Three Molecular Developmental Pathways of Remnant Pancreatic Cancer after Resection: A Nationwide Project Study of Japan Pancreas Society.

OBJECTIVE: This study aimed to clarify the molecular mechanism of remnant pancreatic cancer (PC) development after primary PC resection. SUMMARY BACKGROUND DATA: Molecular mechanisms of the development of remnant PCs following primary PC resection are largely unknown. METHODS: Forty-three patients undergoing remnant PC resection after primary PC resection between 2001 and 2017 at 26 institutes were retrospectively analyzed. Clinicopathological features and molecular alterations detected by targeted amplicon sequencing of 36 PC-associated genes were evaluated. RESULTS: These patients showed significantly lower body mass indices and higher hemoglobin A1c values at remnant PC resection than at primary PC resection. A comparison of the molecular features between primary and remnant PCs indicated that remnant PCs were likely to develop via three different molecular pathways: successional, showing identical and accumulated alterations (n=14); phylogenic, showing identical and distinct alterations (n=26); and distinct, showing independent distinctive alterations (n=3). The similarity of gene alterations was associated with time to the remnant PC development (r=－0.384, P=0.0173). Phylogenic pathways were significantly associated with the intraductal spread of carcinoma (P=0.007). Patient survival did not differ significantly depending on these molecular pathways. CONCLUSION: Molecular profiling uncovered three pathways for the development of remnant PCs, namely, successional, phylogenic, and distinct pathways. The vast majority of remnant PCs are likely to be molecularly associated with primary PCs either in the successional or phylogenic way. This information could impact the design of a strategy for monitoring and treating remnant PCs.

Factors Affecting Nonfunctioning Small Pancreatic Neuroendocrine Neoplasms and Proposed New Treatment Strategies.

BACKGROUND & AIMS: Despite previously reported treatment strategies for nonfunctioning small (≤20 mm) pancreatic neuroendocrine neoplasms (pNENs), uncertainties persist. We aimed to evaluate the surgically resected cases of nonfunctioning small pNENs (NF-spNENs) in a large Japanese cohort to elucidate an optimal treatment strategy for NF-spNENs. METHODS: In this Japanese multicenter study, data were retrospectively collected from patients who underwent pancreatectomy between January 1996 and December 2019, were pathologically diagnosed with pNEN, and were treated according to the World Health Organization 2019 classification. Overall, 1490 patients met the eligibility criteria, and 1014 were included in the analysis cohort. RESULTS: In the analysis cohort, 606 patients (59.8%) had NF-spNENs, with 82% classified as grade 1 (NET-G1) and 18% as grade 2 (NET-G2) or higher. The incidence of lymph node metastasis (N1) by grade was significantly higher in NET-G2 (G1: 3.1% vs G2: 15.0%). Independent factors contributing to N1 were NET-G2 or higher and tumor diameter ≥15 mm. The predictive ability of tumor size for N1 was high. Independent factors contributing to recurrence included multiple lesions, NET-G2 or higher, tumor diameter ≥15 mm, and N1. However, the independent factor contributing to survival was tumor grade (NET-G2 or higher). The appropriate timing for surgical resection of NET-G1 and NET-G2 or higher was when tumors were >20 and >10 mm, respectively. For neoplasms with unknown preoperative grades, tumor size >15 mm was considered appropriate. CONCLUSIONS: NF-spNENs are heterogeneous with varying levels of malignancy. Therefore, treatment strategies based on tumor size alone can be unreliable; personalized treatment strategies that consider tumor grading are preferable.

Gene Rearrangement and Expression of PRKACA and PRKACB Govern Morphobiology of Pancreatobiliary Oncocytic Neoplasms.

