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ORIGINAL
Preoperative predictors of extended resection in patients withcomplicated acute appendicitis undergoing surgery
Yuhei Waki1, MD, Masanori Hotchi1, MD, PhD, Daichi Utsunomiya2, MD, Takeshi Inoue3 MD, PhD,
and Masayoshi Obatake1, MD
Division of Digestive Surgery, Ehime Prefectural Central Hospital, Ehime, Japan, 2Division of General Surgery, Ehime Prefectural Imabari
Hospital, Ehime, Japan, 3Division of Radiology, Ehime Prefectural Central Hospital, Ehime, Japan
1

Abstract : Background : Appendectomy can be challenging and occasionally converted to extensive resection
for complicated appendicitis. However, optimal treatment strategies can be developed using preoperative risk
assessment. Thus, we aimed to investigate the preoperative predictors of extensive resection in complicated appendicitis patients undergoing surgery. Materials and methods : In total, 173 complicated appendicitis patients
undergoing surgery between 2014 and 2019 were classified into the appendectomy (n = 153) or extensive resection(n = 20) groups. Clinicopathological factors and surgical outcomes were compared between groups. Results : Extensive resection was performed in 20 of 173 complicated appendicitis patients (11.5%). The rates of having defects
in the wall structure at the appendix root on computed tomography images were significantly higher, and theduration from onset to surgery was significantly longer in the extensive resection group. Significant differenceswere found in operative duration, blood loss and postoperative hospitalization, but none in the incidence of postoperative complications between groups. Multivariate analyses showed that defects in the wall structure at the
appendix root and five days or longer from onset were identified as independent predictors of extensive resection. Conclusions : Defects in the wall structure at the appendix root and five days or longer from onset predictextensive resection performance in complicated appendicitis patients. J. Med. Invest. 68 : 334-341, August, 2021
Keywords : complicated acute appendicitis, extensive resection, predictive factors, days from onset, surgery

INTRODUCTION
Complicated appendicitis is defined as appendix perforation
with an abdominal abscess or peritonitis (1). Acute appendicitis with delayed detection frequently results in complicatedappendicitis (2, 3). Although surgery has been considered themost effective treatment for complicated appendicitis for several
decades, conservative treatment strategies, including antibiotic
drugs with or without percutaneous drainage of abdominal
abscess, are the preferred treatment of choice for complicatedappendicitis according to the guidelines for appendicitis in theEuropean Association of Endoscopic Surgery (EAES) (1) or
the first choice of treatment according to the World Society ofEmergency Surgery (WSES) (4). Furthermore, conservative
treatment was successful in 93% of complicated appendicitis
patients (2). Despite the high success rate of conservative treatment, recurrent appendicitis occurs in 5–27% of cases (2, 5-7).
Therefore, optimal treatment is still controversial in complicatedappendicitis patients.
Appendectomy is considered a gold standard for the treatmentof appendicitis patients. In complicated appendicitis patients,
appendectomy can be technically challenging and occasionallyconverted to extensive resection, such as an ileocecal resection
or right hemicolectomy in the presence of an abdominal abscess(8). ER has been reported to be performed on approximately
3–30% of appendicitis patients with abscess and is associatedwith more technical demands and higher rates of morbidity thanReceived for publication May 10, 2021 ; accepted August 5, 2021.
Address correspondence and reprint requests to Yuhei Waki, MD,
Division of Digestive Surgery, Ehime Prefectural Central Hospital, 83 Kasuga-cho, Matsuyama, Ehime 790-0024, Japan andFax : +81-89-943-4136.

appendectomy (9, 10). Recently, several studies have reported
that interval / delayed appendectomy not only reduces morbidity rates but also avoids recurrent appendicitis and extensive
resection (11). Thus, preoperative risk assessment for extensive
resection can be used to develop an optimal treatment strategy
for surgery for complicated appendicitis. However, little is known
about the preoperative predictors of extensive resection in complicated appendicitis patients. Therefore, this study aimed toinvestigate the preoperative predictors of extensive resection incomplicated appendicitis patients treated with surgery.

