The efficacy of wrapping with polyglycolic acid mesh and fibrin glue in preventing clinically relevant pancreatic fistula after minimally invasive distal pancreatectomy (WRAP Study): study protocol for a multicenter randomized controlled trial in Japan.

BACKGROUND: Postoperative pancreatic fistula (POPF) continues to be the most common complication after distal pancreatectomy (DP). Recent advancements in surgical techniques have established minimally invasive distal pancreatectomy (MIDP) as the standard treatment for various conditions, including pancreatic cancer. However, MIDP has not demonstrated a clear advantage over open DP in terms of POPF rates, indicating the need for additional strategies to prevent POPF in MIDP. This trial (WRAP study) aims to evaluate the efficacy of wrapping the pancreatic stump with polyglycolic acid (PGA) mesh and fibrin glue in preventing clinically relevant (CR-) POPF following MIDP. METHODS: This multicenter, randomized controlled trial will include patients scheduled for laparoscopic or robotic DP for tumors in the pancreatic body and/or tail. Eligible participants will be centrally randomized into either the control group (Group A) or the intervention group (Group B), where the pancreatic stump will be reinforced by PGA mesh and fibrin glue. In both groups, pancreatic transection will be performed using a bioabsorbable reinforcement-attached stapler. A total of 172 patients will be enrolled across 14 high-volume centers in Japan. The primary endpoint is the incidence of CR-POPF (International Study Group of Pancreatic Surgery grade B/C). DISCUSSION: The WRAP study will determine whether the reinforcement of the pancreatic stump with PGA mesh and fibrin glue, a technique whose utility has been previously debated, could become the best practice in the era of MIDP, thereby enhancing its safety. TRIAL REGISTRATION: This trial was registered with the Japan Registry of Clinical Trials on June 15, 2024 (jRCTs032240120).

Evaluation of whole genome sequencing utility in identifying driver alterations in cancer genome.

In cancer genome analysis, identifying pathogenic alterations and assessing their effects on oncogenic processes is important. Although whole exome sequencing (WES) can effectively detect such changes, driver alterations could not be identified in 27.8% of the cases, according to a previous study. The objectives of the present study were to evaluate the utility of whole genome sequencing (WGS) and clarify its differences with WES in terms of driver alteration detection. For this purpose, WGS analysis was conducted on 177 driverless WES samples, selected from 5,480 fresh frozen samples derived from 5,140 Japanese patients with cancer. These samples were selected as primary tumor, both WES and transcriptome profiling were performed, estimated tumor content of ≥ 30%, and no driver alterations were identified by WES. WGS identified driver and likely driver alterations in 68.4 and 22.6% of the samples, respectively. The most frequent alteration type was oncogene amplification, followed by tumor suppressor gene deletion and small variants located outside the coding region. In the remaining 9.0% of samples, no such signals were identified; therefore, further investigations are required. The current study clearly demonstrated the role and utility of WGS in identifying genomic alterations that contribute to tumorigenesis.

Is multidisciplinary treatment effective for invasive intraductal papillary mucinous carcinoma?

Background: Surgical resection is standard treatment for invasive intraductal papillary mucinous carcinoma (IPMC); however, impact of multidisciplinary treatment on survival including postoperative adjuvant therapy (AT), neoadjuvant therapy (NAT), and treatment for recurrent lesions is unclear. We investigated the effectiveness of multidisciplinary treatment in prolonging survival of patients with invasive IPMC. Methods: This retrospective multi-institutional study included 1183 patients with invasive IPMC undergoing surgery at 40 academic institutions. We analyzed the effects of AT, NAT, and treatment for recurrence on survival of patients with invasive IPMC. Results: Completion of the planned postoperative AT for 6 months improved the overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) of patients with stage IIB and stage III resected invasive IPMC, elevated preoperative carbohydrate antigen 19-9 level, lymphovascular invasion, perineural invasion, serosal invasion, and lymph node metastasis on un-matched and matched analyses. Of the patients with borderline resectable (BR) invasive IPMC, the OS (p = 0.001), DSS (p = 0.001), and RFS (p = 0.001) of patients undergoing NAT was longer than that of those without on the matched analysis. Of the 484 invasive IPMC patients (40.9%) who developed recurrence after surgery, the OS of 365 patients who received any treatment for recurrence was longer than that of those without treatment (40.6 vs. 22.4 months, p < 0.001). Conclusion: Postoperative AT might benefit selected patients with invasive IPMC, especially those at high risk of poor survival. NAT might improve the survivability of BR invasive IPMC. Any treatment for recurrence after surgery for invasive IPMC might improve survival.