Intraductal oncocytic papillary neoplasms (IOPNs) are distinct from intraductal papillary mucinous neoplasms based on characteristic morphologic and genetic features represented by fusion genes involving PRKACA or PRKACB (PRKACA/B). However, pancreatic and biliary tumors with partial oncocytic features are often encountered clinically, and their molecular features are yet to be clarified. This study included 80 intraductal papillary neoplasms: 32 tumors with mature IOPN morphology (typical), 28 with partial or subclonal oncocytic features (atypical), and 20 without oncocytic features (control). We analyzed PRKACA/B fusion genes, including ATP1B1::PRKACA, DNAJB1::PRKACA, and ATP1B1::PRKACB, by reverse-transcription PCR; mRNA expression of fusion genes and nonrearranged PRKACA/B genes by quantitative reverse-transcription PCR; mutations in KRAS, BRAF, and GNAS by targeted sequencing or droplet digital PCR; and the expression of cyclic adenosine monophosphate (cAMP)-dependent protein kinase catalytic subunits α (PRKACA) and ß (PRKACB), phosphorylated cAMP response element-binding protein, and aberrations of p16, p53, SMAD4, STK11, and ß-catenin by immunohistochemistry. PRKACA/B fusion genes were detected in 100% (32/32) of typical, 46% (13/28) of atypical, and 0% (0/20) of control (P < .05). Expression of PRKACA, PRKACB, and phosphorylated cAMP response element-binding protein was upregulated in neoplasms with PRKACA/B fusion genes (P < .05). mRNA expression of the PRKACA/B fusion genes and protein expression of PRKACA or PRKACB tended to be higher in typical than in atypical cases (mRNA, P = .002; protein expression, P = .054). In some atypical neoplasms with mixed subtypes, PRKACA/B fusion genes were superimposed exclusively on oncocytic components. Typical IOPNs harbored fewer KRAS and GNAS mutations than control samples and fewer alterations in p53 and STK11 than atypical samples (P < .05). In conclusion, PRKACA/B fusion genes not only are the characteristic drivers of IOPNs but also play a crucial role in the development of subclonal oncocytic neoplasms. Moreover, oncocytic morphology is strongly associated with upregulation of PRKACA/B, which may provide clues for potential therapeutic options.

Impact of S-1 adjuvant chemotherapy longer than 6 months on survival in patients with resected pancreatic cancer: a nationwide survey by the Japan Pancreas Society based on real-world data.

BACKGROUND: Based on the Japan Adjuvant Study Group of Pancreatic Cancer 01 study, the standard duration of adjuvant chemotherapy with S-1 (an oral 5-fluorouracil prodrug consisting of tegafur, gimeracil, and oteracil) in patients with resected pancreatic ductal adenocarcinoma (PDAC) was considered to be 6 months, but the impact of increasing its duration on postoperative survival was unknown. Here, the authors investigated this question by reviewing real-world data from a large cohort of patients with PDAC. METHODS: In total, 3949 patients who underwent surgery for PDAC during the study period followed by S-1 adjuvant chemotherapy in board-certified institutions were included. Based on the duration of S-1 chemotherapy, two subgroups were defined: a standard-duration group that included patients who were treated for 180 ± 30 days and a longer duration group that included patients who received treatment for >210 days. RESULTS: The median duration of S-1 chemotherapy was 167 days, with a mean ± standard deviation of 200 ± 193 days. After excluding patients who had a recurrence within 210 days after the initiation of adjuvant chemotherapy, postoperative recurrence-free survival (RFS) and overall survival (OS) in the standard-duration group (n = 1473) and the longer duration group (n = 975) were compared. RFS and OS did not differ significantly between the standard-duration and longer duration groups (5-year RFS: 37.8% vs. 36.2% respectively; p = .6186; 5-year OS: 52.8% vs. 53.4%, respectively; p = .5850). The insignificant difference was verified by multivariate analysis and propensity-score matching analysis. CONCLUSIONS: The current findings suggest that extending S-1 adjuvant chemotherapy beyond 6 months has no significant additional effect on survival in patients with PDAC. This could be useful in determining whether to extend S-1 chemotherapy in patients who have completed the standard 6-month treatment.

Serine/Threonine Kinase 11 Plays a Canonical Role in Malignant Progression of KRAS -Mutant and GNAS -Wild-Type Intraductal Papillary Mucinous Neoplasms of the Pancreas.

