cancers
ArticleEffects of In-Hospital Exercise on Frailty in Patients with
Hepatocellular Carcinoma
Jin Tsuchihashi 1 , Shunji Koya 2 , Keisuke Hirota 2 , Noboru Koga 3 , Hayato Narao 4 , Manabu Tomita 5 ,Takumi Kawaguchi 6, * , Ryuki Hashida 2,7 , Dan Nakano 6 , Tsubasa Tsutsumi 6 , Sachiyo Yoshio 8 ,Hiroo Matsuse 2,7 , Taku Sanada 9 , Kazuo Notsumata 9 and Takuji Torimura 6
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Citation: Tsuchihashi, J.; Koya, S.;
Hirota, K.; Koga, N.; Narao, H.;
Tomita, M.; Kawaguchi, T.; Hashida,R.; Nakano, D.; Tsutsumi, T.; et al.
Effects of In-Hospital Exercise on
Frailty in Patients with Hepatocellular
Carcinoma. Cancers 2021, 13, 194.
https://doi.org/10.3390/cancers
13020194
Received: 25 October 2020
Accepted: 4 January 2021
Published: 7 January 2021
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

*

Division of Rehabilitation, Fukui-ken Saiseikai Hospital, Fukui 918-8503, Japan;tsuchihashi.jin8044@fukui.saiseikai.or.jp
Division of Rehabilitation, Kurume University Hospital, Kurume 830-0011, Japan;
kouya_shunji@kurume-u.ac.jp (S.K.); hirota_keisuke@kurume-u.ac.jp (K.H.);hashida_ryuuki@med.kurume-u.ac.jp (R.H.); matsuse_hiroh@kurume-u.ac.jp (H.M.)
Department of Rehabilitation, Chikugo City Hospital, Chikugo 833-0041, Japan;
koga.nationalhospital@gmail.com
Department of Rehabilitation, Yame General Hospital, Yame 834-0034, Japan; hayatonarao198071@gmail.com
Department of Rehabilitation, Saga Central Hospital, Saga 849-8522, Japan; sp4u7m99@ray.ocn.ne.jp
Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine,
Kurume 830-0011, Japan; nakano_dan@med.kurume-u.ac.jp (D.N.);
tsutsumi_tsubasa@med.kurume-u.ac.jp (T.T.); tori@med.kurume-u.ac.jp (T.T.)
Department of Orthopedics, Kurume University School of Medicine, Kurume 830-0011, Japan
Department of Liver Disease, Research Center for Hepatitis and Immunology, National Center for Global
Health and Medicine, Kohnodai 272-8516, Japan; sachiyo@hospk.ncgm.go.jp
Department of General Internal Medicine, Fukui-ken Saiseikai Hospital, Fukui 918-8503, Japan;
sanada.taku3054@fukui.saiseikai.or.jp (T.S.); notsumata.kazuo6017@fukui.saiseikai.or.jp (K.N.)
Correspondence: takumi@med.kurume-u.ac.jp; Tel.: +81-942-31-7561

Simple Summary: Frailty including physical inactivity is associated with the survival of patientswith hepatocellular carcinoma (HCC). We aimed to investigate the effects of in-hospital exercise on
frailty in patients with HCC. This was a multi-center observational study. Patients with HCC wereclassified into exercise (n = 114) and non-exercise (n = 67) groups. The exercise group was treatedwith a mixture of aerobic and resistance exercises (20–40 min/day, median four days). Frailty wasassessed using the liver frailty index (LFI). In multivariate analysis, exercise (odds ratio (OR) 2.38,
95% confidence interval (CI) 1.240–4.570, p = 0.0091) as an independent factor for the improvement of
LFI. In the decision-tree analysis, exercise was identified as an initial classifier associated with the
improvement of LFI. We demonstrated that in-hospital exercise improved frailty in patients with
HCC, which was confirmed by propensity score matching analysis. Thus, in-hospital exercise may
be beneficial for improving physical function in patients with HCC.
Abstract: Frailty including physical inactivity is associated with the survival of patients with hepatocellular carcinoma (HCC). We aimed to investigate the effects of in-hospital exercise on frailty inpatients with HCC. This was a multi-center observational study. Patients with HCC were classified
into exercise (n = 114) and non-exercise (n = 67) groups. The exercise group was treated with amixture of aerobic and resistance exercises (20–40 min/day, median four days). Frailty was assessedusing the liver frailty index (LFI). Factors for changes in LFI were examined by multivariate anddecision-tree analyses. The factors were also examined after propensity score matching. Duringhospitalization, LFI was significantly improved in the exercise group compared to the non-exercisegroup (∆LFI −0.17 vs. −0.02, p = 0.0119). In multivariate analysis, exercise (odds ratio (OR) 2.38, 95%
confidence interval (CI) 1.240–4.570, p = 0.0091) and females (OR 2.09; 95%CI, 1.062–4.109; p = 0.0328)
were identified as independent factors for the improvement of LFI. In the decision-tree analysis,
exercise was identified as an initial classifier associated with the improvement of LFI. Similar findings
were also seen in the propensity score matching analyses. We demonstrated that in-hospital exercise
improved frailty in patients with HCC. Thus, in-hospital exercise may be beneficial for improving
physical function in patients with HCC.

Cancers 2021, 13, 194. https://doi.org/10.3390/cancers13020194https://www.mdpi.com/journal/cancers

Cancers 2021, 13, 194

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Keywords: frailness; physical dysfunction; rehabilitation; hepatoma