Clinical Implications of the Degree of Pancreatic Invasion in Ampulla of Vater Carcinoma.

BACKGROUND: Ampulla of Vater carcinoma (AVC) stage T3 was subdivided according to the degree of pancreatic invasion into T3a (≤ 0.5 cm) and T3b (> 0.5 cm) by the 8th edition of the Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) cancer staging system. However, the differences in clinicopathological features and survival outcomes between the two categories have not been well discussed. PATIENTS AND METHODS: We retrospectively analyzed 133 consecutive patients who underwent pancreatoduodenectomy for AVC at our institution between 2002 and 2020. Clinicopathological features and survival outcomes of patients with AVC were analyzed, with a focus on the depth of pancreatic invasion. In addition, the survival outcomes of patients with T3 AVC were compared with those of patients with resectable pancreatic head carcinoma (R-PhC) who underwent pancreatoduodenectomy during the same period. RESULTS: The overall survival (OS) in patients with T3b AVC (n = 12) was significantly worse than that in patients with T3a AVC (n = 39) [median survival time (MST) 9.2 vs. 74.5 months, p < 0.001). A multivariate analysis identified T3b tumor (hazard ratio 5.64, p = 0.009) as an independent prognostic factor. The OS of patients with T3a AVC was significantly better than that of patients with R-PhC who received adjuvant chemotherapy (n = 276, MST 35.0 months, p = 0.007). In contrast, the OS of patients with T3b AVC tended to be worse than that of patients with R-PhC managed without adjuvant chemotherapy, although this difference was not statistically significant (n = 163; MST, 17.5; p = 0.140). CONCLUSIONS: AVC with > 0.5 cm invasion into the pancreas was associated with poor survival and represented advanced tumor progression to systemic disease.

Clinical utility of the forward-viewing echoendoscope in patients after pancreatoduodenectomy: A prospective study.

Background and Objectives: Endoscopic treatment of obstructive jaundice and pancreatitis due to hepaticojejunostomy (H-J), pancreatojejunostomy (P-J) strictures, and tumor recurrence after pancreatoduodenectomy (PD) is technically challenging. Treatment of P-J strictures results in poor outcomes. Although conventional EUS that has an oblique view is not suitable for such patients, forward-viewing EUS (FV-EUS) may become a useful option. This study aimed to evaluate the feasibility and efficacy of FV-EUS in patients who have undergone PD. Methods: Patients with PD who were scheduled to undergo diagnosis and treatment using FV-EUS for H-J or P-J lesions were enrolled in this single-center prospective study. After observation of the P-J and H-J using FV-EUS according to a predetermined protocol, treatment using FV-EUS was performed as needed. Results: A total of 30 patients were enrolled, and FV-EUS was used to observe P-J and H-J in 24 and 28 patients, respectively. The detection rates of P-J and H-J by endoscopy were 50% (12/24) and 96.4% (27/28), respectively, and by EUS were 70.8% (17/24) and 100% (28/28), respectively. Of these, P-J and H-J were found by endoscopy only after EUS observation in 3 and 1 patient, respectively. The success rates of endoscopic treatment using FV-EUS were 66.7% (2/3), 95.2% (20/21), and 25% (1/4) for benign P-J strictures, benign H-J strictures, and tumor recurrence, respectively. Conclusions: Endoscopic treatment using FV-EUS is feasible and effective for patients after PD. Moreover, FV-EUS increases the P-J lesion detection rate by adding EUS observation.

The KRAS G12D mutation increases the risk of unresectable recurrence of resectable colorectal liver-only metastasis.