OBJECTIVE: We aimed to elucidate the clinicopathobiological significance of Serine/Threonine Kinase 11 (STK11) in pancreatic intraductal papillary mucinous neoplasms (IPMNs). BACKGROUND: STK11 is a tumor suppressor involved in certain IPMNs; however, its significance is not well known. METHODS: In 184 IPMNs without Peutz-Jeghers syndrome, we analyzed expression of STK11 and phosphorylated-AMPKa in all cases, and p16, p53, SMAD4, and ß-catenin in 140 cases by immunohistochemistry; and we analyzed mutations in 37 genes, including whole coding exons of STK11, CDKN2A, TP53, and SMAD4, and hotspots of KRAS, BRAF, and GNAS in 64 cases by targeted sequencing. KRAS and GNAS were additionally analyzed in 86 STK11-normal IPMNs using digital-PCR. RESULTS: Consistent loss or reduction of STK11 expression was observed in 26 of 184 (14%) IPMNs. These STK11-aberrant IPMNs were 17 of 45 (38%) pancreatobiliary, 8 of 27 (30%) oncocytic, 1 of 54 (2%) gastric, and 0 of 58 (0%) intestinal subtypes ( P = 8.5E-11), and 20 of 66 (30%) invasive, 6 of 74 (8%) high-grade, and 0 of 44 (0%) low-grade ( P = 3.9E-06). Sixteen somatic STK11 mutations (5 frameshift, 6 nonsense, 1 splicing, and 4 missense) were detected in 15/26 STK11-aberrant IPMNs ( P = 4.1E-06). All STK11-aberrantIPMNs were GNAS -wild-type and 96% of them were KRAS or BRAF -mutant.Morphologically, STK11-aberrant IPMNs presented "fern-like" arborizing papillae with thin fibrovascular core. Phosphorylated-AMPKa was down-regulated in STK11-aberrant IPMNs (92%, P = 6.8E-11). Patients with STK11-aberrant IPMNs showed poorer survival than patients with STK11-normal IPMNs ( P = 3.6E-04 overall; P = 6.1E-04 disease-free). CONCLUSION: STK11 may play a canonical role in malignant progression and poor survival of patients with IPMNs. Aberrant STK11-driven phosphorylated AMPK downregulation may provide therapeutic opportunities with mTOR inhibitors/AMPK activators.

Insights from managing clinical issues in distal pancreatectomy with en bloc coeliac axis resection: experiences from 626 patients.

BACKGROUND: Distal pancreatectomy with en bloc coeliac axis resection (DP-CAR) for pancreatic body cancer has been reported increasingly. However, its large-scale outcomes remain undocumented. This study aimed to evaluate DP-CAR volume and mortality, preoperative arterial embolization for ischaemic gastropathy, the oncological benefit for resectable tumours close to the bifurcation of the splenic artery and coeliac artery using propensity score matching, and prognostic factors in DP-CAR. METHODS: In a multi-institutional analysis, 626 DP-CARs were analysed retrospectively and compared with 1325 distal pancreatectomies undertaken in the same interval. RESULTS: Ninety-day mortality was observed in 7 of 21 high-volume centres (1 or more DP-CARs per year) and 1 of 41 low-volume centres (OR 20.00, 95 per cent c.i. 2.26 to 177.26). The incidence of ischaemic gastropathy was 19.2 per cent in the embolization group and 7.9 per cent in the no-embolization group (OR 2.77, 1.48 to 5.19). Propensity score matching analysis showed that median overall survival was 33.5 (95 per cent c.i. 27.4 to 42.0) months in the DP-CAR and 37.9 (32.8 to 53.3) months in the DP group. Multivariable analysis identified age at least 67 years (HR 1.40, 95 per cent c.i. 1.12 to 1.75), preoperative tumour size 30 mm or more (HR 1.42, 1.12 to 1.80), and preoperative carbohydrate antigen 19-9 level over 37 units/ml (HR 1.43, 1.11 to 1.83) as adverse prognostic factors. CONCLUSION: DP-CAR can be performed safely in centres for general pancreatic surgery regardless of DP-CAR volume, and preoperative embolization may not be required. This procedure has no oncological advantage for resectable tumour close to the bifurcation of the splenic artery, and should be performed after appropriate patient selection.

Whole-exome Sequencing Reveals New Potential Susceptibility Genes for Japanese Familial Pancreatic Cancer.

OBJECTIVE: The primary objective of this study was to identify novel genes that predispose people in the Japanese population to FPC. SUMMARY OF BACKGROUND DATA: Familial history of pancreatic cancer is an important risk factor but, to date, few genes predisposing individuals to increased risk of developing FPC have been identified. METHODS: We performed whole-exome sequencing of germline DNA from 81 Japanese FPC patients. We also investigated somatic gene alterations in 21 matched tumor tissues through whole-exome sequencing and copy number analysis. RESULTS: Our germline variants identified previously known FPC susceptibility genes such as ATM and BRCA2, and several novel tumor suppressor genes with potentially deleterious variants for FPC. Interestingly, somatic whole-exome analysis demonstrated that most tumor samples with suspicious loss of heterozygosity of candidate genes were KRAS wild-types, implying that these cases may not have required KRAS activation as a driver event for carcinogenesis. CONCLUSIONS: Our findings indicate that FPC patients harbor potentially deleterious causative germline variants in tumor suppressor genes, which are known to acquire somatic mutations in pancreatic cancer, and that somatic loss of heterozygosity of some FPC susceptibility genes may contribute to the development of FPC in the absence of somatic KRAS-activating mutation. Genetic testing for a wider variety of FPC-predisposition genes could provide better screening approach for high-risk groups of pancreatic cancer.

