BSC until treatment
discontinuation.

Statistical analysis
Formal statistical power considerations are not provided dueto the descriptive nature of the study. The final data cutoff
was March 31, 2020. Continuous variables are describedwith mean, standard deviation, median, and ranges. Categorical variables are reported as counts and proportions.
Time-to-event data were estimated using the Kaplan–Meiermethod, with median time and 95% confidence intervals(CIs) reported.

Results
Baseline demographics and patient disposition
In total, the CURRENT study enrolled 1,762 patients across
22 countries. The highest recruitment was from the Japanand Asia–Pacific region (n = 610; 35%), including 199
patients who were enrolled from Japan. The majority ofpatients treated in Japan were male (n = 125; 63%) and older
than age 75 years at diagnosis (n = 116; 58%). Most patients
had intermediate (n = 88; 44%) or poor (n = 76; 38%) cytogenetic risk and 42% (n = 27) of those with available data carried a mutation.
Of the 199 patients enrolled from Japan, 121 (61%)
received first-line systemic therapy: 38 (31%) received
CA ± G; 37 (31%) received AZA; 7 (6%) received
LDAC; and 39 (32%) received other systemic therapy
which included cytarabine, aclarubicin, FLT3 inhibitors,

gemtuzumab ozogamicin, enocitabine, venetoclax, andtherapy combinations which included CA ± G, AZA, andLDAC. The remaining 78 patients (39%) received BSC,
which included transfusions as needed (n = 63; 81%), infection management (n = 47; 60%), pain relief (n = 27; 35%),
nutritional support (n = 19; 24%), and other supportive
measures (n = 6; 8%).
Baseline characteristics were generally similar between
the systemic therapy and BSC cohorts, although the LDAC
group had a higher proportion of patients older than age
75 years at diagnosis (86 vs 59% of all patients who received
first-line systemic therapy) and the majority of patients inthis group had secondary AML (71%) versus 32–46% in theother treatment groups. The AZA group and CA ± G groups
had a higher proportion of patients with ECOG performancestatus 0–1 (70 and 58%, respectively, vs 31–49% in the othertreatment groups), and the AZA and other systemic therapy
groups had a higher proportion of patients with poor cytogenetic risk (43 and 59%, respectively, vs 28–34% in the othertreatment groups; Table 1). Overall, there were no consistentimbalances of comorbidities across groups.
For patients with available data, the median proportion of blast cells in bone marrow aspirate at baseline was
46% (range 2.0–96.0%) for patients who received CA ± G,
30% (10.0–88.0%) for AZA, 42% (22.0–99.0%) for LDAC,
65% (22.8–98.5%) for other systemic therapy, and 41%(0.8–97.4%) for BSC, respectively.
At the time of the data cutoff, first-line treatment had
been discontinued by 95% of patients in the CA ± G group,
95% of the AZA group, 100% of the LDAC group, 97%of the other systemic therapy group, and 90% of the BSC
group (Fig. 1). The most common reasons for discontinuation across the systemic treatment groups were diseaseprogression (n = 49; 42%), treatment completion (n = 28;24%), and death (n = 20; 17%). The most common reasonsfor discontinuation of BSC were death (n = 47; 67%) andpatient preference (n = 11; 16%).
Second-line systemic therapy was received by 49 (25%)
patients, the majority of whom received CA ± G (n = 13;
27%) or AZA (n = 12; 24%) (Fig. 2A). The majority ofpatients who went on to receive BSC had initially received
first-line AZA. Most patients who initially received BSC did
not receive any subsequent therapy (Fig. 2B).

Primary endpoint
There were 166 (85%) deaths by the final data cutoff on
March 31, 2020, which included 84% (n = 32), 81% (n = 30),
86% (n = 6), 92% (n = 35), and 83% (n = 63) of patients who
received CA ± G, AZA, LDAC, other systemic therapy
and BSC, respectively. Median OS from diagnosis was
4.0 months (95% CI 3.1–5.1) for the overall population.
Median (95% CI) OS from diagnosis was 5.4 (2.7–14.6)

13

C. Yoshida et al.
Table 1  Baseline demographics and disease characteristics
First-line systemic therapy (n = 121)

GenderMale
Age at diagnosis
Age, median (range), years> 75 years
Secondary AML
YesNo
Unknown
ECOG performance status
0–1≥2
Unknown
AML classification (WHO)AML with recurrent genetic abnormalities
AML with MDS-related changes
Therapy-related myeloid neoplasms
AML not otherwise specified
Myeloid sarcoma
Unknown
Molecular features i­dentifiedb
Any ­mutationc
TP53 mutation
FLT3 ­mutationd
FLT3ITD mutation
No mutation
Unknown molecular profile
Cytogenetic risk
Favorable
Intermediate
Poor
Unknown
Comorbiditiesb
Any
Myocardial infarction
Angina/coronary artery disease
Congestive heart failure
Arrhythmias
Restrictive lung disease or COPD
Liver cirrhosis (Child Pugh A, B, or C)
Elevated transaminases (elevation not related to liver cirrhosis)
Renal failure or CKD stage 3, 4 or 5
Other
None
Unknown
Elevated transaminases (elevation not related to liver cirrhosis) OR
Renal failure or CKD stage 3, 4

13

a

BSC
n = 78CA ± Gn = 38AZA
n = 37

LDAC
n=7

Other
n = 3921 (55)22 (60)4 (57)

21 (54)57 (73)77 (52–89)
22 (58)78 (64–88)
22 (59)80 (70–85)
6 (86)

76 (57–89)
21 (54)77 (49–89)
45 (58)12 (32)25 (66)1 (3)

17 (46)19 (51)1 (3)5 (71)
2 (29)0

13 (33)25 (64)1 (3)35 (45)38 (49)5 (6)22 (58)11 (29)5 (13)

26 (70)8 (22)3 (8)

3 (43)
3 (43)
1 (14)

19 (49)19 (49)1 (3)

24 (31)38 (49)16 (21)4 (11)
17 (45)2 (5)9 (24)
1 (3)
5 (13)

027 (73)1 (3)6 (16)
03 (8)03 (43)
0
2 (29)
0
2 (29)

4 (10)
13 (33)1 (3)
12 (31)1 (3)9 (23)7 (9)
33 (42)2 (3)17 (22)019 (24)

2 (5)
0
0
0
6 (16)
30 (79)2 (5)1 (50)00
12 (32)23 (62)0000
2 (29)
5 (71)

11 (28)1 (9)1 (9)4 (36)
8 (21)
20 (51)

12 (15)3 (25)
1 (8)
2 (17)
10 (13)56 (72)4 (11)
20 (53)
13 (34)1 (3)0
19 (51)16 (43)2 (5)0
4 (57)
2 (29)
1 (14)

1 (3)
12 (31)23 (59)
3 (8)

4 (5)
33 (42)22 (28)19 (24)30 (79)1 (3)0
6 (16)
2 (5)
0
2 (5)
2 (5)
1 (3)
22 (58)8 (21)0
4 (11)

26 (70)1 (3)5 (14)2 (5)1 (3)
5 (14)
0
2 (5)
2 (5)
20 (54)10 (27)
1 (3)
2 (5)

5 (71)0
1 (14)0
1 (14)000
0
4 (57)
2 (29)00

32 (82)3 (8)5 (13)
1 (3)
2 (5)
2 (5)
1 (3)
0
2 (5)
23 (59)7 (18)02 (5)

67 (86)
4 (5)
3 (4)
2 (3)
5 (6)
5 (6)
2 (3)
1 (1)
8 (10)
56 (72)10 (13)1 (1)8 (10)

Real‑world treatment patterns and clinical outcomes in patients with AML in Japan who were…
Table 1  (continued)
Data are n (%) unless otherwise stated
AML acute myeloid leukemia, ASXL1 additional sex comb-like 1, AZA azacitidine, BSC best supportive care, CA ± G cytarabine aclarubicin ± granulocyte colony-stimulating factor, CKD chronic kidney disease, COPD chronic obstructive pulmonary disease, C-P Child Pugh,
ECOG Eastern Cooperative Oncology Group, FLT3 FMS-like tyrosine kinase-3, FLT3ITD FLT3 mutation with the internal tandem duplication,
FLT3TKD FLT3 mutation in the tyrosine kinase domain, G-CSF granulocyte colony-stimulating factor, JAK2 Janus kinase 2, LDAC low-dose
cytarabine, MDS myelodysplastic syndrome, TET2 Ten-Eleven-Translocation-2, TP53 tumor protein p53, WHO World Health OrganizationaOther includes cytarabine, aclarubicin, FLT3 inhibitors, gemtuzumab ozogamicin, enocitabine, venetoclax, and therapy combinations which
included AZA, LDAC, and CA ± Gbcd

Percentages may sum up to > 100% as multi-selection was permitted
Used as a denominator for the following subcategories
Not specified as FLT3ITD or FLT3TKD mutation

Data collected for
199 anonymized patientsBest supportive care
N=78

First-line systemic therapy
N=121

CA±G
n=38

AZA
n=37

LDAC
n=7

Other systemic therapy
n=39

Treatment ongoing: 5%
Discontinued: 95%a
• Diseaseprogression: 36%• Toxicity: 8%• Decline in performancestatus: 6%• Financial: 0%• Completed
treatment: 36%• Death: 17%• Patient preference: 6%• Physician
preference: 3%• Other: 6%• Unknown: 3%

Treatment ongoing: 3%
Discontinued: 95%a
• Diseaseprogression: 54%• Toxicity: 23%• Decline in performancestatus: 3%• Financial: 0%• Completed
treatment: 11%• Death: 9%• Patient preference: 9%• Physician
preference: 0%• Other: 3%• Unknown: 6%

Treatment ongoing: 0%
Discontinued: 100%a• Diseaseprogression: 14%• Toxicity: 0%• Decline in performancestatus: 14%• Financial: 0%• Completed
treatment: 29%• Death: 29%• Patient preference: 0%• Physician
preference: 14%• Other: 0%• Unknown: 14%

Treatment ongoing: 0%
Discontinued: 97%a
• Diseaseprogression: 42%• Toxicity: 8%• Decline in performancestatus: 8%• Financial: 3%• Completed
treatment: 24%• Death: 24%• Patient preference: 13%• Physician
preference: 0%• Other: 5%• Unknown: 0%

Treatment ongoing: 0%
Discontinued: 90%a
• Diseaseprogression: 7%• Toxicity: 0%• Decline in performancestatus: 1%• Financial: 0%• Completed
treatment: 1%• Death: 67%• Patient preference: 16%• Physician
preference: 1%• Other: 14%• Unknown: 4%

Fig. 1  Patient disposition. aPercentages may sum up to > 100% as multi-selection was permitted. AZA azacitidine, CA ± G cytarabine, aclarubicin ± granulocyte colony-stimulating factor, LDAC low-dose cytarabinemonths for patients who received CA ± G, 9.2 (5.0–13.1)
months for patients who received AZA, 2.2 (0.1–16.6)
months for patients who received LDAC, 3.8 (1.4–9.1)
months for patients who received other systemic therapy,
and 2.2 (1.7–3.6) months for patients who received BSC(Fig. 3).

Secondary efficacy endpoints
The median PFS was 3.0 months (95% CI 2.2–3.8) for
the overall population. The median (95% CI) PFS was 3.4(1.7–5.7), 7.7 (3.4–10.1), 1.6 (0.1–2.3), 2.3 (0.9–4.4), and

2.1 (1.6–3.1) months for patients who received CA ± G,
AZA, LDAC, other systemic therapy, and BSC, respectively(Fig. 4). The median (95% CI) TTF was 1.5 (0.5–23.3), 5.8(2.1–10.5), 0.3 (0.1–not estimable), 1.3 (0.3–8.0), and 1.5(0.7–1.9) months, respectively (Fig. 5).
Of the 121 patients who received first-line systemic
therapy, CR/CRi was achieved by 19 (16%) patients,
including 12 (32%) who received CA ± G, 1 (3%) who
received AZA, none who received LDAC, and 6 (15%)
who received other systemic therapy (Table 2). The
median time to best response was 34, 64, 38, and 29 days
for patients who received CA ± G, AZA, LDAC, and13

C. Yoshida et al.

AFirst-line therapy
N=199

Second-line therapy
N=70

Systemictherapies

Systemictherapies

CA±G
38 (19%)BSC
78 (39%)Othera39 (20%)B

BSC
21 (30%)CA±G
13 (19%)AZA
12 (17%)AZA
37 (19%)Othera21 (30%)LDAC
7 (4%)LDAC
3 (4%)

n=203b
200

LDAC
AZA

150
N patients

CA±G

100

Other
LDAC
AZA

50

CA±G

BSC

Other

LDAC
AZA
CA±G
Other

BSC
BSC

0
1
First line of treatment
LDAC
AZA
CA±G

2
Lines of treatment
Othera

BSC

Fig. 2  Overview of first-and second-lines of treatment received (A)and an alluvial plot detailing treatment patterns over four lines oftreatments (B). aOther includes cytarabine, aclarubicin, FLT3 inhibitors, gemtuzumab ozogamicin, enocitabine, venetoclax, and therapy
combinations which included AZA, LDAC, and CA ± G. bFour
patients are included who did not have first-line therapy data; theseother systemic therapy, respectively. The median durationof CR/CRi for patients who received first-line systemic
therapy was 189 days (range 47–648), including 191, 80,

13

3

NA

patients were not included in the main analysis but are shown here
because they had recorded data for subsequent lines of therapy. AZA
azacitidine, BSC best supportive care, CA ± G cytarabine, aclarubicin ± granulocyte colony-stimulating factor, LDAC low-dose cytarabine

Real‑world treatment patterns and clinical outcomes in patients with AML in Japan who were…

Median OS(95% CI), months

AZA(n=37)LDAC(n=7)

Othera(n=39)

BSC(n=78)

5.4(2.7–14.6)

9.2(5.0–13.1)

2.2(0.1–16.6)

3.8(1.4–9.1)

2.2(1.7–3.6)

0.8

0.6

0.4

0.2
Censored

0.0

Number at risk
CA±G
AZA
LDAC
Other
BSC

0

10

20
Months

30

40

38
37
7
38
76

16
16
1
10
7

8
2
0
4
2

2
1

0
0

1
1

0
0

Median PFS(95% CI), months

CA±G(n=38)

AZA(n=37)LDAC(n=7)

Othera(n=39)

BSC(n=78)

3.4(1.7–5.7)

7.7(3.4–10.1)

1.6(0.1–2.3)

2.3(0.9–4.4)

2.1(1.6–3.1)

1.0

0.8
Probability of PFS

Fig. 4  KM curves for PFS inpatients who received CA ± G,
AZA, LDAC, other systemic
therapy and BSC. aOther
includes cytarabine, aclarubicin,
FLT3 inhibitors, gemtuzumab
ozogamicin, enocitabine,
venetoclax, and therapy
combinations which included
AZA, LDAC, and CA ± G. AZA
azacitidine, BSC best supportive
care, CA ± G cytarabine, aclarubicin ± granulocyte colony-stimulating factor, CI confidence
interval, KM Kaplan–Meier,
LDAC low-dose cytarabine, PFS
progression-free survival

CA±G(n=38)

1.0

Probability of OS

Fig. 3  KM curves for OS inpatients who received CA ± G,
AZA, LDAC, other systemic
therapy and BSC. aOther
includes cytarabine, aclarubicin,
FLT3 inhibitors, gemtuzumab
ozogamicin, enocitabine,
venetoclax, and therapy
combinations which included
AZA, LDAC, and CA ± G. AZA
azacitidine, BSC best supportive
care, CA ± G cytarabine, aclarubicin ± granulocyte colony-stimulating factor, CI confidence
interval, KM Kaplan–Meier,
LDAC low-dose cytarabine, OSoverall survival

0.6

0.4

0.2
Censored

0.0

Number at risk
CA±G
AZA
LDAC
Other
BSC

0

10

20
Months

30

40

38
37
7
39
76

10
13
0
6
7

3
0

1

0

1
2

0
1

0

and 214 days for patients who received CA ± G, AZA, andother systemic therapy, respectively.
MRD assessments were carried out for 7 (6%) patients
who received first-line systemic treatment. All 7 patients
received just one assessment which was evaluated byreal-time quantitative polymerase chain reaction. Peripheral blood was used for analysis in 5 (71%) patients andbone marrow was used for 2 (29%) patients. One patient had
undetectable MRD, 5 had detectable MRD, and MRD status
was unknown for one.

13

C. Yoshida et al.
Fig. 5  KM curves for TTF in
patients who received CA ± G,
AZA, LDAC, other systemic
therapy and BSC. aOther
includes cytarabine, aclarubicin,
FLT3 inhibitors, gemtuzumab
ozogamicin, enocitabine,
venetoclax, and therapy
combinations which included
AZA, LDAC, and CA ± G. AZA
azacitidine, BSC best supportive
care, CA ± G cytarabine, aclarubicin ± granulocyte colony-stimulating factor, CI confidence
interval, KM Kaplan–Meier,
LDAC low-dose cytarabine, TTF
time to treatment failure

Median TTF(95% CI), months

CA±G(n=38)

AZA(n=37)LDAC(n=7)

Othera(n=39)

BSC(n=78)

1.5(0.5–23.3)

5.8(2.1–10.5)

0.3(0.1–NE)

1.3(0.3–8.0)

1.5(0.7–1.9)

1.0

Probability of TTF

0.8

0.6

0.4

0.2
Censored

0.0

Number at risk
CA±G
AZA
LDAC
Other
BSC

0

10

20
Months

30

40

33
34
5
38
65

5
9
0
3
5

3
1

1
0

0

0
2

0

Table 2  Response outcomes offirst-line systemic treatment

First-line systemic therapy (n = 121)Best response, n (%)
CR
CRi
PR
SD
PD
Unknown
Median time from start of treatment to best
response, days (range)
Median duration of CR/CRi, days (range)
Median time from start of treatment todisease progression, days (range)

CA ± Gn = 38AZA
n = 37LDAC
n=7Otheran = 3910 (26)2 (5)4 (11)
9 (24)
7 (18)
6 (16)
34 (6–126)

1 (3)0
10 (27)
11 (30)7 (19)
8 (22)
64 (3–477)

00
1 (14)
1 (14)
0
5 (71)
38 (22–54)

6 (15)0
4 (10)
8 (21)
8 (21)
13 (33)29 (0–81)

191 (47–648)
69 (9–676)

80 (80–80)
203 (8–553)–
51 (2–150)

214 (132–362)
119 (0–356)

AZA azacitidine, CA ± G cytarabine aclarubicin ± granulocyte colony-stimulating factor, CR complete
response, CRi CR with incomplete hematologic recovery, FLT3 FMS-like tyrosine kinase-3, LDAC lowdose cytarabine, PD disease progression, PR partial response, SD stable diseasea

Other includes cytarabine, aclarubicin, FLT3 inhibitors, gemtuzumab ozogamicin, enocitabine, venetoclax, and therapy combinations which included AZA, LDAC, and CA ± G

Healthcare resource utilization
Hospitalization rates were high in all treatment groups,
with 84% of patients who received CA ± G, 92% of patients
who received AZA, 86% of patients who received LDAC,
90% of patients who received other systemic therapy, and
90% of patients who received BSC admitted to hospitalduring first-line treatment (Table 3). The median number

13

of days hospitalized was 21 for patients who received firstline systemic therapy and 14 for patients who received
BSC. The most common reasons for hospitalization during
first-line systemic therapy were treatment administration(79%) and infection (26%). Among patients who received
BSC, the most common reasons for hospitalization were
infection (43%) and transfusion (36%).

Real‑world treatment patterns and clinical outcomes in patients with AML in Japan who were…
Table 3  Healthcare resource utilization during first-line systemictreatment or BSC

Hospitalized, n (%)
Median days hospitalized(range)Outpatient consultations,n (%)
Median number of visits(range)RBC/platelet transfusions,n (%)
Median number of RBC
transfusions (range)
Median number of platelet transfusions (range)
Antibiotic or antiviral use,n (%)
Prophylatic ­usea, n (%)
Curative ­usea, n (%)­Unknowna, n (%)
Median days on treatment(range)Antifungal use, n (%)
Prophylatic ­usea, n (%)
Curative ­usea, n (%)­Unknowna, n (%)
Median days on treatment(range)Growth factor use, n (%)
Prophylatic ­usea, n (%)
Curative ­usea, n (%)­Unknowna, n (%)
Median days on treatment(range)First-line systemic therapy
n = 121BSC
n = 78107 (88)
21 (1–933)

70 (90)14 (1–99)

64 (53)37 (47)

8 (1–296)

9 (1–250)

51 (42)39 (50)5 (0–71)

5 (0–42)

4 (0–129)

2 (0–42)104 (86)

56 (72)54 (52)74 (71)6 (6)25 (1–370)

25 (45)45 (80)7 (13)
20 (3–740)

84 (69)59 (70)31 (37)5 (6)33 (1–548)

30 (39)17 (57)15 (50)7 (23)
29 (8–724)

28 (23)2 (7)
25 (89)1 (4)
14 (2–56)

3 (4)0
3 (100)0–

AZA azacitidine, BSC best supportive care, CA ± G cytarabine, aclarubicin ± granulocyte colony-stimulating factor, FLT3 FMS-like tyrosine kinase-3, LDAC low-dose cytarabine, RBC red blood cellaPercentages may sum up to more than 100% as multi-selection isallowedThe majority of patients received antibiotics or antivirals
during first-line treatment (86% of patients in the first-line
systemic therapy groups and 72% of patients in the BSC
group). Antibiotics and antivirals were most often used in
response to infection rather than prophylactically in thefirst-line systemic therapy (71 and 52%) and BSC groups(80 and 45%). Patients received antibiotics and antivirals
for a median of 25 days (range 1–370) across the first-line
systemic therapy groups and 20 days (range 3–740) in the
BSC group. Antifungals were received by 69% of patientsin the first-line systemic therapy groups and 38% of patients

who received BSC. Antifungals were more frequently usedprophylactically than in response to infection (70 and 37% in
the first-line systemic therapy groups, and 57% and 50% in
the BSC group). Patients received antifungals for a medianof 33 days (range 1–548) across the first-line systemic therapy groups and 29 days (range 8–724) in the BSC group. A
minority of patients received growth factors (23% of patients
who received first-line systemic therapy and 4% of patients
who received BSC), which were most often used in response
to infection rather than prophylactically in the first-line systemic therapy (89 and 7%) and BSC groups (100 and 0%).
Growth factors were received for a median of 14 days (range
2–56) across the first-line systemic therapy groups (unknown
duration for the patients who received BSC; Table 3).

Discussion
This noninterventional, retrospective chart review assessed
the clinical outcomes and treatment patterns of patientswith AML who were ineligible for intensive therapy andwho instead received treatment with CA ± G, AZA, LDAC,
other systemic therapy, or BSC in Japan. The cohort of 199
patients recruited from Japan was generally older than theoverall CURRENT cohort, with 58 versus 47% older thanage 75 years at diagnosis [30]. Patients treated in Japan also
had a higher rate of intermediate (44 vs 32%) and poor (38vs 25%) cytogenetics than those in the overall cohort, which
may reflect the increased likelihood of unfavorable cytogenetics observed in older patients [12, 30].
The majority of patients treated in Japan received firstline systemic treatment (61%), with approximately equal
proportions (~ 20% each) receiving CA ± G, AZA, and othersystemic therapy. LDAC was not commonly selected, despite
being recommended by Japanese guidelines [32], and BSC
was received by 39% of patients. Contrary to guideline
recommendations, use of AZA and CA ± G was common
and use of LDAC was infrequent, showing the gap between
these guidelines and real-world practice. In the overall CURRENT cohort a higher proportion (74%) received first-line
systemic therapy and 26% received BSC. Furthermore, of
those patients who received first-line systemic therapy in theoverall cohort, the majority (62%) received hypomethylating
agents, and CA ± G was not a common choice. The differences in treatment patterns between cohorts may be partly
reflective of the older age and more unfavorable cytogenetics
of patients treated in Japan.
The median OS of the Japan cohort ranged from
2.2 months (LDAC and BSC groups) to 9.2 months (AZA
group). Patients who received CA ± G had a numerically shorter median OS than those who received AZA(5.4 months vs 9.2 months) despite a numerically higher
rate of CR/CRi (32 vs 3%). Although baseline characteristics

13

C. Yoshida et al.

were broadly comparable between these groups, it is noteworthy that the AZA group had a higher proportion ofpatients with secondary AML and poor cytogenetic risk thanthe CA ± G group.
Of patients who received first-line systemic therapy,
the LDAC group had particularly poor outcomes. The percentage of patients older than age 75 years at diagnosis
was higher in the LDAC group (86 vs 59% of all patients
who received first-line systemic therapy) and most patients
who received LDAC had secondary AML (71%), whereas
the majority of patients in other therapy groups had primary AML. However, it is worth noting that just 7 patients
received LDAC therapy in Japan so these data should beinterpreted with particular caution.
Median OS was numerically lower in this cohort fromJapan compared with the overall CURRENT cohort (4.0 vs
6.2 months), which, again, may reflect the older age andmore unfavorable cytogenetics of patients treated in Japan.
However, median OS was consistent between the Japan andoverall cohorts for patients who received hypomethylating
agents (9.2 and 9.9 months, respectively) and BSC (2.2
and 2.5 months), but lower for those who received LDAC
(2.2 and 7.9 months) or other systemic therapy (3.8 and5.4 months) in Japan [30]. Although meaningful comparison
with previous studies is limited by inter-study variability andsmall patient numbers, survival outcomes in this cohort fromJapan were broadly comparable with previous reports for
those who received AZA, but lower for the CA ± G, LDAC,
and BSC groups [15, 17, 18, 22–27].
Rates of CR/CRi were also consistently lower acrossthe groups for patients treated in Japan compared with theoverall cohort (16 vs 21% for all patients who received firstline systemic therapy); however, the CR/CRi rate was notably higher for the CA ± G group versus the other groups inJapan, a treatment group not stratified in the overall cohort
due to low utilization [30]. This is consistent with previous
reports of complete remission rates for CA ± G of 20–58%[13–15, 26].
This subanalysis highlights the rationale for use of
CA ± G and AZA in Japan for patients who are consideredineligible for standard intensive chemotherapy. Although
AZA use in this study may have been limited as it was not
approved for the treatment of AML in Japan during the follow-up period, these data support its use as a practical option
for this patient population in the real-world scenario. It isalso notable that almost 40% of patients received BSC. In
this subanalysis, there was no substantial difference in age,
ECOG performance status, and comorbidities between thepatient groups receiving BSC and first-line systemic therapies. It is possible that the attending physicians factored in
all these biometrics when making treatment decisions inselecting BSC or first-line systemic therapy. In addition, theintentions of the patients and their families might have had

13

impacted treatment decisions. Therefore, how these factors
have influenced the treatment outcome is not clear and isbeyond the scope of this retrospective chart review.
HRU was consistently high between this analysis andthe overall CURRENT cohort, with consistently high rates
of hospitalization across the treatment groups. The highest
rates of outpatient consultations and RBC/platelet transfusions were reported for the AZA group (65% for both, vs
29–53% and 29–50% for the other treatment groups). A
lower proportion of patients in the Japan cohort had outpatient consultations or transfusions compared with the realworld cohort across all treatment groups [33]. These data
are consistent with previous reports of high HRU by patientswith AML [29, 34] and reflects a need to alleviate the burden
on healthcare systems.
The treatment landscape has evolved since the inceptionof this study, with increased understanding of the molecular heterogeneity of AML driving the emergence of novel,targeted therapies [1, 2, 9]. Notably, 67% of patients in thissubanalysis did not have molecular profiling, compared with
47% in the overall CURRENT cohort, which may be reflective of insurance coverage and limited access to molecularprofiling in clinical practice in Japan. Subsequently, only
20% of patients received other systemic therapies. Consensus guidelines are needed to guide treatment selection andoptimize outcomes, alongside a greater understanding of
how to best utilize novel therapies.
The results of this chart review are limited by several
factors which should be considered when interpretingthese data. The design is uncontrolled and nonrandomized,
increasing the potential for patient selection bias. Smallgroup sizes, particularly for those who received LDAC
(n = 7), limit meaningful conclusions. The findings arealso limited by missing data (26% of patients were missing
response data). The extensive number of treatment combinations utilized within the “other systemic therapy” groupconfound interpretation of these data. The limited use ofsome targeted agents reflects their approval status in Japan
during the study period.
This subanalysis of CURRENT, a large real-world study,
provides insight into treatment patterns and their associatedoutcomes for patients with AML in Japan at a time of landscape evolution. Overall, the clinical outcomes for patientswith AML in Japan who are ineligible for intensive chemotherapy remain poor and HRU by this population is high.
There is an unmet need to develop novel therapies and newer
combination regimens for this patient population to improveoutcomes and alleviate the burden on healthcare systems.
Acknowledgements Medical writing support was provided by Hayley
Ellis, PhD, of Fishawack Communications Ltd, and funded by AbbVie.

Real‑world treatment patterns and clinical outcomes in patients with AML in Japan who were…
Author contributions Study conception and design: Yoshiko
Kawakami, Tetsuo Morita, Ikue Taneike, Masahiko Nakayama, Yinghui Duan, Belen Garbayo Guijarro, Alexander Delgado, and Cynthia
Llamas. Collection and assembly of data: All authors. Analysis andinterpretation of data: All authors. Manuscript writing, editing, andapproval: All authors.
Funding AbbVie funded this study and participated in the study
design, research, analysis, data collection, interpretation of data,
reviewing, and approval of the publication. All authors had access torelevant data and participated in the drafting, review, and approval ofthis publication. No honoraria or payments were made for authorship.
Data sharing statement AbbVie is committed to responsible data
sharing regarding the clinical trials we sponsor. This includes accessto anonymized, individual, and trial-level data (analysis data sets), as
well as other information (e.g., protocols and Clinical Study Reports),
as long as the trials are not part of an ongoing or planned regulatory
submission. This includes requests for clinical trial data for unlicensed
products and indications. This clinical trial data can be requested by
any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval ofa research proposal and Statistical Analysis Plan (SAP) and executionof a Data Sharing Agreement (DSA). Data requests can be submitted
at any time and the data will be accessible for 12 months, with possible extensions considered. For more information on the process, orto submit a request, visit the following link: https://​www.​abbvie.​com/​our-s​ cien​ce/c​ lini​cal-t​ rials/​clini​cal-​trials-​data-​and-​inform​ ation-​shari​ng/​
data-​and-​infor​mation-​shari​ng-​with-​quali​fied-​resea​rchers.​html.

Declarations
Conflict of interest C. Yoshida: Investigator on AbbVie-funded clinical study. Honoraria from Bristol Myers Squibb, Novartis Pharma
KK, Pfizer Japan Inc., Otsuka Pharmaceutical., AbbVie, Janssen Pharmaceutical KK, Nippon Shinyaku Co., Ltd., Chugai PharmaceuticalCo., Ltd. Research funding from Bristol Myers Squibb. T. Kondo:
Advisory role for Astellas Pharma, Otsuka Pharmaceutical. Honoraria
from Astellas Pharma, Bristol Myers Squibb, Otsuka Pharmaceutical,
Novartis, and Sumitomo Dainippon Pharma. T. Ito: Research funding from AbbVie and Bristol Myers Squibb. Honoraria from AbbVie,
Bristol Myers Squibb, Takeda Pharmaceutical Sanofi, CSL Behring,and Novartis. M. Kizaki, Y. Morita, T. Eto, Y. Katsuoka, N. Takezako,
N. Uoshima, J. Ando, A. Mori, A. Satake, J. Watanabe: No potential
conflicts of interest are reported. K. Yamamoto, T. Komeno: Investigator on AbbVie-funded clinical study. T. Miyamoto: Honoraria from
AbbVie, Astellas Pharmaceutical, Astellas Amgen Pharmaceutical,
Bristol Myers Squibb, Celgene, Merck Sharp & Dohme, Otsuka Pharmaceutical, and Takeda Pharmaceutical. K. Imada: Honoraria from
Astellas Pharma, Bristol Myers Squibb, Celgene, Chugai Pharmaceutical, Kyowa Hakko Kirin, Nippon Shinyaku, Novartis, Otsuka Pharmaceutical, and Takeda Pharmaceutical. Y. Ishikawa: Personal feesfrom AbbVie, Astellas Pharma, Chugai Pharmaceutical, Daiichi-Sankyo, FUJIFILM, Kyowa Hakko Kirin, Nippon Shinyaku, Novartis, andPfizer. Y. Kawakami, T. Morita, I. Taneike, M. Nakayama, Y. Duan,
B. Garbayo Guijarro, A. Delgado, C. Llamas: Employees of AbbVie
and may hold stock or options. H. Kiyoi: Research funding from AbbVie, Astellas Pharma, Bristol Myers Squibb, Chugai Pharmaceutical,
CURED Inc., Daiichi Sankyo, Eisai, FUJIFILM, Kyowa Hakko Kirin,
Nippon Shinyaku, Novartis, Otsuka Pharmaceutical, Perseus Proteomics, Pfizer, Sanofi, Sumitomo Dainippon Pharma, Takeda Pharmaceutical, and Zenyaku Kogyo. Honoraria from Astellas Pharma, Bristol
Myers Squibb, and Novartis.

References
1. Hou HA, Tien HF. Genomic landscape in acute myeloid leukemia
and its implications in risk classification and targeted therapies. J
Biomed Sci. 2020;27:81.
2. Kantarjian H, Kadia T, DiNardo C, Daver N, Borthakur G, Jabbour E, et al. Acute myeloid leukemia: current progress and future
directions. Blood Cancer J. 2021;11:41.
3. National Cancer Institute. Cancer stat facts: leukemia—acute
myeloid leukemia (AML) 2020 [Available from: https://​seer.​cancer.​gov/​statf​acts/​html/​amyl.​html.
4. Cancer Information Service NCC, Japan. Chronic lymphocytic
leukemia/small lymphocytic lymphoma. 2016. Available from:https://​ganjo​ho.​jp/​public/​cancer/​CLL/.
5. Yi M, Li A, Zhou L, Chu Q, Song Y, Wu K. The global burden
and attributable risk factor analysis of acute myeloid leukemia in
195 countries and territories from 1990 to 2017: estimates basedon the global burden of disease study 2017. J Hematol Oncol.
2020;13:72.
6. Thein MS, Ershler WB, Jemal A, Yates JW, Baer MR. Outcome ofolder patients with acute myeloid leukemia: an analysis of SEER
data over 3 decades. Cancer. 2013;119:2720–7.
7. Miyamoto K, Minami Y. Precision medicine and novel moleculartarget therapies in acute myeloid leukemia: the background ofhematologic malignancies (HM)-SCREEN-Japan 01. Int J Clin
Oncol. 2019;24:893–8.
8. Palmieri R, Paterno G, De Bellis E, Mercante L, Buzzatti E,
Esposito F, et al. Therapeutic choice in older patients with acute
myeloid leukemia: a matter of fitness. Cancers (Basel). 2020.
https://​doi.​org/​10.​3390/​cance​rs120​10120.
9. National Comprehensive Cancer Network. Clinical practice guidelines in oncology. Acute Myeloid Leukemia. 2020;2:2021.
10. Heuser M, Ofran Y, Boissel N, Brunet Mauri S, Craddock C,
Janssen J, et al. Acute myeloid leukaemia in adult patients: ESMO
clinical practice guidelines for diagnosis, treatment and follow-up.
Ann Oncol. 2020;31:697–712.
11. Kiyoi H, Yamaguchi H, Maeda Y, Yamauchi T. JSH practical guidelines for hematological malignancies, 2018: I. Leukemia-1. Acute myeloid leukemia (AML). Int J Hematol.
2020;111:595–613.
12. Naoe T. Editors’ choice how to improve outcomes of elderly
patients with acute myeloid leukemia: era of excitement. Nagoya
J Med Sci. 2020;82:151–60.
13. Wei G, Ni W, Chiao JW, Cai Z, Huang H, Liu D. A meta-analysis
of CAG (cytarabine, aclarubicin, G-CSF) regimen for the treatment of 1029 patients with acute myeloid leukemia and myelodysplastic syndrome. J Hematol Oncol. 2011;4:46.
14. Minakata D, Fujiwara S, Ito S, Mashima K, Umino K, Nakano H,
et al. A low-dose cytarabine, aclarubicin and granulocyte colonystimulating factor priming regimen versus a daunorubicin plus
cytarabine regimen as induction therapy for older patients withacute myeloid leukemia: a propensity score analysis. Leuk Res.
2016;42:82–7.
15. Jin J, Chen J, Suo S, Qian W, Meng H, Mai W, et al. Low-dose
cytarabine, aclarubicin and granulocyte colony-stimulating factor
priming regimen versus idarubicin plus cytarabine regimen as
induction therapy for older patients with acute myeloid leukemia.
Leuk Lymphoma. 2015;56:1691–7.
16. MHLW approval of ­Vidaza® (azacitidine) for the treatment of
acute myeloid leukemia. [press release]. 2021.
17. Dombret H, Seymour JF, Butrym A, Wierzbowska A, Selleslag
D, Jang JH, et al. International phase 3 study of azacitidine vsconventional care regimens in older patients with newly diagnosed
AML with >30% blasts. Blood. 2015;126:291–9.

13

C. Yoshida et al.
18. Amadori S, Suciu S, Selleslag D, Aversa F, Gaidano G, Musso
M, et al. Gemtuzumab ozogamicin versus best supportive carein older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol.
2016;34:972–9.
19. Ma E, Bonthapally V, Chawla A, Lefebvre P, Swords R, LafeuilleMH, et al. An evaluation of treatment patterns and outcomes inelderly patients newly diagnosed with acute myeloid leukemia:
a retrospective analysis of electronic medical records from US
community oncology practices. Clin Lymphoma Myeloma Leuk.
2016;16:625-36 e3.
20. Medeiros BC, Satram-Hoang S, Hurst D, Hoang KQ, Momin F,
Reyes C. Big data analysis of treatment patterns and outcomesamong elderly acute myeloid leukemia patients in the UnitedStates. Ann Hematol. 2015;94:1127–38.
21. DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker
PS, et al. Venetoclax combined with decitabine or azacitidine intreatment-naive, elderly patients with acute myeloid leukemia.
Blood. 2019;133:7–17.
22. Seymour JF, Dohner H, Butrym A, Wierzbowska A, Selleslag D,
Jang JH, et al. Azacitidine improves clinical outcomes in older
patients with acute myeloid leukaemia with myelodysplasiarelated changes compared with conventional care regimens. BMC
Cancer. 2017;17:852.
23. Kantarjian HM, Thomas XG, Dmoszynska A, Wierzbowska A,
Mazur G, Mayer J, et al. Multicenter, randomized, open-label,phase III trial of decitabine versus patient choice, with physician
advice, of either supportive care or low-dose cytarabine for thetreatment of older patients with newly diagnosed acute myeloid
leukemia. J Clin Oncol. 2012;30:2670–7.
24. Wei AH, Montesinos P, Ivanov V, DiNardo CD, Novak J, Laribi
K, et al. Venetoclax plus LDAC for newly diagnosed AML ineligible for intensive chemotherapy: a phase 3 randomized placebocontrolled trial. Blood. 2020;135:2137–45.
25. DiNardo CD, Jonas BA, Pullarkat V, Thirman MJ, Garcia JS, Wei
A, et al. Azacitidine and venetoclax in previously untreated acute
myeloid leukemia. N Engl J Med. 2020;383(7):617–29.
26. Chen Y, Yang T, Zheng X, Yang X, Zheng Z, Zheng J, et al. The
outcome and prognostic factors of 248 elderly patients with acute

27.

28.
29.

30.

31.

32.
33.

34.

myeloid leukemia treated with standard-dose or low-intensity
induction therapy. Medicine (Baltimore). 2016;95:e4182.
Xu J, Lv TT, Zhou XF, Huang Y, Liu DD, Yuan GL. Efficacy ofcommon salvage chemotherapy regimens in patients with refractory or relapsed acute myeloid leukemia: a retrospective cohort
study. Medicine (Baltimore). 2018;97:e12102.
Venclexta PI (Japanese label). 2021.
Griffin JD, Yang H, Song Y, Kinrich D, Shah MV, Bui CN. Treatment patterns and healthcare resource utilization in patients with
FLT3-mutated and wild-type acute myeloid leukemia: a medical
chart study. Eur J Haematol. 2019;102:341–50.
Miyamoto T, Sanford D, Tomuleasa C, Hsiao HH, Olivera LJE,
Enjeti AK, et al. Real-world treatment patterns and clinical outcomes in patients with AML unfit for first-line intensive chemotherapy. Leuk Lymphoma. 2022. https://​doi.​org/​10.​1080/​10428​
194.​2021.​20023​21.
DiNardo CD, Pratz KW, Letai A, Jonas BA, Wei AH, Thirman
M, et al. Safety and preliminary efficacy of venetoclax with decitabine or azacitidine in elderly patients with previously untreatedacute myeloid leukaemia: a non-randomised, open-label, phase1b study. Lancet Oncol. 2018;19:216–28.
Miyawaki S. JSH guideline for tumors of hematopoietic and lymphoid tissues: leukemia 1. Acute myeloid leukemia (AML). Int J
Hematol. 2017;106:310–25.
Ito T, Sanford D, Tomuleasa C, Hsiao H-H, Enciso Olivera L,
Enjeti A, et al. Patterns of healthcare resource utilization (HRU)
in unfit patients with acute myeloid leukemia (AML) receiving
first-line systemic treatment or best supportive care (BSC): a multicenter international study (CURRENT). Lawrenceville: ISPOR;
2021.
Stein EM, Bonifacio G, Latremouille-Viau D, Guerin A, Shi
S, Gagnon-Sanschagrin P, et al. Treatment patterns, healthcare
resource utilization, and costs in patients with acute myeloid leukemia in commercially insured and Medicare populations. J Med
Econ. 2018;21:556–63.

Publisher's Note Springer Nature remains neutral with regard tojurisdictional claims in published maps and institutional affiliations.

Authors and Affiliations
Chikashi Yoshida1 · Takeshi Kondo2 · Tomoki Ito3 · Masahiro Kizaki4 · Kazuhiko Yamamoto5 · Toshihiro Miyamoto6 ·Yasuyoshi Morita7 · Tetsuya Eto8 · Yuna Katsuoka9 · Naoki Takezako10 · Nobuhiko Uoshima11 · Kazunori Imada12 ·Jun Ando13 · Takuya Komeno1 · Akio Mori2 · Yuichi Ishikawa14 · Atsushi Satake3 · Junichi Watanabe4 ·Yoshiko Kawakami15 · Tetsuo Morita15 · Ikue Taneike15 · Masahiko Nakayama15 · Yinghui Duan16 ·Belen Garbayo Guijarro17 · Alexander Delgado18 · Cynthia Llamas16 · Hitoshi Kiyoi14* Chikashi Yoshidac.yoshida@mitomedical.org
1

Department of Hematology, National Hospital Organization
Mito Medical Center, Ibaraki‑machi, Japan

2

Blood Disorders Center, Aiiku Hospital, Sapporo, Japan

3

First Department of Internal Medicine, Kansai Medical
University, Osaka, Japan

4

Department of Hematology, Saitama Medical Center,
Saitama Medical University, Saitama, Japan

13

5

Department of Hematology, Okayama City Hospital,
Okayama, Japan

6

Medicine and Biosystemic Science, Graduate Schoolof Medical Sciences, Kyushu University, Fukuoka, Japan

7

Division of Hematology and Rheumatology, Department
of Internal Medicine, Kindai University, Osaka, Japan

8

Department of Hematology, Hamanomachi Hospital,
Fukuoka, Japan

Real‑world treatment patterns and clinical outcomes in patients with AML in Japan who were…
9

Department of Hematology, Sendai Medical Center, National
Hospital Organization, Sendai, Japan

14

Department of Hematology and Oncology, Nagoya
University Graduate School of Medicine, Nagoya, Japan10

Department of Hematology, Disaster Medical Center, Tokyo,
Japan

15

AbbVie GK, Tokyo, Japan

16

AbbVie, Inc., North Chicago, IL, USA

17

AbbVie, Inc., Madrid, Spain

18

AbbVie, Inc., Singapore, Singapore

11

Department of Hematology, Kyoto Second Red Cross
Hospital, Kyoto, Japan

12

Department of Hematology, Japanese Red Cross Osaka
Hospital, Osaka, Japan

13

Department of Hematology, Juntendo University Schoolof Medicine, Tokyo, Japan

13

Open Access Original
Article

DOI: 10.7759/cureus.24178

Analyzing Chronological Change in Postoperative
Magnetic Resonance Imaging Results in Patients
With Kienböck’s Disease by Using an Original
Grading System

Review began 03/22/2022
Review ended 04/13/2022
Published 04/16/2022© Copyright 2022
Ogawa et al. This is an open access article
distributed under the terms of the Creative

Takeshi Ogawa 1 , Akira Ikumi 2 , Sho Kohyama 3 , Yuki Hara 4 , Yuichi Yoshii 5 , Naoyuki Ochiai 3 , Masashi
Yamazaki 4

Commons Attribution License CC-BY 4.0.,
which permits unrestricted use, distribution,and reproduction in any medium, provided
the original author and source are credited.

1. Department of Orthopedic Surgery, National Hospital Organization, Mito Medical Center, Ibaraki, JPN 2.
Department of Orthopedic Surgery and Sports Medicine, Tsukuba University Hospital Mito Clinical Education andTraining Center, Mito, JPN 3. Department of Orthopedic Surgery, Kikkoman General Hospital, Noda, JPN 4.
Department of Orthopedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, JPN 5. Department ofOrthopedic Surgery, Tokyo Medical University Ibaraki Medical Center, Ibaraki, JPN
Corresponding author: Takeshi Ogawa, ogawat@tsukuba-seikei.jp

Abstract
Background and objective
Signal changes in MRI for Kienböck’s disease have only been qualitatively assessed so far. In light of this, we
proposed a new grading system for quantitative analysis with an ordinal scale.

Methods
The study included 31 patients (17 men, 14 women) with Kienböck's disease. By referring to Nakamura’s MRI
grading system, we devised a grading system with five grades (Grades 1-5) using proton density-weighted(PDW) coronal images with respect to the signal intensity of the lunate. All cases were examined by using the
MRI grading system by three hand surgeons, both preoperatively and postoperatively. We evaluated theinter-rater reliability of our grading system by using the interclass correlation coefficient. After surgery, we
implemented annual MRI evaluation for as long as possible and quantitatively assessed changes in MRI
grades. We also investigated the correlation between postoperative MRI grades, Mayo Wrist Scores (MWS),and age at the surgery by using Pearson’s coefficient.

Results
The MRI evaluation was performed 2-15 years after surgery. The reliability of our grading system was high;inter-rater interclass correlation coefficients were 0.783 (examiners 1-2), 0.780 (examiners 1-3), and 0.825(examiners 2-3), representing a substantial agreement. The correlation coefficient between the MRI gradeand MWS was -0.31, suggesting a mild negative correlation; postoperative MRI grade also correlated withage at surgery (Pearson’s coefficient: 0.447).

Conclusions
Our proposed MRI grading system has high reliability and could be used to assess the regeneration of anecrotic lunate for quantitative analysis on an ordinal scale. Improvements were observed one to four years
postoperatively, demonstrating a mild correlation with the clinical results.

Categories: Radiology, Orthopedics
Keywords: ordinal scale, quantitative analysis, proton density weighted image, magnetic resonance imaging, necrotic
lunate, kienböck’s disease

Introduction
Kienböck’s disease was first described in 1910 by radiologist Robert Kienböck, who described radiographic
changes associated with lunate malacia [1]. The exact mechanism of Kienböck’s disease is not yet fully
understood. It is believed to be an interaction between altered vascular perfusion, repeated microtrauma,changes in lunate bone structure, changes in loading and movement, and potential systemic disease [2].
Signal changes during MRI evaluation for Kienböck’s disease have been qualitatively assessed [3]. In order toproperly diagnose Kienböck’s disease and its progression, it is necessary to establish a standardized test
based on MRI analysis. In this study, we developed a new evaluation method by using an ordinal scale thatcan be classified into five levels according to the degree of disease progression based on MRI signal
intensity. MRI analysis by using this ordinal scale is expected to assess the effectiveness of the treatment
and progress of necrosis. In patients with Kienböck’s disease, we performed a combined therapy that
included non-concentrated bone marrow transfusion, low-intensity pulsed ultrasound, and external fixation

How to cite this article
Ogawa T, Ikumi A, Kohyama S, et al. (April 16, 2022) Analyzing Chronological Change in Postoperative Magnetic Resonance Imaging Results inPatients With Kienböck’s Disease by Using an Original Grading System. Cureus 14(4): e24178. DOI 10.7759/cureus.24178

[3,4]; however, this treatment did not result in better outcomes than other treatments [5-9]. There are somequestions that remain unanswered regarding this method, such as when is the improvement of MRI signal
after surgery observed, whether the improvement is continuous, and whether MRI signal improvement
correlates with clinical results or patients’ age. In this study, we, therefore, assessed the validity of thegrading system, quantitatively evaluated postoperative MRI changes over time, and evaluated thecorrelation between MRI signal improvement and clinical results following our procedure for Kienböck’s
disease.

Materials And Methods
Our study involved 31 patients (17 men, 14 women) with Kienböck’s disease by using Ogawa’s procedure[3,4]. This retrospective study was approved by our hospital’s ethical committee (R02-106), and written
informed consent was obtained from all participants. Our indications for surgical intervention werediagnosis of Kienböck’s disease at stages II, IIIa, and IIIb. Preoperative Lichtman stages observed were as
follows: stage II in nine patients, stage IIIa in 16 patients, and stage IIIb in six patients; the mean age at thetime of surgery was 43.6 (16-78) years. A 1.5- or 3-T magnetic resonance apparatus (Gyroscan NT Intera,
Philips Medical Systems, Amsterdam, Netherlands), with a small-diameter surface coil (Philips Medical
Systems), was used for MRI evaluation [10]. We referred to Nakamura’s MRI grading system [11] to devise anindividual grading system using proton density-weighted (PDW) coronal images. On this scale, with respect
to the signal intensity of the lunate, Grade I was considered almost normal; Grade II indicated localized
regions of slightly decreased signal intensity; Grade III indicated a slight, generalized decrease in signal
intensity; Grade IV represented a low signal intensity with regions of high or isointense signals; and Grade V
indicated a low, generalized signal intensity (Figure 1).

FIGURE 1: MRI grading system using the T1 or PDW coronal image
On this scale, with respect to the signal intensity of the lunate, Grade I was considered almost normal; Grade II
indicated localized regions of slightly decreased signal intensity; Grade III indicated a slight, generalized decreasein signal intensity; Grade IV represented low signal intensity with regions of high or isointense signals, and Grade
V indicated generalized low signal intensity
MRI: magnetic resonance imaging; PDW: proton density-weighted

Grades were determined by using the most severe coronal slice on MRI. Using the MRI grading system, allcases were both preoperatively and postoperatively examined by three hand surgeons. We then evaluated theinter-rater reliability of the grading system by using the interclass correlation coefficient. After surgery, we
implemented an annual MRI evaluation and assessed the changes in MRI grade on an ordinal scale. We also
investigated the correlation between MRI grade at the final follow-up, Mayo Wrist Score (MWS) [12], and age
at the time of surgery, by using Pearson’s coefficient.

Statistical analysis
We evaluated the inter-rater reliability of our MRI grading system by using the interclass correlation
coefficient. We evaluated the correlation between the clinical results, MWS, and age using Pearson’s
correlation coefficient; the significance level was set at p=0.05. All statistical analyses were performed with
Bellcurve for Excel version 3.20 (SSRI Co., Tokyo, Japan).

Results
MRI evaluation was performed for 2-15 years after surgery. The reliability of our MRI grading system washigh, with inter-rater interclass correlation coefficients of 0.783 (examiners 1-2), 0.780 (examiners 1-3), and0.825 (examiners 2-3), representing a substantial or near-perfect agreement. Improvements were observed
one to four years postoperatively (Figure 2), from an average grade of 4.5 (range: 3-5) preoperatively to 2.75
(range: 1-5) at the final follow-up.

2022 Ogawa et al. Cureus 14(4): e24178. DOI 10.7759/cureus.24178

2 of 6FIGURE 2: Chronological change in postoperative MRI grade for all
patients
MRI: magnetic resonance imaging

Improved MRI signal intensity was observed in 23 patients (74%): 13 cases within one year, six patients after
one to two years, and four patients after more than two years. To date, none of the improved patients
have deteriorated since experiencing improvement. A satisfactory improvement in MRI Grade I or II wasobserved in 17 patients (74%); additionally, there were no cases in which the recovered intensity of the
lunate worsened. The average MWS at the last follow-up was 83.4 (65-100), and the Pearson’s coefficient
was -0.315, which slightly correlated with the MRI grade at the last follow-up (Figure 3).

2022 Ogawa et al. Cureus 14(4): e24178. DOI 10.7759/cureus.24178

3 of 6FIGURE 3: Pearson’s coefficient between MWS and MRI grades
Pearson’s coefficient was -0.315
MRI: magnetic resonance imaging; MWS: Mayo Wrist Score

The postoperative MRI grade also correlated with age at the time of surgery (Pearson’s coefficient: 0.447)(Figure 4).

FIGURE 4: Pearson’s coefficient between age at the surgery and MRI
grade at the final follow-up
Pearson’s coefficient was 0.447
MRI: magnetic resonance imaging

By contrast, there was no correlation between MWS and age (Pearson’s coefficient: 0.068).
The representative case involved a 41-year-old man who underwent surgery. His preoperative MRI Gradewas IV, which improved to Grade IV at one year, Grade IV at two years, and Grade II at five years
postoperatively (Figures 5A-5D). He reported no pain at three months postoperatively, and his MWS was 90
points at one year postoperatively; therefore, MRI was not performed at three and four years
postoperatively.

2022 Ogawa et al. Cureus 14(4): e24178. DOI 10.7759/cureus.24178

4 of 6FIGURE 5: Chronological change in the postoperative MRI results of a
41-year-old man before and after surgery for Kienböck’s disease
A. Preoperative magnetic resonance image (Grade IV). B. One year postoperatively (Grade IV). C. Two years
postoperatively (Grade IV). D. Three years postoperatively (Grade II)
MRI: magnetic resonance imaging

Discussion
We investigated the chronological change in postoperative MRI results in 31 patients with Kienböck’s
disease by using a novel grading system. The validity of the grading system was assessed and changes inpostoperative MRI over time were evaluated on an ordinal scale. Improved MRI signal intensity wasobserved in 23 patients, with changes appearing within one year in 13 patients. Furthermore, the MRI grade
exhibited a slight correlation with the clinical results.
Very few reports have quantitatively evaluated the MRI findings in Kienböck’s disease. Nakamura et al. [11]classified the appearance of the lunate; its signal intensity was graded on a scale of I to V, and theyevaluated T1- and T2-weighted images both preoperatively and postoperatively. Imaeda et al. [13] also
concluded that the intensity of the signal of the lunate on T2-weighted images indicates the severity of thedisease, with a decreased signal containing a high spot or an increased signal suggesting revascularization.
Conversely, Ogawa et al. [10] described that PDW (T1-weighted) MRI accurately reflects the vascular statusof the lunate, as evidenced by comparison with histological analyses of lunate specimens. They also reported
that in the fast-field echo (T2-weighted) images, there were no correlations with histopathologicalobservations.
T2-weighted images reflect various changes, including bone marrow edema, blood vessels, and bleeding. We,
therefore, attempted to quantitatively evaluate lunate regeneration using the PDW images. By contrast,
Schmitt et al. [14] described gadolinium-enhanced MRI-based classification to delineate the pattern ofosteonecrosis in different parts of the lunate bone; middle reparative zone; and distal, normal, viable lunate
bone. Based on the signal intensity in different zones of the lunate on MRI, Schmitt et al. classified threestages of Kienböck’s disease: stage A was "Marrow edema with viable and intact bony trabeculae", stage B
was "Early marrow necrosis with fibrovascular reparative tissue", and stage C was ‘Necrotic bone marrow
with collapse [14]". We also considered the best way to investigate the recovery from bone avascular necrosis
using both gadolinium-enhanced MRI and PDW imaging. Gadolinium-enhanced MRI may reflect blood flow
and may be useful in combination with PDW, which reflects bone regeneration, to assess treatment efficacy
and stage. This is one of the limitations of the present study. Consequently, the reliability of ourclassification was high, demonstrating a slight correlation with the clinical results. Nakamura et al. [11]reported that there was no significant correlation between lunate signal intensity and clinical outcomes.
Although there were good clinical outcomes in our case, some patients exhibited poor MRI recovery, which
is another limitation of this study. Additionally, we believe that considering the correlation between MRI
and clinical outcomes, it may be useful to employ gadolinium-enhanced MRI together with our MRI grading
system.
Regarding the age of patients with Kienböck’s disease, van Leeuwen et al. [15] described age as a risk factor
for lunate collapse, while Koh et al. [16] reported that the younger generation had better radiologicalimprovement, implying more revascularization of the lunate. The correlation between age and MRI
improvement remains unclear, and there are no reports pertaining to age and MRI improvement in theliterature. Matsui et al. [17] reported that younger patients had a tendency toward improvement in MRI
findings; however, no significant differences in the clinical outcomes, regardless of whether MRI
improvement was achieved, were observed. In our study, there was a significant difference between older
and younger patients in terms of MRI improvement (Figure 4); however, our study included nine women inmenopause. The conditions of Kienböck’s disease may differ between younger and older individuals; hence,
our data remain theoretical.

Conclusions
Our proposed MRI grading system demonstrated high reliability and could be used to assess the regenerationof the necrotic lunate on an ordinal scale. Using this MRI ordinal scale, the correlation between the clinical2022 Ogawa et al. Cureus 14(4): e24178. DOI 10.7759/cureus.24178

5 of 6

outcomes after treatment for Kienböck’s disease was recognized, and improvements in MRI grade wereobserved one to four years postoperatively. Furthermore, the recovered intensity of the lunate remained at
the same level as the intensity.

Additional Information
Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. The Ethical Committee atthe University of Tsukuba Hospital issued approval R02-106. Animal subjects: All authors have confirmedthat this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the
ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors havedeclared that no financial support was received from any organization for the submitted work. Financial
relationships: All authors have declared that they have no financial relationships at present or within theprevious three years with any organizations that might have an interest in the submitted work. Other
relationships: All authors have declared that there are no other relationships or activities that could appear
to have influenced the submitted work.

Acknowledgements
The authors would like to thank Dr. Yoshio Nakata, an associate professor at the Faculty of Medicine at the
University of Tsukuba, for his advice regarding statistical analysis.

References
1.
2.
3.

4.

5.
6.
7.
8.
9.

10.
11.

12.
13.
14.
15.
16.

17.

Wagner JP, Chung KC: A historical report on Robert Kienböck (1871-1953) and Kienböck's disease . J Hand
Surg Am. 2005, 30:1117-21. 10.1016/j.jhsa.2005.08.002
Lichtman DM, Lesley NE, Simmons SP: The classification and treatment of Kienbock's disease: the state of
the art and a look at the future. J Hand Surg Eur Vol. 2010, 35:549-54. 10.1177/1753193410374690
Ogawa T, Ochiai N, Nishiura Y, Tanaka T, Hara Y: A new treatment strategy for Kienböck's disease:combination of bone marrow transfusion, low-intensity pulsed ultrasound therapy, and external fixation. J
Orthop Sci. 2013, 18:230-7. 10.1007/s00776-012-0332-7
Ogawa T, Ochiai N, Hara Y: Bone marrow from the iliac crest versus from the distal radius for revitalizing
the necrotic lunate for Kienböck disease. J Hand Surg Eur Vol. 2020, 45:299-301.
10.1177/1753193419886724
Nakamura R, Tsuge S, Watanabe K, Tsunoda K: Radial wedge osteotomy for Kienböck disease . J Bone Joint
Surg Am. 1991, 73:1391-6.
Fujiwara H, Oda R, Morisaki S, Ikoma K, Kubo T: Long-term results of vascularized bone graft for stage III
Kienböck disease. J Hand Surg Am. 2013, 38:904-8. 10.1016/j.jhsa.2013.02.010
Watanabe T, Takahara M, Tsuchida H, Yamahara S, Kikuchi N, Ogino T: Long-term follow-up of radial
shortening osteotomy for Kienbock disease. J Bone Joint Surg Am. 2008, 90:1705-11. 10.2106/JBJS.G.00421
Arimitsu S, Shimada K, Moritomo H: Lunate fracture healing after partial capitate shortening in Kienböck
disease. J Orthop Sci. 2020, 25:428-34. 10.1016/j.jos.2019.06.001
De Carli P, Zaidenberg EE, Alfie V, Donndorff A, Boretto JG, Gallucci GL: Radius core decompression for
Kienböck disease stage IIIA: outcomes at 13 years follow-up. J Hand Surg Am. 2017, 42:752.e1-6.
10.1016/j.jhsa.2017.05.017
Ogawa T, Nishiura Y, Hara Y, Okamoto Y, Ochiai N: Correlation of histopathology with magnetic resonanceimaging in Kienböck disease. J Hand Surg Am. 2012, 37:83-9. 10.1016/j.jhsa.2011.09.027
Nakamura R, Watanabe K, Tsunoda K, Miura T: Radial osteotomy for Kienböck's disease evaluated bymagnetic resonance imaging. 24 cases followed for 1-3 years. Acta Orthop Scand. 1993, 64:207-11.
10.3109/17453679308994572
Amadio PC, Berquist TH, Smith DK, Ilstrup DM, Cooney WP 3rd, Linscheid RL: Scaphoid malunion. J Hand
Surg Am. 1989, 14:679-87. 10.1016/0363-5023(89)90191-3
Imaeda T, Nakamura R, Miura T, Makino N: Magnetic resonance imaging in Kienböck’s disease . J Hand Surg
Br. 1992, 17:12-9. 10.1016/0266-7681(92)90006-n
Schmitt R, Heinze A, Fellner F, Obletter N, Strühn R, Bautz W: Imaging and staging of avascularosteonecroses at the wrist and hand. Eur J Radiol. 1997, 25:92-103. 10.1016/s0720-048x(97)00065-x
van Leeuwen WF, Tarabochia MA, Schuurman AH, Chen N, Ring D: Risk factors of lunate collapse in
Kienböck disease. J Hand Surg Am. 2017, 42:883-8. 10.1016/j.jhsa.2017.06.107
Koh S, Nakamura R, Horii E, Nakao E, Inagaki H, Yajima H: Surgical outcome of radial osteotomy for
Kienböck’s disease-minimum 10 years of follow-up. J Hand Surg Am. 2013, 28:910-6. 10.1016/s03635023(03)00490-8
Matsui Y, Funakoshi T, Motomiya M, Urita A, Minami M, Iwasaki N: Radial shortening osteotomy for
Kienböck disease: minimum 10-year follow-up. J Hand Surg Am. 2014, 39:679-85.
10.1016/j.jhsa.2014.01.020

2022 Ogawa et al. Cureus 14(4): e24178. DOI 10.7759/cureus.24178

6 of 6

ANTICANCER RESEARCH 42: 2583-2590 (2022)
doi:10.21873/anticanres.15736

Prognostic Implication of PD-L1 Expression on Osimertinib
Treatment for EGFR-mutated Non-small Cell Lung Cancer
TOSHIHIRO SHIOZAWA1*, TAKESHI NUMATA2*, TOMOHIRO TAMURA3, TAKEO ENDO2,TAKAYUKI KABURAGI3, YUSUKE YAMAMOTO4, HIDEYASU YAMADA5, NORIHIRO KIKUCHI6,
KAZUHITO SAITO7, MASAHARU INAGAKI7, KOICHI KURISHIMA8, YASUNORI FUNAYAMA9,KUNIHIKO MIYAZAKI10, NOBUYUKI KOYAMA11, KINYA FURUKAWA12,
HIROYUKI NAKAMURA12, SHINJI KIKUCHI13, HIDEO ICHIMURA13,
YUKIO SATO13, IKUO SEKINE14, HIROAKI SATOH15 and NOBUYUKI HIZAWA1
1Department of Respiratory Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan;
2Division of Respiratory Medicine, Mito Medical Center, Mito, Japan;

3Respiratory Center, Ibaraki Prefectural Central Hospital, Kasama, Japan;

4Division of Respiratory Medicine, Hitachi General Hospital, Hitachi, Japan;

5Division of Respiratory Medicine, Hitachinaka Medical Center, University of Tsukuba, Hitachinaka, Japan;
6Division of Respiratory Medicine, Kasumigaura Medical Center, Tsuchiura, Japan;

7Divisions of Respiratory Medicine and Thoracic Surgery, Tsuchiura Kyodo General Hospital, Tsuchiura, Japan;
8Division of Respiratory Medicine, Tsukuba Medical Center Hospital, Tsukuba, Japan;
9Division of Respiratory Medicine, Tsukuba Gakuen Hospital, Tsukuba, Japan;

10Division of Respiratory Medicine, Ryugasaki Saiseikai Hospital, Ryugasaki, Japan;

11Department of Respiratory Medicine, Saitama Medical Center, Saitama Medical University, Saitama, Japan;
12Divisions of Respiratory Medicine and Thoracic Surgery,Tokyo Medical University, Ibaraki Medical Center, Ami, Japan;

13Department of Thoracic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan;

14Department of Medical Oncology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan;
15Division of Respiratory Medicine, Mito Kyodo General Hospital-Mito Medical Center,

University of Tsukuba, Mito, Japan

Abstract. Background/Aim: Real-world data on the clinicaloutcomes of first-line osimertinib treatment for non-small
cell lung cancer (NSCLC) with epidermal growth factor
receptor (EGFR) mutations is lacking. This study aimed toreveal the treatment outcomes and prognostic factors ofosimertinib as first-line therapy in clinical practice settings.
Patients and Methods: We retrospectively evaluated clinical*These Authors contributed equally to the present study.

Correspondence to: Toshihiro Shiozawa, MD, Department ofRespiratory Medicine, Faculty of Medicine, University of Tsukuba, 11-1 Tennoudai, Tsukuba, Ibaraki 305-8575, Japan. Tel: +81 298533144,
Fax: +81 298533144, e-mail: t-shiozawa@md.tsukuba.ac.jp

Key Words: Lung cancer, EGFR mutation, osimertinib, PD-L1.

This article is an open access article distributed under the terms andconditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0

international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

outcomes of patients with EGFR-mutated NSCLC treatedwith osimertinib as first-line therapy across 12 institutionsin Japan between August 2018 and March 2020. Results:
Among 158 enrolled patients, the objective response rate(ORR) was 68%, and the estimated median progression-freesurvival (PFS) was 17.1 months [95% confidence interval(CI)=14.5-19.7]. Subgroup analysis showed that PFS in thegroup with high programmed death-ligand 1 (PD-L1)
expression was significantly shorter than that in groups withlow or no PD-L1 expression (10.1 vs. 16.1 vs. 19.0 months;
p=0.03). Univariate and multivariate analyses demonstrated
that high PD-L1 expression was the only independent
adverse prognostic factor of osimertinib outcome related to
PFS (hazard ratio=2.71; 95%CI=1.26-5.84; p=0.01). In
terms of anti-tumor response, there was no statisticallysignificant correlation between PD-L1 expression and theORR (67% vs. 76% vs. 65%; p=0.51). No significant
correlation was also found between PD-L1 and the incidence
of de novo resistance to osimertinib (p=0.39). Conclusion:
Although PD-L1 expression was not associated with either
2583

ANTICANCER RESEARCH 42: 2583-2590 (2022)

the ORR or frequency of de novo resistance, high PD-L1
expression could be an independent adverse prognostic
factor related to PFS in osimertinib treatment.

Molecularly targeted therapies have contributed to an
improvement in the survival of patients with recurrent oradvanced non-small cell lung cancer (NSCLC) harboring
driver oncogenes. Mutations in the epidermal growth factor
receptor (EGFR), which is a driver oncogene in NSCLC, leadto tumorigenesis and tumor growth via the activated EGFR
signaling pathway (1). Previous phase III studies demonstrated
that EGFR tyrosine kinase inhibitors (EGFR-TKIs) as firstline therapy for EGFR-mutated NSCLC had better outcomesthan a platinum-based regimen in terms of both progressionfree survival (PFS) and objective response rate (ORR) (2-4).
EGFR-TKIs are thus the current standard first-line agents fortreating patients with EGFR-mutated advanced NSCLC.
First- to third-generation EGFR-TKIs are available inclinical practice. Of these, osimertinib, categorized as a thirdgeneration EGFR-TKI, has irreversible anti-tumor activity
against both EGFR-sensitizing and EGFR-resistant T790M
mutations. In the global phase III FLAURA trial involving
patients with untreated EGFR-mutated recurrent or advanced
NSCLC, osimertinib prolonged PFS and overall survival (OS)compared with the standard of care achieved by firstgeneration EGFR-TKIs (5, 6). Thus, osimertinib is regarded as
the most recommended first-line agent in these patients (7).
In clinical practice, osimertinib is indicated for aheterogeneous population, including patients with decreased
performance status, symptomatic brain or leptomeningeal
metastases, and uncommon mutations. However, as per thecriteria of FLAURA trials, these patient groups are ineligible
for osimertinib treatment. This discrepancy in recommendations
suggests that there is a data gap regarding treatment outcomes
between the results of the FLAURA trial and those noted incurrent clinical practice. Therefore, in addition to pivotal clinical
trial data, it is important to collect and analyze post-marketingclinical data. Although the use of osimertinib as a first-line
agent has increased since its approval, data regarding outcomesand prognostic factors with this treatment in clinical practice arestill lacking.
To bridge this knowledge gap, we conducted this multiinstitutional, retrospective, observational study to evaluate
the treatment outcomes and prognostic factors of first-line
osimertinib for treatment of patients with recurrent oradvanced EGFR-mutated NSCLC.

Patients and Methods

Data collection. Twelve institutions in Ibaraki Prefecture, Japan
participated in this study. We enrolled patients with recurrent oradvanced NSCLC with EGFR mutations who received osimertinib
as a first-line agent between August 2018 and March 2020. The data
cut-off was May 31, 2020.

2584

The following clinical data were collected: age, sex, smoking
status (current, former, or never), Eastern Cooperative Oncology
Group performance status (PS), stage at diagnosis according to the
TNM Classification of Malignant Tumors (eighth edition),
histology, type of EGFR mutation, presence of central nervous
system (CNS) metastasis, and programmed death-ligand 1 (PD-L1)
expression status using immunohistochemistry. Based on previous
studies, PD-L1 expression was classified as none, low, and high if
the tumor percentage score (TPS) of PD-L1 was <1%, 1%-49%, and> 50%, respectively (8, 9).

Statistical analysis. The endpoints in this study were the efficacy
outcomes. The radiological anti-tumor response was evaluated basedon the Response Evaluation Criteria in Solid Tumors (version 1.0.10).
The ORR was defined as the proportion of patients who achieved
anti-tumor response with complete response (CR) or partial response(PR). The disease control rate (DCR) was defined as the ORR plus
the proportion of patients achieving stable disease (SD).
The definition of de novo resistance was based on a previous
report as those whose best overall response was PD or whose PFS
was less than 6 months (10). PFS was defined as the duration fromthe initiation of osimertinib treatment to disease progression ordeath from any cause. OS was defined as the duration from theinitiation of osimertinib treatment to death from any cause. If death
did not occur at the cut-off date, patients were censored. If patientswere lost during the observation period, they were censored on thelast day of confirmed survival. Clinical evaluations of PFS and OS
were conducted using the Kaplan–Meier method. The log-rank test
was used to compare two different survival curves. A Cox
regression model was applied to examine prognostic factors related
to survival. Univariate and multivariate hazard ratios (HRs) werereported with 95% confidence intervals (CIs). Statistical analysis
was performed using IBM SPSS Statistics for Windows (version
24.0; IBM Corp., Armonk, NY, USA). All tests were two-sided andjudged statistically significant if the calculated p-values were <0.05.

Ethical approval. This study was initiated after the study protocol
was approved by the institutional review board of all institutions(approval number in Tsukuba University Hospital: R01-385). This
retrospective observational study was conducted in compliance with
the Helsinki Declaration. Individual patient data were anonymized
prior to enrollment.
Informed consent was waived because the present study was a
retrospective, observational research. Opt-out was done on thewebsite of each institution.

Results

Patient characteristics. Among 161 patients initially enrolled,three were excluded from the analysis owing to the lack ofdata, resulting in a total of 158 eligible patients for the current
study. Table I shows the patient characteristics. The medianage was 73 years (range=39-93 years). Females accounted for
58% of the sample population, and adenocarcinoma waspresent in 95% of all cases. The proportions of EGFR
mutation subtypes were 52% exon19 deletion, 43% exon21
L858R point mutation, and 5% uncommon mutation. Fortyfive patients (28%) had CNS metastases at the time ofdiagnosis. The TPS of PD-L1 was none, low, and high in 60

Shiozawa et al: Association Between PD-L1 and Osimertinib Treatment
Table I. Patient characteristics.
Age (years)
Sex
Male
FemaleSmoking status
Never
Former or current
UnknownPS
0/1/2/3/4/unknown
Clinical stage
3/4/recurrent/other
Histology
Adenocarcinoma
Squamous cell carcinoma
Other
EGFR mutation
Exon 19 del
L858R
UncommonCNS metastasis
Yes
No
PD-L1 expression
None
Low
High
Unknown

N=158

73 (39-93)
66
92

83
74
1

50/79/18/7/2/2
15/120/22/1
150
5
3
82
68
8

45
113
60
41
27
30

PS: Performance status; EGFR: epidermal growth factor receptor; CNS:
central nervous system; PD-L1: programmed death-ligand 1.

(38%), 41 (26%), and 27 (17%) patients, respectively. The
remaining 30 patients (19%) had unknown TPS.

Survival. The median follow-up period of the present study
was 12.5 months. The estimated median PFS was 17.1
months (95%CI=14.5-19.7). OS did not reach the median.
We examined the outcomes of osimertinib therapy
according to patient subgroups of age, sex, smoking status,
PS, stage, mutation subtype, CNS metastases, and TPS. No
significant difference in PFS was observed with respect toage (<70 vs. ≥70 years, Figure 1A), sex (male vs. female,
Figure 1B), smoking status (never vs. current or former,
Figure 1C), PS (0-1 vs. 2-4, Figure 1D), stage (III orrecurrent vs. IV, Figure 1E), mutation subtype (Exon 19 delvs. L858R vs. uncommon, Figure 1F), and CNS metastasis(present vs. absent Figure 1G). However, the high TPS group
had a significantly poorer PFS of 10.1 months comparedwith the low and no TPS groups that had a PFS of 16.1 and19.0 months, respectively (log-rank p=0.03, Figure 1H).
Next, we performed univariate and multivariate analyses
to evaluate prognostic factors associated with PFS. Amongcollected patient characteristics, we selected the eight factors
mentioned above. As shown in Table II, only high TPS was
found to be a statistically significant adverse prognostic
factor related to PFS (HR=2.71; 95%CI=1.26-5.84; p=0.01).

Anti-tumor response. At the cut-off date, a response
assessment was obtained for 140 patients. The best overall
responses to osimertinib in the overall population included a
CR of 3% (n=6), PR of 65% (n=102), SD of 14% (n=22),
and PD of 6% (n=10), with an ORR of 68% and a DCR of
82%. We further compared best overall responses toosimertinib focusing on PD-L1 expression (Figure 2). There
was no statistically significant difference in the ORR among
the high, low, and no TPS groups (67%, 76%, and 65%,
respectively; p=0.51, Figure 2A). DCR was also similar
among the high, low, and no TPS groups (81%, 88%, and80%, respectively; p=0.57, Figure 2B).
De novo resistance to osimertinib. We further evaluated therelationship between PD-L1 expression and the incidence of denovo resistance. We excluded cases whose best overall
response was not evaluable and whose information regarding
PD-L1 expression was not obtained; as a result, 114 cases were
included. As shown in Table III, there was no statisticallysignificant correlation between PD-L1 expression and theincidence of de novo resistance to osimertinib (p=0.39).

Discussion

The present study investigated the clinical outcomes andprognostic factors of osimertinib as a first-line treatment foradvanced or recurrent NSCLC harboring EGFR mutations ina clinical practice setting. The results showed that the efficacy
of osimertinib in the overall population was favorable, similar
to that in the FLAURA trial. Although there was no
statistically significant difference in the ORR and theincidence of de novo resistance among the high, low, and no
TPS groups, the PFS of osimertinib in the high TPS group wasinferior to that in the low or no TPS groups. Furthermore,univariate and multivariate analyses showed that high PD-L1
expression was an independent adverse prognostic factor
associated with PFS in osimertinib treatment.
Compared to the FLAURA study, there were several
differences in baseline patient characteristics in the present
study. Specifically, in our study, there were more elderly
patients and a higher frequency of decreased PS andpresence of CNS metastases, while there was a lower
frequency of never smokers. Racial differences were also
observed. Some clinical factors, such as decreased PS andthe presence of CNS metastasis, are poor prognostic factors
for advanced NSCLC. Therefore, we conducted a subgroup
analysis to evaluate whether these clinical factors affected
the efficacy of osimertinib. The results showed that factors
2585

ANTICANCER RESEARCH 42: 2583-2590 (2022)

Figure 1. Progression-free survival according to age (A), sex (B), smoking status (C), PS (D), stage (E), mutation subtype (F), CNS metastasis (G),and PD-L1 expression levels (H). PS: Performance status; CNS: central nervous system; PD-L1: programmed death-ligand 1; CI: confidence
interval; NR: not reached.

2586

Shiozawa et al: Association Between PD-L1 and Osimertinib Treatment
Table II. Univariate and multivariate analyses of factors related to PFS.
VariablesAge<70 years≥70 years
Sex
Male
FemaleSmoking
Never
Current/former
Ps
0-1
2-4
Stage
III or recurrent
IV
Mutation type
Exon 19 del
L858r
CNS metastasis
AbsentPresent
TPS
None or low
HighHR 95%CI

Univariate

ref0.73 (0.37-1.44)

ref1.56 (0.79-3.50)

ref1.06 (0.54-2.07)

ref1.48 (0.57-3.85)

ref0.66 (0.33-1.32)
ref1.41 (0.62-3.11)

ref1.18 (0.57-2.43)

ref2.37 (1.16-4.83)

p-Value

HR 95%CI

0.36

ref1.00 (0.47-2.11)

0.20
0.87
0.41
0.24
0.42
0.65
0.02

Multivariate

ref1.58 (0.064-3.84)
ref0.98 (0.39-2.45)

ref1.67 (0.60-4.63)

ref0.40 (0.13-1.21)

ref1.97 (0.86-4.50)

ref1.20 (0.53-2.68)

ref2.71 (1.26-5.84)

p-Value
0.99
0.32
0.96
0.32
0.10
0.10
0.66
0.01

PFS: Progression-free survival; HR: hazard ratio; CI: confidence interval; PS: performance status; CNS: central nervous system TPS: tumor
proportion score; ref: reference.

other than TPS did not affect the outcome (PFS) of
osimertinib treatment. A previous phase II trial showed thatosimertinib treatment provides a clinical benefit for patientswith EGFR T790M-mutated NSCLC whose PS score has
declined to 2-4 (11). In the FLAURA study, osimertinib
resulted in significantly longer survival than the standard ofcare with first-generation EGFR-TKIs, even in patients who
had CNS metastases at diagnosis (12). Together with theseprevious reports, the present study indicates that osimertinib
could be administered to such patients in clinical practice.
In the present study, the estimated median PFS of osimertinibin the high TPS group was 10.1 months (95%CI=7.3-13.0),
which was significantly shorter than that in the low or no TPS
groups. Additionally, the present study showed that high TPS
was an independent adverse factor associated with the PFS of
osimertinib treatment. The subset analysis from the FLAURA
trial examined the clinical outcomes of osimertinib, focusing on
PD-L1 expression (13). Although the PFS of osimertinib wascomparable in both PD-L1 positive and negative groups, thethreshold for PD-L1 expression in the tumor cells (TCs) was set
at 1%. Additionally, evaluation for TC≥50% of the population
was lacking in a few cases (n=7). A recent study with 71
patients who received first-line osimertinib revealed thatpatients with high PD-L1 expression had poorer PFS than thosewith low or negative PD-L1 (median PFS, 5.0 vs. 17.4 months,
p<0.001) (14). The present study demonstrated results similar
to that study in a larger sample size.
The present study suggested that the patients with high
TPS had a higher risk of acquired resistance to osimertinib,
because there was no statistically significant difference in theincidence of de novo resistance between the group with high
TPS and the other two groups, despite of the inferior PFS in
the group with high TPS. Accordingly, physicians should beaware of the acquired resistance to osimertinib for patientswith high PD-L1 expression, even though they initially had
favorable anti-tumor response. There was a discrepancy in theanti-tumor response and de novo resistance rate between theprevious and present studies. Previous studies reported thatpatients with high PD-L1 expression had lower ORR andmore frequent de novo resistance to EGFR-TKIs comparedwith the group with low or no PD-L1 expression (14, 15). It
remains controversial whether increased PD-L1 expression
contributed to primary or acquired resistance to osimertinib
treatment. One speculation to the result of the present study
is the association between Yes-associated protein (YAP)
activity and PD-L1 expression on the EGFR signaling
2587

ANTICANCER RESEARCH 42: 2583-2590 (2022)
Table III. Relationship between PD-L1 expression and de-novo
resistance to osimertinib.

De novo
Non-de novo

N

15
99

None

5 (33%)
19 (19%)TPS

Low

5 (33%)
33 (33%)High

5 (33%)
47 (48%)p-value
0.39

PD-L1: Programmed death-ligand 1; TPS: tumor proportion score.

Figure 2. Best overall response according to tumor proportion score(TPS). Objective response rate stratified by TPS (A) and disease control
rate stratified by TPS (B). CR: Complete response; PR: partial
response; SD: stable disease.

pathway. Positive association was reported between EGFR
pathway activation and PD-L1 expression in EGFR-mutated
NSCLC (16). Specifically, the activated EGFR signaling
pathway increased PD-L1 expression via IL-6/JAK/STAT3,
or p-ERK1/2/p-c-JUN signaling pathway. Previous studies
also reported that PD-L1 expression was decreased due to theblockade of the EGFR signaling pathway by EGFR-TKI
administration (17-19). Recent studies reported that YAP,
known to be associated with acquired resistance to EGFRTKI therapy, had an important role as a regulator of PD-L1
expression (20-22). Accordingly, in patients with high PD-L1
expression, down-regulation of PD-L1 by osimertinib
administration might lead to YAP-1 activation, resulting in
the induction of acquired resistance to osimertinib treatment.
Resistance to osimertinib is a current unmet need in EGFRmutant NSCLC, and the development of novel therapeuticstrategy to overcome it is under investigation (23). Further
basic research to reveal the molecular mechanism of thecorrelation between response to osimertinib and PD-L1
expression and clinical validation with a large cohort are
warranted.
2588This study had some limitations. First, there was a bias
originating from the study’s retrospective nature. Second, OS
was not reached owing to the short observation period.
Third, information regarding TPS was not obtained inapproximately 20% of the participants. Finally, the current
study included only Japanese patients; hence, ethnic
differences may affect the results.
In conclusion, the present study provided clinically
relevant data on the outcomes of first-line osimertinib foradvanced or recurrent NSCLC with EGFR mutations. The
favorable efficacy of osimertinib in this study was similar
to that observed in the FLAURA trial. High TPS could be
an independent adverse prognostic factor for PFS in
osimertinib therapy, though the ORR and incidence of denovo resistance were similar regardless of PD-L1
expression. For patients with EGFR-mutated advanced
NSCLC with high PD-L1 expression, physicians should beaware of the risk of acquired resistance to osimertinib, eventhough osimertinib initially showed favorable anti-tumor
response.

Conflicts of Interest

There are no relevant conflicts of interest to be disclosed.

Authors’ Contributions

Toshihiro Shiozawa, Hiroaki Satoh, and Nobuyuki Hizawa planned anddesigned this study. Toshihiro Shiozawa, Takeshi Numata, Tomohiro
Tamura, Takeo Endo, Takayuki Kaburagi, Yusuke Yamamoto, Hideo
Ichimura, Hideyasu Yamada, Norihiro Kikuchi, Kazuhito Saito,
Masaharu Inagaki, Koichi Kurishima, Yasunori Funayama, Kunihiko
Miyazaki, Nobuyuki Koyama, Kinya Furukawa, Hiroyuki Nakamura,
Shinji Kikuchi, Yukio Sato, Ikuno Sekine, and Hiroaki Satoh collected
the data. Toshihiro Shiozawa and Tomohiro Tamura analyzed the data.
Toshihiro Shiozawa and Takeshi Numata wrote the original draft.
Nobuyuki Hizawa supervised the manuscript preparation. All Authors
discussed the results and agreed on the final draft.

Acknowledgements

The Authors would like to acknowledge Editage (https://www.editage.jp) for English language editing.

References

Shiozawa et al: Association Between PD-L1 and Osimertinib Treatment

1 Jorissen RN, Walker F, Pouliot N, Garrett TP, Ward CW andBurgess AW: Epidermal growth factor receptor: mechanisms ofactivation and signalling. Exp Cell Res 284(1): 31-53, 2003.
PMID: 12648464. DOI: 10.1016/s0014-4827(02)00098-8
2 Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S,
Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita
Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando
M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S,
Nukiwa T and North-East Japan Study Group: Gefitinib or
chemotherapy for non-small-cell lung cancer with mutated
EGFR. N Engl J Med 362(25): 2380-2388, 2010. PMID:
20573926. DOI: 10.1056/NEJMoa0909530
3 Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, Zhang S,
Wang J, Zhou S, Ren S, Lu S, Zhang L, Hu C, Hu C, Luo Y,
Chen L, Ye M, Huang J, Zhi X, Zhang Y, Xiu Q, Ma J, Zhang
L and You C: Erlotinib versus chemotherapy as first-line
treatment for patients with advanced EGFR mutation-positive
non-small-cell lung cancer (OPTIMAL, CTONG-0802): a
multicentre, open-label, randomised, phase 3 study. Lancet
Oncol 12(8): 735-742, 2011. PMID: 21783417. DOI:
10.1016/S1470-2045(11)70184-X
4 Sequist LV, Yang JC, Yamamoto N, O’Byrne K, Hirsh V, Mok T,
Geater SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J,
Kato T, Gorbunova V, Lee KH, Shah R, Massey D, Zazulina V,
Shahidi M and Schuler M: Phase III study of afatinib or cisplatin
plus pemetrexed in patients with metastatic lung adenocarcinoma
with EGFR mutations. J Clin Oncol 31(27): 3327-3334, 2013.
PMID: 23816960. DOI: 10.1200/JCO.2012.44.2806
5 Soria JC, Ohe Y, Vansteenkiste J, Reungwetwattana T,
Chewaskulyong B, Lee KH, Dechaphunkul A, Imamura F,
Nogami N, Kurata T, Okamoto I, Zhou C, Cho BC, Cheng Y,
Cho EK, Voon PJ, Planchard D, Su WC, Gray JE, Lee SM,
Hodge R, Marotti M, Rukazenkov Y, Ramalingam SS andFLAURA Investigators: Osimertinib in untreated EGFR-mutatedadvanced non-small-cell lung cancer. N Engl J Med 378(2): 113125, 2018. PMID: 29151359. DOI: 10.1056/NEJMoa1713137
6 Ramalingam SS, Vansteenkiste J, Planchard D, Cho BC, Gray
JE, Ohe Y, Zhou C, Reungwetwattana T, Cheng Y,
Chewaskulyong B, Shah R, Cobo M, Lee KH, Cheema P, Tiseo
M, John T, Lin MC, Imamura F, Kurata T, Todd A, Hodge R,
Saggese M, Rukazenkov Y, Soria JC and FLAURA
Investigators: Overall survival with osimertinib in untreated,
EGFR-mutated advanced NSCLC. N Engl J Med 382(1): 41-50,
2020. PMID: 31751012. DOI: 10.1056/NEJMoa1913662
7 Hanna NH, Robinson AG, Temin S, Baker S Jr, Brahmer JR,
Ellis PM, Gaspar LE, Haddad RY, Hesketh PJ, Jain D, Jaiyesimi
I, Johnson DH, Leighl NB, Moffitt PR, Phillips T, Riely GJ,
Rosell R, Schiller JH, Schneider BJ, Singh N, Spigel DR,
Tashbar J and Masters G: Therapy for stage IV non-small-celllung cancer with driver alterations: ASCO and OH (CCO) joint
guideline update. J Clin Oncol 39(9): 1040-1091, 2021. PMID:
33591844. DOI: 10.1200/JCO.20.03570
8 Herbst RS, Baas P, Kim DW, Felip E, Pérez-Gracia JL, Han JY,
Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, deCastro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E,
Dolled-Filhart M and Garon EB: Pembrolizumab versus
docetaxel for previously treated, PD-L1-positive, advanced nonsmall-cell lung cancer (KEYNOTE-010): a randomised

controlled trial. Lancet 387(10027): 1540-1550, 2016. PMID:
26712084. DOI: 10.1016/S0140-6736(15)01281-7
9 Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T,
Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O’Brien M,
Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y,
Rangwala R, Brahmer JR and KEYNOTE-024 Investigators:
Pembrolizumab versus chemotherapy for PD-L1-positive nonsmall-cell lung cancer. N Engl J Med 375(19): 1823-1833, 2016.
PMID: 27718847. DOI: 10.1056/NEJMoa1606774
10 Jackman D, Pao W, Riely GJ, Engelman JA, Kris MG, Jänne PA,
Lynch T, Johnson BE and Miller VA: Clinical definition of acquired
resistance to epidermal growth factor receptor tyrosine kinase
inhibitors in non-small-cell lung cancer. J Clin Oncol 28(2): 357360, 2010. PMID: 19949011. DOI: 10.1200/JCO.2009.24.7049
11 Nakashima K, Ozawa Y, Daga H, Imai H, Tamiya M, Tokito T,
Kawamura T, Akamatsu H, Tsuboguchi Y, Takahashi T,
Yamamoto N, Mori K and Murakami H: Osimertinib for patientswith poor performance status and EGFR T790M mutationpositive advanced non-small cell lung cancer: a phase II clinical
trial. Invest New Drugs 38(6): 1854-1861, 2020. PMID:
32424780. DOI: 10.1007/s10637-020-00943-0
12 Reungwetwattana T, Nakagawa K, Cho BC, Cobo M, Cho EK,
Bertolini A, Bohnet S, Zhou C, Lee KH, Nogami N, Okamoto I,
Leighl N, Hodge R, McKeown A, Brown AP, Rukazenkov Y,
Ramalingam SS and Vansteenkiste J: CNS response to osimertinib
versus standard epidermal growth factor receptor tyrosine kinase
inhibitors in patients with untreated EGFR-mutated advanced nonsmall-cell lung cancer. J Clin Oncol: JCO2018783118, 2018.
PMID: 30153097. DOI: 10.1200/JCO.2018.78.3118
13 Brown H, Vansteenkiste J, Nakagawa K, Cobo M, John T,
Barker C, Kohlmann A, Todd A, Saggese M, Chmielecki J,
Markovets A, Scott M and Ramalingam SS: Programmed cell
death ligand 1 expression in untreated EGFR mutated advanced
NSCLC and response to osimertinib versus comparator in
FLAURA. J Thorac Oncol 15(1): 138-143, 2020. PMID:
31605792. DOI: 10.1016/j.jtho.2019.09.009
14 Yoshimura A, Yamada T, Okuma Y, Fukuda A, Watanabe S,
Nishioka N, Takeda T, Chihara Y, Takemoto S, Harada T,
Hiranuma O, Shirai Y, Nishiyama A, Yano S, Goto Y, Shiotsu
S, Kunimasa K, Morimoto Y, Iwasaku M, Kaneko Y, Uchino J,
Kenmotsu H, Takahashi T and Takayama K: Impact of tumor
programmed death ligand-1 expression on osimertinib efficacy
in untreated EGFR-mutated advanced non-small cell lungcancer: a prospective observational study. Transl Lung Cancer
Res 10(8): 3582-3593, 2021. PMID: 34584858. DOI:
10.21037/tlcr-21-461
15 Su S, Dong ZY, Xie Z, Yan LX, Li YF, Su J, Liu SY, Yin K,
Chen RL, Huang SM, Chen ZH, Yang JJ, Tu HY, Zhou Q,
Zhong WZ, Zhang XC and Wu YL: Strong programmed deathligand 1 expression predicts poor response and de novo
resistance to EGFR tyrosine kinase inhibitors among NSCLC
patients with EGFR mutation. J Thorac Oncol 13(11): 16681675, 2018. PMID: 30056164. DOI: 10.1016/j.jtho.2018.07.016
16 Bassanelli M, Sioletic S, Martini M, Giacinti S, Viterbo A,
Staddon A, Liberati F and Ceribelli A: Heterogeneity of PD-L1
expression and relationship with biology of NSCLC. Anticancer
Res 38(7): 3789-3796, 2018. PMID: 29970498. DOI: 10.21873/
anticanres.12662
17 Zhang N, Zeng Y, Du W, Zhu J, Shen D, Liu Z and Huang JA: The
EGFR pathway is involved in the regulation of PD-L1 expression

2589

ANTICANCER RESEARCH 42: 2583-2590 (2022)

via the IL-6/JAK/STAT3 signaling pathway in EGFR-mutated nonsmall cell lung cancer. Int J Oncol 49(4): 1360-1368, 2016. PMID:
27499357. DOI: 10.3892/ijo.2016.3632
18 Chen N, Fang W, Zhan J, Hong S, Tang Y, Kang S, Zhang Y, He
X, Zhou T, Qin T, Huang Y, Yi X and Zhang L: Upregulation of
PD-L1 by EGFR activation mediates the immune escape in
EGFR-driven NSCLC: Implication for optional immune targeted
therapy for NSCLC patients with EGFR mutation. J Thorac
Oncol 10(6): 910-923, 2015. PMID: 25658629. DOI:
10.1097/JTO.0000000000000500
19 Lin K, Cheng J, Yang T, Li Y and Zhu B: EGFR-TKI downregulates PD-L1 in EGFR mutant NSCLC through inhibiting
NF-ĸB. Biochem Biophys Res Commun 463(1-2): 95-101, 2015.
PMID: 25998384. DOI: 10.1016/j.bbrc.2015.05.030
20 McGowan M, Kleinberg L, Halvorsen AR, Helland Å andBrustugun OT: NSCLC depend upon YAP expression andnuclear localization after acquiring resistance to EGFR
inhibitors. Genes Cancer 8(3-4): 497-504, 2017. PMID:
28680534. DOI: 10.18632/genesandcancer.136
21 Lee JE, Park HS, Lee D, Yoo G, Kim T, Jeon H, Yeo MK, Lee
CS, Moon JY, Jung SS, Kim JO, Kim SY, Park DI, Park YH,
Lee JC, Oh IJ, Lim DS and Chung C: Hippo pathway effector

2590

YAP inhibition restores the sensitivity of EGFR-TKI in lungadenocarcinoma having primary or acquired EGFR-TKI
resistance. Biochem Biophys Res Commun 474(1): 154-160,
2016. PMID: 27105908. DOI: 10.1016/j.bbrc.2016.04.089
22 Tung JN, Lin PL, Wang YC, Wu DW, Chen CY and Lee H: PDL1 confers resistance to EGFR mutation-independent tyrosine
kinase inhibitors in non-small cell lung cancer via upregulation
of YAP1 expression. Oncotarget 9(4): 4637-4646, 2017. PMID:
29435131. DOI: 10.18632/oncotarget.23161
23 Takano N, Seike M, Sugano T, Matsuda K, Hisakane K, Yoshikawa
A, Nakamichi S, Noro R and Gemma A: A novel molecular target
in EGFR-mutant lung cancer treated with the combination ofosimertinib and pemetrexed. Anticancer Res 42(2): 709-722, 2022.
PMID: 35093869. DOI: 10.21873/anticanres.15529

Received March 7, 2022
Revised March 27, 2022
Accepted March 28, 2022

Case report

Koji Nakano,1 Tomomi Koizumi ‍ ‍,1 Yuto Abe,1 Masao Ono2
1

Department of Cardiovascular
Medicine, National Hospital
Organization Mito Medical
Center, Higashi-­Ibarakigun,
Japan
2
Department of Laboratory
Medicine, National Hospital
Organization Mito Medical
Center, Higashi-­Ibarakigun,
Japan
Correspondence to
Dr Tomomi Koizumi;​tomomikzm2014@​gmail.​com
Accepted 5 April 2022

SUMMARY
While the vascular healing process after drug-­eluting
stent implantation is not fully elucidated, it is generally
accepted that macrophages play an important rolein inflammation. It is also known that macrophages
involved in the pathogenesis of atherosclerosis may
stem from several origins, that is, monocyte-­derived
macrophages versus resident macrophages. However,
little is known about the role of human macrophages
on reperfusion of culprit coronary arteries in patientswith atherosclerotic disease who have sustained acutecoronary syndrome. In this present case report, we
describe the presence of cluster of differentiation (CD)163-­positive macrophages in close proximity to thestent struts at the luminal site 72 hours after drug-­eluting stent implantation in the culprit coronary lesion
for ST elevation myocardial infarction by postmortem
examination.