MATERIALS AND METHODSPatients

A total of 423 acute appendicitis patients who underwent surgery at our institute between January 2014 and December 2019were included in the study. All patients were diagnosed withacute appendicitis using computed tomography (CT). Complicated appendicitis was defined as either gangrenous inflammation
with or without perforation, and with abdominal abscess or
inflammatory mass according to WSES guidelines (4). Amongthem, 173 patients (40.9%) diagnosed with complicated appendicitis using CT records reviewed by at least two radiologists wereselected. In patients diagnosed with complicated appendicitis
preoperatively, surgery was basically the first choice. However,conservative treatment was sometimes given depending on
patient’s wishes and condition. Finally, 173 complicated appendicitis patients who underwent surgery were included in thisstudy. Of these, 153 underwent appendectomy and 20 underwent
extensive resection (Fig. 1). This study was approved by the institutional review board of our hospital (02-46). Informed consent
was waived by the ethical committee due to the retrospective
nature of the study.

The Journal of Medical Investigation Vol. 68 2021

The Journal of Medical Investigation Vol. 68 August 2021
CT imaging and evaluation
All preoperative multidetector-row CT images were acquired
using a multidetector-row scanner (Siemens Healthineers,
Erlangen, Germany). An intravenous contrast scan was obtained following the injection of nonionic iodinated agents using
an automated injector, unless contraindicated. CT images werereviewed and reported by at least two radiologists.

Factors analyzed
Clinicopathological data, including those on age, sex, bodymass index, operative history, Charlson comorbidity index (12),comorbidities (heart disease ; history of heart failure, angina,
myocardial infarction and arrhythmia, cerebrovascular disease : history of cerebral infarction, subarachnoid hemorrhage,
cerebral hemorrhage, hypertension with medical treatment, anddiabetes mellitus with medical treatment), steroid use, American
Society of Anesthesiology Physical Status (ASA-PS), days from335

onset to surgery, treatment, use of preoperative percutaneous
drainage, and pathological findings were collected from all
patients. Data on preoperative radiologic findings suggestive of
gangrenous / perforated appendix, abdominal abscess, appendicolith, and defects in partial or complete wall structures at the
appendix root (Fig. 2) were also collected from the CT records.
Results of preoperative laboratory examination, including whiteblood cell count and C-reactive protein level, were collected.
Surgical outcomes included surgical approach (open or laparoscopic surgery, or conversion to open surgery), intraoperative
findings, duration of operation, amount of blood loss, length of
postoperative hospitalization, rate of readmission within lessthan 30 days, and postoperative complications according to
the Clavien-Dindo classification (13). Moreover, intraoperative
findings of the patients with uncomplicated appendicitis were reviewed to determine the diagnostic accuracy of CT for detecting
complicated appendicitis.

Fig 1. Flowchart of the study population.

Fig 2. CT images of wall structure defects at the appendix root. (a) Coronal and (b) multi-planarreconstruction contrast-enhanced CT images showing partial wall structure defects at the appendix root
(white arrow) and normal appendix wall at the appendix tip (white arrowhead). (c) Axial contrast CT image
showing large pelvic abscess (red arrowhead) with an incomplete appendiceal wall structure (white arrow).

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Y. Waki, et al. Extended resection for appendicitis

Statistical analyses
All statistical analyses were performed using the R version
4.0.0 software package (R Foundation for Statistical Computing,
Vienna, Austria). Continuous data are presented as medians(interquartile ranges), and continuous variables were nonparametrically analyzed using the Mann-Whitney test. Categoricalvariables were compared using Fisher’s exact test. The sensitivity, specificity, positive and negative predictive values, anddiagnostic accuracy of CT for complicated appendicitis were calculated using intraoperative findings as the gold standard. Allvariables with p-values < 0.05, in the univariate analyses, were
included and analyzed in the multivariate logistic regression
analysis. Statistical significance was set at p < 0.05.

RESULTS

Patients’ characteristics and clinicopathological findings
Patient characteristics and clinicopathological findings
were compared between groups (Table 1). Extensive resection
was performed in 20 of 173 (11.5%) patients with complicated

Table 1. Patients’ characteristics and clinicopathological findings
VariablesAge [years ; median (IQR)]
Age ≥ 65 years, n (%)

Appendectomy (n = 153)

Extensive resection (n = 20)

61.0 (46.0–73.0)

65.5 (52.3–78.3)

80 (52.3)

13(65.0)

Sex, n (%)
89 (58.2)

8 (40.0)

Female64 (41.8)

12 (60.0)

Charlson comorbidity index [median (IQR)]

0.131
0.345
0.153

Male
BMI [kg / m2 ; median (IQR)]

p-value

22.3 (20.2–25.0)