Examination of the characteristics of long-term survivors among patients with gallbladder cancer with liver metastasis who underwent surgical treatment: a retrospective multicenter study (ACRoS1406).

BACKGROUND: Gallbladder cancer (GBC) with liver metastasis is considered unresectable. However, there have been infrequent reports of long-term survival in patients with GBC and liver metastases. Therefore, we examined the characteristics of long-term survivors of gallbladder cancer with liver metastasis. METHODS: A retrospective multicenter study of 462 patients with GBC (mean age, 71 years; female, 51%) was performed. Although patients with pre-operatively diagnosed GBC and liver metastasis were generally excluded from resection, some cases identified during surgery were resected. RESULT: In patients with resected stage III/IV GBC (n = 193), the period 2007-2013 (vs. 2000-2006, hazard ratio 0.63), pre-operative jaundice (hazard ratio 1.70), ≥ 2 liver metastases (vs. no liver metastasis, hazard ratio 2.11), and metastasis to the peritoneum (vs. no peritoneal metastasis, hazard ratio 2.08) were independent prognostic factors for overall survival, whereas one liver metastasis (vs. no liver metastasis) was not. When examining the 5-year overall survival and median survival times by liver metastasis in patients without peritoneal metastasis or pre-operative jaundice, those with one liver metastasis (63.5%, not reached) were comparable to those without liver metastasis (40.4%, 33.0 months), and was better than those with ≥ 2 liver metastases although there was no statistical difference (16.7%, 9.0 months). According to the univariate analysis of resected patients with GBC and liver metastases (n = 26), minor hepatectomy, less blood loss, less surgery time, papillary adenocarcinoma, and T2 were significantly associated with longer survival. Morbidity of Clavien-Dindo classification ≤ 2 and received adjuvant chemotherapy were marginally not significant. Long-term survivors (n = 5) had a high frequency of T2 tumors (4/5), had small liver metastases near the gallbladder during or after surgery, underwent minor hepatectomy without postoperative complications, and received postoperative adjuvant chemotherapy. CONCLUSIONS: Although there is no surgical indication for GBC with liver metastasis diagnosed pre-operatively, minor hepatectomy and postoperative chemotherapy may be an option for selected patients with T2 GBC and liver metastasis identified during or after surgery who do not have other poor prognostic factors.

Perihilar Cholangiocarcinoma - Novel Benchmark Values for Surgical and Oncological Outcomes From 24 Expert Centers.

OBJECTIVE: The aim of this study was to define robust benchmark values for the surgical treatment of perihilar cholangiocarcinomas (PHC) to enable unbiased comparisons. BACKGROUND: Despite ongoing efforts, postoperative mortality and morbidity remains high after complex liver surgery for PHC. Benchmark data of best achievable results in surgical PHC treatment are however still lacking. METHODS: This study analyzed consecutive patients undergoing major liver surgery for PHC in 24 high-volume centers in 3 continents over the recent 5-year period (2014-2018) with a minimum follow-up of 1 year in each patient. Benchmark patients were those operated at high-volume centers (≥50 cases during the study period) without the need for vascular reconstruction due to tumor invasion, or the presence of significant co-morbidities such as severe obesity (body mass index ≥35), diabetes, or cardiovascular diseases. Benchmark cutoff values were derived from the 75th or 25th percentile of the median values of all benchmark centers. RESULTS: Seven hundred eight (39%) of a total of 1829 consecutive patients qualified as benchmark cases. Benchmark cut-offs included: R0 resection ≥57%, postoperative liver failure (International Study Group of Liver Surgery): ≤35%; in-hospital and 3-month mortality rates ≤8% and ≤13%, respectively; 3-month grade 3 complications and the CCI: ≤70% and ≤30.5, respectively; bile leak-rate: ≤47% and 5-year overall survival of ≥39.7%. Centers operating mostly on complex cases disclosed better outcome including lower post-operative liver failure rates (4% vs 13%; P = 0.002). Centers from Asia disclosed better outcomes. CONCLUSION: Surgery for PHC remains associated with high morbidity and mortality with now the availability of benchmark values covering 21 outcome parameters, which may serve as key references for comparison in any future analyses of individuals, group of patients or centers.

