Preoperative CT anthropometric measurements and pancreatic pathology increase risk for postoperative pancreatic fistula in patients following pancreaticoduodenectomy.

Postoperative pancreatic fistula (POPF) is a common complication following pancreaticoduodenectomy (PD). However, risk factors for this complication remain controversial. We conducted a retrospective analysis of 107 patients who underwent PD. POPF was diagnosed in strict accordance with the definition of the 2016 update of pancreatic fistula from the International Study Group on Pancreatic Fistula (ISGPF). Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for POPF. A total of 19 (17.8%) subjects of pancreatic fistula occurred after PD, including 15 (14.1%) with grade B POPF and 4 (3.7%) with grade C POPF. There were 33 (30.8%) patients with biochemical leak. Risk factors for POPF (grade B and C) were larger area of visceral fat (odds ratio [OR], 1.40; p = 0.040) and pathology other than pancreatic adenocarcinoma or pancreatitis (OR, 12.45; p = 0.017) in the multivariate regression analysis. This result could assist the surgeon to identify patients at a high risk of developing POPF.

Introduction

Pancreaticoduodenectomy (PD) is a standard procedure for patients with benign or malignant tumors involving the head of the pancreas and periampullary regions [1-3]. Attributable to advancements in surgical techniques and perioperative management, the mortality rate after PD has improved significantly, reportedly reaching 1–2% at high volume centers [4-6]. However, the postoperative morbidity rate remains high, ranging from 27.1% to 43% [6-8].

Among the reported complications, postoperative pancreatic fistula (POPF) is the most common complication following PD and is associated with delayed gastric emptying, intra-abdominal abscess and hemorrhage, and superimposed infection and sepsis, consequently increasing the length of stay and even leading to reoperation in some cases [9-11]. Therefore, reducing the rate of POPF after PD is a serious challenge for clinicians.

Various risk factors for POPF have been suggested, including sex, body mass index (BMI), pancreatic duct size, pancreatic texture, blood transfusion, intraoperative blood loss, operation time, and visceral fat area [9,12,13]. However, definite causal factors for developing POPF after PD remain controversial. Recently, some studies have suggested a relationship between surgical outcomes and anthropometric measurements, such as the core muscle mass and body fat area. Depleted skeletal muscle mass and visceral obesity increased postoperative complications after total gastrectomy, major hepatectomy, and colorectal cancer [14-16]. With respect to PD, patients with sarcopenia and visceral obesity showed decreased survival and increased morbidity [12,17,18]. As the POPF criteria were updated in 2016, biochemical leak (POPF A) is no longer considered true POPF [19]. A few studies had reported on the association of anthropometric measurement with POPF according to the revised criteria [20,21].

In this study, we performed a retrospective study to evaluate the association and predictive value of anthropometric measurements and other pre- and perioperative variables for POPF.

Methods

Subjects

This retrospective study was approved by the institutional review board (IRB) of Hanyang University Hospital. All experiments were performed in accordance with the relevant guidelines and regulations.

One-hundred and twenty-four consecutive subjects who underwent PD between October 2007 and October 2017 were enrolled into this study. The exclusion criteria were as follows: lack of clinical information (hardness of pancreas [n = 9], BMI [n = 1]); interval between preoperative computed tomography (CT) and surgery >40 days (n = 3); unavailability of preoperative CT (n = 3); and difficulty evaluating POPF (n = 1). Finally, 107 subjects (male: female = 64:43; mean age, 65.9 years; range, 35–82 years) who underwent PD were included. Detailed information was obtained from electronic medical records. For each subject, the following data were collected: (1) subjects’ demographic and clinical features, including age, sex, BMI, preoperative albumin, and total bilirubin; (2) operative details, including pancreatic texture, operation time, performance of intraoperative blood transfusion, and the use of a pancreatic stent; and (3) final diagnosis of the tumor. The pancreatic texture of all subjects was examined by the surgeon during the operation and classified as either soft or hard. A pancreatic duct stent was occasionally used during reconstruction following PD according to the surgeon’s judgment. External drains were inserted in proximity to the pancreatic anastomosis for each surgery, and the amylase level of drain fluid was routinely measured during the inserted period.