1. Introduction
Frailty is a geriatric syndrome of physiological decline that includes physical inactivity [1]. Frailty increases the risk of other geriatric syndromes and adverse health outcomesin older populations [2]. The incidence of frailty is especially high in elder patients withcancer. Over half of elder patients with cancer have frailty or pre-frailty because of bothcancer itself and the therapies offered [3]. Frailty has been shown to predict the extent ofmuscle atrophy [4,5] as well as poorer mental and physical conditions in patients withchronic liver disease [6]. Frailty is also associated with the length of hospital stay in patientswith hepatocellular carcinoma (HCC) who underwent orthotopic liver transplantation [7].
In addition, frailty is associated with poor prognosis in patients with HCC [8].
The liver frailty index (LFI) has recently been created to objectively quantify frailty inpatients with chronic liver disease [9]. The LFI is calculated using three performance-based
physical tests consisting of grip strength, chair stands, and balance [9]. According to the
LFI score, patients are classified as robust, pre-frail, or frail [9]. We previously reported
that pre-frail/frail determined by LFI was independent of the risk of muscle atrophy inpatients with HCC [4]. The LFI predicts muscle atrophy with high sensitivity, even inpatients with normal grip strength [4]. In addition, frailty assessed by LFI is reported to
be independently associated with liver transplantation waitlist mortality [10]. Thus, LFIscores can be used to objectively quantify the risk of adverse outcomes, including mortality,in patients with chronic liver disease.
Muscle mass is known to significantly decrease during hospitalization for HCC treatment [11]. Exercise is a fundamental treatment for frailty and has been reported to improvephysical frailty such as functional/aerobic capacity and sarcopenia in patients with chronic
liver disease [12]. In Japan, in-hospital exercise for patients with cancer is an approved
health care service by the Japanese Ministry of Health, Labor, and Welfare [13]. Recently,
we developed an in-hospital exercise program for patients with HCC, which consists ofstretching, strength training, balance practice, and aerobic training [14]. We previously
described that in-hospital exercise did not worsen liver function [14] and increased muscle
mass in patients with HCC who underwent transcatheter arterial chemoembolization(TACE) [15]. However, the impact of in-hospital exercise on frailty in patients with HCC
remains unclear.
This study aimed to investigate the effects of in-hospital exercise on frailty assessedby LFI in patients with HCC.
2. Results
2.1. Differences in Patient Characteristics between the Exercise and Non-Exercise Groups
Patient characteristics are summarized in Table 1. Patients in the exercise group weresignificantly older than those in the non-exercise group. There was no significant differencein the female-to-male ratio or BMI between the two groups. No significant difference wasseen in the etiology of liver disease, treatment of HCC, or tumor nodes metastasis (TNM)
stage between the two groups. There was no significant difference in the albumin-bilirubin(ALBI) grade or the prevalence of branched-chain amino acids (BCAA) supplementation
between the two groups. No significant difference was seen in biochemical examinations,
including hemoglobin A1c (HbA1c) value and estimated glomerular filtration rate (eGFR),
between the exercise and the non-exercise groups (Table 1).

Cancers 2021, 13, 194

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Table 1. Patients’ characteristics.

Variable
NumberAge (years)
Sex (female/male)
Body mass index (kg/m2 )Etiology of liver disease(Alcohol/HBV/HCV/
NAFLD/Others)
Treatment of HCC(HAIC/TACE/Sorafenib/
Ramucirumab/
Lenvatinib/Others)
TNM stage(I/II/III/IVa/IVb)
Albumin-bilirubin (ALBI)
grade (1/2/3)
BCAA supplementation(yes/no)LFI (score)
LFI(Robust/Pre-frail-Frail)
Sarcopenia(Sarcopenia/Nonsarcopenia)
Barthel Index (0–100)

Reference
Value
N/A
N/A
N/A
18.5–24.9
N/A

N/A

N/A
N/A
N/A
<3.20
N/A
N/A
N/A

ExerciseMedian (IQR)
114
79 (74–83)
42.1%/57.9%(48/66)
22.9 (21.0–25.2)
7.9%/11.4%/57.0%/
14.0%/9.7%(9/13/65/16/11)
3.5%/85.1%/1.8%/0.9%/7.9%/0.9%(4/97/2/1/9/1)
16.7%/37.7%/35.1%/6.1%/4.4%(19/43/40/7/5)
67.5%/28.1%/4.4%(77/32/5)
22.8%/77.2%(26/88)3.84 (3.27–4.27)
20.2%/79.8%(23/91)
32.5%/67.5%(37/77)

Non-Exercise
Range(Min–Max)
N/A
57–94
N/A
15.6–32.7
N/A

N/A

N/A
N/A
N/A
2.37–5.48
N/A
N/A
50–100Median (IQR)
67
76 (70–81)
38.8%/61.2%(26/41)
23.6 (21.5–25.8)
16.4%/7.5%/58.2%/4.5%/13.4%(11/5/39/3/9)
0.0%/98.5%/0.0%/0.0%/1.5%/0.0%(0/66/0/0/1/0)
13.4%/38.8%/
31.3%/9.0%/7.5%(9/26/21/6/5)
65.7%/32.8%/1.5%(44/22/1)
35.8%/64.2%(24/43)
3.57 (3.08–4.03)
28.4%/71.6%(19/48)22.4%/77.6%(15/52)Range(Min–Max)

p-Value

N/A
49–92
N/A
18.1–31.3

N/A
0.02000.66290.2118N/A

0.1048N/A

0.1227

N/A

0.7975

N/A

0.4943

N/A

0.0587

1.95–5.51

0.0234N/A

0.3368N/A

0.148455–1000.0342

SMI (low/high)

N/A

VFA (cm2 )Hospitalization (days)
Exercise days
Exercise implementation
rate (%)
Biochemical examinations
alpha-fetoprotein (AFP)(ng/mL)des-γ-carboxy
prothrombin (DCP)(mAU/mL)
AST (IU/L)
ALT (IU/L)
Lactate dehydrogenase(IU/L)ALP (IU/L)
GGT (IU/L)
Cholinesterase (U/L)
Total protein (g/dL)
Albumin (g/dL)
Total bilirubin (mg/dL)
BUN (mg/dL)
Creatinine (mg/dL)
eGFR (mL/min/1.73 m2 )Sodium (mmol/L)
Total cholesterol (mg/dL)
Triglyceride (mg/dL)

N/A
N/A
N/A

100 (100–100)
49.1%/50.9%(56/58)86.9 (54.5–152.3)
9 (9–11)
4 (3–5)

N/A

0.0770

9.7–310.9
6–24
1–13

100 (100–100)
62.7%/37.3%(42/25)100.4 (72.4–120.0)
12 (11–13)
N/A

17.6–206.5
6–22
N/A

0.63270.0001
N/A

N/A

100.0 (75.0–100.0)

25.0–100.0

N/A

N/A

N/A

≤10.0

10.0 (3.6–85.4)

1.0–64458.0

11.7 (3.3–275.3)

1.0–146556.0

0.8543≤40.0

49.0 (22.0–239.0)

6.3–292689.0

110.5 (24.8–960.5)

1.1–138123.0

0.0600

13–30
10–30

32 (25–43)
23 (18–33)