Prognostic Factors for Surgically Resected Intraductal Papillary Neoplasm of the Bile Duct: A Retrospective Cohort Study.

BACKGROUND: To date, postoperative prognostic factors for intraductal papillary neoplasm of the bile duct (IPNB) have not been well-established. This study aimed to examine the histopathologic features and postoperative prognosis of the two IPNB subclassifications, as well as factors affecting prognosis, based on the authors' experience at a single institution. METHODS: The study enrolled 83 patients who underwent surgical resection for pathologically diagnosed IPNB at the authors' institution. The clinicopathologic features and postoperative outcomes for these patients were examined. The study also investigated postoperative prognostic factors for IPNB using uni- and multivariate analyses. RESULTS: More than half of the tumors (64%) diagnosed as IPNB were early-stage cancer (UICC Tis or T1). However, none were diagnosed as benign. The multivariate analysis showed that lymph node metastasis (hazard ratio [HR], 5.78; p = 0.002) and bile duct margin status with carcinoma in situ (D-CIS; HR, 5.10; p = 0.002) were independent prognostic factors, whereas MUC6 expression showed only a marginal influence on prediction of prognosis (HR, 0.32; p = 0.07). The tumor recurrence rate and the proportion of locoregional recurrence were significantly greater among the patients with D-CIS than among those with negative bile duct margins, including those patients with low-grade dysplasia. The patients with D-CIS showed a significantly poorer prognosis than those with negative bile duct margins (5-year survival, 38% versus 87%; p = 0.0002). CONCLUSIONS: Evaluation of resected IPNBs showed cancer in all cases. Avoiding positive biliary stumps during surgery, including resection of carcinoma in situ, would improve the prognosis for patients with IPNB.

Synthesis and Properties of Spiro-double Sila[7]helicene: The LUMO Spiro-conjugation.

A double helicene with a spiro-Si linker (4) was synthesized by four successive nucleophilic substitutions on SiCl4 . Its (P,P), (M,M) and (P,M) isomers were isolated and characterized by single crystal X-ray analysis. Due to the central spirosilabi[fluorene] moiety, the two helicene units in 4 are symmetrically and nearly perpendicularly arranged. (P,P)-4 and (M,M)-4 exhibit unique optical properties attributable to the LUMO spiro-conjugation between the two sila[7]helicene units.

Evaluation of the significance of adjuvant chemotherapy in patients with stage â A pancreatic ductal adenocarcinoma.

BACKGROUND: Although adjuvant chemotherapy is considered a standard treatment for resected pancreatic ductal adenocarcinoma (PDAC), its utility in stage ⅠA patients is unclear. We aimed to investigate the recurrence rate, surgical outcome, prognostic factors, effectiveness of adjuvant chemotherapy, and determination of groups in whom adjuvant chemotherapy is effective in patients with stage ⅠA PDAC. METHODS: We retrospectively analyzed 73 patients who underwent pancreatectomy and were pathologically diagnosed with stage ⅠA PDAC between 2000 and 2018. We evaluated the relation between clinicopathological factors, recurrence rates, and outcomes such as the recurrence-free and disease-specific survival rates (RFS and DSS, respectively). RESULTS: The 5-year RFS and DSS rates were 52% and 58%, respectively. In multivariate analysis, a platelet-to-lymphocyte ratio (PLR) ≥ 170, prognostic nutrition index (PNI) < 47.5, and pathological grade 2 or 3 constituted risk factors for a shorter DSS (hazard ratios: 4.7, 4.6, and 4.1, respectively). Patients with 0-1 of these risk factors (low-risk group; n = 47) had significantly higher 5-year DSS rates than those with 2-3 risk factors (high-risk group; n = 26) (80% vs. 23%; P < 0.001). Patients in the low-risk group showed similar 5-year RFS rates regardless of whether they received or not adjuvant chemotherapy (75% vs 70%, respectively; P = 0.49). Contrarily, high-risk patients who underwent adjuvant chemotherapy had higher 5-year RFS rates than those who did not receive adjuvant chemotherapy (32% vs 0%; P = 0.045). CONCLUSIONS: In stage IA PDAC, adjuvant chemotherapy seems to be effective only in a subgroup of high-risk patients.