Measurement of anthropometric measurements

We measured subjects’ abdominal circumference, visceral and subcutaneous fat, and total abdominal muscle area on preoperative CT scans at the level of the third lumbar vertebra (L3). Distinction among the muscle, fat, and different tissues was based on Hounsfield units (HU) using AquariusNET Server (TaraRecon, Foster City, CA, USA). A threshold range of -29 to 150 HU was used to define muscle and a range of -190 to -30 HU was used to define fat. Hand adjustment of the selected area was performed (Figs 1 and 2). Skeletal muscle mass was normalized for the subjects’ heights to calculate the skeletal muscle mass index (SMI, cm2/m2). The ratio of visceral fat to SMI (VF/SMI) was also calculated. Sarcopenia was defined as SMI ≤52.4 cm2/m2 for men and ≤38.5 cm2/m2 for women based on a study by Prado et al. These cutoff values are accepted by an international consensus group on the diagnostic criteria for cachexia associated with cancer [22,23]. Visceral obesity was defined as a visceral fat area ≥100 cm2 in both sexes. This value is widely used as a cutoff to define sarcopenic obesity in Asian populations and is equivalent to that used for the diagnosis of metabolic syndrome in Japan [24,25].

Fig 1

A 58-year-old woman treated with pancreaticoduodenectomy for ampulla of Vater cancer without POPF.

(A) Axial contrast enhanced CT taken 8 days following surgery show small amount of fluid collection around pancreaticojejunal anastomosis, but the amylase level in the drained fluid is not greater than three times the upper normal serum value. (B,C) On the preoperative axial CT, the scan was segmented into subcutaneous fat in blue, total abdominal muscle area in read and visceral fat area in green. The patient shows a visceral fat area of 76 cm2 and VF/SMI of 1.6.

Fig 2

A 65-year-old man treated with pancreaticoduodenectomy for ampulla of Vater cancer.

(A) Axial contrast enhanced CT taken 7 days after surgery show fluid collection around the pancreaticojejunal anastomosis with suspicious dehiscence. The patient was treated with percutaneous drainage of fluid collection around the anastomosis. (B,C) On the preoperative axial CT, the patient shows a visceral fat area of 240 cm2 and VF/SMI of 5.8.

Definition of postoperative pancreatic fistula

Pancreatic fistula was defined according to the revised 2016 International Study Group on Pancreatic Fistula (ISGPF) classification and grading [19]. The previous ‘grade A’ POPF is newly classified as ‘biochemical leak’, which refers to a transient and asymptomatic biochemical fistula. Grade B and C POPF are clinically relevant fistulae, which require a change in postoperative management. If peripancreatic drainage persists for more than 3 weeks or is repositioned through interventional procedures, it is classified as Grade B. Grade C POPF refers to those with POPF-related organ failure, reoperation, or death.

Statistical analysis

Normally distributed numerical variables are presented as mean and standard deviation (SD) and were compared using the independent t-test, and non-normally distributed numerical variables are presented as median (the first quartile–the third quartile) and were compared using the Mann-Whitney test. Categorical variables are presented as frequencies with percentage and were tested using the chi-squared test or Fisher's exact test. Univariate logistic analysis and backward stepwise multivariate logistic regression analysis were performed to identify the independent risk factors for POPF after PD. Variables with P-values of <0.05 on univariate analyses were entered into the final multivariate model to reveal risk factors for POPF. For each parameter, an odds ratio (OR) for POPF was provided with a 95% confidence interval (CI). All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC). P-values of <0.05 were considered statistically significant.

Results

Demographic and clinical characteristics are shown in Table 1. The median time interval between preoperative CT and surgery was 14 days (mean, 15 days; range, 3–40 days). A total of 19 (17.8%) patients developed a pancreatic fistula after PD, including 15 (14.1%) with grade B POPF, and 4 (3.7%) with grade C POPF. In this study, all patients with POPF C underwent reoperation. There were 33 (30.8%) patients with biochemical leak.

Table 1

Baseline characteristics of subjects.

Characteristics
Demographic data
Subjects, no.	107
Age, years	65.9 ± 9.9
Male, no. (%)	64 (59.8)
Body mass index, kg/m2	23.2 ± 3.0
Final diagnosis, no. (%)
Benign disease	10 (9.3)
Chronic pancreatitis	3
Pseudocyst	1
Malignant disease	97 (90.7)
CBD cancer	34
Pancreatic head cancer	31
AOV cancer	23
Intraductal papillary mucinous neoplasm	7
Duodenal cancer	2
POPF, no. (%)
Absence	55 (51.4)
Biochemical leak	33 (30.8)
POPF grade B	15 (14.1)
POPF grade C	4 (3.7)

Note. Data are presented as mean ± standard deviation or number of subjects with percentage in parentheses.