BACKGROUND© BMJ Publishing Group
Limited 2022. Re-­use
permitted under CC BY-­NC. No
commercial re-­use. See rights
and permissions. Publishedby BMJ.
To cite: Nakano K, Koizumi T,
Abe Y, et al. BMJ Case
Rep 2022;15:e248539.
doi:10.1136/bcr-2021248539

The healing process after coronary artery stentimplantation is dependent on the resolution of theinflammatory reaction that drives atherogenesis.
Macrophages are known to play an important rolein the development of atherosclerotic lesions1 withtwo macrophage phenotypes having been associated with different areas of the lesions: M1 (proinflammatory) macrophages that have been detectedin the rupture-­prone area of the intima, and M2(anti-­
inflammatory) macrophages that have been
localised in the adventitia underlying advanced
plaques.2–5
However, little is known about which type ofmacrophage is mobilised just after stent implantation on vulnerable plaques in a culprit coronary
artery after ST elevation myocardial infarction(STEMI).6 Behaviour of human macrophages justafter stent implantation in the infarct-­related arteryin STEMI patients is rarely investigated because
the only definitive examination could occur postmortem. As such, we describe a postmortem casewith the presence of cluster of differentiation (CD)163-­positive macrophages in close proximity to thestent struts 72 hours after drug-­eluting stent implantation in the culprit coronary lesion for STEMI.

CASE PRESENTATION

The patient was a man in his 80s transferred toour hospital with chief complaint of chest pain.
Interval of symptom onset to hospital arrival was
110 min. The patient reported a medical history of

hypertension which was controlled by medication.
On initial examination, his systolic blood pressure
was 70 mm Hg, heart rate was 60 beats per minuteand pulse oximetric oxygen saturation was 94% onroom air.

INVESTIGATIONS

A 12-­lead ECG revealed sinus rhythm and ST-­segment elevation in leads II, III, aVF and ST-­segment
depression in leads I, aVL, V2-­V5. Transthoracic
echocardiogram illustrated hyokinesis in the inferolateral wall and left ventricular ejection fraction of
40%. Initial coronary angiography showed total
occlusion of the proximal left circumflex artery(LCX) (figure 1A).

TREATMENT

Primary percutaneous coronary intervention (PCI)
to the proximal LCX was performed and a biodegradable polymer-­based sirolimus-­eluting stent(Orsiro 2.5×15 mm; Biotronik, Bülach, Switzerland) was implanted (figure 1B) in the culprit
lesion. Although reperfusion therapy was successful
with resultant thrombolysis in myocardial infarction flow grade 3 (door to balloon time was 81 min)(figure 1C), the patient’s continued haemodynamic
instability required both mechanical (intra-­aorticballoon pumping and percutaneous cardiopulmonary support) and pharmacological circulatory
support with catecholamines.

OUTCOME AND FOLLOW-UP

Unfortunately, the patient’s blood pressure did notrecover, and 72 hours after PCI, he passed away.
Postmortem examination was performed 3 hours
50 min after death. His autopsy revealed extensive
lateral wall myocardial infarction with haemorrhage
on macroscopic examination. The coronary arteries
were extracted and the LCX (figure 1D) was incised
to examine the stent (figure 1E). The dissected coronary artery with the stented segment was fixed with
5% formalin. After excision of the metal struts, thestented region (figure 2B), with reference segments(figure 2A,C) within 5 mm of both the proximaland distal ends, was processed for H&E staining or
immunohistochemical staining. Immunohistochemical staining for CD68, CD80, CD163 and arginase
1 was performed.
Light microscopy of cross-­sections of the artery,stained by H&E, revealed eccentric arteriosclerotic plaques in reference segments (figure 2 A#
C#) and stented segment (figure 2 B#). On higher

Nakano K, et al. BMJ Case Rep 2022;15:e248539. doi:10.1136/bcr-2021-248539

1

BMJ Case Rep: first published as 10.1136/bcr-2021-248539 on 3 May 2022. Downloaded from http://casereports.bmj.com/ on April 6, 2023 by guest. Protected by copyright.

Macrophage behaviour 72 hours after implantationof biodegradable polymer-­based sirolimus-­eluting
stent in a case of ST elevation myocardial infarction

Case reportmagnification, the stented segment appeared hypocellular, withscant inflammatory cells including lymphocytes or neutrophils
observed around the stent struts (figure 2D,E). By immunohistochemical staining, CD80-­positive cells were not observed ineither the luminal site or the vessel wall, including around thestent struts and both the distal and proximal vessel ends. Both
CD163-­positive cells and arginase 1-­positive cells were identified at the border of the vascular lumen (CD163 and arginase 1,
figure 3A,C) and appeared to be in close proximity to the edgeof each stent strut (※ shows site of the stent strut, CD163 andarginase 1, figure 3B,D) in the culprit lesion. Moreover, bothFigure 2 Left panel: The extracted proximal LCX segment with a stent.
Blue lines A, B and C correspond to the sites of cross-­sectioning of theartery. Middle panel: Cross-­sectional images of the proximal LCX (A#),
stented segment (B#) and distal LCX (C#) stained for H&E. Right panel:
D, E represent high magnification H&E-­stained images of the stented
segment around the stent struts. LCX: left circumflex.
2

Figure 3 (A, B): CD163 stain, (C,D): arginase 1 stain of the culprit
lesion after stent implantation. Black square frames in A and C are
magnified in B and D. Note that both CD163-­positive cells and arginase1-­positive cells (red arrows) are next to the stent struts (※ shows siteof the stent strut). CD: cluster of differentiation.
CD163-­positive cells and arginase 1-­positive cells were detectedin the adventitia of the stented segment of the coronary artery.

DISCUSSION

To the best of our knowledge, this is the first report of both
CD163-­
positive macrophages and arginase 1-­
positive macrophages detected close to the stent struts in the context of
STEMI in humans. It has been reported that M2 macrophages
play a reparative role.4 Indeed, the present images suggest that
vascular injury repair by M2 macrophages may start 3 days after
sirolimus-­eluting stent implantation for STEMI.
M2 macrophages were also detected in the adventitia of thestented segment of the culprit coronary artery, which is consistent
with a former report.5 There were almost no M2 macrophages
either in the subintimal area or the intima 3 days after stentimplantation. This leads us to deduce that the M2 macrophages
in close proximity to the stent struts only at luminal site might
not have migrated from the adventitia to the luminal site within
3 days, but may have originated from circulating monocytes.
However, the role of M2 macrophages in atherosclerosis
progression remains controversial. Recent reports indicate that
CD163 macrophages are associated with plaque progression7
and that CD163-­expressing macrophages have a protective role
during the progression of atherosclerosis.8 Moreover, the role of
CD163 macrophages in adventitia has not been fully elucidated;
therefore, further studies are warranted to understand the roleof CD163 in culprit coronary artery in patients with STEMI.
Of note, scant number of inflammatory cells were detected in
the stented segment of the culprit coronary artery and in both theproximal and distal segments of the artery shortly after STEMI,
although, the culprit arterial wall was expected to be filled with
abundant inflammatory cells.9 Taking into account that plaquemorphology and cellar composition of coronary atherosclerosis
leading to thrombosis is a heterogeneous process, and coronary
erosion has less macrophages than plaque rupture, the formation of thrombosis is probably due to superficial erosion in thepresent case.9 Therefore, accumulation of pathological data
including inflammatory cells will elucidate the mechanisms ofcoronary atherothrombosis at the very onset of STEMI.

CONCLUSION

CD163-­
positive macrophages and arginase 1-­
positive macrophages were detected in close proximity to drug-­eluting stent
Nakano K, et al. BMJ Case Rep 2022;15:e248539. doi:10.1136/bcr-2021-248539

BMJ Case Rep: first published as 10.1136/bcr-2021-248539 on 3 May 2022. Downloaded from http://casereports.bmj.com/ on April 6, 2023 by guest. Protected by copyright.

Figure 1 (A) The left coronary artery in initial coronary angiography in
the RAO 30 and CAU 20 view. Total occlusion in the proximal circumflex
artery is observed (white arrow). (B) RAO 24 and CAU 17 view,illustrating a balloon (yellow arrow) inflating stent in the occlusion
lesion (white arrow). (C) Final angiography by RAO 24 and CAU 17 view,
indicating TIMI flow grade 3 in the circumflex artery. (D) Magnification
image of (C). White double-­sided arrow represents the length of theextracted segment of the LCX. Yellow double-­sided arrow represents theactual stent. (E) Autopsy specimen of the extracted segment of the LCX.
Yellow double-­sided arrow demonstrates the length of the implanted
stent that is visible with the artery. CAU: caudal, LCX: left circumflex,
RAO: right anterior oblique, TIMI: thrombolysis in myocardial infarction.

Case report► Acute coronary syndrome is a leading cause of death,provoked by acute coronary thrombosis, where inflammation
has been reported as its main processes.
► Macrophages play an important role in inflammation,
but behaviour of human macrophages just after coronary
thrombosis and stent implantation in the infarct-­related
artery (IRA) is not fully elucidated.
► Present ST elevation myocardial infarction (STEMI) caseshows that CD163-­positive macrophages are neighbouring
on stent struts 72 hours after stent implantation in IRA,
indicating CD163-­positive macrophages were recruited forhealing process after stent implantation in IRA in patient withSTEMI.
► The present results give us an opportunity to clarify a part ofthe process of healing vasculature after stent implantation inhuman coronary atherothrombosis.
struts deployed 3 days prior in the culprit coronary artery inpatient with STEMI, giving us an opportunity to clarify a partof the process of healing vasculature after stent implantation inatherothrombosis.
Acknowledgements The authors thank Heidi N Bonneau, RN, MS, CCA for reviewof this report.
Contributors KN, TK helped in writing. KN, YA, TK contributed in collecting data.
MO has done pathological assessment.
Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests None declared.

Patient consent for publication Consent obtained from parent(s)/guardian(s).
Provenance and peer review Not commissioned; externally peer reviewed.
Open access This is an open access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-­commercially,and license their derivative works on different terms, provided the original work
is properly cited and the use is non-­commercial. See: http://creativecommons.org/​
licenses/by-nc/4.0/.
Case reports provide a valuable learning resource for the scientific community andcan indicate areas of interest for future research. They should not be used in isolation
to guide treatment choices or public health policy.
ORCID iD
Tomomi Koizumi http://orcid.org/0000-0001-7984-0755

REFERENCES

1 Robbins CS, Hilgendorf I, Weber GF, et al. Local proliferation dominates lesional
macrophage accumulation in atherosclerosis. Nat Med 2013;19:1166–72.
2 Colin S, Chinetti-­Gbaguidi G, Staels B. Macrophage phenotypes in atherosclerosis.
Immunol Rev 2014;262:153–66.
3 Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003;3:23–35.
4 Murray PJ, Wynn TA. Protective and pathogenic functions of macrophage subsets. Nat
Rev Immunol 2011;11:723–37.
5 Stöger JL, Gijbels MJJ, van der Velden S, et al. Distribution of macrophage polarization
markers in human atherosclerosis. Atherosclerosis 2012;225:461–8.
6 Honold L, Nahrendorf M. Resident and monocyte-­derived macrophages in
cardiovascular disease. Circ Res 2018;122:113–27.
7 Guo L, Akahori H, Harari E, et al. CD163+ macrophages promote angiogenesis andvascular permeability accompanied by inflammation in atherosclerosis. J Clin Invest
2018;128:1106–24.
8 Gutiérrez-­Muñoz C, Méndez-­Barbero N, Svendsen P, et al. CD163 deficiency
increases foam cell formation and plaque progression in atherosclerotic mice. Faseb J
2020;34:14960–76.
9 van der Wal AC, Becker AE, van der Loos CM, et al. Site of intimal rupture or erosionof thrombosed coronary atherosclerotic plaques is characterized by an inflammatory
process irrespective of the dominant plaque morphology. Circulation 1994;89:36–44.

Copyright 2022 BMJ Publishing Group. All rights reserved. For permission to reuse any of this content visit
https://www.bmj.com/company/products-services/rights-and-licensing/permissions/
BMJ Case Report Fellows may re-use this article for personal use and teaching without any further permission.
Become a Fellow of BMJ Case Reports today and you can:► Submit as many cases as you like
► Enjoy fast sympathetic peer review and rapid publication of accepted articles► Access all the published articles► Re-use any of the published material for personal use and teaching without further permission
Customer Service
If you have any further queries about your subscription, please contact our customer services team on +44 (0) 207111 1105 or via email at support@bmj.com.
Visit casereports.bmj.com for more articles like this and to become a Fellow

Nakano K, et al. BMJ Case Rep 2022;15:e248539. doi:10.1136/bcr-2021-248539

3

BMJ Case Rep: first published as 10.1136/bcr-2021-248539 on 3 May 2022. Downloaded from http://casereports.bmj.com/ on April 6, 2023 by guest. Protected by copyright.

Learning points

Received: 8 September 2021

Revised: 13 February 2022

Accepted: 10 March 2022

DOI: 10.1111/tid.13845

ORIGINAL ARTICLE

Impact of COVID-19 on living donor liver and kidneytransplantation programs in Japan in 2020
Kaori Kuramitsu1
Mikiko Yoshikawa5
Minoru Ono6
Harumi Yano10

Shigeyoshi Yamanaga2
Ryosuke Osawa3
Taizo Hibi4
Mariko Toyoda2
Keita Shimata4
Ebisu Yosuke3

Takashi Kenmochi7
Hiroshi Sogawa8
Yoichiro Natori9
Toyofumi Chen-Yoshikawa11
Kazunari Yoshida12

Takumi Fukumoto1

Kenji Yuzawa13

Hiroto Egawa14

1

Department of Surgery, Division of Hepato-Biliary and Pancreatic Surgery, Graduate School of Medicine, Kobe University, Hyogo, Japan2

Department of Surgery, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan3

Department of Infectious Disease, Kameda Medical Center, Chiba, Japan

4

Department of Pediatric Surgery and Transplantation, Kumamoto University Hospital, Kumamoto, Japan

5

Department of Transplant and Regenerative Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan

6

Department of Cardiac Surgery, Tokyo University, Tokyo, Japan

7

Department of Transplantation, Fujita Health University, Aichi, Japan

8

Department of Surgery, Westchester Medical Center/New York Medical College, New York, USA

9

Division of Infectious Disease, Department of Medicine, University of Miami, Florida, USA

10

Department of Public Health, International University of Health and Welfare, Chiba, Japan

11

Department of Thoratic Surgery, Nagoya University, Aichi, Japan

12

Department of Organ Transplant Medicine, Kitasato University, Kanagawa, Japan

13

Department of Transplant Surgery, Mito Medical Center, Ibaraki, Japan

14

Department of Surgery, Institute of Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan

Correspondence
Kaori Kuramitsu, Department of Surgery,
Division of Hepato-Biliary and Pancreatic
Surgery, Kobe University Graduate School of
Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe
City, Hyogo, Japan.
Email: kkuramit@med.kobe-u.ac.jp

Abstract
Background: Although many transplant programs have been forced to suspend living donor transplants due to the emergence of coronavirus disease (COVID-19), there
are relatively few real-time databases to assess center-level transplant activities. We
aimed to delineate the actual impact of COVID-19 on living donor transplant programsand the resumption process in Japan.
Methods: In a nationwide survey, questionnaires were sent to 32 liver transplant programs that had performed at least more than one case of living donor liver transplantation in 2019 and 132 kidney transplant programs that had performed more than one
living donor kidney transplantation in 2018.
Results: Thirty-one (96.9%) and 125 (94.7%) liver and kidney transplant programs
responded, respectively. In the early pandemic period, 67.7% (21/31) of liver programs

COVID-19, coronavirus disease; DDKT, deceased donor kidney transplantation; DDLT, deceased donor liver transplantation; JST, Japan Society for Transplantation; LDKT, living donor kidneytransplantation; LDLT, living donor liver transplantation; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.

Transpl Infect Dis. 2022;24:e13845.
https://doi.org/10.1111/tid.13845

wileyonlinelibrary.com/journal/tid© 2022 Wiley Periodicals LLC.

1 of 11

KURAMITSU ET AL .

and 29.8% (37/125) of kidney programs were able to maintain transplant activities similar to those during the pre-pandemic period. After temporal suspension, 58.1% of kidney programs resumed their transplant activity after the number of local COVID-19
cases peaked. Establishing institutional COVID-19 screening, triage, and therapeutic
management protocols was mandatory to resume transplant activity for 64.5% and67.7% of liver and kidney programs, respectively. In the future wave of COVID-19,
67.7% of liver programs would be affected by institutional COVID-19 intensive careunit-bound patient numbers, and 55.7% of kidney programs would stop if hospitalacquired severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection
spreads.
Conclusions: This nationwide survey revealed for the first time how living donor liverand kidney: transplant programs changed in response to the COVID-19 pandemic in acountry where living donor transplantations are predominant.
KEYWORDS

COVID-19, living donor kidney transplantation, living donor liver transplantation

1

INTRODUCTION

Most recently, the JST announced the fifth edition of the guidelines on
November 8, 2021 (version 5) and proposed a checklist to help deter-

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) wasmine de novo transplantation for both living donors and recipients who

identified in December 2019 and was subsequently determined to be

recovered from COVID-19.

the cause of coronavirus disease (COVID-19).1,2 The risk of death from

Each transplant facility faced a difficult situation in which they

COVID-19 is higher among immunosuppressed patients than in the

had to make decisions individually to resume or postpone transplant

general population.3 Accordingly, elective surgeries, including living

surgeries. Since there are relatively few real-time databases to assess

donor transplant procedures, were paused in many countries.4,5 It iscenter-level transplant activities and no evidence-based guidelines forimportant to note that organ transplantation in Japan depends heavily

the management of transplant patients (especially from living donors inon living donors due to a shortage of deceased donors. Responding toJapan), communication of knowledge is vital.6

the inquiries from multiple transplant programs, the Japan Society forThis study aimed to understand the impact of COVID-19 on

Transplantation (JST) published a set of guidelines on March 6, 2020

transplant activities across Japan and to explore center-level varia-(version 1). In the guidelines, the JST recommended continuing trans-

tions in activity, clinical practice, testing, and policies. Through thisplants for immediate life-saving organs such as the heart, lung, andstudy, we examined how living donor transplant programs in Japan

liver (for fulminant liver failure) after performing a risk–benefit assess-were previously suspended or continued; this information is criticalment for each case. Nonurgent transplants of the kidney, pancreas, andfor the maintenance of programs and for the future if COVID-19

bowel, as well as all nonlife-threatening living donor transplantations,re-spikes.

were recommended to be postponed. For urgent living donor transplants, including living donor liver transplantation (LDLT), preventative measures such as 14 days of home or inpatient quarantine and a2

MATERIALS AND METHODSCOVID-19 screening test for both donors and recipients were recommended. Many transplant programs have suspended their living donor

The survey was conducted from October 20, 2020, to November 30,

transplants in response to the guidelines in Japan.

2020. Questionnaires were constituted only for this survey. The sur-As the first wave of COVID-19 peaked, the JST announced theveys were reviewed by the project members of the grant and adapted

fourth edition of the guidelines on May 29, 2020 (version 4) and pro-based on the feedback. Questionnaires were sent via e-mail to 32 liver

posed a checklist to help determine the appropriate time to resume liv-transplant programs that had performed at least more than one caseing donor kidney transplantation (LDKT) programs. These guidelinesof LDLT in 2019 and 132 kidney transplant programs that had per-also recommended resuming living donor transplant activities based

formed more than one LDKT in 2018. Data were collected from 96.9%

on the local community and institutional transmission risk. For liv-

(31/32) of the LDLT programs and 94.7% (125/132) of the LDKT pro-ing donor liver and kidney transplant donors and recipients, preven-grams. One answer from the two LDKT programs (Hirosaki University

tive measures, such as 14 days of home or inpatient quarantine andand Oyokyo Kidney Research Institute Hirosaki Hospital, run by the

COVID-19 polymerase chain reaction (PCR) tests, were recommended.

same team) was counted as one program for the analysis. The ques-

13993062, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tid.13845 by Cochrane Japan, Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

2 of 11tionnaire consisted of four sections: (1) institutional transplant activi-

3.1

Institutional transplantation activities

ties, (2) influence of COVID-19 on the institutional transplantation program, (3) institutional transplant outpatient practices, and (4) institutional COVID-19 treatment practices (Table S1).

3.1.1
Transplantation numbers in the
pre-pandemic era

Section 1 focused on the number of LDLT, LDKT, deceased donorliver transplantation (DDLT), and deceased donor kidney transplanta-

The yearly number of cases of living donor liver and kidney transplanta-

tions (DDKT) performed in 2017, 2018, and 2019, as well as the num-

tions was 334/1402 in 2017, 343/1555 in 2018, and 312/1701 in 2019.

ber of LDLT, LDKT, DDLT, and DDKT performed per month in 2020.

From deceased donors, the number of yearly liver/kidney transplant

Section 2 focused on the present status of the institutional trans-

cases was 63/127 in 2017, 59/121 in 2018, and 88/176 in 2019. Cate-plant program at the time of the survey (October 2020). The sur-gorized by zone, 219 (70.2%) LDLTs, 66 (75.0%) DDLTs, 1192 (70.1%)

vey asked who approved the institutional transplant activities (institu-

LDKTs, and 135 (76.7%) DDKTs were performed in 2019 in the redtion, department, or government) during the pandemic, if there werezone.

any adverse effects on the recipients by resuming the transplant program, how to manage future transplant programs and the preoperative
COVID-19 preventative measures for both donors and recipients.
Section 3 focused on outpatient management. Specifically, items
about the recipient routine check-up list, number of donor/recipient

3.2
Transplantation numbers in the
pandemic era

outpatients, number of patients who delayed their routine visits, andinstitutional measures taken to reduce the risk of COVID-19 in outpa-

Figure 1C shows the total number of transplantations per monthtient clinics were included.

from January to September 2020. Although LDLTs were routinely

Section 4 focused on the hospital’s experience in dealing withperformed at 25 cases per month on average, the number of LDKTs

COVID-19. Items about center-level COVID-19 treatment systems

dropped to 55% (an average of 115 cases per month) from March towere included.

June; the rate increased gradually thereafter. In total, 229 LDLTs andAn additional survey was performed to reveal the COVID-19 test

1034 LDKTs were performed. The number of deceased donor trans-

status of the donors and the recipients who underwent transplantation

plantations decreased slightly at an earlier stage. On average, six cases

during the survey period. Twenty-eight (85.7%) liver transplant pro-of DDLTs and 11 cases of DDKTs were performed per month from Jan-grams and 111 (89.5%) kidney transplant programs responded to theuary to September 2020. In total, 52 DDLTs and 97 DDKTs were per-additional survey.

formed. To examine the regional impact of COVID-19, the total num-On April 7, 2020, to prevent the spread of COVID-19, a state of

ber of transplantations was sorted according to the red and blue zones.

emergency was declared in seven prefectures (Saitama, Chiba, Tokyo,

Figure 1D shows the total number of LDLT cases per month, which

Kanagawa, Osaka, Hyogo, and Fukuoka), which had an increasing num-

were routinely performed during the study period. Figure 1E shows theber of new cases. On April 16, six prefectures (Hokkaido, Ibaraki,

total number of DDLT cases per month. The total number decreased

Ishikawa, Gifu, Aichi, and Kyoto) were added. These 13 prefecturesin March, April, and May, and a decrease was observed in both the redeither had a high population density and high levels of traffic or had

and blue zones. The number of DDLT cases increased in June. In total,clusters of COVID-19. In general, for living donor transplantation pro-

22 liver transplantations (18 LDLTs and four DDLTs) were performed

grams in Japan, recipients and donors are from the same or neighboring

per month in the red zone, whereas only nine (eight LDLTs and one

prefectures, except in pediatric cases. We categorized the transplan-

DDLT) were performed in the blue zone. Throughout the pandemic

tation programs into two groups based on their location: red zone—

era, 161 (70.3%) LDLTs and 39 (75.0%) DDLTs were performed in thetransplant programs located in the 13 prefectures where the state of

red zone. Figure 1F,G shows the total number of kidney transplanta-

emergency was declared (Figure 1A), and blue zone—the remaining 34

tion cases per month. The number of LDKT cases decreased drasti-

prefectures where a state of emergency was not issued. Based on thiscally in April and May and that of DDKT cases decreased in Marchdefinition, 58.1% of the transplantation programs were categorized as

and April. A decrease was observed in both the red and blue zones.

the red zone group, and the remaining 41.9% were categorized as the

The number of LDKT started to increase in June and DDKT in May.

blue zone group (Figure 1B).

In total, 89 kidney transplantations (81 LDKTs and eight DDKTs) were
performed per month in the red zone, and 36 (33 LDKTs and three
DDKTs) were performed per month in the blue zone. Throughout the

3

RESULTSpandemic era, 759 (73.4%) LDKTs and 71 (73.2%) DDKTs were performed in the red zone. In short, although the number of cases of LDLT

Answers from 31 LDLT and 124 LDKT programs were analyzed in the

did not change, DDLT and kidney transplantation decreased in the pan-study.

demic era.

13993062, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tid.13845 by Cochrane Japan, Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

3 of 11

KURAMITSU ET AL .

KURAMITSU ET AL .

(A) Location of 13 red zone transplant programs(C)(B) Liver/kidney transplant programs categorized
by red/blue zones

State of emergency
declared

Government
Academic(Japan Society forTransplantation)

Guideline Ver.1

Guideline Ver.4

Monthly COVID-19 positive Pt.

Total number of liver/kidney transplantations per month
Jan

Feb

Mar

Apr

May

June

July

Aug

Sep

Living donor
Liver

25

26

24

27

22

22

25

24

34

Kidney

141

122

112

51

58

96

155

140

159

Deceased donor
Liver

7

7

4

3

3

5

6

8

9

Kidney

10

12

7

7

9

9

15

15

13

(D)

Total number of LDLT per month(E)average; 115 cases/monthaverage; 25 cases/month(F)

Total number of DDLT per month

Total number of LDKT per month(G)

Total number of DDKT per monthaverage; 11 cases/monthaverage; 6 cases/month

13993062, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tid.13845 by Cochrane Japan, Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

4 of 11

TA B L E 1

TA B L E 2

Institutional transplantation activities
Liver

Reasons to resume the institutional transplant program

KidneyInstitutional activity on October 2020

Liver

KidneyInstitutional

Without any regulation

67.7%

29.8%

Operation restriction was released

22.6%

26.6%

Only urgent/selectedtransplantation

19.4%

6.5%

COVID-19 treatment system wasconstituted

64.5%

67.7%

Resume after local COVID-19
peak out

9.7%

58.1%

COVID-19 infection status was improved 25.8%

25.0%

No COVID-19 spread

51.6%

42.7%

Pause

3.2%

COVID-19 infection status was improved 41.9%

46.0%

5.6%

Institutional approval for transplantation activities
Institutional board

61.3%

52.4%

Department board

67.7%

68.6%

Government guidelines

0%

1.6%

Abbreviation: COVID-19, coronavirus disease.

Regional

Abbreviation: COVID-19, coronavirus disease.

TA B L E 3
by zones

Institutional liver transplantation activities categorized

Red zone

3.3
Influence of COVID-19 on institutionaltransplantation programs
3.3.1

Institutional transplantation activities

Twenty-seven (87.1%) LDLT and 117 (94.4%) LDKT programs followed
the guidelines proposed by the JST on the management of COVID-Blue zone

Institutional activity on October 2020
Without any regulation

72.2%

61.5%

Only urgent/selected transplantation

16.7%

23.1%

Resume after local COVID-19 peak
out

11.1%

7.7%

Pause

0%

7.7%

Abbreviation: COVID-19, coronavirus disease.

19. In addition, 110 (88.7%) LDKT programs referred to the checklist in the JST guidelines. Table 1 shows the institutional transplantation activities at the end of October 2020. Although almost 70% of the(n = 1), and deterioration of patient condition beyond the indication

LDLT programs could continue transplant activities without any regu-(n = 2) were reported from LDLT programs, and patient death due tolations, almost 60% of the LDKT programs resumed after the number

acute myocardial infarction (n = 1), deterioration of patient conditionof local COVID-19 patients peaked. Most transplant programs were(n = 3), and unexpected temporal introduction of hemodialysis (n = 16)

approved by either an institutional or departmental board. As an indi-

were reported from LDKT programs.

cator of urgent LDLT, the Model for End-Stage Liver Disease score wasTable 2 indicates the reasons that led to institutional trans-

used, ranging from 15 to 30 (average, 22). Acute liver failure (n = 29)

plant resumption. Most of the transplant programs were resumed

and pediatric transplantation (n = 14) were also evaluated to deter-

because institutional COVID-19-related treatment and the screen-mine the urgency of LDLT. For LDKT, difficulty in creating vascular

ing system were established. Additional analyses were performed

access (n = 48), preemptive cases (n = 53), pediatric cases (n = 36),

to examine the regional impacts of COVID-19. Tables 3 and 5

and marginal donors (n = 26) were considered factors for immediateshow institutional liver/kidney transplantation activities, and Tables 4transplantation. Although most of the transplant programs indicatedand 6 indicate the reasons for resuming liver/kidney transplant pro-that interruption of transplant programs did not impact the awaiting

grams categorized by red and blue zones. Although liver transplant

donors and recipients, death of the recipient during the waiting time

programs could continue without any regulations regardless of theF I G U R E 1 (A) The 13 prefectures where the state of emergency was declared in Japan on April 7 and 16, 2020 to prevent the spread ofcoronavirus disease (COVID-19) (Saitama, Chiba, Tokyo, Kanagawa, Osaka, Hyogo, Fukuoka, Hokkaido, Ibaraki, Ishikawa, Gifu, Aichi, and Kyoto).
(B) Red zone: transplant programs located in the 13 prefectures where the state of emergency was issued. Blue zone: the remaining 34 prefectures
where the state of emergency was not issued. (C) The monthly case numbers of liver and kidney transplantations in 2020 along with the timing ofwhen the state of emergency was declared; the first and fourth versions of the guidelines were published by the Japan Society for Transplantation(JST). In version 1, the JST recommended continuing transplants for life-saving organs such as the heart, lungs, and status 1 livers, requiring arisk–benefit assessment for each case. The JST recommended postponing any nonurgent transplants of the kidney, pancreas, and bowel, as well as
all nonlife-threatening living donor transplantations. In version 4, the JST recommended resuming living donor transplant programs based on thelocal community and institutional transmission risk. They also proposed a checklist to help determine the restart of the living donor kidneytransplantation (LDKT) programs. The JST guidelines are summarized in Table S2. (D)–(G) The monthly case numbers of liver and kidneytransplantations in 2020 categorized by blue and red zone groups. The straight line indicates the average transplantation case number during therespective period. (D) Living donor liver transplantation (LDLT); (E) deceased donor liver transplantation (DDLT); (F) LDKT; (G) deceased donor
kidney transplantation (DDKT). Blue zones indicate prefectures where emergency measures were not implemented; red zones indicate
prefectures where emergency measures were implemented

13993062, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tid.13845 by Cochrane Japan, Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

5 of 11

KURAMITSU ET AL .

KURAMITSU ET AL .

TA B L E 4 Reasons to resume the institutional liver transplant
program categorized by zones

TA B L E 7

Items that affect future transplant activities
Liver

KidneyRed zoneBlue zone

Stop once institutional COVID-19 infection 29.0%
appears

55.7%

Operation restriction was released

11.1%

23.1%

Institutional COVID-19 patient number

35.5%

42.0%

COVID-19 treatment system wasconstituted

66.7%

61.5%

Institutional COVID-19 ICU-bound patient 67.7%
number40.3%

COVID-19 infection status was
improved

33.3%

30.8%

Will not stop transplant program

8.9%

No COVID-19 spread

44.4%

46.2%

22.2%

69.2%

Institutional

22.6%

Abbreviations: COVID-19, coronavirus disease; ICU, intensive care unit.

Regional
COVID-19 infection status was
improved

TA B L E 8 Items that affect future liver transplant activities
categorized by zones

Abbreviation: COVID-19, coronavirus disease.

Red zone Blue zone

TA B L E 5 Institutional kidney transplantation activities
categorized by zones
Red zone Blue zone
Institutional activity on October 2020
Without any regulation

29.2%

30.1%

Only urgent/selected transplantation

8.3%

3.8%

Resume after local COVID-19 peak out

58.3%

57.7%

Pause

4.2%

7.7%

Abbreviation: COVID-19, coronavirus disease.

Stop once institutional COVID-19 infection 22.2%
appears

38.5%

Institutional COVID-19 patient number

33.3%

38.5%

Institutional COVID-19 ICU-bound patient 55.6%
number

92.3%

Will not stop transplant program

7.7%

27.8%

Abbreviations: COVID-19, coronavirus disease; ICU, intensive care unit.

TA B L E 9 Items that affect future kidney transplant activities
categorized by zones
Red zone Blue zone

TA B L E 6
program

Reasons to resume the institutional kidney transplant

Red zone Blue zone
Institutional
Operation restriction was released

30.6%

21.2%

COVID-19 treatment system wasconstituted

70.8%

63.5%

Stop once institutional COVID-19 infection 54.2%
appears

51.9%

Institutional COVID-19 patient number

43.1%

44.2%

Institutional COVID-19 ICU-bound patient 41.7%
number

38.5%

Will not stop transplant program

7.7%

9.7%

Abbreviations: COVID-19, coronavirus disease; ICU, intensive care unit.

COVID-19 infection status was improved 31.9%

26.9%

No COVID-19 spread

25.0%

48.6%

19-related screening system, most of the LDLT programs could con-

Regional
COVID-19 infection status was improved 34.7%

59.6%

tinue transplantation activities, and the number of transplantations
that can be performed in the future would be affected by institu-

Abbreviation: COVID-19, coronavirus disease.

tional COVID-19 ICU-bound patient numbers regardless of the facility
location. Although LDKT programs in the red zone resumed as there

zones, kidney transplant programs in the red zone resumed once

was no institutional COVID-19 spread and blue zone groups resumed

there was no institutional COVID-19 spread, and the blue zone groups

as the regional SARS-CoV-2 infection status improved, future trans-

resumed once the regional SARS-CoV-2 infection status improved.

plant activity would be stopped once institutional COVID-19 infection

Table 7 shows the items that would affect transplant activities if

appears.

there were to be a future wave of COVID-19. Although most of the
LDLT programs said that they would depend on the COVID-19 intensive care unit (ICU)-bound patient number, LDKT programs said thatthey would stop if institutional transmission of COVID-19 occurred.

3.3.2
Preoperative check-up system for donors
and recipients

Tables 8 and 9 list the items that would affect transplant activities
stratified by red and blue zones; these were not significantly differ-

Table 10 shows the preoperative check-up systems for the donors andent between the groups. In short, after the constitution of the COVID-

recipients. A preoperative COVID-19 screening test was performed

13993062, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tid.13845 by Cochrane Japan, Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

6 of 11

TA B L E 1 0
recipients

Preoperative check-up system for donors and

TA B L E 1 1Management of fever transplant patients
Liver

Liver

KidneyCOVID-19 preoperative screening test

KidneyManagement of the patient
At fever clinic

61.3%

66.9%

Recipient

93.6%

87.9%

At transplant clinic

58.1%

48.4%

Donor

90.3%

86.3%

COVID-19 screening test

Nasopharyngeal swab

71.0%

56.5%

Nasal swab

25.8%

21.8%

Sputum3.2%

3.2%

Saliva

19.4%

32.3%

RT-PCR

96.8%

93.6%

Qualitive antigen test

3.2%

12.1%

Quantitative antigen test

3.2%

6.5%

COVID-19 test samples

COVID-19 screening test

Antibody test

Routinely performed

19.4%

20.2%

Only suspicious cases

83.9%

66.1%

Routinely performed

19.4%

30.7%

Only with cough cases

41.9%

30.7%

Chest CT

Abbreviations: COVID-19, coronavirus disease; CT, computed tomography.

3.4

Institutional transplant outpatient practices

0%

3.2%

Routinely performed

83.9%

65.3%

nary volume (kidney transplant), adherence to medication, number of

Performed initially but stopped

0%

12.1%

steps (liver transplant), and glucose level at outpatient clinics with mod-Not performed

16.1%

22.6%

ifications at each facility. In total, 5842 (average 195, 5–1000) liver

Chest CT scan for the recipient

The usual check-up list for the recipients included patients’ bodyweight, blood pressure, heart rate, body temperature, water intake, uri-transplant recipients and 3280 (average 106, 0–700) donors visited

Chest CT scan for the donor
Routinely performed

54.8%

58.9%

Performed initially but stopped

0%

12.1%

Not performed

45.2%

29.0%

Preoperative self-quarantine period for the recipient

the outpatient clinic, whereas 20 451 (average 165, 10–2500) kidneytransplant recipients and 10 365 (average 86, 0–700) donors visitedthe outpatient clinic. From January 1, 2020, to September 30, 2020,
a total of 991 (average 32, 0–95) LDLT recipients and 5079 (average41, 0–100) LDKT recipients postponed their consultation at the out-

28 days

3.2%

3.2%

patient clinic. Most of the programs implemented several preventa-

14 days

67.7%

60.5%

tive measures to reduce COVID-19 transmission risk, such as reduc-7 days0%

12.9%

ing the frequency of outpatient clinic visits, extending the interval for

Not fixed

29.0%

23.4%

refilling prescriptions, reducing the frequency of tests, shortening thelength of hospital stay, and minimizing contact between other patients.

Preoperative self-quarantine period for the donor
28 days0%

1.6%

14 days

48.4%

53.2%

7 days

19.4%

9.7%

Not fixed

32.3%

35.5%

Abbreviations: COVID-19, coronavirus disease; CT, computed tomography;
RT-PCR, reverse transcription polymerase chain reaction.

To reduce the frequency of outpatient visits, 38.7% of LDLT and 21.8%
of LDKT programs conducted telemedicine. Moreover, 87% of LDLT
and 66.9% of LDKT facilities utilized an application system to support
remote consultations.

3.5

Institutional COVID-19 treatment practices

The facilities of 27 (87.1%) LDLT and 106 (85.5%) LDKT programs had
in almost 90% of transplant programs for both recipients and donors.

experience accepting COVID-19 patients. The outpatient fever clinic

A nasopharyngeal swab was mainly used for test samples, and as awas established in 27 (87.1%) LDLT and 99 (79.8%) LDKT programs.

COVID-19 screening test, more than 90% of the transplant programs

The general ward was used for COVID-19 patients in 27 (87.1%) LDLT

used reverse transcription polymerase chain reaction (RT-PCR. Com-and 102 (82.3%) LDKT programs, and COVID-19 patients were treated

puted tomography (CT) chest scans for the recipients were routinely

in the ICU in 29 (93.6%) LDLT and 84 (67.7%) LDKT programs. The

performed in 83.9% of the LDLT and 65.3% of the LDKT programs, androutes for transplant and COVID-19 patients were separated into 26

for donors, the proportion decreased to 54.8% and 58.9%, respectively.

(83.9%) LDLT and 108 (87.1%) LDKT programs, and 31 (100%) LDLT

More than 60% of the transplant programs set the preoperative self-

and 112 (90.3%) LDKT programs had already established a collabo-

quarantine period for the recipients as 14 days. In terms of the preop-

ration system between infectious disease specialists and intensivists

erative isolation period for donors, almost 50% of the transplant pro-to treat transplant recipients who had COVID-19. Table 11 shows

grams set the period as 14 days.

the management of febrile transplant patients. More than half of the13993062, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tid.13845 by Cochrane Japan, Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

7 of 11

KURAMITSU ET AL .

KURAMITSU ET AL .

patients were referred to fever clinics or managed at transplant out-

19 illness due to chronic immunosuppression than the generalpatient clinics. COVID-19 testing was mainly performed if the disease

population.7,8 International and national registries showed a mortal-

was suspected after a medical history interview. Of the LDLT and LDKT

ity rate between 19% and 32% among solid organ transplant recipients

programs, 40% and 30.7% performed chest CT if the recipients pre-with COVID-19.9–11 Regarding the clinical outcomes of liver trans-

sented with cough, respectively.

plant recipients with COVID-19, international registries reported amortality rate of 18%–19%.12,13 In Japan, the Japanese registry by JST,
accessed on February 8, 2021, reported that the case-fatality rate for

3.6

Impact of COVID-19 on transplantation

organ transplant recipients was 7.1% (accessed at http://square.umin.
ac.jp/jst-covid-19 [in Japanese]). Based on the Johns Hopkins Coron-

Twenty-eight (87.5%) liver transplant programs responded to theavirus Resource Center accessed on February 11, 2021 (accessed atadditional survey. Among the living donors and the recipients who

https://coronavirus.jhu.edu/data/mortality), the case-fatality rate forunderwent LDLT from January to September 2020, no patient was

the general population was 2.9% in the United Kingdom, 1.7% in the

diagnosed with COVID-19 before transplantation. After transplan-

United States, 2.1% in Spain, 2.3% in France, and 1.6% in Japan. To

tation, one donor (3.57%) and four recipients (10.71%) were diag-date, some studies have concluded that there is no difference in over-

nosed with COVID-19. Based on the national registry of the Japanese

all mortality between the general population and solid organ transplant

Liver Transplant Society, the 1-year patient survival after LDLT wasrecipients,14,15 and there is also an opinion that this conclusion needs

85.4% and after DDLT was 89.2% during the pre-COVID period

further analysis because the study group was limited only to inpatients(accessed at http://jlts.umin.ac.jp/images/annual/JLTSRegistry2019.

or ICU-bound patients.16 As LDLT and LDKT programs are performed

pdf [in Japanese]). For the patients who underwent liver transplanta-in the presence of living donors, concrete policies to reduce the risktion during the COVID-19 era from January to September 2020, theof COVID-19 infections should be thoroughly discussed at each trans-

1-year survival for LDLT was 90.2% and 88.1% for DDLT.

plant center.

One hundred and eleven (89.5%) kidney transplant programs

The response rate for this study was as high as ≥90%, implying

responded to the additional survey. There were no donors or recipi-

a strong national need to better understand the impact of COVID-

ents who were diagnosed with COVID-19 before transplantation. After

19. In short, the results of the study can be summarized as follows:transplantation, one donor (0.92%) and 15 recipients (11.82%) were

(1) although the LDKT program decreased drastically, the LDLT pro-diagnosed with COVID-19. Based on the national registry, the 1-year

gram was not affected by the emergence of COVID-19; (2) transplantpatient survival was 99.5%, and graft survival was 98.8% in the pre-programs stopped once and restarted based on either institutional

COVID period. For the patients who underwent kidney transplan-or department policies; (3) almost 20% of the transplanted recipientstation during the COVID-19 era from January to September 2020,

postponed their routine check-up at the outpatient clinic; (4) more

the 1-year patient survival was 99.8%, and the graft survival wasthan 85% of transplant programs accepted COVID-19 patients, and99.2%.

(5) short-term patient/graft survival was not affected by the emergence of COVID-19. In the raw data, there were some differences
between liver and kidney transplant programs. In general, LDKT pro-4

DISCUSSION

grams implemented more rigorous restrictions than LDLT programs.
While most liver patients require urgent transplantation, kidney trans-

To the best of our knowledge, this is the first national survey that has

plantation is an alternative option for renal replacement therapy. As

been conducted to examine the impact of COVID-19 on institutional

resources outlining safety measures for COVID-19 in the early phaseliving donor transplantation programs. We found that although mostof the pandemic were scarce, most kidney transplant programs wereof the LDLT programs continued liver transplantation without any reg-more cautious in avoiding potential harm to both recipients and donors.

ulations, most of the LDKT programs were forced to pause; accord-

Moreover, the JST recommended postponing nonurgent kidney trans-

ingly, the number of cases substantially decreased during this period.

plants. All these factors decreased the total number of kidney trans-

Most transplant programs resumed living donor transplant activities

plantations that were performed during the COVID-19 era. How-

after constituting an institutional COVID-19 treatment system. Almost

ever, a recent report from Belgium found that the cumulative inci-

70% of transplantations were performed before and during the era

dence of COVID-19 was 5.31% in hemodialysis patients, 1.82% in peri-of the COVID-19 pandemic in areas where the state of emergency

toneal dialysis patients, and 1.40% in kidney transplant patients,17

was declared. In areas where the state of emergency was not issued,

suggesting that transplant patients have a decreased chance of con-the regional SARS-CoV-2 infection status had to be considered. In the

tracting COVID-19, possibly due to less frequent visits to the hos-case of a future COVID-19 wave, liver transplant activity would con-pital compared to dialysis patients. Furthermore, delaying kidneytinue if the number of ICU-bound COVID-19 patients was not too high,transplantation by 1 year would decrease patient survival.18 A risk–

while kidney transplant activity would stop if institutional SARS-CoV-2

benefit analysis should be carefully performed for each patient con-spread appeared.

sidering the availability of resources, the intensity of the pandemic

Several systematic reviews and meta-analyses have shown thatin the patient’s region, and their comorbidities.19 COVID-19 preop-transplant recipients have a higher risk of developing critical COVID-

erative screening was performed in more than 90% of transplant

13993062, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tid.13845 by Cochrane Japan, Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

8 of 11

programs, as recommended in the JST guidelines (accessed at https://the monthly number of newly introduced ECMO ranged from 6 (insquare.umin.ac.jp/jst-covid-19/images/guidance4.1.pdf [in Japanese]).

June) to 110 (in April) (https://www.ecmonet.jp/crisis). These data sug-

The RT-PCR assay was used in most cases; however, since RT-PCR

gest that although the actual ICU utilization rate did not drasticallywas not available in Japan during the early phases of the pandemic,change, ICU-bound patient disease distribution shifted to COVID-19.

less sensitive antigen assays were performed in two (6.4%) LDLT

Despite the negative surroundings, the total number of LDLTs was pre-and 23 (18.6%) LDKT programs. Although RT-PCR is highly sensi-

served, which was the result of an excellent team effort of all concerned

tive, a single negative result is insufficient to exclude the diagnosis

with transplantation.

of COVID-19 if the suspicion of COVID-19 remains high.20 Thus, theIn conclusion, this nationwide survey in Japan revealed that trans-

JST guidelines emphasize the importance of practices that minimize

plant programs for LDKT decreased drastically at one point andthe risk of COVID-19 exposure, including social distancing and self-

recovered after institutional resumption policies were implemented.

quarantine for 14 days before donation and transplantation for both

Most of the transplant programs complied with the JST guidelines,

donors and recipients. Our survey found that approximately 20% of

including performing preoperative COVID-19 tests and promoting

transplant programs did not encourage self-quarantine before dona-

self-quarantine for both donors and recipients, while also consider-tion or transplantation. Although the reasons why these measures

ing the regional COVID-19 infection status. Although vaccination andwere not implemented were unknown, pre-transplant self-quarantine

therapeutics were introduced after the survey era, how the living

may not be feasible for some donors and recipients, especially whendonor transplant program was modified in Japan at the early phasethey can still work before transplantation. In such cases, simple mea-of the pandemic was elucidated through the study. There were nosures such as social distancing, universal masking, and frequent handdonors/recipients who were diagnosed with COVID-19 before trans-

washing should be advised to minimize the risk of COVID-19 dur-

plantation, thus affirming self-quarantine. The maintained LDLT caseing the pre-transplant period. Importantly, there were no liver/kidney

numbers with shifted COVID-19 ICU surroundings suggested efforts

donors or recipients who were diagnosed with COVID-19 before

by the transplant team with the ICU team to protect end-stage liver dis-transplantation, thus supporting the JST guidelines of preoperative

ease patients. Supported by preserved transplant patient survival dur-

self-quarantine.

ing the era of COVID-19, this study provides valuable information to

A limitation of the study is that because this survey collectedtransplant facilities on how to prepare for future pandemics so that we

responses from transplant surgeons, the results may have been dif-can ensure that such living donor transplant programs continue unhin-

ferent if the survey answers were collected from referring physi-dered.

cians, as they evaluate transplant indication. Accordingly, the number of transplants is extensively influenced by the number of referred

ACKNOWLEDGMENTS

patients from physicians. Another limitation is that because the sur-This study was supported by grants from the Ministry of Health, Labor,

vey was conducted to clarify general practices and policies at eachand Welfare in Japan. We are grateful to our colleagues at the trans-

transplant program, patient-level data on COVID-19 treatments orplant institutions who responded to the questionnaires and made thischanges in immunosuppressant regimens were not collected. In the

study possible. For the revised analysis, Dr. Koji Umeshita (Osaka Uni-

study, more transplants occurred in the red zone than in the blue zone.

versity, Osaka) and Dr. Yuki Nakagawa (Juntendo University, Tokyo)

Based on the Japan Statistical Yearbook 2022, the total population

performed the national data analysis. We are also grateful to Mrs. Mineof 13 red zone prefectures was 77 million, which was almost 61.6%

Yamanaga, who helped edit the entire manuscript. This study was sup-of the total Japanese population as of December 1, 2020 (accessed

ported by grants from the Ministry of Health, Labor, and Welfare in

at https://www.stat.go.jp/English/data/nenkan/71nenkan/index.html).

Japan.

Transplant centers and universities were historically established in the

LDLT facilities: Okinawa Chubu Hospital (Dr. Murakami), Fujita

area, which had a large population and convenient location. Judging

Health University (Dr. Suzuki), Kanagawa Children’s Medical Cen-from the fact that almost 70% of transplantations were already per-ter (Dr. Shinkai), Kyoto University (Dr. Ito), Nagasaki University (Dr.

formed in the red zone before the era of the COVID-19 pandemic, theSoyama), Kumamoto University (Dr. Shimata), Chiba University (Dr.

case number bias was caused by the definition of the red zone itself that

Otsuka), Hiroshima University (Dr. Ohira), Tokyo Medical Univer-these areas had a high population density and high levels of traffic orsity (Dr. Kawachi), Okayama University (Dr. Yagi), Saitama Medical

had clusters of COVID-19.

Center (Dr. Maki), Iwate Medical University (Dr. Takahara), Tokyo

Based on the Japanese Ministry of Health, Labor, and Welfare data,

Women’s Medical University (Dr. Egawa), Mie University (Dr. Tane-

the actual ICU utilization rate ranged from approximately 70% to 75%mura), Hokkaido University (Dr. Goto), Tokyo University (Dr. Aka-

during the survey period (https://www.mhlw.go.jp/stf/seisakunitsuite/matsu), Jichi Medical University (Dr. Sakuma), Nagoya University (Dr.

bunya/0000121431_00180.html). As the ICU utilization rate itself

Ogura), Osaka University (Dr. Goto), Asahikawa Medical University (Dr.

does not reflect the availability of ICUs for transplant patients, we

Furukawa), Yamaguchi University (Dr. Nagano), Tohoku University (Dr.

focused on the monthly number of newly introduced respirators andMiyagi), Kyushu University (Dr. Yoshizumi), National Center for Childextracorporeal membrane oxygenation (ECMO). Based on the cross-

Health and Development (Dr. Kasahara), Tokyo Jikei University School

ICU searchable information system data, the monthly number of newlyof Medicine (Dr. Ikegami), Shinshu University (Dr. Soejima), Saitama

introduced respirators ranged from 20 (in June) to 393 (in April), andChildren’s Medical Center (Dr. Mizuta), Ehime University (Dr. Takada),

13993062, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tid.13845 by Cochrane Japan, Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

9 of 11

KURAMITSU ET AL .

KURAMITSU ET AL .

Fukushima Medical University (Dr. Maruhashi), Keio University (Dr.

Tojinbara), Wakayama Medical University Hospital (Dr. Yoshikawa),

Hasegawa), and Kobe University.

Shizuoka General Hospital (Dr. Shiraishi), Yokohama City University

LDKT facilities: Nagano Red Cross Hospital (Dr. Imao), Yokkaichi

Medical Center (Dr. Teranishi), Hospital of Hyogo College of Medicine

Municipal Hospital (Dr. Okumura), University Hospital Kyoto Prefec-(Dr. Yamada), Mie University (Dr. Nishikawa), Toda Chuo General Hos-

tural University of Medicine (Dr. Ushigome), Tokyo Dental College

pital (Dr. Shimizu), Tokushima University (Dr. Yamaguchi), Kobe Uni-

Ichikawa General Hospital (Dr. Kohno), Nagoya University (Dr. Kato),

versity (Dr. Ishimura), Hyogo Prefectural Nishinomiya Hospital (Dr.

Okayama Medical Center (Dr. Fujiwara), Kinki University (Dr. Nose),

Kishikawa), Osaka University (Dr. Imamura), Saitama Medical Center

Kawashima Hospital (Dr. Minakuchi), Toyama Prefectural Central Hos-(Dr. Maki), Kameda Medical Center (Dr. Ochi), Shinshu University (Dr.

pital (Dr. Seto), Toyooka Public Hospital (Dr. Machida), Kanazawa Med-Minagawa), St. Luke’s International Hospital (Dr. Nagahama), Hama-

ical University Hospital (Dr. Tanaka), Kure Medical Center (Dr. Tashiro),

matsu University (Dr. Isobe), Hiroshima Prefectural Hospital (Dr. Ishi-

Hidaka Hospital (Dr. Soeno), Juntendo University Urayasu Hospital (Dr.

moto), National Center for Child Health and Development (Dr. Sato),

Nosaki), Kitano Hospital (Dr. Ikeuchi), Okinawa Chubu Hospital (Dr.

Ohkubo Hospital (Dr. Shirakawa), Hiroshima University (Dr. Ide), Japan

Shimabukuro), Kagawa University (Dr. Taoka), Yamaguchi University

Community Health Care Organization Osaka Hospital (Dr. Fujimoto),(Dr. Isoyama), Edogawa Hospital (Dr. Koga), Miyazaki University (Dr.

Kyoto University (Dr. Kobayashi), Osaka City University Hospital (Dr.

Uemura), Ehime Prefectural Central Hospital (Dr. Okamoto), Saga-ken

Uchida), Kushiro City General Hospital (Dr. Morita), St. Marianna Uni-

Medical Center Koseikan (Dr. Tokuda), Iwate Medical University (Dr.

versity (Dr. Marui), Toho University Omori Medical Center (Dr. Shin-

Sugimura), Showa University (Dr. Yoshitake), Ota Memorial Hospitaloda), Aichi Medical University (Dr. Kobayashi), Hirosaki University (Dr.

(Dr. Mizutani), Tokyo Women’s Medical University (Dr. Unagami), Jikei

Hatakeyama), Oyokyo Kidney Research Institute Hirosaki Hospital (Dr.

University School of Medicine (Dr. Yamamoto), National Defense Med-Hatakeyama), St. Mary Hospital (Dr. Taniguchi), Tokyo Women’s Medi-

ical College Hospital (Dr. Tasaki), Niigata University (Dr. Saito), Masuko

cal University Yachiyo Medical Center (Dr. Inui), Kanazawa University

Memorial Hospital (Dr. Uchida), Joban Hospital (Dr. Shinmura), Sum-

(Dr. Kadono), Nagasaki University (Dr. Mochizuki), Kitasato University

itomo Hospital (Dr. Ichimaru), Tokyo University (Dr. Yamada), Yuuai(Dr. Yoshida), Ryukyu University (Dr. Kimura), Saiseikai Yahata Gen-

Medical Center (Dr. Ota), Akita University (Dr. Sato), Toranomon Hos-eral Hospital (Dr. Yasunaga), Oita University (Dr. Ando), Yamagata Uni-pital (Dr. Nakamura), Tokyo Medical University (Dr. Iwamoto), Kochi

versity (Dr. Nishida), Fukuoka University (Dr. Nakamura), Iwate Pre-

Health Sciences Center (Dr. Shibuya), Osaka Medical College Hospital

fectural Isawa Hospital (Dr. Yoneda), Tohoku University (Dr. Tokodai),(Dr. Hirano), Japan Community Health care Organization Sendai Hos-

Fukushima Medical University (Dr. Hata), Sapporo Medical University

pital (Dr. Haga), Sapporo Hokuyu Hospital (Dr. Miura), Okayama Uni-

(Dr. Tanaka), and the Japanese Red Cross Kumamoto Hospital (Dr.

versity (Dr. Araki), Komaki City Hospital (Dr. Uehira), Osaka City Gen-

Yamanaga).

eral Hospital (Dr. Asai), Shizuoka Children’s Hospital (Dr. Kitayama),
Kansai Medical University Hospital (Dr. Yanishi), Gifu University (Dr.

CONFLICT OF INTEREST

Tsuchiya), Japanese Red Cross Medical Center (Dr. Ishibashi), Toy-

The authors declare no conflicts of interest.

ohashi Municipal Hospital (Dr. Nagasaka), Osaka Women’s and Children’s Hospital (Dr. Yazawa), International University of Health and

AUTHOR CONTRIBUTIONS

Welfare Mita Hospital (Dr. Tonsho), Osaka General Medical Center (Dr.

All authors contributed to the manuscript and fulfilled criteria

Tsutahara), Nara Medical University Hospital (Dr. Yoneda), Ehime Uni-

as per the uniform requirements set forth by the Internationalversity (Dr. Miyauchi), Mito Medical Center (Dr. Yuzawa), Saku Central

Committee of Medical Journal Editors (ICJME) guidelines. All

Hospital (Dr. Murakami), Dokkyo Medical University Saitama Medical

authors have reviewed and approved the final version of theCenter (Dr. Tokumoto), Jichi Medical University Hospital (Dr. Iwami),

manuscript.

Hokkaido University (Dr. Hotta), Kagoshima University (Dr. Yamada),
Tokyo Women’s Medical University (Dr. Hattori), Tokyo Metropolitan

ORCID

Children’s Medical Center (Dr. Sato), Itabashi Chuo Medical Center

Kaori Kuramitsu

https://orcid.org/0000-0002-9843-6800(Dr. Koyama), Fujita Health University (Dr. Itoh), Yamanashi Univer-

Yoichiro Natori

https://orcid.org/0000-0002-4938-125X

sity (Dr. Kamiyama), Shonan Kamakura General Hospital (Dr. Igarashi),
Fukui University (Dr. Fukiage), Keio University (Dr. Morita), Japanese
Red Cross Fukuoka Hospital (Dr. Motoyama), University of Tsukuba
Hospital (Dr. Takahashi), Japanese Red Cross Wakayama Medical Center (Dr. Itoh), Yonago Medical Center (Dr. Sugitani), Japanese Red
Cross Nagoya Daini Hospital (Dr. Watarai), Nagasaki Medical Center (Dr. Onita), Chiba University (Dr. Maruyama), Miyazaki Prefectural Miyazaki Hospital (Dr. Terasaka), Tokai University (Dr. Nakamura),
Sapporo City General Hospital (Dr. Sasaki), Saitama University (Dr.
Okada), Toranomon Hospital (Dr. Ishii), Kyushu University (Dr. Okabe),International University of Health and Welfare Atami Hospital (Dr.

REFERENCES
1. Morens DM, Daszak P, Taubenberger JK. Escaping Pandora’s box—
another novel coronavirus. N Engl J Med. 2020;382(14):1293-1295.
10.1056/NEJMp2002106.
2. Morens DM, Fauci AS. Emerging pandemic diseases: how we got to
COVID-19. Cell. 2020;182(5):1077-1092. 10.1016/j.cell.2020.08.021.
3. Caillard S, Chavarot N, Francois H, et al. COVID-19 infection
more severe in kidney transplant recipients? Am J Transplant.
2021;21(3):1295-1303. 10.1111/ajt.16424.
4. Ahn C, Amer H, Anglicheau D, et al. Global transplantation COVID
report March 2020. Transplantation. 2020;104(10):1974-1983. 10.
1097/TP.0000000000003258.

13993062, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tid.13845 by Cochrane Japan, Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

10 of 11

5. Kumar D, Manuel O, Natori Y, et al. COVID-19: a global transplant
perspective on successfully navigating a pandemic. Am J Transplant.
2020;20(7):1773-1779. 10.1111/ajt.15876.
6. Strauss AT, Boyarsky BJ, Garonzik-Wang JM, et al. Liver transplantation in the United States during the COVID-19 pandemic: nationaland center-level responses. Am J Transplant. 2021;21(5):1838-1847.
10.1111/ajt.16373.
7. Azzi Y, Bartash R, Scalea J, Loarte-Campos P, Akalin E. COVID19 and solid organ transplantation: a review article. Transplantation.
2021;105(1):37-55. 10.1097/TP.0000000000003523.
8. Raja MA, Mendoza MA, Villavicencio A, et al. COVID-19 in solid organtransplant recipients: a systematic review and meta-analysis of current literature. Transplant Rev (Orlando). 2021;35(1):100588. 10.1016/
j.trre.2020.100588.
9. Cravedi P, Mothi SS, Azzi Y, et al. COVID-19 and kidney transplantation: results from the TANGO International Transplant Consortium.
Am J Transplant. 2020;20(11):3140-3148. 10.1111/ajt.16185.
10. Sánchez-Álvarez JE, Pérez Fontán M, Jiménez Martín C, et al. SARSCoV-2 infection in patients on renal replacement therapy. Report of
the COVID-19 Registry of the Spanish Society of Nephrology (SEN).
Nefrologia. 2020;40(3):272-278. 10.1016/j.nefro.2020.04.002.
11. Caillard S, Anglicheau D, Matignon M, et al. An initial report from the
French SOT COVID Registry suggests high mortality due to COVID-19
in recipients of kidney transplants. Kidney Int. 2020;98(6):1549-1558.
10.1016/j.kint.2020.08.005.
12. Webb GJ, Marjot T, Cook JA, et al. Outcomes following SARS-CoV-2
infection in liver transplant recipients: an international registry study.
Lancet Gastroenterol Hepatol. 2020;5(11):1008-1016. 10.1016/S24681253(20)30271-5.
13. Colmenero J, Rodríguez-Perálvarez M, Salcedo M, et al. Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplantpatients. J Hepatol. 2021;74(1):148-155. 10.1016/j.jhep.2020.07.040.
14. Molnar MZ, Bhalla A, Azhar A, et al. Outcomes of critically ill solidorgan transplant patients with COVID-19 in the United States. Am J
Transplant. 2020;20(11):3061-3071. 10.1111/ajt.16280.
15. Chaudhry ZS, Williams JD, Vahia A, et al. Clinical characteristics
and outcomes of COVID-19 in solid organ transplant recipients:

a cohort study. Am J Transplant. 2020;20(11):3051-3060. 10.1111/
ajt.16188.
16. Mendoza MA, Raja M, Villavicencio A, Anjan S, Natori Y. Is the outcome of SARS-CoV-2 infection in solid organ transplant recipients
really similar to that of the general population? Am J Transplant.
2021;21(4):1670-1671. 10.1111/ajt.16370.
17. De Meester J, De Bacquer D, Naesens M, et al. Incidence, characteristics, and outcome of COVID-19 in adults on kidney replacement therapy: a regionwide registry study. J Am Soc Nephrol. 2021;32(2):385396. 10.1681/ASN.2020060875.
18. Massie AB, Boyarsky BJ, Werbel WA, et al. Identifying scenarios of
benefit or harm from kidney transplantation during the COVID-19
pandemic: a stochastic simulation and machine learning study. Am J
Transplant. 2020;20(11):2997-3007. 10.1111/ajt.16117.
19. Thaunat O, Legeai C, Anglicheau D, et al. IMPact of the COVID-19
epidemic on the moRTAlity of kidney transplant recipients and candidates in a French Nationwide registry sTudy (IMPORTANT). Kidney Int.
2020;98(6):1568-1577. 10.1016/j.kint.2020.10.008.
20. Arevalo-Rodriguez I, Buitrago-Garcia D, Simancas-Racines D, et al.
False-negative results of initial RT-PCR assays for COVID-19: a systematic review. PLoS One. 2020;15(12):e0242958. 10.1371/journal.
pone.0242958.

SUPPORTING INFORMATION
Additional supporting information can be found online in the Supporting Information section at the end of this article.

How to cite this article: Kuramitsu K, Yamanaga S, Osawa R,
et al. Impact of COVID-19 on the living donor liver and kidneytransplantation programs in Japan in 2020. Transpl Infect Dis.
2022;24:e13845. https://doi.org/10.1111/tid.13845

13993062, 2022, 3, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/tid.13845 by Cochrane Japan, Wiley Online Library on [02/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

11 of 11

KURAMITSU ET AL .

International Journal of Colorectal Disease (2022) 37:1393–1402
https://doi.org/10.1007/s00384-022-04162-2

ORIGINAL ARTICLE

Prospective analysis of the expression status of FGFR2 and HER2
in colorectal and gastric cancer populations: DS‑Screen Study
Hisateru Yasui1 · Atsushi Takeno2 · Hiroki Hara3 · Hiroshi Imamura4 · Hiroki Akamatsu5 · Kazumasa Fujitani6 ·Minoru Nakane7 · Chihiro Nakayama Kondoh8 · Seigo Yukisawa9 · Junichiro Nasu10 · Yoshinori Miyata11 ·Akitaka Makiyama12,13 · Hiroyasu Ishida14 · Norimasa Yoshida15 · Eiji Matsumura16 · Masato Ishigami16 ·Masahiro Sugihara16 · Atsushi Ochiai17 · Toshihiko Doi18
Accepted: 17 April 2022 / Published online: 19 May 2022
© The Author(s) 2022

Abstract
Purpose Fibroblast growth factor receptor 2 (FGFR2) and human epidermal growth factor receptor 2 (HER2) proteins areboth molecular targets for cancer therapy. The objective of this study was to evaluate the expression status of FGFR2 andHER2 in patients with gastric cancer (GC) or colorectal cancer (CRC).
Methods Archived tumor tissue samples from patients with histologically-confirmed GC or CRC suitable for chemotherapy
were analyzed for FGFR2 and HER2 expression using immunohistochemistry and fluorescence in situ hybridization (HER2
in CRC only).
Results A total of 176 GC patients and 389 CRC patients were enrolled. Among patients with GC, 25.6% were FGFR2positive and 26.1% were HER2-positive. Among patients with CRC, 2.9% were FGFR2-positive and 16.2% were HER2positive. No clear relationship was found between FGFR2 and HER2 status in either GC or CRC. In GC, FGFR2 and HER2
statuses did not differ between different primary cancer locations, whereas there were some differences between histologicaltypes. Based on FGFR2- and/or HER2-positive status, 117 patients were identified as potentially suitable for inclusion inclinical trials of therapeutic agents targeting the relevant protein (GC = 45, CRC​= 72; FGFR = 56, HER2 = 62), of whom 7
were eventually enrolled into such clinical trials.
Conclusions This study indicated the prevalence of FGFR2 and HER2 in GC and CRC in the Japanese population. The
screening performed in this study could be useful for identifying eligible patients for future clinical trials of agents targetingthese proteins.
Trial registration Clinical trial registration Japic CTI No.: JapicCTI-163380. https://​www.​clini​caltr​ials.​jp/​cti-​user/​trial/​
ShowD​irect.​jsp?​direc​tLink=​RNlzx​1PPCuT.​PrVNP​xPRwA.
Keywords Colorectal cancer · FGFR2 · Gastric cancer · HER2

* Toshihiko Doi
tdoi@east.ncc.go.jp

10

Okayama Saiseikai General Hospital, Okayama, Japan

11

Saku Central Hospital Advanced Care Center, Nagano, Japan

1

Kobe City Medical Center General Hospital, Hyogo, Japan

12

2

Kansai Rosai Hospital, Hyogo, Japan

Japan Community Healthcare Organization Kyushu Hospital,
Fukuoka, Japan

3

Saitama Cancer Center, Saitama, Japan13

Gifu University Hospital, Gifu, Japan

14

Mito Medical Center, Ibaraki, Japan

15

Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan

16

Daiichi Sankyo Co., Ltd, Tokyo, Japan

17

National Cancer Center Exploratory Oncology Research &Clinical Trial Center, Tokyo, Japan18

National Cancer Center Hospital East, Chiba, Japan

4
5
6

Toyonaka Municipal Hospital, Osaka, Japan
Osaka Police Hospital, Osaka, Japan
Osaka General Medical Center, Osaka, Japan

7

Japanese Red Cross Musashino Hospital, Tokyo, Japan

8

Toranomon Hospital, Tokyo, Japan

9

Tochigi Cancer Center, Tochigi, Japan

13

Vol.:(0123456789)

1394

International Journal of Colorectal Disease (2022) 37:1393–1402

Introduction

Patients and methods

An increasing number of molecular-targeted therapies areavailable in the field of oncology. When using such treatmentsin the clinical setting, it is desirable to be able to identify thosepatients in whom the target molecule is expressed and who are
therefore expected to benefit from the therapy.
Fibroblast growth factor receptor 2 (FGFR2) and humanepidermal growth factor receptor 2 (HER2) proteins are wellknown molecular targets for cancer therapy. FGFR2 consistsof an extracellular ligand-binding region consisting of three
Ig-like domains, a single transmembrane region, and an intracellular tyrosine kinase region [1]. Various cellular functions,
including cell proliferation, migration, and differentiation,
are regulated by the FGF signaling pathway [1, 2]. HER2, a
receptor tyrosine kinase belonging to the epidermal growth
factor receptor family, is involved in regulating the proliferation and differentiation of normal cells and also acts as an
oncogene, driving gene amplification and mutation [3]. Novelagents targeting these proteins are emerging, including several
next-generation antibodies with enhanced antibody-dependent
cellular cytotoxicity (ADCC) activity [4] and antibody–drugconjugates [5, 6].
HER2 is overexpressed in 10–20% of gastric cancers(GCs), and assessment of HER2 status is necessary to
identify patients eligible for treatment with drugs such as
trastuzumab [7]. Less is known about the expression status of FGFR2 in GC or about HER2 and FGFR2 in othergastrointestinal cancers, such as colorectal cancer (CRC).
Accurate characterization of HER2 and FGFR2 expressionin specific types of cancer is important for determining therelevance of these proteins as markers for identifying potential candidates for treatment with relevant targeted therapies. Furthermore, to optimize the clinical development
strategies of these emerging agents, it would be useful toinvestigate FGFR2 and HER2 expression patterns, such aswhether they are co-expressed or expressed in a mutuallyexclusive manner.
The primary objectives of this study were to investigate
the expression status of FGFR2 and HER2 in tissue samples
from patients with GC or CRC, and to evaluate the relationship between background factors and protein expression status. A secondary objective was to identify patients who werepotentially eligible for clinical trials involving the therapeutic agents DS-1123 (a monoclonal antibody directed against
FGFR2) or trastuzumab deruxtecan (DS-8201, T-DXd; anantibody–drug conjugate with a HER2 antibody, tetrapeptidebased cleavable linker, and a novel topoisomerase I inhibitor
payload).

This prospective, multicenter study, which was conductedin a routine clinical practice setting between November
2016 and June 2018, enrolled patients aged ≥20 years withhistologically confirmed GC (including gastroesophageal
junction [GEJ] cancer) or CRC for which chemotherapy
was indicated. Enrollment of GC patients was stopped on
April 2017 due to completion of a relevant clinical trial,
DS1123-A-J101 (NCT02690337). To be eligible, patientswere required to have archived tumor tissue samples that
had been collected during surgery, endoscopy, or needle
biopsy, and that were preserved as formalin-fixed paraffinembedded blocks. Patients judged by the investigator to beinappropriate as study subjects were excluded.
The study was conducted in accordance with the principals of the Declaration of Helsinki. Ethical approval
was obtained from the relevant ethical review board foreach participating center, and patients provided written
informed consent. Japic CTI No.: JapicCTI-163380.

13

Patient data
Patient details were collected using an electronic data
capture system. This included demographics (age, sex);
tumor characteristics (histopathological diagnosis and dateof diagnosis, primary location, major histological type,stage, HER2 expression [for any patients with GC who
had been tested for HER2 prior to the study], and presence/absence of rat sarcoma viral oncogene homolog (RASgene) mutations [for any patients who had been confirmed
as having a mutation prior to the study]); and tumor sampling information (date and location of sampling, primaryor metastatic).

Tumor sample analysis
FGFR2 and HER2 expressions in GC and CRC samples
were assessed using immunohistochemistry (IHC) at a central laboratory (SRL Medisearch Inc., Japan). For GC, theresults of HER2 IHC performed at local laboratories werealso collected, where available (HER2 IHC in GC patients is
performed in routine clinical practice in Japan). In addition,
samples from patients with CRC enrolled before December
2017 which were found to be HER2 IHC 2 + (in ≥ 10% cells)
were assessed for HER2 gene amplification using fluorescence in situ hybridization (FISH) at a central laboratory,

International Journal of Colorectal Disease (2022) 37:1393–1402

if the patient had a suitable sample for testing and provided
consent. Samples from patients with CRC enrolled after
December 2017 were all assessed for HER2 FISH, regardless of HER2 IHC score.
IHC staining for FGFR2 was performed using a mouse chimeric anti-FGFR2 antibody produced in-house with Agilent
DAKO EnVision™ FLEX + Mouse (LINKER) and Agilent
DAKO Autostainer Link 48, which captures FGFR2 isoforms
IIIb and IIIc. IHC staining for HER2 was performed using
the Ventana I-VIEW pathway HER2 (4B5) kit. IHC scoring
was evaluated based on three elements — IHC staining intensity, cellularity, and location — at the National Cancer Center
Exploratory Oncology Research and Clinical Trial Center,
Chiba, Japan (Online Resource). FISH was performed using
Abbott PathVysion® HER2 DNA probe kit. HER2 amplification was considered positive if the ratio of HER2/CEP17
was ≥ 2.0 when counting total number of HER2 and CEP17
signals in at least 20 tumor cells.
FGFR2 positivity was defined as FGFR2 IHC 1 + to 3 + for
both GC and CRC. HER2 positivity was defined as IHC 2 + or
3 + in GC, and HER2 IHC 2 + or 3 + in ≥ 10% of cells in CRC(Online Resource).

Clinical trial participation
Patients who were found to be potentially eligible for participation in clinical trials of therapeutic agents targeting therelevant protein (i.e., GC patients with FGFR2 IHC 1 + to
3 + and CRC patients with FGFR2 IHC 1 + to 3 + or HER2
Table 1  Patient demographics
Parameter

Age (years)
Mean ± SD
Median (range)
Female, n (%)
Stage, n (%)
I
II
III
IV
Unknown
Systemic chemotherapy prior to
sampling, n (%)
History of radiation therapy tosampling location, n (%)
a

Gastric
cancera(n = 176)

Colorectal
cancer(n = 384)

Total (n = 560)

67.4 ± 9.5
68.0 (34–93)
39 (22.2)

62.1 ± 10.3
64.0 (29–83)
172 (44.8)

63.8 ± 10.3
66.0 (29–93)
211 (37.7)

3 (1.7)
12 (6.8)47 (26.7)
114 (64.8)
0 (0)27 (15.3)

3 (0.8)38 (9.9)
86 (22.4)
251 (65.4)
6 (1.6)55 (14.3)

82 (14.6)

0 (0.0)10 (2.6)

10 (1.8)

Gastric cancer included 16 patients with gastroesophageal cancer

1395

IHC 2 + or 3 + in ≥ 10% of cells) were referred to ongoingclinical trials. Information on whether these patients went on
to participate in the relevant clinical trial, including any reason for non-participation, was recorded.

Study outcomes
The primary endpoint was the percentage of patients withtumor samples in which FGFR2/HER2 protein expression
was confirmed. In addition, the relationship between patient
background factors and FGFR2/HER2 expression was also
evaluated. Secondary endpoints included the proportion ofpatients with confirmed FGFR2 and HER2 expression who
subsequently participated in clinical trials of therapeutic agentstargeting the relevant protein.

Statistical analysis
FGFR2 and HER2 expression statuses were analyzed descriptively using central laboratory data. Summary statistics forpatient characteristics and protein expression included meanand standard deviation, median (minimum‒maximum), andnumber (percentage), as appropriate.

Results
A total of 565 patients (GC = 176, CRC​= 389) were enrolled
in the study between November 2016 and June 2018 from
15 sites across Japan. The full analysis set (FAS) included
560 patients (176 with GC, including 16 GEJ patients, and384 with CRC); the majority of patients had stage III or IV

Fig. 1  Patient distribution by FGFR2 and HER2 IHC scores in gastriccancer13

1396

GC or CRC (Table 1). Five patients were excluded from the
FAS because of discontinuation after informed consent due
to disease worsening or no available tissue sample to submit.

Gastric cancer
Among patients with GC, 25.6% (45/176) were FGFR2-positiveand 26.1% (46/176) were HER2-positive. Among the subgroup

International Journal of Colorectal Disease (2022) 37:1393–1402

with GEJ, 43.8% (7/16) were positive for FGFR2 and 43.8%
were positive for HER2.
There was no clear association between FGFR2 andHER2 status in patients with GC (Fig. 1). The proportionof FGFR2-positive patients among the whole population
was 25.6% and among the HER2-positive population it was
30.4%. Similarly, the proportion of HER2-positive patientsamong the whole population was 26.1% and among the
FGFR2-positive population it was 31.1%.

Fig. 2  FGFR2 and HER2 IHC scores by primary location and major histology in gastric cancer

13International Journal of Colorectal Disease (2022) 37:1393–1402

1397

conclusions could not be drawn because of the small number of FGFR2-positive patients (Fig. 3). The proportion of
FGFR2-positive patients among the whole population was
2.9% and among the HER2-positive population it was 1.6%.
Similarly, the proportion of HER2-positive patients among
the whole population was 16.2% and among the FGFR2positive population it was 9.1%.
No differences in FGFR2 or HER2 status according toprimary cancer location or histological type could be identified because of the small number of FGFR2-positive patients(Fig. 4A, B). HER2 status appeared to be the same for rightside and left-side primary cancer locations (Fig. 4A).

Referral to clinical trials

Fig. 3  Patient distribution by FGFR2 and HER2 IHC scores in colorectal cancer

FGFR2 and HER2 statuses did not differ substantiallybetween different primary cancer locations (Fig. 2A).
With respect to major histological types, although sample
numbers are low in these observations, the proportion of
FGFR2-positive patients was numerically higher than thatof HER2-positive patients for signet-ring carcinoma. On theother hand, for papillary adenocarcinoma and moderately
differentiated tubular adenocarcinoma, the proportions of
HER2-positive patients were numerically higher than thosefor FGFR2-positive patients (Fig. 2B).

Colorectal cancer
Among patients with CRC, 2.9% (11/383) were FGFR2positive and 16.2% (62/383) were HER2-positive.
There was no clear association between FGFR2
and HER2 status in patients with CRC, although firm
Table 2  Determination ofeligibility and enrolment of
FGFR2- or HER2-positive
patients into clinical trials

Among the study population, 117 patients were identified
as being potentially suitable for inclusion in clinical trials,
based on FGFR2- and/or HER2-positive status (GC = 45,
CRC​= 72; FGFR = 56, HER2 = 62 [1 patient was FGFR2and HER2-positive]). Ultimately, 7 of these patients (GC = 4,
CRC​= 3) were enrolled into clinical trials (Table 2).

Other findings
Among patients with CRC, the proportion with HER2 IHC
3 + tumors was higher in those who were KRAS/NRAS
wild type positive (10/167) compared to those who werepositive for KRAS or NRAS mutants (3/156), although theprevalence of HER2 IHC 3 + in these populations was low(Fig. 5).
Among patients with CRC, all those who were HER2
IHC 3 + were also HER2 amplified using FISH (n = 3).
There were also some patients who were HER2 amplified
using FISH in patients who were HER2 IHC 0, 1 + , and2 + (Table 3).
In an assessment of the concordance of IHC scores for
GC samples tested at local and central laboratories, the rate

Parameter, n (%)

Gastric cancer(n = 176)

Colorectal cancer(n = 384)

Total (n = 560)

FGFR2 IHC 1 + to 3 +HER2 IHC 2 + or 3 + in GC, or HER2 IHC
2 + or 3 + in ≥ 10% of cells in CRC​
Potentially suitable for clinical t­rialsa
Referral to clinical ­trialsb
Enrolled into clinical trials

45 (25.6)
46 (26.1)

11 (2.9)62 (16.1)

56 (10.0)108 (19.3)

45 (25.6)
5 (2.8)4 (2.3)72 (18.8)
4 (1.0)3 (0.8)117 (20.9)
9 (1.6)7 (1.3)

CRC​ colorectal cancer, FGFR2 fibroblast growth factor receptor 2, GC gastric cancer, HER2 human epidermal growth factor receptor 2, IHC immunohistochemistryab

For gastric cancer, only FGFR2-positive patients were potentially eligible

The major reasons that patients were not referred to clinical trials were as follows in descending order: theclinical trial recruitment period had ended, patients had been continuing prior therapy at the time of entry,
or primary disease had worsened

13

1398

International Journal of Colorectal Disease (2022) 37:1393–1402

Fig. 4  FGFR2 and HER2 IHC scores by primary location and major histology in colorectal cancerof matched HER2 IHC scores (allowing 1 level difference)was 89.8% and the rate for completely matched cases was
59.9% (Fig. 6). The rate of concordance was not affectedby a difference in the sample collection date between thelaboratories or by the type of IHC testing kit used (Table 4).

13

Discussion
There is a need for additional information about the expression status of FGFR2 and HER2 in patients with gastrointestinal cancers. In our study, we evaluated patients with GC

International Journal of Colorectal Disease (2022) 37:1393–1402
Table 4  IHC scores concordance between local and central testing in
gastric cancer
Concordance between
IHC scores from local
and central testing,n (%)
Matched a
Difference between sample collection
dates, days
0 (n = 107)>0b (n = 50)
IHC kit for local laboratory ­testingc
Ventana I-VIEW pathway HER2(n = 98)
Daco HercepTest II (n = 32)
Histofine HER2 kit (poly) (n = 4)
Unknown (n = 6)
Others (n = 17)

Completely
matched94 (87.9)
47 (94.0)

63 (58.9)
31 (62.0)

90 (91.8)

55 (56.1)

30 (93.8)
4 (100.0)
6 (100.0)
11 (64.7)

20 (62.5)
3 (75.0)
5 (83.3)
11 (64.7)

HER2 human epidermal growth factor receptor 2, IHC immunohistochemistryabc“Matched” allows 1 level difference
Mean 196.7 ± 258.7 days; median 51.5 days (min 1, max 842 days)
Central laboratory testing used Ventana I-VIEW pathway HER2

and CRC being managed in routine clinical practice. This is
the first study to concurrently investigate the protein expression status of FGFR2 and HER2 in human tumor tissue frompatients with CRC.
The HER2 positivity rate of 26.1% in GC found in the
study is consistent with previous reports of HER2 overexpression of 10–23% [7–9]. HER2 expression is reported
to be more common in GEJ cancer than in cancer locatedwithin the stomach [8, 9], and the rate in the GEJ subgroupin our study is consistent with this. With respect to FGFR2
positivity, the rate of 25.6% in GC in our study is within therange reported for previous studies (2.5–61%) [10].

Fig. 5  HER2 IHC scores by RAS mutation status in colorectal cancer

1399
Table 3  HER2 IHC scores and FISH status in colorectal cancer
HER2 IHC scores, n (%)
0 (n = 44) 1 + (n = 21) 2 + (n = 15) 3 + (n = 3)
HER2 FISH­statusa­Positiveb
Negative

1 (2.3)43 (97.7)

2 (9.5)19 (90.5)

1 (6.6)14 (93.3)

3 (100)0 (0)FISH fluorescence in situ hybridization, HER2 human epidermal
growth factor receptor 2, IHC immunohistochemistryab

HER2 FISH analysis was done for 83 CRC patients
In the FISH analysis, HER2/CEP17 ratio ≥ 2 was defined as positive

Among patients with CRC, we found that 16.2% werepositive for HER2, which lies within the range of rates
reported in previous studies (0.5–54%) [3]. The most recent
studies tend to suggest that HER2 overexpression accounts
for 1–6% of CRCs, with HER2-positivity rates of around 5%
reported in RAS wild-type tumors [3, 11]. Consistent with
this, we found that among our CRC patients, the proportionof HER2 IHC 3 + cases was greater in RAS wild-type cancers
compared with RAS-mutated cancers. There have been few
reports of FGFR2 expression levels in patients with CRC,
but our rate of 2.9% is consistent with the 1.4% reported ina previous study [12]. Although it was previously reported
that HER2 + CRC tumors are usually left-sided [13], HER2
status appeared to be the same for right-side and left-side
primary cancer locations in our study.

Fig. 6  HER2 IHC scores from local and central laboratories for gastric cancer

13

1400

Overall, we found no clear relationship between FGFR2
and HER2 status in either GC or CRC patients. Previous
studies that focused specifically on amplifications found that
HER2 and FGFR2 gene amplifications were usually mutually exclusive [14–16]. In our GC patients, neither FGFR2
nor HER2 expression status differed according to the primary cancer location; however, there were some differences
between histological types. Previous reports have suggested
that HER2 expression may vary between GC histologicaltypes, with higher rates reported for intestinal versus diffuse
cancers [8, 9]. Although this study could not provide sufficient evidence to enable a clear conclusion to be reached,further investigation of the relationship between HER2
expression and GC histological type, with the molecularmechanism which defines the histological type, may provide insights to expand the indication for HER2 therapies.
The limited number of FGFR2-positive CRC patients in ourstudy meant that the relationship between FGFR2 and HER2
status in CRC could not be fully assessed with respect todifferences between primary cancer locations and histological types. Despite this study not being able to reveal a relationship between FGFR2 and HER2 expression, it would bevaluable to consider re-testing FGFR2 expression in tumor
tissues of patients after HER2-targeted therapy to analyze
the relationship between FGFR2 expression changes after
HER2-targeted therapy and drug resistance, because studies
have indicated the role of FGFR2 in HER2-targeted lapatinib
resistance [17, 18].
Several studies have reported that gene amplification is
generally present in CRC tumors that are strongly positivefor HER2 overexpression on IHC [11, 19, 20]. Consistent
with this, we found that CRC samples which were strongly
positive for HER2 on IHC were also FISH positive.
More than 100 FGFR2- and/or HER2-positive patientswere found in the current study, who were therefore
potentially suitable for inclusion in clinical trials of targeted agents. Seven of these patients were successfully
enrolled in other clinical trials, including DS1123-A-J101(NCT02690337), DS8201-A-J101 (NCT02564900), andDS8201-A-J203 (NCT03384940). This suggests that thescreening performed in the current study may be useful for
identifying patients potentially eligible for clinical trials.
This could be especially relevant for early phase trials targeting rare populations, such as patients with low biomarker
prevalence. Moreover, this screening is a universal screening
with IHC including pathological review by one pathologist
to achieve standardized evaluation, with a cost of about US$1700 per patient, which is almost comparable to that ofnext-generation sequencing (NGS). Therefore, this screening
method may be useful for efficient acceleration of studies
which require an eligibility check with IHC.
We used a central laboratory to perform IHC and FISH
for the current study. IHC of GC tissue samples was also

13International Journal of Colorectal Disease (2022) 37:1393–1402

performed at some local laboratories as part of routine clinical practice. This provided an opportunity to compare theresults obtained in these different laboratory settings. We
found that the results of HER2 IHC testing in GC matchedbetween central and local laboratories in approximately 90%
of cases (allowing for 1 level difference of IHC score). However, the rate of completely matched cases was only around60%. The rate of matching was independent of whether or
not the same sample was used for central and local testing(which could be assumed based on whether or not there wasa difference in the sample collection dates) and was also
independent of the type of IHC kit used. Overall, this suggests that improvements to, or standardization of, HER2 IHC
laboratory methods may be desirable in the future.
In conclusion, this study determined the prevalence of
FGFR2 and HER2 in Japanese patients with GC and CRC,
and the values were concordant with previous reported
prevalence rates. No clear relationship was found between
FGFR2 and HER2 status in either the GC or CRC populations. FGFR2 and HER2 status did not differ according to
the primary cancer location in GC, but there were somedifferences between GC histological types. These relationships could not be assessed properly in CRC, due to thelimited number of FGFR2-positive patients. The screening performed in this study could be useful for identifying
eligible patients for clinical trials of agents targeting these
proteins.
Supplementary Information The online version contains supplementary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 00384-0​ 22-0​ 4162-2.
Acknowledgements We thank the patients who participated in thisstudy, as well as their families and caregivers. We also thank Dr. Akiko
Nagatsuma and Dr. Takeshi Kuwata of National Cancer Center Hospital East, and Yoshinobu Shiose, Tomoko Shibutani, Kokichi Honda,
and Toshihiro Oguma of Daiichi Sankyo Co., Ltd. for their suggestions
for our study. Medical writing assistance was provided by Content EdNet, which was funded by Daiichi Sankyo Co., Ltd.
Author contribution TD, AO, EM, and MS were involved in study
design and data interpretation. HY, AT, HH, HI, HA, KF, MN, CK,SY, JN, YM, AM, HI, and NY contributed to the acquisition of data.
MS and EM were involved in the data analysis. AO was involved in
the FGFR2 and HER2 scoring. HY, EM, MI, MS, and TD provided theidea to draft the manuscript. All authors reviewed and commented ondrafts of the manuscript and approved the final manuscript.
Funding This study was sponsored by Daiichi Sankyo Co., Ltd.
Availability of data and materials There were no agreements from theparticipants for their data, so data sharing is not available.