4–111
5–126

33 (26–47)
23 (14–33)

16–152
6–139

0.41980.4038120–240205 (183–234)

114–428204 (189–229)

153–487

0.7743

115–359
13–64
201–421
6.6–8.1
4.1–5.1
0.20–1.20
8.0–22.0
0.65–1.07>90.0
138–145
150–199
35–149317 (239–413)
47 (29–85)
208 (172–238)
7.1 (6.8–7.4)
3.8 (3.3–4.1)
0.70 (0.50–1.00)
18.2 (13.2–22.8)
0.82 (0.67–1.00)
63.5 (49.6–74.3)
140 (139–142)
167 (144–193)
93 (73–126)

150–3021
12–65973–411
5.9–8.7
2.0–4.7
0.30–2.90
7.0–59.0
0.44–5.11
7.0–140.9
127–146
89–23529–305372 (252–495)
53 (35–90)
214 (133–259)
7.2 (6.7–7.6)
3.8 (3.3–4.2)
0.80 (0.60–1.10)
17.0 (12.0–21.0)
0.79 (0.64–0.92)
66.5 (54.2–81.7)
140 (139–142)
170 (145–198)
97 (76–133)

148–967
10–421
63–380
5.9–8.2
2.6–4.6
0.30–3.20
10.0–53.0
0.41–3.80
9.5–116.3
130–147
104–267
27–3010.2476
0.52930.91940.38030.79320.27720.24500.39410.07260.58040.64820.2524

N/A

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Table 1. Cont.

Variable
Creatine kinase (U/L)
Glucose (mg/dL)
HbA1c (%)
Ammonia (µg/dL)
Prothrombin activity (%)
Hemoglobin (g/dL)
White blood cellcount (/µL)
Platelet count(× 103 /mm3 )Neutrophil/Lymphocyte
Ratio

Exercise

Non-Exercise

Reference
Value

Median (IQR)

Range(Min–Max)

Median (IQR)

Range(Min–Max)

p-Value

59–2480–99
4.3–5.8
13–86
80–12013.7–16.8

88 (60–129)
113 (97–135)
6.1 (5.7–6.6)
46 (35–67)
93 (84–103)
12.5 (10.8–13.6)

17–65665–495
5.1–10.5
17–18030–130
7.3–15.7

81 (58–124)
111 (99–152)
6.1 (5.7–6.8)
41 (31–70)
96 (79–108)
12.6 (10.5–13.9)

31–33882–316
4.7–9.3
13–130
11–130
8.1–16.2

0.5646
0.6741
0.99420.27800.81350.89943300–8600

4400 (3500–5450)

1000–8900

4600 (3300–5900)

500–8700

0.910415.8–34.8

134.0 (93.0–179.5)

62.0–368.0

129.0 (80.0–180.0)

40.0–419.0

0.4327

0.86–2.77

2.46 (1.71–3.67)

0.62–11.17

2.44 (1.68–3.45)

0.50–11.71

0.5402Note. Data are expressed as median (interquartile range (IQR)), range, or number. Abbreviations: N/A; not applicable, HBV; hepatitis B
virus, HCV; hepatitis C virus, NAFLD; non-alcoholic fatty liver disease, HCC; hepatocellular carcinoma, HAIC; hepatic arterial infusion
chemotherapy, TACE; transcatheter arterial chemoembolization, TNM; tumor nodes metastasis, BCAA; branched-chain amino acids,
LFI; liver frailty index, SMI; skeletal muscle index, VFA; visceral fat area, AFP; alpha-fetoprotein, DCP; des-γ-carboxy prothrombin,
AST; aspartate aminotransferase, ALT; alanine aminotransferase, ALP; alkaline phosphatase, GGT; gamma-glutamyl transpeptidase,
BUN; blood urea nitrogen, eGFR; estimated glomerular filtration rate, HbA1c; hemoglobin A1c, PT–INR; prothrombin time international
normalized ratio.

In the exercise group, the LFI score was significantly higher than in the non-exercisegroup at baseline; however, there was no significant difference in the prevalence of prefrail/frail between the two groups (Table 1). There was no significant difference in thepresence of sarcopenia or visceral fat area (VFA) between the two groups. The hospitalization period was significantly shorter in the exercise group than in the non-exercise group.
In the exercise group, the median exercise time was four days and the median exercise
implementation rate was 100% (Table 1).
2.2. Differences in LFI Changes during Hospitalization between the Exercise and
Non-Exercise Groups

Cancers 2021, 13, x

Changes in LFI were evaluated based on the differences between the admission anddischarge days. The ∆LFI was significantly lower in the exercise group than in the nonexercise group (Figure 1).
5 of 18

Figure 1. The difference in ΔLFI between the exercise group and the non-exercise group. Abbrevi-

ations: LFI; liver1.
frailtyindex. difference in ∆LFI between the exercise group and the non-exercise group. AbbreviaFigureThe
2.3. Logistic Regression
Analysis andDecision-TreeAnalysis for Improvement of LFItions:
LFI; liver
frailtyindex.

The independent factors associated with an improvement in LFI are summarized in
Figure 2A. Group, sex, and ALBI grade were selected by stepwise regression, and the inhospital exercise group and females were identified as independent factors associatedwith an improvement of LFI (Figure 2A).

Cancers 2021, 13, 194

5 of 162.3. Logistic Regression Analysis and Decision-Tree Analysis for Improvement of LFICancers 2021, 13, x

The independent factors associated with an improvement in LFI are summarized inof 18
Figure 2A. Group, sex, and ALBI grade were selected by stepwise regression, and6 thein-hospital exercise group and females were identified as independent factors associatedwith an improvement of LFI (Figure 2A).

Figure 2. Factors associated with improvement of LFI. (A) Logistic regression analysis for improvement of LFI, (B) decisionFigure
2. Factors
withofimprovementof LFI.
Logistic
regression
LFI, (B)withdecitreealgorithm
for associatedimprovement
LFI in patientswith(A)HCC.
The piegraphs analysis
indicate fortheimprovement
proportion ofofpatientssion-tree
algorithm
forimprovement
of
LFI
in
patients
with
HCC.
The
pie
graphsindicatetheproportionofpatients
withimprovement in LFI (white) and patients without improvement in LFI (black). Abbreviations: LFI; liver frailty index, HCC;
improvement
in
LFI(white)andpatients
without
improvementin
LFI(black).
Abbreviations:
LFI;
liver
frailtyindex,
hepatocellular carcinoma.
HCC; hepatocellular carcinoma.