PURPOSE: Unresectable recurrence is a critical predictor of outcomes for colorectal cancer patients. We attempted to identify the prognostic factors, especially for unresectable recurrence-free survival (URFS) as a new endpoint, in patients with resectable colorectal liver-only metastasis (CRLOM). METHODS: We investigated patients with resectable CRLOM, who underwent an R0 resection for both CRC and CRLOM between January, 2014 and March, 2019 at a single institution. The exclusion criteria were patients who received neoadjuvant treatment, the absence of data for genetic analyses, and the presence of multiple cancers, synchronous CRC, or familial adenomatous polyposis. The prognostic factors were examined retrospectively using data on pre-hepatectomy factors, including primary tumor molecular profiling results. RESULTS: We analyzed the data of 101 patients who underwent curative-intent surgery for CRLOM. Multivariate analysis revealed that KRAS G12D mutation-positivity (hazard ratio [HR]: 7.69; p < 0.01), RYR2 mutation-positivity (HR: 4.03; p < 0.01), and KRAS G12S mutation-positivity (HR: 3.96; p = 0.03), CA19-9 > 37 U/ml before hepatectomy (HR: 3.62; p < 0.01), and primary tumor pN2 stage (HR: 3.22; p = 0.03) were significant predictors of the URFS. CONCLUSIONS: This is the first study to show that specific KRAS and RYR2 mutations were associated with the URFS.

Prognosis of Postoperative Cholangitis Following Pancreaticoduodenectomy: A Single-Centered Retrospective Cohort Study.

Introduction Postoperative cholangitis (POC) after pancreaticoduodenectomy is a serious complication. However, the prognostic factors are unclear. We aimed to investigate the relationships between biliary lesions and prognosis in patients with cholangitis after pancreaticoduodenectomy. Methods We conducted a single-centered retrospective cohort study. The unit of analysis was hospital admissions. We extracted patients who underwent pancreaticoduodenectomy from 2010 to 2018, and have a record of hospitalization of cholangitis from January 2010 to October 2019. We defined the bile duct lesions as the presence of one of the following: biliary stent, intrahepatic bile duct dilatation, intrahepatic bile duct stones, or common bile duct stones on imaging studies. The primary outcome was the treatment failure of POC. We defined the failure as a composite outcome of death within 30 days of initiation of treatment, relapse during treatment, or recurrence of cholangitis. We used logistic regression analysis to examine the association between the presence of bile duct lesions and the occurrence of outcomes. Results Of 154 admissions included in the present study, 120 cases (77.9%) were with bile duct lesions. Bile duct lesions were associated with the treatment failure (crude odds ratio [OR] 2.56, 95% confidence intervals [CI] 1.08 to 6.32; adjusted OR 2.81, 95%CI 1.08 to 7.34). Conclusions Clinicians should follow the patient of POC with bile duct lesions on imaging carefully because of the high risk of treatment failure, especially for recurrence. Further studies are warranted to confirm our results.

Positive impact of laparoscopic hepatectomy versus open hepatectomy on body size-corrected bleeding in obese patients.

PURPOSE: Laparoscopic hepatectomy (LH) is reported to cause less bleeding than open hepatectomy (OH) in obese patients; however, there are no reports addressing this issue in terms of body size-corrected bleeding. METHODS: The subjects of this study were 31 obese and 149 non-obese patients who underwent LH and 32 obese and 245 non-obese patients who underwent OH. Bleeding corrected for body surface area (C-BL) was compared between the obese and non-obese patients who underwent each procedure. A multivariate analysis for increased C-BL was performed using the median C-BL for each procedure. RESULTS: The median C-BL tended to be higher in the obese patients than in the non-obese patients who underwent LH, but there was no significant difference (72 vs. 42 mL/m2, P = 0.050). However, it was significantly higher in the obese patients than in the non-obese patients who underwent OH (542 vs. 333 mL/m2, P = 0.002). In a multivariate analysis, for OH, sectionectomy or more (OR 3.20, P < 0.001) and a high BMI (OR 2.76, P = 0.018) were found to be independent risk factors, whereas for LH, a high BMI was not (OR 1.58, P = 0.301). CONCLUSIONS: Obesity was identified as a risk factor for increased bleeding with body size correction for OH, but the risk was reduced for LH.