Impact of the controlling nutritional status score on severe postoperative complications of pancreaticoduodenectomy for pancreatic cancer.

PURPOSE: The controlling nutritional status (CONUT) score is a useful biomarker to evaluate undernutrition. However, there have been few reports describing the correlation between postoperative complications and the CONUT score for pancreatic cancer. Therefore, this study aimed to assess the impact of the CONUT score on the postoperative complications of pancreaticoduodenectomy (PD) in patients with pancreatic cancer. METHODS: We retrospectively analyzed 206 consecutive patients with pancreatic cancer who underwent PD over a 12-year duration at our institution. The patients were divided into two groups based on preoperative CONUT scores; their clinicopathological characteristics and surgical outcomes were compared. Furthermore, we compared the CONUT score with preoperative clinical factors and several nutritional biomarkers for postoperative complications using univariate and multivariate analyses. RESULTS: Postoperative complications of Clavien-Dindo grade ≥ IIIa and those of Clavien-Dindo grade ≥ IIIb occurred in 29 (14.1%) and 9 (4.4%) patients, respectively. The high CONUT score (≥5) group indicated that patients with an undernutrition status had a higher postoperative complication rate, poorer relapse-free survival, and overall survival rates than the low CONUT score (≤4) group. Among preoperative clinical factors, a high CONUT score was an independent risk factor for severe postoperative complications. CONCLUSIONS: The CONUT score may be a useful parameter in the identification of patients undergoing pancreatic surgery who are susceptible to postoperative complications.

Evaluation of the validity of pancreatectomy for very elderly patients with pancreatic ductal adenocarcinoma.

PURPOSE: The role of pancreatectomy for very elderly patients with pancreatic adenocarcinoma is controversial. This study aimed to clarify the validity of pancreatic resection in octogenarian patients with pancreatic ductal adenocarcinoma. METHODS: We compared 31 patients aged ≥ 80 years and 548 patients aged < 80 years who underwent pancreatectomy for pancreatic ductal adenocarcinoma and evaluated the relationship between age, clinicopathological factors, recurrence, and outcomes. RESULTS: Postoperative mortality, morbidity, and completion of adjuvant chemotherapy rates did not differ between groups. There were no significant differences in median recurrence-free survival, disease-specific survival, and overall survival between groups (1.0, 2.3, and 2.2 years in patients ≥ 80 years and 1.2, 2.8, and 2.7 years in patients < 80 years; P = 0.67, 0.47, and 0.46, respectively). The median time from recurrence to death of octogenarian patients was significantly shorter than that of younger patients (0.6 vs. 1.1 years, P = 0.0070). In multivariate analysis, age ≥ 80 years (hazard ratio, 1.5), resection of other organs (hazard ratio, 1.8), pathological grade 2/3 (hazard ratio, 1.6), and failure to implement of treatment after recurrence (hazard ratio, 3.6) were independent risk factors for a short time from recurrence to death. Furthermore, age ≥ 80 years (odds ratio, 0.32) was an independent risk factor for the implementation of treatment after recurrence. CONCLUSIONS: Pancreatectomy for octogenarians may be acceptable, but median survival time from recurrence to death was shorter due to lower rates of implementation of treatment after recurrence in octogenarian patients.

Hepatic artery resection without reconstruction in pancreatoduodenectomy.

PURPOSE: It has been reported that there are left and right hepatic arterial arcades via the blood vessels around the hilar bile duct; therefore, when the hilar bile duct is preserved, hepatic artery reconstruction may not be necessary. We compared the short-term and long-term outcomes in patients with distal cholangiocarcinoma who underwent pancreatoduodenectomy (PD) with right hepatic artery resection without right hepatic artery reconstruction (RHAR group) with those patients who underwent conventional PD. METHODS: All data were retrospectively collected from patient records. A 1:4-propensity score-matched case-control study was conducted in patients with distal cholangiocarcinoma who received treatment at Tokyo Women's Medical University from February 1985 to April 2015. RESULTS: There was no statistical difference in the overall morbidity rate between the two groups. No patient in the RHAR group (10 patients) had liver failure, liver abscess, or cholangitis in the postoperative period; one patient died postoperatively because of a bleeding pseudoaneurysm in the gastroduodenal artery. The PD group (40 patients) had a significantly better median time regarding the recurrence (34 vs. 11 months, p=0.027) and 5-year disease-free survival (35% vs. 10%, p=0.027) rates than the RHAR group, which may be attributed to the presence of a more severe disease in patients in the RHAR group. CONCLUSION: We concluded that pancreaticoduodenectomy with right hepatic artery resection without reconstruction has a comparable overall morbidity rate with that of a conventional pancreaticoduodenectomy surgery and may be performed as an alternative procedure when tumor invasion of the right hepatic artery is suspected.