21.8 (20.4–23.4)

0.494

0 (0–1)

1 (0–1)

0.507

Comorbidity, yes, n (%)
Cardiovascular disease

15 (9.8)

3 (15.0)

0.422

Cerebral infarction

6 (3.9)2 (10.0)

0.233

Hypertension

31 (20.3)

6 (30.0)

0.383

Diabetes mellitus

15 (9.8)

1 (5.0)0.698

Steroid use, yes, n (%)

1 (0.6)

0 (0)

1.000

1

39 (25.5)

1 (5.0)2

84 (54.9)

12 (60.0)327 (17.6)

6 (30.0)43 (2.0)1 (5.0)

History of operation, n (%)

18 (11.8)

4 (20.0)

0.291

Received preoperative abdominal ultrasonography, n (%)

5 (3.3)0 (0.0)1.000

ASA-PS, n (%)

0.755

Diagnosis of CT images, n (%)

0.851

Perforation

112 (73.2)

15 (75.0)

1.000

Intra-abdominal abscess

104 (68.0)

16 (80.0)

0.315

Appendicolith

68 (44.4)

8 (40.0)

0.813

Defects in the wall structure at the appendix root

31 (20.3)

11 (55.0)

0.001*

Preoperative WBC, [ / uL ; median (IQR)]

12360 (10020–14680)

12980 (10420–16100)

Preoperative CRP, [mg / L ; median (IQR)]

13.6 (7.66–21.9)

14.0 (11.9–24.0)

0.295

Days from onset to surgery, [median (IQR)]

3 (2.0–7.0)

8 (3.8–11.3)

0.010*

Treatment, n (%)

0.168

Emergent surgery

133 (86.9)

16 (80.0)

Unplanned surgery due to conservative treatment failureor recurrent appendicitis

12 (7.8)

4 (20.0)

Elective surgery after conservative treatment

8 (5.2)0 (0.0)2 (1.3)0 (0)Catarrhal or phlegmonous appendicitis

37 (24.2)2 (10.0)

Gangrenous appendicitis

Preoperative percutaneous drainage, n (%)

0.482

Pathological findings, n (%)

1.000
0.078

105 (68.6)

15 (75.0)

Chronic appendicitis or fibrosis

8 (5.2)

1 (5.0)

Low-grade pseudomyxoma

3 (2.0)1 (5.0)Adenocarcinoma

0 (0)1 (5.0)

IQR, interquartile range ; ASA-PS, the American Society of Anesthesiology performance status ; BMI, body mass index ;CT, computed tomography ; WBC, white blood cell count ; CRP, C-reactive protein. *Statistically significant.

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The Journal of Medical Investigation Vol. 68 August 2021
appendicitis. The median age was comparable between the twogroups. Charlson comorbidity index, the preoperative comorbidity rates, and the ASA-PS were not significantly different
between the two groups. Although the CT diagnostic rates of perforation, intra-abdominal abscess, and appendicolith were notdifferent between the two groups, the rate of defects in the wall
structure at the appendix root was higher in the extensive resection group (appendectomy group : 20.3% vs. extensive resectiongroup : 55.0%, p = 0.001). Days from onset were significantly
longer in the extensive resection group (median, appendectomy
group : 3 days vs. extensive resection group : 8 days, p = 0.010).
Conservative treatment was intended in 24 (13.9%) of 173
patients with complicated appendicitis. Among these patients,
16 (66.7%) patients underwent unplanned surgery due to conservative treatment failure or recurrent appendicitis. Only one
patient had appendiceal adenocarcinoma in the extensive resection group. The other patient characteristics, clinical findings,
and hematologic examinations were not significantly different
between the two groups.

Surgical outcomes and postoperative complications
The surgical outcomes were compared between the two groups(Table 2). Fifteen patients in the appendectomy group werediagnosed with uncomplicated appendicitis intraoperatively.
The duration of operation, amount of blood loss, and postoperative hospitalization were significantly different between thetwo groups. The postoperative complications were compared

between the two groups (Table 3). The incidence of postoperativecomplications according to Clavien-Dindo classification grade
II or higher was not significantly different between the twogroups (appendectomy group, 18.3% ; extensive resection group,
20.0% ; p = 0.768). No surgery-related deaths were observed inthis study.