To clarify the profile associated with an improvement in LFI, a decision-tree algorithm was created using three divergence variables and patients were classified into four
profiles (Figure 2B). The group was identified as the initial divergence variable forCancers 2021, 13, 194

6 of 16

To clarify the profile associated with an improvement in LFI, a decision-tree algorithm
was created using three divergence variables and patients were classified into four profiles(Figure 2B). The group was identified as the initial divergence variable for changes in LFI.
An improvement in LFI was seen in 74% of patients in the exercise group (Profile 1 inFigure 2B). On the other hand, an improvement in LFI was seen in 54% of patients in the
non-exercise group. Among patients in the non-exercise group, sex was selected as thesecond divergence variable for changes in LFI. An improvement in LFI was seen in 73% offemales and 41% of males (Profile 2 in Figure 2B). Among females, BCAA supplementation
was selected as the third divergence variable for changes in LFI. An improvement in LFI
was seen in 89% of patients with BCAA supplementation (Profile 3 in Figure 2B), while
improvement in LFI was seen in 65% of patients with no BCAA supplementation (Profile 4
in Figure 2B).
In this analysis, the following factors were not identified as divergence variables for
improvement of LFI: age, BMI, ALBI grade, TNM stage, presence of sarcopenia, VFA, andhospitalization period.
2.4. Differences in Patient Characteristics between the Exercise and Non-Exercise Groups after
Propensity Score Matching
Patient characteristics after propensity score matching are summarized in Table 2.
Propensity scores for all patients were estimated using the following baseline characteristics
as covariates: age, sex, and BMI. No significant difference was seen in the etiology of liverdisease, treatment of HCC, or TNM stage between the two groups. There was no significant
difference in ALBI grade or the prevalence of BCAA supplementation between the twogroups. No significant difference was seen in biochemical examinations between theexercise and the non-exercise groups, except for blood ammonia levels (Table 2).
Table 2. Patients’ characteristics after propensity score matching.

Variable

Reference
Value

NumberAge (years)

N/A
N/A

Sex (female/male)

N/A

Body mass index (kg/m2 )Etiology of liver disease(Alcohol/HBV/HCV/
NAFLD/Others)
Treatment of HCC(HAIC/TACE/Sorafenib/
Lenvatinib/Other)

18.5–24.9
N/A

N/A

TNM stage(I/II/III/IVa/IVb)

N/A

ALBI grade (1/2/3)

N/A

BCAA supplementation(yes/no)LFI
Frailty determination by
LFI(Robust/Pre-frail-Frail)
Sarcopenia(Sarcopenia/Nonsarcopenia)
Barthel Index (0–100)

N/A
<3.20

ExerciseMedian (IQR)
59
77 (73–81)
33.9%/66.1%(20/39)23.2 (21.0–25.9)
6.8%/15.2%/50.9%/15.2%/11.9%(4/9/30/9/7)
1.7%/89.8%/1.7%/5.1%/1.7%(1/53/1/3/1)
15.2%/39.0%/
33.9%/5.1%/6.8%(9/23/20/3/4)
64.4%/30.5%/5.1%(38/18/3)
23.7%/76.3%(14/45)3.80 (3.22–4.30)

Non-Exercise
Range(Min–Max)
N/A
59–94
N/A
17.1–31.3
N/A

N/A

N/A
N/A
N/A
2.37–4.87

Median (IQR)
59
77 (72–81)
39.0%/61.0%(23/36)23.5 (21.4–25.1)
18.6%/6.8%/55.9%/5.1%/13.6%(11/4//33/3/8)
0.0%/98.3%/0.0%/1.7%/0.0%(0/58/0/1/0)
10.1%/44.1%/33.9%/6.8%/5.1%(6/26/20/4/3)
67.0%/28.8%/1.7%(41/17/1)
32.2%/67.8%(19/40)3.51 (3.08–4.10)

Range(Min–Max)

p-Value

N/A
58–92

N/A
0.9227N/A

0.5661

18.1–31.3

0.8866

N/A

0.0780N/A

0.3764N/A

0.8991

N/A

0.5648N/A

0.3051

2.21–5.51

0.1230N/A

22.0%/78.0%(13/46)N/A

28.8%/71.2%(17/42)

N/A

0.5382

N/A

22.0%/78.0%(13/46)N/A

25.4%/74.6%(15/44)N/A

0.6652

N/A

100 (100–100)

65–100100 (100–100)

55–1000.2043

Cancers 2021, 13, 194

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Table 2. Cont.

Variable

Reference
Value

Median (IQR)

Non-Exercise
Range(Min–Max)

Median (IQR)

Range(Min–Max)

p-Value

N/A

0.039910.1–252.0
6–24
1–13

67.8%/32.2%(40/19)98.3 (61.4–122.6)
12 (11–13)
N/A

17.6–206.5
6–20
N/A

0.53790.0001
N/A

83.0 (75.0–100.0)

25.0–100.0

N/A

N/A

N/A

≤10.0
≤40.0
13–30
10–30

11.3 (4.1–147.0)
54.0 (22.0–450.0)
35 (26–44)
28 (18–36)

1.0–64458.0
6.3–292689.0
14–103
5–126

12.7 (2.8–267.0)
107.0 (25.0–841.0)
34 (26–47)
23 (14–33)

1.0–146556.0
1.1–86289.0
16–152
8–139

0.56110.2876
0.72840.1171

120–240200 (182–243)

143–428205 (189–229)

153–487

0.8230

115–359
13–64
201–421
6.6–8.1
4.1–5.1
0.20–1.20
8.0–22.0
0.65–1.07>90.0
138–145
150–199
35–14959–2480–99
4.3–5.8
13–86
80–12013.7–16.8

316 (229–424)
52 (31–112)
218 (147–239)
7.1 (6.8–7.4)
3.8 (3.3–4.1)
0.80 (0.50–1.00)
18.5 (13.0–22.9)
0.82 (0.68–0.97)
65.8 (52.2–77.0)
140 (139–142)
170 (145–196)
93 (66–125)
97 (66–147)
110 (96–134)
6.1 (5.7–6.6)
52 (39–85)
92 (84–105)
12.5 (10.8–13.3)