Comparison of Clinicopathological Features of Biliary Neuroendocrine Carcinoma with Adenocarcinoma.

OBJECTIVE: This study aimed to demonstrate the clinical features and postoperative outcomes of extrahepatic bile duct (EHBD) neuroendocrine carcinoma (NEC) and compared with those of adenocarcinoma. METHODS: We retrospectively analyzed patients with EHBD cancer operated in our institution between 1995 and 2015. RESULTS: Of 475 patients, 468 had adenocarcinoma, while 7 had NEC/mixed adenoneuroendocrine carcinoma (MANEC) in this study. There were no notable preoperative and pathological features in patients with NEC/MANEC. However, patients with NEC/MANEC had a higher recurrence rate (51.8 vs. 100%, p = 0.016), poorer relapse-free survival (RFS) time (the median RFS time: 35 vs. 12 months, p = 0.006), and poorer overall survival (OS) time (the median OS time: 60 vs. 19 months, p = 0.078) than those with adenocarcinoma. Furthermore, patients with NEC/MANEC had higher rates of liver metastasis (11.9 vs. 85.7%, p < 0.001) than those with adenocarcinoma. In multivariable regression analysis, pathological type with NEC/MANEC was a risk factor for poorer RFS (p = 0.022, hazard ratio: 6.09). CONCLUSIONS: Patients with NEC/MANEC have high malignant potential and poor outcomes. It is necessary to develop an effective approach and postoperative adjuvant treatment for patients with NEC/MANEC.

Narrowing of the remnant portal vein diameter and decreased portal vein angle are risk factors for portal vein thrombosis after perihilar cholangiocarcinoma surgery.

PURPOSE: To evaluate the incidence, risk factors, management options, and outcomes of portal vein thrombosis following major hepatectomy for perihilar cholangiocarcinoma. METHODS: A total of 177 perihilar cholangiocarcinoma patients who (1) underwent major hepatectomy and (2) underwent investigating the portal vein morphology, which was measured by rotating the reconstructed three-dimensional images after facilitating bone removal using Aquarius iNtuition workstation between 2002 and 2018, were included. Risk factors were evaluated using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: Six patients developed portal vein thrombosis (3.4%) within a median time of 6.5 (range 0-22) days. Portal vein and hepatic artery resection were performed in 30% and 6% patients, respectively. A significant difference in the probability of the occurrence of portal vein thrombosis (PV) within 30 days was found among patients with portal vein resection, a postoperative portal vein angle < 100°, remnant portal vein diameter < 5.77 mm, main portal vein diameter > 13.4 mm, and blood loss (log-rank test, p = 0.003, p = 0.06, p < 0.0001, p = 0.01, and p = 0.03, respectively). Decreasing the portal vein angle and narrowing of the remnant PV diameter remained significant predictors on multivariate analysis (p = 0.027 and 0.002, respectively). Reoperation with thrombectomy was performed in four patients, and the other two patients were successfully treated with anticoagulants. All six patients subsequently recovered and were discharged between 25 and 70 days postoperatively. CONCLUSION: Narrowing of the remnant portal vein diameter and a decreased portal vein angle after major hepatectomy for perihilar cholangiocarcinoma are significant independent risk factors for postoperative portal vein thrombosis.

Resectional surgery in gallbladder cancer with jaundice-how to improve the outcome?