The area of visceral fat, VF/SMI ratio, pancreas hardness and pathology were significantly different between the two groups (Table 2). Subjects with POPF had a significantly larger area of visceral fat (159.6 cm2 vs. 120.3 cm2, p = 0.022), higher VF/SMI ratio (3.30 vs. 2.54, p = 0.030), more frequently had a soft pancreas (78.9% vs. 53.4%, p = 0.045), and more frequently had pathology other than pancreatic adenocarcinoma or pancreatitis (97.4% vs. 62.5%, p = 0.045) than patients without POPF. However, sex, BMI, pancreatic duct diameter, operation time, intraoperative blood transfusion and use of a pancreatic stent were not significantly different between the two groups.

Table 2

Subject demographics and clinical characteristics.

	POPF (-) (n = 88)	POPF (+) (n = 19)	p-value
Age, years	65.8 ± 9.9	65.9 ± 10.4	0.983
Sex			0.074
Male, no. (%)	49 (55.7)	15 (78.9)
Female, no. (%)	39 (44.3)	4 (21.1)
Body mass index, kg/m2	23.1 ± 2.9	23.9 ± 3.2	0.273
Preoperative albumin, g/dL	3.75 ± 0.52	3.9 ± 0.59	0.085
Preoperative total bilirubin, mg/dL (IQR)	1.73 (0.69–4.28)	1.90 (0.58–5.80)	0.453
Pancreatic duct diameter, mm (IQR)	3.5 (1–6)	2 (1–4)	0.858
Skeletal muscle index (SMI), cm2	46.9 ± 9.1	47.2 ± 9.8	0.902
Visceral fat (VF), cm2	120.3 ± 62.2	159.6 ± 84.8	0.022 *
Subcutaneous fat, cm2	109.7 ± 59.3	104.3 ± 57.3	0.718
Abdominal circumference, cm	83.3 ± 8.5	87.3 ± 9.5	0.067
VF/SMI	2.54 ± 1.32	3.30 ± 1.57	0.030 *
Sarcopenia, no. (%)			0.493
No	40 (45.5)	7 (36.8)
Yes	48 (54.5)	12 (63.2)
Visceral obesity, no. (%)			0.067
No	34 (38.6)	3 (15.8)
Yes	54 (61.4)	16 (84.2)
Pancreatic hardness, no. (%)			0.045 *
Soft	47 (53.4)	15 (78.9)
Hard	41 (46.6)	4 (21.1)
Operation time, minutes	441 ± 71	476 ± 71	0.051
Transfusion, no. (%)			0.481
No	54 (61.4)	10 (52.6)
Yes	34 (38.6)	9 (47.4)
Stent, no. (%)			0.207
No	11 (12.5)	0
Yes	77 (87.5)	19 (100)
Pathology, no. (%)			0.006*
PDAC or pancreatitis	33 (37.5)	1 (5.3)
Other pathology	55 (62.5)	18 (94.7)

Note. Data are presented as mean ± standard deviation, median with interquartile range, or number of subjects with percentage in parentheses. * are the parameters with p<0.05.

Univariate regression analysis showed significant correlation between POPF and the following factors (Table 3): higher visceral fat (odds ratio [OR]: 1; 95% confidence interval [CI]: 1.00–1.02, p = 0.026), higher VF/SMI ratio (OR: 1.46; 95% CI: 1.03–2.07; p = 0.036), a soft texture of the pancreas (OR: 3.27; 95% CI: 1.01–10.64; p = 0.049), and pathology other than pancreatic adenocarcinoma or pancreatitis (OR: 2.38; 95% CI: 1.38–84.69; p = 0.024).

Table 3

Univariate risk factor analysis for postoperative pancreatic fistula.

Variable	Odds ratio	95% C.I.	p-value
Sex [Female]	2.99	0.92, 9.72	0.069
BMI	1.1	0.93, 1.31	0.272
Preoperative albumin	2.23	0.88, 5.63	0.9
Preoperative total bilirubin	1.06	0.94, 1.20	0.326
Pancreatic duct diameter	0.99	0.86, 1.13	0.856
SMI	1	0.95, 1.06	0.901
Visceral fat	1	1.00, 1.02	0.026 *
Subcutaneous fat	0.99	0.99, 1.01	0.715
Abdominal circumference	1.56	0.99, 1.12	0.07
VF/SMI	1.46	1.03, 2.07	0.036 *
Sarcopenia [Absence]	0.7	0.25, 1.95	0.494
Visceral obesity [Absence]	0.3	0.08, 1.10	0.069
Pancreatic hardness [Hard]	3.27	1.01, 10.64	0.049 *
Operation time	1.01	1.00, 1.01	0.055
Transfusion [Absence]	0.7	0.26, 1.90	0.483
Stent [Absence]	0	0	0.999
Pathology [PDAC or pancreatitis]	2.38	1.38, 84.69	0.024*

Note. Reference categories are in square brackets.