Cutoff point of days from onset to surgery
Receiver operating characteristic curves were plotted to selectthe cutoff value of the days from onset to surgery (area under the
curve : 0.675, 95% confidence interval [CI] : 0.567-0784) (Fig. 3).
The optimal cutoff values were selected based on Youden’s index{the maximum value of (sensitivity + specificity - 1)} in relation tothe outcome of the extensive resection procedure (14). Accordingly, the cutoff value of days from onset to surgery was calculated
as 5 (sensitivity : 0.70, specificity : 0.65).

Diagnostic accuracy of CT for detecting complicated appendicitis
Preoperative CT reported that there were 40.9% (173 / 423)
patients who had complicated appendicitis and 59.1% (250 / 423)
patients had uncomplicated appendicitis. However, intraoperative findings showed 46.8% (198 / 423) patients had complicatedappendicitis and 53.2% (225 / 423) patients had uncomplicatedappendicitis. The sensitivity, specificity, positive and negative
predictive values, and the accuracy of CT for detecting complicated appendicitis, were 79.8%, 93.3%, 91.3%, 84.0%, and 87.0%
respectively (Table 4).

Table 2. Surgical outcomes
Variables

Appendectomy (n = 153)

Extensive resection (n = 20)

Surgical approach, n (%)

p-value
1.000

Open

95 (62.1)

13 (65.0)

Laparoscopic

58 (37.9)

7 (35.0)

Conversion to open surgery

0 (0)

0 (0)

Intraoperative findings, n (%)

0.222

Uncomplicated appendicitis

15 (9.8)

0 (0.0)Complicated appendicitis

138 (90.2)

20 (100.0)

Operative duration [min ; median (IQR)]

78 (63.0–93.0)

144 (127.2–180.2)< 0.001*

Blood loss [mL ; median (IQR)]

0 (0–60.0)

135.5 (65.5–372.5)< 0.001*

Postoperative hospitalization [day ; median (IQR)]

7 (5.0–8.0)

9.5 (8.0–13.3)< 0.001*

Postoperative readmission rate, n (%)

9 (5.9)1 (5.0)1.000

IQR, interquartile range. *Statistically significant.

Table 3. Postoperative complications according to the Clavien-Dindo classification (grade II or higher)
Appendectomy (n = 153)

Extensive resection (n = 20)

p-value

All complications

28(18.3)

4(20.0)0.768

Intra-abdominal abscess

18(11.7)3(15.0)

0.715
0.233

Paralytic ileus6(3.9)

2(10.0)Superficial surgical site infection

7(4.8)

0(0)

1.000

Respiratory diseases

2(1.3)

0(0)

1.000

Bleeding

1(0.7)

1(5.0)

0.218

Pseudomembranous colitis

1(0.7)

0(0)

1.000

Drug eruption

1(0.7)

0(0)

1.000

Mortality

0(0)

0(0)

-

Data are shown as n (%).

Y. Waki, et al. Extended resection for appendicitis

338

Univariate and multivariate analyses for extensive resection
The results of univariate and multivariate analyses are presented in Table 5. Univariate analysis showed that defects inthe wall structure at the appendix root and 5 days or longer fromonset to surgery were associated with predictors of extensive
resection. In addition, multivariate analysis showed that defects
in the wall structure at the appendix root (odds ratio, 4.31 ; 95%
CI, 1.38–13.84 ; p = 0.004) and 5 days or longer from onset tosurgery (odds ratio, 2.58 ; 95% CI, 1.15-6.40 ; p = 0.011) wereidentified as independent predictors for extensive resection.
The predictive score of need for extensive resection was created with the two variables (Table 6). The presence of bothvariables had a predictive probability of 53.8% that extensive
resection will be required. Conversely, the absence of both variables had a predictive probability of 4.0% for same event.

DISCUSSION

Fig 3. Receiver operating characteristic curve analysis for
identification of the optimal cutoff value of the number of days fromsymptom onset to surgery to predict the outcome of the extensive
resection procedure. The area under the curve was 0.675 (95%
confidence interval: 0.567-0.784), and the threshold number ofdays from onset to surgery was 5, with a sensitivity of 70.0% and a
specificity of 64.7%

In this single-institution retrospective study, 20 of 173 patientswith complicated appendicitis underwent extensive resection.
The days from onset to surgery were significantly longer in theextensive resection group than in the appendectomy group. Our
study demonstrated that wall structure defects at the appendix
root and 5 days or longer from onset are independent predictive
factors of extensive resection in patients with complicated appendicitis. The presence of both variables had a predictive probability of 53.8% that extensive resection will be needed.