Declarations
Ethics approval and consent to participate This study was conductedwith the approval of the ethical review board at each study site. All
patients provided written informed consent.

International Journal of Colorectal Disease (2022) 37:1393–1402

1401

Consent for publication Not applicable.
Competing interests The first author (H. Yasui) declares the following
conflict of interests: Research funding and honoraria for lectures from
Daiichi Sankyo. H. Hara declares the following conflict of interests:
Grants and personal fees from Daiichi Sankyo, Sumitomo Dainippon
Pharma, Merck Biopharma, MSD, Taiho Pharma, Chugai Pharmaceutical, Boehringer Ingelheim, Ono Pharmaceutical, Bristol-Myers
Squibb, and Bayer; Grants from AstraZeneca, Eisai, Elevar Therapeutics, Incyte, Pfizer, BeiGene, Astellas Pharm, and GSK; Personal feesfrom Eli Lilly Japan, Yakult Honsha, Sanofi, Takeda Pharmaceutical, and Kyowa Kirin. A. Makiyama declares the following conflictof interests: Honoraria from Eli Lilly Japan, Taiho Pharmaceutical,
Ono Pharmaceutical, Bristol-Myers Squibb, and Daiichi Sankyo. T.
Doi declares the following conflict of interests: Grants and personal
fees from MSD, Daiichi Sankyo, Sumitomo Dainippon Pharma, Taiho
Pharma, Novartis, Janssen Pharmaceutical, Boehringer Ingelheim,
Bristol-Myers Squibb, and Abbvie; Grants from Lilly, Merck Serono
Pharmaceutical, Pfizer, Quintiles (IQVIA), and Eisai; Personal feesfrom Amgen, Takeda Pharmaceutical, Chugai Pharmaceutical, Bayer,
Rakuten Medical, Ono Pharmaceutical, Astellas Pharma, Oncolys
BioPharma, and Otsuka Pharmaceutical. E. Matsumura, M. Ishigami
and M. Sugihara are employees of Daiichi Sankyo. All other authors
declare that they have no competing interests.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article areincluded in the article's Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in
the article's Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you willneed to obtain permission directly from the copyright holder. To view acopy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.

6.

7.

8.
9.

10.
11.

12.

13.

References
1. Brooks AN, Kilgour E, Smith PD (2012) Molecular pathways:
fibroblast growth factor signaling: a new therapeutic opportunity
in cancer. Clin Cancer Res 18:1855–1862. https://d​ oi.o​ rg/1​ 0.1​ 158/​
1078-​0432.​CCR-​11-​0699
2. Eswarakumar VP, Lax I, Schlessinger J (2005) Cellular signalingby fibroblast growth factor receptors. Cytokine Growth Factor Rev
16:139–149. https://​doi.​org/​10.​1016/j.​cytog​fr.​2005.​01.​001
3. Siena S, Sartore-Bianchi A, Marsoni S, Hurwitz HI, McCall SJ,
Penault-Llorca F, Srock S, Bardelli A, Trusolino L (2018) Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer. Ann Oncol 29:1108–1119. https://​doi.​
org/​10.​1093/​annonc/​mdy100
4. Gemo AT, Deshpande AM, Palencia S, Bellovin D, Brenna T,
Patil N, Huang C, Los G, Pierce K (2014) FPA144: A therapeutic
antibody for treating patients with gastric cancers bearing FGFR2
gene amplification. Cancer Res 74(Suppl):5446. https://​doi.​org/​
10.​1158/​1538-​7445.​AM2014-​5446
5. Sommer A, Kopitz C, Schatz CA, Nising CF, Mahlert C, Lerchen
HG, Stelte-Ludwig B, Hammer S, Greven S, Schuhmacher J,
Braun M, Zierz R, Wittemer-Rump S, Harrenga A, Dittmer F,
Reetz F, Apeler H, Jautelat R, Huynh H, Ziegelbauer K, Kreft B(2016) Preclinical efficacy of the auristatin-based antibody–drugconjugate BAY 1187982 for the treatment of FGFR2-positive

14.

15.

16.

17.

solid tumors. Cancer Res 76:6331–6339. https://​doi.​org/​10.​1158/​
0008-​5472.​CAN-​16-​0180
Black J, Menderes G, Bellone S, Schwab CL, Bonazzoli E, Ferrari
F, Predolini F, De Haydu C, Cocco E, Buza N, Hui P, Wong S,
Lopez S, Ratner E, Silasi DA, Azodi M, Litkouhi B, Schwartz PE,
Goedings P, Beusker PH, van der Lee MM, Timmers CM, Dokter
WH, Santin AD (2016) SYD985, a novel duocarmycin-based HER2targeting antibody–drug conjugate, shows antitumor activity in uterine serous carcinoma with HER2/Neu expression. Mol Cancer Ther
15:1900–1909. https://​doi.​org/​10.​1158/​1535-​7163.​MCT-​16-​0163
Grillo F, Fassan M, Sarocchi F, Fiocca R, Mastracci L (2016)
HER2 heterogeneity in gastric/gastroesophageal cancers: Frombenchside to practice. World J Gastroenterol 22:5879–5887.
https://​doi.​org/​10.​3748/​wjg.​v22.​i26.​5879
Gravalos C, Jimeno A (2008) HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 19:1523–
1529. https://​doi.​org/​10.​1093/​annonc/​mdn169
Van Cutsem E, Bang YJ, Feng-Yi F, Xu JM, Lee KW, Jiao SC,
Chong JL, López-Sanchez RI, Price T, Gladkov O, Stoss O, Hill
J, Ng V, Lehle M, Thomas M, Kiermaier A, Rüschoff J (2015)
HER2 screening data from ToGA: targeting HER2 in gastric andgastroesophageal junction cancer. Gastric Cancer 18:476–484.
https://​doi.​org/​10.​1007/​s10120-​014-​0402-y
Kim HS, Kim JH, Jang HJ (2019) Pathological and prognostic
impacts of fgfr2 overexpression in gastric cancer: a meta-analysis.
J Cancer 10:20–27. https://​doi.​org/​10.​7150/​jca.​29184
Richman SD, Southward K, Chambers P, Cross D, Barrett J,
Hemmings G, Taylor M, Wood H, Hutchins G, Foster JM, Oumie
A, Spink KG, Brown SR, Jones M, Kerr D, Handley K, Gray R,
Seymour M, Quirke P (2016) HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer:
analysis of 3256 patients enrolled in the QUASAR, FOCUS andPICCOLO colorectal cancer trials. J Pathol 238:562–570. https://​doi.​org/​10.​1002/​path.​4679
Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R(2016) The FGFR landscape in cancer: analysis of 4,853 tumors
by next-generation sequencing. Clin Cancer Res 22:259–267.
https://​doi.​org/​10.​1158/​1078-​0432.​CCR-​14-​3212
Sartore-Bianchi A, Amatu A, Porcu L, Ghezzi S, Lonardi S, Leone
F, Bergamo F, Fenocchio E, Martinelli E, Borelli B, Tosi F, Racca P,
Valtorta E, Bonoldi E, Martino C, Vaghi C, Marrapese G, CiardielloF, Zagonel V, Bardelli A, Trusolino L, Torri V, Marsoni S, Siena S(2019) HER2 positivity predicts unresponsiveness to EGFR-targeted
treatment in metastatic colorectal cancer. Oncologist 24:1395–1402.
https://​doi.​org/​10.​1634/​theon​colog​ist.​2018-​0785
Su X, Zhan P, Gavine PR, Morgan S, Womack C, Ni X, Shen D,
Bang YJ, Im SA, Ho Kim W, Jung EJ, Grabsch HI, Kilgour E(2014) FGFR2 amplification has prognostic significance in gastriccancer: results from a large international multicentre study. Br J
Cancer 110:967–975. https://​doi.​org/​10.​1038/​bjc.​2013.​802
Deng N, Goh LK, Wang H, Das K, Tao J, Tan IB, Zhang S, Lee
M, Wu J, Lim KH, Lei Z, Goh G, Lim QY, Tan AL, Sin Poh DY,
Riahi S, Bell S, Shi MM, Linnartz R, Zhu F, Yeoh KG, Toh HC,
Yong WP, Cheong HC, Rha SY, Boussioutas A, Grabsch H, Rozen
S, Tan P (2012) A comprehensive survey of genomic alterations
in gastric cancer reveals systematic patterns of molecular exclusivity and co-occurrence among distinct therapeutic targets. Gut
61:673–684. https://​doi.​org/​10.​1136/​gutjnl-​2011-​301839
Das K, Gunasegaran B, Tan IB, Deng N, Lim KH, Tan P (2014)
Mutually exclusive FGFR2, HER2, and KRAS gene amplifications in gastric cancer revealed by multicolour FISH. Cancer Lett
353:167–175. https://​doi.​org/​10.​1016/j.​canlet.​2014.​07.​021
Kim ST, Banks KC, Pectasides E, Kim SY, Kim K, Lanman RB,
Talasaz A, An J, Choi MG, Lee JH, Sohn TS, Bae JM, Kim S,
Park SH, Park JO, Park YS, Lim HY, Kim NKD, Park W, Lee
H, Bass AJ, Kim K, Kang WK, Lee J (2018) Impact of genomic

13

1402
alterations on lapatinib treatment outcome and cell-free genomic
landscape during HER2 therapy in HER2+ gastric cancer patients.
Ann Oncol 29:1037–1048. https://​d oi.​o rg/​ 1 0.​ 1 093/​ a nnonc/​
mdy034
18. Azuma K, Tsurutani J, Sakai K, Kaneda H, Fujisaka Y, Takeda
M, Watatani M, Arao T, Satoh T, Okamoto I, Kurata T, Nishio
K, Nakagawa K (2011) Switching addictions between HER2 andFGFR2 in HER2-positive breast tumor cells: FGFR2 as a potential target for salvage after lapatinib failure. Biochem Biophys Res
Commun 407:219–224. https://d​ oi.o​ rg/1​ 0.1​ 016/j.b​ brc.2​ 011.​03.​002
19. Nathanson DR, Culliford AT 4th, Shia J, Chen B, D’Alessio M,
Zeng ZS, Nash GM, Gerald W, Barany F, Paty PB (2003) HER

13

International Journal of Colorectal Disease (2022) 37:1393–1402
2/neu expression and gene amplification in colon cancer. Int J
Cancer 105:796–802. https://​doi.​org/​10.​1002/​ijc.​11137
20. Wang XY, Zheng ZX, Sun Y, Bai YH, Shi YF, Zhou LX, Yao YF,
Wu AW, Cao DF (2019) Significance of HER2 protein expression and HER2 gene amplification in colorectal adenocarcinomas.
World J Gastrointest Oncol 11:335–347. https://​doi.​org/​10.​4251/​
wjgo.​v11.​i4.​335
Publisher's Note Springer Nature remains neutral with regard tojurisdictional claims in published maps and institutional affiliations.

Japanese Journal of Clinical Oncology, 2022, 1–11
https://doi.org/10.1093/jjco/hyac073
Original Article

Original Article
Downloaded from https://academic.oup.com/jjco/advance-article/doi/10.1093/jjco/hyac073/6573953 by Tsukuba Univ user on 26 April 2022

Impact of chronological age on efﬁcacy andsafety of ﬂuoropyrimidine plus bevacizumab inolder non-frail patients with metastatic
colorectal cancer: a combined analysis ofindividual data from two phase II studies ofpatients aged >75 years
Toshikazu Moriwaki 1 ,*, Tomohiro Nishina2 , Yoshinori Sakai3 ,Yoshiyuki Yamamoto1 , Mitsuo Shimada4 , Hiroyasu Ishida5 ,Kenji Amagai6 , Mikio Sato7 , Shinji Endo8 , Yuji Negoro9 ,Hidekazu Kuramochi10 , Tadamichi Denda11 , Yukimasa Hatachi12,† ,Kazuto Ikezawa13 , Go Nakajima14 , Yoshiaki Bando15 , Akihito Tsuji16 ,Yuji Yamamoto17,‡ , Masamitsu Morimoto18 , Kazuma Kobayashi 19 , andIchinosuke Hyodo2
1

Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba City, Japan, 2 Department of
Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama City, Japan,
3
Department of Gastroenterology, Tsuchiura Kyodo General Hospital, Tsuchiura City, Japan, 4 Department of Surgery,
Tokushima University, Tokushima City, Japan, 5 Department of Gastroenterology, National Hospital Organization Mito
Medical Center, Higashi Ibaraki gun, Japan, 6 Division of Gastroenterology, Ibaraki Prefectural Central Hospital andCancer Center, Kasama City, Japan, 7 Department of Gastroenterology and Hepatology, Ryugasaki Saiseikai
Hospital, Ryugasaki City, Japan, 8 Department of Gastroenterology and Hepatology, Shinmatsudo Central General
Hospital, Matsudo City, Japan, 9 Department of Oncological Medicine, Kochi Health Sciences Center, Kochi City,
Kochi, Japan, 10 Department of Chemotherapy and Palliative Care, Tokyo Women’s Medical University, Shinjuku-ku,
Japan, 11 Division of Gastroenterology, Chiba Cancer Center, Chiba City, Japan, 12 Department of Medical Oncology,
Kobe City Medical Center General Hospital, Kobe City, Japan, 13 Division of Gastroenterology, Tsukuba Memorial
Hospital, Tsukuba City, Japan, 14 Department of Chemotherapy and Palliative Care, Tokyo Women’s Medical
University, Shinjuku-ku, Japan, 15 Department of Surgery, Tokushima Prefecture Naruto Hospital, Naruto City, Japan,
16
Department of Clinical Oncology, Kagawa University Faculty of Medicine, Kita-gun, Japan, 17 Department of
Gastrointestinal Surgery and Surgical Oncology, Ehime University Graduate School of Medicine, Toon City, Japan,
18
Department of Surgery, National Hospital Organization Ehime Medical Center, Toon City, Japan and 19 Departmentof Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki City, Japan*For reprints and all correspondence: Toshikazu Moriwaki, Faculty of Medicine, Department of Gastroenterology,
University of Tsukuba, 1-1-1 Tennodai, Tsukuba City 305-8575, Japan. E-mail: tmoriwak@md.tsukuba.ac.jp†
Present address: Department of Clinical Oncology, Kansai Rosai Hospital, Amagasaki City, Hyogo, Japan.
‡
Present address: Division of Surgery, Minami Matsuyama Hospital, Matsuyama City, Ehime, Japan.
Received 29 November 2021; Editorial Decision 22 March 2022; Accepted 13 April 2022

Abstract
Objective: Many clinical trials for older patients with metastatic colorectal cancer have been conducted, and ﬂuoropyrimidine and bevacizumab are standard treatments. However, the relationship© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.

1

2

Age and outcomes in older CRC patients

Key words: adverse event, age, bevacizumab, chemotherapy, colon cancer, older patients, ﬂuoropyrimidine, rectal cancer, toxicity,vulnerability

Introduction
As the average life span increases, the number of elderly patients withcancer has also increased globally. Colorectal cancer (CRC) is thethird most common cancer worldwide and the most common type ofcancer in Japan (1,2). CRC is common in populations over 75 yearsof age, and mortality is known to increase with age (2). Older patientswith CRC are less likely to be diagnosed at a metastatic stage than
younger patients; however, older patients have the lowest survival
rates because of age-related disadvantages, such as comorbidities(3). Although older patients do not commonly receive aggressive
treatments, systemic chemotherapy can improve the overall survival(OS) of older patients with metastatic CRC (mCRC), similar toyounger patients (4).
Fluoropyrimidine plus oxaliplatin, or irinotecan combined witha molecularly targeted agent, such as bevacizumab, cetuximab or
panitumumab, is recommended as the standard chemotherapy for
mCRC (5). These treatments are also offered to older patients toprolong their OS and maintain their general condition. However,
the efficacy of doublet chemotherapy with/without a moleculartargeted agent is controversial because of the higher incidence ofadverse events (AEs) compared with fluoropyrimidine with or without a molecularly targeted agent (6–8), despite the patients being
eligible for doublet chemotherapy, defined as fit patients. Recently,
capecitabine, an oral fluoropyrimidine, plus bevacizumab has beenreported to improve progression-free survival (PFS) compared withcapecitabine alone in older patients with mCRC who were incompatible for oxaliplatin- or irinotecan-containing chemotherapy, defined
as vulnerable patients (9). Thus, fluoropyrimidine plus bevacizumab
is recommended as an optional treatment for fit or vulnerable older
patients in the National Comprehensive Cancer Network, European
Society of Medical Oncology and Pan-Asian practice guidelines (10–12). In previous clinical studies on fluoropyrimidine plus bevacizumab for older patients with mCRC, the median PFS and OS were
8.1–9.9 and 20.7–25.0 months, respectively (9,13–15). However,grade 3 or higher AEs were observed in 29–40% of the older patients,
and 11–32% terminated treatment due to AEs. It remains unclearthat age of non-frail older patients is associated with the outcomesof fluoropyrimidine plus bevacizumab, which is recognized as mild
chemotherapy. Due to the diversity of older patients, various comprehensive geriatric assessments have been actively studied, but nostandard evaluation methods have been established (16–18). Thus, it
is difficult to determine whether patients can tolerate chemotherapy.
Even in patients with mCRC with no vulnerabilities except forchronological age, there are still concerns regarding the impact ofage on outcomes.
This study therefore aimed to investigate the association between
chronological age and the efficacy and safety of fluoropyrimidine
plus bevacizumab using individual data from two phase II trials forolder non-frail patients with mCRC.

Materials and methods
Patients
The individual data of patients participating in either phase
II studies of uracil-tegafur and oral leucovorin combined with
bevacizumab (J-BLUE study) or S-1 on alternate days combinedwith bevacizumab (J-SAVER study), for non-frail patients with
mCRC aged ≥75 years were collected (13,19). These studies were
multicenter, single-arm phase II studies conducted by the nonprofit organization Tsukuba Cancer Clinical Trial Group andthe Shikoku Gastrointestinal Oncology Study Group in Japan.
The study protocols were approved by the ethics committee of
each participating institution and registered at the University
Hospital Medical Information Network, UMIN000003515 and
UMIN000010402. Both studies showed similar results. Briefly,
the J-BLUE study, comprising 52 patients, showed a medianPFS of 8.2 months and OS of 23.0 months. The most common
grade 3 and grade 4 AEs were hypertension (12%), fatigue (8%),

Downloaded from https://academic.oup.com/jjco/advance-article/doi/10.1093/jjco/hyac073/6573953 by Tsukuba Univ user on 26 April 2022

between age and the efﬁcacy and safety of this treatment is unclear in older metastatic colorectal
cancer patients.
Methods: Individual data from two phase II studies on older (≥75 years), non-frail patients withmetastatic colorectal cancer treated with uracil-tegafur/leucovorin or S-1 combined with bevacizumab were collected. Patient characteristics were evaluated with multiple regression analyses
for survival outcomes, using the Cox proportional hazard model and linear regression analyses forthe worst grade of adverse events.
Results: We enrolled 102 patients with a median age of 80 years (range, 75–88 years). Of the
70 patients who died, seven (10%) died of causes unrelated to disease or treatment. The study
treatment was discontinued due to adverse events in 19 patients (18.6%), with 63% aged ≥85 years.
The adverse event that most commonly resulted in treatment discontinuation was grade 2 fatigue(21%). Chronological age was not associated with progression-free survival (Hazard ratio, 1.03;
P = 0.40) or overall survival (Hazard ratio, 1.02; P = 0.65). Age was weakly associated with nonhematologic adverse events (regression coefﬁcient [R], 0.27; P = 0.007), especially fatigue (R, 0.23;
P = 0.02) and nausea (R, 0.19; P = 0.06), but not with hematologic (R, 0.05; P = 0.43) or bevacizumabrelated (R, −0.06; P = 0.56) adverse events.
Conclusions: The efﬁcacy of ﬂuoropyrimidine plus bevacizumab was age-independent in patientswith metastatic colorectal cancer aged ≥75 years, and attention should be paid to non-hematologic
adverse events as age increases.

Jpn J Clin Oncol, 2022
anaemia (8%), nausea (6%) and diarrhoea (6%). Treatmentrelated deaths occurred in two patients. The J-SAVER study,
comprising 50 patients, showed a median PFS of 8.1 months and OSof 23.1 months. The most common grade 3 and grade 4 AEs were
hypertension (11%), fatigue (6%), anaemia (6%), nausea (6%) andproteinuria (6%). Treatment-related death occurred in one patient.

The following individual pre-treatment clinical data and baselinelaboratory values were collected and used in the analysis: age, sex,
body mass index, Eastern Cooperative Oncology Group performancestatus (ECOG-PS), metastasis at diagnosis, resection of the primary
tumour, site of the primary tumour, pathological type, number ofmetastatic organs, metastatic organs, RAS gene mutation status,
white blood cell counts, neutrophil counts, platelet counts, andlevels of haemoglobin, aspartate transaminase (AST), total bilirubin,creatinine clearance, serum carcinoembryonic antigen (CEA) andcancer antigen (CA)19–9.

Statistical analysis
PFS was defined as the time from enrollment to disease progression
or death from any cause. OS was defined as the time from enrollment
to death from any cause. Tumour assessments were performed every
8 weeks according to the Response Evaluation Criteria in Solid
Tumors. AEs were assessed according to the Common Terminology
Criteria for Adverse Events, version 3.0, in the J-BLUE study and version 4.0, in the J-SAVER study. In addition to hematologic and nonhematologic AEs, bevacizumab-related AEs, including hypertension,
proteinuria, haemorrhage, thromboembolic events and gastrointestinal perforation, were defined and evaluated.
Survival outcomes were estimated using the Kaplan–Meiermethod and analysed by regression analysis using the Cox
proportional hazard model. Associations between continuous clinicaldata and the worst grade of AEs were evaluated using regression
analysis. Factors with P < 0.2 were used in the multivariate analysis.
Differences in PFS and OS between the groups were evaluated using
the log-rank test. For all statistical analyses, SPSS software package,
version 27.0 (SPSS Inc., Tokyo, Japan) was used, and a value ofP < 0.05 was considered significant.

Results
Patients
A total of 102 patients were enrolled, including 52 from the JBLUE study and 50 from the J-SAVER study (Table 1). The medianage was 80 (range: 75–88) years, and 65% had an ECOG-PS of 0.
The patient’s body mass index was normal. The median number ofmetastatic organs was two (range: 1–5), and the prevalence of RAS
gene mutations was 35%. Creatinine clearance was <60 ml/min in
38% of patients.

Efﬁcacy
The median follow-up was 33.7 months (95% CI: 22.3–45.1). The
protocol treatment was terminated in 98 patients (96.1%), including 19 (19.4%) patients due to AEs. Of the 70 patients (71.4%)
who died, seven died of causes other than disease progression ortreatment-related death. The median PFS was 8.2 months (95% CI:

7.1–9.3), and the median OS was 23.0 months (95% CI: 18.2–27.8)(Supplementary Fig. 1).

SafetyAmong treatment-related AEs (Supplementary Table 1), the mostcommon hematologic AEs were anaemia of any grade (52.0%)
and grade 3 (6.9%). The most common non-hematologic AEs were
fatigue of any grade (41.2%) and grade 3 (6.9%). The most common
bevacizumab-related AEs were proteinuria of any grade (39.2%) andhypertension of grade 3 or higher (11.8%). Treatment-related death
was observed in three patients (n = 1; diarrhoea, n = 1; cerebral
infarction, n = 1; sudden death due to myocardial infarction). The
AEs that resulted in treatment discontinuation were grade 2 fatigue(n = 4), liver disorders (n = 2), skin disorders (n = 1), diarrhoea(n = 1) and edema (n = 1); grade 3 nausea (n = 1), hypertension withproteinuria (n = 1) and neutropenia (n = 1); grade 4 thromboembolic
events (n = 1); and treatment-related death (n = 3).
The incidences of grade 2 non-hematologic and grade 3 or higher
non-hematologic AEs were significantly higher in the AE discontinuation group than in the non-AE discontinuation group (57.9% vs.
31.6%, P = 0.03; 26.3% vs. 8.9%, P = 0.04, respectively) (Table 2).
In the AE discontinuation group, grade 2 or higher fatigue wasobserved in eight patients (42.1%), followed by nausea or stomatitis
in seven patients (36.8%).

Efﬁcacy outcomes and reasons for treatment
discontinuation
The individual PFS, status of disease progression or death andreasons for treatment discontinuation by age are shown in Fig. 1A.
Patients with PFS over the median PFS were widely distributed
among the ages, while patients who discontinued treatment due to
AEs were older than 85 years (n = 5/8). No consistency was observedin the relationship between the OS duration and age (Fig. 1B). Deaths
due to treatment-related toxicities and causes other than cancer
progression were also widely distributed over the ages.

Associations of efﬁcacy and patients’ backgroundfactors
The association between PFS and age was not significant in the univariate analysis (HR, 1.03; 95% CI: 0.96–1.10, P = 0.40) (Table 3).
In the multivariate analysis for PFS, metastasis at diagnosis, numberof metastatic organs, CEA level and AST level were significant
independent factors. The association between OS and age was also
not significant in the univariate analysis (HR, 1.02; 95% CI: 0.95–
1.09; P = 0.65) (Table 3). Resection of the primary tumour and ASTlevel were significant independent factors for OS.
Efficacy parameters were compared between the three groups
divided according to age groups: 75–79 years, 80–84 years
and ≥85 years. Median PFS was 8.8 months (95% CI: 7.2–10.4)
in the 75–79 years group, 7.8 months (95% CI: 7.2–8.4) in the
80–84 years group and 11.1 months (95% CI: 4.6–17.6) in the≥85 years group (P = 0.88) (Fig. 2A). PFS, which was adjusted byindependent factors, was not statistically significant between threegroups (Supplementary Table 2). Median OS was 23.8 months (95%
CI: 16.1–31.5) in the 75–79 years group, 18.9 months (95% CI: 9.8–28.0) in the 80–84 years group and 25.9 months (95% CI: 0.0–52.1)
in the ≥85 years group (P = 0.53) (Fig. 2B). OS, which was adjusted

Downloaded from https://academic.oup.com/jjco/advance-article/doi/10.1093/jjco/hyac073/6573953 by Tsukuba Univ user on 26 April 2022

Data collection

3

4

Age and outcomes in older CRC patients

Table 1. Patient characteristics

Trial
Age

Body mass index
ECOG-PS
Metastasis at diagnosis
Resection of primary tumour
Site of primary tumour∗
Pathological type

Number of metastatic organs
Metastatic organ

KRAS/RAS gene status

WBC counts
Neutrophil counts
Haemoglobin level
Platelet counts
AST level
Total bilirubin level
Creatinine clearance

CEA level

CA 19–9 level

Reason for discontinuation of
protocol treatment

%

52
50
80 (75–88)
50
44
8
57
45
21.4 (15.2–34.0)
66
36
69
33
81
21
26
76
90
11

51.0
49.0

1
2 (1–5)
14
61
42
31
20
16
41
36
25
5965 (3300–10 750)
3840 (1587–83,00)
11.5 (9.0–15.3)
21.8 (10.8–55.8)
15 (5–84)
0.6 (0.1–4.3)
66.3 (25.3–203.0)
19
44
38
1
19.8 (1.0–12854.0)
791
58.4 (0.0–37660.6)
54
2
74
19†
6
3

1.0

49.0
43.1
7.8
55.9
44.1
64.7
35.3
67.6
32.4
79.4
20.6
25.5
74.5
88.2
10.8

13.7
59.8
41.2
30.4
19.6
15.7
40.2
35.3
24.5

18.6
43.1
37.3
1.0
77.5
1.0
52.9
2.0
72.5
18.6
5.9
2.9

AST: aspartate transaminase, CA 19–9: cancer antigen 19–9, CEA: carcinoembryonic antigen, ECOG-PS: Eastern Cooperative Oncology Group performancestatus, WBC: white blood cell.
∗ Right included cecum, ascending colon and transverse colon, Left included descending colon, sigmoid colon and rectum. † Three patients had treatment-related
deaths.

Downloaded from https://academic.oup.com/jjco/advance-article/doi/10.1093/jjco/hyac073/6573953 by Tsukuba Univ user on 26 April 2022

Sex

J-BLUE
J-SAVERMedian (range), years
75–79
80–84
≥85
Male
FemaleMedian (range)
01Synchronous
Metachronous
Yes
No
Right
Left
Well and moderate differentiatedPoorly differentiated and signet-ringcellOthersMedian (range)
≥3
Liver
Lung
Lymph node
Peritoneum
OthersWild
MutantUnknown
Median (range), mg/dl
Median (range), mg/dl
Median (range), g/dl
Median (range), x104 mg/dl
Median (range), IU/LMedian (range), mg/dl
Median (range), ml/min≥80<80, ≥60<60, ≥30<30
Median (range), IU/L
Abnormally
Missing
Median (range), IU/L
Abnormally
Missing
Progressive disease
Adverse event
OthersOngoingnJpn J Clin Oncol, 2022

5

Table 2. The comparison of experienced maximum toxicity grade according to AE discontinuation
Category

Non-AE discontinuation(n = 19)(n = 79)

P value

n

(%)

n

(%)

4
6
2

(21.1)(31.6)(10.5)

3513
6(44.3)(16.5)
(7.6)

0.06
0.13
0.68

2
11
5

(10.5)(57.9)(26.3)

2325
7(29.1)(31.6)
(8.9)

0.10
0.03
0.04

3
5
5

(15.8)(26.3)(26.3)

1922
13(24.1)(27.8)(16.5)

0.44
0.89
0.33

AE, adverse event.

Figure 1. Progression-free survival or overall survival and the reasons for the event in individual patients. A: progression-free survival; B: overall survival. Solidhorizontal line denotes median time.

Downloaded from https://academic.oup.com/jjco/advance-article/doi/10.1093/jjco/hyac073/6573953 by Tsukuba Univ user on 26 April 2022

Hematologic AEs
Grade 1
Grade 2
Grade ≥3
Non-hematologic AEs
Grade 1
Grade 2
Grade ≥3
Bevacizumab-related AEs
Grade 1
Grade 2
Grade ≥3

AE discontinuation

6

Age and outcomes in older CRC patients

Table 3. Regression analyses with Cox proportional hazard model for progression-free survival and overall survival
Progression-free survival

Overall survival

Univariate

Univariate

Multivariate

Unit or GroupHR

P value

Age
Body mass index
Tumour location∗
Sex
ECOG-PS
Metastasis at
diagnosis
Resection ofprimary tumour
Pathological type
Liver metastasis
Peritoneal
dissemination
No. of metastaticorgansRAS gene status

Year
kg/m2
Left vs Right
Female vs Male
1 vs 0
Metachronous vsSynchronousYes vs No

1.03
0.93
1.10
1.37
1.38
0.53

0.40
0.041
0.70
0.14
0.15
0.01

1.51

Other vs Por vs Tub
No vs Yes
No vs Yes
Organ

Unknown vs Wild vsMutant
CEA level
IU/ml
CA19–9 level
IU/ml
Haemoglobin level g/ml
Platelet counts/ml
WBC counts/ml
Neutrophil counts /ml
AST level
IU/ml
Total bilirubin
mg/dl
level
Creatinine
ml/minclearance

HR (95% CI)

P valueHR

P value

0.008

1.02
0.96
0.99
1.03
1.54
0.66

0.65
0.30
0.97
0.92
0.08
0.12

0.11

2.44

0.002

1.42
0.70
1.09

0.28
0.11
0.75

2.50
0.64
0.78

0.009
0.085
0.40

1.36

0.008

1.51

0.001

0.91

0.47

1.13

0.44

0.50
0.76
0.87
1.02
1.13
1.17
1.17
1.02

0.008
0.21
0.027
0.27
0.06
0.033
0.013
0.90

0.47
0.87
0.92
1.01
1.13
1.14
1.25
0.83

0.019
0.56
0.26
0.59
0.087
0.11
0.002
0.43

1.00

0.85

1.00

0.85

0.51 (0.31–0.84)

1.36 (1.06–1.74)

0.015

0.98 (0.97–1.00)

0.044

1.21 (1.05–1.38)

0.009

HR (95% CI)

P value

2.68 (1.53–4.70) <0.001

1.26 (1.09–1.46) 0.001

CI: confidence interval, HR: hazard ratio, WBC: white blood cell.
∗ Right included cecum, ascending colon and transverse colon, Left included descending colon, sigmoid colon and rectum.

by independent factors, was not statistically significant between threegroups (Supplementary Table 2).

Associations of subsequent chemotherapy and age
Among 98 patients who discontinued protocol treatment, 65 patients(66.3%) received any subsequent chemotherapy (Table 4). In the 75–
79 years group, oxaliplatin plus fluoropyrimidine combined witha molecular targeted agent, irinotecan combined with a moleculartargeted agent and irinotecan alone were used in 22 (45.8%), 11(22.9%) and 10 (20.8%) patients, respectively. In the 80–84 years
group, oxaliplatin plus fluoropyrimidine combined with a moleculartargeted agent, irinotecan combined with a molecular targeted agent
and fluoropyrimidine combined with bevacizumab were used in
5 (11.9%), 4 (9.5%) and 4 (9.5%) patients, respectively. In the≥85 years group, fluoropyrimidine alone and irinotecan alone wereused in three (37.5%) and two (25.0%) patients, respectively.

and Supplementary Table 3. The association between age and hematologic AEs was not significant in the univariate analysis (regression
coefficient [R], 0.05; P = 0.43). Hematologic AEs were weakly
associated with resection of the primary tumour (partial R [pR], 0.20;
P = 0.034) and creatinine clearance (pR, −0.25; P = 0.009) in themultivariate analysis. Non-hematologic AEs were weakly associatedwith age (pR, 0.25, P = 0.009), sex (pR, 0.19; P = 0.046) and platelet
count (pR, −0.23; P = 0.019) in the multivariate analysis. The
association of age with bevacizumab-related AEs was not significant
in the univariate analysis (R, −0.06; P = 0.56). Bevacizumab-related
AEs were weakly associated with the pathologic type (pR, 0.20;
P = 0.046), neutrophil counts (pR, 0.30; P = 0.003) and ASTlevel (pR, −0.25; P = 0.014). Among non-hematologic AEs, fatigue(R, 0.23; P = 0.02) and nausea (R, 0.19; P = 0.06) were weakly
associated with age (Table 5). The four patients who discontinued
treatment due to grade 2 fatigue were aged 77, 81, 86 and 86 years,
and one of them also developed grade 3 nausea.

Association of safety and patients’ background factors

Discussion

The regression analyses between the continuous variables of patients’background factors and the worst grades of AEs are shown in Fig. 3This study showed that age was weakly associated with nonhematologic AEs, but not PFS and OS in non-frail patients with

Downloaded from https://academic.oup.com/jjco/advance-article/doi/10.1093/jjco/hyac073/6573953 by Tsukuba Univ user on 26 April 2022

Variable

Multivariate

7

Jpn J Clin Oncol, 2022
Table 4. Subsequent chemotherapy according to age
80–84 years≥85 yearsn = 48n = 42

n=8

n

(%)

n

(%)

n

(%)

12
22
5
2
11
10
6
3
2
5
2

(25.0)(45.8)(10.4)(4.2)(22.9)(20.8)(12.5)(6.3)(4.2)(10.4)
(4.2)

18
5
2
0
4
2
4
2
3
1
0

(42.9)(11.9)
(4.8)
(0)
(9.5)
(4.8)
(9.5)
(4.8)
(7.1)
(2.4)
(0)

3
1
1
0
0
2
1
3
1
0
0

(37.5)(12.5)(12.5)(0)(0)(25.0)(12.5)(37.5)(12.5)(0)(0)

CapeIRI, capectabine+irinotecan; CapeOX, capecitabine+oxaliplatin;
fluorouracil+leucovorin; UFT-LV, uracil-tegafur+leucovorin.

Figure 2. Kaplan–Meier curves for each of the age groups: 75–79 years, 80–84 years and ≥85 years. A: progression-free survival; B: overall survival.

mCRC >75 years of age who received fluoropyrimidine plus
bevacizumab.
Before these analyses, we hypothesized that age probably affected
OS because chronological age in some of the patients was around
the Japanese average life span (male: 81 years and female: 87 years,
in 2018). Although OS in patients over 80 years of age showed ashorter trend than the others, there was no statistically significant
difference. The proportion of patients aged ≥80 years who received
any subsequent chemotherapy was lower than that of the 75–79 years

FOLFOX,

infusional

fluorouracil+leucovorin+oxaliplatin;

FL,

bolus

group. In particular, oxaliplatin- or irinotecan-containing therapy
was less common in patients aged ≥80 years. Although the patient’s
condition after failure of first-line treatment affected the selectionof subsequent treatment, age may be a factor for the decision. The
PFS did not differ between these patients. These results suggest thata therapeutic effect could be expected regardless of age in older
patients eligible for fluoropyrimidine plus bevacizumab treatment.
The prognostic factors for PFS and OS obtained in this study havebeen reported in many previous reports, including younger patients(20–23). It is noteworthy that patients older than 85 years were more
likely to discontinue treatment due to AEs, although the PFS was notnecessarily short. This may indicate poor long-term tolerability inolder patients.
The Cancer and Aging Research Group chemotherapy toxicity
tool questionnaire was developed to predict chemotherapy-related
severe toxicity in older cancer patients in Western countries (24–26).
Geriatric assessment tools such as the G8 screening tool to separate
older patients with cancer who are eligible to receive standard
doublet treatment have also been developed (18). Although thesetools were developed focusing on the onset of severe toxicity, ourresults suggest that the prediction of toxicity, including those withlower severity, is important. In this study, only non-hematologic AEs,
particularly fatigue and nausea, were significantly associated withage, and these were generally mild or moderate (grade 3 of 5–7%).
However, these mild or moderate AEs had a negative impact on
treatment continuity, resulting in the discontinuation of treatment
in 19 (19%) patients, and the AE that was most associated withtreatment discontinuation was grade 2 fatigue. In addition, thesepatients experienced grade 2 or higher non-hematologic AEs more
frequently than patients with non-AE discontinuation, and fatigue
was the most common. Five of eight patients over 85 years ofage discontinued treatment due to AEs. Two of these five patients
had grade 2 fatigue (data not shown). In this patient population,
earlier rest or dose reduction of fluoropyrimidine administration
should be considered, despite not having severe toxicities. In one
study using patient-reported data of the incidence of symptoms withnew treatment regimens in older adults receiving chemotherapy foradvanced cancer, ∼60% experienced mild-to-moderate fatigue (18).
The effective management of chemotherapy-related fatigue should

Downloaded from https://academic.oup.com/jjco/advance-article/doi/10.1093/jjco/hyac073/6573953 by Tsukuba Univ user on 26 April 2022

No subsequent chemotherapy
FOLFOX/CapeOX/SOX+bevacizumab/panitumumab
FOLFOX/CapeOX/SOXFOLFIRI/CapeIRI+bevacizumab
Irinotecan+bevacizumab/cetuximab/panitumumab
Irinotecan
FL/S-1/Capecitabine/UFT-LV + bevacizumab
S-1/UFT-LVPanitumumab/cetuximab
Trifluridine-tipiracil
Regorafenib

75–79 years

8

Age and outcomes in older CRC patients
Table 5. Regression analysis for age and worst grade of nonhematologic adverse events
Adverse events–

Figure 3. Scatterplots of age and worst grade of adverse events. A: hematologic adverse events; B: non-hematologic adverse events; C: bevacizumabrelated adverse events. Circle size denotes the number of patients. NE, notevaluated; pR, partial regression coefﬁcient; R, regression coefﬁcient.

thus be considered an important issue for chemotherapy continuationin older patients. Hematologic AEs were not associated with age.
The incidence of hematologic AEs of any grade was 67.6%, but
most patients had grade 1 hematologic AEs. Hematologic AE grades

0.27
–
0.07
−0.01
0.04
0.19
0.11
0.08
0.23
−0.10
−0.10
−0.11

<0.01
–
0.47
0.87
0.40
0.06
0.26
0.81
0.02
0.33
0.34
0.29

Unanalysable.

with these regimens were too mild to investigate their relevancewith age. However, creatinine clearance was significantly associatedwith hematologic AEs, because decreased creatinine clearance could
lead to increased fluoropyrimidine concentration in the blood (27–29). Although this occurs regardless of age, it should be carefully
monitored as decreased renal function is common in older patients.
Bevacizumab-related AEs were weakly associated with pathologic
type, neutrophil counts and AST levels. These relationships cannot
be explained and further validation studies are required.
Recently, a randomized phase III trial (JCOG 1018) of fluoropyrimidine plus bevacizumab vs. oxaliplatin-containing therapy plus
bevacizumab in older patients eligible for intensive chemotherapy
was reported in ASCO-GI 2022 (30). PFS and OS in the oxaliplatinadded group did not improve survival compared with the fluoropyrimidine plus bevacizumab group. Moreover, grade 2 or higher
nausea, diarrhoea and fatigue were common in the oxaliplatin-addedgroup. As a result, 46% of patients terminated oxaliplatin-containing
therapy plus bevacizumab treatment due to AEs. The association ofage with clinical outcomes in this study is expected to be evaluated.
This study has some limitations. First, no comprehensive geriatricassessment was conducted. Although it was previously reported as apredictor of survival and AEs in various cancers, including mCRC, astrong relationship between the comprehensive geriatric assessment
and chronological age has not been found in older patients withcancer (31,32). Second, our results did not reflect the clinical outcomes of fluoropyrimidine plus bevacizumab in the real world as
the patients enrolled in this study were limited to those eligible forthe phase II trials. Third, the number of patients was small, and therobustness of the results was weak. Therefore, a validation study
with a large-scale sample or real-world setting is needed. Fourth,the data of patients who received different regimens were analysedin this study. However, the PFS and OS were similar between the
two treatment groups, as well as the incidence of AEs except for theslightly higher incidence of any grade of thrombocytopenia, anorexia
and proteinuria in the J-SAVER trial (13,19). Finally, the AEs were
evaluated using different versions of the CTC-AE between the twostudies. The corresponding AEs were vomiting, fatigue, hypertension,
proteinuria, thromboembolic events and gastrointestinal perforation,but, except for vomiting and hypertension, these AEs did not affectgrading.
In conclusion, this study suggested that the efficacy of fluoropyrimidine combined with bevacizumab was age-independent in

Downloaded from https://academic.oup.com/jjco/advance-article/doi/10.1093/jjco/hyac073/6573953 by Tsukuba Univ user on 26 April 2022

Any
Febrile neutropenia
Infection
Liver disfunction
Stomatitis
NauseaVomiting
Diarrhoea
Fatigue
Watering eyes
Skin disorder
Anorexia

Regression coefficient P valueJpn J Clin Oncol, 2022
patients ≥75 years of age with mCRC who were not considered frail,
and attention should be paid to non-hematologic AEs for patients as
age increases.

Acknowledgments

Author Contributions

References

Funding
The authors received no specific funding for this work.

Declaration of Completing Interest
Toshikazu Moriwaki reports grants and personal fees from Taiho,
grants and personal fees from Chugai, personal fees from Sanofi,
personal fees from Bayer, grants and personal fees from Yakult andpersonal fees from Eli Lilly, outside the scope of the submitted
work. Tomohiro Nishina reports grants and personal fees from
Taiho, grants and personal fees from Chugai, grants from MSD,
grants and personal fees from Ono, grants and personal fees from
Bristol Myers Squibb, grants and personal fees from Lilly, grants
from Dainippon Sumitomo and grants from AstraZeneca, outside
the submitted work. Mitsuo Shimada reports grants from Taiho,
grants from Takeda, grants from Ono, grants from Chugai and grants
from AbbVie GK, outside the submitted work. Kenji Amagai reports
grants from MSD, grants from Taiho, grants from Daiichi-Sankyo,
grants from Nippon Zoki and grants from Hisamitsu, outside thesubmitted work. Hidekazu Kuramochi reports personal fees fromTakeda, personal fees from Chugai, personal fees from Taiho, personal fees from Eli Lilly, personal fees from Yakult, personal feesfrom Bayer, personal fees from Ono, personal fees from Daiichi
Sankyo, outside the submitted work; and scholarship donation to
the clinical department: Chugai and Taiho. Tadamichi Denda reports
personal fees from Sysmex, personal fees from Ono and personal
fees from Sawai outside the submitted work. Kazuto Ikezawa reports
personal fees from Takeda, personal fees from Olympus, personal
fees from MOCHIDA, personal fees from Otsuka, personal feesfrom DAIICHI SANKYO, personal fees from Mitsubishi Tanabe,
personal fees from Janssen, personal fees from EA Pharma, personal
fees from TSUMURA, personal fees from AstraZeneca, personal feesfrom Astellas, personal fees from Eisai, personal fees from Gilead
Sciences, outside the submitted work. Akihito Tsuji reports grants
and personal fees from Chugai, grants and personal fees from Taiho,
personal fees from Ono, personal fees from Eli Lilly Japan, personal
fees from Sanofi, personal fees from Pfizer Japan, personal feesfrom Kyowa Hakko Kirin, personal fees from Eisai, personal feesfrom MSD, personal fees from Toray Medical, personal fees from
Daiichi Sankyo, personal fees from Bristol-Myers Squibb, outside
the submitted work. Ichinosuke Hyodo reports personal fees from
Ono, personal fees from Chugai, personal fees from Daiichi-Sankyo,
personal fees from Taiho, personal fees from Merck Serono, andpersonal fees from Asahi-Kasei, outside the submitted work. The
remaining authors declare that they have no conflict of interest.

We would like to thank Editage (www.editage.jp) for English language editing.

1. Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin DM, PinerosM, et al. Estimating the global cancer incidence and mortality in 2018:
GLOBOCAN sources and methods. Int J Cancer 2019;144:1941–53.
2. Cancer Statistics. [cited 1 September 2021 2021]. Available from: https://
ganjoho.jp/reg_stat/statistics/stat/cancer/67_colorectal.html.
3. Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF, Anderson JC, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin
2020;70:145–64.
4. Grande R, Natoli C, Ciancola F, Gemma D, Pellegrino A, Pavese I, et al.
Treatment of metastatic colorectal cancer patients >/=75 years old inclinical practice: a Multicenter analysis. PLoS One 2016;11:e0157751.
5. Biller LH, Schrag D. Diagnosis and treatment of metastatic colorectal
cancer: a review. JAMA 2021;325:669–85.
6. Aparicio T, Lavau-Denes S, Phelip JM, Maillard E, Jouve JL, Gargot D,
et al. Randomized phase III trial in elderly patients comparing LV5FU2
with or without irinotecan for first-line treatment of metastatic colorectal
cancer (FFCD 2001-02). Ann Oncol 2016;27:121–7.
7. Landre T, Uzzan B, Nicolas P, Aparicio T, Zelek L, Mary F, et al. Doublet chemotherapy vs. single-agent therapy with 5FU in elderly patientswith metastatic colorectal cancer. A meta-analysis. Int J Colorectal Dis
2015;30:1305–10.
8. Landre T, Maillard E, Taleb C, Ghebriou D, Guetz GD, Zelek L, et al.
Impact of the addition of bevacizumab, oxaliplatin, or irinotecan tofluoropyrimidin in the first-line treatment of metastatic colorectal cancer
in elderly patients. Int J Colorectal Dis 2018;33:1125–30.
9. Cunningham D, Lang I, Marcuello E, Lorusso V, Ocvirk J, Shin DB,
et al. Bevacizumab plus capecitabine versus capecitabine alone in elderly
patients with previously untreated metastatic colorectal cancer (AVEX):
an open-label, randomised phase 3 trial. Lancet Oncol 2013;14:1077–85.
10. Benson AB, Venook AP, Al-Hawary MM, Arain MA, Chen YJ, Ciombor
KK, et al. Colon cancer, version 2.2021, NCCN clinical practice guidelines
in oncology. J Natl Compr Canc Netw 2021;19:329–59.
11. Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, AderkaD, et al. ESMO consensus guidelines for the management of patients withmetastatic colorectal cancer. Ann Oncol 2016;27:1386–422.
12. Yoshino T, Arnold D, Taniguchi H, Pentheroudakis G, Yamazaki K,
Xu RH, et al. Pan-Asian adapted ESMO consensus guidelines for the
management of patients with metastatic colorectal cancer: a JSMO-ESMO
initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol
2018;29:44–70.
13. Nishina T, Moriwaki T, Shimada M, Higashijima J, Sakai Y, Masuishi T,
et al. Uracil-Tegafur and oral Leucovorin combined with bevacizumab inelderly patients (aged >/= 75 years) with metastatic colorectal cancer: aMulticenter, phase II trial (joint study of bevacizumab, oral Leucovorin,
and uracil-Tegafur in elderly patients [J-BLUE] study). Clin Colorectal
Cancer 2016;15:236–42.
14. Mizushima T, Tamagawa H, Matsuda C, Murata K, Fukunaga M, Ota
H, et al. Phase II study of oral Tegafur/uracil and Leucovorin plus
bevacizumab as a first-line therapy for elderly patients with advanced ormetastatic colorectal cancer. Oncology 2015;89:152–8.
15. Yoshida M, Muro K, Tsuji A, Hamamoto Y, Yoshino T, Yoshida K,
et al. Combination chemotherapy with bevacizumab and S-1 for elderly
patients with metastatic colorectal cancer (BASIC trial). Eur J Cancer
2015;51:935–41.
16. Rostoft S, O’Donovan A, Soubeyran P, Alibhai SMH, Hamaker
ME. Geriatric assessment and Management in Cancer. J Clin Oncol
2021;39:2058–67.
17. Soto-Perez-de-Celis E, Li D, Yuan Y, Lau YM, Hurria A. Functional versus
chronological age: geriatric assessments to guide decision making in older
patients with cancer. Lancet Oncol 2018;19:e305–e16.

Downloaded from https://academic.oup.com/jjco/advance-article/doi/10.1093/jjco/hyac073/6573953 by Tsukuba Univ user on 26 April 2022

Study concepts: T. Moriwaki; Study design: T. Moriwaki and
I.Hyodo; data acquisition: all authors; quality control of data
and algorithms: T. Moriwaki and T. Nishina; Data analysis andinterpretation: T. Moriwaki, T. Nishina, I. Hyodo; statistical analysis:
T. Moriwaki; manuscript preparation: T. Moriwaki; manuscript
editing: T. Nishina, I. Hyodo; Manuscript review: All authors;
Approval of Final Article: All authors.

910

Age and outcomes in older CRC patients

25. Hurria A, Mohile S, Gajra A, Klepin H, Muss H, Chapman A, et al.
Validation of a prediction tool for chemotherapy toxicity in older adults
with cancer. J Clin Oncol 2016;34:2366–71.
26. Hurria A, Togawa K, Mohile SG, Owusu C, Klepin HD, Gross CP, et al.
Predicting chemotherapy toxicity in older adults with cancer: a prospective
multicenter study. J Clin Oncol 2011;29:3457–65.
27. Yamanaka T, Matsumoto S, Teramukai S, Ishiwata R, Nagai Y,
Fukushima M. Safety evaluation of oral fluoropyrimidine S-1 for shortand long-term delivery in advanced gastric cancer: analysis of 3,758
patients. Cancer Chemother Pharmacol 2008;61:335–43.
28. Walko CM, Lindley C. Capecitabine: a review. Clin Ther 2005;27:23–44.
29. Gieschke R, Reigner B, Blesch KS, Steimer JL. Population pharmacokinetic analysis of the major metabolites of capecitabine. J Pharmacokinet
Pharmacodyn 2002;29:25–47.
30. Hamaguchi T, Takashima A, Mizusawa J, Shimada Y, Nagashima F, Ando
M, et al. A randomized phase III trial of mFOLFOX7 or CapeOX plus
bevacizumab versus 5-FU/l-LV or capecitabine plus bevacizumab as initial
therapy in elderly patients with metastatic colorectal cancer: JCOG1018
study (RESPECT). J Clin Oncol 2022;40:10.
31. Garcia MV, Agar MR, Soo WK, To T, Phillips JL. Screening tools for
identifying older adults with cancer who may benefit from a geriatricassessment: a systematic review. JAMA Oncol 2021;7:616–27.
32. Decoster L, Van Puyvelde K, Mohile S, Wedding U, Basso U, Colloca G,
et al. Screening tools for multidimensional health problems warranting
a geriatric assessment in older cancer patients: an update on SIOG
recommendationsdagger. Ann Oncol 2015;26:288–300.

Downloaded from https://academic.oup.com/jjco/advance-article/doi/10.1093/jjco/hyac073/6573953 by Tsukuba Univ user on 26 April 2022

18. Flannery MA, Culakova E, Canin BE, Peppone L, Ramsdale E, Mohile SG.
Understanding treatment tolerability in older adults with cancer. J Clin
Oncol 2021;39:2150–63.
19. Moriwaki T, Sakai Y, Ishida H, Yamamoto Y, Endo S, Kuramochi H, et al.
Phase II study of S-1 on alternate days plus bevacizumab in patients aged>/= 75 years with metastatic colorectal cancer (J-SAVER). Int J Clin Oncol
2019;24:1214–22.
20. Kohne CH, Cunningham D, Di Costanzo F, Glimelius B, Blijham G,
Aranda E, et al. Clinical determinants of survival in patients with 5fluorouracil-based treatment for metastatic colorectal cancer: resultsof a multivariate analysis of 3825 patients. Ann Oncol 2002;13:308–17.
21. Chibaudel B, Bonnetain F, Tournigand C, Bengrine-Lefevre L, Teixeira L,
Artru P, et al. Simplified prognostic model in patients with oxaliplatinbased or irinotecan-based first-line chemotherapy for metastatic colorectal
cancer: a GERCOR study. Oncologist 2011;16:1228–38.
22. Song A, Eo W, Lee S. Comparison of selected inflammation-based prognostic markers in relapsed or refractory metastatic colorectal cancer
patients. World J Gastroenterol 2015;21:12410–20.
23. Liu Z, Xu Y, Xu G, Baklaushev VP, Chekhonin VP, Peltzer K, et al.
Nomogram for predicting overall survival in colorectal cancer with distantmetastasis. BMC Gastroenterol 2021;21:103.
24. Ostwal V, Ramaswamy A, Bhargava P, Hatkhambkar T, Swami R, Rastogi
S, et al. Cancer aging research group (CARG) score in older adults
undergoing curative intent chemotherapy: a prospective cohort study.
BMJ Open 2021;11:e047376.

Original research

Proportion attributable to contextual effects ingeneral medicine: a meta-­epidemiological study
based on Cochrane reviews
Yusuke Tsutsumi ‍ ‍,1,2 Yasushi Tsujimoto,3,4 Aran Tajika,5Kenji Omae,3,6 Tomoko Fujii,7,8 Akira Onishi,9 Yuki Kataoka,3,10
Morihiro Katsura,11 Hisashi Noma,12 Ethan Sahker,7,13
Edoardo Giuseppe Ostinelli,14 Toshi A Furukawa7
10.1136/bmjebm-2021-111861►► Additional supplemental

material is published online
only. To view, please visit
the journal online (http://​dx.​doi.​org/​10.​1136/​
bmjebm-​2021-​111861).
For numbered affiliations see
end of article.

Correspondence to:
Dr Yusuke Tsutsumi, Kyoto
University, Kyoto, Japan; ​tsutsumi.​yusuke.​84x@​st.​kyoto-​u.​ac.​jp© Author(s) (or theiremployer(s)) 2023. Re-­use
permitted under CC
BY-­NC. No commercial
re-­use. See rights andpermissions. Publishedby BMJ.
To cite: Tsutsumi Y,
Tsujimoto Y, Tajika A,
et al. BMJ Evidence-­Based
Medicine 2023;28:40–47.

40

Abstract
Objectives Our objectives were to examine
the magnitude of the proportion attributable
to contextual effects (PCE), which shows what
proportion of the treatment arm response canbe achieved by the placebo arm across various
interventions, and to examine PCE variability byoutcome type and condition.
Design We conducted a meta-­epidemiologicalstudy.
Setting We searched the Cochrane Database of
Systematic Reviews with the keyword ‘placebo’ intitles, abstracts and keywords on 1 January 2020.
Participants We included reviews that showedstatistically significant beneficial effects of theintervention over placebo for the first primary
outcome.
Main outcome measures We performed a random-­
effects meta-­analysis to calculate PCEs based on
the pooled result of each included review, groupedby outcome type and condition. The PCE quantifies
how much of the observed treatment response canbe achieved by the contextual effects.
Public and patient involvement statement No
patient or member of the public was involved in
conducting this research.
Results We included 328 out of 3175 Cochranesystematic reviews. The results of meta-­analyses
showed that PCEs varied greatly depending on
outcome type (I2=98%) or condition (I2=98%), but
mostly lie between 0.40 and 0.95. Overall, thePCEs were 0.65 (95% CI 0.59 to 0.72) on average.
Subjective outcomes were 0.50 (95% CI 0.41 to0.59), which was significantly smaller than thoseof semiobjective (PCE 0.78; 95% CI 0.72 to 0.85)
or objective outcomes (PCE 0.94; 95% CI 0.91 to0.97).
Conclusions The results suggest that much of
the observed benefit is not just due to the specificeffect of the interventions. The specific effects ofinterventions may be larger for subjective outcomesthan for objective or semiobjective outcomes.
However, PCEs were exceptionally variable. When
we evaluate the magnitude of PCEs, we should
consider each PCE individually, for each condition,intervention and outcome in its context, to assess
the importance of an intervention for each specificclinical setting.

BMJ Evidence-­Based Medicine February 2023 | volume 28 | number 1 |WHAT IS ALREADY KNOWN ON THISTOPIC⇒⇒ Although the proportion attributable
to contextual effects (PCE) is highly
important to interpreting the resultsof clinical trials and selecting theappropriate treatment in the clinicalsetting, a comprehensive review ofPCEs among several outcome types
and conditions was not yet available.
WHAT THIS STUDY ADDS⇒⇒ This study showed that the overall PCE

was 0.65 (95% CI 0.59 to 0.72).

⇒⇒ The PCE of subjective outcomes was

0.50 (95% CI 0.41 to 0.59), whilethat of semiobjective and objective
outcomes were 0.78 (95% CI 0.72 to0.85) and 0.94 (95% CI, 0.91 to 0.97),
respectively.

HOW THIS STUDY MIGHT AFFECTRESEARCH, PRACTICE AND/OR POLICY⇒⇒ The results suggest that much of theobserved benefits in clinical trials
are actually due to factors other thanspecific intervention effects. A smaller
PCE may indicate that the effect ofinterventions on subjective outcomesis larger than on different types ofoutcomes.
⇒⇒ We should consider each PCE
individually, for each condition,intervention and outcome in its
context, to assess the importanceof an intervention for each specificclinical setting.

Introduction
Placebo has long been used as a dummy treatment in control groups of randomised controlled
trials (RCTs) to control for non-­specific factors.1 2
Improvement seen in the intervention group (treatment response) can often be seen in the placebogroup and is understood to be due to three contextual effects: the placebo effect, the natural courseof the disease or regression to the mean.3 While theOriginal research
nature and degree of the placebo effect itself have been controversial,4–6 assessing the amount of response due to contextual effects
helps to explain the benefits specific to an intervention.
The proportion attributable to contextual effects (PCE) is ametric indicating what proportion of the treatment arm response
can be achieved by the placebo arm. Response may be beneficial
for a dichotomous outcome (eg, survival, remission) or a beneficial
change for a continuous outcome (eg, reduction in pain, increasein quality of life (QoL)). Therefore, the PCE corresponds with thecontextual effects (placebo effect +natural course +regression
to the mean) divided by the intervention arm response (specificeffect +placebo effect +natural course +regression to the mean).
The PCE ranges from 0 to 1. A score of 0 means that none of thetreatment response is due to the contextual effects. Conversely, a
PCE score of 1 means that all of the treatment response is due tothe contextual effects. A larger PCE reflects a larger contextual
effect, or a smaller specific effect of the intervention.7–9
An RCT usually focuses on the specific treatment effect, whichis the difference in the outcome between the treatment arm andthe placebo arm. However, in clinical practice, the overall treatment effect includes not only the specific treatment effect, butalso the contextual effects. As a result, a treatment that did notshow a large specific effect in an RCT, can still show a larger
response in clinical practice than a treatment with large beneficial contextual effects. This phenomenon is called the Efficacy
Paradox.10 Therefore, clinicians and patients should consider boththe overall treatment effect and the PCE to interpret clinical trials
properly and select appropriate treatments. A large PCE meansthat a large amount of response seen in patients receiving thetreatment can also be seen in patients without receiving the active
intervention. Some studies have shown that the PCE might reach
0.65–0.75.11 12 However, there has been no systematic attempt toreview PCEs across various current healthcare interventions.
In this study, we examine the magnitude of PCEs. This will
inform how much of an intervention’s beneficial effect can beachieved by the contextual effects. In addition, we evaluate PCE
variability by outcome type and condition when contextual effects
also show a beneficial effect. To achieve this, we systematicallysurveyed all relevant Cochrane reviews, calculated the PCEs in all
fields of medicine, and compared them by the outcome, conditionand degree of the certainty of evidence from existing reviews.

in the outcome equated to more beneficial changes. We excluded
initial reviews that had been updated (ie, we included only themost recent version), reviews of studies other than placebo-­
controlled trials (eg, sham-­controlled trials, non-­RCTs, diagnostic
test accuracy studies or prognostic studies), overviews of reviews
and methodological reviews. We extracted the numerical datafrom the forest plot of the first meta-­analysis. Therefore, we were
obliged to exclude reviews that did not show the forest plot of
their primary outcome.
Search strategy and study selection
We searched the Cochrane Database of Systematic Reviews withthe keyword ‘placebo’ in titles, abstracts and keywords on 1
January 2020 and selected all the available reviews, regardless ofthe publication date. Two authors independently performed theinitial screening of the titles and abstracts of all studies identified
by the search and examined the potential eligibility for inclusion. After initial screening, the same authors assessed the eligibility based on a full-­text review. Disagreements were resolved bydiscussion between the authors, with another author acting as anarbiter when necessary.

Data extraction
Two authors independently used a structured data extraction
form to collect data from the included studies. Differences wereresolved by consensus. We extracted the pooled RR, SE, and 95%
CI when the review reported RR. We extracted the pooled OR, SE,
95% CI and the average control event rate (CER) when the review
reported OR. When the review reported a mean difference (MD)of change scores, we extracted the change score and the numberof participants for the intervention and placebo arms separately.
When the review reported the standardised MD, we extracted thechange score of the outcome, SE and the number of participants
for the intervention and placebo arms separately.
In addition, we extracted the following information: thenumber of participants and trials in the meta-­
analysis of thefirst primary outcome, the sample size of intervention andplacebo arms, outcome data type (dichotomous or continuous),
outcome type, condition, intervention type (pharmacological ornon-­pharmacological), Cochrane review group and the Gradingof Recommendations Assessment, Development and Evaluation(GRADE) category of the outcome.
Methods
We categorised outcome types and conditions following the
We followed the published reporting guideline for a meta-­
categories used in previous studies.13–15 We modified the category
epidemiological study.13
of outcome types, in which we translated harmful outcomes into
equivalent beneficial outcomes (eg, from mortality to survival).
Eligibility criteria
We categorised outcome types as follows, following typologies
We included all systematic reviews (SRs) of randomised placebo-­
used in the literature.14–16
controlled trials published in the Cochrane Database of Systematic Reviews that showed statistically significant beneficial effectsof the intervention over placebo in the first primary outcome.
Objective outcome
We regarded a two-­tailed p<0.05 as statistically significant. We
Survival.
excluded interventions whose efficacy is not established because
it would be meaningless to examine PCEs for non-­beneficial
Semiobjective outcomesinterventions. When there were multiple comparisons for theNo major morbidity events, improved obstetric outcomes, lessfirst primary outcome due to multiple intervention arms in aresource use/shorter hospital stay, improved internal structure
review, we selected the first comparison. We included reviews that(structural outcome within the internal body such as radiographreported a risk ratio (RR) or an OR for dichotomous outcomes.
outcomes), improved external structure (structural outcomes which
We excluded reviews reporting other effect sizes, such as HRs
can be externally observed such as eczema), improved biologin survival analyses. For continuous outcomes, we were able toical markers, no unpleasant composite endpoint, no composite
calculate PCE only when: (1) the meta-­analysis reported change
mortality/morbidity events, less drop-­out from the treatment, noscores, (2) the weighted mean of both intervention and control
adverse events and othersarm showed the same direction of change and (3) larger changes
BMJ Evidence-­Based Medicine February 2023 | volume 28 | number 1 |41

Original research
Subjective outcomes
Pain relief, QoL improvement, mental health improvement, lessconsumption/satisfaction with care, cure of condition, no newsigns of infection/disease and others
We categorised conditions as follows14–16: cardiovascular,
central nervous system/musculoskeletal, digestive system,
infectious disease, mental health and behavioural conditions,obstetrics and gynaecology, respiratory disease, urogenital andothers.

Statistical analyses
The definition of beneficial and harmful outcome measures
Some reviews used an outcome measure in which the higher
number of events is better (eg, survival), while others examined the same outcome but used the opposite measure in which
the lower number of events is better (eg, death). We defined theoutcome measure in which the higher number of events is betteras a beneficial outcome and the outcome measure in which thelower number of events is better as a harmful outcome.

Calculation of the CE for each intervention over placebo
We defined and calculated the PCE to designate how much of thebeneficial outcome observed in the intervention group is realisedin the placebo group. We assumed the independence between thespecific treatment effect and the contextual effects.
Beneficial dichotomous outcomes
When the meta-­analysis reported an RR for a beneficial outcome(RR >1 expected), we defined the PCE as follows:

	﻿‍

‍

(1)

where the CER refers to the proportion of outcome events inthe placebo group, and the experimental event rate (EER) refers to
the proportion of outcome events in the intervention group. We
calculated PCE as the inverse of the pooled RR.
When the meta-­analysis reported an OR, we first converted the
OR to an RR using the average CER obtained in the meta-­analysis:

	﻿‍

‍

(2)

PCE was then calculated using the RR according to the formulaContinuous outcomes
We define the PCE for the continuous outcome as follows inaccordance with a previous study.7

	﻿‍

(4)
‍

In this study, we calculated the mean change score of each arm
based on multiple studies rather than a single study. Therefore, wefirst calculated the standardised weighted change score means forboth the intervention and placebo arms by meta-­analysis, using
the DerSimonian-­Laird method for continuous outcomes.17
The PCE was then calculated as:

	﻿‍

‍

(5)

The conditions to calculate PCEs by formula (5) were thatboth groups showed the same direction of change (same positiveor negative direction), and the change in the treatment group
was greater than the change in the placebo group. Therefore,
we excluded Cochrane reviews when the weighted mean of theintervention and control arms did not show the same direction of change or when the weighted standardised mean change
score of the placebo arm was greater than that of the intervention arm.
To construct the CI of PCE, the ordinary Wald-­type CI is unsuitable for the original scale because PCE is a ratio measure andusually has an asymmetric sample distribution. Thus, we adopted
the approximate CI for log-­transformed PCE. Using the Deltamethod, we obtained the SE estimator of the log(PCE) as follows18:

	﻿‍

‍

(6)

where SE [log(PCE)] was the SE of log(PCE), SEintervention andSEplacebo represent the SE of the weighted change score meansof the intervention and placebo arms, respectively. WSMintervenand WSMplacebo were the weighted standardised change scoretion
means of the intervention and placebo arms, respectively. The
weighted standardised means were defined as pooled summaries
of standardised mean change scores from the intervention andplacebo arms of individual studies. The weights were defined by
the corresponding meta-­analysis methods. We could then obtain
the Wald-­type 95% CI for log(PCE) by the conventional normal
approximation.19 The 95% CI of PCE can be calculated by back-­transformation (exponential transformation) of the confidence
limits.

(1).
Harmful dichotomous outcomes
When the meta-­analysis reported an RR for a harmful outcome,we converted the RR to an OR using the CER:

	﻿‍

‍

(3)

Then we converted the OR of harmful outcomes to that of beneficial outcomes. For example, ORs for mortality were converted to
ORs for survival, taking the inverse of the OR. Finally, we calculated the PCE using formulae (2) and (1).
When the meta-­analysis reported an OR, we took the inverseof the OR to represent the OR for a beneficial outcome. Then we
calculated the PCE using formulae (2) and (1).
For RRs and ORs, we calculated the 95% CI and SEs of the
PCE using a formula for the variance estimators of log(RR) andlog(OR), respectively. For dichotomous outcomes, the PCE meansthat the probability, given an individual had a positive outcome
after treatment, would also have had a positive outcome after
placebo.

42

Meta-analyses of PCEs
We pooled the logarithm-­transformed PCEs for each outcome
type, condition and GRADE category, using the DerSimonian-­
Laird method.17 We performed all analyses using meta (V.4.15–1)
package of R V.4.0.0.20 21

Changes from the protocol
The study protocol was uploaded to the Department of Health
Promotion and Human Behaviour website, Kyoto University Graduate School of Medicine/School of Public Health (http://ebmh.​
med.kyoto-u.ac.jp/r-meta.html, attached as online supplemental
file 1) on 4 September 2018. Changes to the protocol are listed in
online supplemental file 2, and all were minor.

Patient and public involvement
No patient or member of the public was involved in conducting
this research.

BMJ Evidence-­Based Medicine February 2023 | volume 28 | number 1 |Original research
Conditions
Figure 3 shows the PCE by condition. PCEs ranged widely from
0.40 in ‘anaesthesia’ to 0.89 in ‘cardiovascular disease’ (I2=98%).
Online supplemental figure S3 and S4 present the results fordichotomous and continuous outcomes separately.
Grade categories
Among 156 Cochrane reviews that had reported a GRADE in thesummary of findings table, the PCEs did not appear to be appreciably influenced by the certainty of evidence (online supplemental
figure S5, I2 = 54%). Online supplemental figures S6 and S7
present these results for dichotomous and continuous outcomesseparately.

Discussion
Figure 1 The flow chart for study selection. PCE, proportion attributable
to contextual effect.

Results
Selected studies
Figure 1 shows the flowchart for study selection. The initial search
identified 3175 Cochrane reviews, from which we excluded 2847
for reasons seen in figure 1. The final selection included 328
reviews. Of these, 282 reviews represent 1755 trials, with 2 625
184 participants reporting dichotomous outcomes. The remaining
46 reviews represent 259 trials, with 42 156 participants reporting
continuous outcomes.
Over half of the reviews were published within the past 10
years. Approximately 70% of the included reviews reported
subjective outcomes. Mental health and behaviour conditions
was the most popular condition (table 1). Online supplemental
file 3 shows all included SRs and their outcomes, conditions
and PCEs calculated from the results of the meta-­analysis fromeach review. For example, Bennett et al22 examined the effect oftranexamic acid on mortality for upper gastrointestinal bleeding.
They reported an RR of 0.6. The CER for mortality was 8.4% andconverted to a positive outcome CER for survival at 91.6%. The
EER of survival was 95.0%. Dividing the CER of survival by the
EER of survival gives a PCE of 0.96. By contrast, Derry et al23
examined the effect of ibuprofen plus codeine for acute postoperative pain and showed an RR of 4.1. Their CER for a 50% reduction of maximum pain was 18.0%, and the EER was 64.0%. Thus,
the calculated PCE was 0.24.

PCEs by outcome types, conditions and GRADE categories
Outcome types
We first pooled PCEs across all outcome types, including bothdichotomous and continuous outcomes (figure 2, table 2). The
pooled PCE across all outcomes was 0.65 (95% CI 0.59 to 0.72).
When the outcome types were divided into subgroups, objective
outcomes showed a PCE of 0.94 (95% CI 0.91 to 0.97), which was
higher than that of semiobjective outcomes (PCE 0.78; 95% CI
0.72 to 0.85, I2=90%) and subjective outcomes (PCE 0.50; 95%
CI 0.41 to 0.59, I2=99%). The PCE of typical patient-­
reportedoutcomes such as pain, QoL, and mental health outcomes ranged
between 0.44 and 0.74.
We next pooled PCEs across all outcome types when theoutcomes were dichotomous (online supplemental figure S1) orcontinuous (online supplemental figure S2).

Key findings
Based on 328 Cochrane reviews representing 2014 trials and 2
667 340 participants, the overall PCE for various interventions incontemporary medicine was 0.65 (0.59 to 0.72). PCEs ranged from
0.28 to 0.94. The subjective outcomes showed lower PCEs thanobjective or semiobjective outcomes. They also varied dependingon the condition. GRADE ratings did not appear to influence PCEs.
These results suggest that PCEs should be considered according tothe outcome type and condition when interpreting study results
and determining the importance of interventions.
Comparisons with the previous literature
As previously stated, there is no study examining the PCE of
several semiobjective outcomes. In our study, PCEs of the objective and semisubjective outcomes were mostly larger than 0.70.
Several studies have reported PCEs for patient-­reported outcomesin the literature. One study revealed a PCE of 0.72 for pain among
burning mouth syndrome patients,24 while another showed a PCE
of 0.82 for antidepressant trials for depression.25 When we examined PCEs for various patient-­reported outcomes and conditions,the average PCE seemed to lie in the medium range between 0.40
and 0.75, which was lower than those reported in previous studies.
The effects of the intervention on the subjective outcomes may belarger than those for the other types of outcomes. Previous studies
suggest larger placebo effects for subjective outcomes than for
objective outcomes.6 26 These findings are in line with the current
findings of contextual effects. This is because, regardless of themagnitude of the placebo effect, PCEs represent the proportion of
the contextual effects of the improvements observed in the active
intervention arm.
Clinical interpretations
The contextual effects have been known to contribute to the treatment response.10 27 However, the magnitude of PCEs had not been
examined in detail or quantified in the literature until this study.
Our study presented the average PCEs across outcome types andconditions.
We found that subjective outcomes, including typical patient-­
reported outcomes such as pain, QoL, and mental health outcomes,
showed PCEs of 0.44–0.74. This may reflect the fact that the specificintervention effect seen in subjective outcomes are likely to be ofmoderate magnitude and clinically important. On the other hand,‘hard’ outcomes, including survival or morbidity events, showed
PCEs above 0.80 or even 0.90. We assume PCEs seen in objective
and semiobjective outcomes may reflect the fact that the natural
disorder course plays a strong role in those outcomes. It would

BMJ Evidence-­Based Medicine February 2023 | volume 28 | number 1 |43

Original research
Table 1

Characteristics of included studies
Dichotomous outcome(n=282)

Continuous outcome(n=46)

No of included primary studies per meta-­analysis, median (IQR)

4 (2–7)

4 (3–7)

No of included participants per meta-­analysis, median (IQR)

557 (283–1490)

511 (229–1094.5)

Years of publication (%)

0 (0)1998–2000

14 (5.0)

2001–200527 (9.6)

10 (21.7)

2006–201057 (20.2)

7 (15.2)

2011–2015

101 (35.8)

12 (26.1)

2016–201983 (29.4)

17 (37.0)

Survival

7 (2.5)0 (0)Outcome type (%) Objective outcome Semiobjective outcomes 

No major morbidity event

14 (5.0)0 (0)Less drop-­outs from the treatment

11 (3.9)

0 (0)
0 (0)

Improved obstetric outcomes

9 (3.2)Less resource use/shorter hospital stay

9 (3.2)0 (0)Improved internal structure

5 (1.8)2 (4.3)

Improved biological markers

4 (1.4)6 (13.0)

Improved external structure

4 (1.4)1 (2.2)No unpleasant composite endpoint

4 (1.4)0 (0)No adverse events

3 (1.1)0 (0)No composite mortality/morbidity events

0 (0)

0 (0)

Others (semiobjective)

1 (0.4)6 (13.0) Subjective outcomes
 
 

 

Pain relief

72 (25.5)

9 (19.6)

Cure of condition

71 (25.2)

4 (8.7)12 (26.1)

Mental health outcomes improvement

35 (12.4)

No new signs of infection/disease

17 (6.0)0 (0.0)Quality of life

13 (4.6)

6 (13.0)

Less consumption, satisfaction with care

1 (0.4)0 (0.0)

Others (Subjective)

2 (0.7)0 (0.0)Conditions (%)

GRADE category (%)*

Mental health and behavioural conditions

56 (19.9)

12 (26.1)

Anaesthesia

48 (17.0)

3 (6.5)Central nervous system/ musculoskeletal

47 (16.7)

7 (15.2)

Digestive system

29 (10.3)

0 (0)Infectious disease

26 (9.2)

1 (2.2)

Respiratory disease

19 (6.7)

3 (6.5)

Obstetrics and gynaecology

16 (5.7)

2 (4.3)

Cardiovascular

12 (4.3)

7 (15.2)

Urogenital

7 (2.5)4 (8.7)

Others22 (7.8)

7 (15.2)

High35 (25.9)2 (9.5)Moderate

53 (39.3)

5 (23.8)Low

36 (26.7)

13 (61.9)

Very low

11 (8.1)

1 (4.8)*A total of 147 dichotomous outcomes and 25 continuous outcomes did not report the GRADE category in their summary of findings table.
GRADE, Grading of Recommendations Assessment, Development and Evaluation.

be relatively difficult for an intervention to show large effects inthese ‘hard’ outcomes.
The pooled estimates are approximate indicators of how much
PCE we can expect for each subgroup. However, the average PCEs
are only a rough guide, and a starting point for clinical evaluation of an intervention effect. Generally, the higher the PCE,
the greater the contextual effects. Therefore, watchful waiting or
careful observation with follow-­ups may be a reasonable choice,44

rather than an active intervention, because much of the benefit
can be expected from the placebo intervention. However, thisgeneral judgement should be tempered by the gravity of theoutcome (eg, a small decrease in death may be as valuable asor even more valuable than a large decrease in some non-­life-­
threatening consequences) and the burdens (side-­effects and costs)of the alternative treatments. Moreover, our study revealed that
PCEs were highly heterogeneous. We must consider the individual

BMJ Evidence-­Based Medicine February 2023 | volume 28 | number 1 |Original research

Figure 3 The proportion attributable to contextual effects (PCE) byconditions (dichotomous and continuous outcomes combined).

Figure 2 The proportion attributable to contextual effects (PCE) byoutcome type (continuous and dichotomous outcomes combined)

condition, intervention and outcome when we evaluate the clinical significance of the PCE.
We also found that PCEs were diverse over several conditions,partly reflecting outcome types commonly used in each condition. For example, the PCEs of cardiovascular disease, infectious
disease, and respiratory disease were over 0.80. Trials examining
these conditions usually select objective or semiobjective outcomessuch as survival, major morbidity, composite endpoints or severityof symptoms as the primary outcome. In fact, 30 of 68 included
reviews among these conditions reported objective or semiobjective outcomes. On the other hand, conditions with subjective main
outcomes, such as pain, mental health or behaviour conditions,showed moderate PCEs.
Additionally, we found no remarkable diversity of PCEs
depending on the GRADE category. However, over half of the
included reviews did not report the GRADE category with asummary of findings table of their first primary outcome, which
led to the loss of power in this analysis. We also found that out of
328 Cochrane reviews, 282 reported a dichotomous outcome, suchas mortality, as their first primary outcome, and we were only
able to identify 46 Cochrane reviews with a primary continuous
outcome reported first.
Strengths and limitations
There are some weaknesses to our study. First, we calculated a
PCE as the proportion of the contextual effects over the intervention response for a beneficial outcome. This might appear
Table 2

counterintuitive when discussing effects on harmful outcome,such as mortality. However, we must note that this proportion fora beneficial outcome is exactly what the PCE means. When something good happens (eg, survival, symptom improvement), we ask
how much of this good outcome would have happened without
the intervention (ie, it can be explained by the contextual effects).
Second, we were unable to calculate PCE when the intervention
showed improvement from baseline while the placebo group
showed deterioration, or when the intervention showed deterioration while the placebo group showed greater deterioration. Thismay have led to overestimation or underestimation of PCE. Thiswas inevitable, given the definition of PCE above. We wanted toquantify when something good happens following treatment andhow much of that good could happen without the intervention.
Third, there is intrinsic heterogeneity among outcomes belonging
to the same type (eg, morbidity event) or used in the same condition (eg, respiratory disease). Each outcome may have different
clinical importance depending on the context. Because PCE is arelative measure, the CER may also influence the absolute benefit.
In other words, the absolute benefit is larger for events with large
CERs, and smaller for events with smaller CERs for a given PCE.
Therefore, each PCE of an intervention must be interpreted in its
specific context and, ultimately, under each patient’s preferencesand values. However, it is scientifically meaningful to know theoverall averages even when the apparent heterogeneity may behigh. Fourth, measurement errors (random errors) are larger for
subjective outcomes than semiobjective or objective outcomes.
How such measurement errors may have contributed to the estimates of PCEs is not straightforward. However, by pooling acrossSRs, the overall averages would be less affected by such random
errors. Fifth, our study calculated PCEs by outcome types andconditions independently. PCE is highly dependent on both thecondition and outcome. For example, the PCE for pain in ‘cardiovascular’ may be larger than that in ‘mental health and behavioural conditions’ because the pain in cardiovascular is more likely

The proportion attributable to contextual effects by outcome type
Outcome category

Outcome type

All

All

Dichotomous

Continuous

Objective

0.94 (0.91 to 0.97)
(NA)

NA

0.94 (0.91 to 0.97)(NA)

Semiobjective

0.81 (0.75 to 0.87)(0.64 to 1.00)

0.54 (0.38 to 0.77)(0.15 to 1.00)

0.78 (0.72 to 0.85)(0.60 to 1.00)

Subjective

0.49 (0.41 to 0.59)(0.26 to 0.94)

0.60 (0.54 to 0.66)(0.46 to 0.79)

0.50 (0.41 to 0.59)(0.26 to 0.94)

0.67 (0.61 to 0.74)(0.45 to 0.99)

0.59 (0.53 to 0.66)(0.47 to 0.75)

0.65 (0.59 to 0.72)(0.44 to 0.97)(Parentheses) show 95% CIs, and (brackets) show 95% prediction intervals.
NA, not applicable.

BMJ Evidence-­Based Medicine February 2023 | volume 28 | number 1 |45

Original researchdue to an organic cause. Finer subgroup analyses examining theirinteractions were impossible in the current study, as we had too
many subgroups, but this would be desirable for future research.
Finally, the specific and contextual effects are not independent ofeach other but may interact with each other when, for example,
the side effects of the intervention may enhance the non-­specificeffects.28 Thus, the same outcome for the same disease may show
different PCEs depending on the intervention. We did not haveenough variability in the interventions in our dataset to appreciatesuch interactions. Further research would be warranted to clarify
the nature and degree of the relationships between specific effects
and contextual effects.
Our study also has several strengths. First, to the best of ourknowledge, this is the first study to examine PCEs comprehensively
across outcome types and conditions. Second, our study is basedon Cochrane reviews which are considered the best resources ofevidence. We searched all the Cochrane reviews that had reported
the results of head-­to-­head meta-­analyses of interventions against
placebo. We pooled these meta-­analyses to calculate the PCEs byoutcome type, condition and GRADE category.

Conclusions
In conclusion, our study showed that the overall PCE was 0.65
(95% CI 0.59 to 0.72). PCEs were smaller for subjective outcomesthan for objective or semiobjective outcomes. The results suggestthat much of the observed benefit is actually due to factors
including the placebo effect, the natural course of the disease, andregression to the mean, rather than just the specific effect of theinterventions. Specific effects of interventions may be larger for
subjective than for objective or semiobjective outcomes. However,
PCEs were exceptionally variable. When we evaluate the magnitude of PCEs, we should consider each PCE individually, for eachcondition, intervention and outcome in its context, to assess theimportance of an intervention for each specific clinical setting.
Author affiliations
1
Human Health Sciences, Kyoto University Graduate School of Medicine,
Kyoto, Japan2
Department of Emergency Medicine, National Hospital Organization Mito
Medical Center, Ibaraki, Japan3
Department of Healthcare Epidemiology, Kyoto University Graduate
School of Medicine/ School of Public Health, Kyoto, Japan
4
Department of Nephrology and Dialysis, Kyoritsu Hospital, Kawanishi,Japan
5
Department of Psychiatry, Kyoto University Hospital, Kyoto, Japan
6
Department of Innovative Research and Education for Clinicians andTrainees (DiRECT), Fukushima Medical University Hospital, Fukushima,Japan
7
Department of Health Promotion and Human Behavior, Kyoto University
Graduate School of Medicine / School of Public Health, Kyoto, Japan
8
Intensive Care Unit, Jikei University Hospital, Tokyo, Japan
9
Department of Rheumatology and Clinical Immunology, Kobe University
Graduate School of Medicine, Hyogo, Japan10
Hospital Care Research Unit/ Department of Respiratory Medicine,
Hyogo Prefectural Amagasaki General Medical Center, Hyogo, Japan
11
Department of Surgery, Okinawa Chubu Hospital, Okinawa, Japan
12
Department of Data Science, The Institute of Statistical Mathematics,
Tokyo, Japan
13
Population Health and Policy Research Unit, Medical Education Center,
Kyoto University Graduate School of Medicine, Kyoto, Japan
14
Oxford Health NHS Foundation Trust, Warneford Hospital /Departmentof Psychiatry, University of Oxford, Oxford, UK

Contributors YTsut, YTsuj, AT and TAF developed theconception and design of the research. YTsut and TAF are fully46

responsible for writing the protocol. YTsut, YTsuj, AT, KO, TF,
AO, YK, MK, ES, EGO extracted the data. YTsut analysed thedata. HN supervised the statistical analyses. TAF supervised theresearch. All authors contributed to draft the manuscript andgave final approval of the manuscript before submission. TAF is
the guarantor of the study.
Funding The authors have not declared a specific grant for thisresearch from any funding agency in the public, commercial ornot-­for-­profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public
were not involved in the design, or conduct, or reporting, ordissemination plans of this research.
Patient consent for publication Not applicable.
Provenance and peer review Not commissioned; externally peer
reviewed.
Data availability statement All data relevant to the study
are included in the article or uploaded as online supplemental
information.
Supplemental material This content has been supplied by
the author(s). It has not been vetted by BMJ Publishing Group
Limited (BMJ) and may not have been peer-­reviewed. Any
opinions or recommendations discussed are solely those of
the author(s) and are not endorsed by BMJ. BMJ disclaims all
liability and responsibility arising from any reliance placedon the content. Where the content includes any translatedmaterial, BMJ does not warrant the accuracy and reliability ofthe translations (including but not limited to local regulations,clinical guidelines, terminology, drug names and drug dosages),and is not responsible for any error and/or omissions arisingfrom translation and adaptation or otherwise.
Open access This is an open access article distributed inaccordance with the Creative Commons Attribution Non
Commercial (CC BY-­NC 4.0) license, which permits others to
distribute, remix, adapt, build upon this work non-­commercially,and license their derivative works on different terms, provided
the original work is properly cited, appropriate credit is given,
any changes made indicated, and the use is non-­commercial.
See: http://creativecommons.org/licenses/by-nc/4.0/.
ORCID iD
Yusuke Tsutsumi http://orcid.org/0000-0002-9160-0241
References
1 Beecher HK. The powerful placebo. J Am Med Assoc 1955;159:1602–6.
2 Blease CR, Bishop FL, Kaptchuk TJ. Informed consent and clinical trials:
where is the placebo effect? BMJ 2017;356:j463.
3 Kirsch I. The placebo effect revisited: lessons learned to date. Complement
Ther Med 2013;21:102–4.
4 Espay AJ, Norris MM, Eliassen JC, et al. Placebo effect of medication
cost in Parkinson disease: a randomized double-­blind study. Neurology
2015;84:794–802.
5 Kaptchuk TJ, Kelley JM, Conboy LA, et al. Components of placebo effect:
randomised controlled trial in patients with irritable bowel syndrome. BMJ
2008;336:999–1003.
6 Hróbjartsson A, Gøtzsche PC. Placebo interventions for all clinicalconditions. Cochrane Database Syst Rev 2010;1:CD003974.
7 Zou K, Wong J, Abdullah N, et al. Examination of overall treatment effectand the proportion attributable to contextual effect in osteoarthritis: meta-­
analysis of randomised controlled trials. Ann Rheum Dis 2016;75:1964–70.
8 Zhang W, Doherty M. Efficacy paradox and proportional contextual effect(PCE). Clin Immunol 2018;186:82–6.

BMJ Evidence-­Based Medicine February 2023 | volume 28 | number 1 |Original research
9 Zhang W, Zou K, Doherty M. Placebos for Knee Osteoarthritis:
Reaffirmation of "Needle Is Better Than Pill". Ann Intern Med
2015;163:392–3.
10 Walach H. Placebo Effects in Complementary and Alternative Medicine:
The Self- Healing Response. In: Colloca L, Arve MA, Meissner K, eds.
Placebo and pain. academic press. Elsevier, 2013: 189–202.
11 Kirsch I, Sapirstein G. Listening to Prozac but hearing placebo: a meta-­
analysis of antidepressant medication. Prev Treat 1998;1:2a.
12 Jonas WB, Crawford C, Colloca L, et al. To what extent are surgery andinvasive procedures effective beyond a placebo response? A systematic
review with meta-­analysis of randomised, sham controlled trials. BMJ
Open 2015;5:e009655.
13 Murad MH, Wang Z. Guidelines for reporting meta-­epidemiologicalmethodology research. Evid Based Med 2017;22:139–42.
14 Davey J, Turner RM, Clarke MJ, et al. Characteristics of meta-­analyses andtheir component studies in the Cochrane database of systematic reviews: across-­sectional, descriptive analysis. BMC Med Res Methodol 2011;11:160.
15 Rhodes KM, Turner RM, Higgins JPT. Predictive distributions weredeveloped for the extent of heterogeneity in meta-­analyses of continuous
outcome data. J Clin Epidemiol 2015;68:52–60.
16 Turner RM, Davey J, Clarke MJ, et al. Predicting the extent ofheterogeneity in meta-­analysis, using empirical data from the Cochrane
database of systematic reviews. Int J Epidemiol 2012;41:818–27.
17 DerSimonian R, Laird N. Chapter 10: meta-­analysis in clinical trials.
Controlled Clinical Trials 1986;7:177–88.