* are the parameters with p<0.05. C.I.: Confidence interval, BMI: Body mass index, PD: Pancreatic duct, VF: Visceral fat, SMI: Skeletal muscle index.

In the multivariate regression analysis, higher visceral fat (OR: 1.40; 95% CI: 1.07–15.43, p = 0.040) and pathology other than pancreatic adenocarcinoma or pancreatitis (OR: 12.45; 95% CI: 1.59–99.28; p = 0.017) were identified as independent risk factors for POPF (Table 4).

Table 4

Multivariable risk factor analysis for postoperative pancreatic fistula.

Variable	Odds ratio	95% C.I.	p-value
Visceral fat	1.40	1.07, 15.43	0.040*
Pathology [PDAC or pancreatitis]	12.45	1.59, 99.28	0.017*

Note. Reference categories are in square brackets. C.I.: Confidence interval, VF/SMI: Visceral fat to skeletal muscle index ratio.

* are the parameters with p<0.05.

Discussion

Pancreatic fistula after PD remains a challenging problem, even in high-volume centers. Identification of patients at a high risk of developing pancreatic fistula helps in a more elaborate risk-benefit assessment before surgery and may allow clinicians to coordinate perioperative care. In our study, we observed POPF in 17.8% (19/107) of patients. Higher visceral fat and pathology other than pancreatic adenocarcinoma or pancreatitis were independent risk factors for developing POPF after PD.

Recently, studies regarding the effects of sarcopenia and visceral obesity on POPF have been conducted. To date, few studies have examined the impact of sarcopenic obesity on survival in patients with pancreaticobiliary tumors [20,21,26,27]. Obesity and sarcopenia were synergistic and believed to exacerbate the risk of death, as well as the risk of metabolic disorders, and the number of related studies is increasing [28].

In our study, a larger area of visceral fat was significantly associated with POPF in both univariate and multivariate analyses, consistent with previous studies. The frequency of visceral obesity was higher in patients with POPF (84.2%, 16/19) compared to those without POPF (61.4%, 54/88), although it was not statistically significant. Percorali et al. also reported that the visceral fat area was an independent predictor of pancreatic fistula in patients undergoing PD [12]. Generally, patients with greater subcutaneous and visceral fat accumulation provide greater technical difficulty for surgeons. The view of the surgical field is deeper and poorer in obese patients, which may increase the risk of pancreatic fistula [14,29,30]. Other than mechanical reasons, excessive visceral fat is associated with insulin resistance [31] and comorbidities such as type 2 diabetes, atherosclerosis and cardiovascular disease [32,33], which may affect surgical outcomes negatively, including a higher rate of wound infection and anastomotic fistula and a longer hospital stay [30,34,35].

The skeletal muscle index and sarcopenia showed little association with POPF in this study. In a meta-analysis by Ratnayake et al., preoperative sarcopenia was not a significant negative predictive factor in postoperative morbidity, including POPF, following pancreatic resection [21]. On the contrary, there are several studies showing that sarcopenia is an independent risk factor for POPF [36,37]. Meanwhile, VF/SMI ratio was higher in POPF group than non-POPF group in our study, although it was not significant at multivariate analysis. High VF/SMI ratio could be referred to as sarcopenic obesity, a condition in which loss of muscle mass is accompanied by increase in fat accumulation [22]. Jang et al. also examined 284 patients who underwent PD between 2005 and 2016, concluded that sarcopenic obesity was the only predictor for POPF [20]. Although our study and study by Jang et al. used predefined cutoff for visceral obesity, sarcopenia, and sarcopenic obesity, an accurate definition of sarcopenic obesity has not yet been established. These various conclusions from existing studies suggest that the impact of sarcopenia and sarcopenic obesity in developing POPF following PD is still inconclusive and therefore further research is needed.