Impact of biliary drainage method before pancreaticoduodenectomy on short- and long-term outcomes in patients with periampullary carcinoma and obstructive jaundice: A multicenter retrospective analysis.

BACKGROUND: The optima preoperative biliary drainage before pancreaticoduodenectomy in patients with biliary tract and pancreatic cancer remains controversial. METHODS: A total of 898 patients who underwent preoperative biliary drainage via endoscopic retrograde biliary drainage, endoscopic transnasal biliary drainage, or percutaneous transhepatic biliary drainage before pancreaticoduodenectomy for biliary tract and pancreatic cancer were included. Perioperative and long-term outcomes were analyzed. RESULTS: The Clavien-Dindo grade ≥3 morbidity rates after pancreaticoduodenectomy were higher in the endoscopic retrograde biliary drainage (21.9%; P = .001) or endoscopic transnasal biliary drainage (20.2%; P = .007) than in the percutaneous transhepatic biliary drainage (9.7%) groups. In biliary tract cancer, the frequency of dissemination after pancreaticoduodenectomy was higher in the percutaneous transhepatic biliary drainage (15.3%) than in the endoscopic retrograde biliary drainage (0.7%; P = .001) and endoscopic transnasal biliary drainage (4.1%; P = .037) groups; percutaneous transhepatic biliary drainage was an independent factor associated with worse disease-free survival (P = .04), whereas in pancreatic cancer the frequency of dissemination and survival was comparable among the 3 preoperative biliary drainage methods. Albumin <3.9 g/dL was independently associated with worse overall survival in patients with both pancreatic (P = .038) and biliary tract (P = .002) cancers, respectively. During biliary drainage, external drainage (P = .038) was independently associated with albumin <3.9 g/dL; albumin was higher in endoscopic retrograde biliary drainage group than in endoscopic transnasal biliary drainage or percutaneous transhepatic biliary drainage groups after 21 days from tube insertion. CONCLUSION: In biliary tract cancer, percutaneous transhepatic biliary drainage may carry the risk of increasing the incidence of disseminative recurrence. In pancreatic cancer, percutaneous transhepatic biliary drainage is preferable owing to fewer complications without influencing recurrence. However, if patients cannot undergo surgery immediately, endoscopic retrograde biliary drainage will be applicable to help the preservation of nutritional status, which can have an impact on survival.

Subdivision of pT1N0 (American Joint Committee on Cancer 8th edition) distal cholangiocarcinoma for adjuvant chemotherapy consideration.

BACKGROUND: The adjuvant S-1 trial affirmed adjuvant chemotherapy for biliary tract cancer but excluded pT1N0 distal cholangiocarcinoma (DCC) according to the seventh edition of the American Joint Committee on Cancer (AJCC) classification. The introduction of tumor depth of invasion (DOI) for T-classification in the eighth edition complicates identifying DCC patients less likely to benefit from adjuvant chemotherapy. METHODS: Our cohort consisted of 185 patients with DCC who underwent pancreaticoduodenectomy between 2002 and 2019. We compared clinicopathological factors and survival outcomes between pT1N0 patients in the seventh edition and those in the eighth edition. New DOI cutoffs for subdividing pT1N0 (8th edition) patients were evaluated to identify patients less likely to benefit from adjuvant chemotherapy. RESULTS: Transitioning to the eighth edition increased in pT1N0 cases from eight to 46. The 5-year cumulative recurrence rates of them were 14.3% for the seventh edition and 28.3% for the eighth edition. We proposed a DOI cutoff of <2 mm, at which the 5-year cumulative recurrence rate was 11.5%. CONCLUSION: The eighth AJCC classification revealed that a significant proportion of pT1N0 DCC patients were at risk for recurrence. A DOI cutoff of <2 mm may be considered to potentially improve patient selection for adjuvant chemotherapy.