150–3021
13–65982–411
5.9–8.7
2.0–4.4
0.30–2.90
7.0–59.0
0.44–2.32
21.9–140.9
134–144
89–23529–305
17–264
71–205
5.1–10.5
24–18030–130
7.3–15.6

363 (239–447)
53 (35–91)
214 (145–261)
7.2 (6.8–7.6)
3.9 (3.3–4.2)
0.80 (0.60–1.00)
17.0 (12.0–22.0)
0.80 (0.64–0.95)
64.6 (53.2–81.7)
140 (139–142)
169 (145–206)
99 (84–139)
82 (64–127)
111 (99–149)
6.1 (5.7–6.8)
38 (30–65)
97 (80–109)
12.6 (10.6–13.5)

148–967
10–421
63–380
5.9–8.2
2.6–4.6
0.30–3.20
10.0–53.0
0.41–3.80
9.5–116.3
130–147
124–267
27–301
31–33882–304
4.7–9.3
13–130
11–130
8.1–15.2

0.46250.69260.9036
0.24580.52060.46040.28260.71030.61100.97180.90240.12850.4887
0.33510.75130.01050.73330.71033300–8600

4200 (3500–5300)

1000–8900

4700 (3300–5900)

500–8700

0.480515.8–34.8

132.0 (94.0–174.0)

62.0–368.0

129.0 (90.0–178.0)

46.0–365.0

0.9828

0.86–2.77

2.37 (1.68–3.36)

0.62–11.2

2.44 (1.68–3.40)

0.50–11.71

0.8568

N/A
N/A
N/A

49.2%/50.9%(29/30)96.1 (66.2–150.0)
9 (9–11)
4 (3–5)

N/A

SMI (low/high)

N/A

VFA (cm2 )Hospitalization (days)
Exercise days
Exercise implementation
rate (%)
Biochemical examinations
AFP (ng/mL)
DCP (mAU/mL)
AST (IU/L)
ALT (IU/L)
Lactate dehydrogenase(IU/L)ALP (IU/L)
GGT (IU/L)
Cholinesterase (U/L)
Total protein (g/dL)
Albumin (g/dL)
Total bilirubin (mg/dL)
BUN (mg/dL)
Creatinine (mg/dL)
eGFR (mL/min/1.73 m2 )Sodium (mmol/L)
Total cholesterol (mg/dL)
Triglyceride (mg/dL)
Creatine kinase (U/L)
Glucose (mg/dL)
HbA1c (%)
Ammonia (µg/dL)
Prothrombin activity (%)
Hemoglobin (g/dL)
White blood cellcount (/µL)
Platelet count(× 103/mm3 )Neutrophil/lymphocyte
Ratio

Exercise

N/A

Note. Data are expressed as median (interquartile range (IQR)), range, or number. Abbreviations: N/A; not applicable, HBV; hepatitis B
virus, HCV; hepatitis C virus, NAFLD; non-alcoholic fatty liver disease, HCC; hepatocellular carcinoma, HAIC; hepatic arterial infusion
chemotherapy, TACE; transcatheter arterial chemoembolization, TNM; tumor nodes metastasis, BCAA; branched-chain amino acids,
LFI; liver frailty index, SMI; skeletal muscle index, VFA; visceral fat area, AFP; alpha-fetoprotein, DCP; des-γ-carboxy prothrombin,
AST; aspartate aminotransferase, ALT; alanine aminotransferase, ALP; alkaline phosphatase, GGT; gamma-glutamyl transpeptidase,
BUN; blood urea nitrogen, eGFR; estimated glomerular filtration rate, HbA1c; hemoglobin A1c, PT–INR; prothrombin time international
normalized ratio.

There was no significant difference in LFI score and the prevalence of pre-frail/frail
between the two groups. There was no significant difference in the presence of sarcopenia
between the two groups. The hospitalization period was significantly shorter in the exercisegroup than in the non-exercise group. In the exercise group, the median exercise time wasfour days and the median exercise implementation rate was 83.0% (Table 2).

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between the two groups. The hospitalization period was significantly shorter in the exercise group than in the non-exercise group. In the exercise group, the median exercise time
was four days and the median exercise implementation rate was 83.0% (Table 2).

2.5. Differences in LFI Changes during Hospitalization between the Exercise and Non-Exercise
Groups after Propensity Score Matching

2.5. Differences in LFI Changes during Hospitalization between the Exercise and Non-Exercise
Groups after Propensity Score Matching

The ∆LFI was significantly lower in the exercise group than in the non-exercise group,
even after propensity score matching (Figure 3).

The ΔLFI was significantly lower in the exercise group than in the non-exercisegroup, even after propensity score matching (Figure 3).

Figure 3. The difference of ∆LFI between the exercise group and the non-exercise group after
propensity score matching. Abbreviations: LFI; liver frailty index.

Figure 3. The difference of ΔLFI between the exercise group and the non-exercise group after propensity score matching. Abbreviations: LFI; liver frailty index.

2.6. Logistic Regression Analysis and Decision-Tree Analysis for Improvement of LFI after
Propensity Score Matching

2.6. Logistic Regression Analysis and Decision-Tree Analysis for Improvement of LFI after
Propensity Score Matching

Independent factors for improvement of LFI after propensity score matching aresummarized in Figure 4A. Sex and group were selected by stepwise regression, and inhospital exercise, and females were identified as independent factors associated with an
improvement in LFI (Figure 4A).

Independent factors for improvement of LFI after propensity score matching aresummarized in Figure 4A. Sex and group were selected by stepwise regression, and inhospital exercise, and females were identified as independent factors associated with an
improvement in LFI (Figure 4A).
To clarify the profile associated with an improvement in LFI, a decision-tree algorithm
was created using four divergence variables and the patients were classified into five groups
after propensity score matching (Figure 4B). Sex was identified as the initial divergencevariable for changes in LFI. Among males, the group was the second divergence variable forchanges in LFI. An improvement in LFI was seen in 69% of the exercise group (Profile 2 inFigure 4B). On the other hand, an improvement in LFI was seen in 42% of the non-exercisegroup (Profile 3 in Figure 4B). Among females, BCAA supplementation and the groupwere the second and third divergence variables for changes in LFI, respectively. In female
patients with no BCAA supplementation, an improvement in LFI was seen in 93% of theexercise group (Profile 4 in Figure 4B). On the other hand, an improvement in LFI was seenin 65% of the non-exercise group (Profile 5 in Figure 4B).
In this analysis, the following factors were not identified as divergence variables for
improvement of LFI: age, BMI, ALBI grade, TNM stage, presence of sarcopenia, VFA, andhospitalization period.