Higher POPF rate was observed in pathology other than PDAC or chronic pancreatitis, which was categorized according to the previously established fistula risk score criteria [38]. The mechanism by which pathologies other than PDAC or chronic pancreatitis increases the risk of POPF is related to the effect of soft pancreas parenchyma. Pathologies with pancreatic adenocarcinoma and chronic pancreatitis are more likely to result in hard parenchyma, therefore there could be a benefit in reducing the incidence of POPF. Hu et al. retrospectively analyzed 536 cases and also found that a soft pancreas was an independent risk factor for developing pancreatic fistula, including biochemical leak and POPF B and C, after PD (OR: 3.05, p<0.001) [9]. Kawai et al. reviewed 1,239 patients from 11 Japanese medical centers and concluded that a soft pancreas was a significant predictive factor for pancreatic fistula (OR: 2.7, p = 0.001) [39]. In this study, among a total of 107 patients, a soft pancreas was more frequent in subjects with POPF than in those without POPF (78.9% vs. 53.4%), although the result was not significant at multivariable analysis. A soft pancreas is more prone to laceration when performing suturing and tying. Moreover, the soft texture of pancreatic remnants induces technical difficulties in performing pancreatoenteric and duct-to-mucosa anastomoses, which increase the risk of anastomotic leakage [40]. Although it is not possible to evaluate soft pancreas before surgery, the possibility of POPF can be assessed by guessing the pathology through preoperative CT.

Our study had several limitations. First, due to its retrospective nature, it may have been influenced by selection and information biases. Second, it is a single-center study, which only includes Koreans; therefore, the findings may not be applicable to other populations. Third, several surgical anastomotic techniques have been established in recent years, but the technique used in each surgery was not analyzed in this study. Also, the pancreatic texture during the operation was evaluated by the surgeon, which may be subjective. Studies related to quantitative measurement of pancreas texture have been reported, such as MR elastography or ultrasound elastography [41,42]. Further research regarding the objective assessment of the pancreas texture is warranted.

In conclusion, larger area of visceral fat and pathology other than pancreatic adenocarcinoma or pancreatitis are independent predictors of POPF after pancreaticoduodenectomy and may allow better preparation of the postoperative care for patients by identifying patients at a high risk of developing pancreatic fistulas.

(XLSX)

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Comparison of clinical characteristics in subjects with and without visceral obesity.

(DOCX)

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18 Aug 2020

PONE-D-20-24280

Predictive value of preoperative CT for postoperative pancreatic fistula in patients following pancreaticoduodenectomy

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Reviewer #1: In this article, the authors conducted a retrospective analysis of 107 patients who underwent pancreaticoduodenectomy (PD). They performed univariate and multivariate logistic regression analyses to identify independent risk factors for POPF. They demonstrated that risk factors for POPF (grade B and C) were larger area of visceral fat and pathology other than pancreatic adenocarcinoma or pancreatitis. This research provides us new insights of preoperative CT for postoperative pancreatic fistula in patients following pancreaticoduodenectomy. However, the study has some weakness and concerns before the paper can be published.

Major revisions:

1. For the “Material and methods” part, the authors did not explain the authors did not explain the uniform standard for tissue sample texture. Moreover, the pancreatic texture of all subjects was examined by the surgeon, which is too subjective.

2. In Table 4, those variable whose p-value was over 0.05 should be listed.

Reviewer #2: This is a study on the prediction and evaluation of pancreatic leakage after pancreatoduodenectomy, which has certain clinical application.However, in this study, the interval between CT detection and surgery was the longest about 50 days, which significantly affected the evaluation effect.If the interval is about a week, the credibility is much higher.

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Reviewer #1: Yes: Weilin Wang

Reviewer #2: No

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10 Sep 2020

Reviewer #1.

1.For the “Material and methods” part, the authors did not explain the uniform standard for tissue sample texture. Moreover, the pancreatic texture of all subjects was examined by the surgeon, which is too subjective.

Recently, studies were conducted to objectify the pancreas texture or fatty pancreas through MR elastography or pancreas CT density measurement [1,2]. However, the analysis is complex and only possible in hospitals with special equipment.

Although it is a retrospective study and the evaluation of pancreas texture was subjective, it could be meaningful. Because, in our hospital, a structured questionnaire was recorded during or immediately after surgery about the surgery by specialized pancreas surgeon as a routine process, and pancreas texture also recorded in the same process. In addition, although the widely accepted definition of pancreas texture is still insufficient, the evaluation of the pancreatic texture in two stage by subjective judgment is still acceptable in systematic review and meta-analysis [3].

2.In Table 4, those variable whose p-value was over 0.05 should be listed.

Thank you for your kind comments. The odds ratio and p-value of the remaining variables are not shown since the stepwise method for multivariable logistic regression analysis was used in the analysis. This is added to the statistical analysis in the text.