18 Oehlert GW. A note on the delta method. Am Stat 1992;46:27–9.
19 Cox DR, Hinkley DV, Statistics T. 1St ED. London. Chapman and Hall 1974.
20 Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-­analysis with
R: a practical tutorial. Evid Based Ment Health 2019;22:153–60.
21 R Core Team. R: a language and environment for statistical computing.
Vienna, Austria: R Foundation for Statistical Computing, 2020.
22 Bennett C, Klingenberg SL, Langholz E, et al. Tranexamic acid for uppergastrointestinal bleeding. Cochrane Database Syst Rev 2014:CD006640.
23 Derry S, Karlin SM, Moore RA. Single dose oral ibuprofen plus codeine
for acute postoperative pain in adults. Cochrane Database Syst Rev
2015;2:CD010107.
24 Kuten-­Shorrer M, Kelley JM, Sonis ST, et al. Placebo effect in burning
mouth syndrome: a systematic review. Oral Dis 2014;20:e1–6.
25 Kirsch I, Deacon BJ, Huedo-­Medina TB, et al. Initial severity andantidepressant benefits: a meta-­analysis of data submitted to the food anddrug administration. PLoS Med 2008;5:e45.
26 Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? an analysisof clinical trials comparing placebo with no treatment. N Engl J Med
2001;344:1594–602.
27 Shaibani A, Frisaldi E, Benedetti F. Placebo response in pain, fatigue, andperformance: possible implications for neuromuscular disorders. Muscle
Nerve 2017;56:358–67.
28 Flaten MA, Simonsen T, Olsen H. Drug-­Related information generates
placebo and nocebo responses that modify the drug response. Psychosom
Med 1999;61:250–5.

BMJ Evidence-­Based Medicine February 2023 | volume 28 | number 1 |47

diagnostics
ArticleIndividual Evaluation of the Common Extensor Tendon andLateral Collateral Ligament Improves the Severity Diagnostic
Accuracy of Magnetic Resonance Imaging for
Lateral Epicondylitis
Kazuhiro Ikeda 1,2, * , Takeshi Ogawa 3 , Akira Ikumi 2 , Yuichi Yoshii 4 , Sho Kohyama 1 , Reimi Ikeda 5
and Masashi Yamazaki 2
1

2

3

4

5

*

Citation: Ikeda, K.; Ogawa, T.; Ikumi,
A.; Yoshii, Y.; Kohyama, S.; Ikeda, R.;
Yamazaki, M. Individual Evaluationof the Common Extensor Tendon andLateral Collateral Ligament Improves
the Severity Diagnostic Accuracy of
Magnetic Resonance Imaging for
Lateral Epicondylitis. Diagnostics
2022, 12, 1871. https://doi.org/
10.3390/diagnostics12081871
Academic Editor: Antonio Barile
Received: 1 July 2022
Accepted: 29 July 2022

Department of Orthopedic Surgery, Kikkoman General Hospital, Noda 278-0005, Chiba, Japan;
sho_kohyama_1025@tsukuba-seikei.jp
Department of Orthopedic Surgery, Faculty of Medicine, University of Tsukuba,
Tsukuba 305-8577, Ibaraki, Japan; ikumi@tsukuba-seikei.jp (A.I.); masashiy@tsukuba-seikei.jp (M.Y.)
Department of Orthopedic Surgery, Mito Medical Center, Mito 311-3193, Ibaraki, Japan;
ogawat@tsukuba-seikei.jp
Department of Orthopedic Surgery, Tokyo Medical University Ibaraki Medical Center,Ami 300-0395, Ibaraki, Japan; yyoshii@tsukuba-seikei.jp
Department of Orthopedic Surgery, Moriya Daiichi General Hospital, Moriya 302-0102, Ibaraki, Japan;
r.ikeda0418@tsukuba-seikei.jp
Correspondence: ikdkzhr1129.med@gmail.com; Tel.: +81-09074199769

Abstract: The effectiveness of magnetic resonance imaging for diagnosing lateral epicondylitis
severity is controversial. We aimed to verify whether individual evaluations of the common extensor
tendon and lateral collateral ligament would improve the severity diagnostic accuracy of magnetic
resonance imaging for lateral epicondylitis. We obtained coronal images of the lateral elbow in threegroups: healthy, clinically mild, and clinically severe. We used our scoring system for evaluation
using combined and individual methods. We developed the receiver operating characteristic curvefor diagnosis using the scores of the healthy and mild groups and that for severity diagnosis using
the scores of the mild and severe groups. The scores, in decreasing value, were those of the severe,
mild, and healthy groups, with a significant difference in both methods. The curve for diagnosis
showed an area under the curve of 0.85 for the combined evaluation and 0.89 for the individual
evaluation, without a significant difference between the methods (p = 0.23). The curve for severity
diagnosis showed an area under the curve of 0.69 for combined and 0.81 for individual evaluation,with a significant difference between the methods (p = 0.046). Individual evaluation of the common
extensor tendon and lateral collateral ligament improved the severity diagnostic accuracy of lateralepicondylitis.

Published: 2 August 2022
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims in

Keywords: lateral epicondylitis; magnetic resonance imaging; severity diagnosis; diagnostic accuracy;
MRI; high-resolution MRI

published maps and institutional affiliations.

1. Introduction
Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms andconditions of the Creative Commons
Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Lateral epicondylitis (LE) is tendinopathy of the common extensor tendon (CET) of
the forearm [1,2], with an estimated prevalence of 1.1–4.9% in the general population [3–6].
Recent studies reported that the lateral collateral ligament (LCL) of the elbow was also
injured along with the CET in LE [7–9].
Imaging studies can detect this degeneration and damage to the CET/LCL complex;
ultrasonography and magnetic resonance imaging (MRI) are used in daily examinations.
Ultrasonography depicts edematous changes and degeneration at the CET/LCL complex
as hypointense changes or thickening, with a sensitivity rate of 64% and specificity rate ofDiagnostics 2022, 12, 1871. https://doi.org/10.3390/diagnostics12081871

https://www.mdpi.com/journal/diagnostics

Diagnostics 2022, 12, 1871

2 of 1382% [10]. However, the accuracy of ultrasonography depends on the examiner’s experience,
resulting in low inter-examiner reliability [11]. The true value of ultrasonography lies in
its simultaneous use in diagnosis and treatment, rather than its diagnostic ability alone.
Ultrasonography is used as an essential tool for LE in accurate injection therapy andpercutaneous needling [12–14].
Meanwhile, the validity of MRI for LE has been controversial. MRI of patients withLE shows high-signal changes in the CET/LCL complex reflecting degeneration or rupture [7,15,16]. Due to its excellent imaging quality, the inter-observer reliability is high [7,15].
However, the diagnosis of LE was based solely on physical examination findings [17,18].
MRI was only a supplemental examination for patients who had not responded to conservative treatment [1,17,19]. Although MRI is performed to diagnose pathogenesis and severity,
in addition, MRI reflects asymptomatic structural abnormalities and degeneration [20,21].
Because of this low specificity, some studies have reported a negative relationship between
MRI findings and clinical severity [22,23]. Conversely, more recent studies have reported
positively, as MRI resolution has improved [7,15]. Despite such conflicting results, comparing the literature has proven difficult because there is no method for standard quantitativeevaluation. For example, some papers evaluate the CET and the LCL together [23], whileothers evaluate them individually [7,15]. Furthermore, no studies have demonstrated theclinical validity for their MRI scoring. As a clinical indicator for LE, the validity of MRI
remained unknown.
Based on these findings, we felt the need to demonstrate the clinical validity of MRI in
the diagnosis of LE. We hypothesized that individual evaluation of the CET and the LCL
would contribute to the accuracy of the assessment of severity. This study aimed to verify
this hypothesis using high-resolution MRI.
2. Materials and Methods
2.1. Study Design and Participants
The study protocol conforms to the principles outlined in the 1964 Declaration of
Helsinki. The study was approved by the institutional review boards of the institutions
involved in this study: Mito Kyodo General Hospital (Study Number: 16–25, approved 7
September 2016) and Takahagi Kyodo General Hospital (Study Number: 10, approved 3
March 2021). We obtained written informed consent from all participating patients.
This was a case–control study. The inclusion criteria were LE patients with highresolution MRI in our hospital and healthy adults without any history of elbow disorder.
Exclusion criteria were a history of elbow trauma, elbow osteoarthritis (Kellgren–Lawrenceclassification 2 or higher), osteochondritis dissecans of the humeral capitellum, and rheumatoid arthritis. Our medical database identified 366 LE patients diagnosed from January 2013
to December 2020. We excluded 258 patients who did not undergo MRI, 7 patients withinappropriate MRI, and 1 patient with rheumatoid arthritis. We reviewed the electronic
medical records of the remaining 100 candidates and classified them according to theirclinical severity at the time of MRI; patients with a Nirschl phase rating scale of III or IV [18]were assigned to the clinically mild group (M group), and those with a score of V to VII
were assigned to the clinically severe group (S group). We included 100 LE patients, ofwhom 41 constituted the M group and 59 the S group. Moreover, we included 30 volunteers
for the healthy group (H group). The volunteers were medical coworkers in our hospital,
and we selected them to match the LE patients in gender and age. The subjects compriseda total of 130 cases (median age, 49 years; age range, 23–78; 64 males, 66 females) (Figure 1).

Diagnostics
2022,
1871 PEER REVIEW
Diagnostics
2022,
12,12,x FOR

3 of3 of1313

Figure 1. Flow diagram of patients included in the study.
Figure 1. Flow diagram of patients included in the study.

Two upper-extremity orthopedic surgeons with 23 and 28 years of experience, reTwo madeupper-extremity
orthopedic
surgeons
and28diagnosis
years of experience,
respecspectively,
all clinical decisionsforpatientswith
with23LE.
Theof LE was based
tively,madeallclinicaldecisionsforpatients
with
LE.
The
diagnosis
of
LE
was
based
on physical findings, positive Thomsen tests or middle finger tests, and tenderness at theonphysicalfindings,
positiveInitially,Thomsenor middle
finger tests,
and tenderness
at thelateralepicondyle[17,18,24].
wetests
providedconservative
treatment
for all patients.
lateralepicondyle[17,18,24].therapy
Initially,
weelbow
providedconservative
treatment
for injections
all patients.
Weprescribedoccupational
and
bands
for all patients.
Steroid
We prescribedoccupationaland elbow bands
all intra-articularly,
patients. Steroid who
injections
were
administeredto patients,therapy
once extra-articularly
andfor
once
did
were
administeredto patients,
once extra-articularly
and once
intra-articularly,
did not
notrespondto occupational
therapyor orthotics. Somepatients
had receivedwho
multiple
respondto occupational
therapy ororthotics.
Some patients
had received
multiplesteroidsteroid
injections
at their previous
medicalinstitutions.
MRI wasperformed
for patients
injectionsattheirprevious
medicalinstitutions.
MRI
wasperformedforpatients
who
were
who were refractory to the aforementioned conservative treatment for at least one monthrefractory
totheaforementioned
conservative
treatment
for
at
least
one
month
and
had
and had severe activity limitation due to pain, (i.e., Nirschl phase rating scale III or higher)
severeactivity
limitation
due
to
pain,
(i.e.,
Nirschlphase
ratingscale
IIIorhigher)
[18].
[18].

2.2. MRI Protocol and Definition of the Structures
2.2. MRI Protocol and Definition of the Structures
We used a clinical 3.0-Tesla imager (Magnetom Symphony, SIEMENS, Munchen,
We used a clinical 3.0-Tesla imager (Magnetom Symphony, SIEMENS, Munchen,
Germany) with a small-diameter surface coil (Loop Flex Coil, SIEMENS) above the lateral
Germany) with a small-diameter surface coil (Loop Flex Coil, SIEMENS) above the lateralepicondyle of the humerus. We placed the patients’ elbows in the center of the MRI scanner,epicondyle of the humerus. We placed the patients’ elbows in the center of the MRI scanwith the elbow extended beside the trunk, and the forearm supinated. We obtained aner, with the elbow extended beside the trunk, and the forearm supinated. We obtained acoronal section of the lateral aspect of the elbow under the following three sequences: T2*coronal section of the lateral aspect of the elbow under the following three sequences: T2*weighted images (T2*WI) using the gradient echo to evaluate synovial folds, proton-densityweighted images (T2*WI) using the gradient echo to evaluate synovial folds, proton-denweighted images (PDWI) using the high-speed spin echo to recognize the morphology ofsity-weighted
images(PDWI)
using thehigh-speed
spin echo
to recognize
the(T2FSWI)
morphol-to
the CET/LCL
complexattachment,
andT2 fat-saturated
weighted
imagesogy
ofthe
CET/LCLcomplexattachment,
andT2
fat-saturated
weighted
images(T2FSWI)
evaluate the severity of LE (Table 1).
to evaluate the severity of LE (Table 1).
Table 1. Imaging parameters.
Table 1. Imaging parameters.
Sequence

T2*WI

PDWI

T2FSWI

Sequence
T2*WI
PDWI
T2FSWI
Voxel size
size
0.2
1.5
0.2 ××0.2
0.2 ××1.5
1.5
0.2××0.2
0.2××
1.5
Voxel
0.2×× 0.2
0.2 ×
× 1.5
0.2
0.2
1.5
Matrix160 × 320
240 × 320
256 × 256
Matrix
160
× 320
240
320
25660× mm
256
FOV
60 mm
60×mm
FOV
60
mm
60
mm
60
mm
Base resolution
320
320
256
Phaseresolution
resolution
50%
50%
50%
Base
320
320
256
Sliceresolution
thickness
1.5
mm
1.5
mm
1.5 mm
Phase
50%
50%
50%
TR
553.0 ms
553.0 ms
3000.0 ms
Slice thickness
1.5
mm
1.5
mm
1.594mm
TE
24 ms
24 ms
ms
TR
553.0
ms
553.0
ms
3000.0ms
Bandwidth
180
Hz/Px
180
Hz/Px
145 Hz/Px
FlipTE
angle
2430ms24170
ms
94 122ms
FOV: field-of-view,TE, echo time, T2*WI,180
T2*-weighted
proton-densityBandwidthTR: repetition time,
180 Hz/Px
Hz/Px imaging; PDWI,
145 Hz/Px
weighted imaging; T2FSWI, T2 fat-saturated weighted imaging.
Flip angle
30
170
122

Diagnostics 2022, 12, x FOR PEER REVIEW

Diagnostics 2022, 12, 1871

4 of 13

FOV: field-of-view, TR: repetition time, TE, echo time, T2*WI, T2*-weighted imaging; PDWI, proton-density-weighted imaging; T2FSWI, T2 fat-saturated weighted imaging.
of 13
FOV: field-of-view, TR: repetition time, TE, echo time, T2*WI, T2*-weighted imaging; PDWI,4 proOur protocol provided
a clear andenlarged viewof theimaging.
lateral aspect of the elbow;
ton-density-weighted
imaging; T2FSWI,
T2 fat-saturated
weighted

we could recognize the CET and the LCL as rather isolated structures. Furthermore, we
protocolprovidedclear
andenlarged
enlargedviewoflateralaspectof2)theelbow;
usedOur
bonyprotocol
landmarks
to definetheandCETand theview
LCL
independently(Figure[25,26].
In
Our
providedaaclearofthethelateralaspectof theelbow;
we
we
could
recognize
the
CET
and
the
LCL
as
ratherisolated
structures.
Furthermore,wethecoronal
MRI
images,wedefined
the
CET
as
the
structureattachedtothesuperior
could recognize the CET and the LCL as rather isolated structures. Furthermore, we used
used
to define
the
CET
and
the
independently(Figure2)intertuber[25,26].
In
tubercleor landmarks
the epicondylar
ridge
and
thetheLCL
asLCL
the structureattachedtobonybony
landmarks
to define
the
CET
and
LCL
independently(Figure2)the[25,26].
In thethecoronalwedefinedtheposterior
thestructureattached
to the superior
cularsulcusortheimages,
inferior
surfaceofCET
thetubercle.
coronalMRIMRI
images,we defined
the
asCET
the asstructureattached
to the superior
tubercletubercleor the epicondylar
andas
the
as the attachedstructuretoattachedto the intertuberor the epicondylar
ridge andridge
the LCL
theLCL
structure
the intertubercularsulcuscular
orsurface
the inferiorof theposterior tubercle.
or thesulcus
inferiorof thesurface
posteriortubercle.

Figure 2. Consecutive MRI slices under PDWI of the unaffected lateral elbow (a) and corresponding
schemas (b). These schemas represent bony landmarks and the CET and the LCL in this study. *superior** anterior
tubercle;posteriortubercle; whitearrow,
sulcus;Consecutive
MRI slices
slicesunder ***PDWIof thethe unaffectedunaffected
lateralelbowintertubercular(a) andand corresponding
corresponding
Figure 2. tubercle;
Consecutive
MRI
under
PDWI
of
lateral
elbow
(a)
black
arrow,
ridge;
green area,
CET;
blue area,
LCL;
MRI,
magnetic
resonance
imaging;(b). epicondylar
These schemas
represent
bony
landmarks
and
the
the
LCL
in in
this
study.
* suschemas
schemasrepresent
bony
landmarks
andtheCET
CETand
and
the
LCL
this
study.
*
PDWI,
proton-density-weighted
imaging;commonextensor
tendon;
LCL,
lateral collateralligsuperior
tubercle;** anterior
tubercle;***CET,
posteriortubercle;whitearrow,
intertubercularsulcus;perior tubercle;** anterior
tubercle;*** posterior
tubercle;whitearrow,
intertubercularsulcus;black
ament.
black
epicondylar
area,blue
CET;area,
blueLCL;area,MRI,LCL;magnetic
MRI, magnetic
resonance
imaging;arrow,arrow,epicondylar
ridge; ridge;
green green
area, CET;
resonance
imaging;
PDWI,
PDWI,
proton-density-weighted
imaging;
CET,commonextensor
tendon;
LCL,
lateralcollateralligproton-density-weighted imaging; CET, common extensor tendon; LCL, lateral collateral ligament.
2.3. MRI Scoring and Evaluation
ament.

2.3. MRI
ScoringT2FSWI
and Evaluation
We chosefor MRI scoring because PDWI and T2*WI had short echo times
2.3.
MRI
Scoringand
Evaluation
We chosefor MRIthe
scoringbecausePDWIand T2*WI had
short echo (Figure
times andand may
have T2FSWI
overestimatedfindings
due tothe magic-angle
phenomenon
3)
T2FSWI for
scoringbecausePDWI andphenomenon
T2*WI had (Figure
short echotimes
may Wehavechoseoverestimatedthe MRI
findings
due tothe magic-angle
3) [27–29].
[27–29].
and may have overestimated the findings due to the magic-angle phenomenon (Figure 3)[27–29].

Figure 3. Differences in signal intensity of the CET/LCL complex by sequence. The unaffected elbow
Figure 3. Differences in signal intensity of the CET/LCL complex by sequence. The unaffected elbow
of a 32-year-old male. These images are same-level slices of the MRI coronal section in each seof a 32-year-old
male.T2*WI
These images
same-levelof the MRIcomplex
coronal section
ina eachsequence.
quence.
this case,
shows
aare
high
signalatslicesthe complex
CET/LCLdespitecompletelowFigure 3.In
Differencesin signal
intensityof theCET/LCLby sequence.
The unaffected
elbow
In
this
case,
T2*WI
shows
a
high
signalatthe
CET/LCLcomplexdespiteacompletelowsignalin thesignalin the sequenceof PDWI
andareT2FSWI.
MRI,slices
magnetic
imaging;of a 32-year-old
male. These
imagessame-levelof theresonance
MRI coronal
sectionT2*WI,
in eachT2*sesequenceInofthis
PDWI
T2FSWI.
MRI,
magnetic
imaging;
T2*WI,
T2*-weighted
images;quence.
case,and
T2*WI
shows
a highsignal resonanceat the CET/LCL
complexdespitea complete
low
PDWI, inproton-density-weighted
T2FSWI,MRI,
T2 fat-saturated
weighted imaging;
images; CET,
commonsignalthe sequence of PDWIimages;
and T2FSWI.
magnetic resonance
T2*WI,
T2*extensor tendon; LCL, lateral collateral ligament.

With reference to the previous literature [30,31], we created an MRI scoring scale
which evaluated the strength and extent of signal changes within a coronal section onDiagnostics 2022, 12, 1871

5 of 13a scale of 0 to 4. The region of interest for our MRI scoring was the CET and the LCL
between the articular surface of the radial head and lateral epicondyle of the humerus.
Using this MRI scoring, we performed two patterns of MRI evaluation. The combined
evaluation method evaluated the CET and the LCL together on a scale of 0–4. In contrast,
the individual evaluation method evaluated the CET and the LCL individually on a scaleof 0–4 and subsequently added the individual scores for a total score of 0–8 (Figure 4).
Two examiners independently assessed the images: an orthopedic surgeon (examiner 1) and a hand surgeon (examiner 2) with 9 and 23 years of experience, respectively. The
examiners repeated the image analysis twice, with the second analysis being performed
one month after the initial analysis. In the MRI evaluation, a third person blinded any
clinical data and randomized the MR images.
2.4. Statistical Analysis
We adopted the values measured by examiner 1 for further analysis. We performed theShapiro–Wilk test for each evaluation item as a normality test, and none of them followed anormal distribution.
We compared all of the groups’ collected variables, including clinical characteristics
and MRI scores. We used the chi-squared test for categorical variables, the Mann–Whitney
U test for continuous variables between two groups, and the Kruskal–Wallis test for comparison among three groups. When the Kruskal–Wallis test showed a significant difference,
we performed Scheffe’s multiple comparison procedure. In cases of missing data for clinicalcharacteristics, we replaced the data with the median scores of the other patients in thesame group.
We created the receiver operating characteristic curve (ROC curve) for the diagnosis
of LE from the MRI scoring of the H and M groups, and the ROC curve for the diagnosis ofseverity from the M and S groups.
We used Fleiss’ kappa analysis to evaluate intra-observer and inter-observer reliability
for the entire MRI scoring process. The interpretation of the kappa coefficient was defined
as follows: 0.81–1.00 = excellent, 0.61–0.80 = good, and 0.41–0.60 = fair.
In principle, we set the level of statistical significance as p < 0.05. In performing thechi-square test among three groups, we corrected the significance level with Bonferroni’s
method (i.e., p < 0.016).
We performed all statistical analyses using Bellcurve for Excel version 3.20 (SSRI Co.,Tokyo, Japan).
2.5. Sample Size
Based on the previous studies [20,32], we predicted the area under curve (AUC) of
ROC curves for diagnosis to be 0.65 to 0.85. Subsequently, we calculated that with a sample
of 30 patients per group, the study would have an 80% power to create an ROC curve withan AUC of 0.68 and a type I error of 5%. For the diagnosis of severity, we predicted the
AUC of ROC curves for severity diagnosis to be 0.6 to 0.8 [15]. We calculated that witha sample of 98 patients, with 49 patients per group, the study would have 80% power tocreate an ROC curve with an AUC of 0.6 and a type I error of 5%. From these results, wecollected 30 cases for the H group and a total of 100 cases for the M and S groups.

Diagnostics 2022, 12, 1871

scale of 0 to 4. The region of interest for our MRI scoring was the CET and the LCL between
the articular surface of the radial head and lateral epicondyle of the humerus. Using this
MRI scoring, we performed two patterns of MRI evaluation. The combined evaluation
method evaluated the CET and the LCL together on a scale of 0–4. In contrast, the individual evaluation method evaluated the CET and the LCL individually on a6 of
scale
13 of 0–4
and subsequently added the individual scores for a total score of 0–8 (Figure 4).

Figure4.4. MRIMRIexamples
examplesofofeach
eachscore
score
and
corresponding
schema.
scoring
criteria
Figureanditsitscorresponding
schema.
The Thescoring
criteria
are asare as fol
lows: (0)(0)(normal),linearlow-signal
low-signal
structure
withoutchanges
in intensity;
signal intensity;
follows:(normal), dark,
dark, linear
structure
withoutchangesin signal(1) (mild (1) (milddegeneration),thickeningor
mild
signalchangebelow
thesignalintensityofthemuscle;degeneration), thickening or mild signal change below the signal intensity of the muscle; (2) (localized(2) (local
ized degeneration),high change
signal change
above
the
signal intensityof themuscle,below
localized
below 50%
degeneration),high signal
above thesignalintensityof the muscle,
localized
50% ofoftheevaluation
range;(3a)(extensive
degeneration),highsignalchangeabove
thesignalthe evaluation range; (3a) (extensive degeneration), high signal change above the signal intensity of intensityof themuscle,beyondthe evaluation(3b) (partialtear),
highchange
signalequivalentchange equivalenthemuscle,beyond
50% 50%of theofevaluation
range;range;(3b) (partialtear), highsignalto joint fluid, within 75% of the tendon or ligament width; (4) (extensive tear), high signal change
equivalent to joint fluid, more than 75% of the tendon or ligament’s width. The yellow area indicates
degeneration; * tear; MRI, magnetic resonance imaging. The blue dotted line surrounds the region ofinterest for MRI scoring in each evaluation method. Black lines are auxiliary lines to determine theevaluation area, which runs parallel to the articular surface of the radial head. † combined evaluation;†† individual evaluation; yellow area, degeneration.

Diagnostics 2022, 12, 1871

7 of 13

3. Results
3.1. Demographic and Clinical Characteristics
Table 2 summarizes the demographic and clinical data of each group. There was no
significant difference in gender or age between the H, M, and S groups. As for comparisons
between the two groups, the S group received more frequent injection therapy and wasaffected for a longer period than the M group. Fifty patients of the S group did not respondto conservative treatment and received surgical treatment; no patients of the M grouprequired surgery.
Table 2. Demographic and clinical data of each group.

Sex Male
FemaleAge (y) †Injection therapy
0
1–2
3≤
unidentifiedDuration of pain
(months) †0–1 month
1–3 months
3–6 months
6–12 months>12 months
Unidentified
Required surgery ††Healthy Group

Mild Group

Severe Group

p-Value1218
49 (27–69)-

21
20
49 (34–77)

31
28
49 (23–78)

p = 0.51

21
17
3
0

6
29
24
0

-

6.4 (2.1–81.0)

12.5 (1.4–133.1)

p = 0.032

-

0
6
12
12
9
2
0/41

0
4
12
12
31
0
50/59

p < 0.001

p = 0.27
p < 0.001† Data are presented as median (minimum–maximum); †† The surgical indication was for the patients with
Nirschl’s clinical scale score of V or higher, who were resistant to the conservative treatment for at least 6 months.

3.2. MRI Scoring
In the combined evaluation, the median MRI score and 25–75 percentile were 1 (1–2), 3(2–3), and 4 (3–4) in the H, M, and S groups, respectively. There was a significant difference
among all groups: p < 0.001 for the H and M groups, p < 0.001 for the H and S groups,
and p = 0.001 for the M and S groups (Figure 5). In the individual evaluation, the median
MRI score and 25–75 percentile were 2 (1–2), 4 (3–5) and 6 (5–6) in the H, M, and S groups,
respectively. There was a significant difference among all groups: p < 0.001 for the H and M
groups, H and S groups, and for the M and S groups (Figure 6). Additionally, we describedthe distribution of the CET and LCL scores in each group in the supplementary materials(Table S1).
3.3. ROC Curve
In the ROC curve for diagnosis, shown in Figure 7, the AUC was 0.84 for combined
evaluation (p < 0.001) and 0.86 for individual evaluation (p < 0.001). In the comparison of
the evaluation methods, there was no significant difference in the AUC (p = 0.63).

Diagnostics
2022,
12, x1871
FOR PEER REVIEW
Diagnostics
2022,
Diagnostics
2022,
12,12,x FOR PEER REVIEW

8 of 138
8 oFigureMRI scoresin combined
evaluation
method.
Dot
plots
show the indifferences
the dFigure5.5.5.
MRI
in combined
evaluation
method.
Dot plotsshow
theshowdifferences
the distri-ininthe
FigureMRIscoresscoresin combined
evaluation
method.
Dotplots
the differencesdbutionof
MRIscoresforeachgroup.
The
MRI
scoreswerevaluedasfollows:
healthygroupbution of
forforeacheachgroup.
The MRI
valuedfollows:ashealthygroup< mildgroup <<mbutionofMRI
MRIscoresscoresgroup.
Thescores
MRI werescoreswereasvalued
follows:
healthygroup< severe group,
significant
differences.
line graph represents
the median
valu
group
< severe
withwithsignificant
differences.
The line The
graphthe median value
and
group
< severegroup,group,
withsignificant
differences.
The
linerepresents
graph represents
the medianvalue
25–75percentile.
percentile.
p < 0.05,
p < 0.01.
25–75* p <* 0.05,** p <**0.01.
25–75 percentile. * p < 0.05, ** p < 0.01.

Figure 6. MRI scores in the individual evaluation method. Dot plots show the differences i
FigureMRI scoresininthethe
individual
evaluation
method.
Dot plots theshow the differencesin
Figure 6.6. MRI
evaluation
Dot plots
indistribution ofscores
MRI scoresindividualfor each group.
Themethod.
MRI scores
were show
valued asdifferences
follows: healthy
gr
distribution
of
MRI
scoresforeachgroup.
The
MRI
scoreswerevaluedasfollows:
healthygro
the distribution of MRI scores for each group. The MRI scores were valued as follows: healthy
mild group < severe group, with significant differences. The line graph represents the medianmildsevere<group,with significant
differences.
The Theline line
graph
represents
themedian v
groupgroup< mild< groupsevere group,with significant
differences.
graph
represents
theand 25–75 percentile. ** p < 0.01.
and
25–75
percentile.
p < 0.01.** p < 0.01.
medianvalue
and 25–75 **percentile.

3.3. ROC Curve
3.3. ROC Curve
In the ROC curve for diagnosis, shown in Figure 7, the AUC was 0.84 for comb
In the ROC curve for diagnosis, shown in Figure 7, the AUC was 0.84 for combi
evaluation (p < 0.001) and 0.86 for individual evaluation (p < 0.001). In the comparis
evaluation (p < 0.001) and 0.86 for individual evaluation (p < 0.001). In the compariso
the evaluation methods, there was no significant difference in the AUC (p = 0.63).
the evaluation methods, there was no significant difference in the AUC (p = 0.63).

Diagnostics 2022, 12, 1871
Diagnostics 2022, 12, x FOR PEER REVIEW

9 of 13
9 of 13

Figure 7. The ROC curve shows the capability of MRI to diagnose lateral epicondylitis for each
Figure 7. The
ROC curve
the capabilityof MRI
diagnoselateral epicondylitis
each evalevaluation
method.
In ashowscomparisonof AUC,
theretowas
no significant
difference forbetweentheuationmethod.
Inacomparison
of
AUC,
there
was
no
significant
difference
betweentheevaluation
evaluation methods (p = 0.23). ROC curve, receiver operating characteristic curve; PPV, positive
methods (p = 0.23). ROC curve, receiver operating characteristic curve; PPV, positive predictive
predictive value; NPV, negative predictive value; NS, not significant.
value; NPV, negative predictive value; NS, not significant.

In the ROC curve for the diagnosis of clinical severity, shown in Figure 8, the AUC
In thecurve for the
diagnosis
severity,shown
in Figure 8,
the AUC
was 0.69
forROCthe combined
evaluation(pof< clinical0.001) and
0.81 forthe individual
evaluation
was
0.69
for
the
combined
evaluation(p<0.001)
and
0.81
for
the
individual
evaluation(p(p < 0.001). In the comparison of the evaluation methods, the AUC of the individual< 0.001). In was
the comparison
the evaluation
methods,
the AUCof the individual
evaluaevaluation
significantlyoflarger
than that of
the combined
evaluation(p = 0.003).
tion was significantly larger than that of the combined evaluation (p = 0.003).
3.4. Repeatability of MRI Scoring in This Study
The kappa values and their 95% confidence intervals for intra-observer agreement
were 0.87 (0.85–0.90: p < 0.001) for examiner 1 and 0.86 (0.84–0.89: p < 0.001) for examiner
2. For inter-observer agreement between examiners 1 and 2, the kappa value was 0.84
(0.82–0.86: p < 0.001). The repeatability of MRI scoring was excellent.

Diagnostics 2022, 12, 1871

10 of 13

Diagnostics 2022, 12, x FOR PEER REVIEW

10 of 13

Figure 8. The ROC curve shows the capability of MRI to diagnose the clinical severity for each
Figure 8. The ROC curve shows the capability of MRI to diagnose the clinical severity for each evalevaluation method. In a comparison of AUCs, individual evaluation was significantly superior touation method. In a comparison of AUCs, individual evaluation was significantly superior to comcombined
evaluation= 0.046).
< 0.05,ROC
curve,
receiveroperatingcharacteristic
characteristiccurve;
curve;PPV,
PPV,
bined
evaluation(p =(p0.046).
** p**< p0.05,
ROC
curve,
receiveroperatingpositive
predictive
value;
NPV,
negative
predictive
value.
positive predictive value; NPV, negative predictive value.

4. Discussion
3.4. Repeatability of MRI Scoring in This Study
The most significant finding of this study was that individual MRI evaluations of the
The kappa values and their 95% confidence intervals for intra-observer agreement
CET and the LCL improved the accuracy of the severity diagnosis of LE. Since MRI images
were 0.87 (0.85–0.90: p < 0.001) for examiner 1 and 0.86 (0.84–0.89: p < 0.001) for examinerreflect pathological change, we can accurately quantify pathological severity with detailed
2.
Forscoring.
inter-observer
examiners
1 and 2, thekappaclinicalvalue was
0.84
MRI
Some ofagreement
the studiesbetween
investigating
the relationshipbetweenand MRI(0.82–0.86:
p<0.001).
The
repeatabilityofMRI
scoringwas
excellent.
severity are commensurate with the results of this study. The literature with quantitative,
individual evaluations of the CET and the LCL reported a positive association between
4.
Discussion
clinicaland MRI severity [7,15]; the studies without quantitative evaluation did not show
The most significant
finding
this study wasthat individual
MRIofevaluationsof thethis association[22]. Studies
withofquantitative,
combined
evaluations
the CET and
CETthe LCL
improved
the accuracyof theseverityof LE.
MRItheimages
LCL andreported
conflicting
conclusions[23,33].
This
study diagnosis
suggests that
theSince
CET and
LCL
reflectchange,we canusing
accurately
quantify
with detailed
shouldpathologicalbe individually
evaluated
MRI toindicatepathological
the severityseverity
diagnosis.
MRI Furthermore,scoring. Someweof demonstrated
the studies investigating
between clinicaland MRI
the accuracytheof relationship
MRI for the diagnosis
of LE. According
severity
arecurvecommensuratewith theof hadthis astudy.
The literature
with quantitative,
to the ROC
for the diagnosis
ofresults
LE, MRI
high diagnostic
capability,
as reported
individual
evaluations oftheNevertheless,
CET and theMRI
LCLisreported
a positive
association
betweenin other tendinopathies[32].
not always
necessaryfor diagnosis
sinceclinicaland MRI
severity
the studies
without
quantitativeevaluation
did not
show
most patientswith
LE can[7,15];be diagnosed
based
on physicalfindings.
We should
perform
MRIassociation
only for patients
who arerefractory
to conservative
Differential
diagnosis
this[22]. Studies
withquantitative,
combinedtreatment.
evaluationsof the CETand theshouldbe consideredwhen
MRI showsan absenceor slightchangein theon
LCL
reported
conflicting
conclusions[23,33].
This study
suggeststhat theCETsignaland theCET/LCL,the entrapmentof the posterior
antebrachialcutaneousnerve[34,35], radial
LCL
shoulde.g.,
be individually
evaluatedusing MRI
to indicate
the severity
diagnosis.
tunnelsyndrome, we
synovial
fold disorder,
posterolateral
inflammatory
Furthermore,demonstrated
the accuracyof MRI elbow
for the instability,
diagnosis of
LE. Accorddisorders,cervicalradiculopathy,
and
so
on
[36].
ing to the ROC curve for the diagnosis of LE, MRI had a high diagnostic capability, asreported in other tendinopathies [32]. Nevertheless, MRI is not always necessary forDiagnostics 2022, 12, 1871

11 of 13

Meanwhile, further study is necessary to demonstrate the validity of MRI-positive
findings for the severity diagnosis. Although MRI scores were higher in the group withhigher clinical severity, there was some variation among cases. As Nirschl et al. showed,
there is interindividual variation in symptoms and pathologic severity of LE [18,37]. Furthermore, some studies reported that psychological factors play a role in the intensity of theclinical symptoms in LE [38,39]. These findings indicate that the symptoms of LE are multifactorial, though based on pathological abnormalities. Thus, the cross-sectional study of thecorrelation between MRI scoring and clinical severity is necessarily limited. A longitudinal
study should be conducted in the future to reveal the validity of positive MRI findings in LE.
Since the literature suggests surgery in cases with severe pathology [18,37,40], MRI severity
may predict the prognosis of conservative treatment. In particular, since posterolateral
instability is reported to be associated with clinical severity [41,42], individual evaluationof LCL is significant. Overall, the findings of this study will be a basis for future research.
Our study had several strengths. Firstly, to our knowledge, this study used thehighest-resolution MRI of any study to date; this allowed us to provide reliable data.
The repeatability of MRI scoring was excellent. Secondly, we conducted a quantitativeevaluation with a sufficient sample size, including the healthy group. Since previous
reports have not quantitatively evaluated healthy subjects, we believe our data will serve
as a basis for future MRI evaluations.
Although the study had many strengths, it also had some limitations. This study was
retrospective, and we collected data on clinical symptoms from medical records. Although
our treatment protocols and MRI indications are standardized at a single institution, there
were some differences in the timing of MRI imaging in some cases. Additionally, our study
included patients who received steroid injection therapy, which may have influenced the
MRI findings or clinical assessment. Finally, we selected the subjects of the H group from a
specific environment of medical coworkers in our hospital. Therefore, there is a possibilityof selection bias that we could not predict.
In conclusion, MRI individual evaluation of the CET and the LCL improved the accuracy of diagnosing the severity of LE. The CET and LCL should be evaluated individually
to reflect the relationship of clinical severity to MRI severity accurately.
Supplementary Materials: The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/diagnostics12081871/s1. Table S1: distribution of the CET and
LCL scores in each group.
Author Contributions: Conceptualization, K.I.; methodology, K.I. and T.O.; validation, K.I. and T.O.;
formal analysis, K.I. and R.I.; investigation, K.I.; resources, T.O. and A.I.; data curation, K.I. andR.I.; writing—original draft preparation, K.I.; writing—review and editing, T.O., A.I., Y.Y. and S.K.;
visualization, K.I.; supervision, T.O. and M.Y.; project administration, M.Y. All authors have read andagreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: The study was conducted according to the guidelines of the
Declaration of Helsinki and approved by the Institutional Review Board of the Mito Kyodo General
Hospital (Study Number: 16–25, approved 7 September 2016) and Takahagi Kyodo General Hospital(Study Number: 10, approved 3 March 2021).
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: Not applicable.
Acknowledgments: We would like to thank Atsushi Hirano and Yuki Hara for providing us with theopportunity to conduct this study. We would also like to thank the radiology groups of Mito Kyodo
Hospital and Takahagi Kyodo Hospital for their cooperation in the MRI examinations.
Conflicts of Interest: The authors declare no conflict of interest.

Diagnostics 2022, 12, 1871

12 of 13

References
1.
2.
3.
4.
5.

6.
7.

8.
9.
10.
11.
12.
13.
14.
15.

16.
17.
18.
19.
20.
21.
22.
23.
24.
25.

26.
27.
28.

Ahmad, Z.; Siddiqui, N.; Malik, S.S.; Abdus-Samee, M.; Tytherleigh-Strong, G.; Rushton, N. Lateral epicondylitis: A review ofpathology and management. Bone Jt. J. 2013, 95B, 1158–1164. [CrossRef] [PubMed]
Runge, F. Zur Genese und Behandlung des schreibe Kranfes. Bed. Klin. Worchenschr. 1873, 10, 245–248.
Shiri, R.; Viikari-Juntura, E. Lateral and medial epicondylitis: Role of occupational factors. Best. Pract. Res. Clin. Rheumatol. 2011,
25, 43–57. [CrossRef] [PubMed]
Wolf, J.M.; Mountcastle, S.; Burks, R.; Sturdivant, R.X.; Owens, B.D. Epidemiology of lateral and medial epicondylitis in a military
population. Mil. Med. 2010, 175, 336–339. [CrossRef]
Fan, Z.J.; Silverstein, B.A.; Bao, S.; Bonauto, D.K.; Howard, N.L.; Spielholz, P.O.; Smith, C.K.; Polissar, N.L.; Viikari-Juntura,
E. Quantitative exposure-response relations between physical workload and prevalence of lateral epicondylitis in a working
population. Am. J. Ind. Med. 2009, 52, 479–490. [CrossRef]
Shiri, R.; Viikari-Juntura, E.; Varonen, H.; Heliövaara, M. Prevalence and determinants of lateral and medial epicondylitis: A
population study. Am. J. Epidemiol. 2006, 164, 1065–1074. [CrossRef]
Cha, Y.K.; Kim, S.J.; Park, N.H.; Kim, J.Y.; Kim, J.H.; Park, J.Y. Magnetic resonance imaging of patients with lateral epicondylitis:
Relationship between pain and severity of imaging features in elbow joints. Acta. Orthop. Traumatol. Turc. 2019, 53, 366–371.
[CrossRef]
Bredella, M.A.; Tirman, P.F.; Fritz, R.C.; Feller, J.F.; Wischer, T.K.; Genant, H.K. MR imaging findings of lateral ulnar collateral
ligament abnormalities in patients with lateral epicondylitis. AJR Am. J. Roentgenol. 1999, 173, 1379–1382. [CrossRef]
Kalainov, D.M.; Cohen, M.S. Posterolateral rotatory instability of the elbow in association with lateral epicondylitis. A report ofthree cases. J. Bone Joint Surg. Am. 2005, 87, 1120–1125. [CrossRef]
Dones, V.C., 3rd; Grimmer, K.; Thoirs, K.; Suarez, C.G.; Luker, J. The diagnostic validity of musculoskeletal ultrasound in lateralepicondylalgia: A systematic review. BMC Med. Imaging 2014, 14, e10. [CrossRef]
Latham, S.K.; Smith, T.O. The diagnostic test accuracy of ultrasound for the detection of lateral epicondylitis: A systematic review
and meta-analysis. Orthop. Traumatol. Surg. Resarch 2014, 100, 281–286. [CrossRef]
Khattab, E.M.; Abowarda, M.H. Role of Ultrasound Guided Platelet-Rich Plasma (PRP) Injection in Treatment of Lateral
Epicondylitis. Egypt. J. Radiol. Nucl. Med. 2017, 48, 403–413. [CrossRef]
Ruiz, A.G.; Diaz, G.V.; Fernandez, B.R.; Vargas, C.E.R.D. Effects of Ultrasound-Guided Administration of Botulinum Toxin(IncobotulinumtoxinA) in Patients with Lateral Epicondylitis. Toxins 2019, 46, e11010046.
Casu, E.; Obradov-Rajic, M. Ultrasound Guided Standalone Percutaneous Needle Tenotomy for Chronic Lateral Epicondylitis: A
Systematic Review. Adv. Tech. Musculoskelet. Surg. 2018, 2, 18–28.
Jeon, J.Y.; Lee, M.H.; Jeon, I.H.; Chung, H.W.; Lee, S.H.; Shin, M.J. Lateral epicondylitis: Associations of MR imaging and clinicalassessments with treatment options in patients receiving conservative and arthroscopic management. Eur. Radiol. 2018, 28,
972–981. [CrossRef]
Lombardi, A.; Ashir, A.; Gorbachova, T.; Taljanovic, M.; Chang, E.Y. Magnetic resonance imaging of the elbow. Pol. J. Radiol. 2020,85, e440–e460. [CrossRef]
Waseem, M.; Nuhmani, S.; Ram, C.S.; Sachin, Y. Lateral epicondylitis: A review of the literature. J. Back Musculoskelet. Rehabil.
2012, 25, 131–142. [CrossRef]
Nirschl, R.P.; Ashman, E.S. Elbow tendinopathy: Tennis elbow. Clin. Sports Med. 2003, 22, 813–836. [CrossRef]
Ma, K.L.; Wang, H.Q. Management of Lateral Epicondylitis: A Narrative Literature Review. Pain Res. Manag. 2020, 2020, e6965381.
[CrossRef]
Pasternack, I.; Tuovinen, E.M.; Lohman, M.; Vehmas, T.; Malmivaara, A. MR findings in humeral epicondylitis. A systematic
review. Acta. Radiol. 2001, 42, 434–440.
Regan, W.; Wold, L.E.; Coonrad, R.; Morrey, B.F. Microscopic histopathology of chronic refractory lateral epicondylitis. Am. J.
Sports Med. 1992, 20, 746–749. [CrossRef]
Savnik, A.; Jensen, B.; Nørregaard, J.; Egund, N.; Danneskiold-Samsøe, B.; Bliddal, H. Magnetic resonance imaging in theevaluation of treatment response of lateral epicondylitis of the elbow. Eur. Radiol. 2004, 14, 964–969. [CrossRef]
Walton, M.J.; Mackie, K.; Fallon, M.; Butler, R.; Breidahl, W.; Zheng, M.H.; Wang, A. The reliability and validity of magnetic
resonance imaging in the assessment of chronic lateral epicondylitis. J. Hand Surg. Am. 2011, 36, 475–479. [CrossRef]
Elisa, L.Z.; Matthijs, P.S.; Francois, M.; Jelle, H.; Denise, E.; Michel, P.B. Physical examination of the elbow, what is the evidence?
A systematic literature review. Br. J. Sports Med. 2018, 52, 1253–1260.
Zoner, C.S.; Buck, F.M.; Cardoso, F.N.; Gheno, R.; Trudell, D.J.; Randall, T.D.; Resnick, D. Detailed MRI-anatomic study of thelateral epicondyle of the elbow and its tendinous and ligamentous attachments in cadavers. Am. J. Roentgenol. 2010, 195, 629–636.
[CrossRef] [PubMed]
Nimura, A.; Fujishiro, H.; Wakabayashi, Y.; Imatani, J.; Sugaya, H.; Akita, K. Joint capsule attachment to the extensor carpi. J.
Hand Surg. Am. 2014, 39, 219–225. [CrossRef] [PubMed]
Bydder, M.; Rahal, A.; Fullerton, G.D.; Bydder, G.M. The magic angle effect: A source of artifact, determinant of image contrast,
and technique for imaging. J. Magn. Reson. Imaging 2007, 25, 290–300. [CrossRef] [PubMed]
Du, J.; Pak, B.C.; Znamirowski, R.; Statum, S.; Takahashi, A.; Chung, C.B.; Bydder, G.M. Magic angle effect in magnetic resonanceimaging of the Achilles tendon and enthesis. Magn. Reson. Imaging 2009, 27, 557–564. [CrossRef]Diagnostics 2022, 12, 1871

29.
30.
31.

32.

33.
34.

35.

36.
37.
38.
39.
40.
41.
42.

13 of 13

Zurlo, J.V.; Blacksin, M.F.; Karimi, S. The influence of flip angle on the magic angle effect. Skeltal Radiolol. 2000, 29, 593–596.
[CrossRef]
Steinborn, M.; Heuck, A.; Jessel, C.; Bonel, H.; Reiser, M. Magnetic resonance imaging of lateral epicondylitis of the elbow with a
0.2-T dedicated system. Eur. Radiol. 1999, 9, 1376–1380. [CrossRef]
Qi, L.; Zhang, Y.-D.; Yu, R.-B.; Shi, H.-B. Magnetic resonance imaging of patients with chronic lateral epicondylitis: Is therea relationship between magnetic resonance imaging abnormalities of the common extensor tendon and the patient’s clinicalsymptom? Medicine 2016, 95, e2681. [CrossRef]
Gatz, M.; Bode, D.; Betsch, M.; Quack, V.; Tingart, M.; Kuhl, C.; Schrading, S.; Dirrichs, T. Multimodal ultrasound Versus MRI
for the diagnosis and monitoring of Ahilles tendinopathy: A prospective longitudinal study. Orthop. J. Sport Med. 2021, 9,23259671211006826. [CrossRef]
Qi, L.; Zhu, Z.-F.; Li, F.; Wang, R.-F. MR imaging of patients with lateral epicondylitis of the elbow: Is the common extensor
tendon an isolated lesion? PLoS ONE. 2013, 8, e79498. [CrossRef]
Chang, K.V.; Mezian, K.; Nanka, O.; Wu, W.T.; Lou, Y.M.; Wang, J.C.; Martinoli, C.; Ozcakar, L. Ultrasound Imaging for the
Cutaneous Nerves of the Extremities and Relevant Entrapment Syndromes: From Anatomy to Clinical Implications. J. Clin. Med.
2018, 7, e7110457. [CrossRef]
Wagle, S.; Glazebrook, K.; Moynagh, M.; Smith, J.; Sellon, J.; Skinner, J.; Morrey, M. Role of ultrasound-guided perineural injectionof the posterior antebrachial cutaneous nerve for diagnosis and potential treatment of chronic lateral elbow pain. Skeltal Radiol.
2021, 50, 425–430. [CrossRef]
Ahmed, A.F.; Rayyan, R.; Zikria, B.; Salameh, M. Lateral epicondylitis of the elbow: An up-to-date review of management. Eur. J.
Orthop. Surg. Traumatol. 2022, 21, e03181. [CrossRef]
Kraushaar, B.S.; Nirschl, R.P. Tendinosis of the elbow (Tennis elbow): Clinical features and findings of histological, immunohistochemical, and electron microscopy studies. J. Bone Jt. Surg. Ser. A. 1999, 81, 259–278. [CrossRef]
Aurelie, A.; Lieven, D.W.; Nadine, H.; Carlos, H.; Marc, V.; Koen, P.; Alexander, V.T. Tennis elbow: Associated psychologicalfactors. J. Shoulder Elb. Surg. 2018, 27, 387–392.
Van, R.R.M.; Huisstede, B.M.; Koes, B.W.; Burdorf, A.B. Associations between work-related factors and specific disorders at the
elbow: A systematic literature review. Rheumatology 2009, 48, 528–536.
Bhabra, G.; Wang, A.; Ebert, J.R.; Edwards, P.; Zheng, M.; Zheng, M.H. Lateral Elbow Tendinopathy: Development of a
Pathophysiology-Based Treatment Algorithm. Orthop. J. Sports Med. 2016, 4, 2325967116670635. [CrossRef]
Kwak, S.H.; Lee, S.J.; Jeong, H.S.; Do, M.U.; Suh, K.T. Subtle elbow instability associated with lateral epicondylitis. BMC
Musculoskeltal Disord. 2018, 19, 136. [CrossRef]
Noh, Y.M.; Kong, G.M.; Moon, S.W.; Jang, H.S.; Kim, S.; Bak, G.G.; Kim, Y. Lateral ulnar collateral ligament (LUCL) reconstruction
for the treatment of recalcitrant lateral epicondylitis of the elbow: A comparison with open débridement of the extensor origin.
JSES Int. 2021, 16, 578–587. [CrossRef]

Leukemia & Lymphoma

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/ilal20

Novel translocation of POGZ/STK11 in de novo mastcell leukemia with KIT D816H mutation
Kantaro Ishitsuka, Yuki Yoshizawa, Hidekazu Nishikii, Manabu Kusakabe,
Yufu Ito, Yukinori Inadome, Tatsuhiro Sakamoto, Takayasu Kato, Naoki
Kurita, Yasuhisa Yokoyama, Naoshi Obara, Yuichi Hasegawa, Yasuhito
Nannya, Seishi Ogawa, Mamiko Sakata-Yanagimoto & Shigeru Chiba
To cite this article: Kantaro Ishitsuka, Yuki Yoshizawa, Hidekazu Nishikii, Manabu Kusakabe, Yufu
Ito, Yukinori Inadome, Tatsuhiro Sakamoto, Takayasu Kato, Naoki Kurita, Yasuhisa Yokoyama,
Naoshi Obara, Yuichi Hasegawa, Yasuhito Nannya, Seishi Ogawa, Mamiko Sakata-Yanagimoto &Shigeru Chiba (2022): Novel translocation of POGZ/STK11 in de�novo mast cell leukemia with KIT
D816H mutation, Leukemia & Lymphoma, DOI: 10.1080/10428194.2022.2123235
To link to this article: https://doi.org/10.1080/10428194.2022.2123235

Published online: 20 Sep 2022.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found athttps://www.tandfonline.com/action/journalInformation?journalCode=ilal20

LEUKEMIA & LYMPHOMA
https://doi.org/10.1080/10428194.2022.2123235

LETTER TO THE EDITOR

Novel translocation of POGZ/STK11 in de novo mast cell leukemia with KIT
D816H mutation
Kantaro Ishitsukaa, Yuki Yoshizawaa, Hidekazu Nishikiia,b , Manabu Kusakabea,b , Yufu Itoc,
Yukinori Inadomed, Tatsuhiro Sakamotoa,b, Takayasu Katoa,b, Naoki Kuritaa,b, Yasuhisa Yokoyamaa,b,
Naoshi Obaraa,b, Yuichi Hasegawaa,b, Yasuhito Nannyae,f, Seishi Ogawaf, Mamiko Sakata-Yanagimotoa,band Shigeru Chibaa,baDepartment of Hematology, University of Tsukuba Hospital, Ibaraki, Japan; bDepartment of Hematology, Faculty of Medicine,
University of Tsukuba, Ibaraki, Japan; cDepartment of Hematology, Tsuchiura Kyodo General Hospital, Ibaraki, Japan; dDepartment of
Pathology, National Hospital Organization Mito Medical Center, Ibaraki, Japan; eDepartment of Hematology/Oncology, Institute ofMedical Science, University of Tokyo, Tokyo, Japan; fDepartment of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan

ARTICLE HISTORY Received 13 April 2022; Accepted 4 September 2022

Introduction
Systemic mastocytosis (SM) is defined as a new distinct
disease category in the 2016 revision of the World HealthOrganization (WHO) classification [1]. It refers to symptoms resulting from the proliferation of abnormal mast
cells (MCs) and their organ infiltration. It was reported
that specific mutations of KIT can cause a ligand-independent activation of the c-Kit signaling pathway in ahuman mast cell leukemia cell line [2]. In fact, KIT D816V
is a hotspot mutation and is associated with disease
onset [3]. Mast cell leukemia (MCL) is the most aggressive
and extremely rare subtype of SM. The prognosis of MCL
is often very poor and there is no standard therapy available [4]. Moreover, a lack of knowledge regarding themolecular mechanisms of the disease, except for KIT
mutation, limits the development of effective therapeuticstrategies. In this report, we describe a novel translocation that is a potential driver of MCL in combination withKIT mutations. We present the first case of a patient with
MCL who carried a KIT D816H mutation and a translocation between the pogo transposable element derived
with ZNF domain (POGZ) and serine/threonine kinase 11(STK11, also known as LKB1) loci. This novel combinationof oncogenic events could explain the pathogenesis andtreatment resistance of MCL in the present case.
A previously healthy 48-year-old woman presented
with a chronic cough and was admitted to the local
clinic. Her complete blood count results showed bicytopenia (hemoglobin 8.6 g/dL, platelet count 92 K/mL).
Subsequently, symptoms of low-grade fever, night
sweats, and systemic edema appeared. Eventually, blood
tests revealed progressive bicytopenia and circulating
atypical MCs (21% of white blood cells). Chest X-ray
showed bilateral pleural effusion and the computed
CONTACT Manabu Kusakabemkusakabe@md.tsukuba.ac.jp
Tennodai, Tsukuba, 305-8575, Ibaraki, Japanß 2022 Informa UK Limited, trading as Taylor & Francis Group

tomography showed hepatosplenomegaly. Atypical MCs
accounted for 92.4% of the nucleated cells in the bonemarrow (BM) aspirate, and they were negative for myeloperoxidase (MPO) and nonspecific esterase staining(Figure 1(A)). No blastic cells were observed.
Immunohistochemical staining revealed that the MCs
were positive for c-KIT and tryptase (Figure 1(A)). Flowcytometric analysis revealed that the MCs were positive
for CD45 (dim), CD13, and CD33 but negative for theother tested markers (CD3, cyCD3, CD10, CD19, CD34,
CD38, CD56, MPO, and terminal deoxynucleotidyl transferase). Cytogenetic analysis showed the presence of acomplex karyotype (Figure 1(B)). Serum tryptase (179 mg/l,
normal range < 11.5 mg/l) and histamine (70.3 ng/ml, normal range 0.15–0.23 ng/ml) levels were markedly elevated. Molecular testing with targeted sequencing
revealed a KIT D816H mutation and the fusion of POGZ/STK11 (Figure 1(C–E)). The patient met the WHO 2016 criteria for MCL without comorbidities. Based on the abovefindings, a diagnosis of de novo MCL was made.
There is no standard treatment for MCL; therefore, theremission induction chemotherapy (idarubicin 12 mg/m2
on days 1–3, cytarabine 100 mg/m2 on days 1–7) used for
acute myeloid leukemia (AML) [5] was selected as the initial treatment. From day 3, systemic erythema occurred,
which may be due to allergic mediators released from theMCs. After the atypical MCs disappeared from the peripheral blood, her symptoms disappeared. Hematologicalremission was achieved after the chemotherapy, following
which, serum tryptase and histamine levels were reduced
to the normal range (Figure 2(A)). After one course of
consolidation chemotherapy (mitoxantrone 7 mg/m2 ondays 1–3, cytarabine 100 mg/m2 on days 1–5), the patient
received a cord blood transplant (CBT) with a 5/8 HLA

Department of Hematology, Faculty of Medicine, University of Tsukuba, 1-1-1

2

K. ISHITSUKA ET AL.

Figure 1. (A) Mast cells (MCs) in the bone marrow (BM) specimen. MCs infiltrate the BM and aggregate together (HE: hematoxylin
and eosin staining (400) and PAS: Periodic acid-Schiff staining (400)). MCs are strongly positive for tryptase (400) and c-KIT(400). (B) G-banded karyotype of BM cells at the onset of disease. (C) The somatic mutation was detected with the BM specimen. NM_ID; Accession ID for transcript, Chr, chromosome; Pos, position; Ref, reference; Alt, alteration; AA amino acid; VAF, variant
allele frequency; SNV, single nucleotide variant. (D) The translocation was detected with the BM specimen. Chr, chromosome; Pos,
position; VAF, variant allele frequency. (E) Genomic breakpoint found in this case. Nucleotide sequencing analysis revealed a junction between POGZ intron 1 and STK11 intron 1. (F) Schematic representation of the POGZ/STK11 fusion. Boxes indicate exons anddotted lines indicate introns. Arrows indicate breakpoints for the fusion found in this case.

allele-matched donor graft (total number of nucleatedcells: 3.48  107 cells/kg, CD34 positive cells: 1.10  105
cells/kg). The conditioning regimen comprised cyclophosphamide (50 mg/kg on days 5 and 4) and total body
irradiation (TBI) (12 Gy/6 fr from day 1 to day 1).
Tacrolimus and mycophenolate mofetil (2000 mg fromday 1 to day 30) were administered as graft versus hostdisease (GVHD) prophylaxis. However, primary graft failure
was diagnosed on day 25 after CBT. After a re-conditioning regimen [6] (fludarabine 30 mg/m2 from day 4 today 2, cyclophosphamide 2 g/m2 on day 2, and TBI
2 Gy on day 1), a second CBT was performed on day 35
after the initial CBT. Neutrophil engraftment was recordedon day 14 after the second CBT. Hematological remission

NOVEL TRANSLOCATION OF POGZ/STK11 IN MCL

3

Figure 2. Clinical course. (A) tryptase and histamine levels during the treatment. IDA, idarubicin; AraC, cytarabine; MIT, mitoxantrone; CBT, cord blood transplant; GO, gemtuzumab ozogamicin; DNR, daunorubicin. (B) variant allele frequencies of KIT p.D816
and POGZ/STK11 during the treatment.
was confirmed on day 28 and acute skin GVHD (stage 3,
grade 2) appeared at the same time but responded tothe topical steroid. She was discharged on day 93 after
the second CBT and there were no signs of chronic
GVHD. On day 240 after the second CBT, atypical MCs
were observed in the BM aspirate, and fluorescence insitu hybridization of the sex chromosome showed therecipient-derived karyotype at a frequency of 6.4%, indicating disease relapse. We started salvage therapy with
gemtuzumab ozogamicin (GO, 6 mg/m2 on days 1 and
15). Following GO administration, hematological remission
was achieved. We then repeated another course of GO
and started imatinib (100 mg/day) as subsequent maintenance therapy. However, a secondary relapse occurred
8 months after the first relapse (Figure 2 (A)). Atypical MCs
constituted almost all of the nucleated cells in the BM
aspirate. The variant allele frequencies (VAFs) of KIT 816H
and POGZ/STK11 were also elevated (Figure 2 (B)). Severe
anaphylactic shock (hypotension, systematic erythema,
and airway obstruction) due to tumor lysis occurred on
the day 1 after another salvage chemotherapy (daunorubicin 50 mg/m2 on days 1–5, cytarabine 50 mg/m2 ondays 1–7). Despite intensive treatment, the patient died ofpneumonia after 1 year and 9 months of MCL onset.

The prognosis of MCL is dismal, and the estimatedoverall survival (OS) is only a few months [4]. De novo
MCL is resistant to many therapeutic agents, including
tyrosine kinase inhibitors, 2-chlorodeoxydenosine, interferon-alpha, and GO, which show some degree of efficacy
against other subtypes of SM [7].
Considering that cytoreductive chemotherapy wasneeded in the case reported here, we opted to employ
the standard remission induction therapy for AML. After
achieving hematological remission, we performed allogeneic hematopoietic stem cell transplantation (HSCT).
Recently, it was reported that allogeneic HSCT for MCL in
12 patients resulted in a 3-year OS in only 17% of thecases [8]. However, most of the patients undergoingtransplantation had not achieved remission before thetransplantation in this study. In this case, hematologicalremission without the detection of both KIT D816H mutation and POGZ/STK11 translocation was achieved; therefore, we hypothesized that allogeneic HSCT would
potentially improve the OS. However, the disease
relapsed 8 months after CBT.
Several driver mutations in KIT have been detected in
80% of SM cases including those of MCL. However, 19%of de novo MCL patients do not exhibit KIT mutations [9].

4

K. ISHITSUKA ET AL.

Additional mutations in SRSF2, ASXL1, and RUNX1,
together with those in KIT, are related to a poor prognosis. Approximately half of the patients with MCL (13 outof 24 patients) exhibited these mutations [9], suggestingthat gene mutations other than KIT might be involved in
the pathogenesis of MCL.
In this case, a KIT D816H mutation and the novel POGZ/STK11 translocation were detected using targeted sequencing with a 390-gene panel for myeloid neoplasms. No
other mutation was detected using this sequencing panel.
We identified the POGZ/STK11 translocation by sequencing
STK11 using genomic DNA from BM cells followed by validation through Sanger sequencing. The fusion occurs
between the POGZ gene intron1 on chromosome 1q21.3
and the STK11 gene intron1 on 19p13.3, which was previously undescribed. Of note, the VAF of KIT D816H was low
compared to the observed number of atypical MCs in the
BM at the onset of MCL, while the VAF of POGZ/STK11 was
proportional to the tumor burden. Considering theseresults and the VAFs of the two mutations during theentire disease course, it is suggested that clonal MCs with
POGZ/STK11 translocation expanded at the onset of MCL,
and then a small subclone with a KIT D816H mutation
dominantly expanded during disease relapse.
The role of the POGZ/STK11 translocation in the pathogenesis of MCL is not elucidated yet because this translocation was not previously reported. However, themutation in STK11, which induces the loss of function,
was associated with tumorigenesis in diseases including
myeloproliferative disease and AML [10,11]. Further, somatic mutations of STK11 are associated with the inherited
cancer predisposition disease, Peutz-Jeghers syndrome[12]. In addition, the deletion of STK11 induces aberrant
mast cell activation through the regulation of AMP-activating protein kinase signaling [13,14]. Therefore, dysfunction in STK11 could be a possible mechanism
underlying MCL induction in this case.
Several fusion genes associated with STK11 weredetected in cancer tissues [15]. Considering that STK11 isa tumor suppressor gene, these fusions would induce
dysfunction of STK11. In this case, the translocationinduced the loss of the promoter region in intron 1 on
STK11, possibly leading to the transcriptional deactivationof the kinase domains (exon 4–6) on STK11.
In summary, this is the first reported case of MCL with
POGZ/STK11 translocation and KIT D816H mutation.
Although the patient achieved hematological remission
once, the KIT D816H-mutated subclone of MCs dominantly
expanded and became refractory to multiple treatments.
This report contributes to understanding the molecularpathogenesis and clinical features of MCL. Further studies
are needed to develop a better treatment strategy.

Ethical statements
The study was approved by the institutional review board atUniversity of Tsukuba Hospital. Written informed consent
was obtained from the patient and her families.

Disclosure statement
The authors declare no conflict of interest.

Funding
This work was supported by Grants-in-Aid for Scientific
Research(KAKENHI:
21J20378[K.I.],
18K16076[M.K.],
21H02945[M.S.-Y.], and 19H03684[S.C.]) from the Ministry of
Education, Culture, Sports, and Science of Japan.

ORCID
Hidekazu Nishikii
Manabu Kusakabe

Data availability statement
All data and materials are available upon request.

References
[1]

[2]

[3]

[4]

[5]

[6]

[7]
[8]

Acknowledgment
The authors thank the patient for providing valuable
information.

http://orcid.org/0000-0002-6277-4082
http://orcid.org/0000-0003-2518-0776[9]

Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to
the world health organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–2405.
Furitsu T, Tsujimura T, Tono T, et al. Identification of mutations in the coding sequence of the proto- oncogene c-kit ina human mast cell leukemia cell line causing ligand-independent activation of c-kit product. J Clin Invest. 1993;92(4):1736–1744.
Piao X, Paulson R, van der Geer P, et al. Oncogenic mutationin the kit receptor tyrosine kinase alters substrate specificity
and induces degradation of the protein tyrosine phosphatase
SHP-1. Proc Natl Acad Sci USA. 1996;93(25):14665–14669.
Pardanani A. Systemic mastocytosis in adults: 2019 update
on diagnosis, risk stratification and management. Am J
Hematol. 2019;94(3):363–377.
Miyawaki S, Sakamaki H, Ohtake S, et al. A randomized, postremission comparison of four courses of standard-dose consolidation therapy without maintenance therapy versus threecourses of standard-dose consolidation with maintenancetherapy in adults with acute myeloid leukemia: the Japan
adult leukemia study group AML97 study. Cancer. 2005;
104(12):2726–2734.
Suma S, Yokoyama Y, Momose H, et al. Salvage cord bloodtransplantation using a short-term reduced-intensity
conditioning regimen for graft failure. Intern Med. 2022;61(11):1673–1679.
Georgin-Lavialle S, Lhermitte L, Dubreuil P, et al. Mast cellleukemia. Blood. 2013;121(8):1285–1295.
Ustun C, Reiter A, Scott BL, et al. Hematopoietic stem-celltransplantation for advanced systemic mastocytosis. J Clin
Oncol. 2014;32(29):3264–3274.
Jawhar M, Schwaab J, Meggendorfer M, et al. The clinicaland molecular diversity of mast cell leukemia with or without

NOVEL TRANSLOCATION OF POGZ/STK11 IN MCL

[10]

[11]

[12]

associated hematologic neoplasm. Haematologica. 2017;
102(6):1035–1043.
Marinaccio C, Suraneni P, Celik H, et al. LKB1/STK11 is atumor suppressor in the progression of myeloproliferative
neoplasms. Cancer Discov. 2021;11(6):1398–1410.
Green AS, Chapuis N, Maciel TT, et al. The LKB1/AMPK signaling pathway has tumor suppressor activity in acute myeloid
leukemia through the repression of mTOR-dependent oncogenic mRNA translation. Blood. 2010;116(20):4262–4273.
Hezel AF, Bardeesy N. LKB1; linking cell structure and tumor
suppression. Oncogene. 2008;27(55):6908–6919.

[13]

[14]

[15]

5

Jin F, Li X, Deng Y, et al. The orphan nuclear receptor NR4A1
promotes Fc e RI – stimulated mast cell activation and anaphylaxis by counteracting the inhibitory LKB1/AMPK axis.
Allergy. 2019;74(6):1145–1156.
Hwang SL, Li X, Lu Y, et al. AMP-activated protein kinase
negatively regulates Fc e RI-mediated mast cell signaling andanaphylaxis in mice. J Allergy Clin Immunol. 2013;132(3):729–736.e12.
Gao Q, Liang WW, Foltz SM, et al. Driver fusions and theirimplications in the development and treatment of humancancers. Cell Rep. 2018;23(1):227–238.e3.

Received: 15 February 2022

Revised: 17 June 2022

Accepted: 16 August 2022

DOI: 10.1002/pmrj.12898

UPDATED SYSTEMATIC REVIEW—CME

The effectiveness of exercise with behavior change
techniques in people with knee osteoarthritis: A systematic
review with meta-analysis
Takashi Ariie PhD, MSc 1,2| Hiroshi Takasaki PhD 3 | Ryota Okoba PhD 1
Hiroki Chiba BSc 4 | Yusuke Handa BSc 4 | Takahiro Miki MSc 4 |Shunsuke Taito PhD 2,5
1

Department of Physical Therapy, School of
Health Sciences at Fukuoka, International
University of Health and Welfare,
Fukuoka, Japan
2
Scientific Research WorkS Peer Support
Group (SRWS-PSG), Osaka, Japan3
Department of Physical Therapy, Saitama
Prefectural University, Saitama, Japan
4
Graduate school of Rehabilitation Science,
Saitama Prefectural University, Saitama,Japan
5
Division of Rehabilitation, Department ofClinical Practice and Support, Hiroshima
University Hospital, Hiroshima, Japan
6
Department of Emergency Medicine,National Hospital Organization Mito Medical
Center, Ibaraki, Japan
7
Department of Physical Therapy, Health
Sciences at Odawara, International University
of Health and Welfare, Kanagawa, Japan

Correspondence
Takashi Ariie, Department of Physical
Therapy, School of Health Sciences at
Fukuoka, International University of Healthand Welfare, 137-1 Enokizu, Okawa-shi,
Fukuoka, Japan.
Email: tariie@iuhw.ac.jp|

Yusuke Tsutsumi DrPH 2,6

Masaharu Morita PhD 7

Abstract
Objective: The purpose of this systematic review with meta-analysis was to
examine the effectiveness of exercise with behavior change techniques (BCTs)
on core outcome sets in people with knee osteoarthritis.
Literature Survey: We searched randomized controlled trials (RCTs) in eightdatabases (MEDLINE, Embase, CENTRAL, CINAHL, PsycINFO, PEDro,
ICTRP, and ClinicalTrials.gov) up to November 4, 2021.
Methodology: Eligible participants were people with knee osteoarthritis. Theintervention was exercise with BCTs. Primary outcomes included physical function, quality of life (QOL) 6 to 12 months after intervention, and adverse events.
Secondary outcomes were knee pain, exercise adherence, mobility, and selfefficacy 3 months or more after intervention. The bias risk was assessed using
the Risk of Bias 2 tool. The random-effects model was used for the metaanalysis.
Synthesis: We found 16 individual BCTs, and 37.7% of trials used a single
BCT. For meta-analysis, we included 21 RCTs (n = 1623). Most outcomes had
a very low certainty of evidence, and the risk of bias was the consistent reason
for downgrading evidence levels. The standardized mean difference (SMD)with 95% confidence interval (95% CI) was 0.00 ( 0.24, 0.24) in physical function, 0.33 ( 0.51, 1.17) in exercise adherence, and 0.04 ( 0.39, 0.47) in selfefficacy. The risk ratio (95% CI) of adverse events was 3.6 (0.79, 16.45). QOL
was not pooled due to insufficient data (very low certainty of evidence). In contrast, the SMD (95% CI) for knee pain reduction and mobility improvement was
0.33 ( 0.53, 0.13) and 0.21 ( 0.05, 0.47) with moderate and low certaintyof evidence, respectively.
Conclusion: The evidence is inconclusive regarding the effectiveness of BCTs
with exercises on core outcome sets. Further research should explore theeffectiveness of BCTs with valid design.
Protocol Registration: PROSPERO (CRD42020212904).

INTRODUCTION
Knee osteoarthritis is one of the leading causes of disability globally.1 The social cost of osteoarthritis has
been estimated to reach 0.50% of a country’s grossdomestic product.2 Non-surgical management, especially exercise, is consistently recommended in clinical
1012

|

|

© 2022 American Academy of Physical Medicine and Rehabilitation.

practice guidelines as first-line treatment.3 However,
exercise adherence is generally poor in people withknee osteoarthritis,4 limiting the short-term (2- to
6-month) benefits.5 Previous systematic reviews6,7 indicate that interventions with behavior change techniques (BCTs) may improve exercise adherence inpeople with musculoskeletal diseases, associated with
http://www.pmrjournal.org

PM&R. 2023;15:1012–1025.

long-term improvement of pain and physical function in
the knee osteoarthritis population.8
Behavior change techniques (BCTs) are “observable, replicable, and irreducible components of an intervention designed to alter or redirect causal processes
that regulate behavior”9 that can be used to improve
exercise adherence.10 BCTs can be incorporated into
exercise programs. For instance, therapists can “askthe person to walk for 100 yards a day for the first
week, then half a mile a day after they have successfully achieved 100 yards, then 2 miles a day after they
have successfully achieved 1 mile” (graded tasks).9 In
addition, BCTs can be provided separately from exercise. Therapists may “prompt the patient to identify barriers preventing them from starting a new exercise
regimen” (problem solving).9
The European League Against Rheumatism recommends exercise intervention, incorporating BCTs toincrease the amount of physical activity.11 However,
the effectiveness of exercise with BCTs on other coreoutcome sets, such as physical function, quality of life
(QOL), or knee pain, has not been investigated.12 The
Outcome Measures in Rheumatology–Osteoarthritis
Research Society International reported core outcome
sets that clinical trials should assess and report, including physical function, QOL, and pain as mandatory
domains in the hip and knee osteoarthritis population.13
The aim of this systematic review was to comprehensively examine the effectiveness of exercise with BCT
on core outcome sets including physical function, QOL,or adverse events, compared to exercise without BCTs,
usual care, or no active intervention in adults with knee
osteoarthritis.

METHODOLOGYThe Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) guidelines were followed,14
and the checklist can be found in Table S1. This review
protocolwas
registered
with
PROSPERO(CRD42020212904).15

Literature search
The following databases were searched on November
4, 2021: MEDLINE, Embase, Cochrane Central Registerof Controlled Trials (CENTRAL), CINAHL, PsycINFO, andPEDro. Ongoing trials in the World Health Organization
International Clinical Trials Registry Platform (http://apps.
who.int/trialsearch/) and Clinical Trials.gov (ClinicalTrials.
gov) were also searched on November 4, 2021. Table S2outlines the search strategy. The references of relevant
guidelines (the European League Against Rheumatism
Recommendations11,12 and the Osteoarthritis ResearchSociety International guidelines16) and all references1013

included in each article were also searched. When theavailable information was insufficient, we contacted thestudy authors via email. A second attempt was made if
the first remained unanswered.

Inclusion and exclusion criteria
Randomized-controlled trials (RCTs), crossover RCTs,
and cluster RCTs were eligible for this systematic
review. Both published and unpublished trials were
included. There were no restrictions on the intervention
duration, follow-up period, language, or study location.
Cluster RCTs were excluded if an intraclass correlation
coefficient (ICC) to consider the variability of clusters
for appropriate analyses was not available. Eligible participants included adults (≥18 years) with knee osteoarthritis with or without radiographic diagnosis, or who
self-reported knee osteoarthritis based on chronic joint
pain as defined by the study author. Participants who
had a knee joint operation within 6 months of the study
were excluded. Interventions containing exercise with
BCTs were eligible. We included any exercise programs aimed at improving symptoms, regardless ofintensity, duration, content, or frequency that can beprovided in any form, such as by health care providers
or booklets including physical activity interventions. If
interventions included other conservative managementthat may influence the outcome, including electrotherapy, diet, or medication, participants were excluded.
For BCTs, an appropriate taxonomy was used to identify the techniques and to categorize the technique
type.9 International experts developed the taxonomy,
and all 93 techniques were defined for coding. We followed the standardized BCT coding9: “(1) containverbs that refer to the action(s) taken by the person/sdelivering the technique and (2) contain the term
behavior referring to a single action or sequence ofactions that includes the performance of wanted
behavior(s) and/or inhibition (non-performance) of
unwanted behavior(s).” The taxonomy of BCT includes
93 techniques, such as “adding objects to the environment” (e.g., providing elastic bands to promote exercise, providing a pedometer to promote walking, orproviding a yoga mat for home exercise), “selfmonitoring of behavior” (e.g., asking patients to record
the daily total number of steps in a diary), and “social
support (unspecified)” (e.g., advising patients to call
staff when they experience difficulty with exercise).9
Any BCTs defined in the taxonomy, such as “gradedtasks,” which may be part of an exercise regimen, or“problem solving,” which may be provided separatelyfrom exercise, were accepted. Prescribing exercise
interventions can potentially include some BCT components, such as “instruction on how to perform a behavior” or “action planning.” Therefore, if interventions did
not explicitly describe BCT components in the articles

19341563, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12898 by Kyoto Universitaet, Wiley Online Library on [12/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

ARIIE ET AL.

or protocols, they were not considered as appropriate
BCTs (e.g., “instruction on how to perform a behavior”
is defined as “advise or agree on how to perform thebehavior.” If the study mentioned that “an intervention
group conducted a walking exercise,” this intervention
was coded as “instruction on how to perform a behavior.” If the study mentioned that “therapists advised
participants on how to walk on a treadmill,” then thisintervention was coded as “instruction on how to perform a behavior.”) In addition, if interventions including
the definition of BCTs were a part of the research procedure (e.g., one of the BCTs, “self-monitoring of
behavior,” should not be just a part of the data collection procedure), it was not considered an appropriate
BCT. A control group was eligible if they received any
exercise program described above. This comparison is
ideal for examining the additional effect of BCTs on
exercise. Therefore, studies were excluded if the control intervention contained BCTs. Usual care was also
included as defined by the authors, and no active intervention, including a waitlist, as the control intervention.
Three primary outcomes and four secondary outcomes were selected as recommended by the Cochrane
Handbook for Systematic Reviews of Interventions.17 The
outcomes were selected based on the core outcome sets
in clinical trials of knee osteoarthritis.13 In addition, we prioritized outcome domains in which the effectiveness waspoorly reported in previous reviews.5,10,12,18 Primary outcomes were physical function, QOL 6 to 12 months after
the end of the intervention, and the number of all adverse
events at any time point. Physical function was defined
as measures used in self-reported questionnaires, suchas the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). QOL included self-reported
questionnaires, such as the Euro QOL 5 Dimensions
Questionnaire or the 36-item Short-Form Survey. The
number of all adverse events as defined by the author,
such as falls, was included.
Secondary outcomes were knee pain as measured
by a self-reported scale (e.g., visual analog scale,numerical rating scale, or a questionnaire, such as
WOMAC); exercise adherence as measured by a selfrated scale, a logbook, or a questionnaire; mobility as
measured by a walking test, like the Six-Minute Walk
Test (6MWT); and self-efficacy related to symptoms or
the ability to perform the exercise as measured by aself-rated scale or questionnaire 3 months or more after
the end of the intervention. If studies reported multiple
eligible outcomes, we prioritized measures that weused as examples in our pre-registered protocol. The
latest follow-up time point was used if the included
studies measured multiple time points.

Study selection
Pairs of review authors (H.T., R.O., H.C., Y.H., T.M.,
and T.A.) independently assessed records from the

EXERCISE WITH BCTs IN KNEE OSTEOARTHRITIS

titles and abstracts to identify eligible studies using
Rayan software (available at https://www.rayyan.ai/).
First, the six authors screened 50 records for calibration
training to find and resolve ambiguity in the eligibility criteria. Then, pairs of review authors (H.T., R.O., H.C., Y.
H., T.M., and T.A.) independently conducted full-text
screening to assess whether the studies met the criteria. If two authors were conflicted in their decision to
include a study, they discussed the matter to reach an
agreement. If they could not do so, the third author (S.
T.) mediated and helped reach a conclusion. After the
full-text screening, eligibility of the intervention components of the included studies was assessed independently by the two authors (Y.H. and T.A.) who hadcompleted an online BCT coding training (available athttps://www.bcttaxonomy.com/). For studies excluded
for having the “wrong intervention,” two authors (Y.H.
and T.A.) assessed the intervention again to avoid dismissing relevant studies.

Methodological quality assessment
Pairs of review authors (R.O., H.C., and T.A.) independently assessed the risk of bias of studies included in
the quantitative analysis using the Risk of Bias 2 tool.19
This tool assesses five domains (the randomization
process, deviations from intended interventions, missing outcome data, outcome measurement, and thereported results). The randomization process domain
assessed the method of randomization, allocation, andbaseline characteristics. The deviations from intended
interventions domain assessed the blinding of participants and therapists, drop out from the intervention, or
the use of intention-to-treat analysis. The missing outcome data domain assessed missing variables and statistical methods. The outcome measurement domain
assessed the validity of the measurement, assessor
blind and outcome characteristics. The tool assessed
these domains for each outcome in RCTs. Thus thistool could consider the difference of risk of bias for eachoutcome in a single RCT. Pairs of review authors
assessed three included studies for calibration training
to find, clarify, and resolve ambiguity between assessors. If two authors had a conflict, they discussed thematter until they reached an agreement. The third
author (S.T.) resolved any remaining conflicts.

Data extraction
Pairs of review authors (H.T., R.O., H.C., Y.H., and T.
A.) independently extracted data using data extraction
forms that were pilot-tested in advance on 10 random
studies. When the two authors were conflicted, they
discussed the matter to reach an agreement. A third
author (S.T.) resolved any remaining conflicts. The
characteristics of the studies (the name of the first

19341563, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12898 by Kyoto Universitaet, Wiley Online Library on [12/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License1014

author, publication year, and study location), participants (sample size, gender, disease condition, andage), interventions (contents, duration, and BCT), outcome measures, and results (post-intervention values)
were extracted.

Statistical analysis
The data were analyzed using Review Manager software (RevMan 5.4). For the meta-analysis, the randomeffects model was used. For dichotomous outcomes,
we used the Mantel–Haenszel method. For continuous
outcomes, we used the Inverse Variance Method tosynthesize the data. All of the data were analyzed fordiscrete variables according to the intention-to-treat(ITT) concept. We did not perform imputation of missing
values for continuous variables, per the Cochranehandbook recommendation.17 The standardized meandifference (SMD) with a 95% confidence interval(CI) for continuous outcome data were calculated if
studies used the same outcomes but different measurement tools. A risk ratio with a 95% CI for dichotomous outcome data was calculated.
We performed the meta-analyses using the originaldata. When the included study used more than two eligible intervention groups, the statistical data (meanvalue, standard deviation, and sample size) of the twogroups were combined following the Cochrane handbook guidelines to present as a single intervention
group using the RevMan calculator.17
We assessed the heterogeneity by observing a forest plot and calculating I-square (I 2) values (I 2 values
of 0% to 40% might not be important; 30% to 60% may
represent moderate heterogeneity; 50% to 90% may
represent substantial heterogeneity; 75% to 100% may
represent considerable heterogeneity).17 The reasonsthat heterogeneity was present (I 2 > 50%) wereassessed and a Cochrane χ 2 test (Q-test) was conducted, with p < .10 considered statistically significant.17 We planned to observe funnel plots andconduct Egger’s test (p < .05) when we found morethan 10 studies. ClinicalTrials.gov and ICTRP weresearched to identify finished but unpublished studies.
When heterogeneity was found in the results, a subgroup analysis was conducted to evaluate inconsistencies in primary outcomes using the following
conditions: (1) mean age (a: 60 years or older, or b:
younger than 60 years); (2) the number of BCT components (a: multiple components [more than two techniques], or b: single component); (3) control types (a:exercise regimen, b: usual care, or c: no active intervention, including waitlist); and (4) intervention duration(a: 6 months or longer, or b: less than 6 months). In
addition, we conducted a sensitivity analysis to assess
the treatment effect in primary outcomes, excluding
studies with some concern or at high risk of bias in the1015

randomization process and those using imputed
statistics.

Summary of findings
A summary of findings was created for physical function, QOL, the number of all adverse events, knee pain,
exercise adherence, mobility, and self-efficacy following the Grading of Recommendations, Assessment,
Development and Evaluation (GRADE) guidelines.20
We used the GRADEpro GDT software. The comparison in the summary of findings included exercise regimen, usual care, or no active intervention. We reported
outcome data for each outcome. The quality assessment of the evidence for each outcome was conductedbased on five domains (limitations, inconsistency, indirectness, imprecision, and publication bias). The limitation domain was downgraded when trials had a highoverall risk of bias and a high risk of bias in the randomization process. The inconsistency domain was downgraded considering heterogeneity (I 2-value) and the
direction of point estimates in each trial. The indirectness domain was downgraded when the included trials
had characteristics different from our primary interest.
The imprecision domain was downgraded when the
95% CI of effect measures was wide and the total sample size was less than 400. The publication bias
domain was downgraded when asymmetrical funnelplots and statistically significant results of Egger’s test
were evident. It is recommended that the findings ofsystematic reviews be based on the effect size and thecertainty of the evidence for better interpretability.21
The point estimate of the SMD or risk ratio was used as
the magnitude of the effect, and 95% CI was used tojudge the imprecision domain for the certainty of evidence. We presented results using a standardized
expression.21

Differences between protocol and thisreview
A post hoc subgroup analysis was conducted based on
the number of BCT components (multiple vs. single
and four or more vs. three or less) for secondary outcomes that showed low to high certainty of evidence toexplore the relevant implications between BCTs andoutcomes.

RESULTS
We identified 8924 records from our initial search andscreened 5470 records after duplicates were removed.
We assessed 238 records for eligibility, and included
52 RCTs22–73 (55 records) for qualitative synthesis and19341563, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12898 by Kyoto Universitaet, Wiley Online Library on [12/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

ARIIE ET AL.

FIGURE 1

EXERCISE WITH BCTs IN KNEE OSTEOARTHRITISThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram.

21 RCTs24,26,27,30,32,36,42,43,45,46,54,55,57–59,61,66,68,69,71,72
with 1623 participants for the meta-analysis (Figure 1).
Of the 52 included RCTs, 47 provided results and5 were ongoing studies. The eligibility of 15 studies
could not be judged due to insufficient information(studies awaiting classification), although the authors of
those studies were contacted. Table S3 lists the studies
excluded from this review and the reasons for their
exclusion.

Characteristics of studies
Thirty-five studies (74.5%) had participants 60 years ofage or older (Table 1). The disease conditions wereassessed using the Kellgren-Lawrence grade and varied widely across the included studies (Table S4). Thirteen studies (27.7%) were from the United States.
Thirty-seven included studies (78.7%) had an intervention duration of 3 months or less, and only three studies(6.4%) continued their intervention for more than
6 months. Through the BCT coding process, we identified 16 individual BCTs, and 20 studies (37.7%) used asingle type of BCT. The most commonly used BCT was“adding objects to the environment,” which was integrated into 43 interventions (81.1%) among 53 interventions. The identification of the BCT used in the included
studies is listed in Table S5. An exercise control group
was used in only seven studies (14.9%), and usual
care and no active intervention groups were used in

15 (31.9%) and 25 (53.2%) studies, respectively. All
included studies had a randomized-controlled design.
Three ongoing studies were identified (Table S6).

Risk of bias within studies
In this systematic review, 21 studies reporting 44 outcomes covered three primary and four secondary outcomes. The overall risk of bias was high in 17 studies
and was of some concern in 4 studies (Tables S7 toS13). Nine of 21 studies (42.9%) were rated as highrisk of bias in deviation from the intended interventions
due to the lack of blinding participants and therapists toallocation, drop out from the intervention, or analysis
other than ITT analysis. In 44 reported outcomes,
27 (61.4%) had high risk of bias in measurement of theoutcome due to invalid measurement or lack of blindedassessors.

Primary outcomes
Five studies36,42,57,58,68 (n = 288) reported physicalfunction outcomes measured using the WOMAC (physical function subscale), Late Life Function and Disability
Index (basic lower limb function subscale), or Arthritis
Impact Measurement Scales (physical activity subscale)
6 to 12 months after the intervention ended (Figure 2,
Table 2). The types of control groups included exercise

19341563, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12898 by Kyoto Universitaet, Wiley Online Library on [12/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

1016

TABLE 1

1017

Characteristics of the included studies

TABLE 1

Sample size(Continued)

Behavioral practice/rehearsal

22Median (range)

50 (17–313)

Problem solving

Total (n)3080

Information about health consequences

2

Action planning

1

Biofeedback

1

Goal setting (behavior)

1

Mean age (n)>60 years

35

Kellgren-Lawrence grade (n)31Types of control group (n)1 or 2

2

No intervention

25

1–3

4

Usual care

15

1–4

2

Exercise7

2 or 34

2–4

9Note: n = 47; 53 interventions.
Abbreviations: BCTs, behavior control techniques; n.r.: not reported.
a
One study was conducted in two countries (USA and Denmark).

3 or 4

2

0–4

1

n.r.

22

Location (n)aUSA

13

Australia

4

Brazil4

Canada

4

China

4

Denmark

4

Finland2

Netherlands

2

Nigeria

2

Other

9

Intervention duration (n)3 months or less37

More than 3 to less than 6 month7

6 month or longer

3

No. of BCTs used in the intervention (n)
1

20

2

15

3

7

4

8

5

2

10

1

Types of BCTs (n)Adding objects to the environment

43

Instruction on how to perform the behavior

19

Self-monitoring of behavior

12

Social support (unspecified)8

Feedback on behavior

8

Monitoring of behavior by others without feedback

8

Demonstration of the behavior

7

Graded tasks

4

Prompts cues

3

Review behavior goal(s)2(one study) and usual care (four studies). The evidence
was very uncertain regarding the effect of exercise withBCT on physical function compared with the control
group (SMD [95% confidence interval (CI)] 0.00 [ 0.24,
0.24], I 2 = 0; very low certainty of evidence).
Two studies36,68 reported a QOL outcome as
assessed by 15D (total score) and SF-36 (physicalfunctioning subscale). The reported results evaluateddifferent domains, and results could not be combined.
Helminen et al.36 reported no significant differences
assessed with 15D 10.5 months after the end of theintervention compared with the usual care control group( 0.40 [95% CI 0.80, 0.00]). Waller et al.68 reported
no significant differences assessed with SF-36 at
12 months after intervention compared with the exercise control group (physical functioning subscale 0.00
[95% CI 7.37, 7.37]). Overall, the evidence of certainty was very low.
Eighteenstudies24,26,27,30,32,36,42,43,45,46,54,55,58,59,61,66,69,71 (n = 1450)
reported adverse events as assessed by questionnaires,
reports from health care providers, or from a logbook ordiary. The types of control groups were exercise (onestudy69), usual care (eight studies30,32,36,42,43,46,54,58), andno active intervention (nine studies24,26,27,45,55,59,61,66,71).
In nine studies,30,32,36,43,55,58,66,69,71 both the intervention
and control groups reported no adverse events. One
study27 reported a reduction in the number of falls in theintervention group during the study, despite an increasein the no intervention control group. The evidence wasvery uncertain regarding the incidence of adverse events
due to exercise with BCT compared with usual care or no
active interventions (risk ratio 3.6 [95% CI 0.79, 16.45],
I 2 = 64%; very low certainty of evidence).