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Figure 4. Factors associated with improvement of LFI after propensity score matching. (A) Logistic regression analysis for
Figure 4. Factors
associatedwith improvementof LFI after
propensity scorematching.
Logistic regression
analysisforwithimprovementof LFI
after propensity
score matching,(B) Decision-tree
algorithm
for(A)
improvementof LFI in
patients
improvementof LFI after
Decision-tree
algorithmoffor
improvementof LFI in patients
with
HCC
after propensity
scorepropensity
matching.score
The matching,pie graphs(B)indicate
the proportion
patients
with improvement
in LFI(white)HCC
after propensity
score matching.
pie graphs
indicate the proportion
patients
withimprovement
in LFI carcinoma.
(white)andpatients
without improvementin The
LFI (black).
Abbreviations:
LFI, liver offrailtyindex;
HCC,
hepatocellularand patients without improvement in LFI (black). Abbreviations: LFI, liver frailty index; HCC, hepatocellular carcinoma.

3. Discussion
To clarify the profile associated with an improvement in LFI, a decision-tree algodemonstrated
that in-hospital
exercise
improved
rithmThis
wasstudy
createdusing four divergencevariables
and thesignificantly
patients wereclassifiedfrailty
into inpatients
with
HCC.
Multivariate
decision-tree
also identified
revealed thatexercisefive groups
after
propensity
scoreandmatching(Figure analyses
4B). Sex wasas theinitial was
an independent factor for an improvement, which was confirmed by the propensity scorematching analysis. In addition, BCAA supplementation was identified as a factor associatedwith the improvement of frailty in female patients with HCC. Thus, our study suggests

Cancers 2021, 13, 194

10 of 16that in-hospital exercise was effective in improving physical function in patients with HCC.
In addition, BCAA supplementation may be effective for female patients with HCC.
In-hospital exercise improved frailty and was an important factor for the improvementof LFI. Our exercise program was a mixture of aerobic and resistance exercises. Previous
research demonstrated that a mixed exercise program significantly improved handgrip
strength in advanced cancer patients [16]. A mixed exercise program was also shown to
improve the time of the chair stand test in elder patients during cancer treatments [17].
Furthermore, a mixed exercise program significantly improved balance function in patientswith metastasized colorectal cancer [18]. In our study, we performed the exercises under thesupervision of physical therapists. The supervised exercise led to a greater improvementin physical function than an unsupervised exercise in a meta-analysis of 34 randomized
controlled trials (n = 4519) [19]. Thus, our results were in agreement with these previous
reports and suggest that physical function in patients with HCC can be improved by inhospital mixed exercise under supervision by physical therapists. In addition, a systematic
review demonstrated that exercise improves physical frailty in patients with chronic liverdisease [12]. Moreover, a meta-analysis showed that exercise is effective in improving frailty
status in frail older individuals [20]. Thus, the beneficial effect of exercise on frailty seems
to be not peculiar to patients with HCC, and in-hospital exercise may be recommended forany patients with frailty or risk of frailty.
In this study, sex was also identified as an independent factor for changes in LFI.
Although LFI was improved in females without exercise, females have been reported to
be at higher risk of developing incident sarcopenia than males [21]. In fact, being female
was identified as an independent factor of muscle atrophy in patients with HCC in aprevious report [4]. Although the reason why frailty was more improved in females thanmales in the non-exercise group remains unclear, adiponectin may be a possible mechanism. Adiponectin has been reported to have important metabolic functions, including
insulin-sensitizing and anti-inflammatory effects [22]. It has been reported that testosterone negatively regulates the secretion of adiponectin from adipocytes, and circulating
adiponectin levels show a sex disparity, being higher in females than in males [23]. Higher
serum adiponectin levels are also known to be associated with better performance on
frailty measures [24]. Thus, the difference in adiponectin levels may be one of the possible
mechanisms of a sex discrepancy in the improvement of LFI.
In this study, BCAA supplementation was also associated with changes in LFI. The
effects of BCAA supplementation on the improvement of LFI were evident in female
patients and were confirmed in the propensity score matching analysis. It has been reported
that there is a positive relationship between plasma BCAA concentration and muscle
function [25]. Uojima et al. [26] demonstrated that BCAA supplementation improved low
muscle strength in patients with chronic liver disease. Leucine is a BCAA that is known
to have anabolic effects on cell signaling and protein synthesis in muscle [27], and it has
been proposed that it augments resistance training-induced changes in body compositionand performance [28]. In addition, BCAA supplementation improves muscle strength bypromoting ammonia clearance from the blood in patients with chronic liver disease [26].
It remains unclear why the beneficial effect of BCAA supplementation was only seen infemales. However, Leahy et al. [29] reported that BCAA supplementation reduced muscle
soreness in females, but not in males, suggesting that this gender difference is related todose-per-body weight differences between male and female subjects.
This study has several limitations. First, this was a retrospective observational study.
Second, data were obtained from hospitals specialized in the treatment of HCC. Third, it
remains unclear whether higher LFI is associated with poor prognosis in patients with
HCC. Fourth, it is unclear if the level of LFI in patients with HCC is peculiar and we did
not evaluate the effects of in-hospital exercise on the recurrence of HCC and post-treatmentcomplications in this study. Thus, it is required to perform a multicenter prospective
cohort study to investigate the impact of exercise on the frailty, the recurrence of HCC,
post-treatment complications, and prognosis of patients with HCC.