Clinical Significance of Primary Tumor Resection in Perihilar Cholangiocarcinoma with Positive Peritoneal Lavage Cytology.

BACKGROUND: The prognostic impact of positive peritoneal lavage cytology (CY+) in patients with perihilar cholangiocarcinoma (PHC) remains unclear. The present study investigated the clinical significance of primary tumor resection of CY+ PHC. METHODS: We retrospectively evaluated 282 patients who underwent surgery for PHC between September 2002 and March 2022. The patients' clinicopathological characteristics and survival outcomes were compared between the CY negative (CY-) resected (n = 262), CY+ resected (n = 12), and CY+ unresected (n = 8) groups. Univariate and multivariate analyses were performed to identify prognostic factors for overall survival. RESULTS: The expected residual liver volume was significantly higher in the CY+ resected group (61%) than in the CY- resected (47%) and CY+ unresected (37%) groups (p = 0.004 and 0.007, respectively). The CY+ resected group had a higher administration rate of postoperative therapy than the CY- resected group (58% vs. 16%, p = 0.002). Overall survival of the CY+ resected group was similar to that of the CY- resected group (median survival time [MST] 44.5 vs. 44.6, p = 0.404) and was significantly better than that of the CY+ unresected group (MST 44.5 vs. 17.1, p = 0.006). CY positivity was not a prognostic factor according to a multivariate analysis in patients with primary tumor resection. CONCLUSIONS: The CY+ resected group showed better survival than the CY+ unresected group and a similar survival to that of the CY- resected group. Resection of the primary tumor with CY+ PHC may improve the prognosis in selected patients.

Predictive score for identifying intrahepatic cholangiocarcinoma patients without lymph node metastasis: a basis for omitting lymph node dissection.

BACKGROUND: This study aimed to develop a predictive score for intrahepatic cholangiocarcinoma (ICC) in patients without lymph node metastasis (LNM) using preoperative factors. METHODS: A retrospective analysis of 113 ICC patients who underwent liver resection with systemic lymph node dissection between 2002 and 2021 was conducted. A multivariate logistic regression analysis was used as a predictive scoring system for node-negative patients based on the ß coefficients of preoperatively available factors. RESULTS: LNM was observed in 36 patients (31.9%). Four factors were associated with LNM: suspicion of LNM on MDCT (odds ratio [OR] 13.40, p < 0.001), low-vascularity tumor (OR 6.28, p = 0.005), CA19-9 ≥500 U/mL (OR 5.90, p = 0.010), and tumor location in the left lobe (OR 3.67, p = 0.057). The predictive scoring system was created using these factors (assigning 3 points for suspected LNM on MDCT, 2 points for CA19-9 ≥500 U/mL, 2 points for low vascularity tumor, and 1 point for tumor location in the left lobe). A score cutoff value of 4 resulted in 0.861 sensitivity and a negative predictive value of 0.922 for detecting LNM. Notably, no patients with peripheral tumors and a score of ≤3 had LNM. CONCLUSION: The developed scoring system may effectively help identify ICC patients without LNM.

Double hepatic vein reconstruction during extended anatomical resection of segment 8 for colorectal liver metastasis.

BACKGROUND: Hepatic vein reconstruction (HVR) is occasionally necessary for resecting hepatic malignancies to ensure surgical margins while preserving remnant liver function [1]. Reports of multiple HVR are rare due to the highly technical demanding procedure and high risk of morbidity [2]. We introduce our procedure of double HVR for metastatic liver tumors invading the right hepatic vein (RHV) and middle hepatic vein (MHV). METHODS: The patient was a 66-year-old man with colorectal liver metastasis in segment 8, invading RHV and MHV. Due to impaired liver function, extended right hemihepatectomy was unsuitable. Thus, extended anatomical resection of segment 8 with double HVR was performed. The liver was completely mobilized and the RHV and MHV were secured. After liver parenchyma dissection, the specimen was connected by RHV and MHV (Fig. 1). The MHV was dissected and reconstructed using a right superficial femoral vein graft while the RHV remained connected [3]. Reconstruction of the MHV was performed on the posterior wall of the proximal side, followed by the anterior wall, using 4-point supporting threads. Anastomosis was performed by the over-and-over suture method. On the distal side, two-point supporting threads were applied. After specimen removal, the RHV was resected and reconstructed in the same manner using a left internal jugular vein graft [4]. RESULTS: The patient was discharged on postoperative day 14 with no signs of liver failure. Computed tomography performed six months after surgery revealed no graft occlusion (Fig. 2). CONCLUSION: In appropriately selected patients, this technique may be a useful option for preserving the remnant liver function.