Secondary outcomes(Continues)

Eight studies32,36,42,46,54,58,68,72 (n = 603) reported
knee pain as assessed by the visual analog scale, the19341563, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12898 by Kyoto Universitaet, Wiley Online Library on [12/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

ARIIE ET AL.

FIGURE 2

EXERCISE WITH BCTs IN KNEE OSTEOARTHRITISForest plots of primary outcome.

WOMAC (pain subscale), the Knee injury and Osteoarthritis Outcome Score (pain subscale), or numerical
pain rating scale 3 to 12 months after the end of theintervention (Figure 3, Table 2). The types of control
groups were exercise (one study68) and usual care(seven studies32,36,42,46,54,58,72). Exercise with BCT likely
reduces knee pain slightly (SMD 0.33 [95% CI 0.53,
0.13], I 2 = 31%; moderate certainty of evidence).
Two studies42,57 (n = 61) reported exercise adherence as assessed by self-reported walking distance orvolume of exercise at 6 to 10 months after the end of
the intervention compared with the usual care control
group. The evidence of the effectiveness of exercise
with BCTs between the groups for exercise adherence

was very uncertain (SMD 0.33 [95% CI 0.51, 1.17],
I 2 = 59%; very low certainty of the evidence).
Four studies32,54,57,58 (n = 231) reported mobility
outcomes as assessed by a 6 minute walking test
(6MWT) or the Long-distance Corridor Walk Test, 3 to
9 months after the end of the intervention. The control
group was usual care. Exercise with BCTs may
improve mobility compared with the control group(SMD 0.21 [95% CI 0.05, 0.47], I 2 = 0; low certaintyof evidence).
Five studies36,42,54,57,72 (n = 329) reported on selfefficacy as assessed by the Arthritis Self-Efficacy Scale(pain subscale), Pain Self-Efficacy Questionnaire, or
the Self-efficacy Scale 3 to 10.5 months after the end of

19341563, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12898 by Kyoto Universitaet, Wiley Online Library on [12/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

1018

SMD 0.33 higher (0.51
lower to 1.17 higher)
SMD 0.21 higher (0.05
lower to 0.47 higher)
SMD 0.04 higher (0.39
lower to 0.47 higher)———

Exercise adherence self-reported walking distance,
volume of exercise (diary) 6–10 months after theend of the intervention

Mobility walking speed, 6MWT, LDCWT 3–12 months
after the end of the intervention

Self-efficacy ASES (pain), PSEQ, SES 3–10.5 months
after the end of the intervention

—

—

—

—

329 (5 RCTs)

231 (4 RCTs)

61 (2 RCTs)

603 (8 RCTs)⨁◯◯◯very lowc,l,m⨁⨁◯◯
lowj,k⨁◯◯◯very lowc,i⨁⨁⨁◯moderateh⨁◯◯◯
very lowe,f,g⨁◯◯◯
very lowc,dvery lowb,c⨁◯◯◯Certainty of theevidence (grade)

It was inappropriate topool the data
because twostudies useddifferent outcome
measures

Comments

1019

19341563, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12898 by Kyoto Universitaet, Wiley Online Library on [12/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Note: GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effectestimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited; the true effect may besubstantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
Abbreviations: AIMS, Arthritis Impact Measurement Scales; ASES, Arthritis Self-Efficacy Scale; BCTs, behavior change techniques; CI, confidence interval; KOOS, Knee Injury and Osteoarthritis Outcome Score;
LDCWT, Long-distance Corridor walk test; LLFDI, Late Life Function and Disability Index; PSEQ, Pain Self-Efficacy Questionnaire; QOL, quality of life; RCTs, randomized controlled trials; RR, risk ratio; SMD,
standardized mean difference; VAS, visual analogue scale; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; 6MWT, 6 minute walking test.
a
The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
b
Downgraded one level for serious risk of bias (four of five studies showed a high overall risk of bias, including two studies with a high risk of bias in the randomization process).
c
Downgraded two levels for very serious imprecision (small sample size [<400] and 95% CI includes 0.2 and 0.2).
dDowngraded one level for serious risk of bias (high overall risk of bias).
e
Downgraded one level for serious risk of bias (15 of 18 studies showed high overall risk).
f
Downgraded one level for serious indirectness (for several studies we assumed that no adverse events occurred in the control group).
g
Downgraded one level for serious imprecision (sample size was lower than optimal information size and 95% CI includes the 1.0).
hDowngraded one level for serious risk of bias (seven of eight studies showed high overall risk).
i
Downgraded one level for serious risk of bias (both studies showed a high overall risk of bias).
j
Downgraded one level for serious imprecision (small sample size [<400]).
k
Downgraded one level for serious risk of bias (four of five studies showed a high overall risk of bias).
l
Downgraded one level for serious risk of bias (all studies showed a high overall risk of bias).
m
Downgraded one level for serious inconsistency (I 2 was 72% and point estimates vary widely among studies).

SMD 0.33 lower (0.53 lower
to 0.13 lower)—

Knee pain VAS, WOMAC (pain), KOOS pain, NRS 3–
12 months after the end of the intervention

Variable according toindividual studies andoutcome measures (2RCTs)

288 (5 RCTs)

No. of participants(studies)

RR 3.60 (0.79–16.45) 1450 (18 RCTs)

87 per 1000 (19–397)—

Adverse event Questionnaire or report from providers or 24 per 1000
participants, including logbook or diary

SMD 0 (0.24 lower to 0.23
higher)——There were no studies thatfound a difference
between the intervention
and control groups for
QOL

Risk with exercise
with BCTQOL Two different outcomes: 15D (Scale from 0 to 1) at —10.5 months after completion of the intervention;
SF-36 (physical functioning; Scale from 0 to 100) at
12 months after completion of the intervention

Physical function WOMAC (physical function; Scalefrom 0 to 68), LLFDI (basic lower limb function;
Scale from 0 to 100), AIMS (physical activity; Scalefrom 0 to 10) 6–12 months after the end of theintervention

Outcomes

Risk with exercise,usual care, or no
active intervention

Anticipated absolute effectsa (95% CI)
Relative
effect (95% CI)

Summary of findings in the comparison between exercise with behavior change techniques (BCTs) and exercise, usual care, or no active intervention.

Patient or population: knee osteoarthritis
Setting: any
Intervention: exercise with BCTs
Comparison: exercise, usual care, or no active intervention

TABLE 2

ARIIE ET AL.

FIGURE 3

EXERCISE WITH BCTs IN KNEE OSTEOARTHRITISForest plots of secondary outcome.

the intervention. The control group was usual care. The
evidence is very uncertain regarding the effectivenessof exercise with BCT on self-efficacy compared with theusual care control group (SMD 0.04 [95% CI 0.39,
0.47], I 2 = 72%; very low certainty of the evidence).

Additional analysis
We conducted a subgroup analysis for the primary outcome of adverse events, as we observed statistical

heterogeneity (I 2 = 64%, p = .04) (Figures S1 and S2).
The subgroup comparison was conducted in numbers of
BCT, control intervention type, and intervention duration.
Only type of control interventions showed significant differences (I 2 = 66%, p = .09). Sensitivity analysis was also
conducted for physical function and adverse events.
Excluding studies with some concern of or at high risk ofbias in the randomization process or studies that used
imputed statistics did not result in any significant difference. We could not conduct observations of funnel plots
and Egger’s test due to an insufficient number of studies.

19341563, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12898 by Kyoto Universitaet, Wiley Online Library on [12/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

1020

Post hoc analysis
We conducted post hoc subgroup analysis for knee
pain and mobility outcomes dividing trials using multiple
BCTs and single BCT (Figure S3). The SMD (95% CI)
among trials using multiple BCTs for knee pain andmobility was 0.35 ( 0.60, 0.09) and 0.29 ( 0.02,0.60), respectively. The SMD (95% CI) for those using
single BCT for knee pain and mobility was 0.27
( 0.65, 0.11) and 0.03 ( 0.45, 0.51), respectively. In
addition, we conducted post hoc subgroup analysis oftrials using four or more BCTs and those using three or
fewer BCTs. The SMD (95% CI) among trials using fouror more BCTs for knee pain and mobility was 0.03
( 0.37, 0.43) and 0.22 ( 1.07, 0.64), respectively.
The SMD (95% CI) for those using three or fewer BCTs
for knee pain and mobility was 0.40 ( 0.59, 0.21)
and 0.26 ( 0.02, 0.53), respectively.

DISCUSSION
This is the first systematic review with meta-analysis
that examined the long-term effectiveness of exercise
with BCT on core outcome sets in people with knee
osteoarthritis, compared with exercise, usual care, or
no active intervention. The certainty of evidence
regarding clinically important outcomes such as physical function, QOL and adverse events was very low.
These findings suggest that the BCTs used in the
included trials might be suboptimal to enhance theexercise intervention.
Potential reasons for the very low certainty of evidence may be the lack of physical function and QOL outcomes measured at long-term time points and the risk ofbiases in each RCT. Only 5 and 2 of 52 RCTs reported
physical function and QOL measured at long-term time
points, respectively. The most common reason for downgrading the certainty of the evidence was the risk of bias
in all outcomes of our review, followed by the imprecision domain in three outcomes, such as a small sample
size. In the detail of risk of bias domains, deviation from
intended interventions and measurement of outcome
was consistently high risk among included trials. Thus
future studies should consider the following four aspects.
First, the authors of RCTs should investigate the effectiveness of exercise with BCTs on core outcome sets
including physical function and QOL. Second, an ITT
analysis should be used to improve the intervention
effectiveness as allocated. Third, although blinding therapists and patients is difficult in non-pharmacologicaltrials,74 assessors should be blinded to decrease the riskof bias in measuring outcomes. Finally, RCTs with alarger sample size are needed to improve the precisionof the estimates.
Our findings could not confirm whether integrating
BCTs with exercise increased adverse events, which is1021

one of our primary outcomes, due to the very low certainty of evidence. Adverse events include non-serious
adverse events such as pain, fatigue, or edema, andserious adverse events that result in death, hospitalization, or a deterioration in health.75 Exercise therapy
itself increases adverse events; however, these aremainly non-serious events including pain or fatigue.75
The addition of BCTs into exercises may not significantly change this outcome. However, more than 70%
of included trials in our review had a high risk of bias in
the measurement of adverse events and 10 of 18 studies reported no description of adverse events, and it
was uncertain if an adverse event was not produced or
was not investigated appropriately. Future researchshould use the measure of adverse events with low riskof bias and should adhere to the use of a proper reporting format for clinical trials, which allows us to analyze
the balance of risk and effectiveness comprehensively.
Regarding the effectiveness of exercises with BCTs
on exercise adherence, our study revealed a very low
certainty of evidence. In a previous review that reported
slight improvement (SMD 0.2) in exercise adherence
measured at 3 to 6 months after intervention by exercises with BCTs, knee osteoarthritis and several otherchronic musculoskeletal conditions were included.6 For
our review, we improved several methodological components (e.g., screening and data extraction conductedby two independent reviewers, excluding trials using
BCTs in control groups, and comprehensive quality
assessment of individual studies and evaluation of thecertainty of evidence by GRADE approach) specifying
the disease condition (knee osteoarthritis), comparedto the previous study. Our findings indicate that further
methodologically rigorous trials measuring exercise
adherence, over the long-term, in the knee osteoarthritis population are needed. Furthermore, people withosteoarthritis may show clinically different responses to
BCTs (calculated SMD 0.15), compared to otherchronic musculoskeletal conditions such as rheumatoid
arthritis (calculated SMD 0.31) or ankylosing spondylitis(calculated SMD 0.61),12 according to a meta-analysis
of six studies.12
Regarding knee pain and mobility, the SMD effectsizes for the improvement of knee pain and mobility
were 0.33 ( 0.53, 0.13) and 0.21 ( 0.05, 0.47),
respectively, and the intervention may have clinicallyimportant effects. However, Angst and colleague
reported that the minimal clinically important difference(MCID) corresponded to an SMD of 0.38 for knee
pain and SMD of 0.26 for mobility.76 Therefore, theeffectiveness on knee pain and mobility remains uncertain since these results cross MCID. There may be two
reasons that the point estimates are below MCID. First,
the number of BCTs used in several trials may be insufficient to improve the effectiveness. The post hoc subgroup analysis showed that exercise incorporating
more than two BCTs tends to have higher SMD. For

19341563, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12898 by Kyoto Universitaet, Wiley Online Library on [12/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

ARIIE ET AL.

mobility, SMD exceeds MCID in trials using more than
two BCTs. In the current review, 40% of the included
trials used only a single BCT. A previous review
showed that a greater number of BCTs had better exercise adherence.6 However, post hoc analysis also
showed that exercise with four or more BCTs tends tobe less effective for both knee pain and mobility outcomes. Therefore, increasing only the number of BCTs
may not be appropriate for optimal intervention. Second,
there may be a possibility that the BCTs used in the
included trials may be inappropriate in terms of the quality
to improve clinical outcomes for people with knee osteoarthritis. Another previous review showed the effectiveness of specific BCTs for people with lower limb
osteoarthritis, namely, “behavioral contract,” “non-specificreward,” “goal setting” (behavior), “self-monitoring of
behavior,” and “social support.”77 The trials included in
our meta-analysis used only “self-monitoring of behavior”(three trials57,70,72), “social support” (two trials57,58), “goalsetting” (behavior) (one trial57). Training needs are higher
for optimal practice, particularly providing effective goal
setting, since this technique requires the patient’s active
involvement, thereby increasing their motivation and confidence.78 Some BCTs may be easy to implement in dailyclinical practice, but further consideration of the quantityand quality of BCTs is needed for appropriate use. Futurestudies using appropriate research methods such as a
Delphi method79 may be required to identify ideal combinations of BCTs for people with knee osteoarthritis. Thenthe combinations should be evaluated by observational
studies and subsequent RCTs.
This review had a limitation. BCT coding was basedon the description in the article and protocol, and BCTs
performed without reporting may inevitably have been
missed. In addition, Michie and colleagues reported
that the behavior change interventions were inadequately described and inconsistent.80 We addressed
these points by using multiple reviewers who had training in BCT coding and classified the BCTs accordingly.
We also contacted the authors to clarify ambiguities intheir descriptions and to further determine eligibility to
reduce the erroneous classification. However, we did
not receive a response from 15 studies, and they could
not be sufficiently evaluated. Researchers shouldreport interventions in detail using the extensive taxonomy such as “BCT taxonomy v1.”9CONCLUSION
Our review found that the certainty of the evidence
regarding the effectiveness of exercise with BCTs on
core outcome sets such as physical function, QOL, oradverse events was very low. Therefore, although
BCTs are commonly used in clinical settings with recommendations from clinical practice guidelines, clinicians should critically appraise which BCTs to integrate

EXERCISE WITH BCTs IN KNEE OSTEOARTHRITIS

with exercise to improve the long-term clinicaloutcomes.
AC KN OW LED GME NT S
We wish to thank Dr. Yuki Kataoka at Department ofInternal Medicine, Kyoto Min-Iren Asukai Hospital forconceptual contributions; and Dr. Eeva-Eerika Helminen, MD, PhD, Psychiatry Department, Helsinki University Hospital; Dr. Neil Segal, MD, MS, Professor of
Rehabilitation Medicine, University of Kansas Medical
Center; Dr. Britt Elin Øiestad; Prof. Rajeshwar Nath Srivastava, Professor at the Department of Orthopedic
Surgery, King George’s Medical University, Lucknow,
India; and Dr. Sudeepti Ratan Srivastava, Research
associate at the Indian Council of Medical Research,
Department of Orthopedic Surgery, King George’s
Medical University, Lucknow, India for information provision. We also wish to thank Ms. Rie Ichinose for her
support in retrieving full-text articles and WORDVICE(wordvice.jp) for editing and reviewing this manuscript
for English language.
DIS CL OS UR ES
None.
DA T A A V A IL A B IL I T Y S T AT E M E N T
The data sets are available from the corresponding
author on reasonable request.
OR CI D
Takashi Ariie

https://orcid.org/0000-0003-1457-3427

REF ER ENC ES
1. Cross M, Smith E, Hoy D, et al. The global burden of hip andknee osteoarthritis: estimates from the global burden of disease2010 study. Ann Rheum Dis. 2014;73(7):1323-1330.
2. Puig-Junoy J, Ruiz ZA. Socio-economic costs of osteoarthritis: asystematic review of cost-of-illness studies. Semin Arthritis
Rheum. 2015;44(5):531-541.
3. Mora JC, Przkora R, Cruz-Almeida Y. Knee osteoarthritis: pathophysiology and current treatment modalities. J Pain Res. 2018;
11:2189-2196.
4. Nicolson PJA, Hinman RS, Kasza J, Bennell KL. Trajectories
of adherence to home-based exercise programs amongpeople with knee osteoarthritis. Osteoarthr Cartil. 2018;26(4):513-521.
5. Fransen M, McConnell S, Harmer AR, Van der Esch M,
Simic M, Bennell KL. Exercise for osteoarthritis of the knee.
Cochrane Database Syst Rev. 2015;1:CD004376.
6. Eisele A, Schagg D, Kramer LV, Bengel J, Gohner W. Behaviourchange techniques applied in interventions to enhance physicalactivity adherence in patients with chronic musculoskeletal conditions: a systematic review and meta-analysis. Patient EducCouns. 2019;102(1):25-36.
7. Nicolson PJA, Bennell KL, Dobson FL, Van Ginckel A,
Holden MA, Hinman RS. Interventions to increase adherence totherapeutic exercise in older adults with low back pain and/or
hip/knee osteoarthritis: a systematic review and meta-analysis.
Br J Sports Med. 2017;51(10):791-799.
8. Pisters MF, Veenhof C, Schellevis FG, Twisk JW, Dekker J, De
Bakker DH. Exercise adherence improving long-term patient

19341563, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12898 by Kyoto Universitaet, Wiley Online Library on [12/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

1022

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

outcome in patients with osteoarthritis of the hip and/or knee. Arthritis Care Res (Hoboken). 2010;62(8):1087-1094.
Michie S, Richardson M, Johnston M, et al. The behavior change
technique taxonomy (v1) of 93 hierarchically clustered techniques:building an international consensus for the reporting of behavior
change interventions. Ann Behav Med. 2013;46(1):81-95.
Room J, Hannink E, Dawes H, Barker K. What interventions areused to improve exercise adherence in older people and what
behavioural techniques are they based on? A systematic review.
BMJ Open. 2017;7(12):e019221.
Osthoff AKR, Niedermann K, Braun J, et al. EULAR recommendations for physical activity in people with inflammatory
arthritis and osteoarthritis. Ann Rheum Dis. 2018;77(9):12511260.
Osthoff AKR, Juhl CB, Knittle K, et al. Effects of exercise andphysical activity promotion: meta-analysis informing the 2018
EULAR recommendations for physical activity in people withrheumatoid arthritis, spondyloarthritis and hip/knee osteoarthritis. RMD Open. 2018;4(2):e000713.
Smith TO, Hawker GA, Hunter DJ, et al. The OMERACT-OARSI
core domain set for measurement in clinical trials of hip and/or
knee osteoarthritis. J Rheumatol. 2019;46(8):981-989.
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020statement: an updated guideline for reporting systematic
reviews. BMJ. 2021;372:n71.
Ariie T, Takasaki H, Okoba R, Taito S, Tsutsumi Y, Miki T, et al.
The effectiveness of behavior change techniques with exercise
for people with knee osteoarthritis: A systematic review andmeta-analysis. PROSPERO 2020 CRD42020212904. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD4202
02129042020. Accessed December 22, 2021.
Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthr Cartil. 2019;27(11):15781589.
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T,
Page MJ, Welch VA. Cochrane handbook for systematic reviewsof interventions version 6.2 (updated February 2021). Cochrane
Database Syst Rev 2021 https://training.cochrane.org/
handbook/current. Accessed December 22, 2021.
Hochberg MC, Altman RD, April KT, et al. American College of
Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of thehand, hip, and knee. Arthritis Care Res (Hoboken). 2012;64(4):465-474.
Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised tool forassessing risk of bias in randomised trials. BMJ. 2019;366:
l4898.
Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings
tables. J Clin Epidemiol. 2011;64(4):383-394.
Santesso N, Glenton C, Dahm P, et al. GRADE guidelines 26:
informative statements to communicate the findings of systematic reviews of interventions. J Clin Epidemiol. 2020;119:126-135.
Australian New Zealand Clinical Trials Registry. The Feldenkrais
method in the Management of Pain, Function and Balance in People with Osteoarthritis of the Knee. Accessed December 22, 2021.
https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=
374306.
Aily J, Castilho de Almeida A, da Silva RG, de Noronha M,
Mattiello S. Is a periodized circuit training delivered by telerehabilitation effective for patients with knee osteoarthritis? A phasei randomized controlled trial. Osteoarthr Cartil. 2020;28:S468S469.
Allen KD, Arbeeva L, Callahan LF, et al. Physical therapy vsinternet-based exercise training for patients with knee

1023

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

osteoarthritis: results of a randomized controlled trial. Osteoarthr
Cartil. 2018;26(3):383-396.
Aoki O, Tsumura N, Kimura A, Okuyama S, Takikawa S,
Hirata S. Home stretching exercise is effective for improving
knee range of motion and gait in patients with knee osteoarthritis. J Phys Ther Sci. 2009;21(2):113-119.
Bennell KL, Hunt MA, Wrigley TV, et al. Hip strengthening
reduces symptoms but not knee load in people with medial knee
osteoarthritis and varus malalignment: a randomised controlled
trial. Osteoarthr Cartil. 2010;18(5):621-628.
Braghin RMB, Libardi EC, Junqueira C, Nogueira-Barbosa MH,
de Abreu DCC. Exercise on balance and function for knee osteoarthritis: a randomized controlled trial. J Bodyw Mov Ther.
2018;22(1):76-82.
Bruce-Brand RA, Walls RJ, Ong JC, Emerson BS, O’Byrne JM,
Moyna NM. Effects of home-based resistance training and neuromuscular electrical stimulation in knee osteoarthritis: a randomized controlled trial. BMC Musculoskelet Disord. 2012;
13:118.
Cheing GL, Hui-Chan CW. Would the addition of TENS to exercise training produce better physical performance outcomes inpeople with knee osteoarthritis than either intervention alone?
Clin Rehabil. 2004;18(5):487-497.
Cheung C, Wyman JF, Resnick B, Savik K. Yoga for managing
knee osteoarthritis in older women: a pilot randomized controlled
trial. BMC Complement Altern Med. 2014;14:160.
Colak TK, Kavlak B, Aydogdu O, et al. The effects of therapeutic
exercises on pain, muscle strength, functional capacity, balanceand hemodynamic parameters in knee osteoarthritis patients: arandomized controlled study of supervised versus home exercises. Rheumatol Int. 2017;37(3):399-407.
de Rooij M, van der Leeden M, Cheung J, et al. Efficacy of tailored exercise therapy on physical functioning in patients withknee osteoarthritis and comorbidity: a randomized controlled
trial. Arthritis Care Res. 2017;69(6):807-816.
DeVita P, Aaboe J, Bartholdy C, Leonardis JM, Bliddal H,
Henriksen M. Quadriceps-strengthening exercise and quadriceps and knee biomechanics during walking in knee osteoarthritis: a two-centre randomized controlled trial. Clin Biomech. 2018;59:199-206.
German Cliniwcal Trials Register. Randomized controlled
study in a wait-list control design to evaluate a 12-weekapp- and orthesis-supported training intervention in patientswith moderate to severe knee osteoarthritis – AppExOA.
https://www.drks.de/drks_web/setLocale_EN.do. Accessed
December 22, 2021.
Fransen M, Crosbie J, Edmonds J. Physical therapy is effective
for patients with osteoarthritis of the knee: a randomized controlled clinical trial. J Rheumatol. 2001;28(1):156-164.
Helminen EE, Sinikallio SH, Valjakka AL, Vaisanen-Rouvali RH,
Arokoski JP. Effectiveness of a cognitive-behavioural groupintervention for knee osteoarthritis pain: a randomized controlled
trial. Clin Rehabil. 2015;29(9):868-881.
Henriksen M, Klokker L, Graven-Nielsen T, et al. Association of
exercise therapy and reduction of pain sensitivity in patients withknee osteoarthritis: a randomized controlled trial. Arthritis CareRes. 2014;66(12):1836-1843.
Hunt MA, Keefe FJ, Bryant C, et al. A physiotherapist-delivered,combined exercise and pain coping skills training intervention
for individuals with knee osteoarthritis: a pilot study. Knee. 2013;20(2):106-112.
Jan MH, Tang PF, Lin JJ, Tseng SC, Lin YF, Lin DH. Efficacy ofa target-matching foot-stepping exercise on proprioception andfunction in patients with knee osteoarthritis. J Orthop Sports
Phys Ther. 2008;38(1):19-25.
Keefe FJ, Blumenthal J, Baucom D, et al. Effects of spouseassisted coping skills training and exercise training in patients

19341563, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12898 by Kyoto Universitaet, Wiley Online Library on [12/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

ARIIE ET AL.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

EXERCISE WITH BCTs IN KNEE OSTEOARTHRITIS

with osteoarthritic knee pain: a randomized controlled study.
Pain. 2004;110(3):539-549.
Kim JS, Kim CJ. Effect of a physical activity promoting program
based on the IMB model on obese-metabolic health outcomesamong obese older adults with knee osteoarthritis. J Korean
Acad Nurs. 2020;50(2):271-285.
Kovar PA, Allegrante JP, MacKenzie CR, Peterson MG,
Gutin B, Charlson ME. Supervised fitness walking in patientswith osteoarthritis of the knee. A randomized, controlled trial.
Ann Intern Med. 1992;116(7):529-534.
Levinger P, Dunn J, Nancy B, Michael B, George E, Hill K.
Safety and feasibility of high speed resistance training with andwithout balance exercises for knee osteoarthritis: a pilot randomised controlled trial. Phys Ther Sport. 2018;34:154-163.
Li L, Sayre EC, Grewal N, et al. Efficacy of a wearable-enabled
physical activity counselling program for people with knee osteoarthritis. Arthritis Rheumatol. 2017;69(suppl 10). https://
acrabstracts.org/abstract/efficacy-of-a-wearable-enabled-physicalactivity-counselling-program-for-people-with-knee-osteoarthritis/.
Accessed December 22, 2021.
Lim BW, Hinman RS, Wrigley TV, Sharma L, Bennell KL. Does
knee malalignment mediate the effects of quadriceps strengthening on knee adduction moment, pain, and function in medialknee osteoarthritis? Arthritis Rheum. 2008;59(7):943-951.
Lund H, Weile U, Christensen R, et al. A randomized controlled
trial of aquatic and land-based exercise in patients with knee
osteoarthritis. J Rehabil Med. 2008;40(2):137-144.
Mazloum V, Rabiei P, Rahnama N, Sabzehparvar E. The comparison of the effectiveness of conventional therapeutic exercises and pilates on pain and function in patients with knee
osteoarthritis. Complement Ther Clin Pract. 2018;31:343-348.
Rogers MW, Tamulevicius N, Semple SJ, Krkeljas Z. Efficacy ofhome-based kinesthesia, balance and agility exercise training
among persons with symptomatic knee osteoarthritis. J Sports
Sci Med. 2012;11(4):751-758.
ClinicalTrials.gov. Efficacy of exercise on quality of life and physical function in patients with knee osteoarthritis. https://clinicaltrials.gov/ct2/show/NCT01682980. Accessed December
22, 2021.
ClinicalTrials.gov. Knee biofeedback rehabilitation interface forgame-based home therapy for patients with knee osteoarthritis(KneeBRIGHT). https://clinicaltrials.gov/ct2/show/NCT04187092.
Accessed December 22, 2021.
ClinicalTrials.gov. Exercise therapy for osteoarthritis pain: how
does it work? (KOA-PAIN). https://clinicaltrials.gov/ct2/show/
NCT04362618. Accessed December 22, 2021.
Odole AC, Ojo OD. A telephone-based physiotherapy intervention for patients with osteoarthritis of the knee. Int J Telerehabilitation. 2013;5(2):11-20.
Odole AC, Ojo OD. Is telephysiotherapy an option for improved
quality of life in patients with osteoarthritis of the knee? Int J Telemed Appl 2014;2014:903816, 1-9.
Rewald S, Lenssen AFT, Emans PJ, de Bie RA, van
Breukelen G, Mesters I. Aquatic cycling improves knee pain andphysical functioning in patients with knee osteoarthritis: a randomized controlled trial. Arch Phys Med Rehabil. 2020;101(8):1288-1295.
Salacinski AJ, Krohn K, Lewis SF, Holland ML, Ireland K,
Marchetti G. The effects of group cycling on gait and painrelated disability in individuals with mild-to-moderate knee osteoarthritis: a randomized controlled trial. J Orthop Sports Phys
Ther. 2012;42(12):985-995.
Schilke JM, Johnson GO, Housh TJ, O’Dell JR. Effects ofmuscle-strength training on the functional status of patients withosteoarthritis of the knee joint. Nurs Res. 1996;45(2):68-72.
Schlenk EA, Lias JL, Sereika SM, Dunbar-Jacob J, Kwoh CK.
Improving physical activity and function in overweight and obese

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

older adults with osteoarthritis of the knee: a feasibility study.
Rehabil Nurs. 2011;36(1):32-42.
Segal NA, Glass NA, Teran-Yengle P, Singh B, Wallace RB,
Yack HJ. Intensive gait training for older adults with symptomatic knee osteoarthritis. Am J Phys Med Rehabil. 2015;94(10):848-858.
Shellington EM, Gill DP, Shigematsu R, Petrella RJ. Innovative exercise as an intervention for older adults with knee
osteoarthritis: a pilot feasibility study. Can J Aging. 2019;38(1):111-121.
Simao AP, Avelar NC, Tossige-Gomes R, et al. Functional performance and inflammatory cytokines after squat exercises andwhole-body vibration in elderly individuals with knee osteoarthritis. Arch Phys Med Rehabil. 2012;93(10):1692-1700.
Takacs J, Krowchuk NM, Garland SJ, Carpenter MG, Hunt MA.
Dynamic balance training improves physical function in individuals with knee osteoarthritis: a pilot randomized controlled trial.
Arch Phys Med Rehabil. 2017;98(8):1586-1593.
Thomas KS, Muir KR, Doherty M, Jones AC, O’Reilly SC,
Bassey EJ. Home based exercise programme for knee pain andknee osteoarthritis: randomised controlled trial. Br Med J. 2002;
325(7367):752.
Thorstensson CA, Roos EM, Petersson IF, Ekdahl C. Six-weekhigh-intensity exercise program for middle-aged patients with knee
osteoarthritis: a randomized controlled trial [ISRCTN20244858].
BMC Musculoskelet Disord. 2005;6:27.
Topp R, Pifer M. A preliminary study into the effect of 2 resistance training modes on proprioception of subjects with knee
osteoarthritis. J Public Health Res. 2017;1(1):26-38.
Topp R, Woolley S, Hornyak J 3rd, Khuder S, Kahaleh B. The
effect of dynamic versus isometric resistance training on pain
and functioning among adults with osteoarthritis of the knee.
Arch Phys Med Rehabil. 2002;83(9):1187-1195.
Trans T, Aaboe J, Henriksen M, Christensen R, Bliddal H,
Lund H. Effect of whole body vibration exercise on muscle
strength and proprioception in females with knee osteoarthritis.
Knee. 2009;16(4):256-261.
Vassao PG, de Souza MC, Silva BA, et al. Photobiomodulation
via a cluster device associated with a physical exercise programin the level of pain and muscle strength in middle-aged and older
women with knee osteoarthritis: a randomized placebocontrolled trial. Lasers Med Sci. 2020;35(1):139-148.
Waller B, Munukka M, Rantalainen T, et al. Effects of high intensity resistance aquatic training on body composition and walking
speed in women with mild knee osteoarthritis: a 4-month RCT with
12-month follow-up. Osteoarthr Cartil. 2017;25(8):1238-1246.
Yan A, Zhang K, Qin WK, et al. Clinical effects of rehabilitation
exercise in the treatment of knee osteoarthritis based on the theory of “treating muscle for bone”. Zhongguo Gu Shang. 2017;30(8):731-734.
Ye J, Simpson MW, Liu Y, et al. The effects of Baduanjin qigong on
postural stability, proprioception, and symptoms of patients withknee osteoarthritis: a randomized controlled trial. Front Med. 2020;6:
1-10.
Ye J, Zheng Q, Zou L, et al. Mindful exercise (Baduanjin) as an
adjuvant treatment for older adults (60 years old and over) of
knee osteoarthritis: a randomized controlled trial. Evid BasedComplement Alternat Med. 2020;2020:9869161-9869169.
Yip YB, Sit JW, Wong DY, Chong SY, Chung LH. A 1-year followup of an experimental study of a self-management arthritis programme with an added exercise component of clients with osteoarthritis of the knee. Psychol Health Med. 2008;13(4):402-414.
Wortley M, Zhang S, Paquette M, et al. Effects of resistance and
Tai Ji training on mobility and symptoms in knee osteoarthritis
patients. J Sport Health Sci. 2013;2(4):209-214.
Boutron I, Tubach F, Giraudeau B, Ravaud P. Blinding was
judged more difficult to achieve and maintain in

19341563, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12898 by Kyoto Universitaet, Wiley Online Library on [12/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

1024

75.

76.

77.

78.

79.

80.

nonpharmacologic than pharmacologic trials. J Clin Epidemiol.
2004;57(6):543-550.
Niemeijer A, Lund H, Stafne SN, et al. Adverse events of exercise therapy in randomised controlled trials: a systematic
review and meta-analysis. Br J Sports Med. 2020;54(18):10731080.
Angst F, Benz T, Lehmann S, Aeschlimann A, Angst J. Multidimensional minimal clinically important differences in knee osteoarthritis after comprehensive rehabilitation: a prospective
evaluation from the bad Zurzach osteoarthritis study. RMD
Open. 2018;4(2):e000685.
Willett M, Duda J, Fenton S, Gautrey C, Greig C, Rushton A.
Effectiveness of behaviour change techniques in physiotherapy
interventions to promote physical activity adherence in lower
limb osteoarthritis patients: a systematic review. PLoS One.
2019;14(7):e0219482.
Driver C, Kean B, Oprescu F, Lovell GP. Knowledge, behaviors, attitudes and beliefs of physiotherapists towards theuse of psychological interventions in physiotherapy practice:a systematic review. Disabil Rehabil. 2017;39(22):22372249.
Eubank BH, Mohtadi NG, Lafave MR, et al. Using the modified
Delphi method to establish clinical consensus for the diagnosis
and treatment of patients with rotator cuff pathology. BMC Med
Res Methodol. 2016;16:56.
Michie S, Fixsen D, Grimshaw JM, Eccles MP. Specifying andreporting complex behaviour change interventions: the need fora scientific method. Implement Sci. 2009;4:40.

SUPPORTING INFORMATION
Additional supporting information can be found online
in the Supporting Information section at the end of thisarticle.
How to cite this article: Ariie T, Takasaki H,
Okoba R, et al. The effectiveness of exercise withbehavior change techniques in people with knee
osteoarthritis: A systematic review with metaanalysis. PM&R. 2023;15(8):1012‐1025. doi:10.
1002/pmrj.12898

1025

CME Question
According to this systematic review with metaanalysis of patients with knee osteoarthritis,
exercise with behavior change techniques(BCTs) demonstrated:
a. Low certainty of evidence for knee pain
reduction.
b. High certainty of evidence for physicalfunctioning.
c. Low certainty of evidence for exercise
adherence.
d. High certainty of evidence for adverse
events.
Answer online at https://onlinelearning.
aapmr.org/
This journal-based CME activity is designated for 1.0 AMA PRA Category 1 Credit
and can be completed online at https://
onlinelearning.aapmr.org/. This activity is
FREE to AAPM&R members and available tononmembers for a nominal fee. CME isavailable for 3 years after publication date.
For assistance with claiming CME for thisactivity, please contact (847) 737–6000.
All financial disclosures and CME information related to this article can be found on theOnline Learning Portal (https://onlinelearning.
aapmr.org/) prior to accessing the activity.

19341563, 2023, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pmrj.12898 by Kyoto Universitaet, Wiley Online Library on [12/10/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

ARIIE ET AL.

Original Article

The Journal of Hand Surgery (Asian-Pacific Volume) 2022;27(5):874-880 • DOI: 10.1142/S242483552250076X‘Hook’ Shape Lister Tubercle Is Associated with a Greater
Incidence of Extensor Pollicis Longus Tendon Rupture
after Distal Radius Fracture
Yosuke OGATA*,†, Takeshi OGAWA‡, Takumi HIRABAYASHI*,†, Sho IWABUCHI*,†,
Yuichi YOSHII§, Masashi YAMAZAKI*

ID:p1258
ID:p1257
ID:p1256
ID:p1255
ID:p1254
ID:p1253

Department of Orthopaedic Surgery, Faculty of Medicine, University of Tsukuba, Japan
Department of Orthopaedic Surgery and Sports Medicine, Mito Clinical Education and Training Centre,
University of Tsukuba Hospital, Mito Kyodo General Hospital, Japan‡
Department of Orthopaedic Surgery, National Hospital Organization Mito Medical Centre, Japan§
Department of Orthopaedic Surgery, Tokyo Medical University Ibaraki Medical Centre, Japan*

ID:p1259

ID:p1260

ID:p1261†

ID:p1262

ID:p0175
ID:ti0010

ID:p0180
ID:ti0015

ID:p0185
ID:ti0020

ID:p0190
ID:ti0025

Background: A rupture of the extensor pollicis longus (EPL) tendon located close to the Lister tubercle is an uncommon complication of distal radius fractures. This study aimed to determine whether the size and shape of Lister tubercle in patients with EPL
rupture differs from a matched group of patients with distal radius fractures without EPL rupture.
Methods: We identified 15 patients with EPL rupture (3.5%) out of 426 with distal radius fractures treated conservatively at our
hospital over 4 years. Out of the remaining 411 patients with distal radius fractures without EPL rupture, we selected patientsusing simple random sampling and pseudo-randomised them such that their age, sex and fracture type were matched with patients
exhibiting EPL rupture. The size and shape of the Lister tubercle and the size of the EPL groove were measured in both groups using
computed tomographic scans and compared.
Results: There was no difference in the size of the Lister tubercle or the EPL groove between both groups. A ‘hook’-shaped Listertubercle was noted in 8 out of 15 patients with EPL rupture but in only 1 out of 15 matched patients without EPL rupture.
Conclusions: A ‘hook’-shaped Lister tubercle was seen more often in patients with EPL rupture following distal radius fracture.
Level of Evidence: Level III (Therapeutic)

ID:p0195
ID:ti0030

Keywords: Lister tubercle, Extensor pollicis longus, Distal radius fracture, Hook shape deformation, Tendon rupture
ID:p0200
ID:ti0035

INTRODUCTION
ID:ti0040

A rupture of the extensor pollicis longus (EPL) tendon
is an uncommon complication of distal radius fractures.1
Different mechanisms have been proposed to explain therupture of the EPL tendon. Rivlin et al2 suggested that thedorsal callus and osteophytes of patients who undergo distal radius osteotomies might contribute to the attritional
rupture of the EPL tendon. Helal et al3 demonstrated that
the EPL tendon is more likely to rupture in patients with
undisplaced fractures due to the integrity of the extensor
retinaculum. Engkvist and Lundborg4 demonstrated that
increased pressure within the non-ruptured tendon sheath
ID:p0205

Received: Dec. 20, 2021; Accepted: May 12, 2022
Published online: Sep. 28, 2022
Correspondence to: Takeshi Ogawa
280 Sakuranosato, Ibarakimachi
Ibaraki 311-3193, Japan
Tel: +81-29-240-7711, Fax: +81-29-240-7788
E-mail: ogawat@tsukuba-seikei.jp
ID:p1278

ID:p1279

ID:p1280

ID:p1281

ID:p1282

875
The Journal of Hand Surgery (Asian-Pacific Volume) • 2022;27(5) • www.worldscientific.com/worldscinet/jhs

jeopardises blood flow in the already poorly vascularisedparts of the tendon that curves around the Lister tubercle,
making it more prone to rupture.
Researchers have previously evaluated the size of
the Lister tubercle in cadavers using callipers.5 In recent
years, improvements in computed tomography (CT)imaging technology have been used to assess the relationship between different fracture types and the risk of tendon ruptures. Cha et al6 proposed that an island-shaped
fracture of the Lister tubercle was associated with ahigher risk of rupture because the callus narrowed the
EPL groove. We hypothesised that there might be somecharacteristics, such as the size and/or shape of the Listertubercle or the EPL groove, that contribute to a rupture of
the EPL. This study aimed to determine whether the sizeand shape of the Lister tubercle in patients with EPL rupture differs from a matched group of patients with distal
radius fractures without any EPL ruptures.
ID:p0210

PATIENTS AND METHODS
ID:ti0045

This retrospective study was approved by the institutional review board of our hospital (H20-3), and written
informed consent was obtained from the patients. We
ID:p0215

looked at all patient records to identify those conservatively treated distal radius fractures that were presented
at our hospital in the period between April 2015 andDecember 2020. The exclusion criteria were as follows:(i) patients <18 years of age, (ii) patients who underwent
surgery, (iii) patients without CT scans during treatmentand (iv) those with <8 weeks of follow-up. Data on age,sex, type of fracture (AO classification) and presenceof EPL rupture were collected. The group of patientswith the EPL rupture was labelled as the rupture group(RG). Out of the remaining patients without an EPL rupture, the same number of patients matched for age, sex
and type of fracture among patients with EPL rupture
were identified using random sampling. This group waslabelled as the intact group (IG). A total of 426 patientswith distal radius fractures treated conservatively presented at our hospital. Among them, 15 (3.5%) suffering from EPL rupture (1 male and 14 females; mean
age: 63.1 [SD 15.6] years) were assigned to the RG. We
selected 15 control patients (2 males and 13 females;mean age: 69.3 [SD 18.9] years) to match the intact EPL
group (IG) (Fig. 1).
A 64-row CT scanner (Canon Aquilion, Toshiba)
was used, and images were obtained with a 2-mm slice
ID:p0225

Fig. 1. Flowchart of the treatment and grouping of patients with distal radius fractures with and without extensor pollicis longus injury.
ID:p0220

876
Ogata Y et al. ‘Hook Shape’ Lister Tubercle and EPL Rupture

thickness. Axial CT images were analysed to determine thesize and shape of the Lister tubercle and the size of the
EPL groove. The axial CT was performed by reconstructing a slice perpendicular to the long axis of the radius. The
slice that showed the Lister tubercle to appear the largest
was used for measurement. The size of the Lister tubercle and the EPL groove was objectively measured using
the method described by Chan and Chong.7 The radial andulnar height of the Lister tubercle were measured using thetransverse line, which acts as a reference line by connecting
the inflexion points of the respective tubercles (Fig. 2). The
depth and width of the EPL groove were also measured.
The shape of the Lister tubercle was subjectively classified,namely the ‘hook’, ‘dome’ and ‘spike’ types, based on the
shape and orientation of its peak. In a ‘hook’, the peak of
Lister tubercle is pointing clearly, in a ‘dome’, the peak isflat and pointing dorsally, whereas, in a ‘spike’, the peakis sharp and pointing dorsally (Fig. 3). Two orthopaedic
surgeons evaluated the images independently. A consensus
was reached when different CT readings were observed
between the two surgeons.
Statistical analysis: A propensity score analysis was
performed to match patients’ age, sex and treatment randomly. The size of the Lister tubercle was evaluated using
ID:p0245

the Student t-test, and the morphometric findings7 were
evaluated using the chi-square test. A p value of <0.05
was considered significant. The ‘dome’ and ‘spike’ types
were combined into a ‘non-hook’ type, and the ‘hook’ and‘non-hook’ types were compared using the chi-square test
(p < 0.05). The Bell curve software for Excel was used
for the above statistical analyses.

RESULTS
ID:ti0050

Fifteen patients were evaluated in each of the RG and
IG. Table 1 shows the fracture types and the shape of the
Lister tubercle in each group of patients. EPL ruptures
occurred 7–90 days (average, 23.2 days) after sustaining
a fracture. Fracture types at the time of injury were classified using the AO classification. In the RG, the mostcommon fracture type was A2 (n = 11), followed by C2(n = 3) and B2 (n = 1). In the IG, the most common
fracture type was A2 (n = 6), followed by A3 (n = 5),
B2, C1, C2 and C3 (n = 1).
Table 2 shows the results of CT measurements for
RG and IG. The size of Lister tubercle did not differ
significantly between the RG and IG with respect to theradial and ulnar tubercle heights or EPL groove depth
ID:p0250

ID:p0910

Fig. 2. Method of evaluating Lister tubercle size. Evaluating Lister tubercle size based on the: (1) radial height, (2) ulnar height, (3) depth of theextensor pollicis longus groove and (4) width of the extensor pollicis longus groove. Arrowheads: the inflexion points, where most change is notedin the slope of the respective tubercles. Line a: the reference line that connects the inflexion points. Line b: The bony landmark is the apex of theulnar height. Line c: perpendicular to line a and passing through the vertex of the ulnar height. Line d: perpendicular to line a and passing throughthe ulnar side of the radial height.
ID:p0230

877
The Journal of Hand Surgery (Asian-Pacific Volume) • 2022;27(5) • www.worldscientific.com/worldscinet/jhs

Fig. 3. Classification of the shape of Lister tubercle.
A. ‘Hook’ type.
B. ‘Dome’ type.
C. ‘Spike’ type.
ID:p0240

ID:p0240a

ID:p0240b

ID:p0240c

Table 1. Clinical Data
ID:p0255

EPL rupture group

EPL intact groupAge(years)Gender

AO classification

Lister tubercle typeAge
(Years)Gender

AO classification

Lister tubercle type

74
70
55
79
68
50
26
84
65
53
65
72
63
67
55

F
F
F
M
F
F
F
F
F
F
F
F
F
F
F

A2
A2
A2
A2
B2
A2
A2
A2
A2
C2
C2
C2
A2
A2
A2

Hook
Hook
Spike
Hook
Hook
Dome
Hook
Dome
Dome
Dome
Spike
Dome
Hook
Hook
Hook

83
72
76
76
88
76
41
67
65
83
58
43
67
72
73

M
F
F
F
F
F
F
F
F
F
F
M
F
F
F

A3
A2
A2
C1
C2
A3
B2
A2
A3
C3
A2
A2
A3
A3
A2

Spike
Dome
Dome
Dome
Dome
Spike
Dome
Dome
Hook
Dome
Dome
Dome
Dome
Dome
Spike

Table 2. Comparison of the Size of Lister Tubercle between the EPL Rupture Group and Intact Groups
ID:p0915

Radial height (mm)Ulnar height (mm)Depth of EPL groove (mm)Width of EPL groove (mm)Rupture group

Intact groupP-value

3.48
1.83
1.16
2.67

3.97
1.86
1.49
3.27

0.19
0.94
0.22
0.17

and width. Table 3 shows the distribution of the shapesof Lister tubercle. On analysis of the shape of Listertubercle, the ‘hook’ shape was observed in 8 of 15 cases(53%) in the RG but only in 1 of 15 cases (6%) in theIG. Moreover, the distribution of the three Lister tubercle
shapes, namely the ‘hook’, ‘dome’ and ‘spike’ types, differed significantly between the RG and IG (p = 0.019).

When ‘dome’ and ‘spike’ types were aggregated into a‘non-hook’ type, the distribution of ‘hook’ and ‘non-hook’
types also differed significantly between the RG and IG(p < 0.01) (Table 4). Overall, two of the 15 patients with
EPL rupture who did not have a ‘hook’ type deformation
had a defect or irregularity of the EPL groove or floor by
the fracture fragment (Fig. 4).

878
Ogata Y et al. ‘Hook Shape’ Lister Tubercle and EPL Rupture

Table 3. The Distribution of the ‘Hook’, ‘Dome’ and ‘Spike’
Deformations of Lister Tubercle Across the EPL Rupture andIntact Groups

DISCUSSION
ID:ti0055

ID:p1020

In the present study, no significant differences wereobserved in the height of Lister tubercle and the depth
and width of the EPL groove between the groups withand without EPL rupture. This indicates that the change
in the size of Lister tubercle is only a few millimetresand that, consequently, the size may not contributeto a subsequent EPL rupture. Instead, we found that
the Lister tubercle more frequently exhibited a ‘hook’
shape, with the point aimed towards the ulnar side in
the EPL rupture group. This suggests that the ‘hook’
shape of the Lister tubercle may be associated with atendon injury. Following a distal radius fracture, if theextensor retinaculum remains intact and the EPL tendon stays within the EPL groove, a hook-shaped Listertubercle may predispose the EPL tendon to injury. If
the ‘hook-shaped’ Lister tuberosity is found during the
ID:p1175

Rupture group
Intact group
Total

Hook

Dome

Spike

8
1
9

5
11
16

2
3
5

Table 4. Distribution of the ‘Hook’ Type and ‘Non-Hook’ Type of Lister
Tubercle in the EPL Rupture and Intact Groups
ID:p1105

Rupture group
Intact group
Total

Hook

Non-hook

8
1
9

7
14
21

Fig. 4. The fracture fragment is sharpened towards the radial side. Arrowhead: Lister tubercle. Arrow: bone spicule by the fracture.
ID:p1170

879
The Journal of Hand Surgery (Asian-Pacific Volume) • 2022;27(5) • www.worldscientific.com/worldscinet/jhs

follow-up period of a distal radius fracture, it could
suggest a greater EPL rupture risk. Therefore, early
detection of EPL injury would be very useful for subsequent treatment. For example, if the pain and difficulty in movement persist after regular examinations,
it may be an option to remove Lister tubercle surgicallyto achieve smooth tendon gliding.
Evaluation of distal radius fractures has mainly been
performed using radiography, thus making it difficult
to evaluate the configuration of the Lister tubercle indetail. Furthermore, EPL rupture was more likely tooccur in undisplaced or minimally displaced fractures,
occurring in a group of patients in whom CT is rarely
performed. However, CT has become widely available
across healthcare centres in recent years and has beenused to evaluate fractures in greater detail. Cha et al6
used three-dimensional CT to identify the ‘island-shape’of Lister tubercle as a risk factor for EPL injury. It wassuggested that island-shaped fractures are associatedwith an increased risk of rupture because callus formation narrows the EPL groove. Our study focused on
the shape and not the narrowing of the EPL groove. We
believe that a ‘hook-shaped’ Lister tubercle protruding towards the EPL tendon has a greater propensity toinjure the EPL tendon. However, we never perform CT
only to visualise Hook deformity, but to evaluate comminuted fractures, to determine bone fusion or to detect
when the unexpected occurs. In addition, it is sometimes
difficult to determine whether the pain is due to fractureor EPL tear. We believe that CT is useful in such cases
as well.
In our study, the two patients with EPL rupture did nothave a ‘hook’ type Lister tubercle. In one patient, the dorsal fragment of radius pointed sharply towards the radialside from the ulnar side of the Lister tubercle (Fig. 4).
In the other patient, there was an irregularity within the
EPL groove. The mechanism of EPL rupture in these twopatients is different from patients with the ‘hook-shaped’
Lister tubercle.
This study has some limitations. Firstly, CT was performed only after EPL rupture became evident; patients
without EPL rupture often underwent imaging immediately after a fracture. As such, the shape of the Listertubercle could change due to osteophytes and callus formation, depending on the timing of CT. Some EPL ruptures
were observed in fractures with small bone irregularities.
Consequently, more large-scale studies are warranted tovalidate our results.
In conclusion, there is no evidence supporting the
hypothesis that the size of Lister tubercle affects EPL
ID:p1180

tendon rupture. Instead, a ‘hook-shaped’ Lister tubercle
may contribute to EPL tendon rupture. If the pain anddifficulty in movement persist after regular examinations,
CT should be performed. We believe that an increased riskof EPL rupture can be detected earlier if a ‘hook-shaped’
Lister tubercle is found during the follow-up period of the
distal radius fracture. This might improve treatment subsequently, which includes EPL tendon release or excisionof the Lister tubercle.

DECLARATIONS
ID:ti0060

ID:p1200
ID:ti0065

ID:p1205
ID:ti0070

ID:p1210
ID:ti0075

ID:p1215
ID:ti0080

ID:p1220
ID:ti0085

REFERENCES

ID:p1185

ID:p1190

ID:p1195

Conflict of Interest: The authors do NOT have any potential
conflicts of interest with respect to this manuscript.
Funding: The authors received NO financial support for the
preparation, research, authorship and/or publication of thismanuscript.
Ethical Approval: Ethical approval for this study was
obtained from the institutional review board of Mito Kyodo
General Hospital (NO 20-3) at 13 May 2020.
Informed Consent: Written informed consent was obtained
from participants under treatment. The patients who completed the treatment were exempted from providing writtenconsent by the institutional review board.
Acknowledgements: We would like to thank Editage forEnglish language editing services.

ID:ti0090

1. Seigerman D, Lutsky K, Fletcher D, et al. Complications in
the management of distal radius fractures: How do we avoid
them? Curr Rev Musculoskelet Med. 2019;12(2):204–212.
https://doi.org/10.1007/s12178-019-09544-8.
2. Rivlin M, Fernández DL, Nagy L, Graña GL, Jupiter J.
Extensor pollicis longus ruptures following distal radius
osteotomy through a volar approach. J Hand Surg Am.
2016;41(3):395–398. https://doi.org/10.1016/j.jhsa.2015.1
0.029.
3. Helal B, Chen SC, Iwegbu G. Rupture of the extensor
pollicis longus tendon in undisplaced Colles’ type of fracture. Hand. 1982;14(1):41–47. https://doi.org/10.1016/
s0072-968x(82)80038-7.
4. Engkvist O, Lundborg G. Rupture of the extensor pollicis longus tendon after fracture of the lower end of theradius – A clinical and microangiographic study. Hand.

880
Ogata Y et al. ‘Hook Shape’ Lister Tubercle and EPL Rupture

1979;11(1):76–86. https://doi.org/10.1016/s0072-968x(79)80015-.7
5. Clement H, Pichler W, Nelson D, Hausleitner L, Tesch NP,
Grechenig W. Morphometric analysis of Lister tubercle
and its consequences on volar plate fixation of distal radius
fractures. J Hand Surg Am. 2008;33(10):1716–1719. https://doi.org/10.1016/j.jhsa.2008.08.012.
6. Cha SM, Shin HD, Lee SH. ’Island-shape’ fracture of Listertubercle have an increased risk of delayed extensor pollicis
longus rupture in distal radial fractures after surgical treatment by volar locking plate. Injury. 2018;49(10):1816–
1821. https://doi.org/10.1016/j.injury.2018.08.019.
7. Chan WY, Chong LR. Anatomical variants of Lister tubercle: A new morphological classification based on magnetic
resonance imaging. Korean J Radiol. 2017;18(6):957–963.
https://doi.org/10.3348/kjr.2017.18.6.957.

8. Roth KM, Blazar PE, Earp BE, Han R, Leung A.
Incidence of extensor pollicis longus tendon rupture after
nondisplaced distal radius fractures. J Hand Surg Am.
2012;37(5):942–947. https://doi.org/10.1016/j.jhsa.2012.
02.006.
9. Naito K, Sugiyama Y, Dilokhuttakarn T, et al. A survey ofextensor pollicis longus tendon injury at the time of distal
radius fractures. Injury. 2017;48(4):925–929. https://doi.
org/10.1016/j.injury.2017.02.033.
10. Hirasawa Y, Katsumi Y, Akiyoshi T, Tamai K, Tokioka T.
Clinical and microangiographic studies on rupture of the
E.P.L. tendon after distal radial fractures. J Hand Surg Br.
1990;15(1):51–57. https://doi.org/10.1016/0266-7681(90)90048-9.

diagnostics
ArticleUse of a Small Car-Mounted Magnetic Resonance Imaging
System for On-Field Screening for Osteochondritis Dissecans of
the Humeral Capitellum
Kazuhiro Ikeda 1,2 , Yoshikazu Okamoto 3 , Takeshi Ogawa 4 , Yasuhiko Terada 5 , Michiru Kajiwara 5 ,Tomoki Miyasaka 5 , Ryuhei Michinobu 2 , Yuki Hara 6 , Yuichi Yoshii 7, * , Takahito Nakajima 3
and Masashi Yamazaki 2
1
2

3

4
5
6

7

*

Citation: Ikeda, K.; Okamoto, Y.;
Ogawa, T.; Terada, Y.; Kajiwara, M.;
Miyasaka, T.; Michinobu, R.; Hara, Y.;
Yoshii, Y.; Nakajima, T.; et al. Use of a
Small Car-Mounted Magnetic
Resonance Imaging System for
On-Field Screening for
Osteochondritis Dissecans of the
Humeral Capitellum. Diagnostics
2022, 12, 2551. https://doi.org/
10.3390/diagnostics12102551
Academic Editor: Rute Santos
Received: 21 September 2022
Accepted: 19 October 2022
Published: 20 October 2022

Department of Orthopedic Surgery, Kikkoman General Hospital, Noda 278-0005, Chiba, Japan
Department of Orthopedic Surgery, Faculty of Medicine, University of Tsukuba,
Tsukuba 305-8577, Ibaraki, Japan
Institute of Clinical Medicine, Department of Diagnostic and Interventional Radiology, University of Tsukuba,
Tsukuba 305-8577, Ibaraki, Japan
Department of Orthopedic Surgery, Mito Medical Center, Ibaraki 311-3193, Ibaraki, Japan
Institute of Applied Physics, University of Tsukuba, Tsukuba 305-8577, Ibaraki, Japan
Department of Orthopedic Surgery, National Center of Neurology and Psychiatry,
Kodaira 187-8551, Tokyo, Japan
Department of Orthopedic Surgery, Tokyo Medical University Ibaraki Medical Center,Ami 300-0395, Ibaraki, Japan
Correspondence: yyoshii@tokyo-med.ac.jp; Tel.: +81-298871161

Abstract: Mobile magnetic resonance imaging (MRI) using a car is a recent advancement in imaging
technology. Specifically, a car-mounted mobile MRI system is expected to be used for medical checkups; however, this is still in the research stage. This study demonstrated the practicality of a small
car-mounted mobile MRI in on-field screening for osteochondritis dissecans (OCD) of the humeral
capitellum. In the primary check-up, we screened the throwing elbows of 151 young baseball players
using mobile MRI and ultrasonography. We definitively diagnosed OCD at the secondary check-up
using X-ray photography and computed tomography or MRI. We investigated the sensitivity andspecificity of mobile MRI and ultrasonography for OCD. Six patients were diagnosed with OCD. The
sensitivity was 83.3% for mobile MRI and 66.7% for ultrasonography, with specificity of 99.3% vs.
100%, respectively. One patient was detected using ultrasonography but was missed by mobile MRI
due to poor imaging quality at the first medical check-up. Following this false-negative case, we
replaced a damaged radio frequency coil to improve the image quality, and the mobile MRI could
detect all subsequent OCD cases. Two patients were diagnosed by mobile MRI only; ultrasonography
missed cases lacking subchondral bone irregularity, such as a healing case, and an early-stage case.
Mobile MRI could screen for OCD from the very early stages through the healing process and istherefore a practical tool for on-field screening.

Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims inpublished maps and institutional affil-

Keywords: magnetic resonance imaging; mobile; portable; osteochondritis dissecans; OCD; baseball;
medical check-up; screening; low-field MRI

iations.

1. Introduction
Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms andconditions of the Creative Commons
Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

The use of mobile imaging tools is increasingly considered an effective way of utilizing
limited medical resources [1–3]. Moreover, mobile imaging enables qualified medical
personnel to practice remotely. It is currently widely applied for medical check-ups at
workplaces or schools, and the time and cost reduction for examinees is expected to increase
the examination rate [4].
In the bone and soft tissue field, mobile imaging tools play an important role in athletic
medical check-ups [5–9]. Osteochondritis dissecans (OCD) of the humeral capitellum is a

Diagnostics 2022, 12, 2551. https://doi.org/10.3390/diagnostics12102551

https://www.mdpi.com/journal/diagnostics

Diagnostics 2022, 12, 2551

2 of 13bone and cartilage disorder for which athletic medical check-ups are useful. OCD occurs
in young baseball players aged 9–12 years, with a prevalence of 2.1–3.4% [7,10]. Early
detection is essential to prevent elbow dysfunction; 90% of patients with stage I OCD
recover with conservative treatment, whereas 50% of patients with stage II OCD require
surgery [11]. Since the early stage of OCD is often asymptomatic [12,13], a medical check-up
is essential for early detection. Moreover, on-field screening is generally performed in Japanbecause it enables the examination of all players of the team. Currently, the gold standard
imaging examination for on-field screening is ultrasonography (US) [7,10,12,13] due to its
advantages, including portability, short examination time, no radiation exposure, and low
cost. In addition, US detects the OCD lesion of subchondral bone irregularity from its earlystage [7,10,12,13], making it an excellent qualitative examination tool for OCD detection.
Conversely, magnetic resonance imaging (MRI) is the gold standard for in-hospitaldiagnosis and evaluation of OCD lesions. MRI visualizes OCD lesions of the subchondral bone as low signal changes on T1-weighted images (T1WI) from the early stage,
which cannot be detected by X-ray photography (X-p), computed tomography (CT) andUS [14–16]. MRI detects qualitative changes in bone marrow edema, whereas X-p, CT,
and US detect morphological changes and subchondral bone irregularities, as in otheroccult fractures [17]. MRI is therefore better suited to detect early cases than other imaging
modalities. Although MRI has never been used for on-field OCD screening because it was
not portable, introducing mobile MRI into OCD screening may help detect earlier cases.
However, the mobilization of MRI is still at the research stage, in contrast to X-p and
US. As a result of prioritizing high resolution, current mobile MRI systems are equippedwith 1.5 T magnets and require a 38-ton trailer [18,19]. Such a large mobile MRI truck
is expensive, must be parked on a level area with reinforced pads, and requires a 480 V
3-phase power supply [3]; this mobile MRI truck has a high threshold for introduction
and operation. Therefore, we proposed that a reduction in size and cost was essential
for widespread use of mobile MRI, and a low-field MRI could realize this [20,21]. Using
low-field MRI, we developed a small car-mounted mobile MRI system for human small
joints [1]. This system, comprising a 0.2 T permanent magnet, enabled us to perform MRI
anywhere using a 100 V external power supply. We have previously demonstrated excellent
imaging using this mobile MRI system with healthy volunteers [1].
In this study, we introduced mobile MRI into OCD screening. This study aimed to
examine the practicality and utility of this mobile MRI in on-field screening forof theDiagnostics 2022, 12, x FOR PEER REVIEW
3 ofOCD
14
humerus (Figure 1).

Figure 1.
resonance
imaging(MRI)
systembesidea baseballFigure
1. PhotographPhotographofofthe
themobilemobilemagnetic
magnetic
resonance
imaging(MRI)
systembesidea baseball field.
field. (Mercedes Benz, GH-639811, width 191 cm, height 193 cm, and length 476 cm). Mobile MRI(Mercedes Benz, GH-639811, width 191 cm, height 193 cm, and length 476 cm). Mobile MRI enables
enables players to practice while awaiting their turn for an MRI scan.
players to practice while awaiting their turn for an MRI scan.

2. Materials and Methods
2.1. Study Design and ParticipantsThis prospective, non-randomized observational study protocol conforms to theprinciples of the 1964 Declaration of Helsinki and its later amendments. The review board

Diagnostics 2022, 12, 2551

3 of 13

2. Materials and Methods
2.1. Study Design and ParticipantsThis prospective, non-randomized observational study protocol conforms to the principles of the 1964 Declaration of Helsinki and its later amendments. The review boardof our institution approved this study (IRB No: 30–144, approved 23 July 2019). Written
informed consent was obtained from all participants. We evaluated 151 throwing-elbows
of 151 young baseball players (149 boys and two girls; mean age 11.6 years; age range
8–15 years) who participated in our baseball medical check-up from October 2019 to May
2021. The median number of players per screening was 16 (8–19) among 10 teams.
2.2. The Mobile MRI system
The mobile MRI system consisted of a permanent magnet, gradient coils, a radio
frequency (RF) probe with shielding cloths, and the MRI console (Figure 2). Since the
RF probes are consumable, we replaced the damaged coil once during the study period;
32 cases were imaged with the first-generation RF probe, and 119 cases with the secondgeneration RF probe. The overall weight of the system was below the maximum authorized
payload, and all the devices could be mounted in the vehicle. All the electronic devices wereoperated at 100 V AC, and the required current was 10 A. A power cable was connected
Diagnostics 2022, 12, x FOR PEER REVIEW
4 of 14from the vehicle to a wall outlet at the nearest building. Hence, we could perform MRI
anywhere. Our mobile MRI system is comprehensively described in our previous paper [1].

Figure2. Themobile(a) Permanent
Permanentmagnet.
magnet.
The
magnetT permanent
magnetFigure2. ThemobileMRI
MRIsystem.
system. (a)Themagnetis a is0.2aT0.2
permanent
magnet(NEOMAXEngineering,
Japan;
200kg;
16
cm-gap;
44
cm
×
50
cm
×
36
cm).
The
magnetwasscrewed(NEOMAX Engineering, Japan; 200 kg; 16 cm-gap; 44 cm × 50 cm × 36 cm). The magnet was screwed
onto
an an
aluminumanchoredtotothe
thesheetsheetof thevehicle;(b)RFanprobeRF probe
onto
aluminumstand
standthatthat waswas anchoredrailrailof thevehicle;(b) anwas wasplacedinsidetheconductive
shielding
cloths(ESD
EMI
Engineering
Corporation,
Tokyo,
Japan).
placed inside the conductive shielding cloths (ESD EMI Engineering Corporation, Tokyo, Japan). The
Thehome-built
home-built
RF
probe
consistedofasolenoid
RF
coil
(12
turns,
130
mm
long,
94
mm
in
diameter)
RF probe consisted of a solenoid RF coil (12 turns, 130 mm long, 94 mm in diameter) andanda arectangular
rectangularshieldbox mm(200(x)mm(x) mm
× 200
(y)mm
× 132
made of 200-µm-thickshieldbox (200
× 200
(y)mm
× 132
(z)) mmmade(z))of 200-µm-thickbrass plates. brass
plates.
The
size
of
the
RF
coil
was
large
enough
to
fit
most
of
the
juniorbaseballplayers;(c) MRI
The size of the RF coil was large enough to fit most of the junior baseball players; (c) MRI
console:console:the
MRI
consoleconsistedofadigitaltransceiver(DTRX6,
MR
Technology,
Japan),
the MRI console consisted of a digital transceiver (DTRX6, MR Technology, Japan), a gradient drivera gradient
10 A,
DSTa Inc.,
Japan),(noisea preamplifier
figurewas
0.5 DST
dB, Inc.,
gainAsaka,
was 30 dB;(20 driverV, 10 A,(20DSTV,Inc.,
Japan),
preamplifier
figure was (noise
0.5 dB, gain
was
30 dB;DSTInc.,
Asaka,
Japan),
anactivetransmit/receive
switch,andatransmitter
(9
MHz,
150
W; DST
Japan), an active transmit/receive switch, and a transmitter (9 MHz, 150 W; DST Inc.), which were
Inc.),
whichonwere
installed
on cm
a 19-inch
× 77Thecm MRI× 60 console
cm, 80 waskg).tightly
The MRI
installed
a 19-inchrack (56
× 77 cmrack× 60(56cm,cm
80 kg).
fixedconsole
to the wastightly
fixed
to
the
front
seat
with
ropes.
front seat with ropes.

OCD
Screening
2.3.2.3.
OCD
Screening
conductedthe
theprimaryprimary medical
at atthethebaseballfieldfield
duringthe practiceWeWe
conducted
medicalcheck-up
check-upbaseballduringthe practicesession of the target teams. In addition, we performed physical examinations, including
session of the target teams. In addition, we performed physical examinations, including
the elbow range of motion (ROM), tenderness to palpation, and moving valgus test. Finally,
thewe
elbow
range of motion (ROM), tenderness to palpation, and moving valgus test. Fiscreened for OCD using the mobile MRI and US independently.

nally, we screened for OCD using the mobile MRI and US independently.
Once in the mobile MRI car, the participants sat on a legless chair and placed theirforearm in the scanner, with the elbow joint in extension and the forearm supinated. The
routine sequence images obtained were the sagittal elbow with T1WI and T2*-weighted
imaging (T2*WI) and the coronal elbow with T2*WI (Figure 3 and Table 1). A musculo-Diagnostics 2022, 12, 2551

4 of 13

Once in the mobile MRI car, the participants sat on a legless chair and placed theirforearm in the scanner, with the elbow joint in extension and the forearm supinated. The
routine sequence images obtained were the sagittal elbow with T1WI and T2*-weighted
imaging (T2*WI) and the coronal elbow with T2*WI (Figure 3 and Table 1). A musculoskeleDiagnostics 2022, 12, x FOR PEER REVIEW
5 of
14
tal radiologist with 25 years’ experience (Examiner A) read the images immediately
anddetermined the presence of OCD.

Figure 3.
3. Mobile
Mobile MRIMRI ofof aa healthy
healthy elbow
elbow ofof aa 12-year-old
12-year-old boy.
boy.
FigureTableWe
1. Imaging
parameters.
can clearly
identify bone morphology with T1WI sagittal images and articularcartilage morphology with T2*WI sagittal and coronal images.
Sequence Type
T1WI
T2*WI
T2*WI
We used a Viamo SV 7 scanner with a 3–10 MHz linear probe (Canon Medical Sysplane
SagittalCoronaltems, Image
Tochigi,
Japan) for US examinations.
The playerSagittal
sat on the chair and placed
the arm3
2
FOV
180 × supinated.
120 × 90 mm
180 ×a180
mm2 longitudinal
180 × 180mm
on the tablewith the forearmWeobtainedposteriorandshortaxis viewwithand an anterior
longitudinaland short-axis
Matrixsizethe elbow fully
256 ×flexed
128 × 32
256 ×
192
256 × 192 view
with
the
elbow
fully
extended[22–24].
Three
orthopedic
surgeons
examined
the US andSlice thickness, mm
33determined the presence of OCD depending on the case: a hand surgeon with 23 years of
TR, ms40
500
500experience (Examiner B) and two general orthopedic surgeons with 9 (Examiner C) and 8
TE,D)msyears of experience,4 respectively. All three
16examiners had at least
16 3 years of(Examiner◦◦
OCD screening
Flip angelexperience.
60
75
75◦
WeScanreferredpatients
diagnosed1 witheithermobile MRI
or38US
time OCD-positive
1 min
22 s
min 38s
1 min
s for asecondarycheck-up.
Consequently,
allthe
OCD-positive
patients
underwent
X-p,
T1WI, T1 weighted images; T2*WI, T2* weighted images; FOV, field of view; TR, repetition time; TE, echowithtime;
ms: millisecond.
computed
tomography (CT) or MRI as an additional imaging examination. Based on theobtained images, a hand surgeon with 23 years of experience (Examiner E), who did not
We canidentifybone morphology
with T1WIsagittal
imagesand diagram
articular
participate
inclearly
the primary
check-up,made a definitive
diagnosisof OCD.
A flow
cartilage
morphology
with
T2*WI insagittalof
our medical
check-upis shown
Figureand4. coronal images.
We used a Viamo SV 7 scanner with a 3–10 MHz linear probe (Canon Medical Systems,
Tochigi, Japan) for US examinations. The player sat on the chair and placed the arm on
the table with the forearm supinated. We obtained a posterior longitudinal and short-axis
view with the elbow fully flexed and an anterior longitudinal and short-axis view with theelbow fully extended [22–24]. Three orthopedic surgeons examined the US and determined
the presence of OCD depending on the case: a hand surgeon with 23 years of experience(Examiner B) and two general orthopedic surgeons with 9 (Examiner C) and 8 (ExaminerDiagnostics 2022, 12, 2551

5 of 13D) years of experience, respectively. All three examiners had at least 3 years of OCD
screening experience.
We referred OCD-positive patients diagnosed with either mobile MRI or US for asecondary check-up. Consequently, all the OCD-positive patients underwent X-p, withcomputed tomography (CT) or MRI as an additional imaging examination. Based on theobtained images, a hand surgeon with 23 years of experience (Examiner E), who did not
Diagnostics 2022, 12, x FOR PEER REVIEW
14
participate in the primary check-up, made a definitive diagnosis 6ofofOCD.
A flow diagramof our medical check-up is shown in Figure 4.

Figure 4. Flow diagram of our medical check-up. * Examiner A, a musculoskeletal radiologist with

Figure 4. Flow diagram of our medical check-up. * Examiner A, a musculoskeletal radiologist withyears
of experience;
B, a with
hand
with 23Examiner
years of
Examiner C, a
25 25
years
of experience;
Examiner ExaminerB, a hand surgeon
23 surgeon
years of experience;
C, experience;a generalgeneralorthopedic
surgeon
with
9
years
of
experience;
ExaminerD,ageneralorthopedic
surgeonwithorthopedic surgeon with 9 years of experience; Examiner D, a general orthopedic surgeon
8 years of experience; and Examiner E, a hand surgeon with 23 years of experience; OCD, osteochonwith
8 yearsof humeral
experience;and Examiner E, a hand surgeon with 23 years of experience; OCD,
dritisdissecansof thecapitellum.

osteochondritis dissecans of the humeral capitellum.
2.4. Evaluation Components

2.4.
Componentsin this study were as follows. First, the sensitivity and
TheEvaluation
evaluation components
specificityofthemobileMRIcomponents
and US. In calculating
and specificity,
we defined
The evaluationin thissensitivity
study wereas follows.
First, the sensitivity andtrue positive cases as the patients with a definitive OCD diagnosis in the secondary checkspecificityofthemobile
MRI
and
US.
In
calculating
sensitivity
andspecificity, we definedup, and true negative cases as the other patients. Second, the details of the OCD-positivetrue
positive
cases
as
the
patients
withadefinitive
OCD
diagnosis
incases, i.e., physical examination findings, position, OCD stage and location, and the max-the secondary checkup,diameterand true
negativecases
as the Third,otherwepatients.
imumof thelesion were
evaluated.
evaluatedSecond,
the OCDthe
stagedetails[11] andof the OCD-positive
itscases,locationi.e.,withan anteroposterior
X-p offindings,
the elbow at
45° of flexion
We alsophysicalexamination
position,
OCD(Xp−45°).
stage andlocation, and the maximeasured the maximum diameter of the lesion with CT or MRI. In CT, we defined themum diameter of the lesion were evaluated. Third, we evaluated the OCD stage [11] andlesion as a subchondral bone irregularity or sclerosis. In MRI, we detected signal
changeswithan anteroposterior X-p of the elbow at 45◦ of flexion (Xp−45◦ ). We also
in itsthe location
subchondralbone.
measured the maximum diameter of the lesion with CT or MRI. In CT, we defined the

3. Results
lesion as a subchondral bone irregularity or sclerosis. In MRI, we detected signal changes
thesubchondral
151 players, 6 (4.0%)
inOf
thebone.were diagnosed with OCD through our medical checkups (Table 2). Three patients with OCD had no elbow pain and positive physical examination
findings for OCD. Out of the six OCD cases, five tested positive on mobile MRI and3. Results
four on US; two were positive only on mobile MRI, and one was positive only on US. One
Of OCD-positive
the 151 players,
6 (4.0%)diagnosed
witha OCD
throughpatient wason mobile
MRI were
but wasdiagnosed withdifferent
disorderourat medical check-ups
the(Tablesecondarycheck-up.
Consequently,
the sensitivity
was 83.3%
forandmobile
MRI and2). Threepatients
with OCD
had no elbow
pain
positive
physical examination
66.7%
in US, withspecificities
100%, withpositivevalue of 83.3%
findings
for OCD.
Outofof99.3%
the andsix OCD
cases,
five predictive
tested positiveon mobile MRI and fourand 100%, respectively (Tables 2–4). Legends of the cases are shown in Figures 5–9.

on US; two were positive only on mobile MRI, and one was positive only on US. One
patient was OCD-positive on mobile MRI but was diagnosed with a different disorder at
the secondary check-up. Consequently, the sensitivity was 83.3% for mobile MRI and 66.7%
in US, with specificities of 99.3% and 100%, with positive predictive value of 83.3% and100%, respectively (Tables 2–4). Legends of the cases are shown in Figures 5–9.

US
Diagnostics 2022, 12, 2551

OCD (+)OCD (−)

Definitive Diagnosis
OCD (+)OCD (−)
4
0
2
145
6
145

4
147
151

6 of 13

Figure 5. A false-negative
case withOCD
mobile
MRImobile(CaseMRI
1): (Case
MobileMRI (−),(+).
Figure 5. OCD
A false-negative
case with
1): Mobile
MRIUS
(−),
US(a)
(+).Mobile(a) Mobile
MR (magnetic resonance)
images:a-1, T1WIsagittal
image;
a-2,image;
T2*WI
image:
MobileMRI
MR (magnetic
resonance)
images:a-1, T1WIsagittal
a-2,sagittal
T2*WI sagittal
image:
MobileMRI
with poor imaging quality with low signal/noise ratio. Although the signal change was barely visible
from the anterior to the humeral capitellum, we could not detect it; (b) US image of the posterior
longitudinal view: US imaging revealed obvious subchondral bone irregularity; (c) X-p AP view withelbow 45◦ flexed: X-p 45◦ showing the lesion with fragmentation in the central capitellum, stage II
OCD; (d) 3T MR images: d-1, proton density-weighted images (PDWI) sagittal image; d-2, PDWIfat-suppressed (FS) sagittal image: 3T MRI easily detected the lesion. HC, humeral capitellum; RH,
radial head; yellow arrowheads, lesions.

Table 2. Results of the medical check-up.
OCD (−)OCD (+)

Cases

145

6

Mean age (years)

11.6 ± 1.3

12.3 ± 1.2

Male: 143

Male: 6

Female: 2

Female: 0Medial elbow pain, n (%)

30 (20.7)

3 (50.0)

Lateral elbow pain, n (%)

6 (4.2)3 (50.0)

No elbow pain, n (%)

113 (77.9)

3 (50.0)

SexDiagnostics 2022, 12, 2551

7 of 13

Table 3. Diagnostic accuracy of OCD using mobile MRI.
Definitive Diagnosis

mobile MRIOCD (+)OCD (−)OCD (+)

5

1

6

OCD (−)

1

144

145

6

145

15114
8 of

FOR PEER REVIEW
Table 4. Diagnostic accuracy of OCD using US.

with poor imaging quality with low signal/noise ratio. Although
the signal
change was barely visiDefinitive
Diagnosis
ble from the anterior to the humeral capitellum, we could notdetect it; (b) US
image of the posterior
OCD (+)OCD (−)
longitudinal view: US imaging revealed obvious subchondral bone irregularity; (c) X-p AP view
OCD (+)
40
4
with elbow 45° flexed: X-p 45°
USshowing the lesion with fragmentation in the central capitellum, stage
OCD (−)
2
145
147
II OCD; (d) 3T MR images: d-1, proton density-weighted
images(PDWI) sagittal
image; d-2, PDWI145 capitellum;151
fat-suppressed (FS) sagittal image: 3T MRI easily detected the 6lesion. HC, humeral
RH,
radial head; yellow arrowheads, lesions.

Figure 6. Typical OCD
case6.(Case
3):OCD
Mobile(+).MRI(a) Mobile
MR(a)images;T1WI sagFigure
TypicalcaseMRI(Case(+),
3): US
Mobile(+), US (+).
Mobile a-1,
MR images;
a-1, T1WI
ittal image; a-2, T2*WIsagittal
sagittal
image:
MobileMRI
depictedtheOCD
lesionasalow-signal
area
inarea inimage; a-2, T2*WI sagittal image: Mobile MRI depicted the OCD lesion as a low-signal
a T1WI sagittal imageaand
high-signal
areaa ina T2* weighted
image;(b) US
image
ofimagethe posterior
T1WIa sagittal
image andhigh-signal
area in a T2*
weighted
image;(b) USof the posterior
longitudinal
US showing
subchondralbone irregularity;
X-p APview
with elbow
longitudinal view: US
showing view:
subchondralbone
irregularity;(c) X-p AP(c)view
with
elbow
45° 45◦◦flexed:45 showing
the lesion with fragmentation,stage
3T MR images:
d-1, PDWI
flexed: X-p 45° showing
theX-plesionwith fragmentation,
stage II-OCD;(d)II-OCD;
3T MR(d)images:d-1, PDWI
sagittal
image;
d-2,
coronalimage:
localizationofthelesionwasconsistent
with
that
of
3T
MRI andsagittal image; d-2, coronal image: localization of the lesion was consistent with that of 3T MRI andmobile MRI.
mobile MRI.

FOR PEER REVIEW

Diagnostics 2022, 12, 2551

9 of 148 of 13

Figure 7. An OCD caseduringhealing
process(Case process5): Mobile(+), US(-).(+),(a)USMobile
MR MR
Figure
7. AntheOCDcase during
the healing(CaseMRI
5): Mobile
MRI(-). (a) Mobile
image of T1WI sagittal:
Mobileshowingsignalintensitychangesreflecting
bone
image
of T1WIMRI
sagittal:
Mobile MRI
showingsignal intensitychangesreflecting
bonemarrow
marrow edema
the anterior
humeral capitellum;(b) US ofimage
the posterior
longitudinalview:
view: b-1,
b-1, theedema in the anterior in
humeralcapitellum;(b) US image
the ofposteriorlongitudinalthecentral
b-2,posterior:the lateral posterior:
US images
showingno significant
findings inposteriorcentral posterior; b-2, posterior;the lateral
US images
showingno significant
findings
inthe
thecentral
centrallongitudinalview.
However,
there
was
a
subchondralbone
discontinuity
inthelateralposteriorposterior longitudinal view. However, there was a subchondral bone discontinuity in the lateral◦ showing delayed ossification
view;(c)view
X-p APview
with elbow
45◦ flexed:
posterior longitudinallongitudinalview; (c) X-p
AP
with
elbow
45° flexed:
X-p X-p45°45
showing
delayed ossiin the lateral capitellum, observed in incomplete healing OCD cases [11]. In addition, there wasfication in the lateral capitellum, observed in incomplete healing OCD cases [11]. In addition, therea translucent area in the central capitellum, stage I-OCD; (d) CT images: d-1, sagittal image; d-2,
was a translucent area in the central capitellum, stage I-OCD; (d) CT images: d-1, sagittal image; dcoronal image; d-3, axial image: CT images showing the subchondral bone sclerosis, and the surface
2, coronal image; d-3, axial image: CT images showing the subchondral bone sclerosis, and the surwas almost repaired. White arrowheads: delayed ossification.
face was almost repaired. White arrowheads: delayed ossification.
The results of the secondary check-up are presented in Table 5. There were three casesof stage I OCD, three cases of stage II OCD, and one case with a different disorder. The twocases that were diagnosed only using mobile MRI included an early OCD case and a healingcase. The case that was diagnosed only with US was stage II OCD, which occurred at thefirst medical check-up using mobile MRI. Representative cases are described in Figures 4–8.

FOR PEER REVIEW

10 of 14

Diagnostics 2022, 12, 2551

9 of 13

Figure 8. A very earlyFigure
stage8.ofA an7): Mobile
MRI(+), US(−).(+),(a)USMobile
image
veryOCD
early casestage (Caseof an OCD
case (Case7): Mobile
MRI(−). (a) MR
MobileMR imageof sagittal T1WI: Mobile
MRI T1WI:
showingsignalchangesreflecting
marrowedemaedemain inof sagittal
Mobile
MRI intensity
showing signal
intensitychanges bonereflectingbone marrow
the anterior humeral thecapitellum;(b) UScapitellum;
image of(b)theUSposterior
longitudinal
view: USview:
did not
show
anterior humeral
image of theposterior longitudinal
US didnot showsubchondral(c)boneX-pelbow
AP view
withelbowX-p
45◦ flexed:
X-p 45◦ showing
a translucent
subchondral bone irregularity;
X-pirregularity;
AP view (c)with45°
flexed:45° showing
a translucent
area in the centralOCD;(d) 3T MR
d-1, PDWI-FS
sagittal image;area in the central capitellum,
stage-Icapitellum,
OCD; (d)stage-I
3T MR
images:d-1,images:
PDWI-FS
sagittal image;d-2, d-2,
PDWI
coronalimage:
localizationofthelesionwasconsistent
with
that
of
3T
MRI
and
mobilePDWI coronal image: localization of the lesion was consistent with that of 3T MRI and mobile MRI. MRI.
Table 5. Characteristics of OCD-positive players.
Primary Check-Up
Case

Age

Sex

Secondary Check-Up

Elbow
Symptom

Mobile MRI(RF ProbeGeneration)

US(Examiner)

Diagnosis

Stage

LesionLocation

LesionDiameter
(mm)

1

12

M

-

− (1st)

+ (B)

OCD

II

lateral

15

2

11

M

+

+ (1st)

+ (B)

OCD

I

central

10

3

12

M

-

+ (2nd)

+ (B)

OCD

II

central

9

4

12

M

+

+ (2nd)

+ (B)

OCD

II

lateral

11

5

12

M

+

+ (2nd)

− (B)

OCD

I

central

3.5

6

15

F

-

+ (2nd)− (C)not OCD

posterior

3.5

7

12

M

-

+ (2nd)

− (D)

OCD

central

5.5IUS, ultrasonography, M, male; F, female; RF probe, radio frequency probe.

Figure 8. A very early stage of an OCD case (Case 7): Mobile MRI (+), US (−). (a) Mobile MR imageof sagittal T1WI: Mobile MRI showing signal intensity changes reflecting bone marrow edema in
the anterior humeral capitellum; (b) US image of the posterior longitudinal view: US did not show
subchondral bone irregularity; (c) X-p AP view with elbow 45° flexed: X-p 45° showing a translucent
area in the central capitellum, stage-I OCD; (d) 3T MR images: d-1, PDWI-FS sagittal image; d-2,10 of 13
Diagnostics 2022, 12, 2551
PDWI coronal image: localization of the lesion was consistent with that of 3T MRI and mobile MRI.

Figure 9. A false-positive
mobilecase
MRI
(Case
6):MRI
Mobile(+), USMR MR
Figurecase
9. A withfalse-positivewithmobile(CaseMRI
6): Mobile
MRI(-).
(+),(a)USMobile(-). (a) Mobile
images: a-1, sagittal T1WI
image;
a-2, sagittal
T2*WI
image;T2*WI
a-3, coronal
T2*WI
image:
MR MR
images:a-1, sagittal
T1WI image;a-2, sagittal
image; a-3,
coronalT2*WImobile
image: mobile
images showing a small subchondral bone-lesion in the posterior capitellum; (b) US images of theposterior longitudinal view: US did not reveal any remarkable findings; (c) X-p AP view with elbow
45◦ flexed: X-p 45◦ showed no significant findings; (d) 3T MR images: d-1, PDWI-FS sagittal image; d2, PDWI-FS coronal image: 3-T MR image showing that the lesion was located in the posterior-central
region of the capitellum and conflicted with the posterior synovial folds in the extended position.
The pathogenesis differed from that of OCD caused by pitching according to the location of the lesion.
Repeated hyperextension may have contributed to the pathology, as in Panner’s disease, based on
the location of the lesion and the patient’s range of motion findings.

4. Discussion
This is the first report to show the clinical validity of a small car-mounted mobile
MRI system. Our mobile MRI detected OCD cases from the very early stage through tothe healing stage. Particularly in cases 5 and 7, mobile MRI detected OCD that was notdetectable using US. One case was in the healing stage and the other was in the very earlystage of OCD, without or with slight subchondral bone irregularity. Since US waves do
not penetrate the subchondral bone, US cannot detect OCD without subchondral boneirregularity. In contrast, mobile MRI shows OCD-positive findings as distinct subchondralbone marrow edema. Mobile MRI has the potential to detect OCD cases without subchondral bone irregularities. Case 5 was in the healing process with a repaired subchondralbone surface. According to previous reports, shorter periods of conservative treatment
tend to result in lower healing rates [11,24,25]. Thus, OCD in the healing stage is also ascreening target. Case 7 was OCD at a very early stage. Although screening for early OCD
before subchondral bone irregularities develop is ideal, this cannot be achieved using US.
Therefore, from the perspective of early detection, mobile MRI is an excellent screening tool.
Meanwhile, there was a false negative case and false positive results with mobile MRI.
The false negative case was due to poor imaging quality during the first medical check-up
using the mobile MRI. The imaging quality of low-field MRI depends on various conditions,Diagnostics 2022, 12, 2551

11 of 13

including the quality of the RF probe, imaging parameters, the patient’s motion, and thepatient’s positioning in the coil [26–29]. In particular, RF probes are consumables, and theimage quality deteriorates over time. Based on our experience of this false-negative case,
we replaced the RF probe to increase its sensitivity and reduce noise, and improved thelegless chair to reduce motion artifacts. Subsequently, the imaging quality was improved,
and the mobile MRI could detect all OCD cases. Although case 7 was a false positive case,mobile MRI detected a small imaging abnormality with excellent imaging quality.
Regarding the practicality of mobile MRI for on-field OCD screening, we overcame
some disadvantages of conventional mobile MRI. Our mobile MRI went to an unpaved
baseball field and obtained MRI images of sufficient quality for diagnosis using a household
power source. As a result, the MRI scan time was relatively short (1.5 min per sequence),
and we could screen all team members within one practice session. Our future aim is tofurther reduce the examination time for screening a large number of players. We havecontinued to improve our RF probes to achieve this. If the imaging quality is high enoughto diagnose OCD with only T1WI sagittal imaging, we can save a considerable amountof examination time. We will continue our research to detect as many early OCD cases as
possible.
This study had some limitations. First, it only demonstrated the clinical use of mobile
MRI and did not include any statistical analysis. In the future, we will recruit more cases tocompare the diagnostic ability of mobile MRI and US. Additionally, multiple examiners
performed the US examinations for participants. Although all examiners had adequate
experience with US, the quality of these examinations might have been inconsistent because
US proficiency could have varied [30]. Finally, we only performed secondary check-up for
patients shown to be positive in the primary check-up, which may affect the sensitivity
and specificity results. However, US has been established as the gold standard for OCDscreening in Japan. Therefore, we considered our study design appropriate to determine
the accuracy of the diagnosis using mobile MRI.
5. Conclusions
Mobile MRI was used for on-field screening for OCD for an entire youth baseball teamof around 20 players during one practice session. Furthermore, the imaging quality was
sufficient to diagnose OCD; mobile MRI could screen for OCD from the very early stages
through to the healing process, including cases without subchondral bone irregularity,
which could not be detected using US. Therefore, mobile MRI is a practical tool for on-field
screening and has the potential to screen all stages of OCD.
Author Contributions: Conceptualization, Y.T. and Y.O.; methodology, Y.T.; software, Y.T.; formal
analysis, K.I.; investigation, K.I., Y.O., T.O., Y.T., M.K., T.M., T.N., R.M. and Y.H.; resources, Y.T.; data
curation, K.I. and Y.T.; writing—original draft preparation, K.I.; writing—review and editing, Y.O.,
T.O. and Y.T.; visualization, K.I.; supervision, T.O. and Y.Y.; project administration, Y.T. and M.Y. All
authors have read and agreed to the published version of the manuscript.
Funding: This work was supported by JSPS KAKENHI Grant Number JP19K11435, and Orthopedic
Network Tsukuba.
Institutional Review Board Statement: The study was conducted according to the guidelines of the
Declaration of Helsinki and approved by the Institutional Review Board of the Tsukuba University(IRB No: 30–144, approved 23 July 2019).
Informed Consent Statement: Informed consent was obtained from all subjects involved in the study.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

Diagnostics 2022, 12, 2551

12 of 13

References
1.

2.
3.
4.

5.

6.

7.
8.
9.

10.

11.
12.
13.
14.

15.

16.
17.
18.

19.

20.
21.
22.
23.
24.