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In conclusion, we showed that in-hospital exercise improved frailty in patients with
HCC, which was confirmed by the propensity score matching analysis. In addition, BCAA
supplementation was a factor associated with the improvement of frailty in female patientswith HCC. Thus, in-hospital exercise may improve physical function in patients with HCC.
Moreover, BCAA supplementation may be beneficial for female patients with HCC.
4. Materials and Methods
4.1. Study Design
We performed a multicenter retrospective observational study to evaluate the effects
of in-hospital exercise on LFI of patients with HCC. All authors had access to the study
data and reviewed and approved the final manuscript.
4.2. Subjects
We enrolled 181 consecutive patients with HCC who are admitted for HCC treatment
from December 2018 to March 2020. Hospitalized patients who met the following criteria
were included in this study: (1) 20 years of age or older, (2) agreed with the evaluation of
LFI as at admission, (3) were treated with hepatic arterial infusion chemotherapy, TACE,
or small-molecule tyrosine kinase inhibitors, and (4) hospitalized for 6 days or more.
Patients were excluded if they had: (1) hepatic encephalopathy grade 2–4 according to theWest Haven Criteria [30], (2) risk of esophageal variceal rupture, (3) heart failure, or (4)respiratory failure.
Exercise was recommended to all patients by medical doctors, nurses, and physicaltherapists. Patients who agreed to exercise were classified as the exercise group (n = 114),
and those who did not agree to exercise were classified as the non-exercise group (n = 67).
4.3. Exercise Regimen
To maintain physical function during hospitalization for HCC treatment, patientsin the exercise group were treated with exercise individually under the supervision ofa physical therapist certified for the rehabilitation of cancer patients. Six physical therapists delivered the exercise program. They were certified for the rehabilitation of cancer
patients and had an average of 14.5 years (range 9–25 years) of clinical experience with
hepatocellular carcinoma. Two (30%) of these physical therapists had Doctor of Philosophy(Ph.D.) degree qualifications. The oral agreements between the patient and the therapist
were reinforced in writing in the form of a “treatment contract”. The exercise was initiatedon the day after HCC treatment unless the patient had a fever of 38.0 ◦ C or greater orliver failure. The frequency of exercise was 5 times/week. The exercise was performed
in a rehabilitation room or hospital ward. The physical therapist attended the exercise
covering the delivery of the exercise program. During the exercise, the therapist gave
comments for the patients’ effort. The adherence to exercise was defined as the percentage
of supervised exercise sessions completed. Besides this exercise program, there were noother exercise and functional tasks. Chemotherapy for HCC and nutritional therapy including BCAA supplementation were non-exercise components. The exercise consisted of
the following four types of training according to the guidelines of the American College ofSports Medicine [31]. The exercise program was described using the Consensus on Exercise
Reporting Template (CERT) by Slade et al. [32] (Table S1).
4.3.1. Stretching
Patients performed a series of stretches that targeted the muscles of the quadriceps
femoris muscles, hamstrings, hip adductor muscles, gastrocnemius, back muscles, andshoulder muscles. Each stretch was held for 10–20 s. Patients progressed each stretch until
a feeling of tightness and slight discomfort was felt [14,15]. The physical therapist showeda role model of the stretch and checked the stretching form, tightness, and discomfort. The
total stretching time was 3–5 min (Table S1).

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4.3.2. Resistance Training
The training included the following four generic exercises: (1) hip hinge movement(good-morning exercise), (2) towel air pull-down, (3) squats, and (4) calf raises. One set
comprised of 10 repetitions, and a maximum of 3 sets was performed. Physical therapists
adjusted the method of exercises and environment to be able to complete 10 repetitions forthe exercise. Exercise load was own weight or own manual resistance. The total resistancetraining time was 5 min (Table S1).
4.3.3. Balance Training
Balance training was performed in both a one-leg stance or tandem stance using
parallel bars and handrails. Patient keep position up to 1 min in one-legged stance andtandem. The tandem stance method maintains a posture while standing in a straight line.
A one-leg stance maintaining a horizontal position in a one-legged position. These weredone once on each side. The total balance training time was 5 min (Table S1).
4.3.4. Aerobic Training
Aerobic training was performed using a bicycle ergometer (Konami Sports Co., Ltd.,Tokyo, Japan, or Senoh Corporation, Chiba, Japan), recumbent cross trainer (NuStep® ,Senoh Corporation) [33], or by walking. The intensity of exercise was adjusted to maintaina subjective rating of perceived exertion of 11–13 points on the Borg scale [28]. The exercise
load was increased according to the patient’s physical condition. The individual exercise
intensity was adapted during each session by adjusting the load or the cycling speed sothat the exercise goals were achieved. The exercise duration was gradually increased up to
15 min (Table S1).
4.4. Nutrition and Diet Therapy
Nutritional care for patients was conducted according to the guidelines on nutritional
management for Japanese patients with liver cirrhosis [34]. Details of these guidelines
include: (1) energy requirements of 25–35 kcal/kg (ideal body weight) per day, (2) required
protein intake of 1.0–1.5 g/kg/day (if there is no protein intolerance), (3) a required fat
intake with a lipid energy ratio of 20–25%, and (4) a 200 kcal late evening snack as adivided meal as recommended by the Evidence-based Clinical Practice Guidelines for Liver
Cirrhosis [35].
4.5. Branched-Chain Amino Acid Supplementation
Branched-chain amino acid (BCAA) supplementation (BCAA granules and BCAAenriched nutrients) is an approved medication for decompensated liver cirrhosis in Japan.
Thus, BCAA supplementation was administered to cirrhotic patients with hepatic encephalopathy or hypoalbuminemia, following the indication criteria [36].
4.6. Measurement of Liver Frailty Index
All patients underwent objective measurements of frailty as previously described [37]:(1) grip strength was evaluated in the subject’s dominant hand by the average of threemeasurements using a digital grip strength meter (DKK5401, Takei Machine Industry,Niigata, Japan), (2) chair stands with the subject’s arms folded across the chest were
evaluated by the time it took for the patient to perform it five times, and (3) balance
testing was evaluated by the time that the subject could balance in three positions (feetplaced side-to-side, semi-tandem, and tandem). The maximum time for each test was 10 s.
These three tests were administered by trained physical therapists. The LFI was calculatedusing the following equation [37] (calculator available at http://liverfrailtyindex.ucsf.edu):(−0.330 × gender-adjusted grip strength) + (−2.529 × number of chair stands per second)+ (−0.040 × balance time) + 6 = LFI.