Efficacy of lymph node dissection for duodenal cancer according to the lymph node station.

Background: Lymph node metastasis (LNM) is associated with poor prognosis in patients with duodenal cancer (DC). However, the efficacy and optimal extent of lymph node (LN) dissection have not been thoroughly discussed. Methods: A total of 98 consecutive patients with DC who underwent surgical resection (pancreatoduodenectomy, n = 55; partial resection, n = 32; pancreas-sparing total duodenectomy, n = 9) were retrospectively analyzed. The LN stations located upstream of the lymphatic flow were defined as Np stations according to tumor location, whereas the others were defined as Nd stations. The association between the dissection of each LN station and survival outcome was investigated using the efficacy index (EI; percentage of metastases to lymph nodes in each station multiplied by the 5-year survival rate of metastatic cases). Results: The survival of patients with LNM at the Nd stations (n = 6) was significantly worse than that of patients with LNM only at the Np stations (n = 20) (relapse-free survival, median survival time [MST], 6.0 vs. 48.4 months, p < 0.001; overall survival, MST, 15.1 vs. 96.0 months, p < 0.001). Multivariate analysis identified LNM at Nd stations as an independent prognostic factor for overall survival (hazard ratio 9.92; p = 0.015). The Np stations had a high EI (range, 8.34-20.88), whereas the Nd stations had an EI of 0, regardless of the tumor location. Conclusions: LN dissection of the Np stations contributed to acceptable survival, whereas LNM of the Nd stations led to poor survival, possibly reflecting advanced tumor progression to systemic disease in patients with DC.

Tumor vascularity on contrast-enhanced computed tomography as a predictive marker of metastatic potential for small nonfunctioning pancreatic neuroendocrine tumors.

BACKGROUND: Although surgical resection is generally suggested for nonfunctioning pancreatic neuroendocrine tumors, observation can be proposed for carefully selected patients with small tumors. However, the indications for observation remain unclear. METHODS: This retrospective study included 77 patients with nonfunctioning pancreatic neuroendocrine tumors, including small tumors (≤2.0 cm, n = 41), who received pancreatectomy. The ratio of the mean computed tomography value of a tumor in the late arterial/equilibrium phase (computed tomography a/e ratio) was used to evaluate tumor vascularity. Pathologic examinations of small tumors were conducted. The associations among the computed tomography a/e ratio, pathologic findings, and survival outcomes were investigated. RESULTS: Small tumors were pathologically categorized by the degree of fibrosis as follows: medullary (n = 20), intermediate (n = 11), and fibrotic (n = 10). The fibrotic type had significantly lower computed tomography a/e ratios than the medullary type (median, 1.42 vs 2.03, P < .001). The median number of vessels with microscopic venous invasion was significantly higher in the fibrotic type than in the medullary type (4.5 vs 0.0, P < .001). The cutoff value of the computed tomography a/e ratio for predicting microscopic venous invasion was determined to be 1.54 by the receiver operating characteristic curve (area under the curve, 0.832; sensitivity, 80.0%; specificity, 83.9%; accuracy, 82.9%). Microscopic venous invasion was an independent prognostic factor for relapse-free survival in overall patients (hazard ratio 5.18, P = .017). CONCLUSION: The computed tomography a/e ratio may be a useful predictor of the metastatic potential of nonfunctioning pancreatic neuroendocrine tumors and may help decide the indications of observation for small nonfunctioning pancreatic neuroendocrine tumors.