Nakagomi, M.; Kajiwara, M.; Matsuzaki, J.; Tanabe, K.; Hoshiai, S.; Okamoto, Y.; Terada, Y. Development of a small car-mounted
magnetic resonance imaging system for human elbows using a 0.2-T permanent magnet. J. Magn. Reson. 2019, 304, 1–6. [CrossRef][PubMed]George, S.S.; Huang, M.C.; Ignjatovic, Z. Portable ultrasound imaging system with super-resolution capabilities. Ultrasonics 2019,94, 391–400. [CrossRef] [PubMed]
Deoni, S.C.; Medeiros, P.; Deoni, A.; Burton, P.; Beauchemin, J.; D’Sa, V.; Boskamp, E.; By, S.; Nulty, C.M.; Mileski, W.; et al.
Development of a mobile low-field MRI scanner. Sci. Rep. 2022, 12, e5690. [CrossRef]
Takahashi, Y.; Doi, M.; Yamada, T.; Tamanoi, T.; Murase, K.; Mochizuki, T. Present status and issues regarding X-ray medical
checkup vehicles in preventive medicine: Usefulness of mass screening for lung cancer by an X-ray medical checkup vehicle.
Nihon Hoshasen Gijutsu Gakkai Zasshi 2005, 61, 847–851. [CrossRef] [PubMed]
Okamoto, Y.; Maehara, K.; Kanahori, T.; Hiyama, T.; Kawamura, T.; Minami, M. Incidence of elbow injuries in adolescent baseballplayers: Screening by a low field magnetic resonance imaging system specialized for small joints. Jpn. J. Radiol. 2016, 34, 300–306.
[CrossRef] [PubMed]
Kimura, M.; Kamada, H.; Tsukagoshi, Y.; Tomaru, Y.; Nakagawa, S.; Tanaka, K.; Mataki, Y.; Takeuchi, Y.; Ymazaki, M. Influenceof commuting methods on low back pain and musculoskeletal function of the lower limbs in elementary school children:
A cross-sectional study. J. Orthop. Sci. 2022, 27, 1120–1125. [CrossRef]
Matsuura, T.; Suzue, N.; Iwame, T.; Nishio, S.; Sairyo, K. Prevalence of osteochondritis dissecans of the capitellum in young
baseball players: Results based on ultrasonographic findings. Orthop. J. Sports. Med. 2014, 2, e2325967114545298. [CrossRef]
Iwame, T.; Matsuura, T.; Suzue, N.; Kashiwaguchi, S.; Iwase, T.; Fukuta, S.; Hamada, D.; Goto, T.; Tsutsui, T.; Wada, K.; et al.
Outcome of an elbow check-up system for child and adolescent baseball players. J. Med. Invest. 2016, 63, 171–174. [CrossRef]
Takagishi, K.; Matsuura, T.; Masatomi, T.; Chosa, E.; Takika, T.; Watanabe, M.; Iwame, T.; Otani, T.; Inagaki, K.; Ikegami, H.; et al.
Shoulder and elbow pain in elementary school baseball players: The results from a nation-wide survey in Japan. J. Orthop. Sci.
2017, 22, 682–686. [CrossRef]
Kida, Y.; Morihara, T.; Kotoura, Y.; Hojo, T.; Tachiiri, H.; Sukenari, T.; Iwata, Y.; Furukawa, R.; Oda, R.; Arai, Y.; et al. Prevalence
and clinical characteristics of osteochondritis dissecans of the humeral capitellum among adolescent baseball players. Am. J.
Sports. Med. 2014, 42, 1963–1971. [CrossRef]
Matsuura, T.; Kashiwaguchi, S.; Iwase, T.; Takeda, Y.; Yasui, N. Conservative treatment for osteochondrosis of the humeral
capitellum. Am. J. Sports. Med. 2008, 36, 868–872. [CrossRef] [PubMed]
Matsuura, T.; Iwame, T.; Iwase, J.; Sairyo, K. Osteochondritis dissecans of the capitellum: Review of the literature. J. Med. Invest.
2020, 67, 217–221. [CrossRef] [PubMed]
Matsuura, T.; Iwame, T.; Suzue, N.; Takao, S.; Nishio, S.; Arisawa, K.; Sairyo, K. Cumulative incidence of osteochondritis dissecansof the capitellum in preadolescent baseball players. Arthroscopy 2019, 35, 60–66. [CrossRef] [PubMed]
Kohyama, S.; Ogawa, T.; Mamizuka, N.; Hara, Y.; Yamazaki, M. A magnetic resonance imaging-based staging system forosteochondritis dissecans of the elbow: A validation study against the International Cartilage Repair Society Classification.
Orthop. J. Sports. Med. 2018, 6, e2325967118794620. [CrossRef] [PubMed]
Kohyama, S.; Nishiura, Y.; Hara, Y.; Ogawa, T.; Ikumi, A.; Okano, E.; Totoki, Y.; Yoshii, Y.; Yamazaki, M. Preoperative evaluationand surgical simulation for osteochondritis dissecans of the elbow using three-dimensional MRI-CT image fusion images.
Diagnostics. 2021, 11, 2337. [CrossRef]
Takahara, M.; Shundo, M.; Kondo, M.; Suzuki, K.; Nambu, T.; Ogino, T. Early detection of osteochondritis dissecans of thecapitellum in young baseball players. Report of three cases. J. Bone. Joint. Surg. Am. 1998, 80, 892–897. [CrossRef]
Carpenter, C.; Pines, J.M.; Schuur, J.D.; Muir, M.; Calfee, R.P.; Raja, A.S. Adult scaphoid fracture. Acad. Emerg. Med. 2014, 21,
101–121. [CrossRef]
Schutz, U.; Ehrhardt, M.; God, S.; Billich, C.; Beer, M.; Trattnig, S. A mobile MRI field study of the biochemical cartilage reactionof the knee joint during a 4,486 km transcontinental multistage ultramarathon using T2* mapping. Sci. Rep. 2020, 10, e8157.
[CrossRef]
Schomoller, A.; Risch, L.; Kaplick, H.; Wochatz, M.; Engel, T.; Schraplau, A.; Sonnenburg, D.; Huppertz, A.; Mayer, F. Inter-raterand inter-session reliability of lumbar paraspinal muscle composition in a mobile MRI device. Br. J. Radiol. 2021, 94, e20210141.
[CrossRef]
Mateen, F.J.; Cooley, C.Z.; Stockmann, J.; Rice, D.R.; Vogel, A.C.; Wald, L.L. Low-field portable brain MRI in CNS demyelinating
Disease. Mult. Scler. Relat. Disord. 2021, 51, e102903. [CrossRef]
Deoni, S.C.L.; Bruchhage, M.M.K.; Beauchemin, J.; Volpe, A.; D’Sa, V.; Huentelman, M.; Williams, S.C.R. Accessible pediatricneuroimaging using a low field strength MRI scanner. Neuroimage 2021, 238, e118273. [CrossRef] [PubMed]
Harada, M.; Takahara, M.; Sasaki, J.; Mura, N.; Ito, T. Using sonography for the early detection of elbow injuries among young
baseball players. Am. J. Roentgenol. 2006, 187, 1436–1441. [CrossRef] [PubMed]
Takahara, M.; Ogino, T.; Tsuchida, H.; Takagi, M.; Kashiwa, H.; Nambu, T. Sonographic assessment of osteochondritis Dissecansof the humeral capitellum. Am. J. Roentgenol. 2000, 174, 411–415. [CrossRef] [PubMed]
Niu, E.L.; Tepolt, F.A.; Bae, T.S.; Lebrun, D.G.; Kocher, M.S. Nonoperative management of stable pediatric osteochondritis
dissecans of the capitellum: Predictors of treatment success. J. Shoulder. Elbow. Surg. 2018, 27, 2030–2037. [CrossRef] [PubMed]

Diagnostics 2022, 12, 2551

25.
26.
27.
28.
29.
30.

13 of 13

Uno, T.; Takahara, M.; Maruyama, M.; Harada, M.; Satake, H.; Takagei, M. Qualitative and quantitative assessments ofradiographic healing of osteochondritis dissecans of the humeral capitellum. JSES Int. 2021, 5, 554–560. [CrossRef]
Marques, J.P.; Simonis, F.F.J.; Webb, A.G. Low-field MRI: An MR physics perspective. J. Magn. Reson. Imaging 2019, 49, 1528–1542.
[CrossRef]
Ghazinoor, S.; Crues, J.V., 3rd; Crowley, C. Low-field musculoskeletal MRI. J. Magn. Reson. Imaging 2007, 25, 234–244. [CrossRef]
Hori, M.; Hagiwara, A.; Goto, M.; Wada, A.; Aoki, S. Low-Field Magnetic Resonance Imaging: Its History and Renaissance. Invest.
Radiol. 2022, 56, 669–679. [CrossRef]
Gach, H.M.; Curcuru, A.N.; Wittland, E.J.; Maraghechi, B.; Cai, B.; Mutic, S.; Green, O.L. MRI quality control for low-field
MR-IGRT systems: Lessons learned. J. Appl. Clin. Med. Phys. 2019, 20, 53–66. [CrossRef]
Blehar, D.J.; Barton, B.; Gaspari, R.J. Learning curves in emergency ultrasound education. Acad. Emerg. Med. 2015, 22, 574–582.
[CrossRef]

Neurological Sciences (2023) 44:451–455
https://doi.org/10.1007/s10072-022-06465-2

COVID-19

First manifestation of AQP4‑IgG‑positive neuromyelitis optica
spectrum disorder following the COVID‑19 mRNA vaccine BNT162b2
Shu Umezawa1,2,3· Katsura Ioka4 · Satoshi Aizawa4 · Yuichi Tashiro4 · Kazuo Yoshizawa4

Received: 8 December 2021 / Accepted: 18 October 2022 / Published online: 27 October 2022
© Fondazione Società Italiana di Neurologia 2022

Abstract
BNT162b2 is one of the effective COVID-19 vaccines. However, some researchers have also reported some neurologicaladverse events after the vaccination. Here, we present a case of a 52-year-old female who developed aquaporin (AQP) 4-IgGpositive neuromyelitis optica spectrum disorder (NMOSD) 14 days after the first dose of BNT162b2. She experienced theneck pain, weakness of the left arm and leg, numbness of the left hand, and impaired temperature sensation of the rightleg. MRI showed T2WI hyperintense lesions in the area postrema and cervical spinal cord ranging from C1 to C6 level andGd-enhanced lesions from C3 to C5 level; especially left lateral column was predominantly enhanced. Cell-based assays
showed anti-AQP4 antibody (AQP4Ab) was positive. We diagnosed AQP4-IgG-positive NMOSD. After high-dose glucocorticoid therapy, she is showing improved symptoms. The present case was characterized by the findings that a Gd-enhanced
lesion in the cervical cord localized dominantly at the left lateral column, consistent with the side of the shoulder where thevaccine was injected. Many studies suggested that AQP4-IgG-positive NMOSD development has multistep mechanisms
following the blood–brain barrier (BBB) breakdown. We suspected that immune responses following vaccination lead to
BBB disruptions. Through the limitedly damaged BBB, the plasma cells producing AQP4Abs might be recruited to CNS,
and AQP4Abs might bind to the cervical cord and the area postrema. A population-based study revealed that neurologicalevents following COVID-19 vaccination were less likely to be observed than COVID-19 infectious symptoms. Considering
rare adverse events, clinicians need to observe any changes in patient condition.
Keywords Neuromyelitis optica spectrum disorder · Myelitis · AQP4 · COVID-19 vaccine

Introduction
Severe acute respiratory syndrome coronavirus 2 (SARSCoV-2), the pathogen that causes coronavirus disease(COVID-19), has been responsible for hospitalizations anddeaths globally. COVID-19 presents with acute respiratory
symptoms and also leads to long-term neurological ones. In* Shu Umezawa
shumez@med.tohoku.ac.jp; umezawa.shu@gmail.com

order to combat the COVID-19 pandemic, several vaccines
have been developed and utilized worldwide.
BNT162b2 (Comirnaty©, BioNTech/Pfizer) is one of
the effective COVID-19 vaccines. Many randomized trials
and real-world studies have revealed that the vaccines are
key to reducing COVID-19 infections, transmissions, hospitalizations, and death. However, some researchers havealso reported that the vaccination leads to some neurologicalevents. Here, we report a case of a patient who developed
aquaporin (AQP) 4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) 2 weeks after vaccination with thefirst dose of BNT162b2.

1

Department of Education and Training, National Hospital
Organization Mito Medical Center, Ibaraki, Japan

2

Graduate Medical Education Center, Tohoku University
Hospital, Miyagi, Japan

Case presentation

3

Department of Neurology, Tohoku University Hospital,
Miyagi, Japan

4

Department of Neurology, National Hospital Organization
Mito Medical Center, Ibaraki, JapanA 52-year-old right-handed female experienced a firstattack of NMOSD after vaccination with the first dose of
BNT162b2. She had a mild fever the day after vaccination

13

Vol.:(0123456789)

452

Neurological Sciences (2023) 44:451–455

but no other inflammation reactions, including local reactions in her left arm around the injection site for 13 days.
Fourteen days after vaccination, she began to feel pain
ranging from the neck to the left shoulder, weakness of
the left arm, numbness of the left hand, and impaired temperature sensation of the right leg. Seventeen days after
vaccination, she complained of weakness of the left leg.
Twenty-one days after vaccination, she was admitted toour department. On admission, she had no visual impairment. Ophthalmological checkups showed no remarkablefindings suggesting optic neuritis. The other cranial nerves
were intact. Distal-dominant moderate to severe weakness of the left upper extremity, mild weakness of the left
lower extremity, and hypesthesia of the abdomen and theright thigh were found. Her left grasp power was 4.5 kg

compared with 19.0 kg for her right. Lhermitte sign was
positive. Neither nausea nor hiccups were observed.
Magnetic resonance imaging (MRI) of the spinal cord
showed that T2-weighted (T2WI) and fluid-attenuated inversion recovery (FLAIR) hyperintense lesions reached fromthe C1 to C6 level. Gadolinium (Gd)-enhancement lesion
was located from the C3 to C5 level, and, especially, leftlateral fasciculus was enhanced predominantly (Fig. 1).
Cerebral MRI showed T2-weighted and double inversion
recovery (DIR) hyperintense lesions in the area postrema
and the obex of the medulla (Fig. 2). These lesions were notenhanced. No other remarkable signal changes were detectedin the cortices or the optic nerves.
Routine blood tests detected no remarkable abnormal
values. Cell-based assays showed that anti-AQP4 antibody(AQP4Ab) was positive. Other autoantibodies were absent.

Fig. 1  Spinal MRI 21 days after vaccination. a T2WI showed hyperintense lesions from the C1 to C6 level. b C3 level. c C5 level. d Gdenhancement image showed lesions from the C3 to C5 level. e C3level. f C5 level. The left column predominantly enhanced at the C4
and C5 level

13

Neurological Sciences (2023) 44:451–455

453

Fig. 2  Brain MRI 21 days after
vaccination. a T2WI showed nosignal changes in the cortex. b
DIR image showed hyperintense
lesions in the area postrema andthe obex of medulla

On cerebrospinal fluid (CSF) analysis, mild pleocytosis (9cells/µL), in which mononuclear cells dominated (7 cells/µL), mildly increased protein (49 mg/dL), and elevatedmyelin basic protein (MBP) (1550 pg/mL) were found.
IgG index was normal (0.54), and oligoclonal bands were
negative.
We ruled out SARS-CoV-2 infection by a negative polymerase chain reaction (PCR) test and the absence of antibodies against the SARS-CoV-2 N protein. In addition, she hadno complaints of fever, cough, or other known COVID-19
symptoms before admission during the pandemic periods.
The patient had a history of Guillain-Barré syndrome(GBS). At the age of 35, she developed weakness of thebilateral lower extremities. The onset was about a monthafter suffering a cervical sprain because of a car accident.
These symptoms progressed for about a month until her
admission to our department. On admission, a nerve conduction study (NCS) showed temporal dispersion findings
and other demyelinating patterns at multiple nerves. MRI
showed no remarkable signal changes in the spinal cord.
We diagnosed GBS, and after intravenous immunoglobulin
therapy, she fully recovered. She had experienced no similar symptoms until the present admission. The present MRI
showed no enlargements of nerve roots or enhancement
lesions in the cauda equina, and NCS showed no demyelinating patterns in the bilateral median nerves and no otherfindings suggesting peripheral neuropathy. The family history was negative for any neurologic disorders and autoimmune diseases.
After other differential diagnoses were excluded, following the 2015 International Consensus Diagnostic Criteria,
we diagnosed AQP4-IgG-positive neuromyelitis optica
spectrum disorder. We conducted two cycles of high-dose
glucocorticoid therapy (each 1000 mg methylprednisolone i.v. for 3 days; the first cycle was initiated at 21 days
after vaccination; the second cycle was at 28 days) and oral

administration of 40 mg prednisolone for 16 days and atapering dose for about 2 weeks.
Twenty-eight days after vaccination, T2WI hyperintense lesions shrank to locate from the C3 to C5 level inthe cervical spinal cord, and lateralization pattern at the leftlateral column remained (Fig. 3). Currently, the patient istaking 25 mg of prednisolone orally and showing improved
symptoms.

Discussion
To our knowledge, this is the first case of AQP4-IgG-positive NMOSD development following the initial dose of
BNT162b2. The present case was noteworthy in terms of
its temporal association with the vaccine, the type of vaccine, and AQP4-IgG status. Previously, there have beensome reports of cases of NMOSD after COVID-19 vaccination, such as AQP4-IgG-positive NMOSD development
2 months after administration of inactivated vaccine [1],AQP4-IgG-positive after Gam-COVID-Vac [2], and AQP4IgG-negative after mRNA-1273 [3]. In the present case,the duration from vaccination to development was 2 weeks.
Considering myelitis and other neurological disorders following the vaccination occurred approximately at the tenthday, ranging from 1 to 2 weeks after vaccination in otherprevious reports, it is reasonable to assume that the present
case followed the timecourse of the post-vaccine adverse
events. Additionally, the available vaccines against COVID19 include mRNA vaccines, BNT162b2 and mRNA-1273,
and adenovirus vector vaccines, ChAdOx1nCoV and GamCOVID-Vac. Recently, a large population-based study in
the UK compared neurological events between BNT162b2
and ChAdOx1nCoV and showed that these have different
risks of adverse events [4]. This study suggested that distinct
mechanisms underlie adverse events following these two

13

454

Neurological Sciences (2023) 44:451–455

Fig. 3  Spinal MRI 28 days after vaccination. a T2WI showed hyperintense lesions from the C3 to C5 level in the cervical spinal cord. b C3
level. c C5 level. The lesions were lateralized to left lateral column from the C3 to C5 leveltypes of vaccine. Furthermore, AQP4Ab is a major diseasespecific biomarker of NMOSD; simultaneously, AQP4Ab
plays a direct role in astrocyte damage in NMOSD. The
pathophysiology behind AQP4-IgG-positive NMOSD lies
in astrocyte lysis, not demyelination, which is thought tounderlie another subtype of NMOSD, namely MOG-IgG
positive NMOSD. Clinically, AQP4-IgG serological status
is incorporated into the International Diagnostic Criteria.
In these regards, the present case is significant as the firstmanifestation of AQP4-IgG-positive NMOSD following
BNT162b2.
The patient had a history of GBS in the present case.
After intravenous immunoglobulin therapy, she recovered
and had no experiences of similar symptoms for about
17 years. In addition, a month before GBS development,
she suffered a cervical sprain because of a car accident. We
are unsure whether this episode was related to the present
NMOSD pathophysiology. At least, we assumed that thepatient has a predisposition to humoral immunologic reactions triggered by exogenous factors.
Moreover, the present case was characterized by the finding that a Gd-enhancement lesion in the cervical spinal cord
localized dominantly at the left lateral column, consistent
with the side of the shoulder where the vaccine was injected.
No local inflammation reactions occurred in her left arm.
Although this feature may be only a coincidence, it does
however need to be discussed in terms of pathophysiology.
Many in vivo and in vitro studies showed that AQP4-IgGpositive NMOSD development has multistep mechanisms,
including complement activations and astrocyte lysis following the blood–brain barrier (BBB) breakdown [5]. It ishypothesized that interleukin-6 (IL-6) signaling pathways

13

and humoral factors lead the BBB to increased permeability and decreased integrity with glial cells in the acutephase. Through damaged BBB, the plasma cells producing AQP4Abs and other inflammatory mediator cells arerecruited to the central nervous system. AQP4Abs binding to
AQP4 interact with complements, and astrocyte lysis follows
by the classical complement cascade. It is also known that
AQP4 is highly expressed in the area postrema, which was
the lesion other than the cervical spinal cord in the present
case. Taken together, we suspected that immune responses
following vaccination lead to BBB disruptions. Throughthe limitedly damaged BBB, the plasma cells producing
AQP4Abs or the other mediators might be recruited to the
CNS, and AQP4Abs might bind to the cervical cord and thearea postrema. One of the possible mechanisms underlying
the present event could be the IL-6 signaling pathways. Thisconcordance remains to be discussed, and further researchis needed.
As mentioned above, there have been some reported casesof neurological events following COVID-19 vaccination
as well as symptoms caused by infection. It has also beenreported that some patients with NMOSD tended to be reluctant to receive vaccines. However, a large population-based
study in the UK recently revealed that neurological events
following COVID-19 vaccination including BNT162b2
and ChAdOx1nCoV-19 were less likely to be observed
than ones caused by COVID-19 infection [4]. For example, there was an increased risk of encephalitis, meningitis,
and myelitis 1–28 days after COVID-19 infection (incident
rate ratio (IRR): 2.70) but not after vaccination (IRR: 1.14
(BNT162b2); 1.07 (ChAdOx1nCoV-19)). Therefore, weighing these two different risks, we recommend vaccination.

Neurological Sciences (2023) 44:451–455

455

To encourage this, healthcare professionals have to provide
more information about the risks of COVID-19-related
neurological complications compared to those following
COVID-19 vaccination. At the same time, considering rareadverse events reported, clinicians need to observe anychanges in their condition after vaccination.

2.

Data availability The datasets generated during and/or analyzed during the current study are available from the corresponding author on
reasonable request.

4.

3.

Declarations
Ethics approval The study was performed in accordance with the Helsinki II Declaration and approved by the Institutional Review Boardof our hospital.
Consent to participate All participants (or their legal representatives)
gave written informed consent.
Consent for publication We thank the patient reported here for theconsent given to describe and publish the case.
Conflict of interest The authors declare no competing interests.

5.

vaccination for COVID-19. Neurol Sci Off J Ital Neurol Soc Ital
Soc Clin Neurophysiol 42(9):3537–3539. https://d​ oi.o​ rg/1​ 0.1​ 007/​
s10072-​021-​05427-4
Badrawi N, Kumar N, Albastaki U (2021) Post COVID-19 vaccination neuromyelitis optica spectrum disorder: case report &MRI findings. Radiol Case Rep 16(12):3864–3867. https://​doi.​
org/​10.​1016/j.​radcr.​2021.​09.​033
Fujikawa P, Shah FA, Braford M, Patel K, Madey J (2021)
Neuromyelitis optica in a healthy female after severe acute respiratory syndrome coronavirus 2 mRNA-1273 vaccine. Cureus
13(9):e17961. https://​doi.​org/​10.​7759/​cureus.​17961
Patone M, Handunnetthi L, Saatci D, Pan J, Katikireddi SV, Razvi
S, Hunt D, Mei XW, Dixon S, Zaccardi F, Khunti K, Watkinson
P, Coupland C, Doidge J, Harrison DA, Ravanan R, Sheikh A,
Robertson C, Hippisley-Cox J (2021) Neurological complications
after first dose of COVID-19 vaccines and SARS-CoV-2 infection.
Nat Med. https://​doi.​org/​10.​1038/​s41591-​021-​01556-7
Takai Y, Misu T, Suzuki H, Takahashi T, Okada H, Tanaka S,
Okita K, Sasou S, Watanabe M, Namatame C, Matsumoto Y, Ono
H, Kaneko K, Nishiyama S, Kuroda H, Nakashima I, Lassmann
H, Fujihara K, Itoyama Y, Aoki M (2021) Staging of astrocytopathy and complement activation in neuromyelitis optica spectrum
disorders. Brain J Neurol 144(8):2401–2415. https://​doi.​org/​10.​1093/​brain/​awab1​02

Publisher's note Springer Nature remains neutral with regard tojurisdictional claims in published maps and institutional affiliations.

References
1. Chen S, Fan XR, He S, Zhang JW, Li SJ (2021) Watch out forneuromyelitis optica spectrum disorder after inactivated virus

13

TYPE Original Research
PUBLISHED

28 October 2022

DOI 10.3389/fmed.2022.1007175

OPEN ACCESSEDITED BY

Sree Bhushan Raju,
Nizam’s Institute of Medical Sciences,
India
REVIEWED BY

Rahul Grover,
Max Super Speciality Hospital, India
Andrea Ranghino,Azienda Ospedaliero Universitaria
Ospedali Riuniti, Italy
Sonu Manuel,
St Mary’s Hospital, India

Prediction of early graft function
after living donor kidneytransplantation by quantifying
the “nephron mass” using
CT-volumetric software

Kazuhiro Takahashi
kazu1123@md.tsukuba.ac.jp

Kazuhiro Takahashi1*† , Kinji Furuya1† , Masahiko Gosho2† ,Joichi Usui3† , Tomokazu Kimura4† , Akio Hoshi4† ,Shinji Hashimoto1† , Hiroyuki Nishiyama4† , Tatsuya Oda1† ,Kenji Yuzawa5† and Kunihiro Yamagata3†† These authors have contributed

1*CORRESPONDENCE

equally to this work
SPECIALTY SECTION

This article was submitted toNephrology,
a section of the journal
Frontiers in Medicine
RECEIVED 30 July 2022
ACCEPTED 10 October 2022
PUBLISHED 28 October 2022
CITATION

Takahashi K, Furuya K, Gosho M,
Usui J, Kimura T, Hoshi A,
Hashimoto S, Nishiyama H, Oda T,
Yuzawa K and Yamagata K (2022)
Prediction of early graft function after
living donor kidney transplantation by
quantifying the “nephron mass” using
CT-volumetric software.
Front. Med. 9:1007175.
doi: 10.3389/fmed.2022.1007175
COPYRIGHT© 2022 Takahashi, Furuya, Gosho,
Usui, Kimura, Hoshi, Hashimoto,
Nishiyama, Oda, Yuzawa andYamagata. This is an open-accessarticle distributed under the terms of
the Creative Commons Attribution
License (CC BY). The use, distribution
or reproduction in other forums ispermitted, provided the original
author(s) and the copyright owner(s)are credited and that the original
publication in this journal is cited, in
accordance with accepted academic
practice. No use, distribution or
reproduction is permitted which does
not comply with these terms.

Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, University of Tsukuba,
Tsukuba, Japan, 2 Department of Biostatistics, University of Tsukuba, Tsukuba, Japan, 3 Departmentof Nephrology, University of Tsukuba, Tsukuba, Japan, 4 Department of Urology, Universityof Tsukuba, Tsukuba, Japan, 5 Department of Transplant Surgery, Mito Medical Center, Mito, Japan

Early renal function after living-donor kidney transplantation (LDKT) depends
on the “nephron mass” in the renal graft. In this study, as a possible
donor-recipient size mismatch parameter that directly reflects the “nephronmass,” the cortex to recipient weight ratio (CRWR) was calculated by CTvolumetric software, and its ability to predict early graft function was
examined. One hundred patients who underwent LDKT were enrolled.
Patients were classified into a developmental cohort (n = 79) and avalidation cohort (n = 21). Using the developmental cohort, the correlation
coefficients between size mismatch parameters, including CRWR, andthe posttransplantation estimated glomerular filtration rate (eGFR) were
calculated. Multiple regression analysis was conducted to define a formula
to predict eGFR 1-month posttransplantation. Using the validation cohort,the validity of the formula was examined. The correlation coefficient
was the highest for CRWR (1-month r = 0.66, p < 0.001). By multiple
regression analysis, eGFR at 1-month was predicted using the linear model:
0.23 × donor preoperative eGFR + 17.03 × CRWR + 8.96 × preemptive
transplantation + 5.10 (adjusted coefficient of determination = 0.54). In
most patients in the validation cohort, the observed eGFR was within a
10 ml/min/1.73 m2 margin of the predicted eGFR. CRWR was the strongest
parameter to predict early graft function. Predicting renal function using thisformula could be useful in clinical application to select proper donors and to
avoid unnecessary postoperative medical interventions.
KEYWORDS

cortex weight recipient weight ratio, estimated glomerular filtration rate (eGFR),
living-donor kidney transplantation (LDKT), multidetector raw CT (MDCT), weightratio (WR)Frontiers in Medicine

01

frontiersin.org

Takahashi et al.

10.3389/fmed.2022.1007175

Introduction

Materials and methods

In most patients undergoing living-donor kidneytransplantation (LDKT), immediate graft function (IGF),
in which grafts show immediate urinary formation, is observed(1, 2). The serum creatinine level declines rapidly, and thelevel reaches nadir within a few weeks posttransplantation.
The loss of nephrons owing to immunological and nonimmunological factors reduces graft function on a yearly basis,and eventually, the function of the transplanted kidney isabolished (3–5). Early posttransplantation renal function affects
subsequent renal function and long-term graft survival (6, 7).
Therefore, maintaining the “nephron mass” of the renal grafts isessential for long-term graft survival. Owing to the progress inimmunosuppressive therapy and the establishment of a highly
accurate diagnostic and elaborate treatment strategy against
immunological complications, the 5-year graft survival rate
now reaches 90% in most countries (1, 8, 9).
Initial renal function after LDKT is affected by donor age,sex, donor preoperative estimated glomerular filtration rate(eGFR), donor-recipient size difference, etc., all of which reflect
the “nephron mass” of the renal graft (10, 11). The donorrecipient size mismatch is manifested by the clearance capacityof the “nephron mass” in the donor graft, which is less than
the recipient’s metabolite production. Because the “nephronmass” cannot be directly measured, alternative parameters thatcan be used as indicators of donor-recipient size mismatch
include the donor to recipient weight ratio (WR), body massindex (BMI) ratio (BMIR), body surface area (BSA) index ratio(BSAR), actual graft weight (Graft-act) to recipient weight ratio(GRWR-act), and Graft-act to recipient BSA ratio, and therelationship between these parameters and posttransplantation
renal function has been discussed in the previous literature (12–16). On the other hand, with the recent developments in medical
technology, the “nephron mass” can be measured directly by
quantifying the renal cortex using 3-dimensional (3D) CTvolumetry based on contrast-enhanced images obtained bymultidetector raw CT (MDCT) (17).
The purpose of this study was to quantify the “nephronmass” of the renal graft using CT-volumetric softwareand examine whether our novel size mismatch parameterthat directly reflects the “nephron mass,” the cortex torecipient weight ratio (CRWR), could determine early renal
function after LDKT compared with other representative size
mismatch parameters.

Study population
Between October 2013 and February 2022, 112 patients
underwent ABO identical/compatible adult-to-adult LDKTat Tsukuba University Hospital (n = 85) and Mito Medical
Center (n = 27). Patient records were identified by anadministrative database. In both cohorts, all LDKTs wereconducted with Asian pairs of donors and recipients,
and none of the recipients demonstrated delayed graftfunction. Eight patients were excluded since the arterial
phase of the contrast-enhanced CT was insufficient forreconstruction. Four patients were excluded since thepatients demonstrated acute rejection within 12 months
posttransplantation. Thus, a final population consistingof 100 pairs of LDKT was enrolled in our study. Patients
who underwent transplantation at Tsukuba University
Hospital (n = 79) were allocated as a developmental
cohort to build a prediction model, and patients who
underwent transplantation at Mito Medical Center (n = 21)
were allocated as a validation cohort. All data for thisstudy were collected in accordance with the Tsukuba
University Hospital and Mito Medical Center Internal
Review Boards.

Immunosuppression
In both centers, basiliximab (20 mg/body) was
introduced on the day of surgery and 4 days after
surgery. Maintenance immunosuppression was conductedwith triple therapy comprising long-acting tacrolimus,
mycophenolate mofetil, and steroids. The troughvalue of tacrolimus was maintained at 7–10 ng/mL
3 months after surgery and 5–8 ng/mL 4–12 months after
transplantation.

CT-volumetric quantification
The Digital Imaging and Communications in Medicine data
were obtained from MDCT with 1–2 mm slices (Brilliance
64 multidetector row CT scanner, Philips, Netherlands)
and transferred to high-end simulation software (Synapse
Vincent§ ver. 6.1; Fujifilm Corporation, Tokyo, Japan), whichsemiautomatically calculates the volume of the kidney graft
and its cortex (Supplementary Figure 1). The collecting
system, vessels, cysts, and sinus were excluded from allparenchymal volume measurements. Graft-act was measured
immediately after the back-table procedure. The simulated
graft weight (Graft-sim) to recipient weight ratio (GRWR-sim),
CRWR, and GRWR-act were defined as Graft-sim divided byAbbreviations: BMI, body mass index; BMIR, body mass index ratio; BSA,
body surface area; BSAR, body surface area index ratio; CRWR, cortex
to recipient weight ratio; eGFR, estimated glomerular filtration rate;
Graft-act, actual graft weight; GRWR-act, actual graft weight to recipient
weight ratio; GRWR-sim, simulated graft weight to recipient weight ratio;
GV, glomerular volume; IGF, immediate graft function; LDKT, livingdonor kidney transplantation; MDCT, multidetector raw CT; WR, weightratio; 3D, 3-dimensional.

Frontiers in Medicine

02

frontiersin.org

Takahashi et al.

10.3389/fmed.2022.1007175

Results

the recipient body weight (before LDKT), calculated cortex
volume divided by the recipient body weight, and Graftact divided by the recipient body weight, respectively. For
the comparison between predicted kidney volume and actual
kidney graft weight, we defined 1 g of kidney tissue as having
a volume of 1 ml.

Demographic and clinicalcharacteristics
Table 1 shows the demographic and clinical characteristicsof the 100 patients. There were no significant differences inbackground factors, except for total ischemia time, between thedevelopmental cohort and the validation cohort (113 min vs.
85.5 min, p < 0.001). The 1-year graft and patient survival rates
were 100% in both cohorts.

Assessment of renal function andurinary protein
Graft function was evaluated based on eGFR
(ml/kg/1.73 m2 ), calculated using the conversion formulafor Japanese individuals. Proteinuria was measured in 24h urine samples. The donor eligibility criterion at both
centers was renal function with an inulin clearance of atleast 70 ml/min. In this study, since postoperative renal
function was assessed by eGFR, eGFR was also used forpreoperative renal function.

Correlation between graft-sim andgraft-act and between cortex torecipient weight ratio and simulated
graft weight to recipient weight ratio
and actual graft weight to recipient
weight ratio

Glomerular morphometry of renal
biopsy specimens

Graft-sim was positively correlated with Graft-act (r = 0.65,
p < 0.001), and Graft-act tended to be heavier than Graftsim (Figure 1A). CRWR and GRWR-sim and GRWR-act werepositively correlated. CRWR was correlated more strongly with
GRWR-sim than with GRWR-act (r = 0.98, p < 0.001 andr = 0.78, p < 0.001, respectively, Figures 1B,C).

All protocol renal biopsy samples were obtained at
12 months posttransplantation using a percutaneous
needle device. A 3 mm section of paraffin-embedded
renal cortex specimen from the recipient was stainedwith hematoxylin-eosin. Glomerular area was measured
by tracing the contour of the outer margins along theglomerular tufts using imaging software (BZ-X Analyzer,
Keyence, Osaka, Japan) (Supplementary Figure 2).
The volume of three glomeruli or more was measured
from each slide, and the average value was used.
The glomerular volume (GV)-ratio was calculated by
dividing GV 12 months after transplantation by GV 1-hposttransplantation.

Correlation between weight ratio,
body mass index ratio, body surface
area index ratio, actual graft weight torecipient weight ratio, simulated graft
weight to recipient weight ratio, cortex
to recipient weight ratio, and urinary
protein and postoperative estimatedglomerular filtration rate

Statistical analysis

Figure 2 demonstrates the correlations between WR,
BMIR, BSAR, GRWR-act, GRWR-sim and CRWR andeGFR at 1, 6, and 12 months posttransplantation. WR and
BSAR were correlated with postoperative renal function,
but the correlation coefficients were low (WR, r = 0.34,
p = 0.003; BSAR, r = 0.37, p < 0.001 for correlation witheGFR 1-month posttransplantation, respectively). BMIR
did not show a significant correlation with postoperative
renal function. Correlation coefficients between CRWR and
posttransplantation eGFR were generally high compared withthose with GRWR-sim and GRWR-act (CRWR r = 0.66,
p < 0.001; GRWR-sim, r = 0.63, p < 0.001; GRWR-act,r = 0.36, p = 0.001 for correlation with eGFR 1-month
posttransplantation, respectively).

Categorical variables are presented as numbers andpercentages, and groups were compared using the chisquare test. Continuous variables were expressed as median,minimum, and maximum values. Groups were comparedusing Student’s t-test. Pearson’s correlation coefficients (r)were calculated, and single and multiple regression analyses
were performed. Analyses were conducted using SPSS 27.0
(SPSS Inc., Chicago, IL, USA) and SAS software V.9.4 (SASInstitute, Cary, NC, USA). All variables that had a p < 0.05
in a single regression model were included in a multiple
regression model. A value of p < 0.05 was considered
statistically significant.

Frontiers in Medicine

03

frontiersin.org

Takahashi et al.

10.3389/fmed.2022.1007175

TABLE 1 Demographic and clinical characteristics.

Developmental
cohort (n = 79)

Validation
cohort (n = 21)

p-valueAge

45 (22–68)

51 (18–72)

0.20

Sex, male

55 (70%)15 (71%)0.87

22.9 (17.6–29.7)

22.1 (16.8–30.4)

0.24

Chronic glomerulonephritis

40 (51%)

11 (52%)0.22

Diabetes mellitus

19 (24%)2 (10%)

Hypertension

7 (9%)

1 (5%)

Others13 (16%)

7 (33%)

Age60 (32–78)

62 (42–73)

0.79

Sex, male

24 (30%)10 (48%)

0.11

BMI, kg/m2

23.7 (16.2–28.9)

23.2 (16.6–25.7)

0.56

69 (87%)21 (100%)

0.08

Recipient

BMI
Background disease

Donor

Body side of the donated kidney, left
Diabetes mellitus, yes

7 (9%)

1 (5%)

0.69

Hypertension

22 (28%)5 (24%)

0.87

81.2 (55.3–126.7)

75.8 (57.8–122.0)

0.09

ABO incompatible, yes

26 (33%)8 (38%)

0.66

PEKT, yes

29 (37%)4 (19%)

0.13

Relationship, parent

43 (54%)7 (33%)

0.23

Spouse31 (39%)12 (57%)Sibling

5 (6%)

2 (10%)HLA mismatch

3 (0–6)

3 (1–5)

0.79

Warm ischemia time, min

3 (1–16)4.5 (2–8)

0.06

Total ischemia time, min

113 (67–202)

85.5 (58–120)<0.001

Bleeding amount, ml

208 (4–2760)

107 (3–871)

0.27

eGFR, ml/min/1.73 m2
Transplant

BMI, body mass index; PEKT, preemptive kidney transplant; eGFR, estimated glomerular filtration rate; HLA, human leucocyte antigen.

Multiple regression analysis using
cortex to recipient weight ratio andestimated glomerular filtration rate at
1-month posttransplantation andvalidation

Correlation between cortex torecipient weight ratio and urinary
protein and glomerular volume-ratio
Cortex to recipient weight ratio demonstrated a weak
reverse correlation with urinary protein at 1 and 6 months
posttransplantation (r = –0.27, p = 0.02 and r = –0.34, p = 0.002,
respectively, Figure 3A), but not with urinary protein at
12 months posttransplantation (r = –0.17, p = 0.16).
The GV ratio showed a weak reverse correlation withCRWR (n = 56, r = –0.35, p = 0.009, Figure 3B). The GV
ratio demonstrated a positive correlation with urinary protein
at 1 and 6 months posttransplantation (n = 55, r = 0.24,
p = 0.07 and r = 0.38, p = 0.004, Figure 3C). On theother hand, the GV ratio showed no correlation with urinary
protein posttransplantation or glomerular sclerosis at 12 months
posttransplantation (n = 55, r = –0.08, p = 0.58; n = 53, r = –0.23,
p = 0.10, Figure 3D).

Frontiers in Medicine

Single regression analysis showed that donor age (β = –0.33, SE = 0.16, p = 0.04), donor preoperative eGFR (β = 0.37,
SE = 0.11, p = 0.001), CRWR (β = 20.38, SE = 2.67, p < 0.001),
and preemptive kidney transplant (PEKT, β = 14.34, SE = 3.43,
p < 0.001) were significantly correlated with recipient eGFR
at 1-month posttransplantation. In multiple regression analysis,
the donor preoperative eGFR (β = 0.23, SE = 0.08, p = 0.006),
CRWR (β = 17.03, SE = 2.49, p < 0.001), and PEKT (β = 8.96,
SE = 2.64, p = 0.001) became significantly associated withthe recipient’s eGFR at 1 month (Table 2). The formula forpredicting eGFR at 1 month was expressed as04

frontiersin.org

Takahashi et al.

10.3389/fmed.2022.1007175

FIGURE 1

Correlation coefficient between Graft-sim and Graft-act and between CRWR and GRWR-act and GRWR-sim. (A) Correlation between Graft-sim
and Graft-act. (B) Correlation between CRWR and GRWR-act. (C) Correlation between CRWR and GRWR-sim.

TABLE 2 Multiple regression analysis related to recipient‘s eGFR
(ml/min/1.73 m2 ) at 1 month.

β

SE

Donor eGFR (ml/min/1.73 m2 )

0.23

0.08

0.006

CRWR

17.03

2.49

<0.001Preemptive kidney transplant, yes

8.96

2.64

0.001

Variable

Center (n = 21). In more than 80% of patients (17/21), theobserved eGFR was within a 10 ml/min/1.73 m2 margin of thepredicted eGFR, showing that the performance of the formula
was good (Figure 4B).

P-value

Discussion

eGFR, estimated glomerular filtration rate; CRWR, cortex recipient weight ratio; β,regression coefficient; SE, standard error.

The novelty of this study is that CRWR was a novel size
mismatch parameter that directly reflected the “nephron mass”
of the allograft and could be calculated form preoperative CT
images using CT-volumetric software. CRWR demonstrated thestrongest correlation with postoperative early renal function
among the representative donor-recipient size mismatch
parameters, and it enabled the prediction of early allograftfunction using a formula.
Factors that influence renal function after LDKT can bedivided into immunologic and non-immunologic factors (5).
In the 21st century, the introduction of immunosuppressive
agents such as calcineurin inhibitors, mycophenolate mofetil,anti-CD25 monoclonal antibody, anti-human thymocyte
rabbit immunoglobulin, and rituximab in blood groupeGFR (ml/min/1.73 m2 )= 0.23 × donor eGFR (ml/min/1.73 m2 )+ 17.03 × CRWR + 8.96 × PEKT
+ 5.10 (adjusted coefficient of determination = 0.54)
This formula is graphically illustrated in Figure 4A. In
this graph, the donor eGFR is divided into approximately
50, 70, 90, and 110 ml/min/1.73 m2 , and it was possible tocalculate the postoperative eGFR for each CRWR according to
the presence or absence of PEKT. Furthermore, the formula
was validated using the external cohort from the Mito Medical

Frontiers in Medicine

05

frontiersin.org

Takahashi et al.

10.3389/fmed.2022.1007175

FIGURE 2

Correlation of donor-recipient size mismatch parameters (WR, BMIR, BSAR, GRWR-act, GRWR-sim, and CRWR) with renal function at 1, 6, and12 months posttransplantation. The correlation coefficients for CRWR were the highest among the other size mismatch parameters.

Frontiers in Medicine

06

frontiersin.org

Takahashi et al.

10.3389/fmed.2022.1007175

FIGURE 3

Correlation between CRWR and GV-ratio and urinary protein. (A) Correlation between CRWR and urinary protein at 1, 6, and 12 months
posttransplantation. (B) Correlation between CRWR and GV-ratio. (C) Correlation between GV ratio and urinary protein at 1, 6, and 12 months
posttransplantation. (D) Correlation between GV ratio and the percentage of glomerular sclerosis.

incompatible transplantation, as well as detailed elucidation of
the pathogenesis of various immunologic rejective reactions,have enabled sustained control of immunological factors. Owing
to these developments, the short- and mid-term outcomes overthe last 20 years have improved dramatically. On the other
hand, non-immunological factors, such as nephrotoxicity
secondary to immunosuppressants, hypertension, obesity,
diabetes, the recurrence of primary disease, donor-recipient size
mismatch, and viral infection, affect not only the short-term
but also the mid- and long-term outcomes. Controlling these
non-immunologic factors to prolong graft survival has received
attention from transplant physicians (4). After LDKT, mostpatients exhibit IGF, in which serum creatinine reaches its
nadir within a few weeks posttransplantation. In this period,
patients are usually under strong immunosuppression due tothe use of anti-CD25 monoclonal antibodies and anti-humanthymocyte rabbit immunoglobulin and high serum levels ofmaintenance calcineurin inhibitors. Thus, renal function in thisearly period is mostly defined by non-immunological factors,
especially the “nephron mass” in the donor graft, reflected bydonor age, donor preoperative eGFR, sex mismatch, and donorrecipient size mismatch, that accomplish subsequent baseline
graft function (10, 11). In particular, the donor-recipient size
mismatch is a direct reflection of the total throughput of therenal graft in the recipient. This can be understood on the basisof two facts: grafts from elderly donors demonstrate declined
renal function because of the reduced “nephron mass” in thedonor graft secondary to glomerulosclerosis due to aging, andgrafts from sex mismatch transplantations, especially female tomale transplantations, show worse posttransplantation renal
function since female kidneys are smaller in size and have less

Frontiers in Medicine“nephron mass” in terms of absolute quantity than male kidneys(18, 19).
The correlation between postoperative renal function andparameters such as BMIR, BSAR, WR, and GRWR-act havepreviously been discussed as indicators of donor-recipient size
mismatch (12–16). Several reports have demonstrated somedegree of correlation, but none of these indices sufficiently
reflect the quantity of the “nephron mass.” Although GRWRact might be a closer indicator than other parameters, it does
not always reflect the “nephron mass” because it includes theweight of perirenal fatty tissue, renal portal vessels, and theureter. In fact, the results of our study showed that Graftact (g) was generally heavier than Graft-sim (g), and thestrength of the correlation between CRWR and GRWR-act was
weaker than that between CRWR and GRWR-sim. Furthermore,
GRWR-act was weaklier correlated with early postoperative
renal function than GRWR-sim and CRWR. Recently, somestudies have reported the usefulness of the calculated renal graftvolume, namely, the Graft-sim in our study, in which graftvolume was measured by contrast-enhanced MDCT using 3Dvolumetry. Saxena et al. used MRI-based 3D volumetric software
to quantify graft volume and reported that its weight ratio
correlated with postoperative eGFR at 6 months and 1 year
posttransplantation (16). Yanishi et al. used Synaps Vincent§to quantify graft volumes and reported that GRWR-sim wascorrelated with eGFR at 1-year postoperation (20). On the other
hand, these reports did not compare GRWR-sim with other size
mismatch parameters, and it was not clear how reliable GRWRsim was compared with other parameters. Moreover, theseresearchers assessed postoperative renal function at the time
when renal function can be modified by immunological factors

07

frontiersin.org

Takahashi et al.

10.3389/fmed.2022.1007175

FIGURE 4

Graphic illustration of the formula for predicting eGFR at 1-month posttransplantation and its validation. (A) Graphic illustration of the formula.
The donor eGFR is divided into approximately 50, 70, 90, and 110 ml/min/1.73 m2 . It was possible to calculate the postoperative eGFR for each
CRWR according to the presence or absence of PEKT (red line; with PEKT, blue line; without PEKT). (B) Validation. In most patients (17/21), theobserved eGFR was within a 10 ml/min/1.73 m2 margin of the predicted eGFR.

Frontiers in Medicine

08

frontiersin.org

Takahashi et al.

10.3389/fmed.2022.1007175

and other non-immunological factors, such as diabetes, obesity,
hypertension, and infection. CRWR, as we propose here, directly
quantifies the renal cortex where functional glomeruli exist.
Because donor non-functional glomeruli, i.e., nephrons withglomerulosclerosis secondary to aging, obesity, infarction, etc.,
are not contrasted by MDCT, these non-functional nephrons
are not counted in CRWR (21). CRWR is more reliable as asurrogate of the “nephron mass” than the GRWR-sim, presented
as the total graft volume. This is intuitively understandable fromthe fact that older donors or obese donors who have a thinning
renal cortex on preoperative CT with a sufficient graft weightshow worse postoperative renal function than expected. Indeed,in our study, CRWR correlated with early renal function morestrongly than GRWR-sim at any time point postoperation.
In this study, eGFR at 1-month posttransplantation was
expressed as a linear equation using donor preoperative
eGFR, CRWR, and PEKT. This provides preoperative
information on the degree to which renal function canbe achieved postoperatively with any one donor in thecase of multiple potential living donors. Therefore, thisformula can be applied as a tool in donor selection. In
addition, the ability to predict peak renal function avoids
unnecessary fluid replacement or diuretic intervention when
postoperative renal function has reached the predicted value,
thereby avoiding prolonged hospitalization and wastefuluse of medical resources. Conversely, if postoperative renal
function is not the predicted value, the involvement of
immunologic and other non-immunologic factors should beconsidered, providing a rationale for invasive interventions
such as renal biopsy.
A decreased renal graft survival rate after LDKT has
been reported in situations where a small donor kidney
is transplanted to a large body size recipient (22–24).
This is due to the increased hemodynamic load on asingle glomerulus in the renal graft, resulting in a stateof hyperfiltration. Chronic hyperfiltration associated with
reduced functioning of the nephron mass damages the
allograft, initiating a vicious cycle of further reduction in thenephron mass, which causes more significant hyperfiltration,
leading to a progressive decline in the GFR, proteinuria,
hypertension, and eventually graft failure. This was proposedas the “hyperfiltration theory” by Brenner et al. in who
demonstrated the relationship between protein intake andthe progression of glomerulosclerosis in small kidneys inanimal experiments (25). These compensatory hemodynamicchanges could also be a proinflammatory trigger leading toalloantigen-dependent kidney damage (22, 26). The resultsof our study demonstrated that CRWR was negatively
correlated with glomerular enlargement. Namely, as thedonor-recipient size mismatch increased, the glomerular sizein the allograft increased, implying the pressure overloadof each glomerulus. Furthermore, glomerular enlargement
demonstrated a positive correlation with proteinuria in the

Frontiers in Medicine

short-term after transplantation, implying glomerular damage.
These results support the mechanisms of the “hyperfiltration
theory” of donor-recipient size-mismatch transplantation. On
the other hand, glomerular enlargement was not directly
correlated with urinary protein or glomerular sclerosis at
12 months. The reason for these phenomena might be because
in addition to hyperfiltration, glomerular damage and sclerosis
at this time could be influenced by other factors, including
immunologic and non-immunologic factors such as obesity,
diabetes, and viral infection (27).
The limitations of this study are as follows. First, thisis a retrospective study of patients at two institutions, andthe sample size is small. Furthermore, since the study was
conducted only in Asian, the size mismatches may not be
as significant as those in other countries. Second, this study
did not measure inulin clearance in the early postoperative
period; thus, eGFR was used as an outcome measure. The
eGFR is generally lower than the true GFR obtained frominulin clearance and therefore may not provide a precise
evaluation of postoperative renal function. Third, GV should be
evaluated by renal biopsies at each time point, but GV obtained
from protocol biopsies at 12 months posttransplantation
was used to evaluate postoperative GV altogether. Despite
these limitations, given that we for the first time proposed
CRWR as a surrogate parameter of the size mismatch that
directly reflects the “nephron mass,” this study provides uniqueimplications for the application of this novel indicator inclinical practice.

Data availability statement
The original contributions presented in the study areincluded in the article/Supplementary material, further
inquiries can be directed to the corresponding author.

Ethics statement
The studies involving human participants were reviewed
and approved by Tsukuba University Hospital and Mito Medical
Center Internal Review Boards. Written informed consent forparticipation was not required for this study in accordance with
the national legislation and the institutional requirements.

Author contributions
KT, KF, and TK collected the data. KT and MG analyzed thedata. KT, KF, and MG wrote the manuscript. JU, AH, SH, HN,
TO, KYu, and KYa did critical comments on the manuscript. All
authors contributed to the article and approved the submitted
version.

09

frontiersin.org

Takahashi et al.

10.3389/fmed.2022.1007175

Conflict of interest

claim that may be made by its manufacturer, is not guaranteedor endorsed by the publisher.

The authors declare that the research was conductedin the absence of any commercial or financial relationshipsthat could be construed as a potential conflictof interest.

Supplementary material
The Supplementary Material for this article can befound online at: https://www.frontiersin.org/articles/10.3389/
fmed.2022.1007175/full#supplementary-material

Publisher’s note

SUPPLEMENTARY FIGURE 1

Measurement of the renal cortex by 3D CT volumetric software (Synaps
Vincent R ).

All claims expressed in this article are solely those of theauthors and do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, or

SUPPLEMENTARY FIGURE 2

The glomerular volume (GV)-ratio was calculated by dividing GV 1-year
after transplantation by GV 1 h after transplantation.

Referencestransplantation. J Am Coll Surg. (2010) 210:718–25.e1. doi: 10.1016/j.jamcollsurg.
2009.12.032

1. Lentine KL, Smith JM, Hart A, Miller J, Skeans MA, Larkin L, et al.
OPTN/SRTR 2020 Annual data report: kidney. Am J Transplant. (2022) 22(Suppl.
2):21–136.
2. Al Otaibi T, Ahmadpoor P, Allawi AA, Habhab WT, Khatami MR, Nafar M,
et al. Delayed graft function in living-donor kidney transplant: a Middle Eastern
perspective. Exp Clin Transplant. (2016) 14:1–11.

15. Lv J, Guga S, Huang H, Wang R, Zhang X, Shou Z, et al. The effect of donorrecipient body surface area ratio on donor age and donor glomerular filtration
rate in Chinese patients undergoing a living-donor kidney transplant. Exp Clin
Transplant. (2014) 12:515–21. doi: 10.6002/ect.2013.0258

3. Jevnikar AM, Mannon RB. Late kidney allograft loss: what we know about it,
and what we can do about it. Clin J Am Soc Nephrol. (2008) 3(Suppl. 2):S56–67.
doi: 10.2215/CJN.03040707

16. Saxena AB, Busque S, Arjane P, Myers BD, Tan JC. Preoperative renal volumes
as a predictor of graft function in living donor transplantation. Am J Kidney Dis.
(2004) 44:877–85.

4. Gaston RS, Fieberg A, Helgeson ES, Eversull J, Hunsicker L, Kasiske BL, et al.
Late graft loss after kidney transplantation: is “death with function” really deathwith a functioning allograft? Transplantation. (2020) 104:1483–90.

17. Torimoto I, Takebayashi S, Sekikawa Z, Teranishi J, Uchida K, Inoue T. Renal
perfusional cortex volume for arterial input function measured by semiautomatic
segmentation technique using MDCT angiographic data with 0.5-mm collimation.
Am J Roentgenol. (2015) 204:98–104. doi: 10.2214/AJR.14.12778

5. Gill JS, Abichandani R, Kausz AT, Pereira BJ. Mortality after kidneytransplant failure: the impact of non-immunologic factors. Kidney Int. (2002) 62:
1875–83.

18. Luyckx VA, Shukha K, Brenner BM. Low nephron number and its clinicalconsequences. Rambam Maimonides Med J. (2011) 2:e0061.

6. Hariharan S, McBride MA, Cherikh WS, Tolleris CB, Bresnahan BA, Johnson
CP. Post-transplant renal function in the first year predicts long-term kidneytransplant survival. Kidney Int. (2002) 62:311–8.

19. Denic A, Lieske JC, Chakkera HA, Poggio ED, Alexander MP, Singh P, et al.
The substantial loss of nephrons in healthy human kidneys with aging. J Am Soc
Nephrol. (2017) 28:313–20. doi: 10.1681/ASN.2016020154

7. Hellegering J, Visser J, Kloke HJ, D’Ancona FCH, Hoitsma AJ, van der Vliet JA,
et al. Poor early graft function impairs long-term outcome in living donor kidneytransplantation. World J Urol. (2013) 31:901–6.

20. Yanishi M, Kinoshita H, Yoshida T, Takayasu K, Yoshida K, Mishima T,
et al. Comparison of live donor pre-transplant and recipient post-transplant renal
volumes. Clin Transplant. (2016) 30:613–8. doi: 10.1111/ctr.12727

8. Transplant JSCR, Transplant JS. Annual progress report from the Japanese
renal transplant registry: number of renal transplantations in 2020 and follow-up
survey. Ishoku. (2022) 56:195–215.

21. Nakazato T, Ikehira H, Imasawa T. An equation to estimate the renal cortex
volume in chronic kidney disease patients. Clin Exp Nephrol. (2018) 22:603–12.
22. el-Agroudy AE, Hassan NA, Bakr MA, Foda MA, Shokeir AA, Shehab el-Dein
AB. Effect of donor/recipient body weight mismatch on patient and graft outcome
in living-donor kidney transplantation. Am J Nephrol. (2003) 23:294–9.

9. Boenink R, Astley ME, Huijben JA, Stel VS, Kerschbaum J, Ots-Rosenberg M,
et al. The ERA registry annual report 2019: summary and age comparisons. Clin
Kidney J. (2022) 15:452–72. doi: 10.1093/ckj/sfab273

23. Miller AJ, Kiberd BA, Alwayn IP, Odutayo A, Tennankore KK. Donorrecipient weight and sex mismatch and the risk of graft loss in renal transplantation.
Clin J Am Soc Nephrol. (2017) 12:669–76.

10. Dick AA, Mercer LD, Smith JM, McDonald RA, Young B, Healey PJ.
Donor and recipient size mismatch in adolescents undergoing living-donor renaltransplantation affect long-term graft survival. Transplantation. (2013) 96:555–9.
doi: 10.1097/TP.0b013e31829d672c

24. Vianello A, Calconi G, Amici G, Chiara G, Pignata G, Maresca MC.
Importance of donor/recipient body weight ratio as a cause of kidney graft loss
in the short to medium term. Nephron. (1996) 72:205–11. doi: 10.1159/000188843

11. Zhao J, Song WL, Mo CB, Wang ZP, Fu YX, Feng G, et al. Factors of
impact on graft function at 2 years after transplantation in living-donor kidneytransplantation: a single-center study in China. Transplant Proc. (2011) 43:3690–3.
doi: 10.1016/j.transproceed.2011.09.066

25. Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and theprogressive nature of kidney disease: the role of hemodynamically mediatedglomerular injury in the pathogenesis of progressive glomerular sclerosis in aging,
renal ablation, and intrinsic renal disease. N Engl J Med. (1982) 307:652–9. doi:
10.1056/NEJM198209093071104

12. Lee BM, Yoon SN, Oh CK, Kim JH, Kim SJ, Kim H, et al. Fractional
creatinine clearance of the donated kidney using Cockcroft-Gault formula as apredictor of graft function after living donor transplantation. Transplant Proc.
(2006) 38:1974–6. doi: 10.1016/j.transproceed.2006.06.024

26. Sanchez-Fructuoso AI, Prats D, Marques M, Pérez-Contín MJ, FernándezPérez C, Contreras E, et al. Does renal mass exert an independent effect on thedeterminants of antigen-dependent injury? Transplantation. (2001) 71:381–6. doi:
10.1097/00007890-200102150-00007

13. Yamakawa T, Kobayashi A, Yamamoto I, Nakada Y, Mafune A, Katsumata H,
et al. Clinical and pathological features of donor/recipient body weight mismatchafter kidney transplantation. Nephrology (Carlton). (2015) 20(Suppl. 2):36–9. doi:
10.1111/nep.12470

27. Naik AS, Sakhuja A, Cibrik DM, Ojo AO, Samaniego-Picota MD, Lentine
KL. The impact of obesity on allograft failure after kidney transplantation: acompeting risks analysis. Transplantation. (2016) 100:1963–9. doi: 10.1097/TP.
0000000000000983

14. McGee J, Magnus JH, Islam TM, Jaffe BM, Zhang R, Florman SS, et al.
Donor-recipient gender and size mismatch affects graft success after kidney

Frontiers in Medicine

10

frontiersin.org

diagnostics
ArticleClinical Relevance of Ultrasonographic andElectrophysiological Findings of the Median Nerve in
Unilateral Carpal Tunnel Syndrome Patients
Takamasa Kudo 1 , Yuichi Yoshii 1, * , Yuki Hara 2 , Takeshi Ogawa 3
1

2
3

*

Citation: Kudo, T.; Yoshii, Y.; Hara,Y.; Ogawa, T.; Ishii, T. ClinicalRelevance of Ultrasonographic andElectrophysiological Findings of theand Tomoo Ishii 1

Department of Orthopedic Surgery, Tokyo Medical University Ibaraki Medical Center,Ami 300-0395, Ibaraki, Japan
Department of Orthopedic Surgery, University of Tsukuba Hospital, Tsukuba 305-8577, Ibaraki, Japan
Department of Orthopaedic Surgery, Mito Medical Center, Mito 311-3193, Ibaraki, Japan
Correspondence: yyoshii@tokyo-med.ac.jp; Tel.: +81-29-887-1161

Abstract: Few studies have compared the unaffected and affected sides in the same carpal tunnel
syndrome (CTS) patients using ultrasonography and electrophysiological tests. We focused on
unilateral idiopathic CTS patients to investigate whether clinical test results differ between theunaffected and affected sides. The bilateral wrist joints of 61 unilateral idiopathic CTS patients were
evaluated. The median nerve cross-sectional area of ultrasound image, and latencies of the compoundmuscle action potential (CMAP) and sensory nerve action potential (SNAP) were measured. The
values obtained were compared between the affected and unaffected sides. The diagnostic accuraciesof each parameter were assessed, and cut-off values were defined. Significant differences wereobserved in all parameters between the affected and unaffected sides (p < 0.01). Area under the curve(AUC) values were 0.74, 0.88, and 0.73 for the cross-sectional area, CMAP distal latency, and SNAP
distal latency, respectively. Cut-off values were 11.9 mm2 , 5.1 ms, and 3.1 ms for the cross-sectionalarea, CMAP distal latency, and SNAP distal latency, respectively. The most reliable parameter thatreflected clinical symptoms was the distal latency of CMAP. Cut-off values for each parameter are
considered to be an index for the onset of the clinical symptoms of CTS.

Median Nerve in Unilateral Carpal
Tunnel Syndrome Patients.

Keywords: carpal tunnel syndrome; nerve conduction study; ultrasound; median nerve

Diagnostics 2022, 12, 2799.
https://doi.org/10.3390/
diagnostics12112799
Academic Editor: Antonio Barile
Received: 19 October 2022
Accepted: 14 November 2022
Published: 15 November 2022
Publisher’s Note: MDPI stays neutral
with regard to jurisdictional claims inpublished maps and institutional affiliations.

Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms andconditions of the Creative Commons
Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

1. Introduction
Carpal tunnel syndrome (CTS) is defined as a compression neuropathy of the median
nerve at the wrist joint. As clinical findings, night pain has been identified as a sensitive
symptom predictor (96%), and the useful signs for the diagnosis are sensory impairment
in the median nerve area of the hand (76%) and Tinel’s sign (71%) [1]. However, clinicalfindings are subjective as they are based on self-reported symptoms by patients. In addition,
symptoms may occur outside of the median nerve control area [2]. Therefore, difficulties areassociated with reliably diagnosing CTS based solely on clinical findings. CTS is commonly
diagnosed by a comprehensive assessment of clinical signs, electrophysiology, and imaging.
Many studies have reported the utility of electrophysiological tests and ultrasonography forcomparing CTS patients with normal subjects [3,4]. However, few studies have compared
the unaffected and affected sides in the same CTS patients because many patients havebilateral symptoms. Therefore, we herein focused on unilateral idiopathic CTS patientsand investigated whether clinical test results differed between the unaffected and affectedsides. The aim of the present study was to characterize the findings of ultrasonography
and nerve conduction studies on the symptomatic and asymptomatic sides of unilateral
CTS patients and to indicate the cutoff values for the symptom expression. This study
attempted to identify the clinical parameters in which patients perceive their symptoms
by comparing the results of clinical examinations of symptomatic and asymptomatic

Diagnostics 2022, 12, 2799. https://doi.org/10.3390/diagnostics12112799

https://www.mdpi.com/journal/diagnostics

Diagnostics 2022, 12, 2799

2 of 9hands. We hypothesized that morphology and nerve conduction of the median nerve differ
between the symptomatic and asymptomatic sides in the CTS patients with unilateral
symptom.
2. Materials and Methods
The protocol for the present study was reviewed and approved by our Institutional
Review Board (approved number T2020-0061). The bilateral wrist joints of 61 unilateral
idiopathic CTS patients (122 wrists, 22 males, 39 females, 30–89 years, mean 65.3 years)
were evaluated. Patients with chronic kidney disease, thyroid disease, and rheumatoid
arthritis were excluded. Patients with a history of upper limb surgery were also excluded.
CTS was diagnosed based on clinical symptoms and the results of motor and sensory
nerve conduction studies as well as ultrasonography. Patients were asked to complete
the JSSH version of the CTS instrument [5]. Clinical evaluation included the presence oftypical sensory symptoms, Phalen’s test and Tinel’s sign, sensory testing by two-point
discrimination on the middle finger, muscle testing, and examination for thenar atrophy.
Informed consent was obtained from all patients for inclusion in the present study. In thisstudy, we defined unilateral CTS as patients with characteristic symptoms on one side of
the hand and no symptoms on the other side. The diagnosis of CTS was confirmed basedon the clinical symptoms of pain, numbness, tingling in the median nerve distribution of
the hand, and the presence of at least one positive provocative test result, in addition tomeeting the criteria of nerve conduction study findings in the American Association ofElectrodiagnostic Medicine (AAEM) guidelines [6]. For the asymptomatic side, the patientswere also asked about the clinical symptoms of pain, numbness, and muscle weakness.
Then, the strength of APB muscle and positivity of provocation tests were evaluated. It
was defined as asymptomatic if none of the above clinical symptoms and evaluations
were observed. A single hand surgeon discriminated between the asymptomatic andsymptomatic sides based on interview and clinical findings. All patients underwent a nerve
conduction study and ultrasound imaging.
The cross-sectional area of the median nerve was measured by following method. Ultrasound imaging was routinely performed in patients with suspected CTS to differentiate
abnormalities around the carpal tunnel. During the diagnostic process, the cross-sectional
area of the median nerve was measured at the wrist crease level (proximal carpal tunnel)(Figure 1). Each patient was asked to sit and place their forearm on the table with thepalmar side up. An ultrasound scanner (Hi Vision Avius; Hitachi Aloka Medical, Ltd.,Tokyo, Japan) equipped with a linear array transducer was set to a depth of 20 mm. The
frequency of the transducer was 15 MHz. Cross-sectional ultrasonographic images of the
carpal tunnel were analyzed using ImageJ Software (National Institutes of Health, Bethesda,
MD, USA). The median nerve was outlined, and its area was calculated. All ultrasoundstudies were performed by a hand surgery specialist. The hand surgeon has been certified
as a specialist and an instructor by the Japanese Society of Surgery of the Hand.
The nerve conduction study was performed on all patients using a standard electromyography system (Neuropack MEB-2208, Nihon Kohden Co., Tokyo, Japan). All
studies were performed by a clinical technician who was blinded to clinical symptoms. At
the time of the nerve conduction study, room temperature was maintained at 27 ◦ C. Among
patients with cold hands, the hands were warmed to bring the skin temperature closer toroom temperature. In the motor conduction study, the compound muscle action potential(CMAP) of the abductor pollicis brevis muscle was recorded. CMAP was induced by astimulation 7 cm proximal to the recording electrode. In the sensory conduction study, astimulating electrode was placed at the index finger, and a recording electrode was placed
at 14 cm proximal to the stimulating electrode. The sensory nerve action potential (SNAP)
was recorded. The latencies of CMAP and SNAP were measured (Figure 2). Results were
excluded from the analysis if there was no action potential in some cases.

Diagnostics
Diagnostics2022,
2022,12,
12,2799
x FOR PEER REVIEW

of 10
9
3 3of

Figure 1. Ultrasound measurement of median nerve cross-sectional area. Cross-sectional area wasmeasured as the only parameter for the image analysis. Measurement of the median nerve crosssectional area was performed at the wrist crease level. The median nerve was outlined, and its area
was calculated.

The nerve conduction study was performed on all patients using a standard electromyography system (Neuropack MEB-2208, Nihon Kohden Co., Tokyo, Japan). All studies
were performed by a clinical technician who was blinded to clinical symptoms. At thetime of the nerve conduction study, room temperature was maintained at 27 °C. Among
patients with cold hands, the hands were warmed to bring the skin temperature closer toroom temperature. In the motor conduction study, the compound muscle action potential(CMAP) of the abductor pollicis brevis muscle was recorded. CMAP was induced by astimulation
7Ultrasoundcm proximal
to the recording
electrode.
In the sensory
study,
Figure1.1.Ultrasoundmeasurement
ofmedian
mediannervecross-sectionalcross-sectional
area.conduction
Cross-sectional
areaawaswas
Figuremeasurement
of
nerve
area.
Cross-sectionalareastimulating
electrodewasplaced attheindex
finger,andMeasurementa recording ofelectrodewasnerve
placedmeasured
as
the
only
parameter
for
the
image
analysis.
themediancrossmeasured as the only parameter for the image analysis. Measurement of the median nerve crossat 14
cm proximal
toperformed
the stimulating
electrode.
nerve
actionsectional
area wasat the wrist
creaseThelevel.sensory
The mediannerve
waspotential
outlined,(SNAP)and its area
sectional area was performed at the wrist crease level. The median nerve was outlined, and its area
calculated.
waswasrecorded.
The latencies of CMAP and SNAP were measured (Figure 2). Results were
was calculated.
excluded from the analysis if there was no action potential in some cases.
The nerve conduction study was performed on all patients using a standard electromyography system (Neuropack MEB-2208, Nihon Kohden Co., Tokyo, Japan). All studies
were performed by a clinical technician who was blinded to clinical symptoms. At thetime of the nerve conduction study, room temperature was maintained at 27 °C. Among
patients with cold hands, the hands were warmed to bring the skin temperature closer toroom temperature. In the motor conduction study, the compound muscle action potential(CMAP) of the abductor pollicis brevis muscle was recorded. CMAP was induced by astimulation 7 cm proximal to the recording electrode. In the sensory conduction study, astimulating electrode was placed at the index finger, and a recording electrode was placed
at 14 cm proximal to the stimulating electrode. The sensory nerve action potential (SNAP)
was recorded. The latencies of CMAP and SNAP were measured (Figure 2). Results were
excluded from the analysis if there was no action potential in some cases.

(a)

(b)

Figure2. Measurement
conditionsof latenciesof (a)
CMAP
andand(b)(b)
SNAP.
Figure2. Measurement
conditionsof latenciesof (a)CMAP
SNAP.

Statisticalanalysiswas
wasevaluatedevaluated by thehere.
Results
are areexpressed
Statisticalanalysisthe method
methoddescribed
described
here.
Resultsexas theasmean± standard
deviation.
Measuredvaluesvalues
were werecompared
betweenthe affectedpressedthe mean± standard
deviation.
Measuredcompared
betweentheand unaffectedsides sides
usingusing
the χ2thetest.
A receiver
operatingcharacteristic
(ROC)
curve
affectedand unaffectedχ2 test.
A receiver
operatingcharacteristic(ROC)
waswascreatedusing
a logistic
analysis.
Diagnostic
accuracy
waswasevaluatedby theunder
curve
createdusing
a logistic
analysis.
Diagnostic
accuracy
evaluatedby area
the area
the curve (AUC value) based on the ROC curve analysis. Cut-off values and sensitivity/specificity were assessed using the Youden Index method. All analyses were performed
using Bellcurve for Excel (version 2.14).
3. Results(b) obtained for each
Table 1 shows the(a)patient demographics. Table 2 shows the resultsparameter.
Figure 3 shows
the ROC
curvesoffor
parameter.
The cross-sectional areas
Figure 2. Measurement
conditionsof latencies(a)eachCMAPand (b) SNAP.
of the median nerve in six cases were larger on the unaffected side than on the affectedside. In
the motor
nerve conduction
study,
was notdescribedderived on
the affectedin
Statisticalanalysis
was evaluatedbyCMAP
the method
here.
Results side
are ex12
cases.
Inthesensory
nerve
conduction
study,
SNAP
wasnotderivedontheaffectedpressed as the mean ± standard deviation. Measured values were compared between theside
in 16andcases.
CMAP and
SNAP
derivedon the unaffectedside(ROC)
in allaffected
unaffected
sides
usingwaveforms
the χ2 test.were
A receiver
operatingcharacteristic
cases.
wereanalysis.
observed
in all parameters
the affectedcurve Significant
was createddifferencesusing a logistic
Diagnostic
accuracybetween
was evaluatedby the andarea
unaffected sides (p < 0.01). AUC values were 0.74, 0.88, and 0.73 for the cross-sectionalDiagnostics 2022, 12, 2799

4 of 9area, CMAP distal latency, and SNAP distal latency, respectively. Cut-off values were 11.9mm2 , 5.1 ms, and 3.1 ms for the cross-sectional area, CMAP distal latency, and SNAP distallatency, respectively.
Table 1. Patient demographics.
GenderMale
Female2239

Age

Ave (SD)
Min
Max

65.3 ± 11.2
30
89Height (cm)Weight (kg)BMI

Ave (SD)
Ave (SD)
Ave (SD)

157.6 ± 8.6
61.3 ± 11.9
24.6 ± 3.8

Manual work
Desk work
UnemployedLess than 3 months
3 months to 1 year
More than 1 year

44.8
13.8
41.4
38.6
33.3
28.1

0~1
2~3
4~5

19.3
40.4
40.4

Work Status (%)

Disease period (%)

APB strength(MMT, %)

Table 2. Results obtained for each parameter.
Affected Side

Unaffected Side

AUC

14.2 ± 4.0
6.6 ± 1.8
3.5 ± 0.8

11.3 ± 2.7
4.4 ± 0.9
2.8 ± 0.4

0.74
0.88
0.73

Cross-sectional area (mm2 )Diagnostics 2022, 12, x FOR PEER REVIEWDistal Latency for CMAP (ms)Distal Latency for SNAP (ms)

(a)

(b)

Cut-Off
Values
11.9
5.15 of 10
3.1

(c)

Figure 3. ROC curves of the (a) cross-sectional area, (b) CMAP latency (c) SNAP latency.
Figure 3. ROC curves of the (a) cross-sectional area, (b) CMAP latency (c) SNAP latency.

Discussion
4.4.Discussions
Inthethepresent
presentstudy,
study,thethecut-off
valueswere
definedin cross-sectional
the cross-sectionalIn
cut-off
valueswere
definedin theareasareas
andand nerve
conduction
distinguishedas symptomaticand asymptomatic.
An
nerve
conduction
studystudy
distinguishedCTS CTSas symptomaticand asymptomatic.
An imimportantpoint
in study
this study
wasitthatit characterize
could characterize
asymptomaticconditions
portant
point
in thiswas that
could
asymptomaticconditions
despitedespite positive
ultrasoundand electrophysiologicalfindings.
Thisbecould
be characterized
positive
ultrasoundand electrophysiologicalfindings.
This could
characterized
by exbyexamining
unilateral
CTS
patients.
The
mostaccurate
diagnostic
parameter
in
this
study
amining unilateral CTS patients. The most accurate diagnostic parameter in this study
wasthedistallatency
of
CMAP.
It
has
been
known
that
most
of
CTS
patients
havebilateral
was the distal latency of CMAP. It has been known that most of CTS patients have bilateral
symptoms. The
The asymptomatic
asymptomatic side
symptoms.
side may
may develop
developsymptoms
symptomsininthe
thefuture.
future.By
Bycharacterizing
characteriza unilateral
asymptomatic
situationin thisit mayearly therapeuticinterventioning
a unilateral
asymptomatic
situationin study,
this study,
it allow
may allow
early therapeuticinterto prevent
progressionof neuropathy.
ventionto prevent
progressionof neuropathy.
The diagnostic accuracy of ultrasonography was previously reported to be similar tothat of the nerve conduction study [7]. Although ultrasonography alone has sufficient diagnostic accuracy, it has been pointed out that combining ultrasonography and nerve conduction study improves diagnostic accuracy [8]. Ultrasonography is less stressful on theDiagnostics 2022, 12, 2799

5 of 9The diagnostic accuracy of ultrasonography was previously reported to be similar
to that of the nerve conduction study [7]. Although ultrasonography alone has sufficient
diagnostic accuracy, it has been pointed out that combining ultrasonography and nerve
conduction study improves diagnostic accuracy [8]. Ultrasonography is less stressful
on the patient and can identify neuromas or space-occupying lesions within the carpal
tunnel, which could not be evaluated electrophysiologically. It can also identify a welldeveloped median artery and the compression of the median nerve associated with that
arterial thrombus. In Nakamichi’s studies, space-occupying lesions were found only inthe unilateral group (7/20 = 35%), and it is said that careful examination of unilateralcarpal tunnel syndrome on suspicion of local pathology, especially space-occupying lesion,is important [9]. Prior confirmation of these findings is useful in selecting a treatment.
However, device/examiner dependency on the visualization of peripheral nerves is alimitation of this technique [10,11]. Furthermore, swelling of the median nerve is difficult
to detect in patients older than 80 years, regardless of their severity of CTS [12]. In addition,
diabetic conditions are known to affect the size of the median nerve [13,14]. These factors
should be considered when assessing median nerve size.
The present study also showed that the cross-sectional area of the median nerve wassignificantly higher on the affected side than on the unaffected side. In the present study,
the cut-off value for the cross-sectional area was 11.9 mm2 and the AUC value was 0.74
(sensitivity: 72%, specificity: 68%). Cut-off values in previous studies varied between 6.5
and 15 mm2 [15–17]. Only three studies defined a cut-off value of 11.9 mm2 or higher. It
has been pointed out that the cutoff value of cross-sectional area changes as conditions
change [18], but in this study, differences within patients are compared, so the conditions
are considered to be relatively homogeneous. Similar to the nerve conduction study, cut-off
values were higher in the present study than that in a study comparing CTS patients withnormal subjects. In addition, the asymptomatic hands of 62–85% of cases met the generaldiagnostic criteria (cross-sectional area 8.5–10 mm2 or higher) [19]. When considered in
the context of the Japanese people, Sugimoto’s studies have shown that the average ofJapanese median nerve cross-sectional area (carpal tunnel inlet at the pisiform bone level)
was 8.5 ± 1.7 mm2 , which is a study of healthy subjects [20]. It has been suggested thatthe physical characteristics such as sex, dominant hand, age, height, weight, body massindex (BMI) and wrist circumference are associated with nerve size [20]. Compared to
Sugimoto’s study, the present case is older, shorter in height and BMI (the average ages ofthe subject were 35 and 65 years, heights were 164 cm and 157 cm, and BMI were 22.3 and24, in the Sugimoto’s and the present studies, respectively). In that study, age and BMI werepositively, and height was negatively correlated with cross-sectional area. Although it ispointed out that these factors may cause the cross-sectional area in this case to be larger, we
think that the value of cross-sectional area was larger even taking these factors into account.
These findings suggest that even patients with unilateral symptoms have morphologicalchanges in the median nerve of the asymptomatic hand.
Additionally, in the previous study, the mean median nerve cross-sectional area for
carpal tunnel inlet seems to be similar for middle east (8.77 mm2 ), Oceania (8.71 mm2 ),Europe (8.90 mm2 ) and Asia (8.68 mm2 ) studies [21]. Although these were not directlycompared, it shows that there is no racial difference in the cross-sectional area of median
nerve. Despite the lack of significant differences between ethnic groups, the cutoff values
for the present cases are larger compared to the general values, which based on values fromprevious literature [19]. One reason is that, as mentioned above, morphological changes
in the median nerve is seen because the subjects of this study are unilateral symptoms.
However, Nakamichi’s study compared the Japanese with normal subjects, and even then,the cutoff value for cross-sectional area was set at 12 mm2 (sensitivity 67%, specificity 97%),
which is a higher value compared to the results of other countries [22]. This suggests thatthe cutoff value may be larger in the Japanese. From this finding, Japanese may be lesslikely to complain about physical symptoms than the patients in other country even when
the swelling of the median nerve is present.

Diagnostics 2022, 12, 2799

6 of 9Because ultrasound can easily observe changes over time, it may help to predict
symptom onset or determine the therapeutic effect. For more accurate diagnosis, we arethinking to use the wrist to forearm ratio for the ultrasound parameter [23]. Ultrasoundcan also detect increased intraneural blood flow of the median nerve with using Doppler
sonography. It has been pointed out that it may be an indicator of early diagnosis andseverity [24]. Nerve compression caused by elevated pressure in the carpal tunnel isbelieved to provoke a three-stage process that is initiated with venous congestion of themedian nerve followed by nerve edema and then by impairment of the venous and arterial
blood supplies. Comparison of findings of sonography and nerve conduction studies
showed that nerve hypervascularization and nerve swelling yielded the best detectabilityof carpal tunnel syndrome [25]. Because there were several methods to identify median
nerve pathological changes, it is clear that cross-sectional area measurement alone is not
sufficient for a comprehensive ultrasound evaluation of peripheral nerves [26]. It may bepossible to improve the accuracy of diagnosis by combining several parameters.
The nerve conduction study is one of a clinical test that is used to diagnose CTS [6]. It
also helps to distinguish CTS from other clinical disorders. Additionally, it has been pointed
out that the severity of CTS can be evaluated. Furthermore, the effects of surgery may beobjectively evaluated by performing the study before and after the surgery [27]. On theother hand, the nerve conduction study is affected by age, height, finger circumference, sex,
and skin temperature [28–32]. Therefore, previous studies adjusted for backgrounds, suchas age/sex and finger usage, to eliminate selection bias in comparisons of healthy subjects
and CTS patients. In the present study, it was possible to define cut-off values for clinicaltests in patients with CTS symptoms by comparing the symptomatic and asymptomaticsides in the same patients. We considered two reasons why the distal latency of CMAP
was found to be the most accurate. First, it has been pointed out that, Japanese may be lesslikely to complain about physical symptoms than the patients in other country even whenneurological abnormalities are present [33]. The average latency of CMAP in asymptomatic
hands in this study was 4.4 ± 0.9 ms, suggesting that the condition progresses to some extent
insidiously according to previous grading [34]. Generally, sensory nerves are damaged
first, and the onset of CTS is confirmed by a decrease in the sensory conduction velocity. In
the case of Japanese patients, it is thought that the first hospital visit is often made after
the symptoms have progressed to the extent that CMAP is impaired. Second, SNAP isaffected by the factors such as body surface and room temperatures, and often becomes
unrecordable when the CTS symptoms become more severe [35]. Because of these factors,
the distal latency of CMAP was found to be the most accurate in the present study.
Individuals with certain occupations, such as postal staff, healthcare professionals,
builders, and assembly workers, are more susceptible to CTS [36]. Evaluations of electrophysiological tests revealed the following prevalence of carpal tunnel syndrome: 20% forforest workers using vibration tools, 23% for staff working in general merchandise stores,
53% for meat workers, 17.8% for furniture makers, and 30% for dentists [37–40]. A common
factor in these occupations is repetitive compression of the median nerve. Abnormal nerve
conduction has been detected in some clinically asymptomatic nerves and has been definedas subclinical CTS [41]. MCV decreases with age, even in healthy subjects [42,43]. Therefore,
the asymptomatic side in unilateral CTS patients is considered to be in a state of subclinical
CTS. A previous study reported that the rate of subclinical CTS was approximately 18% [33].
Cut-off values were higher in the present study than in a previous study that comparednormal subjects and CTS patients. This difference was attributed to the values measured
being higher in the asymptomatic hands of unilateral CTS patients than in normal subjects.
Among asymptomatic hands, there were cases in which 34% of sensory nerve conduction
study and 50% of motor nerve conduction study met the diagnostic criteria of carpal tunnel
syndrome [7]. To improve diagnostic accuracy, it may be necessary to devise diagnostic
criteria that combine ultrasonography and nerve conduction studies [17].
Since symptoms such as numbness and pain are subjective, they are difficult to quantify
and adapt to all patients. Furthermore, these symptoms may be hidden by patients. ThisDiagnostics 2022, 12, 2799

7 of 9study compared values in symptomatic and asymptomatic hands in Japanese patients.
Therefore, the cut-off values obtained are close to the values at which symptoms reach alevel that interferes with daily activity. A previous study reported that approximately 30%
of CTS patients showed significant improvements in their natural course [44]. Based on
the values measured in the present study, patients with values near the cut-off values may
be able to improve with conservative treatment. In addition, these values may be used as
reference values for the selection of surgical treatment for patients.
There were several limitations that need to be addressed. First, sex, dominant hand,age, height, weight, BMI and wrist circumference were not evaluated in this study. There
have been no reports of differences in nerve size between Japanese and other ethnic groups.
In the present study, the cutoff value for symptom onset may be higher in Japanese, andthus, we think additional studies are needed. Second, the cross-sectional area was measured
at wrist crease level without bony landmark. Nakamichi et al. reported the ultrasoundmeasurements at three levels, and described that reliable data were obtained [20]. One of
the levels was based on wrist crease, and reliable data were obtained even without bonylandmarks. On the other hand, many papers measured with bony landmarks (at the levelof pisiform). We may need to consider the differences of nerve size in the different levelsof median nerve. In addition, automatic image analysis procedures have been reported
recently [11]. The results of our manual measurement may need to compare the results with
automatic analyzing procedure. Third, the characteristics of patients in which SNAP or
CMAP was not derived were not evaluated. Lastly, cut-off values were not confirmed when
symptoms appeared on the asymptomatic side. These limitations should be considered in
the future study.
5. Conclusions
In conclusions, the ultrasonographic and electrophysiological features of unilateral
idiopathic CTS patients were evaluated. It was found that the most reliable parameter thatreflected clinical symptoms was the distal latency of CMAP. The cut-off values of eachparameter are considered to be an index for the onset of the clinical symptoms of CTS.
Author Contributions: T.K.: acquisition and analysis of data and writing the manuscript, Y.Y.:
research design, acquisition and analysis of data and writing the manuscript, Y.H.: acquisition andanalysis of data and writing the manuscript, T.O.: acquisition and analysis of data and writing themanuscript, T.I.: acquisition and analysis of data and writing the manuscript. All authors have readand agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: This study protocol was approved by our Institutional
Review Board (T2020-0061).
Informed Consent Statement: Written consent was obtained from all study participants.
Data Availability Statement: The datasets analyzed during the present study are available from thecorresponding author upon reasonable request.
Conflicts of Interest: The authors declare no conflict of interest.

References
1.
2.
3.
4.
5.

Robert, M.S.; Robert, R.S.; Thomas, B.F.; Donna, B.S.; Wahida, K.S. The Value of Diagnostic Testing in Carpal Tunnel Syndrome. J.
Hand Surg. 1999, 24, 704–714. [CrossRef]
Stevens, J.C.; Smith, B.E.; Weaver, A.L.; Bosch, E.P.; Deen Jr, H.G.; Wilkens, J.A. Symptoms of 100 patients with electromyographically verified carpal tunnel syndrome. Muscle Nerve 1999, 22, 1448–1456. [CrossRef]
Padua, L.; Lo, M.M.; Valente, E.M.; Tonali, P.A. A useful electrophysiologic parameter for diagnosis of carpal tunnel syndrome.
Muscle Nerve 1996, 19, 48–53. [CrossRef]
Pinilla, I.; Martin-Hervas, C.; Sordo, G.; Santiago, S. The usefulness of ultrasonography in the diagnosis of carpal tunnel syndrome.
J. Hand Surg. Eur. Vol. 2008, 33, 435–439. [CrossRef] [PubMed]
Imaeda, T.; Toh, S.; Nakao, Y.; Nishida, J.; Hirata, H.; Ijichi, M.; Kohri, C.; Nagano, A. Validation of the Japanese Society for
Surgery of the Hand version of the Carpal Tunnel Syndrome Instrument. J. Orthop. Sci. 2007, 12, 14–21. [CrossRef]Diagnostics 2022, 12, 2799

6.

7.
8.

9.
10.
11.
12.
13.

14.
15.
16.
17.
18.
19.

20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.