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4.7. Changes in Liver Frailty Index
Changes in LFI (∆LFI) were evaluated by the difference between the admission andthe discharge days.
4.8. Measurement of Skeletal Muscle Index, and Visceral Fat Area
Skeletal muscle mass and visceral fat area (VFA) were evaluated using computed
tomography (CT) scan images obtained before and after HCC treatment. CT images
were taken for HCC assessment. The lower border of the third lumbar vertebra and theumbilical line were used as standard landmarks for measuring skeletal muscle mass and
VFA, respectively. Skeletal muscle mass and VFA were measured using Image-J software
version 1.80 (National Institutes of Health, Bethesda, MD, USA) [38] or Slice Omatic V
5.0 rev-8 software (Montreal, Quebec, Canada Tomovision) as previously described [39].
Skeletal muscle mass was normalized by the square of height, and the data were expressedas skeletal muscle index (SMI) [39].
4.9. Diagnosis of Sarcopenia
Sarcopenia was diagnosed according to the Japan Society of Hepatology (JSH) diagnostic criteria for sarcopenia in patients with liver disease [40]. According to the JSH
criteria, patients with decreased grip strength were defined as those with grip strength<26 kg for males or <18 kg for females. Patients with decreased skeletal muscle mass were
defined as those with SMI < 42 cm2 /m2 for males or <38 cm2 /m2 for females. Patients withdecreased grip strength and decreased SMI were diagnosed with sarcopenia. The other
patients were classified as having non-sarcopenia.
4.10. Diagnosis, Tumor Node Metastasis Staging, and Treatment of Hepatocellular Carcinoma
HCC was diagnosed using a tumor biopsy or a combination of tests for serum tumor
markers, such as alpha-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP), andimaging procedures such as ultrasonography, CT, magnetic resonance imaging, and/or
angiography. The clinical-stage of HCC was evaluated by TNM staging based on theLiver Cancer Study Group of Japan criteria [41]. Treatment for HCC was selected basedon the evidence-based clinical practice guidelines for HCC from The Japan Society of
Hepatology [42].
4.11. Biochemical Tests
Blood biochemical tests included serum levels of AFP, DCP, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase, alkaline phosphatase(ALP), gamma-glutamyl transpeptidase (GGT), cholinesterase, total protein, albumin, total bilirubin, blood urea nitrogen (BUN), creatinine, estimated glomerular filtration rate(eGFR), sodium, potassium, chlorine, total cholesterol, triglyceride, creatine kinase, glucose,hemoglobin A1c (HbA1c), ammonia, prothrombin activity, and prothrombin time international normalized ratio. In addition, red blood cell count, hemoglobin level, white blood
cell count, platelet count, neutrophil count, lymphocytes, and neutrophil/lymphocyte ratio
were measured.
4.12. Propensity Score Matching
Propensity scores for all patients were estimated with a logistic regression model using
the following baseline characteristics as covariates: age, sex, and body mass index (BMI).
A one-to-one nearest-neighbor matching algorithm with an optimal caliper of 0.2 without
replacement was used to generate 118 pairs of patients, as previously described [43,44].
Thus, 118 patients with HCC (exercise group (n = 59) and non-exercise group (n = 59))
were analyzed.

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4.13. Statistical Analysis
Data are expressed as median (interquartile range (IQR)), range, or number. All
statistical analyses were performed using Statistical Analysis Software (JMP Pro version
15.0; SAS Institute, Cary, NC, USA). Differences between the exercise and non-exercisegroups were analyzed using Wilcoxon rank-sum tests. The level of statistical significancewas set at p < 0.05. Changes in LFI between admission and discharge were evaluatedusing the ∆LFI. In addition, independent factors associated with an improvement in LFI
were analyzed using logistic regression analysis and decision-tree analysis, as previously
described [15,45]. Furthermore, to overcome possible selection bias between the groups,
we performed one-to-one propensity score matching as previously described [44]. We thenperformed similar analyses, such as Wilcoxon rank-sum tests, a logistic regression analysis,
and a decision-tree analysis to investigate the effects of in-hospital exercise on frailty.
5. Conclusions
In-hospital exercise improved frailty in patients with HCC, which was confirmedby the propensity score matching analysis. In addition, BCAA supplementation was afactor associated with the improvement of frailty in female patients with HCC. Thus,
in-hospital exercise may improve physical function in patients with HCC. Moreover, BCAA
supplementation may be beneficial for female patients with HCC.
Supplementary Materials: The following are available online at https://www.mdpi.com/2072-6
694/13/2/194/s1, Table S1: Consensus on Exercise Reporting Template (CERT) for the exercise
program of this study.
Author Contributions: Conceptualization, J.T., S.K., K.H. and T.K.; methodology, N.K., H.N. and
M.T.; validation, R.H., D.N., T.T. (Tsubasa Tsutsumi) and S.Y.; formal analysis, T.K.; investigation, J.T.,
S.K., K.H., N.K., H.N. and M.T.; resources, T.K. and S.Y.; data curation, R.H., D.N. and T.T. (Tsubasa
Tsutsumi); writing—original draft preparation, J.T., S.K., K.H. and T.K.; writing—review and editing,
H.M., T.S., K.N. and T.T. (Takuji Torimura); visualization, T.K.; supervision, H.M., T.S., K.N. and T.T.
(Takuji Torimura); project administration, T.K.; funding acquisition, T.K. and S.Y. All authors haveread and agreed to the published version of the manuscript.
Funding: This research was funded by the Research Program on Hepatitis from Japan Agency for
Medical Research and Development, AMED under JP20fk0210045.
Institutional Review Board Statement: The study protocol conformed to the ethical guidelines of
the Declaration of Helsinki, as reflected in the prior approval given by the institutional review boardof Fukui-ken Saiseikai Hospital (approval #2019-042; date 3 September 2019), Kurume University(approval #19098; date 31 August 2020), Chikugo City Hospital (approval #2019-04; date 1 April2019), Yame General Hospital (approval # 19-003; date 17 May 2019), and Saga Central Hospital(approval #31014; date 14 March 2019). Therapeutic exercise in hospitalized patients with cancer isan approved health care service covered by the Ministry of Health, Labour, and Welfare of Japan
health insurance. Therefore, a randomized controlled study, which intentionally set the control group(non-exercise group) was contrary to medical ethics.
Informed Consent Statement: An opt-out approach was used to obtain informed consent frompatients, and personal information was protected during data collection.
Data Availability Statement: The data presented in this study are available on request from thecorresponding author. The data are not publicly available due to ethical issue.
Conflicts of Interest: Takumi Kawaguchi received lecture fees from Mitsubishi Tanabe Pharma
Corporation and Otsuka Pharmaceutical Co., Ltd. The other authors have no conflicts of interest
to declare.

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