Table 4. Diagnostic accuracy of CT for detecting complicated appendicitis

Complicated atsurgery

Uncomplicatedat surgery

Total

Complicated on CT

158

15

173

Uncomplicated on CT

40

210

250

Total

198

225

423

(Number)

95% CI(Percent)

Lower

Upper

Sensitivity

79.8

73.5

85.2

Specificity

93.3

89.2

96.2

Positive predictive value

91.3

86.1

95.1

Negative predictive value

84.0

78.9

88.3

Accuracy

87.0

83.4

90.1

CT, computed tomography ; CI, confidence interval.

Table 5. Univariate and multivariate analyses of predictors for extensive resection
Univariate
OR

95% CI

Defects in the wall structure at the appendix root, yes vs. no4.81

1.60–15.01

Days from onset (vs. < 5 days)

2.79

1.28-6.80

Multivariate
p-valueOR

95% CI

0.001*

4.31

1.38–13.84

0.004*

0.005*

2.58

1.15-6.40

0.011*

CRP, C-reactive protein ; OR, odds ratio ; CI, confidence interval ; *Statistically significant.

p-value

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The Journal of Medical Investigation Vol. 68 August 2021
Table 6. Predicted need for extensive resection according to the number of risk factors
Risk factors (number)

Number ofpatients

Predicted rate forextensive resection (%)

OR

95% CI

p-value

2

13

53.8

27.7

5.44–173.62< 0.001*

1

61

14.8

4.11

1.08–19.66

0.024*

None

99

4.0

1.00

-

-

OR, odds ratio; CI, confidence interval. *Statistically significant.