Reviewer #2

3.This is a study on the prediction and evaluation of pancreatic leakage after pancreatoduodenectomy, which has certain clinical application. However, in this study, the interval between CT detection and surgery was longest about 50 days, which significantly affected the evaluation effect. If the interval is about a week, the credibility is much higher.

Thank you for your kind comment. Previous study of sarcopenia showed that CT scan taken within 30 days were used for analysis [4]. In our study, the median time interval between preoperative CT and surgery was 14 days (mean, 15 days; range, 3-40 days). Although if the Interval was shorter, it would be expected to have higher credibility, it could not be done due to limited subjects. The interval between preoperative CT and surgery was added in the result part.

References

1. Shi Y, Liu Y, Gao F, Liu Y, Tao S, Li Y et al. Pancreatic Stiffness Quantified with MR Elastography: Relationship to Postoperative Pancreatic Fistula after Pancreaticoenteric Anastomosis. Radiology. 2018 Aug;288(2):476-484.

https://doi.org/10.1148/radiol.2018170450 PMID: 29664337

2. Fukuda Y, Yamada D, Eguchi H, Hata T, Iwagami Y, Noda T et al. CT Density in the Pancreas is a Promising Imaging Predictor for Pancreatic Ductal Adenocarcinoma. Ann Surg Oncol. 2017;24(9):2762-2769. https://doi.org/10.1245/s10434-017-5914-3 PMID: 28634666

3. Eshmuminov D, Schneider MA, Tschuor C, Raptis DA, Kambakamba P, Muller X et al. Systematic review and meta-analysis of postoperative pancreatic fistula rates using the updated 2016 International Study Group Pancreatic Fistula definition in patients undergoing pancreatic resection with soft and hard pancreatic texture. HPB (Oxford). 2018;20(11):992-1003. https://doi.org/10.1016/j.hpb.2018.04.003 PMID: 29807807

4. Prado CM, Lieffers JR, McCargar LJ, Reiman T, Sawyer MB, Martin L, Baracos VE. Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol. 2008;9(7):629-635. https://doi.org/10.1016/S1470-2045(08)70153-0 PMID: 18539529

13 Oct 2020

PONE-D-20-24280R1

Predictive value of preoperative CT for postoperative pancreatic fistula in patients following pancreaticoduodenectomy

PLOS ONE

Dear Dr. Kim,

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Reviewer #3: This is a well written paper looking for associations that lead to post operative pancreatic fistulas, which is an important sequelae following pancreaticoduodenectomy.

I have a few comments:

1. I agree with reviewer 1, that points out that pancreatic texture hardness/softness is a subjective measure, though from clinical experience I agree that a 'soft' pancreas is more likely to lead to a leak. I accept that the authors have responded to the reviewer's comments: I would add that perhaps the authors add a sentence or two in the limitations of their work that this is a subjective measure, and more work needs to be done to be able to characterise pancreatic tissue density (and also reference the work relating to MR elastogram etc) within the actual paper.

2. Can the authors just clarify which multivariate logistic regression was used, it is mentioned it is stepwise, but was it forwards or backwards entered?

3. I may have missed it in the text, but re: the CT performed preoperatively, I note that the median time was 14 days, but why was it done? i.e. as part of the preoperative staging? Secondly re: CT postoperatively, I note that the exclusion criteria was any CTs beyond 50 days were excluded, but again in your unit did all your patients have CT scans post operatively, or was it due to post operative management looking for a complication?

4. I think the title is slightly misleading, as the title suggests that the CT scans preoperatively can identify potential patients who develop postoperative pancreatic fistula - however even in the abstract the finding of patients with pathologies other Pancreatic adenocarcinoma or pancreatitis is a significant finding (but not a radiological diagnosis!). Hence I would probably alter the title to reflect factors that may lead to POPF instead??

Reviewer #4: The authors assessed the risk factor of postoperative pancreatic fistula in patients who underwent pancreaticoduodenectomy (PD). Multivariate analysis showed the larger area of visceral fat and pathology other than pancreatic ductal adenocarcinoma (PDAC) or pancreatitis as risk factor of clincially-relevant POPF (CR-POPF). Authors reported that anthropometric measurement might be useful in detecting high risk patients with CR-POPF.

The following issues need to be thoroughly reviewed.

Major problems

1. Authors should analysis the previous established risk factor of CR-POPF such as drain amylase fluid on postoperative day 1 if they use final diagnosis of the tumor.

2. Authors should show the clinical characteristics of patients who with visceral obesity and those without.

3. In discussion (Page 11, Line 18), author speculated that the difficulty of operation in patients with greater visceral fat is the reason of high rate of CR-POPF. Do authors have objective data that shows the difficulty of pancreas anastomosis.