PURPOSE: To evaluate the surgical outcomes of patients with gallbladder cancer (GBC) with jaundice due to as-yet unelucidated prognostic factors. METHODS: A total of 348 GBC patients underwent resection at our institute between 1985 and 2016. Of these, 67 had jaundice (serum total bilirubin ≥ 2 mg/dL). Preoperative biliary drainage was performed, with portal vein embolization as required. All patients underwent radical surgery. We retrospectively evaluated the outcomes, performed multivariate analysis for overall survival, and compared our findings to those reported in the literature. RESULTS: The 5-year survival rate of M0 (no distant metastasis) GBC patients with jaundice, who underwent resectional surgery, was 21.9%, versus 68.3% in those without jaundice (p < 0.05). Since 2000, surgical mortality in GBC patients with jaundice has decreased from 12 to 6.8%. Patients with jaundice had more advanced disease and underwent major hepatectomies and vascular resections; however, preoperative jaundice alone was not a prognostic factor. Multivariate analysis of jaundiced patients revealed that percutaneous biliary drainage (PTBD) (vis-à-vis endoscopic drainage [EBD], hazard ratio [HR] 2.82), postoperative morbidity (Clavien-Dindo classification ≥ 3, HR 2.31), and distant metastasis (HR 1.85) were predictors of poor long-term survival. The 5-year survival and peritoneal recurrence rates in M0 patients with jaundice were 16% and 44%, respectively, for patients with PTBD and 39% (p < 0.05) and 13% (p = 0.07) for those with EBD. CONCLUSION: M0 GBC patients with jaundice should undergo surgery if R0 resection is possible. Preoperative EBD may be superior to PTBD in M0 GBC patients with jaundice, although further studies are needed.

Negative prognostic outcomes of percutaneous transhepatic biliary drainage in distal cholangiocarcinoma: a retrospective analysis using propensity score matching.

BACKGROUND: The efficacy of different types of preoperative biliary drainage for cholangiocarcinoma has been debated over the past two decades. Controversy concerning the use of percutaneous transhepatic biliary drainage (PTBD) versus endoscopic biliary drainage (EBD) still exists. This study aimed to compare the long-term outcomes between PTBD and EBD in patients with distal cholangiocarcinoma. METHODS: Data of patients diagnosed with distal cholangiocarcinoma who underwent preoperative PTBD or EBD from January 1999 to December 2017 were analyzed retrospectively. Post-surgical outcomes, including the incidence of post-operative complications, peritoneal metastasis, disease-free survival, and overall survival, were analyzed. Survival analyses were also performed after propensity score matching in the PTBD and EBD groups. RESULTS: The incidence of post-operative complications was similar in both groups. The 5-year estimated cumulative incidences for peritoneal metastasis were 14.7% and 7.2% in the PTBD and EBD groups, respectively (p = 0.192). The 5-year disease-free survival rates were 23.7% and 47.3% in the PTBD and EBD groups, respectively (p = 0.015). In the multi-variate analysis for overall survival, PTBD was an independent poor prognostic factor. The 5-year overall survival rates were 35.9% and 56.3% in the PTBD and EBD groups, respectively (hazard ratio 1.85, confidence interval 1.05-3.26, p = 0.035). The results after propensity score matching indicated a poorer prognosis in the PTBD group, with a 5-year survival rate of 35.9% in the PTBD group vs 56.0% in the EBD group (p = 0.044). CONCLUSION: PTBD should be considered as a negative prognostic factor in distal cholangiocarcinoma patients.

Limited resection vs. pancreaticoduodenectomy for primary duodenal adenocarcinoma: a systematic review and meta-analysis.

It is well known that surgery is the mainstay treatment for duodenal adenocarcinoma. However, the optimal extent of surgery is still under debate. We aimed to systematically review and perform a meta-analysis of limited resection (LR) and pancreatoduodenectomy for patients with duodenal adenocarcinoma. A systematic electronic database search of the literature was performed using PubMed and the Cochrane Library. All studies comparing LR and pancreatoduodenectomy for patients with duodenal adenocarcinoma were selected. Long-term overall survival was considered as the primary outcome, and perioperative morbidity and mortality as the secondary outcomes. Fifteen studies with a total of 3166 patients were analyzed; 995 and 1498 patients were treated with limited resection and pancreatoduodenectomy, respectively. Eight and 7 studies scored a low and intermediate risk of publication bias, respectively. The LR group had a more favorable result than the pancreatoduodenectomy group in overall morbidity (odd ratio [OR]: 0.33, 95% confidence interval [CI] 0.17-0.65) and postoperative pancreatic fistula (OR: 0.13, 95% CI 0.04-0.43). Mortality (OR: 0.96, 95% CI 0.70-1.33) and overall survival (OR: 0.61, 95% CI 0.33-1.13) were not significantly different between the two groups, although comparison of the two groups stratified by prognostic factors, such as T categories, was not possible due to a lack of detailed data. LR showed long-term outcomes equivalent to those of pancreatoduodenectomy, while the perioperative morbidity rates were lower. LR could be an option for selected duodenal adenocarcinoma patients with appropriate location or depth of invasion, although further studies are required.