Surgery has been the gold standard treatment for acute appendicitis for several decades. Recently, conservative treatment
for appendicitis has been reported to be safe and feasible for
adults and children (2, 15). Appendicitis is classified into two
types : uncomplicated without signs of gangrene, perforation, an
abdominal abscess, or purulent free fluid, and complicated witheither gangrenous inflammation with or without perforation,
intra-abdominal abscess, or inflammatory mass (4). For uncomplicated appendicitis, either surgical or conservative treatment
is selected owing to the surgeon and / or hospital situation (1,4). Meanwhile, complicated appendicitis occasionally makes
it difficult for surgeons to decide whether to select surgical orconservative treatment because of the difficulty of surgical techniques and the relatively high failure rate for conservative treatment (16). According to the WSES guidelines for appendicitis,
conservative treatment is a reasonable first-line treatment for
appendicitis with phlegmon or abscess, while surgical treatment
is a safe alternative to conservative treatment under experienced
surgeons (4). Thus, the optimal treatment for complicated appendicitis remains controversial.
Initial conservative treatment following interval / delayed
appendectomy has been reported to reduce not only missing an
underlying and untreated malignancy but also undergoing extensive resection (9). Furthermore, several studies have suggested that interval / delayed appendectomy has advantages only forthe treatment of appendicitis with an abdominal abscess (17, 18).
However, the preoperative criterion for decision-making of initialconservative treatment with or without interval / delayed appendectomy for complicated appendicitis is still unclear according to
the EAES and WSES guidelines (1, 4). Therefore, there is a needto develop preoperative criteria that can guide the therapeuticstrategy for patients with complicated appendicitis.
In a previous study, conservative treatment including intravenous antibiotic therapy with or without abscess drainage was
successful in 93% patients with acute appendicitis (2). However,in our study, 16 of 24 patients scheduled to undergo conservative
treatment underwent unplanned surgery due to treatment failure or recurrent appendicitis. A reason for this discrepancy may
be the low performance rate of preoperative percutaneous abscess drainage in our hospital possibly due to lack of experience
with the procedure. Therefore, percutaneous abscess drainage
should be actively performed to increase the success rate of conservative treatment following interval or delayed appendectomy.
In approximately 20% of patients, acute appendicitis is diagnosed as a complicated type, leading to local or diffuse peritonitis(19). In our study, 173 of 423 patients (40.9%) were diagnosed
with complicated appendicitis, which was approximately twice
as high as that in a previous study. A possible reason for this discrepancy was that patients who initially received conservative
treatment were excluded, and only patients who needed surgicaltreatment for some reasons were referred to our hospital in thetertiary emergency facility. Therefore, the rate of complicatedappendicitis was relatively high in our study.
Generally, appendectomy can be technically challenging andoccasionally converted to extensive resection in the presence ofan abdominal abscess (16). Extensive resection has been reported to be performed approximately 3–30% of appendicitis patientswith abscess and is associated with more technical demands andhigher rates of morbidity than appendectomy (2, 9, 10). Similarly,
in our study, approximately 10% of complicated appendicitis patients underwent extensive resection. Thus, surgical indications
for extensive resection were comparable between our study andprevious studies.
Although the useful diagnostic modalities for acute appendicitis include ultrasonography, CT, and magnetic resonanceimaging, CT is generally accepted as the most reliable tool forthe diagnosis of appendicitis (20). A previous meta-analysis
has reported that CT has relatively low sensitivity and highnegative predictive value for complicated appendicitis (mean sensitivity : 78%, mean specificity : 91%, mean positive predictive
value : 74%, mean negative predictive value : 93%) (21). In ourstudy, the diagnostic accuracy of CT for complicated appendicitis
was comparable to that reported in the abovementioned study,
supporting the reliability of our findings.
Recently, appendiceal mass and non-visualization of the appendix using CT images have been reported to be independent
predictive factors for performing extensive resection in both
uncomplicated and complicated acute appendicitis patients (9).
Similarly, defects in the wall structure at the appendix root
detected by CT images were associated with conversion to extensive resection procedure in our study. This result suggested thatthe defects in the wall structure at the appendix root indicatedgangrenous inflammation and / or formation of an inflammatory
mass around the root of the appendix, which made it difficult toligate and to resect the root of the appendix during appendicitis
surgery. Thus, for patients with complicated appendicitis, confirmation of wall structure defects at the appendix root using preoperative CT is clinically important to avoid extensive resection.
Surgical timing for appendicitis is reportedly associated withthe length of hospital stay and postoperative outcome (22). Several studies have reported that the relationship between a delay
in surgery from symptom onset and complicated appendicitis
and delayed surgery for more than 36 or 48 h increased postoperative complications (23, 24). Conservative treatment has beenreported to reduce postoperative complications and to mitigate
the risk of needing extensive resection (22). However, few reports
have shown the optimal surgical timing for complicated appendicitis. In our study, five days or longer from onset was identified
as a predictor of extensive resection. Moreover, the presence ofthe two factors including the duration of five days or longer fromonset and defects in the wall structure at the appendix root highly predicted the need for extensive resection. Therefore, surgeons
may choose conservative treatment in complicated appendicitis
patients with the two predictive factors for extensive resection
to decrease postoperative complications and the risk of needingextensive resection.
The present study has some limitations. First, this was a retrospective analysis of a small number of patients from a single

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Y. Waki, et al. Extended resection for appendicitis

institute. Second, in this study, the cutoff value of days fromonset was established based on the data of patients from a single
institution. Thus, a multicenter study or studies on other patient
populations are needed to verify these results and to determine
a comprehensive cutoff value of days from onset.

CONCLUSION
In complicated appendicitis patients, defects in the wall structure at the appendix root and the duration of five days or longer
from onset were preoperative predictors of extensive resection.
These factors may help surgeons avoid extensive resection and in
determine the therapeutic strategy for complicated appendicitis
patients.

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

FUNDING
The authors did not receive support from any organization forthe submitted work.

CONFLICTS OF INTEREST / COMPETING INTERESTS
The authors have no relevant financial or non-financial interests to disclose.

ETHICAL APPROVAL
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and / or national research committee and with the 1964
Helsinki Declaration and its later amendments or comparable
ethical standards. The study was approved by the Institutional
Review Board of Ehime Prefectural Central Hospital (approval
no. 02-46).
Ethical approval was waived by the Institutional Review
Board of Ehime Prefectural Central Hospital in view of theretrospective nature of the study and all the procedures being
performed were part of the routine care.

AUTHOR’S CONTRIBUTIONS
All authors contributed to the study conception and design.
Material preparation and data collection were performed by
Yuhei Waki, Daichi Utsunomiya and Masayoshi Obatake, andanalysis were performed by Yuhei Waki and Masanori Hotchi.
The first draft of the manuscript was written by Yuhei Waki andall authors commented on previous versions of the manuscript.
All authors read and approved the final manuscript.

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