4. Moreover, do authors have objective data that excessive visceral fat is associated with insulin resistance and other morbidities in their study.

5. In discussion (Page 12, Line 18), authors stated “The mechanism by…soft pancreas parenchyma”. Is it correct? Many studies reported that PDAC decreased the risk of POPF.

6. Please describe about drain management in Method. Did authors place drain in all patients? And, did authors measure amylase level of drain fluid in all patients?

7. In statistics, authors used P-values of <0.05 on univariate analyses to select factors that were entered into multivariate analysis. This cut off of p-value is not common so that author should explain why they used this method.

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Reviewer #3: Yes: Franscois Runau

Reviewer #4: No

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6 Nov 2020

Reviewer #3.

1. I agree with reviewer 1, that points out that pancreatic texture hardness/softness is a subjective measure, though from clinical experience I agree that a 'soft' pancreas is more likely to lead to a leak. I accept that the authors have responded to the reviewer's comments: I would add that perhaps the authors add a sentence or two in the limitations of their work that this is a subjective measure, and more work needs to be done to be able to characterise pancreatic tissue density (and also reference the work relating to MR elastogram etc) within the actual paper.

Thank you for your advice. We added that the subjective nature of the surgeon's perception of the pancreas’ texture was a potential limitation in this study and that further research is warranted to quantitatively characterize the pancreatic texture using methods such as MR elastography or US elastography.

2. Can the authors just clarify which multivariate logistic regression was used, it is mentioned it is stepwise, but was it forwards or backwards entered?

We used the backward stepwise method for multivariable logistic regression analysis. This has been included in the statistical analysis portion of the text.

3. I may have missed it in the text, but re: the CT performed preoperatively, I note that the median time was 14 days, but why was it done? i.e. as part of the preoperative staging? Secondly re: CT postoperatively, I note that the exclusion criteria was any CTs beyond 50 days were excluded, but again in your unit did all your patients have CT scans post operatively, or was it due to post operative management looking for a complication?

The CT scans were performed as a preoperative assessment in all subjects. Regarding the exclusion criteria, the “interval between CT and surgery >50 days” was deemed to be misleading. The interval was corrected to 40 days in the previous revision. Therefore, we worded the sentence as “interval between preoperative CT and surgery >40 days” in the text. All subjects routinely underwent postoperative CT scanning for postoperative complications.

4. I think the title is slightly misleading, as the title suggests that the CT scans preoperatively can identify potential patients who develop postoperative pancreatic fistula - however even in the abstract the finding of patients with pathologies other Pancreatic adenocarcinoma or pancreatitis is a significant finding (but not a radiological diagnosis!). Hence I would probably alter the title to reflect factors that may lead to POPF instead??

Thank you for the suggestion. Accordingly, we changed the title to "Preoperative CT anthropometric measurements and pancreatic pathology increase risk for postoperative pancreatic fistula in patients following pancreaticoduodenectomy" to reflect factors that could cause POPF.

Reviewer #4

1. Authors should analysis the previous established risk factor of CR-POPF such as drain amylase fluid on postoperative day 1 if they use final diagnosis of the tumor.

According to the 2016 update issued by the International Study Group of Pancreatic Fistula, POPF can be diagnosed when any measurable volume of drain fluid on or after postoperative day (POD) 3 with amylase levels exceeding 3 times the upper limit of normal amylase for each specific institution is detected. Although several studies have been conducted to understand the impact of day 1 drain amylase in predicting POPF after pancreaticoduodenectomy, they all presented different cutoff values for day 1 drain amylase concentration [1]. Molinari et al. [2] reported that a drain amylase value >5000 U/L was a predictive factor for pancreatic fistula development. Jin et al. [3] suggested an amylase level of 2365 U/L in the drainage fluid as the optimal cutoff value for predicting pancreatic fistula.

Drain amylase fluid levels on POD 1 may indeed be a useful marker for the identification of POPF. However, further evaluation is needed to determine the optimal cutoff value. Moreover, since other well-established risk factors for POPF, such as sex, body mass index (BMI), pancreatic duct size, pancreatic texture, blood transfusion, intraoperative blood loss, and operation time, were included in our study, we believe the result to be meaningful.

2. Authors should show the clinical characteristics of patients who with visceral obesity and those without.

Thank you for your advice. We have added a supplementary table containing the clinical characteristics of the subjects with and without visceral obesity.

Please refer to the attached file 'S2 Table (DOCX)'.