8 of 9Jablecki, C.K.; Andary, M.T.; Floeter, M.K.; Miller, R.G.; Quartly, C.A.; Vennix, M.J.; Wilson, J.R. Practice parameter: Electrodiagnostic studies in carpal tunnel syndrome. Report of the American Association of Electrodiagnostic Medicine, American Academyof Neurology, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2002, 58, 1589–1592. [CrossRef]
Fowler, J.R.; Cipolli, W.; Hanson, T. A comparison of three diagnostic tests for carpal tunnel syndrome using latent class analysis.
J. Bone Jt. Surg. Am. 2015, 97, 1958–1961. [CrossRef]
Ooi, C.C.; Wong, S.K.; Tan, A.B.H.; Chin, A.Y.H.; Bakar, R.A.; Goh, S.Y.; Mohan, P.C.; Yap, R.T.J.; Png, M.A. Diagnostic criteria ofcarpal tunnel syndrome using high-resolution ultrasonography: Correlation with nerve conduction studies. Skelet. Radiol 2014,
43, 1387–1394. [CrossRef]
Nakamichi, K.; Tachibana, S. Unilateral carpal tunnel syndrome and space-occupying lesions. J. Hand Surg. Br. 1993, 18, 748–749.
[CrossRef]
Nakamichi, K. Ultrasonography for the management of carpal tunnel syndrome. Clin. Neurol. 2013, 23, 1217–1219. [CrossRef]
Obuchowicz, R.; Kruszynska, J.; Strzelecki, M. Classifying median nerves in carpal tunnel syndrome: Ultrasound image analysis.
Biocybern. Biomed. Eng. 2021, 41, 335–351. [CrossRef]
Miwa, T.; Miwa, H. Ultrasonography of carpal tunnel syndrome: Clinical significance and limitations in elderly patients. Intern.
Med. 2011, 50, 2157–2161. [CrossRef] [PubMed]
Chen, I.J.; Chang, K.V.; Lou, Y.M.; Wu, W.T.; Özçakar, L. Can ultrasound imaging be used for the diagnosis of carpal tunnel
syndrome in diabetic patients? A systemic review and network meta-analysis. J. Neurol. 2020, 267, 1887–1895. [CrossRef][PubMed]Byra, M.; Hentzen, E.; Du, J.; Andre, M.; Chang, E.Y.; Shah, S. Assessing the performance of morphologic and echogenic featuresin median nerve ultrasound for carpal tunnel syndrome diagnosis. J. Ultrasound Med. 2020, 39, 1165–1174. [CrossRef]
Fowler, J.R.; Gaughan, J.P.; Ilyas, A.M. The sensitivity and specificity of ultrasound for the diagnosis of carpal tunnel syndrome:
A meta-analysis. Clin. Orthop. Relat. Res. 2011, 469, 1089–1094. [CrossRef]
Ozsoy-Unubol, T.; Bahar-Ozdemir, Y.; Yagci, I. Diagnosis and grading of carpal tunnel syndrome with quantitative ultrasound: Is
it possible? J. Clin. Neurosci. 2020, 75, 25–29. [CrossRef]
Fujimoto, K.; Kanchiku, T.; Kido, K.; Imajo, Y.; Funaba, M.; Taguchi, T. Diagnosis of severe carpal tunnel syndrome using nerve
conduction study and ultrasonography. Ultrasound Med. Biol. 2015, 41, 2575–25780. [CrossRef]
Padua, L.; Coraci, D.; Erra, C.; Pazzaglia, C.; Paolasso, I.; Loreti, C.; Caliandro, P.; Hosbon-Webb, L.D. Carpal tunnel syndrome:
Clinical features, diagnosis, and management. Lancet Neurol. 2016, 15, 1273–1284. [CrossRef]
Cartwright, M.S.; Hobson-Webb, L.D.; Boon, A.J.; Alter, K.E.; Hunt, C.H.; Flores, V.H.; Werner, R.A.; Shook, S.J.; Thomas, T.D.;
Primack, S.J.; et al. Evidence-based guideline: Neuromuscular ultrasound for the diagnosis of carpal tunnel syndrome. Muscle
Nerve 2012, 46, 287–293. [CrossRef]
Nakamichi, K.; Tachibana, S. Enlarged median nerve in idiopathic carpal tunnel syndrome. Muscle Nerve 2000, 23, 1713–1718.
[CrossRef]
Audrey, J.T.N.; Ramya, C.; Prakash, A.; Mogali, S.R. A systematic review: Normative reference values of the median nerve
cross-sectional area using ultrasonography in healthy individuals. Sci. Rep. 2022, 12, 9217. [CrossRef]
Nakamichi, K.; Tachibana, S. Ultrasonographic measurement of median nerve cross-sectional area in idiopathic carpal tunnel
syndrome: Diagnostic accuracy. Muscle Nerve 2002, 26, 798–803. [CrossRef] [PubMed]
Hobson-Webb, L.D.; Massey, J.M.; Juel, V.C.; Sandres, D.B. The ultrasonographic wrist-to-forearm median nerve area ratio in
carpal tunnel syndrome. Clin. Neurophysiol. 2008, 119, 1353–1357. [CrossRef] [PubMed]
Venderschueren, G.A.; Meys, V.E.; Beekman, R. Doppler sonography for the diagnosis of carpal tunnel syndrome: A criticalreview. Muscle Nerve 2014, 50, 159–163. [CrossRef]
Mallouhi, A.; Pülzl, P.; Trieb, T.; Piza, H.; Bodner, G. Predictors of carpal tunnel syndrome: Accuracy of gray-scale and color
Doppler sonography. AJR Am. J. Roentgenol. 2006, 186, 1240–1245. [CrossRef]
Tagliafico, A.S. Peripheral nerve imaging: Not only crosssectional area. World J. Radiol. 2016, 8, 726–728. [CrossRef]
El-Hajj, T.; Tohme, R.; Sawaya, R. Changes in electrophysiological parameters after surgery for the carpal tunnel syndrome. J.
Clin. Neurophysiol. 2010, 27, 224–226. [CrossRef]
Rivner, M.H.; Swift, T.R.; Malik, K. Influence of age and height on nerve conduction. Muscle Nerve 2001, 24, 1134–1141. [CrossRef]
Stetson, D.S.; Albers, J.W.; Silverstein, B.A.; Wolfe, R.A. Effects of age, sex, and anthropometric factors on nerve conduction
measures. Muscle Nerve 1992, 15, 1095–1104. [CrossRef]
Huang, C.R.; Chang, W.N.; Chang, H.W.; Tsai, N.W.; Lu, C.H. Effects of age, gender, height, and weight on late responses andnerve conduction study parameters. Acta Neurol. Taiwan 2009, 18, 242–249.
Ludin, H.P.; Bayeler, F. Temperature dependence of normal sensory nerve action potentials. J. Neurol. 1977, 216, 173–180.
[CrossRef] [PubMed]
Werner, R.A.; Andary, M. Carpal tunnel syndrome: Pathophysiology and clinical neurophysiology. Clin. Neurophysiol. 2002, 113,
1373–1381. [CrossRef]
Nathan, P.A.; Takigawa, K.; Keniston, R.C.; Meadows, K.D.; Lockwood, R.S. Slowing of sensory conduction of the median nerveand carpal tunnel syndrome in Japanese and American industrial workers. J. Hand Surg. Br. 1994, 19, 30–34. [CrossRef]
Hirani, S. A study to further develop and refine carpal tunnel syndrome (CTS) nerve conduction grading tool. BMC Musculoskelet.
Disord. 2019, 20, 581. [CrossRef]Diagnostics 2022, 12, 2799

35.
36.

37.
38.
39.
40.
41.
42.

43.
44.

9 of 9Sonoo, M.; Menkes, D.L.; Bland, J.D.P.; Burke, D. Nerve conduction studies and EMG in carpal tunnel syndrome: Do they add
value? Clin. Neurophysiol. 2018, 3, 78–88. [CrossRef] [PubMed]
Tanaka, S.; Wild, D.K.; Seligman, P.J.; Halperin, W.E.; Behrens, V.J.; Putz-Andeson, V. Prevalence and work-relatedness of
self-reported carpal tunnel syndrome among U.S. workers: Analysis of the Occupational Health Supplement data of 1988
National Health Interview Survey. Am. J. Ind. Med. 1995, 27, 451–470. [CrossRef] [PubMed]
Koskimies, K.; Färkkilä, M.; Pyykkö, I.; Jäntti, V.; Aatola, S.; Starck, J.; Inaba, R. Carpal tunnel syndrome in vibration disease. Br. J.
Ind. Med. 1990, 47, 411–416. [CrossRef]
Osorio, A.M.; Ames, R.G.; Jones, J.; Castorina, J.; Rempel, D.; Estrin, W.; Thompson, D. Carpal tunnel syndrome among grocery
store workers. Am. J. Ind. Med. 1994, 25, 229–245. [CrossRef]
Isolani, L.; Bonfiglioli, R.; Raffi, G.B.; Violante, F.S. Different case definitions to describe the prevalence of occupational carpal
tunnel syndrome in meat industry workers. Int. Arch. Occup. Environ. Health 2002, 75, 229–234. [CrossRef]
Hamann, C.; Werner, R.A.; Franzblau, A.; Rodgers, P.A.; Siew, C.; Gruinger, S. Prevalence of carpal tunnel syndrome and medianmononeuropathy among dentists. J. Am. Dent. Assoc. 2001, 132, 163–170. [CrossRef]
Neary, D.; Ochoa, J.; Gilliatt, R.W. Sub-clinical entrapment neuropathy in man. J. Neurol. Sci. 1975, 24, 283–298. [CrossRef]
Bouche, P.; Cattelin, F.; Saint-Jean, O.; Léger, J.M.; Queslati, S.; Guez, D.; Moulonguet, A.; Brault, Y.; Aquino, J.P.; Simunek, P.
Clinical and electrophysiological study on the peripheral nerves system in the elderly. J. Neurol. 1993, 240, 263–268. [CrossRef][PubMed]
Verdú, E.; Ceballos, D.; Vilches, J.J.; Navarro, X. Influence of aging on peripheral nerve function and regeneration. J. Peripher.
Nerv. Syst. 2000, 5, 191–208. [CrossRef]
Futami, T.; Kobayashi, A.; Ukita, T.; Endoh, T.; Fujita, T. Carpal tunnel syndrome; Its natural history. Hand Surg. 1997, 2, 129–130.
[CrossRef]diagnostics
ArticleClinical Significance of Maximum Intensity Projection Method
for Diagnostic Imaging of Thoracic Outlet Syndrome
Takeshi Ogawa 1,2 , Shinzo Onishi 2,3 , Naotaka Mamizuka 4 , Yuichi Yoshii 5, * , Kazuhiro Ikeda 6 ,Takeo Mammoto 2 and Masashi Yamazaki 3
1

2

3
4

5
6

*

Citation: Ogawa, T.; Onishi, S.;
Mamizuka, N.; Yoshii, Y.; Ikeda, K.;

Department of Orthopedic Surgery, National Hospital Organization Mito Medical Center, 280 Sakuranosato,
Ibarakimachi 311-3193, Japan
Department of Orthopedic Surgery and Sports Medicine, Mito Clinical Education and Training Center,
University of Tsukuba Hospital, Mito Kyodo General Hospital, 3-2-7 Miya-Machi, Mito 310-0015, Japan
Department of Orthopedic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8577, Japan
Baseball and Sports Clinic, 2-228-1 Kosugi, Park City Musashikosugi the Garden Towers West 1st Floor W4,
Nakahara-Ward, Kawasaki 211-0063, Japan
Department of Orthopedic Surgery, Tokyo Medical University Ibaraki Medical Center, Ami 300-0395, Japan
Department of Orthopedic Surgery, Kikkoman General Hospital, Noda 278-0005, Japan
Correspondence: yyoshii@tokyo-med.ac.jp; Tel.: +81-298871161

Abstract: The aim of this study was to use the magnetic resonance imaging maximum-intensity
projection (MRI-MIP) method for diagnostic imaging of thoracic outlet syndrome (TOS) and toinvestigate the stricture ratios of the subclavian artery (SCA), subclavian vein (SCV), and brachial
plexus bundle (BP). A total of 113 patients with clinically suspected TOS were evaluated. MRI was
performed in a position similar to the Wright test. The stricture was classified into four grades.
Then, the stricture ratios of the SCA, SCV, and BP in the sagittal view were calculated by dividing
the minimum diameter by the maximum diameter of each structure. Patients were divided into
two groups: surgical (n = 22) and conservative (n = 91). Statistical analysis was performed using
the Mann–Whitney U test. The stricture level and ratio in the SCV were significantly higher inthe surgical group, while the stricture level and the ratio of SCA to BP did not show significant
differences between the two groups. The MRI-MIP method may be helpful for both subsidiary andsevere diagnoses of TOS.

Mammoto, T.; Yamazaki, M. ClinicalSignificance of Maximum Intensity

Keywords: maximum intensity projection; subclavian vein; thoracic outlet syndrome

Projection Method for Diagnostic
Imaging of Thoracic Outlet
Syndrome. Diagnostics 2023, 13, 319.
https://doi.org/10.3390/
diagnostics13020319
Academic Editor: Riemer H.J.A. Slart
Received: 15 December 2022
Revised: 4 January 2023
Accepted: 12 January 2023
Published: 15 January 2023

Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms andconditions of the Creative Commons
Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

1. Introduction
Thoracic outlet syndrome (TOS) is probably more common than is believed, especiallyamong young people. Diagnosing TOS is difficult because no reliable mechanical examination has been shown [1–7]. However, TOS has a wide variety of symptoms, and its
pathogenesis is still debated. The diagnosis of TOS is also dependent on various evoked
tests, and a classification of disputed neurogenic TOS has been proposed [8–12]. Patientswith no abnormal findings on electrophysiological examination but with a variety of subjective symptoms are difficult to diagnose, and cases suspected to have TOS may actually
be diagnosed with hysterical paralysis. One possible method, although not very reliable, todiagnose disputed neurogenic TOS is a medial antebrachial cutaneous nerve conduction
study [13,14]. Imaging tests such as 3D-CT angiography, 3D-MR angiography, brachial
plexus angiography, and angiography are used to visualize stenotic areas in blood vessels
and nerves [15–20]; however, these cause problems related to radiation exposure and theuse of contrast media. In this study, we report the application of the maximum intensity
projection (MIP) method in MRI, which is well known for the depiction of the cerebral vasculature, and its use in the diagnosis of TOS. MIP is used to represent the highest intensity
values along one axis of a three-dimensional volume in a two-dimensional (2D) image,Diagnostics 2023, 13, 319. https://doi.org/10.3390/diagnostics13020319

https://www.mdpi.com/journal/diagnostics

Diagnostics 2023, 13, x FOR PEER REVIEW

Diagnostics 2023, 13, 319

2 of 112 of 10intensity projection (MIP) method in MRI, which is well known for the depiction of thecerebral vasculature, and its use in the diagnosis of TOS. MIP is used to represent thehighest intensity values along one axis of a three-dimensional volume in a two-dimensional (2D)
image,
allowing rapid
interpretationof theentirevolumebased on this2D 1A,B).
allowing
rapid
interpretationof theentire volume
based
on this2D projection(Figureprojection(Figure1A,B).
The
objective
of
this
study
was
to
evaluatethediagnostic
signifThe objective of this study was to evaluate the diagnostic significance of the MIP method
icancethealso
MIP classified
method for
TOS.
We alsoclassifiedof stenosis
in(SCA),the subclafor
TOS.ofWe
thedegreeof stenosis
inthe
thedegree
subclavian
arterysubclavian
vianartery(SCA),
subclavian
vein(SCV),
andbrachial
plexusandcalculatedthevein (SCV), and brachial plexus and calculated the stricture rate to evaluatestricture
the usefulness
rate to evaluate the usefulness of MRI-MIP images in the diagnosis of TOS.

of MRI-MIP images in the diagnosis of TOS.

Figure 1. MRI-MIP display from the chest to the upper arm. (A) Raised right arm. (B) Raised left

Figure 1. MRI-MIP display from the chest to the upper arm. (A) Raised right arm. (B) Raised leftarm. MRI-MIP, magnetic resonance imaging maximum-intensity projection.
arm. MRI-MIP, magnetic resonance imaging maximum-intensity projection.

2. Materials and Methods

2. Materials and Methods

This study included 113 patients (60 men and 53 women) with clinically suspected
included
113 patients(60 menand
53 2014
women)
with 2021,
clinicallysuspected
TOSThiswho study
underwent
MRI-MIPat our hospital
fromMay
to MarchconsecuTOS
who
underwent
MRI-MIPatourhospital
from
May
2014
to
March
2021,
consecutively.
tively. The patients had an average age of 32.5 (14–67) y. The institutional review board ofThepatients had
an averageage of32.5 (14–67)
yr. Theinstitutional
review
the Universityof Tsukuba
Hospital
approved
this study(StudyNumber: NO
22-44).board
Sub- of the
Universityof Tsukuba
Hospital
approvedthisandstudy(StudyinNumber:
22-44).
Subjective
jective symptoms
variedfrom pain,
numbness,lethargy
the upperNO
limbs
and finsymptoms
varied infrompain, numbness,andlethargy
in thespace,
upperorlimbs
and mifingers togers to tenderness
the obliqueinterosseousmuscle,intercostal
pectoralis
nor tendoninarea.
with positive muscle,
Roos test,
Wright test,
Adson
test, or Eden
test tendon
tenderness
the Patientsoblique interosseousintercostal
space,or pectoralis
minor
results
were includedin this study.
area.
Patients
with positive
Roos test, Wright test, Adson test, or Eden test results were
MRI inwas
performed
included
thisstudy. using a clinical 3 Tesla machine (Magneton Skyra 3T, Siemens,
Berlin,Germany).
The patientsplaced3ina supine
positionwith theSkyra
upper3T,limb
MRI
was performed
usingwerea clinicalTeslamachine(Magneton
Siemens,raised Germany).
further thanThethatpatientsin the Wrightposition(Figureposition
2A). Imaging
performed
Berlin,were test
placedin a supine
with wasthe upper
limb raisedwith the upper limb and trunk firmly fixed with a whole-body coil and bandages (Figure
furtherthan that in the Wright test position (Figure 2A). Imaging was performed with
2B). The imaging conditions were as follows: 3D-STIR with a slice thickness of 1.3 m; FOV,
the upper limb and trunk firmly fixed with a whole-body coil and bandages (Figure 2B).
380 mm; TR/TE, 387/50; matrix, 320 × 256; and flip angle, 120°. A special pulse monitor
The imaging conditions were as follows: 3D-STIR with a slice thickness of 1.3 m; FOV,
was attached to the healthy index finger to synchronize imaging withthe heartbeat. The
380mm; TR/TE,
matrix,
320 ×veins
256; andflip
angle,
120◦ . A special
pulse
subclavian
arteries387/50;(SCA) andsubclavian
(SCV)
were
reconstructedusing MIP
andmonitor
wasattached
tothehealthyindex
fingertosynchronize
imagingwith
theheartbeat.
The3 of 11
Diagnostics 2023, 13,evaluatedx FOR PEERinREVIEW
the intercostal space.

subclavian arteries (SCA) and subclavian veins (SCV) were reconstructed using MIP and
evaluated in the intercostal space.

Figure 2. limb
MRI imaging
limb(A) Thepatient is
in aposition
supine positionwiththe upper
Figure 2. MRI imaging
position.
(A)position.
The patientis placedinplaceda supinewith theupper
limb further elevated than in the Wright test position. (B) The upper extremities from the trunk arelimb further elevated than in the Wright test position. (B) The upper extremities from the trunk aresecured. MRI, magnetic resonance imaging.
secured. MRI, magnetic resonance imaging.

The degree of SCA and SCV stenosis in MRI-MIP images were classified into four
grades: grade 0 = no stenosis; grade 1 = stenosis < 50% of the maximum diameter of the
SCA or SCV; grade 2 = stenosis > 50% of the maximum diameter of the SCA or SCV; andgrade 3 = stenosis to the point of interruption (Figure 3). On the second evaluation, weused proton-density-weighted (PDW) sagittal images to quantitatively evaluate the stric-Diagnostics 2023, 13, 319

Figure 2. MRI imaging limb position. (A) The patient is placed in a supine position with the upper
3 of 10limb further elevated than in the Wright test position. (B) The upper extremities from the trunk aresecured. MRI, magnetic resonance imaging.

Thedegreedegree ofof SCASCA andand SCVSCV stenosis
stenosis inThein MRI-MIP
MRI-MIP images
imageswere
wereclassifiedclassifiedinto
intofourfourgrades:
grade
0
=
no
stenosis;
grade
1=
stenosis
<
50%
of
the
maximum
diameter
grades: grade 0 = no stenosis; grade 1 = stenosis < 50% of the maximum diameterofofthe
the
SCAor
orSCV;
SCV;grade
grade22== stenosis
stenosis >
> 50%
SCA
50% ofof thethe maximum
maximumdiameter
diameterofofthe
theSCA
SCAororSCV;SCV;andandgrade3 3= =stenosis
stenosistoto
the
point
interruption(Figuresecondevaluation,
we
grade
the
point
of of
interruption(Figure3). 3).
OnOn
thethesecondevaluation,
we usedused proton-density-weighted(PDW)
sagittal
imagesto quantitatively
evaluate
stricproton-density-weighted(PDW)
sagittal
imagesto quantitatively
evaluatethethestricturetureofrate
the SCA,and nerve
bundlethe costovertebral
strictureratetheofSCA,
SCV, SCV,
and nerve
bundleat theatcostovertebral
gap.gap.
TheThestricture
raterate
was
was
calculatedbydividingtheminimum
diameter
(a)
of
each
SCA,
SCV,
and
nerve
buncalculated by dividing the minimum diameter (a) of each SCA, SCV, and nerve bundle
in PDW
the PDW
sagittal
image
themaximum
maximumdiameter
diameter (b)(b) as100 (Figindle
thesagittal
image
byby
the
as follows:
follows:(1-a/b)(1 − xa/b)
× 100
ure
4).
A
slice
in
which
the
first
rib
was
the
longestinaplate-like
shape
was
used
as theas(Figure 4). A slice in which the first rib was the longest in a plate-like shape was usedreference
position.
Themaximumandminimum
diameters
weremeasured
inin
the
the
reference
position.
Themaximumandminimum
diameters
weremeasuredthearea
area
where
the
first
rib
was
located.
The
stricture
grade
and
rate
of
SCA,
SCV,
and
nerve
bunwhere the first rib was located. The stricture grade and rate of SCA, SCV, and nerve bundle
dle werestatisticallycompared.
werestatisticallycompared.

Grade 0

Grade 1

Grade 2

Grade 3Figure3.3.The
Thedegreedegreeof
ofstenosis
stenosisof
ofSCA
SCAandandSCV
SCVisisclassifiedclassifiedinto
into44levels.
levels. Upper
Upper rowrow (dotted(dotted arrow),arFigurerow), a stenosis part of SCA. Lower row (solid line arrow), a stenosis part of SCV. Grade 0; no stea stenosis part of SCA. Lower row (solid line arrow), a stenosis part of SCV. Grade 0; no stenosis.
Diagnostics 2023, 13, x FOR PEER REVIEW
4 of3;11
nosis. Grade 1; mild stenosis, less than 50%. Grade 2; moderate stenosis, more than 50%. Grade
Grade 1; mild stenosis, less than 50%. Grade 2; moderate stenosis, more than 50%. Grade 3; severe
severe stenosis to the point of discontinuity. SCA, subclavian artery; SCV, subclavian vein.
stenosis to the point of discontinuity. SCA, subclavian artery; SCV, subclavian vein.

Figure4.4.Left
Leftsagittal
sagittalview.
view.(A)(A)TheTheSCVSCV(star),(star),SCA
SCA(asterisk),(asterisk),and
andnerve
nervebundle
bundle(dot(dotline)line)areareshown.
Figureshown. (B) Scout view of MRI-MIP image. (C) SCA, SCV, and nerve bundle diameter measure(B) Scout view of MRI-MIP image. (C) SCA, SCV, and nerve bundle diameter measurements (arrows).
ments (arrows). MRI-MIP, magnetic resonance imaging maximum-intensity projection; SCA, subMRI-MIP, magnetic resonance imaging maximum-intensity projection; SCA, subclavian artery; SCV,
clavian artery; SCV, subclavian vein.
subclavian vein.

A total of 22 patients underwent surgery (first rib resection), and 91 successfully underwent conservative treatment. The Mann–Whitney U test was used for statistical analysis, and a p-value of less than 0.05 was considered significant. Indications for surgery
were defined as patients who were clinically diagnosed with TOS, refractory to conservative treatment such as oral medication and rehabilitation, or who requested surgery. In
addition, only some cases from both groups were compared in terms of the stenosis rate

Diagnostics 2023, 13, 319

4 of 10

A total of 22 patients underwent surgery (first rib resection), and 91 successfully
underwent conservative treatment. The Mann–Whitney U test was used for statisticalanalysis, and a p-value of less than 0.05 was considered significant. Indications for surgery
were defined as patients who were clinically diagnosed with TOS, refractory to conservative
treatment such as oral medication and rehabilitation, or who requested surgery. In addition,
only some cases from both groups were compared in terms of the stenosis rate between theaffected and normal sides. None of the patients had symptoms on the healthy side, andonly those cases for which data were available were included in this study.
3. Results
A total of 22 patients (13 men and 9 women) belonged to the surgical group, with amean age of 34.8 yr (14–56 yr), and 91 patients (47 men and 44 women) in the conservative
group, with a mean age of 33.0 yr (15–67 yr). No significant differences were reported in
the demographic profile between the two groups. The main indications for surgery weresports such as baseball in six cases, numbness and pain in the upper limbs that persisted
for many years in twelve cases, and a strong cold sensation in addition to numbness in thehands in four cases. The background characteristics of the patients in the surgical groupare shown in Table 1. The average duration of illness was 4.6 yr (2–15 yr). A total of threecases were arterial TOS, while the other cases involved neurogenic TOS. Patient satisfaction
after surgery at the final follow-up was excellent in seven cases, good in thirteen cases, fairin two cases, and no case was classified as unsatisfactory.
Table 1. Background of patients in the surgery group.
Age atSurgery

AffectedSide

Cause orOccupation

Symptom

Duration ofIllness (Years)

Classificationof TOS

Co-Morbid Disease
or Symptom

1

37

L

BaseballNumbness
after throwing

2

Disputedneurogenic

Good

2

15

R

BaseballNumbness
after throwing

2

Disputedneurogenic

Good

3

41

R

BaseballNumbness
after throwing

4

Disputedneurogenic

Good

4

17

R

BaseballNumbness
after throwing

2

Disputedneurogenic

5

20

R

BaseballNumbness
after throwing

2

Disputedneurogenic

Good

6

19

R

BaseballNumbness
after throwing

3

Disputedneurogenic

Good

7

14

R

TennisNumbnessand pain2

Disputedneurogenic

Excellent

8

40

R

Reseaercher

Cold sensationand numbness

5

Arterial

Skin lesion of fingers,
upper limb weakness

Excellent

9

43

L

Office worker

Cold sensationand numbness

3

Arterial

Numbness after
jogging

Excellent

10

15

R

Malformation of
first rib

Cold sensationand numbness

2

Arterial

Malformation of
first rib

Excellent

11

56

L

Service industry

Cold sensationand numbness

6

Disputedneurogenic

Post operation of
cervical stenosis

Good

12

32

L

Traffic accident

Numbnessand pain2

Disputedneurogenic

Fair

13

48

R

Service industry

Numbnessand pain

6

Disputedneurogenic

Excellent

14

47

R

Nurse

Numbnessand pain

5

Disputedneurogenic

Good

15

22

L

Office worker

Numbnessand pain

3

DisputedneurogenicGood

UCL injury of sameside elbow

Satisfaction
after Surgery

ExcellentDiagnostics 2023, 13, 319

5 of 10

Table 1. Cont.
Age atSurgery

AffectedSide

Cause orOccupation

Symptom

Duration ofIllness (Years)

Classificationof TOS

Co-Morbid Disease
or Symptom

Satisfaction
after Surgery

16

51

L

Care worker

Numbnessand pain

15

Disputedneurogenic

Post operation ofsame side cubital
tunnel syndrome

Good

17

26

L

Service industry

Numbnessand pain

4

Disputedneurogenic

Good

18

24

R

Service industry

Numbnessand pain

4

Disputedneurogenic

Excellent

19

55

L

Constructionindustry

Numbnessand pain

4

Disputedneurogenic

Fair

20

53

L

Forestry industry

Numbnessand pain

5

Disputedneurogenic

Good

21

44

L/R

Unemployed

Numbnessand pain

10

Disputedneurogenic

Post operation of
cervical stenosis

Good

TOS, thoracic outlet syndrome.

Table 2 shows the breakdown of SCA and SCV stricture grades in MRI-MIP images.
The SCV showed a significantly stronger stricture in the surgery group (p < 0.01), whereas
the SCA showed more grade 0 patients without stricture in both groups, showing nodifference between the two groups (p = 0.33).
Table 2. Breakdown of SCV and SCA stenosis grade in MRI-MIP images.

SCV

SCA

Surgery(n = 22)
Conservative(n = 91)
Surgery(n = 22)
Conservative(n = 91)

Grade 0

Grade 1

Grade 2

Grade 3

0

3

4

15

5

35

20

31

11

7

2

2

59

22

8

2

p-Value

0.0113

0.33

MRI-MIP, magnetic resonance imaging maximum-intensity protection; SCA, subclavian artery; SCV, subclavian vein.

The mean stricture rates of SCA, SCV, and nerve bundle were 34.6%, 76.7%, and 34.5%
in the surgical group, and 28%, 67.7%, and 34.5% in the conservative group. There was asignificantly higher stricture rate in the surgery group for SCV (p = 0.036). In contrast, the
SCA (p = 0.21) and nerve bundle stenosis rates (p = 0.53) did not differ between the twogroups (Table 3).
Table 3. Stenosis rates of SCV, SCA, and nerve bundle.
Surgery (%)
n = 22

Conservative (%)
n = 91

p-Value

SCV

76.7

67.7

0.036

SCA

34.6

28

0.21

Nerve bundle

34.5

34.5

0.53

SCA, subclavian artery; SCV, subclavian vein.

In a comparative study of the affected and normal sides, there were seven and 24 casesin the surgical and conservative groups, respectively (Table 4). A trend was reported
towards greater strictures on the affected side of the SCA in the surgery group (p = 0.064).

Diagnostics 2023, 13, x FOR PEER REVIEW

7 of 11

Diagnostics 2023, 13, 319

6 of 10

In a comparative study of the affected and normal sides, there were seven and 24
cases in the surgical and conservative groups, respectively (Table 4). A trend was reported
However,no significant
differenceswere foundotherbetweenthetowards greater
strictureson the affectedside ofin
the
SCAendpoints
in the surgery
group(paffected= 0.064).
andnormalnosides.
However,significant differences were found in other endpoints between the affected
and normal sides.

Table 4. Stricture rate of SCV, SCA, and nerve bundle on surgery and conservative group. There wasaTabletrend 4.
towardgreateron theandaffectedof thein thesurgerygroup. group. There
Stricture
rate stenosis
of SCV, SCA,
nervesidebundleonSCA
surgery
andconservative

was a trend toward greater stenosis on the affected side of the SCA in the surgery group.
Surgery (n = 7)
Affected Side
Normal Side
p-Value
Conservative
Surgery(n = 7)断(n = 24)
SCV

Conservative(n = 24)
Surgery
Conservative
Surgery断Conservative
Surgery
Surgery断Conservative

SCV
SCA
SCA
Conservative
Nerve
Surgery断Conservative
Surgery
bundleNerve
bundleAffected side

Conservative
SCA, subclavian artery; SCV,
subclavian vein.

66.7
67.1
66.7断67.1

47.4
47.4断29.3

Normal sidep-value

28.5
28.5断32.5

0.47
0.20断0.47
0.064
0.064断0.28

74.4
66.9
74.4断66.9

29.3

32.5

46.0断74.8

40.3断71.2

46.0
74.8

40.3
71.2

0.20

0.28

0.24断0.36
0.24
0.36

SCA, subclavian artery; SCV, subclavian vein.

3.1. Representative Case
Representative Case
A 40-year-old man presented with weakness in the right upper limb. He has been
A 40-year-old
manofpresented
weaknesstheyears,
right which
upper limb.
He has been
experiencing
lethargy
the right withupper
limb forin
five
was aggravatedbyexperiencing
lethargy
of
the
right
upper
limb
for
five
years,
whichwas
aggravatedbyrunning. He worked as a researcher, and his symptoms worsened three months ago, makrunning.
He worked
as atoresearcher,and his symptoms
worsenedwith
threerightmonthsmakinging it difficultfor himhandle a pipette.
He was diagnosed
TOSago,by hislocal
itdoctordifficult
for
him
to
handleapipette.
Hewasdiagnosed
with
right
TOS
by
his
local
doctorand referred to our hospital. He had numbness in the right fingertips, epidermal
and referred to our hospital. He had numbness in the right fingertips, epidermal avulsion
avulsion of the fingertips, and nail deformity (Figure 5A). The Roos and Wright test resultsof the fingertips, and nail deformity (Figure 5A). The Roos and Wright test results were
were positive. He was limited to 20 s in the Roos test due to numbness and sluggishness
positive. He was limited to 20 s in the Roos test due to numbness and sluggishness inin his right arm, and his hand turned pale. Radiography showed no cervical ribs, while
his right arm, and his hand turned pale. Radiography showed no cervical ribs, while
MRI-MIP image and 3D-CT angiography showed stenosis of the SCA (grade 1) and SCV
MRI-MIP image and 3D-CT angiography showed stenosis of the SCA (grade 1) and SCV(grade 3) in the intercostal space (Figure 6A,B,D). The patient opted to undergo surgery;(grade 3) in the intercostal space (Figure 6A,B,D). The patient opted to undergo surgery;hence, first rib resection using the transaxial approach [7] was performed. Postoperatively,
hence, first rib resection using the transaxial approach [7] was performed. Postoperatively,
numbness in the right upper extremity decreased, and skin lesions on the tips of the finnumbness in the right upper extremity decreased, and skin lesions on the tips of the fingers
gers improved after three months (Figure 5B). Limping of the upper extremities during
improved after three months (Figure 5B). Limping of the upper extremities during runningrunning also disappeared. One year after surgery, the MRI-MIP images showed no stenoalso disappeared. One year after surgery, the MRI-MIP images showed no stenosis of thesis of the SCA (grade 0), and the sagittal section showed that the anterior scalene muscle,
SCA (grade 0), and the sagittal section showed that the anterior scalene muscle, which was
which
was
in contact
withthe surgery,
SCA before
had disappeared(Figure 6C, E).
incontact
withthe SCA
beforehadsurgery,
disappeared(Figure 6C,E).

Figure5.5.Skin
Skinmanifestations
manifestationsofofthe
theright
rightfingers:
fingers:(A)(A)
preoperative
finding;
postoperative
findFigure
preoperative
finding;(B)(B)
postoperative
finding.
ing.

Diagnostics 2023, 13, 319
Diagnostics 2023, 13, x FOR PEER REVIEW

7 of 108 of 11

Figure 6. Preoperative and postoperative images. (A) Preoperative MRI-MIP image showing grade
Figure 6. Preoperative and postoperative images. (A) Preoperative MRI-MIP image showing grade 1
1 stenosis of the SCA (arrow). (B) Preoperative 3D-CT angiography showing stenosis from below
stenosis of the SCA (arrow). (B) Preoperative 3D-CT angiography showing stenosis from below at theat the site where the SCA meets the clavicle (arrow). (C) Postoperative MRI-MIP image revealing
sitewhereofthe
SCAmeets the andclavicle(arrow).
Postoperative
MRI-MIP
image revealing
stenosis
SCA
disappeared
identified
as (C)
grade
0 (arrowhead).
(D) Preoperative
sagittalstenosis
view
ofshows
SCA disappeared
and scalene
identified
as grade(arrowhead).
(D)
Preoperative
sagittal
view showsthat the anterior
muscleis in0contact
with theSCA,
and the SCV
is disrupted.
(E) that
Preoperative
sagittalmuscle
view showsthat thewith
firsttherib SCA,was resected,
anterior scalene
muscle,theanterior scalene
is in contact
and the and
SCVtheis disrupted.
(E) Preoperative
which wascontactthat
with
the
SCA,
Stenosisof theSCV remained.
MRI-MIP,magnetic
sagittal
viewinshows
the
first
ribwaswasabsent.
resected,
and theanterior
scalene muscle,
which
was inresonance
imaging
maximum-intensity
projection;
SCA,
subclavian
artery;SCV,subclavianvein.
contact with the SCA, was absent. Stenosis of the SCV remained. MRI-MIP, magnetic resonanceimaging maximum-intensity projection; SCA, subclavian artery; SCV, subclavian vein.

4. Discussion
4. Discussion
In this study, MRI-MIP imaging showed that the stricture rate of the SCV reflected

In this study,
MRI-MIP
showedthatSCAthe andstrictureof thewas
SCVindependent
reflected thethe severityof TOS,
whereasimaging
the strictureof thenerverate
bundlesseverityof TOS,
whereasthe strictureof theTOS.
SCATheandapplication
nerve bundles
was independentofof severity,
despitethe absenceof venousof MRI-MIP
imaging inseverity,
despiteof reported
venous TOS.
Theoneapplicationof MRI-MIP
in thethe diagnosisof theTOSabsence
has been
in onlycase by Esposito
et al. imaging[21]. Zhang
etdiagnosis
of TOS
has been reported
in only one magnetic
case by Esposito
et angiography
al. [21]. Zhangal.
al. described
the usefulnessof contrast-enhanced
resonance
foret
thedescribed
usefulnessof contrast-enhanced
magnetic resonanceangiography
for thediagnosis theof TOSin 27 cases[22]. Hardy et al. investigated
the accuracyof MRI diagnosis
diagnosis
TOS andin 27reported
cases [22].
et al.[23].
investigatedaccuracy113
of MRI
diagnosis
in 48 TOSofcases
its Hardy
usefulness
This studytheevaluated
MRI-MIPiminages,
48 TOScasesitand
its usefulness[23].
makingthe reported
largest survey
conducted
toThisdate.study evaluated 113 MRI-MIP images,
makingit thesurveyconducted
to date.
Withthelargest
increasing
resolutionof MRI,it has become possible to evaluate the pathoWith theofincreasing
resolution invasive,of MRI, itnon-contrast-enhanced
has become possible tomethod,
evaluatewhich
the pathophysiology
TOS in a minimallywasphysiology
TOS in a minimallyinvasive,
non-contrast-enhanced
method,which
previously of
considereddifficult. On
the otherhand, Furushima et al.
reported
that wasthepreviously
difficult.
On theandotherFurushima
et al.
reported
that themaximum consideredsystolic bloodflow velocity
the hand,distance
between thebasesof the obliquemaximum
systolicon
blood
flowrib
velocity
and the distance
betweenbases ofof thethe disease
obliquemuscle triangles
the first
on ultrasonography
reflected
thetheseverity
muscletriangles
on
the
first
rib
on
ultrasonography
reflected
theseverityofthedisease[7].
[7]. Ultrasound is less invasive, but there are still problems in terms of procedural reproUltrasoundis less
invasive,but
therearearealsostillcases
problems
inwithterms
procedural
reproducibilducibility andaccuracy
[24].
There
of TOS
noofobvious
upperextremity
ity
[24].
There
casescharacteristicof TOS with no
obviousupper extremity
or backor andbackaccuracy
pain, andthey
may arenotalsodevelopclinical
symptoms[3,14].
pain, andthey may not develop
clinical
symptoms[3,14].requires a detailed
A comprehensive
diagnosischaracteristicof TOS, which
is a complex
disease,A comprehensive
diagnosis
of TOS,
which is aandcomplexdisease,requires a detailed
medicalhistory, assessmentof clinicalsymptoms,
neurologicalexamination.
Hence,
medicalhistory,of clinicaland neurologicalexamination.
the presenceof assessment
SCV disconnection
on symptoms,
MRI-MIP images
does not necessarily
lead Hence,
to thethepresence
SCV disconnection
MRI-MIP
imagesdoes notlead
toobthediagnosis
of ofvenous
TOS, and thereon
havebeen cases
in which
SCAnecessarily
stenosis wasnotdiagnosis
ofvenous
TOS,
and
there
have
been
cases
in
which
SCA
stenosiswasnotobserved
served on MRI-MIP images despite the presence of symptoms of SCA stenosis. The caseson
MRI-MIPdespitethe include
presence“Trueof symptomsof SCA
stenosis.
The cases
includedincluded
in images
this study
did not
TOS” [10,14],
which
is difficult
to diagnose
inusing
this study
did not
include disputed“True TOS”
[10,14], which
is difficult
to diagnose
usingfalse
MRI
MRI alone.
However,neurogenic
TOS maybe effective
in excluding
alone.
However,
disputed
TOS maytobe
effective
in excluding
positives.
positives.
Apart fromcasesneurogenic
clearly attributable
sports,the absenceof anyfalse
vascularsteApartcases clearly
attributable
sports, theabsenceof anyvascularstenosis oncases
MRInosis fromon MRI-MIP
imagesin cases ofto
suspected
cervicalspine
originor psychological
MIP
images toin indicate
cases of severe
suspected
spine
originMRI-MIP
or psychologicalcases
is unlikelytois unlikely
TOScervicalrequiringsurgery.
images areusefulin dailyDiagnostics 2023, 13, 319

8 of 10indicate severe TOS requiring surgery. MRI-MIP images are useful in daily practice because
they can be visually explained to the patients themselves. Moreover, when combined withsagittal and axial images taken simultaneously, as in Figure 4, it is possible to pick up thebone and soft tissue abnormalities and inflammation of the brachial plexus. However, if
only MIP is used, only blood vessels can be detected.
In surgery, 3D-CT angiography is more useful than MRI because of its short imaging
time to determine the position of the blood vessels in relation to the clavicle and ribs.
However, it is difficult to perform this procedure in all patients with suspected TOS
considering the use of contrast media and exposure to radiation. In this study, SCVs insurgical cases that were considered more severely stenosed showed a higher stenosis rate.
Therefore, it is recommended that 3D-CT angiography be performed only in cases in which
surgery is clinically indicated to avoid the unnecessary use of contrast media and exposure
to radiation.
As to the cause of stenosis, the SCA, SCV, and nerve bundles are often stenosed evenin the normal position, depending on the imaging position, as shown in previous studies incomparison to the normal side. In reviewing our surgical cases, most of the stenoses werecaused by fibrous bands of the anterior scalene muscle and other anatomical factors [18,19]. In
comparison with the healthy side, only the SCA in the surgery group tended to show strong
stenosis, suggesting that anatomical factors of the anterior scalene muscle may be consideredin cases in which there is a difference between the normal and affected sides of the SCA,
which is less affected by posture. Moreover, the comparison with normal cases is warranted.
This study has two major limitations, which include the imaging of limb position anddiagnosis of severity. The MRI imaging position was supine, and although the patient
was in the Wright test position, there is a high likelihood that the SCA was not adequately
compressed owing to high intravascular pressure and strong elasticity. The SCV also hada non-physiological compression and was not considered to fully reflect stenosis in theactual examination technique. Another problem with this method is that the patient must
be in a symptomatic position for at least 20 min during imaging. Regarding TOS severity,in this study, surgical cases were compared with conservative treatment cases as severe.
However, because surgery was decided solely based on the patient’s subjective assertion, it
may not reflect severe organic stenosis, which may have caused variation in the data. Since
the TOS itself lacks a clear quantitative index, further studies are needed to accumulate
more cases in the future. In addition, other factors need to be considered for future study,
which include cost-effectiveness, utility, indications for use, homogenization of sample size,
and the ability to rule out other diagnoses.
5. Conclusions
On MRI-MIP images, the degree of stenosis of the SCV and SCA was classified into four
grades, and the SCV was significantly more severely stenosed in the operated cases. Sagittal
section images of the SCV, SCA, and nerve bundle showed significantly greater stenosis of the
SCV in the operated cases but no significant difference in the SCA or nerve bundle between theoperated and conservative treatment cases. MRI-MIP may be a useful adjunctive diagnostic
method for understanding the stenosis status of vascular nerve bundles.
Author Contributions: Conceptualization, T.O. and N.M.; methodology, T.O.; software, T.O.; formal
analysis, T.O.; investigation, T.O., S.O., N.M., T.M. and K.I.; resources, T.O., S.O. and N.M.; data curation, T.O.; writing—original draft preparation, T.O.; writing—review and editing, Y.Y.; visualization,
T.O. and S.O.; supervision, N.M. and Y.Y.; project administration, Y.Y. and M.Y. All authors have readand agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: This study was approved by the Institutional Review Boardof the Mito Clinical Education and Training Center, University of Tsukuba Hospital, Mito Kyodo
General Hospital (IRB No:22–44, approved 6 December 2022).

Diagnostics 2023, 13, 319

9 of 10

Informed Consent Statement: Informed consent was obtained from all the subjects involved inthis study.
Data Availability Statement: Not applicable.
Acknowledgments: The authors thank Katsuhiko Kobayashi and Takuya Hirochi, a radiology technician, and other members of the radiology department at Mito Kyodo General Hospital for theircooperation in MRI imaging.
Conflicts of Interest: The authors declare no conflict of interest.

References
1.
2.
3.
4.
5.

6.
7.
8.

9.

10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.

21.
22.

Ruopsa, N.; Ristolainen, L.; Vastamäki, M.; Vastamäki, H. Neurogenic Thoracic Outlet Syndrome with Supraclavicular Release:Long-Term Outcome without Rib Resection. Diagnostics 2021, 11, 450. [CrossRef] [PubMed]
Povlsen, S.; Povlsen, B. Diagnosing Thoracic Outlet Syndrome: Current Approaches and Future Directions. Diagnostics 2018, 8, 21.
[CrossRef] [PubMed]
Kuhn, J.E.; Lebus, G.F.; Bible, J.E. Thoracic Outlet Syndrome. J. Am. Acad. Orthop. Surg. 2015, 23, 222–232. [CrossRef] [PubMed]
Peek, J.; Vos, C.G.; Ünlü, Ç.; van de Pavoordt, H.D.W.M.; van den Akker, P.J.; de Vries, J.-P.P. Outcome of Surgical Treatment forThoracic Outlet Syndrome: Systematic Review and Meta-Analysis. Ann. Vasc. Surg. 2017, 40, 303–326. [CrossRef]
Beteck, B.; Shutze, W.; Richardson, B.; Shutze, R.; Tran, K.; Dao, A.; Ogola, G.O.; Pearl, G. Comparison of Athletes and Nonathletes
Undergoing Thoracic Outlet Decompression for Neurogenic Thoracic Outlet Syndrome. Ann. Vasc. Surg. 2018, 54, 269–275.
[CrossRef]
Burks, S.S.; Wolfe, E.M.; Yoon, J.W.; Levi, A.D. Supraclavicular Resection of a Cervical Rib Causing Thoracic Outlet Syndrome:
2-Dimensional Operative Video. Oper. Neurosurg. 2020, 19, E520. [CrossRef]
Furushima, K.; Funakoshi, T.; Kusano, H.; Miyamoto, A.; Takahashi, T.; Horiuchi, Y.; Itoh, Y. Endoscopic-Assisted Transaxillary
Approach for First Rib Resection in Thoracic Outlet Syndrome. Arthrosc. Sport. Med. Rehabil. 2021, 3, e155–e162. [CrossRef]
Ransom, E.F.; Minton, H.L.; Young, B.L.; He, J.K.; Ponce, B.A.; McGwin, G.; Meyer, R.D.; Brabston, I.E.W. Intermediate andLong-Term Outcomes Following Surgical Decompression of Neurogenic Thoracic Outlet Syndrome in an Adolescent Patient
Population. Hand 2020, 17, 43–49. [CrossRef]
Perchoc, A.; Andro, C.; Letissier, H.; Schiele, P.; Le Nen, D. Long-term functional outcomes after surgical treatment of nonspecificthoracic outlet syndrome: Retrospective study of 70 cases at a mean of 8 years’ follow-up. Hand Surg. Rehabil. 2019, 38, 195–201.
[CrossRef] [PubMed]
Wilbourn, A.J. Thoracic outlet syndrome is over diagnosed. Muscle Nerve 1999, 22, 130–136. [CrossRef]
Ferrante, M.A.; Ferrante, N.D. The thoracic outlet syndromes: Part 2. The arterial, venous, neurovascular, and disputed thoracic
outlet syndromes. Muscle Nerve 2017, 56, 663–673. [CrossRef] [PubMed]
Masocatto, N.O.; Da-Matta, T.; Prozzo, T.G.; Couto, W.J.; Porfirio, G. Thoracic outlet syndrome: A narrative review. Rev. Col. Bras.
Cir. 2019, 46, e20192243. [CrossRef]
Seror, P. Medial antebrachial cutaneous nerve conduction study, a new tool to demonstrate mild lower brachial plexus lesions. A
report of 16 cases. Clin. Neurophysiol. 2004, 115, 2316–2322. [CrossRef] [PubMed]
Sonoo, M. Thoracic outlet syndrome. Brain Nerve 2014, 66, 1429–1439. (In Japanese) [CrossRef]
Remy-Jardin, M.; Remy, J.; Masson, P.; Bonnel, F.; Debatselier, P.; Vinckier, L.; Duhamel, A. Helical CT Angiography of Thoracic
Outlet Syndrome. Am. J. Roentgenol. 2000, 174, 1667–1674. [CrossRef] [PubMed]
Demondion, X.; Herbinet, P.; Van Sint Jan, S.; Boutry, N.; Chantelot, C.; Cotten, A. Imaging Assessment of Thoracic Outlet
Syndrome. Radiographics 2006, 26, 1735–1750. [CrossRef]
Likes, K.; Rochlin, D.H.; Call, D.; Freischlag, J.A. Coexistence of Arterial Compression in Patients With Neurogenic Thoracic
Outlet Syndrome. JAMA Surg. 2014, 149, 1240–1243. [CrossRef]
Sanders, R.J.; Annest, S.J. Thoracic outlet and pectoralis minor syndromes. Semin. Vasc. Surg. 2014, 27, 86–117. [CrossRef]
Raptis, C.A.; Sridhar, S.; Thompson, R.W.; Fowler, K.; Bhalla, S. Imaging of the Patient with Thoracic Outlet Syndrome.
Radiographics 2016, 36, 984–1000. [CrossRef]
Ersoy, H.; Steigner, M.L.; Coyner, K.B.; Gerhard-Herman, M.D.; Rybicki, F.J.; Bueno, R.; Nguyen, L.L. Vascular Thoracic Outlet
Syndrome: Protocol Design and Diagnostic Value of Contrast-Enhanced 3D MR Angiography and Equilibrium Phase Imaging on
1.5- and 3-T MRI Scanners. Am. J. Roentgenol. 2012, 198, 1180–1187. [CrossRef]
Esposito, M.D.; Arrington, J.A.; Blackshear, M.N.; Murtagh, F.R.; Silbiger, M.L. Thoracic outlet syndrome in a throwing athlete
diagnosed with MRI and MRA. J. Magn. Reson. Imaging 1997, 7, 598–599. [CrossRef] [PubMed]
Zhang, T.; Xu, Z.; Chen, J.; Liu, Z.; Wang, T.; Hu, Y.; Shen, L.; Xue, F. A Novel Approach for Imaging of Thoracic Outlet Syndrome
Using Contrast-Enhanced Magnetic Resonance Angiography (CE-MRA), Short Inversion Time Inversion Recovery Sampling
Perfection with Application-Optimized Contrasts Using Different Flip Angle Evolutions (T2-STIR-SPACE), and VolumetricInterpolated Breath-Hold Examination (VIBE). Med. Sci. Monit. 2019, 25, 7617–7623. [CrossRef] [PubMed]

Diagnostics 2023, 13, 319

23.
24.

10 of 10Hardy, A.; Pougès, C.; Wavreille, G.; Behal, H.; Demondion, X.; Lefebvre, G. Thoracic Outlet Syndrome: Diagnostic Accuracy of
MRI. Orthop. Traumatol. Surg. Res. 2019, 105, 1563–1569. [CrossRef] [PubMed]
Brownie, E.R.; Abuirqeba, A.A.; Ohman, J.W.; Rubin, B.G.; Thompson, R.W. False-negative upper extremity ultrasound in theinitial evaluation of patients with suspected subclavian vein thrombosis due to thoracic outlet syndrome (Paget-Schroetter
syndrome). J. Vasc. Surg. Venous Lymphat. Disord. 2020, 8, 118–126. [CrossRef] [PubMed]

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual
author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury topeople or property resulting from any ideas, methods, instructions or products referred to in the content.

International Journal of Hematology
https://doi.org/10.1007/s12185-023-03549-3

ORIGINAL ARTICLE

Importance of TKI treatment duration in treatment‑free remissionof chronic myeloid leukemia: results of the D‑FREE study
Chikashi Yoshida1 · Hiroki Yamaguchi2 · Noriko Doki3 · Kazunori Murai4 · Masaki Iino5 · Yoshihiro Hatta6 ·Makoto Onizuka7 · Norio Yokose8 · Katsumichi Fujimaki9 · Masao Hagihara10 · Gaku Oshikawa11 ·Kayoko Murayama12 · Takashi Kumagai13 · Shinya Kimura14 · Yuho Najima3 · Noriyoshi Iriyama6 · Ikuyo Tsutsumi1 ·Koji Oba15 · Hiroshi Kojima16 · Hisashi Sakamaki3 · Koiti Inokuchi2 on behalf of the Kanto CML Study Group
Received: 10 October 2022 / Revised: 21 January 2023 / Accepted: 22 January 2023
© The Author(s) 2023

Abstract
Treatment-free remission (TFR) is a new goal for patients with chronic myeloid leukemia in chronic phase (CML-CP) witha sustained deep molecular response (DMR) to treatment with tyrosine kinase inhibitors (TKIs). However, optimal conditions for successful TFR in patients treated with second-generation (2G)-TKIs are not fully defined. In this D-FREE study,
treatment discontinuation was attempted in newly diagnosed CML-CP patients treated with the 2G-TKI dasatinib whoachieved BCR-ABL1 levels of ≤ 0.0032% (MR4.5) on the international scale (BCR-ABL1IS) and maintained these levels forexactly 1 year. Of the 173 patients who received dasatinib induction therapy for up to 2 years, 123 completed and 60 (48.8%)
reached MR 4.5. Among the first 21 patients who maintained MR4.5 for 1 year and discontinued dasatinib, 17 experienced
molecular relapse defined as loss of major molecular response (BCR-ABL1IS > 0.1%) confirmed once, or loss of MR4 (BCRABL1IS > 0.01%) confirmed on 2 consecutive assessments. The estimated molecular relapse-free survival rate was 16.7% at
12 months. This study was prematurely terminated according to the protocol’s safety monitoring criteria. The conclusion
was that sustained DMR for just 1 year is insufficient for TFR in CML-CP patients receiving dasatinib for less than a totalof 3 years of treatment.
Keywords Chronic myeloid leukemia · Dasatinib · Treatment-free remission* Chikashi Yoshidac.yoshida@mitomedical.org
1

2

Department of Hematology, National Hospital Organization
Mito Medical Center, 280 Sakuranosato, Ibarakimachi,
Higashiibarakigun, Ibaraki 311‑3193, Japan
Department of Hematology, Nippon Medical School, Tokyo,
Japan

8

Department of Hematology, Nippon Medical School Chiba
Hokusoh Hospital, Inzai, Japan

9

Department of Hematology, Fujisawa City Hospital,
Fujisawa, Japan10

Department of Hematology, EIJU General Hospital,
Taito‑Ku, Japan

11

Japanese Red Cross Musashino Hospital, Musashino, Japan

12

Division of Hematology, Gunma Prefectural Cancer Center,
Ohta, Japan

13

Department of Hematology, Ome Municipal General
Hospital, Ome‑Shi, Tokyo, Japan

14

Division of Hematology, Respiratory Medicine
and Oncology, Department of Internal Medicine, Facultyof Medicine, Saga University, Saga, Japan

3

Hematology Division, Tokyo Metropolitan Cancer
and Infectious Diseases Center, Komagome Hospital, Tokyo,
Japan

4

Department of Hematology, Iwate Prefectural Central
Hospital, Morioka, Japan

5

Department of Medical Oncology, Yamanashi Prefectural
Central Hospital, Kofu, Japan

6

Division of Hematology and Rheumatology, Nihon
University School of Medicine, Tokyo, Japan

15

Department of Biostatistics, The University of Tokyo, Tokyo,
Japan

7

Department of Hematology and Oncology, Tokai University
School of Medicine, Isehara, Japan

16

Ibaraki Clinical Education and Training Center, Universityof Tsukuba Hospital, Kasama, Japan

13

Vol.:(0123456789)

C. Yoshida et al.

Introduction
Prognosis of chronic myeloid leukemia in chronic phase(CML-CP) has improved dramatically since the approvalof imatinib mesylate, the first-generation tyrosine kinase
inhibitor (TKI), in 2001 [1]. In addition, second-generation TKIs (2G-TKIs) were developed for patients who areresistant and/or intolerant to imatinib and later approved
for newly diagnosed patients [2–4]. With the developmentof these TKIs, the life expectancy of patients with CMLCP has become almost the same as that of age-matchedhealthy individuals [5]. However, long-term treatment
with TKIs has raised new concerns, such as adverse
events including cardiovascular side effects, avoidanceof pregnancy by women due to possible teratogenicity,and increased health care costs [6–8]. Thus, discontinuation of TKI therapy has been attempted in patients witha sustained deep molecular response (DMR), and it has
been reported that about half of them can maintain atreatment-free remission (TFR), which has become a newgoal [9]. However, it is still difficult to predict in advancethe chance of relapse for each patient. Although several
guidelines have proposed clinical factors for successful
TFR, they are primarily based on evidence with imatinib[10–12]. Since 2G-TKIs induce a molecular response
faster than imatinib [2–4], it is possible that they lead to
TFR in a larger number of patients and after a shorter
treatment period, potentially minimizing the problems
caused by TKI therapy. The multicenter phase II study
D-FREE was conducted to clarify optimal conditions for
TFR in newly diagnosed patients with CML-CP treatedwith the 2G-TKI dasatinib. We attempted discontinuationof dasatinib treatment for patients who achieved DMR andsustained it for exactly 1 year.

Materials and methods
Patients
Eligible patients were adults (≥ 18 years) with confirmed
newly diagnosed CML-CP who had received no prior antileukemia treatment (except ≤ 1 months of hydroxyurea),
Eastern Cooperative Oncology Group (ECOG) performance status groups of 0 to 2, and with adequate functions of major organs (liver, kidney, and lung). Patients
whose BCR-ABL1 mRNA levels could not be assessedby real-time quantitative polymerase chain reaction (RQPCR) based on an international scale (BCR-ABL1IS) were
excluded. Patients were excluded if they had active multiple cancers, were pregnant, lactating, with a history or

13complications of myocardial infarction within the previous
6 months, with a history of angina pectoris, or gastrointestinal hemorrhage, or congestive cardiac failure within
the previous 3 months, plural effusion, electrocardiogramQTc interval exceeding 450 ms prolongation, or present/
past history of pulmonary hypertension. Similarly, patientswith a history or complications of diseases judged by theinvestigators as inappropriate for study implementation
were not eligible. This study was conducted in accordance with the Ethical Guidelines for Medical and HealthResearch Involving Human Subjects, the Clinical Trials
Act in Japan, and the Declaration of Helsinki. All patientsprovided written informed consent. The study protocol was
reviewed by the institutional review board for each centerat the start of study, then reviewed again by the Certified Review Board, Institutional Review Board of Nippon Medical School Foundation, after the enforcement of
the Clinical Trials Act established in 2018. The trial was
registered at the University Hospital Medical Information
Network (UMIN000022254) and Japan Registry of Clinical Trails (jRCTs031180332).

Study design and treatment
D-FREE was an open-label, multicenter, phase II study. Its
design is shown in Fig. 1. In the induction phase, newly
diagnosed CML-CP patients were treated with dasatinib at
100 mg once daily. The maximum daily dose was 140 mg,
and the dose could be adjusted or temporarily stopped at thediscretion of investigators as needed. Molecular response
was assessed by measuring BCR-ABL1 mRNA levels inperipheral blood every 3 months by RQ-PCR standardized on an international scale in one of three commercial
laboratories (BML, Inc., SRL, and LSI Medience Corporation) using an RT-qPCR kit, ODK-1201 (Otsuka Pharmaceutical Co. Ltd) validated by SA Pathology, Adelaide,
Australia, a recognized reference laboratory [13]. Whenpatients achieved MR4.5 (BCR-ABL1IS ≤ 0.0032%) during
the induction phase for up to two years, they were immediately entered into the consolidation phase, where dasatinib
was administered for 12 months. Sustained MR4.5 in thisphase was defined as confirmation of this level of molecularresponse on 5 consecutive RQ-PCR tests three months apart.
Patients who did not achieve MR4.5 during the induction
phase or did not sustain it during the consolidation phasewere removed from the study and its follow-up. Patients
who sustained MR.4.5 throughout the consolidation phasewere eligible to enter the stop phase and discontinue dasatinib treatment. During the stop phase, molecular response
was assessed every month in the first year and every threemonths thereafter. Molecular relapse was defined as loss ofmajor molecular response (MMR) (BCR-ABL1IS > 0.1%)
confirmed once, or loss of MR4 (BCR-ABL1 IS > 0.01%)

Importance of TKI treatment duration in treatment‑free remission of chronic myeloid leukemia:…
••

Newly diagnosed CML-CP patients ≥ 18 years
BCR-ABL1 transcripts assessable by RQ-PCR standardized on an IS
Enrolled

RQ-PCRevery 3 months

Dasatinib
induction phase(up to 2 years)

RQ-PCRevery month for the first year,
then every 3 months

RQ-PCRevery 3 months

Achieved MR4.5

Dasatinib
consolidation phase (1 year)

Sustained MR4.5*1

Stop phase(up to 4 years)
RelapseLoss of MMR or
confirmed loss of MR4*2

Dasatinib
Retreatment phase (up to 1 year)
RQ-PCRevery month

Fig. 1  D-FREE study design. CML-CP chronic myeloid leukemia inchronic phase, RQ-PCR real-time quantitative polymerase chain reaction, IS international scale, MR4.5 BCR-ABL1 mRNA levels assessedby RQ-PCR based on an IS (BCR-ABL1IS) ≤ 0.0032%), MMR major

molecular response. *1 Defined as maintaining MR 4.5 with 5 RQPCR assessments every 3 months. *2 Defined as BCR-ABL1IS > 0.01%
on two consecutive assessments

confirmed on 2 consecutive assessments. Currently, mostrecent trials consider molecular relapse as loss of MMR [9,14], but since this D-FREE was a study in which dasatinib
was discontinued after a shorter DMR period, the loss of
MR4 confirmed on 2 consecutive assessments was also considered as molecular relapse for safety reasons. In the caseof molecular relapse during the stop phase, patients wereimmediately retreated with dasatinib at the consolidation
phase final dose. Molecular response was assessed every
month by RQ-PCR until patients regained MR4 (BCRABL1IS ≤ 0.01%), and every three months thereafter, for up
to one year. Adverse events were graded according to the
National Cancer Institute Common Terminology Criteria for
Adverse Events (CTCAE) version 4.0. In this study, hematologic adverse events with grade 4 and non-hematologicaladverse events with grade 3 or higher were reported.

sustained TFR for risk scores (EUTOS Score, Sokal Score,
Hasford Score), gender, molecular response 3 and 6 months
after start of dasatinib treatment, dasatinib treatment period,
and time to MMR, MR4.0, and MR4.5. MRFS was definedas duration of survival from the date of dasatinib discontinuation in the stop phase to molecular relapse or death. EFS
was defined as the duration from the date of registration todisease progress or death. If patients died without diseaseprogress, they were regarded as having progress at the dateof death. If patients received dasatinib and did not have disease progression or death, the study was discontinued at thedate when hematologic, cytogenetic, or molecular evaluation
was finally done during dasatinib treatment. If patients did
not receive dasatinib and did not have disease progression
or death, the study was discontinued at the date of registration. Disease progression was defined as loss of complete
hematologic response, loss of major cytogenetic response orcomplete cytogenetic response, loss of molecular response,
progression to accelerated or blastic phase, or death during
dasatinib treatment.

Study endpoints and assessments
The primary endpoint was the proportion of patients in
TFR who showed no molecular relapse and did not need toresume dasatinib 12 months after treatment discontinuation.
Secondary endpoints included the proportion of patients in
TFR 24, 36, and 48 months after discontinuation of dasatinib treatment, molecular relapse-free survival (MRFS)
12 months after discontinuation of dasatinib treatment,
overall survival (OS) including all causes of death 12, 24,
36, and 48 months after discontinuation of dasatinib treatment, dasatinib doses and time to MR4.5, event-free survival(EFS) during the dasatinib treatment period, and frequency
and degree of TKI withdrawal syndrome after discontinuation of dasatinib treatment. Exploratory endpoints included
analysis of factors related to achievement of MR4.5 andStatistical analyses
The threshold value of TFR rate and expected value at
12 months after discontinuation of dasatinib treatment werehypothesized to be 41% and 55%, respectively, based on
historical data [15, 16]. Based on the above hypothesis, therequired number of patients eligible for treatment discontinuation (Stop phase) was calculated to be 83 with a powerof 80% and a one-sided alpha of 5%. Considering about 20%
dropouts due to MR4.5 loss during the 12-month consolidation phase and consent withdrawal, etc., and the historical
data of a 35% MR4.5 achievement rate after 24 months [17],13C. Yoshida et al.

the planned number of registered patients with first-onset
CML-CP was calculated as 300, including 5% ineligible
patients.
Two safety monitoring criteria were included in D-FREE
to assess the appropriateness of continuing the study. Thus,
the trial should be suspended if (1) more than 15% of thepatients who lost MMR in the Stop phase did not reach
MMR by 12 months of dasatinib retreatment and (2) the
TFR rate was less than or equal to 25% when 20 patientsreached the primary endpoint. On the 6th November 2019,15 patients out of 20 patients after discontinuation of dasatinib treatment relapsed during the stop phase. Data andsafety monitoring board recommended stopping the study
on the basis of the efficacy concerns. When the study was
stopped on the 3rd December 2019, 17 out of 21 patients inthe stop phase relapsed. Thereafter, all participant patientswere recommended to receive standard treatment based on
consultation with their physicians. Baseline characteristics,
efficacy, and safety results are reported for patients whoentered the induction phase. MRFS was depicted using the
Kaplan–Meier method. Other time-to-event data were also
analyzed by the Kaplan–Meier method. An assessment ofprognostic factors for achieving MR4.5 within 24 monthsof dasatinib treatment in the induction phase was conductedusing univariate and multivariable logistic regression analyses. The frequencies of AEs, laboratory abnormalities, andpredefined groupings of AE types of special interest weresummarized for the induction and consolidation phases. The
data presented herein are based on a cutoff date of September 30th, 2021, at which time all patients had finished thesafety follow-up after the termination of study treatment.
The significance level of the two-sided p values was 0.05 forall statistical tests. Analyses were done with SAS Release
9.4 (SAS Institute, Cary, NC).

Results
Characteristics of patients
Between July 2016 and May 2019, a total of 181 patientswith newly diagnosed CML-CP were enrolled in 41 centers in Japan. Patients’ disposition is shown in Fig. 2. Fourpatients were excluded after screening, and no further information was available for 4 patients. Overall, 173 patients
received treatment according to the study protocol. Demographics and baseline disease characteristics are listed inTable1. The median patient age was 54 years (18–83 years).
The rates of Sokal low-, intermediate-, high-risk groups, andunknown were 45.7, 38.2, 15.6, and 0.6%, respectively. The
rates of Hasford low-, intermediate-, high-risk groups, andunknown were 39.9, 50.9, 8.7, and 0.6%, respectively. The

13

rates of EUTOS low- and high-risk groups were 89.6 and10.4%, respectively.

Treatment responses
Of the 123 patients who completed the induction phase, 60(48.8%) achieved MR4.5 for up to 2 years. The median duration of dasatinib for achieving MR4.5 was 7.7 months (range
3.0–21.1 months). We evaluated the relationship between
cumulative dose and MR4.5 attainment rate and calculated
the cumulative dose corresponding to MR4.5 attainment
rate of 50% (for one subject there was no dose information).
The total dasatinib dose corresponding to 50% MR4.5 by
the Kaplan–Meier method was 63,600 mg (95% confidence
interval 43,500 to N.A.), but the 95% confidence interval
was wide due to the small number of patients who reachedMR4.5, and the upper limit of the 95% confidence interval
could not be estimated (data now shown). Single and multivariate analyses showed that the achievement of MMR at
3 months, but not gender, Sokal risk score, Hasford risk
score, EUTOS risk score, or age (< 60 vs. ≥ 60), was predictive of the achievement of MR4.5 within 2 years (Table 2).
Patients who achieved MR 4.5 in the induction phase
immediately entered the consolidation phase and received
dasatinib treatment for one year. Fifteen patients could notsustain MR4.5 and finished study treatment during the consolidation phase. EFS for patients treated with dasatinib during the induction and consolidation phases was estimated tobe 94.9% for 1 year and 63.5% for 2 years. A large numberof patients were censored due to early discontinuation of thestudy, as described above.

Discontinuation of dasatinib in the stop phase
Among the first 20 patients who could sustain MR4.5 for
12 months in the consolidation phase and discontinued
dasatinib treatment in the stop phase, 15 experienced molecular relapse within 12 months and required retreatment withdasatinib as of November 6, 2019. The study was terminatedprematurely on December 3, 2019, in accordance with thedata and safety monitoring board’s recommendation, basedon the pre-specified interim analysis criterion that it would
be stopped if the TFR rate was less than or equal to 25% in
the first 20 patients of the stop phase. At that point in time,
17 out of 21 patients in the stop phase had molecular relapse
within 12 months and were being retreated with dasatinib(Table 3). Molecular relapse was determined by the loss of
MMR in 11 patients and two consecutive losses of MR4 in
6 patients. The estimated MRFS was 16.7% at 12 months(Fig. 3). As a result, the proportion of patients in TFR who
showed no molecular relapse and did not need to resume
dasatinib 12 months after treatment discontinuation was not
estimated, because only one subject was confirmed to haveImportance of TKI treatment duration in treatment‑free remission of chronic myeloid leukemia:…

181 patients were registered
4 Were excluded after screening due to
1 Pulmonary arterial hypertension
1 Cardiac effusion
1 Gastric cancer
1 BCR-ABL1 could not assessed by RQ-PCR
standardized on an IS
177 were eligible

4 No further information available due to
3 withdrawn by physician
1 No information provided

173 were treated with dasatinib in the induction phase
37 Did not achieve MR4.5 during 24 months of treatment
26 Had resistance, progression, and/or adverse events
3 Could not be traced because of moving
1 Died46 Discontinued study treatment because of study termination
60 entered the consolidation phase

15 Lost MR4.5
5 Had resistance, progression, and/or adverse events
2 Withdrew consent
17 Discontinued study treatment because of study termination

21 discontinued dasatinib in the stop phase

17 Were retreated with dasatinib due to molecular relapse

4 were in the stop phase at study termination

Fig. 2  Patient disposition. RQ-PCR real-time quantitative polymerase chain reaction, IS international scale, MR4.5 BCR-ABL1 mRNA levels
assessed by RQ-PCR based on an IS ≤ 0.0032%)

TFR at 12 months after discontinuation of dasatinib. The
median time of molecular relapse after the cessation was
3.5 months (range 2.0–6.4). In those patients, the median
duration of dasatinib treatment, including the induction andthe consolidation phases, was 18.9 months (range 14.9–25.5)
before the cessation of dasatinib. At termination, 46 patientswere in the induction, 17 were in the consolidation, and 4
were in the stop phase. Of note, one patient (no. 7) remained
in TFR for 17.8 months after receiving dasatinib treatment
for only 18.6 months during the induction and consolidation
phases (Table 3). All 17 patients who entered the dasatinib

retreatment phase due to molecular relapse regained MR4(Table 3 and Fig. 4). The median duration of dasatinib
retreatment until MR4 re-achievement was 2.3 months(range 1.0–5.1).

SafetyNo patients progressed to the accelerated/blastic phase ordied due to CML during the study treatment. Grade 4 hematologic and grade 3/4 non-hematologic AEs were reported inthis study. Among patients who were treated with dasatinib

13

C. Yoshida et al.
Table 1  Baseline characteristics at study entry
Characteristic

Total population (n = 173)

Age, median (range) (years)
Males, n (%)
Sokal risk score, n (%)
Low
IntermediateHigh
NR
Hasford risk score, n (%)
Low
IntermediateHigh
NR
EUTOS risk score, n (%)
Low
HighPrior hydroxyurea treatment, n (%)
NoYes

54 (18–83)
100 (57.8)
79 (45.7)
66 (38.2)
27 (15.6)
1 (0.6)69 (39.9)
88 (50.9)
15 (8.7)
1 (0.6)155 (89.6)
18 (10.4)
124 (71.7)
49 (28.3)

NR not reported

in the induction phase, grade 4 neutropenia, anemia, andthrombocytopenia were reported in 2.3% (n = 4), 0.6%
(n = 1), and 1.2% (n = 2), respectively. There were no grade 4
Table 2  Prognostic factors
for achieving MR4.5 within
24 months of dasatinib
treatment in the induction phase13

hematologic AEs reported in consolidation, stop, and dasatinib retreatment phases. Grade 3/4 non-hematologic AEs
were reported as a total of 8.1% (n = 14) in the combined
induction, consolidation, and retreatment phases. Amongthem, death in one patient (unknown cause; family refused
to report) and hospitalization due to gallstones, both occurring in the induction phase, were reported as grade 4 AEs.
Cardiovascular events were reported in 2 patients (1.2%),
one with grade 3 ischemic syndrome during the consolidation phase and the other with grade 3 ischemic cerebrovascular disease during the dasatinib retreatment phase. Amongthe 21 patients who entered the stop phase, TKI withdrawal
syndrome was observed in 2 (no. 1 and no. 20, Table 3). Twopatients (9.5%) had arthralgia grade 1 and one (4.8%) had
myalgia grade 1, both of whom recovered. The two patients
who developed TKI withdrawal syndrome both had molecular relapse at 2.6 and 6.3 months.

Discussion
Discontinuation of treatment in newly diagnosed CMLCP patients after up to 2 years of induction therapy withdasatinib followed by 1 year of MR4.5 did not show TFR
rates comparable to previous TKI discontinuation studies,
which have reported rates of approximately 50% [18–21].
This indicates that dasatinib treatment for 3 years or less,

Univariate
Odds ratio
GenderMale
0.853
Female1
Sokal risk score
High
1.133
Intermediate
1.419
Low
1
Hasford risk score
High
1.25
Intermediate
1.238
Low
1
EUTOS score
High
0.814
Low
1
Age, years
60 ≥
1.55
60 <
1
MMR at 3 months
Yes
9.412
No
1

Adjusted
95% CIp

Odds ratio

95% CIp

0.458–1.589

0.853

0.768
1

0.370–1.596

0.47970.456–2.812
0.723–2.785

0.78790.3088

1.466
1.002
1

0.451–4.767
0.404–2.484

0.52530.9966

0.398–3.931
0.644–2.381

0.7026
0.52190.290–2.284

0.69520.604

0.153–2.384

0.47150.830–2.893

0.16871.531
10.668–3.512

0.31444.058–21.831< 0.0001

11.192
1

4.583–27.334< 0.0001

77
72
68
62
64
38
53
72
77
49
57
29
63
68
64
38
69
54
27
70
46

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21

F
F
M
M
F
M
F
F
F
F
M
F
F
F
F
F
F
M
M
M
M

Gender

H
H
H
I
I
L
H
I
I
I
L
I
I
I
I
L
I
L
L
I
L

Sokal risk
score
H
H
I
I
I
L
I
I
I
L
I
L
I
I
I
L
I
I
L
L
L

Hasford risk
score
L
H
H
L
L
L
L
L
L
L
H
L
L
L
L
L
L
L
L
L
H

EUTOS score

3.1
3.4
13.3
6.0
8.9
6.4
5.8
6.5
6.3
12.2
8.7
6.0
3.5
6.3
8.8
5.7
6.0
6.0
5.8
6.2
6.9

Duration of induction phase, mo
15.7
14.9
25.5
18.9
22.0
18.9
18.6
19.4
18.3
24.8
21.7
18.6
16.2
19.2
21.6
18.8
18.9
18.7
17.8
18.6
18.9

Duration of DAS
treatment, mo
6.3
3.2
2.5
2.4
3.4
4.8
17.8
2.5
5.0
3.9
3.8
4.4
2.3
9.2
4.8
5.3
7.1
4.6
4.1
4.4
2.6

Duration of stop
phase, mo*4Reached MR4 after 2.8 months of DAS retreatment phase and simultaneously discontinued study treatment due to adverse events

Pt patient, no. number, y. years, F female, M male, L low risk, I intermediate risk, H high risk, mo. Months, DAS dasatinib, —, not applicableAge, yPt no.

Table 3  Details of patients in the stop phase

Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
No
Yes
Yes
No
Yes

Relapse after
DAS discontinuation

1.9
3.7
2.8*4
3.1
1.0
5.1
–
2.1
1.0
3.0
2.1
3.0
1.8
–
2.3
1.1
–
1.9
4.6
–
3.1

Achievement of MR4
after DAS retreatment,moImportance of TKI treatment duration in treatment‑free remission of chronic myeloid leukemia:…

13

C. Yoshida et al.

Molecular relapse free survival

100
75
50

25
0

0

1

2

3
4
5
6
7
8
9
Months since discontinuation of dasatinib

10

11

12

Number at risk 21

21

19

15

1

1

1

11

5

4

3

2

2

Fig. 3  Kaplan–Meier estimate of molecular relapse-free survival after
discontinuation of dasatinib in the first 21 patients who entered thestop phase100

MR4 (%)

75

50

25

0

0

1

2

3
4
5
6
7
8
9
Months since dasatinib retreatment

10

11

12

Number at risk 17

17

11

7

0

0

0

2

1

0

0

0

0

Fig. 4  Cumulative incidence of MR4 in patients who entered thedasatinib retreatment phase due to molecular relapse. MR4 BCRABL1 mRNA levels assessed by RQ-PCR based on an international
scale ≤ 0.01%

including just 1 year of MR4.5 maintenance, is not sufficientfor successful TFR in untreated patients with CML-CP.
2G-TKIs, including dasatinib and nilotinib, are stronger
inhibitors of ABL kinase activity than imatinib and havebeen the subject of several clinical trials because of theirpotential to improve TFR rates. Comparisons of TKI discontinuation trials in patients who received 2G-TKI as firstline treatment, including D-FREE study, are summarized inTable 4. The ENESTfreedom study enrolled patients who
were treated with nilotinib ≥ 2 years and reached MR4.5[20]. Those patients were treated with nilotinib for an additional 52 weeks and stopped the treatment. A total of 51.6%
of patients remained in MMR without treatment reinitiation
after 48 weeks of nilotinib cessation. The median duration ofnilotinib therapy was 43.5 (32.9–88.9) months in that study.
Kimura et al. reported the results of the first-line DADI trial
where treatment was stopped for patients who had received
first-line dasatinib for at least 36 months with a sustained
DMR (defined as ≤ 0.0069%) for at least one year [21].

13

The TFR at 6 months was 55.2%. The duration of dasatinib
treatment and of DMR was 40.4 months (38.1–51.1) and23.3 months (15.7–29.4), respectively. Although these trials could not demonstrate a clear improvement in TFR rates
compared to the discontinuation trials with imatinib [14,19], they suggested that a shorter treatment period could
result in similar TFR rates if 2G-TKIs were used for at least
3 years, and DMR was maintained for at least 1 year. However, the optimal duration of treatment with a 2G-TKI andmaintenance of DMR for successful TFR was not clear.
This is because the duration of TKI treatment and DMR
maintenance in those trials was “at least” and not a fixed
duration. Shorter treatment periods for TFR would minimize
the problems associated with TKI therapy. We therefore
conducted two TKI discontinuation studies in patients with
newly diagnosed CML-CP, imposing a fixed DMR duration
before cessation of TKI. In the earlier D-News trial, patientswith newly diagnosed CML-CP were enrolled and treatedwith dasatinib for up to 2 years during the induction phaseto achieve DMR (defined as 0.0069% or less), then stopped
dasatinib treatment after just 2 years of sustained DMR[22]. The median duration of dasatinib treatment before
the cessation was 995 days (33.1 months). The 12-month
MRFS was 38.5%. In contrast, the estimated MRFS waseven lower, at 16.7% at 12 months, in the present D-FREE
study. Compared to the D-NewS trial, the duration of theinduction phase with dasatinib in the D-FREE study was thesame, with a maximum of 2 years, but the duration of DMR
was shorter, exactly 1 year. Considering the more stringent
definition of DMR (MR4.5) in D-FREE, the decrease in the
MRFS rate is presumably due to the shorter duration of TKI
treatment, in addition to the shorter DMR duration, although
direct comparison between different trials is not possible.
The European LeukemiaNet (ELN) published a recommendation of requirements for TKI discontinuation,of which the optimal condition was the duration of TKI
therapy > 5 years and of DMR > 2 years if MR4.5 [10]. The
National Comprehensive Cancer Network (NCCN) guidelines describe criteria for TKI discontinuation as being theduration of approved TKI therapy for at least 3 years andstable MR4 for ≥ 2 years [12], which is less strict than the
ELN recommendations. Etienne et al. published the resultsof their evaluation of the rate of patients eligible for TKI
discontinuation and MRFS after stopping according to several recommendations/guidelines, including the ELN and
the NCCN [23]. They found that the MRFS of patients
who fulfilled the selection criteria proposed by the ELN
was significantly different from that of those who did not,whereas no difference in MRFS was observed regarding thecriteria proposed by the NCCN. In addition, meeting theselection criteria suggested by the ELN recommendations
and front-line 2G-TKIs led to the highest MRFS, reaching 80%, suggesting that TKI therapy for at least 5 years

190

ENEST freedom

dasatinib Up to
2 years

26

21

D-NewS

D-FREE

1 year

2 years

1 year

1 year(52 weeks)

Duration of
consolidation phasewith sustained DMR

Definition of
relapse forreinitiating TKI

Loss of MMR
MR4.5
for ≥ 1 year
(52 weeks)
Loss of DMR
DMR
at two(BCRconsecutive
ABL1IS ≤ 0.0069%)
timepoints orfor ≥ 1 year
loss of MMR
at a single
timepoint
DMR
Loss of DMR(BCRat two
ABL1IS ≤ 0.0069%)
consecutive
timepoints orfor 2 years
loss of MMR
at a single
timepoint
MR4.5
Loss of MR4
for 1 year
at twoconsecutive
timepoints orloss of MMR
at a single
timepoint

TFR eligibility

51.6%;
48 weeks
55.2%;
6 months

38.5%;
1 year

30.3*1
23.3(median)

24*2

12.7
(median)

43.5
40.4

33.1

18.9

16.7%;
1 yearTFR/MRFS
rate (%); timeafter discontinuation

DMR duration
before TKI
discontinuation(months)

Total TKI
treatment duration, median(months)

–

[22]

[21]

[20]

References*2Duration as specified in the study protocol*1Calculated from the median time from first achievement of MR4.5 to study entry (18.3 months) and the duration of consolidation phase (52 weeks) specified in the study protocol

TKI, tyrosine kinase inhibitor; DMR, deep molecular response; TFR, treatment-free remission; MRFS, molecular relapse-free survival; Ref., references; BCR-ABL1IS, BCR-ABL1 levels on aninternational scale; MR4.5, BCR-ABL1IS ≤ 0.0032%; MR4, BCR-ABL1IS ≤ 0.01%; MMR, major molecular response (BCR-ABL1IS ≤ 0.1%); –, not applicable

dasatinib Up to
2 years

dasatinib At least
2 years

At least
2 years

Duration of
TKI treatment
before consolidation phase

Study criteriaFirst-line DADI 58

nilotinib

TKI
Number ofpatients discontinuing TKI

Trial

Table 4  Published TKI discontinuation clinical trials using second-generation TKIs as first-line treatment

Importance of TKI treatment duration in treatment‑free remission of chronic myeloid leukemia:…

13

C. Yoshida et al.

as recommended by the ELN, which is longer than thatrecommended by the NCCN, may improve TFR. Rea et al.
reported on the TFR after two different durations of nilotinib
consolidation in patients previously treated with imatinib[24]. They registered the patients who did not achieve
MR4.0 after ≥ 24 months of imatinib treatment and treatedthem with nilotinib. After 1 year of induction, the patients
who achieved MR4.0 were randomized to 1 or 2 years ofconsolidation with nilotinib followed by discontinuation oftreatment. The treatment-free survival rate of one and two
years of consolidation was 34.5% and 42.5%, respectively,
and was not significantly different, suggesting that there isno significant benefit for successful TFR from an additional
year of consolidation treatment with nilotinib for patients
who achieved sustained DMR after 2 years on nilotinib following a switch from imatinib. It suggests that the durationof DMR may not be the most important factor for the success of TFR. Indeed, the final analysis of the EURO-SKI
trial evaluating 755 patients mostly treated with imatinib
was recently reported: the prognostic factor for MMR loss
after 6 months of TKI discontinuation was the duration of
TKI treatment but not the duration of DMR [25]. Althoughmost molecular relapses occurred within 6 months of dasatinib discontinuation in the D-FREE study, the duration of
TKI treatment may be important for improving TFR even inpatients treated with 2G-TKIs, which are more potent thanimatinib. However, there is overlap between the TKI treatment and the DMR periods, making it difficult to analyze
which one is more important. The incidence of TKI withdrawal syndrome in this study (2 of 21patiens) was lower
than in previous TFR trials (23–30%) [26–28]. This may berelated to the short duration of treatment, as a previous study
has shown that longer treatment duration predisposes to TKI
withdrawal syndrome [28].
It is not known by which mechanism the duration of
TKI treatment affects the success of TFR. Previous reports
showed that the patients with successful discontinuation hadlarger and more functional NK cells than the failed patients[29, 30]. Although not examined in our study, it is possiblethat anti-tumor NK cells may not be able to be maintainedby short-term TKI administration. It is also possible that ashort TKI treatment period may not reduce CML stem cells
to a sufficient level to prevent relapse after treatment cessation. However, the relationship between CML stem cells
and TFR is still controversial, as there is a report that CML
stem cells can be detected in the peripheral blood of patientsduring successful TKI discontinuation [31].
Interestingly, one patient maintained TFR for 17.8 months
after 18.6 months of dasatinib treatment in our study. It isdifficult to detect the difference in patient’s backgroundbetween successful and unsuccessful TFR in our patients
because of its limited number. However, it is very importantto find the prognostic factors of successful TFR, so that it

13

may prove possible to shorten duration of TKI treatment
in a good prognosis group, thus minimizing AEs, avoiding
restriction of pregnancy in women, and reducing the financial challenge of TKI treatment.
This D-FREE study is the largest prospective clinical trial
to register newly diagnosed CML-CP patients treated withdasatinib in Japan. In this study, a high MR4.5 attainment
rate of 48.8% within 2 years was observed. Although notdirectly comparable, this rate was higher than that of other
trials previously reported worldwide [2, 32, 33]. A similar
trend was reported in the Japanese cohort analysis of the
DASISION trial [17]. This may be due to the inclusion ofa large number of low-risk patients in Japan, where healthcheckups are well developed and blood cell abnormalities
are easily detected at an early stage. Although the study did
not focus on collecting safety information during dasatinib
treatment, no new serious adverse events were reported. The
incidence of cardiovascular events grade 3 or higher during
the study period was 1.2%.
In conclusion, DMR for just one year is not enoughfor successful TFR in CML-CP patients treated with
2G-TKIs for less than three years. A yet unknown sufficientduration of treatment before discontinuation of TKIs is
important for improving the TFR treatment goal.
Acknowledgements This study was supported by the Ibaraki Hematology, Oncology & Palliation Expert Meeting (IB-HOPE). This research
was conducted as an Investigator Sponsored Research with financial
support by Bristol-Myers Squibb Co., Ltd (BMS). The authors thankKazuteru Ohashi (Tokyo Metropolitan Cancer and Infectious Diseases
Center, Komagome Hospital), Hideharu Muto (Tokyo Metropolitan
Ohtsuka Hospital), Kensuke Usuki (NTT Medical Center Tokyo),
Kenji Yokoyama (Tokai University Hachioji Hospital), Koh Yamamoto (Yokohama City Minato Red Cross Hospital), Nobuyuki Aotsuka(Japanese Red Cross Narita Hospital), Kenichi Ishizawa (Yamagata
University Hospital), Naoki Takezako (Nerima Hikarigaoka Hospital),
Takuto Miyagishima (Kushiro Rosai Hospital), Tadao Ishida (Japanese
Red Cross Medical Center), Atsushi Shinagawa (Hitachi General Hospital), Kentaro Wakasa (Obihiro-Kosei General Hospital), Tsuyoshi
Nakamaki (Showa University School of Medicine), Naoto Tomita (St.
Marianna University School of Medicine), Katsutoshi Ozaki (Nippon
Medical School Tama Nagayama Hospital), Takayoshi Itoh (JA Toride
Medical Center), Shugo Kowata (Iwate Medical University School of
Medicine), Kenji Tajika (Yokohamaminami-Kyousai Hospital), Takayuki Fujio (Ibaraki Prefectural Central Hospital), Masahiro Onozawa(Hokkaido University Faculty of Medicine), Masahide Yamamoto(Tokyo Medical and Dental University), and Takeshi Kondo (Aiiku
Hospital) for participating in this study. They thank Akiko Yamana,
Hitomi Miyata, and Yumi Terakado at IB-HOPE. They are grateful toProf. Junia V. Melo (University of Adelaide, Australia) for language
editorial assistance.
Data availability The data that support the findings of this study areavailable from the corresponding author, CY, upon reasonable request.

Declarations
Conflict of interest CY received research funding from BMS andhonoraria from BMS, Novartis, Pfizer, Janssen, Chugai, Ono, Otsuka,
AbbVie, Nippon Shinyaku, and Takeda and from advisory board of

Importance of TKI treatment duration in treatment‑free remission of chronic myeloid leukemia:…
Novartis and AbbVie. HY received research funding from BMS andOtsuka; consulting fee from Novartis; and honoraria from Novartis,
Otsuka, and Pfizer. ND received honoraria from Novartis and Janssen.
KM received honoraria from BMS, Otsuka, Chugai, Ono, Novartis,
Pfizer, and Takeda. YH received honoraria from BMS. MO received
honoraria from Novartis, Pfizer, Otsuka, Jansen, and Nihon Shinyaku.
NY received research funding from Chugai, Kyowa Kirin, and Takeda
and honoraria from BMS. KF received honoraria from BMS, Novartis,
Pfizer, Nippon Shinyaku, Meiji Seika, CSL Behring, Otsuka, AbbVie, Jansen, Chugai, and Takeda. GO received honoraria from BMS,
Novartis, Pfizer, Nippon Shinyaku, Kyowa Kirin, Celgene, SymBio,
Sanofi, Ono, Meiji, Nippon Kayaku, Alexion, Otsuka, AbbVie, Janssen, Chugai, Astellas, Sumitomo Dainippon, Takeda, Eisai, MSD,
Mundiphama, and AstraZeneca. TK received honoraria from BMS,
Novartis, Chugai, Ono, and Pfizer. SK received research funding from
BMS and Pfizer and honoraria from BMS, Novartis, Pfizer, and Otsuka. NI received honoraria from BMS, Novartis, Pfizer, and Otsuka.
IT received research funding from National Hospital Organization andhonoraria from Life Science Publications and Medical View. KO received honoraria from Chugai and Daiichi Sankyo and payment fromTakeda and from data safety monitoring/advisory board of Ono, Eisai,
and Janssen. HK received honoraria from Taiho, AbbVie, AstraZeneca, and Chugai. KI received research funding from BMS and honoraria
from BMS, Otsuka, and Novartis. MI, MH, KM, YN, and HS havenothing to disclose.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source,
provide a link to the Creative Commons licence, and indicate if changes
were made. The images or other third party material in this article areincluded in the article's Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in
the article's Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you willneed to obtain permission directly from the copyright holder. To view acopy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by/4.​0/.

References
1. Hochhaus A, Larson RA, Guilhot F, Radich JP, Branford S,
Hughes TP, et al. Long-term outcomes of imatinib treatment forchronic myeloid leukemia. N Engl J Med. 2017;376:917–27.
2. Cortes JE, Saglio G, Kantarjian HM, Baccarani M, Mayer J,
Boqué C, et al. Final 5-year study results of DASISION: thedasatinib versus imatinib study in treatment-naïve chronic myeloid
leukemia patients trial. J Clin Oncol. 2016;34:2333–40.
3. Kantarjian HM, Hughes TP, Larson RA, Kim DW, Issaragrisil
S, le Coutre P, et al. Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis. Leukemia.
2021;35:440–53.
4. Cortes JE, Gambacorti-Passerini C, Deininger MW, Mauro MJ,
Chuah C, Kim DW, et al. Bosutinib versus imatinib for newly
diagnosed chronic myeloid leukemia: results from the randomized
BFORE trial. J Clin Oncol. 2018;36:231–7.
5. Bower H, Bjorkholm M, Dickman PW, Hoglund M, Lambert PC,
Andersson TM. Life expectancy of patients with chronic myeloid
leukemia approaches the life expectancy of the general population.
J Clin Oncol. 2016;34:2851–7.
6. Aghel N, Delgado DH, Lipton JH. Cardiovascular toxicities of
BCR-ABL tyrosine kinase inhibitors in chronic myeloid leukemia:

7.
8.

9.
10.

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

preventive strategies and cardiovascular surveillance. Vasc Health
Risk Manag. 2017;13:293–303.
Berman E, Druker BJ, Burwick R. Chronic myelogenous leukemia: pregnancy in the era of stopping tyrosine kinase inhibitor
therapy. J Clin Oncol. 2018;36:1250–6.
Yamamoto C, Nakashima H, Ikeda T, Kawaguchi SI, Toda Y, Ito
S, et al. Analysis of the cost-effectiveness of treatment strategies
for CML with incorporation of treatment discontinuation. Blood
Adv. 2019;3:3266–77.
Cortes J, Rea D, Lipton JH. Treatment-free remission with firstand second-generation tyrosine kinase inhibitors. Am J Hematol.
2019;94:346–57.
Hochhaus A, Baccarani M, Silver RT, Schiffer C, Apperley
JF, Cervantes F, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia.
2020;34:966–84.
Rea D, Ame S, Berger M, Cayuela JM, Charbonnier A, Coiteux
V, et al. Discontinuation of tyrosine kinase inhibitors in chronic
myeloid leukemia: recommendations for clinical practice fromthe French Chronic Myeloid Leukemia Study Group. Cancer.
2018;124:2956–63.
Deininger MW, Shah NP, Altman JK, Berman E, Bhatia R, Bhatnagar B, et al. Chronic myeloid leukemia, version 2.2021, NCCN
clinical practice guidelines in oncology. J Natl Compr Canc Netw.
2020;18:1385–415.
Yoshida C, Nakamae H, Fletcher L, Koga D, Sogabe T, Matsumura I, et al. Validation of a rapid one-step high sensitivity
real-time quantitative PCR system for detecting major BCR-ABL1
mRNA on an International Scale. Springerplus. 2016;5:569.
Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini FE, Varet B, et al. Loss of major molecular response as a
trigger for restarting tyrosine kinase inhibitor therapy in patientswith chronic-phase chronic myelogenous leukemia who havestopped imatinib after durable undetectable disease. J Clin Oncol.
2014;32:424–30.
Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F,
et al. Discontinuation of imatinib in patients with chronic myeloid
leukaemia who have maintained complete molecular remission for
at least 2 years: the prospective, multicentre Stop Imatinib (STIM)
trial. Lancet Oncol. 2010;11:1029–35.
Rea D, Nicolini FE, Tulliez M, Rousselot P, Guilhot F, Gardembas
M, et al. Dasatinib or Nilotinib discontinuation in chronic phase(CP)-chronic myeloid leukemia (CML) patients (pts) with durably
undetectable BCR-ABL transcripts: Interim Analysis of the STOP2G-TKI Study with a Minimum Follow-up of 12 Months – on
Behalf of the French CML Group Filmc. Blood. 2014;124:811.
Fujisawa S, Nakamae H, Ogura M, Ishizawa K-I, Taniwaki M,
Utsunomiya A, et al. Efficacy and safety of dasatinib versus
imatinib in Japanese patients with newly diagnosed chronicphase chronic myeloid leukemia (CML-CP): subset analysisof the DASISION trial with 2-year follow-up. Int J Hematol.
2014;99:141–53.
Saussele S, Richter J, Guilhot J, Gruber FX, Hjorth-Hansen H,
Almeida A, et al. Discontinuation of tyrosine kinase inhibitor therapy in chronic myeloid leukaemia (EURO-SKI): a prespecified
interim analysis of a prospective, multicentre, non-randomised,
trial. Lancet Oncol. 2018;19:747–57.
Takahashi N, Tauchi T, Kitamura K, Miyamura K, Saburi Y, Hatta
Y, et al. Deeper molecular response is a predictive factor for treatment-free remission after imatinib discontinuation in patients withchronic phase chronic myeloid leukemia: the JALSG-STIM213
study. Int J Hematol. 2018;107:185–93.
Hochhaus A, Masszi T, Giles FJ, Radich JP, Ross DM, Gomez
Casares MT, et al. Treatment-free remission following frontline
nilotinib in patients with chronic myeloid leukemia in chronic

13

C. Yoshida et al.

21.

22.

23.

24.

25.

26.

27.

phase: results from the ENEST freedom study. Leukemia.
2017;31:1525–31.
Kimura S, Imagawa J, Murai K, Hino M, Kitawaki T, Okada M,
et al. Treatment-free remission after first-line dasatinib discontinuation in patients with chronic myeloid leukaemia (first-line DADI
trial): a single-arm, multicentre, phase 2 trial. Lancet Haematol.
2020;7:e218–25.
Yamaguchi H, Takezako N, Ohashi K, Oba K, Kumagai T, Kozai
Y, et al. Treatment-free remission after first-line dasatinib treatment in patients with chronic myeloid leukemia in the chronic
phase: the D-NewS Study of the Kanto CML Study Group. Int J
Hematol. 2020;111:401–8.
Etienne G, Faberes C, Bauduer F, Adiko D, Lifermann F, Dagada
C, et al. Relevance of treatment-free remission recommendations
in chronic phase chronic leukemia patients treated with frontline
tyrosine kinase inhibitors. Cancer Med. 2021;10:3635–45.
Rea D, Kyrcz-Krzemien S, Sportoletti P, Mayer J, Illes A, Angona
A, et al. Treatment-Free Remission (TFR) after two different durations of nilotinib consolidation in patients with chronic myeloid
leukemia (CML) previously treated with imatinib: Enestpath study
results. Blood. 2021;138:635.
Mahon F-X, Richter J, Hochhaus A, Panayiotidis P, Medina deAlmeida A, Mayer J, et al. FINAL analysis of a PAN European
STOP tyrosine kinase inhibitor trial in chronic myeloid leukemia:
the EURO-SKI study. Blood. 2021;138:633.
Richter J, Söderlund S, Lübking A, Dreimane A, Lotfi K, Markevärn B, et al. Musculoskeletal pain in patients with chronic myeloid leukemia after discontinuation of imatinib: a tyrosine kinase
inhibitor withdrawal syndrome? J Clin Oncol. 2014;32:2821–3.
Lee SE, Choi SY, Song HY, Kim SH, Choi MY, Park JS, et al.
Imatinib withdrawal syndrome and longer duration of imatinib
have a close association with a lower molecular relapse after
treatment discontinuation: the KID study. Haematologica.
2016;101:717–23.

13

28. Berger MG, Pereira B, Rousselot P, Cony-Makhoul P, Gardembas M, Legros L, et al. Longer treatment duration and history ofosteoarticular symptoms predispose to tyrosine kinase inhibitor
withdrawal syndrome. Br J Haematol. 2019;187:337–46.
29. Imagawa J, Tanaka H, Okada M, Nakamae H, Hino M, Murai K,
et al. Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response forlonger than 1 year (DADI trial): a multicentre phase 2 trial. Lancet
Haematol. 2015;2:e528–35.
30. Ilander M, Olsson-Stromberg U, Schlums H, Guilhot J, Bruck O,
Lahteenmaki H, et al. Increased proportion of mature NK cells
is associated with successful imatinib discontinuation in chronic
myeloid leukemia. Leukemia. 2017;31:1108–16.
31. Bocchia M, Sicuranza A, Abruzzese E, Iurlo A, Sirianni S,
Gozzini A, et al. Residual peripheral blood CD26(+) leukemic stem cells in chronic myeloid leukemia patients during
TKI therapy and during treatment-free remission. Front Oncol.
2018;8:194.
32. Marin D, Hedgley C, Clark RE, Apperley J, Foroni L, Milojkovic
D, et al. Predictive value of early molecular response in patientswith chronic myeloid leukemia treated with first-line dasatinib.
Blood. 2012;120:291–4.
33. Breccia M, Stagno F, Luciano L, Abruzzese E, Annunziata M,
D’Adda M, et al. Dasatinib first-line: multicentric Italian experience outside clinical trials. Leuk Res. 2016;40:24–9.
Publisher's Note Springer Nature remains neutral with regard tojurisdictional claims in published maps and institutional affiliations.

Case Reports

Sustained Lumen Area by Paclitaxel-Coated Balloon
Following Rotational Atherectomy for Napkin-Ring
Left Main Trunk Ostial Lesion
Takumi Osawa, MD; Tomomi Koizumi, MD, PhD; Yuta Ito, MD
Department of Cardiovascular Medicine, National Hospital Organization Mito Medical Center, Ibaraki, Japan

Abstract
Late lumen enlargement after percutaneous coronary intervention (PCI) with drug-coated balloon has contributed to good clinical results. However, late lumen enlargement with drug-coated balloon following rotational atherectomy has not been well reported. This report describes a case of calcified napkin-ring ostial
lesion at the left main trunk that showed a sustained lumen area after PCI with drug-coated balloon following
rotational atherectomy. An 85-year-old female patient was admitted to the hospital with dyspnea. Echocardiography showed hypokinesis in the anteroseptal and inferior walls. Electrocardiograph-gated cardiac
computed tomography showed a calcified ostial lesion in the left main trunk. Invasive angiography of thecoronary artery showed severe stenosis in the left main trunk ostium. Percutaneous coronary intervention
was performed with a drug-coated balloon after rotational atherectomy. The minimal lumen area measured
by intravascular ultrasound grew mildly from 4.09 to 4.17 mm2 immediately after PCI. Follow-up angiography and intravascular ultrasound performed after 6 months showed that the minimal lumen area in the left
main trunk ostium was further enlarged from 4.17 to 4.69 mm2. The presence of sustained lumen area after
PCI with drug-coated balloon following rotational atherectomy for a napkin-ring left main trunk ostial lesion
was confirmed. This case demonstrates sustained lumen area after drug-coated balloon following rotational
atherectomy in the left main trunk ostium, improving the patient’s chest symptom. Hence, drug-coated balloon after rotational atherectomy may be an option for complex stent sites, such as the left main trunk ostium
in geriatric patients and sites with highly calcified lesions.
Keywords: Atherectomy; coronary artery disease; percutaneous coronary intervention

Introduction

Rotational atherectomy is a recently established procedure for calcified plaque debulking. Most calcified lesions
are treated by stenting following rotational atherectomy. However, percutaneous coronary intervention (PCI)
with a drug (paclitaxel)–coated balloon (DCB) is a well-established stentless strategy for in-stent restenosis
and small vessel disease. The use of DCB could cause an increase in the late lumen area in the chronic phase without
extensive dissection and recoil.1 Late lumen enlargement (LLE) after PCI with DCB has contributed to good clinicaloutcomes.1,2 Although these 2 strategies (rotational atherectomy and DCB) each have advantages, LLE with DCB
following rotational atherectomy for severely calcified lesions has not been well reported.
This report describes a case of napkin-ring calcified ostial lesion at the left main trunk (LMT) that showed sustained
lumen area confirmed by intravascular ultrasound (IVUS) after PCI with rotational atherectomy and DCB.

Citation: Osawa T, Koizumi T, Ito Y. Sustained lumen area by paclitaxel-coated balloon following rotational atherectomy for napkin-ringleft main trunk ostial lesion. Tex Heart Inst J. 2023;50(2):e227883. doi:10.14503/THIJ-22-7883
Corresponding author: Takumi Osawa, MD, Department of Cardiovascular Medicine, National Hospital Organization Mito Medical
Center, Sakuranosato, 280, Ibaraki-machi, Higashi-Ibarakigun, Ibaraki, Japan (tosawa49710@gmail.com)© 2023 by The Texas Heart® Institute, Houston

The Texas Heart Institute Journal • 2023, Vol. 50, No. 2https://doi.org/10.14503/THIJ-22-7883

1/6

Osawa, et al

Case Report
An 85-year-old female patient was admitted to the hospital because of dyspnea on exertion in March 2020.
The patient reported no medical history except rheumatoid arthritis and glaucoma. She had no cardiovascularrisk factors. On initial physical examination, her bloodpressure was 116/64 mm Hg, heart rate was 81 beats
per minute, respiratory rate was 12 breaths per minute,pulse oximetric oxygen saturation was 98% on room air,and body temperature was 36.6 °C. The patient’s height
and weight were 140.0 cm and 34.8 kg, respectively.
Examination of her cardiovascular system revealed noabnormal murmurs, and lung sounds were clear. Her
jugular venous pressure was not elevated, and she did
not exhibit heart failure symptoms, such as shortness ofbreath or leg edema.
An electrocardiogram showed atrial fibrillation at 75
beats per minute, horizontal ST depression, and negative T wave in the V4, V5, and V6 leads. Transthoracic
echocardiography revealed hypokinesis in the anteroseptal and inferior walls with an ejection fraction of
54%. Electrocardiograph-gated cardiac computed tomography revealed a stenotic calcified ostial lesion at
the LMT (Fig. 1A and 1B). Hence, invasive coronary
angiography (CAG) was performed (Fig. 2A), revealing
severe stenosis of the LMT ostium, wherein a 5F diagnostic catheter could be wedged into the LMT ostium.

A

Paclitaxel-Maintained Highly Calcified Lumen Area

Abbreviations and Acronyms
CAG
DCB
LLE
LMT
MLA
PCI

coronary angiography
drug-coated balloon
late lumen enlargement
left main trunk
minimal lumen area
percutaneous coronary intervention

Ischemic functional evaluations, including single‐photon emission computed tomography or fractional flow
reserve, were not performed. The electrocardiogram
showed no abnormal Q waves, and the myocardium
appeared to be viable.
Percutaneous coronary intervention was planned for
the LMT ostial lesion, considering the patient’s Synergy Between Percutaneous Coronary Intervention With
TAXUS and Cardiac Surgery (SYNTAX) score of 20,
advanced age, and frailty. Intra-aortic balloon pumpinsertion was performed before PCI. A 7F Glidesheath
Slender (Terumo) was inserted into the right radial
artery. Percutaneous coronary intervention was thenperformed using a 7F JL 3.5 guide catheter. The LMT
and left anterior descending artery were crossed withthe guide wire (ASAHI SION blue; ASAHI Intecc).
Intravascular ultrasound (OptiCross Imaging Catheter;
Boston Scientific) examination was performed fromthe left anterior descending artery to LMT ostium,
which showed a highly calcified lesion with a calcium

B

Fig. 1 Electrocardiograph-gated cardiac computed tomogram reveals severe stenosis in the calcified ostial lesion at the left
main trunk (arrows) in A) coronal and B) axial views.

The Texas Heart Institute Journal • 2023, Vol. 50, No. 2https://doi.org/10.14503/THIJ-22-7883

2/6

Osawa, et alarc of 360°, that is, “napkin ring” (Fig. 2B). Therefore, rotational atherectomy (Rotalink Plus, 1.5-mm
and 2.0-mm burrs; Boston Scientific) was performed
and a cutting balloon (Wolverine Cutting Balloon,
3.0/10 mm; Boston Scientific) was inflated. Thrombolysis in Myocardial Infarction flow grade 3 and theabsence of a flow-limiting dissection were confirmed.
Hence, a DCB (SeQuent Please, 3.5/15 mm; B. Braun)
was inflated in the LMT ostium owing to the possibility of aortic dissection by pressure expanding metallic
stent or stent edge exiting into the aorta. The minimal
lumen area (MLA) was mildly enlarged from 4.09 to
4.17 mm2 after PCI, and the 7F guide catheter was nolonger wedged into the LMT ostium (Fig. 3A and 3B).
A staged PCI was scheduled with a rotational atherectomy and drug-eluting stent, using a larger burr size(≥2.15 mm) with PCI, if necessary, at follow-up CAG.
In October 2020, follow-up CAG showed no restenosis in the LMT ostium (Fig. 4A). Intravascular ultrasound examination confirmed sustained lumen area of
the LMT ostial lesion. The MLA in the LMT ostium
was enlarged to 4.69 mm2, compared with 4.17 mm2
after the previous PCI (Fig. 4B). Although other factors, including differences in catheter position for eachA

Paclitaxel-Maintained Highly Calcified Lumen Area

procedure, might be related, the sustained left main result (LLE, based on the numerical value) after PCI with
DCB following rotational atherectomy for a napkinring LMT ostial lesion was verified. This MLA is acceptable for a smaller Asian woman, such as the patientin the present case (height of 140 cm and weight of 34.8kg), according to the 2018 European Society of Cardiology/European Association for Cardio-Thoracic Surgery
Guidelines on myocardial revascularization.3 Therefore,
the choice was made to defer further PCI with additional rotational atherectomy. The patient has remained
free of chest pain for 10 months from the procedure.

Discussion
Late lumen enlargement with DCB following rotational
atherectomy for severe calcified ostial lesions has notbeen well reported. This article reports a case of sustained lumen area confirmed by IVUS after PCI withrotational atherectomy and DCB for a napkin-ring
LMT ostial lesion.
A growing body of evidence suggests that the efficacy
of DCB for the treatment of in-stent restenosis or small
vessel disease has been established.4-7 However, there are

B

Fig. 2 Angiogram of the coronary artery and intravascular ultrasound before the procedure. A) Pre-PCI angiogram (leftcranial view) demonstrates severe stenosis of the LMT ostium (arrows). The supplemental motion image also shows severe
stenosis lesion at the LMT. B) Pre-PCI intravascular ultrasound at the LMT ostium shows a minimal lumen area of 4.09 mm2.
Supplemental motion image is available for Figure 2.
LMT, left main trunk; PCI, percutaneous coronary intervention.

The Texas Heart Institute Journal • 2023, Vol. 50, No. 2https://doi.org/10.14503/THIJ-22-7883

3/6

Osawa, et alA

Paclitaxel-Maintained Highly Calcified Lumen Area

B

Fig. 3 Angiogram of the coronary artery and intravascular ultrasound immediately after the procedure. A) Post-PCI
angiogram (left cranial view) indicates a mildly enlarged lesion at the LMT (arrows). There was a coronary dissection (National
Heart, Lung, and Blood Institute coronary dissection criteria type A) at the LMT without flow limit. The supplemental motion
image also shows the lesion following the procedure. B) Post-PCI intravascular ultrasound at the LMT ostium shows aminimal lumen area of 4.17 mm2.
Supplemental motion image is available for Figure 3.
LMT, left main trunk; PCI, percutaneous coronary intervention.

limited data regarding its efficacy for calcified lesions.
A previous trial that used DCB for the treatment ofcalcified lesions showed comparable late lumen loss andrestenosis rates between calcified and noncalcified lesions.8 Rissanen et al9 reported outcomes of 65 patientswith calcified lesions treated with DCB following rotational atherectomy, who showed low rates of major
adverse cardiovascular events and target-lesion revascularization. In a study by Nagai et al,10 approximately
39% of lesions showed LLE after PCI with rotational
atherectomy and DCB. There were no cardiac deaths,
and the target lesion revascularization rate was 16.4%
during the midterm follow-up. Drug-coated balloon
after rotational atherectomy seems to be a feasible andsafe procedure.
In this case, rotational atherectomy and cutting balloon
modified the napkin-ring calcified lesion, and paclitaxel
might have penetrated easily. Although little is known
about how paclitaxel works on calcium to modify calcified lesions, there are several reports of paclitaxel action
on vascular calcification. Shimizu et al11 reported vascular calcification closely related to morphogenic protein signaling and gene regulators of osteogenesis, suchas the Msx2 gene and osteoprotegerin. Also, apoptosis
The Texas Heart Institute Journal • 2023, Vol. 50, No. 2

of smooth muscular cells and release of matrix vesicles
are important factors in coronary artery calcification.12
Paclitaxel attenuates differentiation of vascular smoothmuscle cells into osteoblast, that is, vascular calcification
by downregulation of osteogenic signal and inhibiting
matrix vesicle release.13
Stent implantation in severely calcified lesions is associated with worse outcomes owing to defective stent expansion and strut apposition.14-16 A previous randomized
trial found that postprocedural stent asymmetry was
associated with 1-year ischemic events.17 In this case, thedisadvantages of stent implantation at calcified LMT
ostial lesion included the possibility of inadequate dilation, the risk of aortic dissection by pressure expanding
the metallic stent, the possibility of stent edge exiting
into the aorta, and the inability to perform a second
PCI with rotational atherectomy. Although the mechanism of LLE in severe calcified lesion by paclitaxel is not
fully understood, further study should be undertaken
to confirm the utility of a paclitaxel-eluting balloon forvery severe calcified coronary artery lesions instead of
deploying stents.
The 2018 European Society of Cardiology/European
Association for Cardio-Thoracic Surgery Guidelines
https://doi.org/10.14503/THIJ-22-7883

4/6

Osawa, et alA

Paclitaxel-Maintained Highly Calcified Lumen Area

B

Fig. 4 Follow-up angiogram of the coronary artery and intravascular ultrasound. A) Follow-up angiogram shows no restenosis in the LMT ostium (arrows). The supplemental motion image also shows the follow-up angiography of the lesion.
B) Follow-up intravascular ultrasound at the LMT ostium shows a minimal lumen area of 4.69 mm2.
Supplemental motion image is available for Figure 4.
LMT, left main trunk.

on myocardial revascularization state that “in Asianpatients with generally smaller heart sizes, studies havesuggested that an IVUS MLA of 4.5-4.8 mm2 may be
the most appropriate.”3 Therefore, the MLA of 4.69mm2 in this case is within the recommended range.

Conclusion
In this patient, paclitaxel-coated balloon after rotational
atherectomy for napkin-ring calcified ostial lesion resulted in a sustained lumen area in the chronic phase.
This treatment option might be considered for lesions
that are not suitable for stent implantation, such as severe calcified LMT ostium.
A small advantage of LLE was seen after local delivery of
paclitaxel in a calcified lesion in the present case. Future
investigation is needed to clarify the mechanism of paclitaxel on calcified lesions, which may provide a treatment
option for severe calcified coronary artery disease.

The Texas Heart Institute Journal • 2023, Vol. 50, No. 2

Acknowledgments

The authors appreciate expert review of this report by
Heidi N. Bonneau, RN, MS, CCA.
Published: 23 March 2023
Conflict of Interest Disclosures: The authors have no relevant
financial relationships to disclose.
Funding/Support: The authors report no specific funding related to this article.

References
1.

2.

3.

Kleber FX, Schulz A, Waliszewski M, et al. Local paclitaxel
induces late lumen enlargement in coronary arteries after
balloon angioplasty. Clin Res Cardiol. 2015;104(3):217-225.
doi:10.1007/s00392-014-0775-2
Scheller B, Fischer D, Clever YP, et al. Treatment of acoronary bifurcation lesion with drug-coated balloons: lumen
enlargement and plaque modification after 6 months. Clin
Res Cardiol. 2013;102(6):469-472. doi:10.1007/s00392-0130556-3
Neumann F-J, Sousa-Uva M, Ahlsson A, et al. 2018 ESC/EACTS guidelines on myocardial revascularization. Eur
Heart J. 2018;40(2):87-165. doi:10.1093/eurheartj/ehy394

https://doi.org/10.14503/THIJ-22-7883

5/6

Osawa, et al

4.

Scheller B, Hehrlein C, Bocksch W, et al. Treatmentof coronary in-stent restenosis with a paclitaxel-coatedballoon catheter. N Engl J Med. 2006;355(20):2113-2124.
doi:10.1056/NEJMoa061254
5. Unverdorben M, Vallbracht C, Cremers B, et al.
Paclitaxel-coated balloon catheter versus paclitaxel-coatedstent for the treatment of coronary in-stent restenosis.
Circulation. 2009;119(23):2986-2994. doi:10.1161/
CIRCULATIONAHA.108.839282
6. Nestelberger T, Jeger R. Drug-coated balloons for small
coronary vessel interventions: a literature review. Interv
Cardiol. 2019;14(3):131-136. doi:10.15420/icr.2019.06.R3
7. Jeger RV, Farah A, Ohlow MA, et al. Drug-coatedballoons for small coronary artery disease (BASKETSMALL 2): an open-label randomised non-inferiority trial.
Lancet. 2018;392(10150):849-856. doi:10.1016/S01406736(18)31719-7
8. Ito R, Ueno K, Yoshida T, et al. Outcomes after drug-coatedballoon treatment for patients with calcified coronary lesions.
J Interv Cardiol. 2018;31(4):436-441. doi:10.1111/joic.12484
9. Rissanen TT, Uskela S, Siljander A, et al. Percutaneous
coronary intervention of complex calcified lesions with drugcoated balloon after rotational atherectomy. J Interv Cardiol.
2017;30(2):139-146. doi:10.1111/joic.12366
10. Nagai T, Mizobuchi M, Funatsu A, Kobayashi T, Nakamura
S. Acute and mid-term outcomes of drug-coated balloon
following rotational atherectomy. Cardiovasc Interv Ther.
2020;35(3):242-249. doi:10.1007/s12928-019-00611-y
11. Shimizu T, Tanaka T, Iso T, et al. Notch signaling induces
osteogenic differentiation and mineralization of vascularsmooth muscle cells: role of Msx2 gene induction via
Notch-RBP-Jk signaling. Arterioscler Thromb Vasc Biol.
2009;29(7):1104-1111. doi:10.1161/ATVBAHA.109.187856

The Texas Heart Institute Journal • 2023, Vol. 50, No. 2

Paclitaxel-Maintained Highly Calcified Lumen Area

12. Otsuka F, Sakakura K, Yahagi K, Joner M, Virmani R.
Has our understanding of calcification in human coronary
atherosclerosis progressed? Arterioscler Thromb Vasc Biol.
2014;34(4):724-736. doi:10.1161/ATVBAHA.113.302642
13. Lee K, Kim H, Jeong D. Microtubule stabilization
attenuates vascular calcification through the inhibition of
osteogenic signaling and matrix vesicle release. Biochem
Biophys Res Commun. 2014;451(3):436-441. doi:10.1016/j.
bbrc.2014.08.007
14. Guedeney P, Claessen BE, Mehran R, et al. Coronary
calcification and long-term outcomes according todrug-eluting stent generation. JACC Cardiovasc Interv.
2020;13(12):1417-1428. doi:10.1016/j.jcin.2020.03.053
15. Hemetsberger R, Abdelghani M, Toelg R, et al. Impact ofcoronary calcification on clinical outcomes after implantationof newer-generation drug-eluting stents. J Am Heart Assoc.
2021;10(12):e019815. doi:10.1161/JAHA.120.019815
16. Généreux P, Madhavan MV, Mintz GS, et al. Ischemic
outcomes after coronary intervention of calcified vessels
in acute coronary syndromes. Pooled analysis from the
HORIZONS-AMI (Harmonizing Outcomes With
Revascularization and Stents in Acute Myocardial
Infarction) and ACUITY (Acute Catheterization and Urgent
Intervention Triage Strategy) trials. J Am Coll Cardiol.
2014;63(18):1845-1854. doi:10.1016/j.jacc.2014.01.034
17. Suwannasom P, Sotomi Y, Ishibashi Y, et al. The impact
of post-procedural asymmetry, expansion, and eccentricity
of bioresorbable everolimus-eluting scaffold and metallic
everolimus-eluting stent on clinical outcomes in the
ABSORB II trial. JACC Cardiovasc Interv. 2016;9(12):12311242. doi:10.1016/j.jcin.2016.03.027

https://doi.org/10.14503/THIJ-22-7883

6/6

Allergology International 72 (2023) 63e74

Contents lists available at ScienceDirect

Allergology International
journal homepage: http://www.elsevier.com/locate/alit

Original Article

Classiﬁcations of moderate to severe asthma phenotypes in Japan andanalysis of serum biomarkers: A Nationwide Cohort Study in Japan(NHOM Asthma Study)
Maho Suzukawa a, **, Ken Ohta a, b, *, Yuma Fukutomi c, Hiroya Hashimoto d, e,Takeo Endo f, Masahiro Abe g, Yosuke Kamide c, Makoto Yoshida h, Yoshihiro Kikuchi i,
Toshiyuki Kita j, Kenji Chibana k, Yasushi Tanimoto l, Kentaro Hyodo m, Shohei Takata n,
Toshiya Inui o, Masahide Yasui p, Yoshinori Harada q, Toshio Sato r, Yumi Sakakibara s,
Yoshiaki Minakata t, Yoshikazu Inoue u, Shinji Tamaki v, Tsutomu Shinohara w,
Kazutaka Takami x, Motofumi Tsubakihara y, Masahide Oki z, Kentaro Wakamatsu aa,
Masahide Horiba bb, Gen Ideura cc, Koko Hidaka dd, Akiko M. Saito d,
Nobuyuki Kobayashi a, ee, Masami Taniguchi c, ff
aClinical Research Center, National Hospital Organization Tokyo National Hospital, Tokyo, Japan
Japan Anti-Tuberculosis Association, JATA Fukujuji Hospital, Tokyo, Japanc
Clinical Research Center, National Hospital Organization Sagamihara National Hospital, Kanagawa, Japand
Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, JapaneCore Laboratory, Nagoya City University Graduate School of Medical Sciences, Nagoya, JapanfNational Hospital Organization Mito Medical Center, Ibaraki, Japang
National Hospital Organization Ehime Medical Center, Ehime, JapanhNational Hospital Organization Fukuoka National Hospital, Fukuoka, Japani
National Hospital Organization Morioka Medical Center, Iwate, Japanj
National Hospital Organization Kanazawa Medical Center, Ishikawa, JapankNational Hospital Organization Okinawa National Hospital, Okinawa, JapanlNational Hospital Organization Minami-Okayama Medical Center, Okayama, Japanm
National Hospital Organization Ibarakihigashi National Hospital, Ibaraki, JapannNational Hospital Organization Fukuokahigashi Medical Center, Fukuoka, JapanoNational Hospital Organization Disaster Medical Center, Tokyo, Japanp
National Hospital Organization Nanao National Hospital, Ishikawa, Japanq
Department of Rheumatology & Allergology, National Hospital Organization Osaka Minami Medical Center, Osaka, Japanr
National Hospital Organization Okayama Medical Center, Okayama, Japans
Federation of National Public Service Personnel Mutual Aid Associations Hiratsuka Kyosai Hospital, Kanagawa, Japant
National Hospital Organization Wakayama Hospital, Wakayama, Japanu
National Hospital Organization Kinki-Chuo Chest Medical Center, Osaka, Japanv
National Hospital Organization Nara Medical Center, Nara, Japanw
National Hospital Organization Kochi National Hospital, Kochi, Japanx
Kanto Central Hospital of the Mutual Aid Association of Public School Teachers, Tokyo, JapanyNational Hospital Organization Yokohama Medical Center, Kanagawa, Japanz
Department of Respiratory Medicine, National Hospital Organization Nagoya Medical Center, Aichi, Japanaa
National Hospital Organization Omuta National Hospital, Fukuoka, Japanbb
Division of Respiratory Medicine, National Hospital Organization Higashisaitama National Hospital, Saitama, Japancc
National Hospital Organization Shinshu Ueda Medical Center, Nagano, Japandd
National Hospital Organization Kokura Medical Center, Fukuoka, Japanee
Fureai Machida Hospital, Tokyo, Japanff
Shonan Kamakura General Hospital, Kanagawa, Japanb* Corresponding author. Japan Anti-Tuberculosis Association, JATA Fukujuji Hospital, 3-1-24 Matsuyama, Kiyose-City, Tokyo 204-8522, Japan.
** Corresponding author. Clinical Research Center, National Hospital Organization Tokyo National Hospital, 3-1-1 Takeoka, Kiyose-City, Tokyo 204-8585, Japan.
E-mail addresses: fueta-tky@umin.ac.jp (M. Suzukawa), kenohta3@gmail.com (K. Ohta).
Peer review under responsibility of Japanese Society of Allergology.
https://doi.org/10.1016/j.alit.2022.06.002
1323-8930/© 2022 Japanese Society of Allergology. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/
licenses/by-nc-nd/4.0/).

64

M. Suzukawa et al. / Allergology International 72 (2023) 63e74

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 18 January 2022
Received in revised form
17 May 2022
Accepted 25 May 2022
Available online 2 July 2022

Background: Asthma is a heterogeneous disease, and phenotyping can facilitate understanding of disease
pathogenesis and direct appropriate asthma treatment. This nationwide cohort study aimed to phenotype asthma patients in Japan and identify potential biomarkers to classify the phenotypes.
Methods: Adult asthma patients (n ¼ 1925) from 27 national hospitals in Japan were enrolled anddivided into Global Initiative for Asthma (GINA) steps 4 or 5 (GINA 4, 5) and GINA Steps 1, 2, or 3 (GINA 1e3) for therapy. Clinical data and questionnaires were collected. Biomarker levels among GINA 4, 5
patients were measured. Ward's minimum variance hierarchical clustering method and tree analysis
were performed for phenotyping. Analysis of variance, the KruskaleWallis, and chi-square tests wereused to compare cluster differences.
Results: The following ﬁve clusters were identiﬁed: 1) late-onset, old, less-atopic; 2) late-onset, old,
eosinophilic, low FEV1; 3) early-onset, long-duration, atopic, poorly controlled; 4) early-onset, young,female-dominant, atopic; and 5) female-dominant, T1/T2-mixed, most severe. Age of onset, disease
duration, blood eosinophils and neutrophils, asthma control questionnaire Sum 6, number of controllers,
FEV1, body mass index (BMI), and hypertension were the phenotype-classifying variables determined bytree analysis that assigned 79.5% to the appropriate cluster. Among the cytokines measured, IL-1RA,YKL40/CHI3L1, IP-10/CXCL10, RANTES/CCL5, and TIMP-1 were useful biomarkers for classifying GINA 4,5 phenotypes.
Conclusions: Five distinct phenotypes were identiﬁed for moderate to severe asthma and may be classiﬁed using clinical and molecular variables (Registered in UMIN-CTR; UMIN000027776.)© 2022 Japanese Society of Allergology. Published by Elsevier B.V. This is an open access article under the
CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords:
AsthmaBiomarkers
Cluster analysis
Phenotype
Tree analysis
Abbreviations:
ACQ, Asthma control questionnaire;
AERD, Aspirin-exacerbated respiratory
disease; FeNO, Fractional exhaled nitricoxide; GERD, Gastroesophageal reﬂux
disease; GINA, Global initiative for asthma;
ICS, Inhaled corticosteroid; OCS, Oralcorticosteroid; SA, Severe asthma;
SAS, Sleep apnea syndrome

Introduction

Methods

Asthma is a global health problem that affects around 300
million patients of all ages.1 Evidence on the diversity and heterogeneity of the pathogenesis, symptoms, triggers, severity, responseto treatment, and prognosis of asthma has been established. Among
patients with asthma, 5%e10% have severe asthma (SA), which isclinically characterized by poor control and treatment refractoriness.2 Even SA patients receiving Global Initiative for Asthma(GINA) Step 4 or 5 treatment (GINA 4, 5), with proper adherence
and correct inhaler technique, may have poor asthma control.2,3
In an attempt to understand the disease background, mechanisms, and clinical characteristics of asthma, cluster analyses oflarge numbers of asthma patients have been employed to determine clinical phenotypes in many different regions in the world.4,5The different phenotypes were identiﬁed to deﬁne different clinicalcharacteristics and were believed to have different underlying
pathophysiologic mechanisms associated with various biomarkers.4,6e12 In addition to the need to identify phenotypes inasthma, the determination of biomarkers remains an importanttask. Biomarkers of type 2 inﬂammation include elevated serum
periostin, blood and sputum eosinophil counts, fractional exhalednitric oxide (FeNO), and antigen-speciﬁc IgE. These biomarkers
have been widely accepted and are now increasingly used to predict response and help in selecting patients for biological drug
treatment.13e17 However, in real-world clinical settings, the use of
these biomarkers to identify asthma phenotypes has not been
established.
In Japan, the population is unique in terms of having a long life
expectancy and a relatively uniform racial background. Moreover,
all Japanese residents have mandatory health insurance. Therefore,a nationwide prospective survey would be necessary to identify thecomponents and distribution of asthma phenotypes, which may bedifferent in Japan compared to other countries. Therefore, we
aimed to elucidate the distribution of asthma phenotypes in Japan
using cluster analysis and characterize the phenotypes and underlying pathogenesis by measuring various serum and urine
biomarkers.

Study design
This study (NHOM Asthma Study) was a multicenter, prospective, observational cohort conducted from July 2017 to September
2018 at 27 participating national hospitals (mainly belonging to the
National Hospital Organization, NHO) across Japan (Supplementary
Fig. 1). The study protocol was approved by the ethics committee of
the National Hospital Organization, and written informed consent
was obtained from all participants. The study was conducted inaccordance with the Ethical Guidelines for Medical and HealthResearch Involving Human Subjects (the Ministry of Education,
Culture, Sports, Science and Technology and the Ministry of Health,
Labor and Welfare, Japan) and complied with the ethical principles
consistent with the Declaration of Helsinki. This study was registered in the University Hospital Medical Information Network
Clinical Trials Registry (UMIN-CTR; UMIN000027776).
Patients
Adult patients (aged 18 years) diagnosed and treated forasthma for more than one year and managed by pulmonary or allergy specialists in the participating hospitals were recruited. In thecohort, patients on medium- or high-dose inhaled corticosteroids(ICS) in combination with more than one asthma controller, i.e.,
long-acting b2 agonist; leukotriene receptor antagonist; sustainedrelease theophylline; tiotropium bromide hydrate, which is a longacting anticholinergic; omalizumab; mepolizumab; and systemic
corticosteroid, were deﬁned as GINA Step 4 or 5 (GINA 4, 5). Other
patients were deﬁned as GINA Step 1, 2, or 3 (GINA 1e3). Patientswere treated based on their physicians’ standard practices in a realworld clinical setting.
Data collection and outcome measures
The physician in charge collected the following clinical datafrom the medical records using an electronic data capture system:M. Suzukawa et al. / Allergology International 72 (2023) 63e74

age, sex, height, weight, asthma treatment status, and laboratory
variables, including lung function, peripheral white blood cell(WBC) and differential count, total and speciﬁc IgE, forced oscillation technique, and FeNO. For biologics, only omalizumab andmepolizumab were available in Japan during the study period.
Patients were requested to complete and send by mail a basic
questionnaire, which included demographic data, such as age, sex,family history, smoking history, medical history, allergy status, petbreeding, and presence of comorbidities; the asthma control
questionnaire (ACQ) 6; the asthma quality of life questionnaire; theself-assessment of allergic rhinitis and asthma questionnaire; andthe adherence starts with knowledge 20. For patients in GINA 4, 5,
and who were able to follow-up for one year, asthma control wasassessed by the physicians based on unscheduled visits, hospital
admission, asthma exacerbation that required systemic corticosteroids, intensive care unit admission, and emergency room visits.
Serum and urine samples were collected and frozen at theparticipating hospitals before being sent to the central laboratory tomeasure the biomarkers.
The primary endpoint was the identiﬁcation of the phenotypesof GINA 4, 5 in the study population. The secondary outcomes
included the characteristics of the GINA 4, 5, compared with GINA
1e3; the distribution of the molecular biomarkers in GINA 4, 5
phenotypes; and identiﬁcation of the determinants of each GINA 4,5 phenotype.
Biomarker measurements
The serum samples from GINA 4, 5 were stored frozen at 20  C
at the Tokyo National Hospital for as long as one year and were
subsequently analyzed for biomarker levels using R&D Systems
Luminex Assay (R&D Systems, Minneapolis, MN, USA) and MAGPIX
System (Luminex, Austin, TX, USA), according to the manufacturers’
instructions. The biomarkers analyzed were eotaxin 1/CCL11, IFN-g,interleukin (IL)-1 RA, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8/CXCL8, IL-12p70,
IL-13, IL-18, IL-25, IL-33, leptin, MCP-1/CCL2, MIP-1a/CCL3, MIP-1b/
CCL4, MMP1, MMP2, MMP3, MMP8, MMP12, IP-10/CXCL10, periostin, PDGF-BB, RANTES/CCL5, ST2/IL-1R4, TARC/CCL17, TIMP-1,
TNF-a, and YKL40/CHI3L1. Before performing the respective assays, the serum samples were diluted 10  for IL-1RA, leptin,
MMP1, MMP3, periostin, and YKL40/CHI3L1 and 30  for MMP2,
PDGF-BB, RANTES, and TIMP-1. Standard curves were generatedusing serial dilutions of the assay standards for quantiﬁcation. The
xPONENT 4.2 Software for MAGPIX was used for bead acquisition
and analysis of median ﬂuorescence intensity. For TGF-b analysis,
the serum samples were diluted 70  before analysis using an ELISA
kit (ThermoFisher Scientiﬁc, Waltham, MA, USA).
Urine LTE4 measurement
The LTE4 concentration in spot urine was measured, as previously described18 and was expressed as pg/mL of creatinine.
Statistical analysis
Ward's minimum variance hierarchical clustering method was
performed. Dendrograms were used to determine the number ofclusters. Variables with a high number of missing values were
excluded from the cluster analysis; if the correlation between
variables was high, cluster analysis was limited to one variablefrom a clinical perspective. Finally, 26 variables from the patient's
background, asthma history, comorbidities, laboratory examinations, asthma treatment, and asthma control were chosen for the
analysis (Supplementary Table 1). For continuous variables, z-

65scores were used, whereas for categorical variables, the designations 0 and 1 were used. Stepwise discriminant analysis was
performed to select the variables that have a signiﬁcant impact onclustering among the variables used in the cluster analysis. The
selected variables were then used to create a decision tree toevaluate patient classiﬁcation. To avoid overﬁtting, the decision
tree was cost-complexity pruned. To compare differences among
the clusters, analysis of variance, KruskaleWallis, and chi-square
tests were used for parametric continuous, nonparametriccontinuous, and categorical variables, respectively. The cytokine
and urine LTE4 measurements were summarized using the geometric mean and standard deviation, and the log-transformed
values were used for statistical tests.
All statistical analyses were conducted using SAS version 9.4(SAS Institute Inc., Cary, NC, USA) and R version 3.6.2 (R Core Team
2019, R Foundation for Statistical Computing, Vienna, Austria). A pvalue of <0.05 was considered statistically signiﬁcant. The tests forthe biomarkers were evaluated with Bonferroni's correction at asigniﬁcance level of 0.00147 (z0.05/34).
Results
Comparison of baseline characteristics between GINA 4, 5, and GINA
1e3 in JapanOf the 1925 patients enrolled in the study, 738 (38.3%) wereclassiﬁed as having GINA 4, 5. Among the enrolled patients, one had
missing baseline data, and 152 did not meet the eligibility criteria. A
total of 1772 patients were analyzed to compare GINA 4, 5, and
GINA 1e3. Further, 498 patients in GINA 4, 5 with the full analysis
set were subjected for cluster analysis (Fig. 1).
As shown in Table 1, compared with patients with GINA 1e3,
those with GINA 4, 5 were signiﬁcantly older, had longer disease
duration, a more frequent family history of asthma, and a higher
proportion of patients with a smoking history. The comorbidities ofsinusitis, pollinosis, drug allergy, chronic obstructive pulmonary
disease (COPD), gastroesophageal reﬂux disease (GERD), sleep apnea syndrome (SAS), hypertension, and aspirin-exacerbated respiratory disease (AERD) were more frequent in patients with GINA 4,
5 than in those with GINA 1e3.
Compared with patients with GINA 1e3, those with GINA 4, 5
had a signiﬁcantly lower lung function, including lower FEV1, %FEV1, and FEV1%. Both FeNO and WBC counts were signiﬁcantly
higher in GINA 4, 5 than in GINA 1e3, but there was no signiﬁcantdifference in the eosinophil count and total IgE. Alternatively,
compared with the GINA 1e3 group, the GINA 4, 5 group had asigniﬁcantly higher proportion of patients who had atopy andpositivity for speciﬁc IgE against molds and pollens.
For asthma therapy, the ICS doses were higher, and there wasmore frequent use of asthma controllers in the GINA 4, 5 group thanin the GINA 1e3 group. Compared with the GINA 1e3 group, the
GINA 4, 5 group had a more frequent intake of oral corticosteroid(OCS) (12.9% vs. 2.3%, p < 0.001) and biologics (11.6% vs. 0.3%,
p < 0.001) for asthma control. Based on the signiﬁcantly higher ACQ
6 and more frequent unscheduled visits and hospital admissions,asthma control was worse among patients with GINA 4, 5 than inthose with GINA 1e3.
Cluster analysis of patients with GINA 4, 5
For cluster analysis of patients with GINA 4, 5 using Ward's
method, only those with a full dataset of the variables shown in
Supplementary Table 1 were selected. In any of the variables, there
were no signiﬁcant differences between the overall GINA 4, 5

66

M. Suzukawa et al. / Allergology International 72 (2023) 63e74

Fig. 1. Patient ﬂow diagram.

population and the population used for the cluster analysis (datanot shown). A total of 498 patients were classiﬁed into ﬁve clusters
by the dendrogram (Fig. 2, Table 2). The characteristics of these ﬁveclusters are given below.

highest following cluster 5. For asthma control, cluster 2 had thehighest ACQ Sum 6 and relatively frequent unscheduled visits,
acute exacerbation, and admission.
Cluster 3: early-onset, long-duration, atopic, poorly controlled

Cluster 1: late-onset, old, less-atopic
A total of 119 patients (23.9%) were grouped in this cluster,
including a relatively old population with equal sex distribution. All
cases in cluster 1 were adult-onset asthma, with the shortest
asthma duration among the clusters. This cluster comprised thelargest proportion of ex-smokers had a high percentage of patientswith COPD, and comprised the smallest percentage of patients withatopy. Interestingly, FEV1 was preserved in this cluster, with patients who used the least ICS dose and the smallest number ofcontrollers and had the least frequent OCS and biologics used. The
ACQ 6 and the number of unscheduled visits, acute exacerbations,and admissions for asthma were the lowest in this cluster.

Cluster 3 included the most number of patients (n ¼ 127, 25.5%).
Subjects in cluster 3 had the youngest disease onset, the longest
duration of asthma, and the highest body mass index (BMI). The
proportion of adult-onset asthma cases was the lowest, and afamily history of asthma was the highest in cluster 3. There was no
characteristic comorbidity, except for a high rate of allergic
conjunctivitis. However, pulmonary function, as assessed by FEV1,
FEV1%, and %FEV1, was the second-lowest in cluster 3. The percentage of patients with atopy was the highest in cluster 3, with thesecond-highest total IgE. For asthma controller therapy, the proportion of patients on high-dose ICS was the second largest among
the clusters. Although the ACQ Sum 6 was not high, the number ofunscheduled visits and acute exacerbations were high in cluster 3.

Cluster 2: late-onset, old, eosinophilic, low FEV1
Cluster 4: early-onset, young, female-dominant, atopic
Cluster 2 included 116 subjects (23.3%) and comprised the oldest
age at enrollment, the least female proportion, and the second
oldest asthma onset. This cluster included more ex-smokers andhad the most frequent comorbidity of Asthma-COPD overlap,
deﬁned as patients with a smoking history of more than 10 packyears and FEV1/FVC <70%, self-reported COPD, and the lowest
FEV1, FEV1%, and %FEV1. Additionally, cluster 2 cases accounted forthe highest FeNO, blood eosinophils, and total IgE, and the secondhighest proportion of positive cases for the speciﬁc IgE against
molds. The ICS dose was lower for asthma treatment, but the
number of controllers was higher in cluster 2 than in the otherclusters. The frequency of OCS and biologics use was the second

Cluster 4 included 104 subjects (20.9%), was female-dominantand comprised the youngest patients with early disease onset.
The proportion of never smokers was the largest in this cluster.
Moreover, the patients in cluster 4 had frequent comorbidities ofother allergic diseases, such as allergic rhinitis, atopic dermatitis,
pollinosis, and AERD. The FEV1 in this cluster was the best among
the clusters. The prevalence of atopy was high, and speciﬁc IgEs
against dust mites, pets, and pollen were frequently detected incluster 4. Asthma controller therapy was relatively not intense inthis cluster, and the asthma control status was good, based on thenumber of unscheduled visits, acute exacerbations, and admissions.

M. Suzukawa et al. / Allergology International 72 (2023) 63e74

67

Table 1Baseline characteristics of GINA 4, 5 and GINA 1e3.
Variables

GINA 1e3 (n ¼ 1073)

GINA 4, 5 (n ¼ 699)

Total (n ¼ 1772)

P valueAge at enrolment, years
Sex, % female
BMI, kg/m2
Age of asthma onset, years
Asthma duration, years
Course of asthma, %Carried over from childhood asthma
Recurred from childhood asthma
Adult onset
Family history of asthma, %Smoking status, %Current smoker
Ex-smoker
Never smoker
Smoking history, pack-years
Comorbidities, %Sinusitis
Allergic rhinitis
Allergic conjunctivitis
Atopic dermatitis
Pollinosis
Food allergy
Drug allergy
Anaphylaxis
Urticaria
COPD
GERD
SAS
Hypertension
Otitis media
AERD
Mental disorder
FEV1, mL
FEV1% pred, %FEV1/FVC, %FeNO, ppb
WBC count,/mL
Blood eosinophils,/mL
Total IgE, IU/mL
Atopyz, %Speciﬁc IgE (dust mites), %Speciﬁc IgE (molds), %Speciﬁc IgE (cats/dogs), %Speciﬁc IgE (pollen), %Speciﬁc IgE (insects), %Treatment
ICS dose, %Low
MediumHigh
Number of controllers
OCS use, %OCS, PSL mg
Use of biologics, %ACQ Sum 6
Asthma control
Unscheduled visits, %
0
1
2
3
4
5e9
10
Admission, %0
1
2

61.7 (15.2)y61.9
23.8 (4.3)
44.1 (21.5)
15.1 (14.8)

63.5 (14.9)
59.4
24.1 (4.4)
42.9 (21.2)
17.8 (14.8)

62.4 (15.1)
60.9
23.9 (4.4)
43.6 (21.4)
16.1 (14.9)

0.011
0.290
0.159
0.295
<0.001
0.840

5.7
10.0
84.3
25.7

5.3
10.8
83.9
30.3

5.6
10.3
84.1
27.5

4.9
35.6
59.5
9.2 (18.3)

4.9
41.7
53.4
11.9 (24.1)

4.9
38.0
57.1
10.3 (20.8)

0.008

36.3
27.9
8.4
8.8
31.5
7.6
9.2
5.9
11.5
5.1
15.5
6.1
27.1
14.6
3.8
9.7
2192 (742)
97 (21)73 (12)33.9 (31.7)
6050 (1676)
279 (297)
489.4 (1236.7)
51.3
38.8
17.2
12.3
45.8
20.8

43.2
27.5
10.5
9.1
37.7
8.2
12.4
5.9
11.0
10.2
20.3
9.0
32.5
15.3
8.2
12.7
2045 (798)
88 (29)70 (14)38.7 (38.8)
6623 (1966)
256 (290)
457.1 (909.2)
57.8
38.6
27.5
15.3
52.8
22.5

39.1
27.7
9.2
8.9
33.9
7.8
10.5
5.9
11.3
7.1
17.4
7.2
29.3
14.9
5.5
10.9
2131 (769)
94 (24)72 (13)35.8 (34.8)
6293 (1827)
269 (294)474.5 (1097.5)
53.8
38.7
21.3
13.5
48.5
21.4

0.004
0.878
0.155
0.819
0.008
0.600
0.036
0.990
0.762
<0.001
0.010
0.024
0.015
0.691
<0.001
0.058<0.001
0.004<0.001
0.015<0.001
0.123
0.575
0.007
0.952
<0.001
0.070
0.004
0.400

61.6
36.7
1.7
1.3 (0.9)
2.3
0.1 (0.9)
0.3
0.6 (0.7)

13.6
49.2
37.3
2.8 (1.1)
12.9
0.9 (3.0)
11.6
1.0 (0.9)

52.0
39.2
8.8
1.9 (1.2)
6.5
0.4 (2.0)
4.7
0.7 (0.8)<0.001

79.4
9.7
3.6%
1.7
2.0
2.8
0.8

62.2
14.3
7.8
4.8
2.6
5.9
2.4

72.6
11.5
5.3
2.9
2.3
4.0
1.4

<0.001

92.2
5.2
1.4

77.6
12.9
4.2

86.4
8.3
2.5

<0.001

0.034
0.037

<0.001<0.001<0.001<0.001<0.001(continued on next page)68

M. Suzukawa et al. / Allergology International 72 (2023) 63e74

Table 1 (continued )Variables
3
4
5e9
10

GINA 1e3 (n ¼ 1073)

GINA 4, 5 (n ¼ 699)

Total (n ¼ 1772)

0.7
0.3
0.2
0.0

2.4
1.1
1.3
0.5

1.4
0.6
0.6
0.2

P value

ACQ, asthma control questionnaire; AERD, aspirin-exacerbated respiratory disease; FeNO, fractional exhaled nitric oxide; GERD, gastroesophageal reﬂux disease; ICS, inhaledcorticosteroid; OCS, oral corticosteroid; SAS, sleep apnea syndrome.
yNumeric data are expressed as mean (SD).
z
Speciﬁc IgE responsiveness to common inhaled allergens.

Cluster 5: female-dominant, T1/T2-mixed, most severe
Cluster 5 was the smallest cluster with 32 subjects (6.4%) andcomprised a female-dominant population with the highest BMI
and, mainly, adult-onset asthma. The proportion of current
smokers was the largest in cluster 5 and had the most frequentcomorbidities of anaphylaxis and otitis media. Cluster 5 had abetter %FEV1 than clusters 2 and 3. Although eosinophil counts ofcluster 5 were low, FeNO was the second highest. Notably, the WBC
and neutrophil counts were the highest in cluster 5. The proportions of patients who used high-dose ICS, OCS, and biologics
were the highest in cluster 5 among all clusters. The ACQ Sum 6 andthe number of unscheduled visits, asthma exacerbations, and admissions were high.
Biomarkers
Table 3 shows a comparison of serum biomarkers and urine
LTE4 levels among the clusters. P-values between the two

respectively clusters analyzed by TukeyeKramer methods areshown in Supplemental Table 2. Cluster 5 had the highest levels of
IL-1RA, MMP3, MMP8, and ST2/IL-1R4 and tended to have thehighest levels of IFN-g, IL-6, IL-7, MCP-1/CCL2, MMP12, and TGF-b.
Among them, IL-1RA and MMP8 were signiﬁcantly higher thanany other cluster. Serum leptin was signiﬁcantly higher thanclusters 2 and 4, and MMP3 was signiﬁcantly higher than clusters
1, 3, and 4. Cluster 4, which included the youngest cases withatopy, showed signiﬁantly lower serum IL-1RA, ST2/IL-1R4, andYKL-40/CHI3L1 compared to all the other clusters. Cluster 4 also
had signiﬁantly higher IL-12p70 and IL-33 than clusters 1, 2, and 3.
Cluster 2, which showed eosinophilia, had signiﬁcantly higher
serum IL-5 and urine LTE4 compared to clusters 1 and 3. Serum
MMP-3 and TIMP1 in cluster 2 was signiﬁcantly higher thanclusters 1 and 4. In cluster 2, MMP-1 was signiﬁcantly higher thancluster 1, and MMP-2 was signiﬁcantly higher than clusters 3 and4. The older cases in clusters 1 and 2 had high levels of periostin
and YKL40/CHI3L1. Overweight patients in clusters 3 and 5 hadsigniﬁcantly high levels of leptin.

Fig. 2. Dendrogram.

M. Suzukawa et al. / Allergology International 72 (2023) 63e74

69

Table 2Cluster analysis of GINA 4, 5.
Summary

Cluster 1 (n ¼ 119)Late onset, Old,
Less-atopic

Cluster 2 (n ¼ 116)
Late onset, Old,
Eosinophilic,
Low FEV1

Cluster 3 (n ¼ 127)
Early onset, Long duration,
Atopic, Poorly controlled

Cluster 4 (n ¼ 104)
Early onset,
Young,
Female-dominant,AtopicCluster 5 (n ¼ 32)
Female-dominant,
T1/T2 mixed,
Most severe

Signiﬁcance(P value)*

Age at enrolment, years
Sex, % female
BMI, kg/m2
Age of asthma onset, years
Asthma duration, years
Course of asthma, %Carried over from childhood asthma
Recurred from childhood asthma
Adult onset
Family history of asthma, %Smoking status, %Current smoker
Ex-smoker
Never smoker
Smoking history, pack-years
Asthma-COPD overlap,z %Comorbidities (self-reported), %Sinusitis
Allergic rhinitis
Allergic conjunctivitis
Atopic dermatitis
Pollinosis
Food allergy
Drug allergy
Anaphylaxis
Urticaria
COPD
GERD
SAS
Hypertension
Otitis media
AERD
Mental disorder
FEV1, mL
FEV1% pred, %FEV1/FVC, %FeNO, ppb
WBC count,/mL
Blood eosinophils,/mL
Blood neutrophils,/mL
Total IgE, IU/mL
Atopyx, %Speciﬁc IgE (dust mites) %Speciﬁc IgE (molds), %Speciﬁc IgE (cats/dogs), %Speciﬁc IgE (pollen), %Speciﬁc IgE (insects), %Treatment
ICS dose, %~ MediumHigh
Number of controllers, %OCS use, %OCS, PSL mg
Use of biologics, %ACQ Sum 6
Asthma control
Unscheduled visits, %
0
1
2
3
4
5e9
10
Acute exacerbation, %0
1
2

69.6 (9.9)y56.3
24.3 (3.2)
61.3 (11.2)
8.3 (7.0)

71.6 (9.4)
47.4
24.2 (3.8)
55.1 (12.5)
16.6 (11.2)

63.2 (13.7)
59.8
25.5 (5.7)
26.3 (16.5)
30.6 (15.6)

47.8 (11.7)
75.0
21.5 (3.3)
29.4 (15.6)
12.5 (9.1)

61.8 (12.5)
75.0
25.5 (3.5)
43.5 (20.3)
14.7 (11.8)<0.001<0.001<0.001<0.001<0.001<0.001

0.0
0.0
100.0
24.4

0.0
0.0
100.0
31.0

11.8
22.8
65.4
40.9

3.8
19.2
76.9
24.0

3.1
9.4
87.5
31.3

1.7
55.5
42.9
15.0 (28.3)
11.8

3.4
50.0
46.6
15.4 (23.8)
31.9

8.7
35.4
55.9
9.0 (15.3)
17.3

2.9
26.9
70.2
3.1 (8.8)
1.0

9.4
43.8
46.9
16.5 (48.6)
18.8<0.001<0.001

46.2
21.0
5.0
3.4
34.5
3.4
10.1
0.8
9.2
12.3
20.2
10.1
41.2
7.6
1.8
11.2
2108 (640)101 (21)73 (10)30.5 (24.4)
5940 (1295)
178 (151)
3393 (1064)
321.2 (562.4)
49.6
23.5
17.6
7.6
46.2
16.0

47.4
19.8
5.2
4.3
31.9
6.0
11.2
6.9
8.6
18.9
24.1
8.6
47.4
19.8
7.3
8.2
1624 (643)
77 (27)63 (14)59.3 (51.7)
6968 (1813)
464 (454)
4059 (1347)
709.7 (1586.7)
60.3
33.6
35.3
11.2
59.5
28.4

46.5
29.9
17.3
13.4
29.9
11.0
12.6
10.2
18.1
5.0
22.8
9.4
31.5
15.0
11.6
15.4
1918 (704)
86 (25)68 (13)33.0 (30.2)
6772 (1810)
216 (212)
4046 (1560)
540.9 (820.8)
70.1
56.7
39.4
18.9
61.4
25.2

46.2
47.1
14.4
17.3
66.3
11.5
21.2
5.8
9.6
0.0
11.5
8.7
5.8
18.3
15.8
20.0
2670 (791)102 (17)79 (10)34.4 (37.5)5673 (1359)
205 (174)
3308 (1066)
245.6 (362.6)
67.3
51.0
21.2
23.1
70.2
26.0

37.5
31.3
15.6
12.5
46.9
15.6
9.4
12.5
9.4
6.5
25.0
12.5
43.8
37.5
6.5
16.1
2023 (796)
93 (27)70 (16)41.2 (46.7)
10,081 (3059)
131 (134)
7538 (2881)
350.9 (568.2)
53.1
37.5
21.9
15.6
43.8
18.8

0.904
<0.001
0.004<0.001<0.001
0.052
0.108
0.023
0.111
<0.0010.139
0.966<0.001<0.001
0.005
0.123<0.001<0.001<0.001<0.001<0.001<0.001<0.001
0.002
0.009<0.001<0.001
0.010
0.002
0.178

60.5
39.5
2.2 (0.8)
1.7
0.1 (0.6)
5.0
0.6 (0.6)

58.7
41.4
3.2 (1.0)
19.0
1.3 (3.8)
17.2
1.4 (1.0)

38.6
61.4
2.9 (1.1)
16.5
0.9 (2.1)
15.0
1.0 (1.0)

50.0
50.0
3.0 (1.1)
15.4
0.8 (2.1)
12.5
0.7 (0.7)

34.4
65.6
3.3 (0.9)
31.3
3.3 (6.7)
28.1
1.3 (0.9)

0.006

84.9
13.4
0.8
0.8
0.0
0.0
0.0

83.6
10.3
1.7
2.6
0.9
0.9
0.0

76.4
11.0
2.4
3.9
2.4
3.9
0.0

83.7
9.6
5.8
1.0
0.0
0.0
0.0

46.9
15.6
15.6
3.1
6.3
9.4
3.1

<0.001

81.5
16.8
0.8

59.5
25.0
6.9

55.9
15.0
7.9

76.9
14.4
6.7

25.0
12.5
9.4

<0.0010.030<0.001<0.001<0.001<0.001
0.005<0.001(continued on next page)70

M. Suzukawa et al. / Allergology International 72 (2023) 63e74

Table 2 (continued )Summary

3
4
5e9
10
Admission, %
0
1
2
3
5e9

Cluster 1 (n ¼ 119)Late onset, Old,
Less-atopic

Cluster 2 (n ¼ 116)
Late onset, Old,
Eosinophilic,
Low FEV1

Cluster 3 (n ¼ 127)
Early onset, Long duration,
Atopic, Poorly controlled

Cluster 4 (n ¼ 104)
Early onset,
Young,
Female-dominant,AtopicCluster 5 (n ¼ 32)
Female-dominant,
T1/T2 mixed,
Most severe

0.8
0.0
0.0
0.0

6.0
0.9
1.7
0.0

5.5
5.5
9.4
0.8

0.0
1.0
1.0
0.0

3.1
0.0
15.6
34.4

95.8
4.2
0.0
0.0
0.0

92.2
5.2
1.7
0.9
0.0

94.5
3.1
2.4
0.0
0.0

95.2
3.8
1.0
0.0
0.0

81.3
9.4
3.1
0.0
6.3

Signiﬁcance(P value)*

0.033

ACQ, asthma control questionnaire; AERD, aspirin-exacerbated respiratory disease; FeNO, fractional exhaled nitric oxide; GERD, gastroesophageal reﬂux disease; ICS, inhaledcorticosteroid; OCS, oral corticosteroid; SAS, sleep apnea syndrome.
*
Using analysis of variance for continuous variables and Chi square test for proportions.
yNumeric data are expressed as mean (SD).
z
Asthma-COPD overlap patients were deﬁned as patients with a smoking history of more than 10 pack-years and FEV1/FVC <70%.
xSpeciﬁc IgE responsiveness to common inhaled allergens.

Tree diagram
Figure 3 shows the tree analysis of the variables used for cluster
analysis to classify patients with GINA 4, 5. The variables chosen for
the tree analysis were the age of onset, disease duration, eosinophils, neutrophils, ACQ Sum 6, number of controllers, FEV1, BMI,
and hypertension; these were deemed to be important in determining the GINA 4, 5 phenotypes. Using this tree analysis, 79.5% of
all subjects were assigned to the appropriate cluster. When thebiomarkers shown in Table 3 were added as variables, only the levelof IL-1RA was selected for inclusion in the tree analysis; however,
the accuracy slightly went down to 78.7%, compared with the accuracy of the tree analysis that included only the clinical variables.
The characteristics of the patients who were not correctly
assigned by the tree analysis are shown in Supplementary Table 3.
Incorrect assignment of patients tended to be more frequent inclusters 2, 4, and 5 than in the others. In particular, cluster 5 cases ofpoorly controlled asthma with intense treatment tended to beincorrectly assigned. Among these incorrectly assigned patients,
use of the IL-1RA, YKL40/CHI3L1, IP-10/CXCL10, RANTES/CCL5, and
TIMP-1 biomarkers to classify patients with SA resulted in 62.4%
accuracy (Supplementary Fig. 2).
Discussion
This nationwide asthma cohort study in Japan revealed thatpatients with GINA 4, 5, as deﬁned by receipt of GINA 2016 treatment steps 4 or 5, were older and had longer disease duration, morefamily history of asthma, and more smoking history, than those
who had GINA 1e3. Moreover, patients with GINA 4, 5 had relatively frequent sinusitis, pollinosis, drug allergy, COPD, GERD, SAS,
hypertension, and AERD; had lower lung function; were on relatively intense asthma therapy, and had relatively poor asthma
control. Among patients with GINA 4, 5, ﬁve distinct phenotypes
were identiﬁed. These phenotypes differed in patient demographics; disease onset and duration; and disease expressions,such as atopy or nonatopy, lung function, asthma symptoms,
medication use, and health care utilization. In addition, thedifferent distributions of multiple serum biomarkers implieddifferent pathophysiologic mechanisms among the ﬁve clinicalphenotypes. The decision tree model that we used in this study
differentiated the patients into ﬁve phenotypes with an accuracy of
79.5%.

This study may be one of the largest nationwide cohort studies
on patients with asthma in Japan. The study population comprised
well-characterized patients who visited core national hospitals that
had advanced medical equipment. The clinical data are presumed
to be reliable because specialists in pulmonary medicine and/or
allergy were the ones who managed the patients. In addition to theclinical information from precise questionnaires, comprehensive
biomarker levels were analyzed among patients with GINA 4, 5.
Most of the characteristics in this present cohort were similar to thepreviously reported baseline characteristics (i.e., age, disease
duration, and smoking history) of GINA 4, 5 cases, including a
recent study in Japan,6,19e21 except for older age, which is likely due
to Japan's high-age society. Moreover, similar to the previously
reported cohorts, this present cohort had relatively frequentcomorbidities, such as sinusitis, other allergic diseases, COPD,
GERD, SAS, hypertension, and aspirin sensitivity, which may partly
be explained by the older age of GINA 4, 5 cases. Interestingly,
similar to a previous report,19 neutrophil count was high in GINA 4,
5; this may have partly resulted from the frequent use of systemic
corticosteroids.
However, there were some differences between the present
and previous studies. A recent report on GINA 4, 5 based on ahealth insurance database in Japan showed a lower percentage ofpatients with GINA 4, 5 (7.8%),22 than that in this study. Moreover,compared with this study, previous studies included GINA 4, 5
cases with lower FEV1 and showed more frequent atopy in GINA
1e3 cases than in GINA 4, 5 cases.6,19e21 These differences may
have resulted from the broader deﬁnition of GINA 4, 5 (i.e., lesssevere) in this study than in previous reports. Notably, the publichealth insurance system is applicable to all residents in Japan. In
certain areas, the medical expenses for asthma caused by air
pollution are subsidized; this intensiﬁed asthma treatment may
have increased the apparent disease severity among patients inJapan. Another feature of the present cohort is that there is a highsmoking history, which is a result of the enrollment setting of thisstudy, where smokers and COPD patients were not excluded.
However, this study represents the real-world clinical practice ofasthma in Japan.
Asthma is characterized by variability in pathogenesis, presenting symptoms, disease severity, response to treatment, andprognosis. With the increasing treatment options for GINA 4, 5,
considering the phenotypes in the decision making would be betterand had been attempted by several clinical studies.4,6e10,23e27 In

M. Suzukawa et al. / Allergology International 72 (2023) 63e74

71

Table 3
Biomarker levels among the GINA 4, 5 clusters.
Summary

Eotaxin 1/CCL11 [pg/mL]
IFN-g [pg/mL]
IL-1RA [ng/mL]
IL-2 [pg/mL]
IL-4 [pg/mL]
IL-5 [pg/mL]
IL-6 [pg/mL]
IL-7 [pg/mL]
IL-8/CXCL8 [pg/mL]
IL-12p70 [pg/mL]
IL-13 [pg/mL]
IL-18 [pg/mL]
IL-25 [pg/mL]
IL-33 [pg/mL]
Leptin [ng/mL]
MCP-1/CCL2 [pg/mL]
MIP-1a/CCL3 [pg/mL]
MIP-1b/CCL4 [pg/mL]
MMP1 [ng/mL]
MMP2 [ng/mL]
MMP3 [ng/mL]
MMP8 [ng/mL]
MMP12 [pg/mL]
IP-10/CXCL10 [pg/mL]
Periostin [ng/mL]
PDGF-BB [ng/mL]
RANTES/CCL5 [ng/mL]
ST2/IL1R4 [ng/mL]
TARC/CCL17 [pg/mL]
TIMP-1 [ng/mL]
TGF-b [ng/mL]
TNF-a [pg/mL]
YKL40/CHI3L1 [ng/mL]
Urine LTE4 [pg/mg creatinine]y*

Cluster 1 (n ¼ 119)

Cluster 2 (n ¼ 116)

Cluster 3 (n ¼ 127)

Cluster 4 (n ¼ 104)

Cluster 5 (n ¼ 32)

Late onset, Old,
Less-atopic

Late onset, Old,
Eosinophilic,
Low FEV1,

Early onset,
Long duration,
Atopic,Poorly controlled

Early onset, Young,Female-dominant,AtopicFemale-dominant,
T1/T2 mixed,
Most severe

143.03 (1.76)y25.29 (2.30)
1.16 (1.35)
36.88 (3.67)
19.50 (3.38)
2.28 (1.51)
2.38 (1.45)
14.07 (1.57)
10.50 (1.98)
75.07 (2.77)
170.69 (1.72)
162.60 (1.70)
98.46 (1.43)
8.21 (2.46)
22.84 (2.13)
367.74 (1.43)
66.51 (1.84)
203.13 (1.81)
3.63 (1.72)
258.27 (1.31)
19.05 (1.64)
0.95 (2.18)
22.07 (2.29)
16.98 (1.43)
365.41 (1.59)
6.63 (1.54)
29.28 (1.64)
7.93 (1.56)
609.43 (1.97)
132.14 (1.22)
16.86 (1.36)
3.66 (1.76)
68.92 (2.35)
89.91 (1.90)

161.43 (2.04)
27.22 (2.79)
1.31 (1.39)
32.51 (4.06)
20.05 (3.12)
2.79 (1.90)
2.69 (1.67)
13.96 (1.58)
10.92 (1.87)
68.55 (2.42)
176.15 (1.72)
172.63 (1.94)
95.56 (1.26)
8.32 (2.83)
20.75 (2.15)
368.93 (1.62)
65.21 (1.89)
190.30 (1.67)
4.56 (1.86)
275.94 (1.30)
24.76 (1.83)
1.21 (1.97)
23.94 (2.58)
18.36 (1.57)
378.08 (1.61)
7.09 (1.63)
29.78 (1.67)
7.99 (1.66)
774.24 (2.02)
142.26 (1.22)
17.08 (1.41)
3.93 (1.85)
68.78 (2.25)
137.90 (2.45)

137.95 (1.81)
29.18 (2.38)
1.27 (1.43)
32.30 (3.63)
22.43 (3.17)
2.20 (1.43)
2.58 (1.60)
14.59 (1.73)
9.52 (2.07)
74.86 (2.40)
167.22 (1.69)
162.32 (1.76)
94.85 (1.30)
8.94 (2.48)
24.78 (2.23)
364.95 (1.42)
71.33 (1.89)
201.42 (1.75)
4.06 (1.83)
250.29 (1.27)
22.13 (1.89)
1.14 (2.04)
22.40 (2.29)
17.45 (1.57)
324.00 (1.56)
7.38 (1.59)
29.19 (1.68)
7.50 (1.58)
612.09 (2.08)
137.29 (1.23)
17.60 (1.50)
3.71 (1.62)
52.80 (2.40)
102.45 (2.11)

138.37 (2.00)
36.10 (3.10)
1.01 (1.39)
48.68 (5.02)
25.24 (3.76)
2.45 (1.65)
2.24 (1.37)
16.48 (1.65)
9.21 (2.09)
110.01 (3.47)
194.98 (2.08)
147.01 (1.82)
106.85 (1.72)
13.10 (3.14)
16.46 (1.97)
301.59 (1.65)
72.73 (2.17)
193.53 (1.76)
4.00 (1.81)
247.30 (1.32)
18.96 (1.84)
0.91 (1.94)
30.24 (2.89)
13.38 (1.43)
303.02 (1.46)
7.81 (1.44)
30.82 (1.55)
6.22 (1.66)
514.35 (1.87)
124.33 (1.20)
19.13 (1.31)
4.70 (2.40)
24.74 (1.94)
105.84 (2.16)

148.21 (2.31)
36.60 (2.73)
1.71 (1.45)
47.40 (3.87)
23.14 (3.36)
2.28 (1.50)
2.89 (1.76)
16.77 (1.43)
9.79 (1.89)
88.00 (2.66)
185.41 (1.69)
198.08 (1.58)
95.54 (1.18)
11.86 (2.74)
31.59 (2.21)
379.58 (1.95)
74.26 (2.03)
220.48 (1.58)
4.17 (1.73)
247.90 (1.30)
34.23 (2.14)
1.99 (1.74)
30.69 (2.61)
16.13 (1.58)
304.71 (1.64)
7.70 (1.55)
27.16 (1.71)
9.00 (1.67)
604.09 (2.04)
135.76 (1.21)
20.03 (1.32)
3.73 (1.58)
52.81 (2.33)
99.23 (2.48)

Signiﬁcance(P value)*

0.348
0.043
<0.001
0.128
0.520
0.002
0.005
0.037
0.334
0.007
0.316
0.096
0.089
0.002
<0.001
0.002
0.640
0.675
0.061
0.014
<0.001<0.001
0.039<0.001<0.001
0.062
0.770<0.001<0.001<0.0010.009
0.028<0.001<0.001

Numeric data expressed as geometric mean (geometric SD).
Signiﬁcance level was set at 0.00147 by Bonferroni's correction.

this study, an unsupervised modeling approach of cluster analysis
was employed for phenotyping GINA 4, 5 in Japan to identify ﬁve
phenotypes. Consistent with previous reports,4,6,8,9 this study
identiﬁed phenotypes that were mainly differentiated by the onset,
allergic/non-allergic pathophysiology, and symptom severity.
Therefore, the characteristics that identify GINA 4, 5 phenotypes
may be universally applicable. Most of the old patients who had
relatively late disease onset were classiﬁed in clusters 1 and 2,
which had different disease severities and degree of eosinophilia.
Cluster 1 had a milder disease and had the best asthma control
status, whereas cluster 2 had the highest percentage of AsthmCOPD overlap, declined pulmonary function, higher ACQ Sum 6,
and more evident eosinophilia. Cluster 2 may be a mixed phenotype of both severe eosinophilic asthma with ﬁxed airway
obstruction6,19e21 and Asthma-COPD overlap as eosinophilic COPD
with elevated IgE has been reported to constitute a phenotype in
COPD.6,19e21 Previous report by Konno et al. clearly demonstrated
that there are two distinct smoking asthma phenotypes, one ofwhich presented high blood eosinophils and serum IgE withelevated sinus scores.28 In the present study, cluster 2 may include
both smoking phenotypes identiﬁed by Konno et al. The high proportion of smokers in the present cohort may have inﬂuenced thecluster analysis, where an independent study may be necessary forpatients with asthma who smoked. Notably, doses of ICS and OCS
and use of biologics were not the highest in cluster 2; this may be
due to the more frequent comorbidities and older age of cluster 2

than in the other clusters. Patients with early-onset asthma withfrequent family history of asthma, high rate of atopy, and otherallergic diseases were classiﬁed in clusters 3 and 4. In cluster 3,
observations, such as long asthma duration, the highest BMI, andthe high percentage of current smokers, may have resulted in
airﬂow limitation and poor asthma control, as seen in the high rateof unscheduled visits and acute exacerbations. Conversely, asthma
control was fair in cluster 4, which comprised the youngest patients. Finally, the most severe cases with female dominance andobesity were classiﬁed as cluster 5. Notably, the use of asthma
controllers and medications was intense, and the asthma control
status was the worst in cluster 5. Therefore, cluster 5 may be thetarget for exploring the underlying pathogenesis and developing
new therapeutic strategies.
In addition to the identiﬁcation of clinical phenotypes, analysisof biomarker distribution was of special interest. One compellingﬁnding was that the most severe cluster 5 showed the highest
levels of multiple inﬂammatory mediators, growth factors, andchemokines (i.e., IL-1RA, MMP3, and MMP8) indicative of underlying systemic inﬂammation in cluster 5. Previous reports supported the concept of low-grade systemic inﬂammation in GINA 4,5, such as elevated serum and tissue IL-6 and TNF-a in bronchoalveolar lavage ﬂuid in asthmatic patients.29e32 It was noteworthy that chemokines for many of the inﬂammatory cells as wellas mediators, which may be involved in airway remodeling, i.e.,
MMPs, were signiﬁcantly elevated in cluster 5 suggestive of

72

M. Suzukawa et al. / Allergology International 72 (2023) 63e74

Fig. 3. Tree analysis. Using variables from the cluster analysis, a tree analysis was performed to assign GINA 4, 5 to ﬁve clusters. Numbers in parenthesis under each cluster indicate
the number of patients belonging to each cluster (Clusters 1, 2, 3, 4, and 5).

promoted airway remodeling in this cluster, which would make thedisease unresponsive to treatment.33e35 However, it is noteworthy
that cluster 5 had the highest rate of OCS and biologics use, which
may inﬂuence the level of serum biomarkers. Indeed, blood eosinophils were low and blood neutrophils were high, which may
have been inﬂuenced by OCS use in cluster 5.
Aside from the elevated biomarkers in cluster 5, some biomarkers showed trends that correlated with clinical characteristics.
The high serum IL-5, TARC/CCL17 and urine LTE4 levels in cluster 2,
characterized by eosinophilia, suggested the potential treatment
indications of eosinophil activating mediators for this cluster. The
high levels of TIMP-1 and MMPs 1e3 in cluster 2 may have been
related to smoking or COPD.36e38 In the overweight phenotypes
clusters 3 and 5, results suggested the pathophysiologic role of theadipokine leptin. Furthermore, age may have inﬂuenced the cytokine levels, as demonstrated by the high levels of periostin and
YKL40/CHI3L1 in the older phenotypes clusters 1 and 2.39,40
Interestingly, the tree analysis in this study revealed that thecytokine that was useful in assigning clusters was IL-1RA, which
was high among the more severe clusters 2, 3, and 5. Although therelationships of IL-1RA with asthma and airway inﬂammation havebeen reported,41e43 the precise role of IL-1RA need to be further
evaluated.
One of the purposes of this study was to improve our understanding of the basis for GINA 4 and 5 and to develop an asthmaclassiﬁcation algorithm using comprehensive phenotyping approaches that reﬂect pathophysiology and disease heterogeneity.
The most important variables for assigning the phenotypes wererelated to the age of onset and disease duration; type of inﬂammation based on the eosinophil or neutrophil count; %FEV1;physical stature and comorbidities; medication use; and asthma
control based on symptoms. Previous studies have similarly

identiﬁed age of asthma onset and current disease activity as the
key features in discriminating the phenotypes.44 Because the algorithm that we used in the present study was successful in classifying about 80% of GINA 4, 5 cases into clusters. It may be utilized
to assign GINA 4, 5 to phenotypes for personalized asthma
management.
The present study had several limitations. First, the deﬁnition of
GINA 4, 5 was based on GINA treatment steps 4 or 5. However, thestandard deﬁnition of SA includes a requirement for treatment withhigh-dose ICS plus a second controller and/or systemic corticosteroids for asthma control.2 Therefore, a simple comparison of ourresults with previously reported data may not be accurate. Second,
because the patients in the present cohort were recruited fromnational hospitals in Japan, their disease may have been more
complex with more comorbidities, compared with those in previous cohorts. Third, the information on comorbidities in the present
study was based on patients’ questionnaires; hence, it may havebeen underestimated. Comorbidity with COPD is particularly
important as previous studies have clearly demonstrated theasthma phenotype with COPD.6,19e21 Therefore, further studies on
asthma phenotypes based on accurate medical examination ofcomorbidities would be valuable in the future. Fourth, this study
did not have enough population to perform validation; therefore, it
may be used for generating hypothesis until appropriate validationof phenotypes found in this study is completed. Lastly, because
cluster analysis is a descriptive method, the clusters may have been
deﬁned without an underlying deﬁnite structure. Moreover, thevariables used for cluster analysis might have conditioned thecharacteristics of the identiﬁed clusters.
In conclusion, the present cohort study on asthma revealed thecharacteristics and ﬁve distinct phenotypes of GINA 4, 5 in Japan.
Well-deﬁned differential molecular biomarkers within the clusters

M. Suzukawa et al. / Allergology International 72 (2023) 63e74

may be useful for asthma phenotyping and may lead to new drugs
for GINA 4, 5.
Acknowledgments
The authors thank all the patients and employees of theparticipating hospitals, Mr. Isao Asari and Mr. Masaaki Minegishi
and Ms. Sayaka Igarashi, for their skilled technical assistance, and
Ms. Taeko Kawabe and Ms. Mariko Yoshizawa for their excellent
secretarial work. We are very grateful to Dr. Hiroyuki Nagase, M.D.,
Ph. D., from Teikyo University, for fruitful discussions. This project
was supported by Grant-in-Aid for Clinical Research from the National Hospital Organization in Japan.
Appendix A. Supplementary data
Supplementary data to this article can be found online athttps://doi.org/10.1016/j.alit.2022.06.002.
Conﬂict of interest
MS received Grants from Astellas, AstraZeneca, GlaxoSmithKline, Kyorin, MSD,
Sanoﬁ, and Shionogi, honoraria for lectures from AstraZeneca, Novartis Pharma, andSanoﬁ. YF received Grants from GlaxoSmithKline and Novartis Pharma, honoraria for
lectures from Kyorin, Mylan, Novartis Pharma, Sanoﬁ, ThermoFisher Diagnostics,
and Torii Pharmaceutical. ST received honoraria for lectures from AstraZeneca,
Boehringer Ingelheim Japan, Bristol-Meyers Squibb, GlaxoSmithKline, Kyorin,
Novartis Pharma, Sanoﬁ, and Teijin Pharma. MTa received Grants from GlaxoSmithKline, Novartis Pharma, and Sanoﬁ. The rest of the authors have no conﬂict ofinterest.

Authors' contributions
MS, KO, YF, NK, and MTa designed the study and wrote the manuscript. TE, MA,
YKa, MYo, YKi, TK, KC, YT, KHy, ST, TI, MYa, YH, TSa, YS, YM, YI, ST, TSh, KT, MTs, MO,
KW, MH, GI, and KHi contributed to data collection. HH performed the statisticalanalysis and interpretation of the results. AMS contributed to data management andcuration. All authors have read and approved the ﬁnal manuscript. KO was a primary
investigator for the grant submission.

References
1. Bousquet J, Mantzouranis E, Cruz AA, Aït-Khaled N, Baena-Cagnani CE,
Bleecker ER, et al. Uniform deﬁnition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation
on Severe Asthma. J Allergy Clin Immunol 2010;126:926e38.
2. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International
ERS/ATS guidelines on deﬁnition, evaluation and treatment of severe asthma.
Eur Respir J 2014;43:343e73.
3. Hermosa JL, Sanchez CB, Rubio MC, Minguez MM, Walther JL. Factors associatedwith the control of severe asthma. J Asthma 2010;47:124e30.
4. Haldar P, Pavord ID, Shaw DE, Berry MA, Thomas M, Brightling CE, et al. Cluster
analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008;178:
218e24.
5. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identiﬁcation ofasthma phenotypes using cluster analysis in the severe asthma research program. Am J Respir Crit Care Med 2010;181:315e23.
6. Moore WC, Bleecker ER, Curran-Everett D, Erzurum SC, Ameredes BT,
Bacharier L, et al. Characterization of the severe asthma phenotype by thenational heart, lung, and blood institute's severe asthma research program.
J Allergy Clin Immunol 2007;119:405e13.
7. Schatz M, Hsu JW, Zeiger RS, Chen W, Dorenbaum A, Chipps BE, et al. Phenotypes determined by cluster analysis in severe or difﬁcult-to-treat asthma.
J Allergy Clin Immunol 2014;133:1549e56.
8. Wu W, Bleecker E, Moore W, Busse WW, Castro M, Chung KF, et al. Unsupervised phenotyping of Severe Asthma Research Program participants using
expanded lung data. J Allergy Clin Immunol 2014;133:1280e8.
9. Siroux V, Basagana X, Boudier A, Pin I, Garcia-Aymerich J, Vesin A, et al.
Identifying adult asthma phenotypes using a clustering approach. Eur Respir J
2011;38:310e7.
10. Lefaudeux D, De Meulder B, Loza MJ, Peffer N, Rowe A, Baribaud F, et al. UBIOPRED clinical adult asthma clusters linked to a subset of sputum omics.
J Allergy Clin Immunol 2017;139:1797e807.

73

11. Pavlidis S, Takahashi K, Ng Kee Kwong F, Xie J, Hoda U, Sun K, et al. “T2-high” insevere asthma related to blood eosinophil, exhaled nitric oxide and serum
periostin. Eur Respir J 2019;53:1800938.
12. Kuo CS, Pavlidis S, Loza M, Baribaud F, Rowe A, Pandis I, et al. T-helper cell type2 (Th2) and non-Th2 molecular phenotypes of asthma using sputum transcriptomics in U-BIOPRED. Eur Respir J 2017;49:1602135.
13. Castro-Rodriguez JA, Holberg CJ, Wright AL, Martinez FD. A clinical index todeﬁne risk of asthma in young children with recurrent wheezing. Am J Respir
Crit Care Med 2000;162:1403e6.
14. Ortega H, Li H, Suruki R, Albers F, Gordon D, Yancey S. Cluster analysis andcharacterization of response to mepolizumab. A step closer to personalized
medicine for patients with severe asthma. Ann Am Thorac Soc 2014;11:1011e7.
15. Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, et al.
Lebrikizumab treatment in adults with asthma. N Engl J Med 2011;365:1088e98.
16. Djukanovic R, Wilson SJ, Kraft M, Jarjour NN, Steel M, Chung KF, et al. Effects oftreatment with anti-immunoglobulin E antibody omalizumab on airway
inﬂammation in allergic asthma. Am J Respir Crit Care Med 2004;170:583e93.
17. Hanania NA, Wenzel S, Rosen K, Hsieh HJ, Mosesova S, Choy DF, et al. Exploring
the effects of omalizumab in allergic asthma: an analysis of biomarkers in the
EXTRA study. Am J Respir Crit Care Med 2013;187:804e11.
18. Kawagishi Y, Mita H, Taniguchi M, Maruyama M, Oosaki R, Higashi N, et al.
Leukotriene C4 synthase promoter polymorphism in Japanese patients withaspirin-induced asthma. J Allergy Clin Immunol 2002;109:936e42.
19. The ENFUMOSA cross-sectional European multicentre study of the clinicalphenotype of chronic severe asthma. European Network for Understanding
Mechanisms of Severe Asthma. Eur Respir J 2003;22:470e7.
20. Shaw DE, Sousa AR, Fowler SJ, Fleming LJ, Roberts G, Corﬁeld J, et al. Clinicaland inﬂammatory characteristics of the European U-BIOPRED adult severe
asthma cohort. Eur Respir J 2015;46:1308e21.
21. Wang E, Wechsler ME, Tran TN, Heaney LG, Jones RC, Menzies-Gow AN, et al.
Characterization of severe asthma worldwide: data from the international
severe asthma Registry. Chest 2020;157:790e804.
22. Nagase H, Adachi M, Matsunaga K, Yoshida A, Okoba T, Hayashi N, et al.
Prevalence, disease burden, and treatment reality of patients with severe,
uncontrolled asthma in Japan. Allergol Int 2020;69:53e60.
23. Kaneko Y, Masuko H, Sakamoto T, Iijima H, Naito T, Yatagai Y, et al. Asthma
phenotypes in Japanese adults - their associations with the CCL5 ADRB2 genotypes. Allergol Int 2013;62:113e21.
24. Gupta S, Hartley R, Khan UT, Singapuri A, Hargadon B, Monteiro W, et al.
Quantitative computed tomography-derived clusters: redeﬁning airway
remodeling in asthmatic patients. J Allergy Clin Immunol 2014;133:729e38. e718.
25. Moore WC, Hastie AT, Li X, Li H, Busse WW, Jarjour NN, et al. Sputum
neutrophil counts are associated with more severe asthma phenotypes using
cluster analysis. J Allergy Clin Immunol 2014;133:1557e63. e1555.
26. Baines KJ, Simpson JL, Wood LG, Scott RJ, Gibson PG. Transcriptional phenotypes of asthma deﬁned by gene expression proﬁling of induced sputum
samples. J Allergy Clin Immunol 2011;127:153e60. 160.e1-9.
27. Yan X, Chu JH, Gomez J, Koenigs M, Holm C, He X, et al. Noninvasive analysis of
the sputum transcriptome discriminates clinical phenotypes of asthma. Am J
Respir Crit Care Med 2015;191:1116e25.
28. Konno S, Taniguchi N, Makita H, Nakamaru Y, Shimizu K, Shijubo N, et al.
Distinct phenotypes of smokers with ﬁxed airﬂow limitation identiﬁed bycluster analysis of severe asthma. Ann Am Thorac Soc 2018;15:33e41.
29. Yokoyama A, Kohno N, Fujino S, Hamada H, Inoue Y, Fujioka S, et al. Circulatinginterleukin-6 levels in patients with bronchial asthma. Am J Respir Crit Care
Med 1995;151:1354e8.
30. Bradding P, Roberts JA, Britten KM, Montefort S, Djukanovic R, Mueller R, et al.
Interleukin-4, -5, and -6 and tumor necrosis factor-alpha in normal and asthmatic airways: evidence for the human mast cell as a source of these cytokines.
Am J Respir Cel Mol Biol 1994;10:471e80.
31. Higashimoto Y, Yamagata Y, Taya S, Iwata T, Okada M, Ishiguchi T, et al. Systemic inﬂammation in chronic obstructive pulmonary disease and asthma:
similarities and differences. Respirology 2008;13:128e33.
32. Howarth PH, Babu KS, Arshad HS, Lau L, Buckley M, McConnell W, et al.
Tumour necrosis factor (TNFalpha) as a novel therapeutic target in symptomatic corticosteroid dependent asthma. Thorax 2005;60:1012e8.
33. Dahlen B, Shute J, Howarth P. Immunohistochemical localisation of the matrix
metalloproteinases MMP-3 and MMP-9 within the airways in asthma. Thorax
1999;54:590e6.
€ E, Reintam MA, Salo T, Sorsa T, et al. Airway obstruction
34. Prikk K, Maisi P, Pirila
correlates with collagenase-2 (MMP-8) expression and activation in bronchialasthma. Lab Invest 2002;82:1535e45.
35. Lavigne MC, Thakker P, Gunn J, Wong A, Miyashiro JS, Wasserman AM, et al.
Human bronchial epithelial cells express and secrete MMP-12. Biochem Biophys
Res Commun 2004;324:534e46.
36. Ostridge K, Williams N, Kim V, Bennett M, Harden S, Welch L, et al. Relationshipbetween pulmonary matrix metalloproteinases and quantitative CT markers ofsmall airways disease and emphysema in COPD. Thorax 2016;71:126e32.
37. Segura-Valdez L, Pardo A, Gaxiola M, Uhal BD, Becerril C, Selman M. Upregulation of gelatinases A and B, collagenases 1 and 2, and increased parenchymal
cell death in COPD. Chest 2000;117:684e94.

74

M. Suzukawa et al. / Allergology International 72 (2023) 63e74

38. Culpitt SV, Rogers DF, Traves SL, Barnes PJ, Donnelly LE. Sputum matrix metalloproteases: comparison between chronic obstructive pulmonary disease andasthma. Respir Med 2005;99:703e10.
39. Johansen JS, Pedersen AN, Schroll M, Jørgensen T, Pedersen BK, Bruunsgaard H.
High serum YKL-40 level in a cohort of octogenarians is associated withincreased risk of all-cause mortality. Clin Exp Immunol 2008;151:260e6.
40. Sakazaki Y, Hoshino T, Takei S, Sawada M, Oda H, Takenaka S, et al. Overexpression of chitinase 3-like 1/YKL-40 in lung-speciﬁc IL-18-transgenic mice,smokers and COPD. PLoS One 2011;6:e24177.
41. Mao XQ, Kawai M, Yamashita T, Enomoto T, Dake Y, Sasaki S, et al. Imbalance
production between interleukin-1beta (IL-1beta) and IL-1 receptor

antagonist (IL-1Ra) in bronchial asthma. Biochem Biophys Res Commun
2000;276:607e12.
42. Sousa AR, Lane SJ, Nakhosteen JA, Lee TH, Poston RN. Expression of interleukin1 beta (IL-1beta) and interleukin-1 receptor antagonist (IL-1ra) on asthmatic
bronchial epithelium. Am J Respir Crit Care Med 1996;154:1061e6.
43. Hernandez ML, Mills K, Almond M, Todoric K, Aleman MM, Zhang H, et al. IL-1
receptor antagonist reduces endotoxin-induced airway inﬂammation in
healthy volunteers. J Allergy Clin Immunol 2015;135:379e85.
44. Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med 2012;18:716e25.