3. In discussion (Page 11, Line 18), author speculated that the difficulty of operation in patients with greater visceral fat is the reason of high rate of CR-POPF. Do authors have objective data that shows the difficulty of pancreas anastomosis.

Obesity has negative effects on the surgical outcome following pancreaticoduodenectomy according to other studies. [4-5] The technical difficulty of treating obese patients may contribute to the development of POPF. Our study also showed that the operation time was significantly longer in subjects with visceral obesity than in those without. Future research focusing on the effect of visceral obesity on pancreatic fistula after pancreatic resection is needed.

4. Moreover, do authors have objective data that excessive visceral fat is associated with insulin resistance and other morbidities in their study.

Thank you for your comment. There is no objective data on this topic in our research because our study focused primarily on the risk factors for POPF. However, many scientific review papers have assessed the role of visceral obesity as an emerging risk factor for type 2 diabetes, atherosclerosis, and cardiovascular disease. More research is needed on the mechanism by which visceral obesity causes POPF. However, we have incorporated additional references into the text.

5. In discussion (Page 12, Line 18), authors stated “The mechanism by…soft pancreas parenchyma”. Is it correct? Many studies reported that PDAC decreased the risk of POPF.

Thank you for your observation. This was a mistake, and we have replaced it with “pathologies other than PDAC or chronic pancreatitis.”

6. Please describe about drain management in Method. Did authors place drain in all patients? And, did authors measure amylase level of drain fluid in all patients?

At our institution, external drains were inserted in proximity to the pancreatic anastomosis during each surgery, at which time the amylase level of drain fluid was routinely measured. We have added this information to the manuscript.

7. In statistics, authors used P-values of <0.05 on univariate analyses to select factors that were entered into multivariate analysis. This cut off of p-value is not common so that author should explain why they used this method.

Multivariate analysis using all variables are ideal because the statistical program automatically applies and analyzes the significant variables, but its suitability depends on the situation. When many explanatory variables are present, only variables with a p-value of 0.05 or less (i.e., statistically significant variables) as determined by univariate analysis could be included in the multivariate analysis. Researchers can perform statistical analysis in several different ways; however, as pointed out by the reviewer, we re-analyzed the results. When multivariate analysis was performed on all variables, the following results were obtained, and visceral fat and pathology were still significant variables.

Please refer to the table attached in the 'Response to Reviewers (DOCX)' file.

References

1. Liu Y, Li Y, Wang L, Peng CJ. Predictive value of drain pancreatic amylase concentration for postoperative pancreatic fistula on postoperative day 1 after pancreatic resection: An updated meta-analysis. Medicine (Baltimore). 2018;97(38):e12487. https://doi.org/10.1097/MD.0000000000012487 PMID: 30235751

2. Molinari E, Bassi C, Salvia R, Butturini G, Crippa S, Talamini G, et al. Amylase value in drains after pancreatic resection as predictive factor of postoperative pancreatic fistula - Results of a prospective study in 137 patients. Annals of Surgery. 2007;246(2):281-287. https://doi.org/10.1097/SLA.0b013e3180caa42f PMID: 17667507

3. Jin S, Shi XJ, Wang SY, Zhang P, Lv GY, Du XH, et al. Drainage fluid and serum amylase levels accurately predict development of postoperative pancreatic fistula. World J Gastroenterol. 2017;23(34):6357-6364. https://doi.org/10.3748/wjg.v23.i34.6357 PMID: 28974903

4. Park CM, Park JS, Cho ES, Kim JK, Yu JS, Yoon DS. The effect of visceral fat mass on pancreatic fistula after pancreaticoduodenectomy. J Invest Surg. 2012;25(3):169-173. Https://doi.org/10.3109/08941939.2011.616255 PMID: 22583013

5. Shamali A, Shelat V, Jaber B, Wardak A, Ahmed M, Fontana M, et al. Impact of obesity on short and long term results following a pancreatico-duodenectomy. Int J Surg. 2017;42:191-196. https://doi.org/10.1016/j.ijsu.2017.04.058 PMID: 28461146

Submitted filename: Responses to Reviewers.docx

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23 Nov 2020

Preoperative CT anthropometric measurements and pancreatic pathology increase risk for postoperative pancreatic fistula in patients following pancreaticoduodenectomy

PONE-D-20-24280R2

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25 Nov 2020

PONE-D-20-24280R2

Preoperative CT anthropometric measurements and pancreatic pathology increase risk for postoperative pancreatic fistula in patients following pancreaticoduodenectomy

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