Reappraisal of Malignant Risk Assessment for Small (≤20 mm) Non-functioning Pancreatic Neuroendocrine Tumors.

BACKGROUND: Optimal management of non-functioning pancreatic neuroendocrine tumors (PanNETs) ≤20 mm is controversial. The biological heterogeneity of these tumors poses challenges when deciding between resection and observation. METHODS: In this multicenter, retrospective cohort study, we analyzed all patients (n = 78) who underwent resection of non-functioning PanNETs ≤20 mm at three tertiary medical centers from 2004 to 2020 to assess the utility of preoperatively available radiological features and serological biomarkers of non-functioning PanNETs in choosing an optimal surgical indication. The radiological features included non-hyper-attenuation pattern on enhancement computed tomography (CT; hetero/hypo-attenuation) and main pancreatic duct (MPD) involvement, and serological biomarkers included elevation of serum elastase 1 and plasma chromogranin A (CgA) levels. RESULTS: Of all small non-functioning PanNETs, 5/78 (6%) had lymph node metastasis, 11/76 (14%) were WHO grade II, and 9/66 (14%) had microvascular invasion; 20/78 (26%) had at least one of these high-risk pathological factors. In the preoperative assessment, hetero/hypo-attenuation and MPD involvement were observed in 25/69 (36%) and 8/76 (11%), respectively. Elevated serum elastase 1 and plasma CgA levels were observed in 1/33 (3%) and 0/11 (0%) patients, respectively. On multivariate logistic regression analysis, hetero/hypo-attenuation (odds ratio [OR] 6.1, 95% confidence interval [CI] 1.7-22.2) and MPD involvement (OR 16.8, 95% CI 1.6-174.3) were significantly associated with the high-risk pathological factors. The combination of the two radiological worrisome features correctly predicted non-functioning PanNETs with high-risk pathological factors, with about 75% sensitivity, 79% specificity, and 78% accuracy. CONCLUSIONS: This combination of radiological worrisome features can accurately predict non-functioning PanNETs that may require resection.

Exosomes in ascites from patients with human pancreatic cancer enhance remote metastasis partially through endothelial-mesenchymal transition.

BACKGROUND: Despite advances in multidisciplinary treatment, the prognosis of pancreatic cancer remains poor. Since distant metastasis defines prognosis, elucidation of the mechanism of metastasis is important for improving survival. Exosomes are extracellular secretory vesicles and are responsible for intercellular communication. In this study, we investigated whether exosomes secreted by human pancreatic cancer cells are involved in promoting distant metastasis of cancer and the mechanism that underlies the promotion of metastasis. METHODS: Exosomes were isolated from ascites of a patient with pancreatic cancer and a patient with liver cirrhosis as a control. Three days after the administration of exosomes to nude mice, GFP-labeled human pancreatic cancer cells were injected via the spleen or tail vein, and then the liver and lungs were histologically analyzed. To elucidate the mechanism, vascular permeability was estimated using FITC-dextran in place of pancreatic cancer cells in vivo and human umbilical vascular endothelial cells (HUVECs) were used to analyze vascular permeability and the induction of endothelial-mesenchymal transition (EndMT) in vitro. RESULTS: Distant metastasis and vascular permeability were significantly enhanced in mice treated with exosomes from pancreatic cancer patients in comparison to exosomes from a control patient in vivo. In addition, exosomes from pancreatic cancer patients significantly enhanced vascular permeability and the induction of EndMT in HUVECs in vitro. CONCLUSION: Exosomes derived from pancreatic cancer cells form a pre-metastatic niche and promote the extravasation and colonization of pancreatic cancer cells to remote organs, partially through endothelial-mesenchymal transition.

Risk Factors for Recurrence of Cholangitis After Pancreaticoduodenectomy and Comparison of Stents in Hepaticojejunostomy.

BACKGROUND: Postoperative cholangitis is a common complication of pancreaticoduodenectomy. Frequent cholangitis impairs patients' quality of life after pancreaticoduodenectomy. However, the risk factors for recurrence of cholangitis remain unclear. Hence, this retrospective study aimed to identify risk factors for recurrence of cholangitis after pancreaticoduodenectomy. METHODS: The medical records of patients who underwent pancreaticoduodenectomy between 2015 and 2019 in our institution were retrospectively reviewed. At least two episodes of cholangitis a year after pancreaticoduodenectomy were defined as 'recurrence of cholangitis' in the present study. Univariate and multivariate analyses were performed. RESULTS: The recurrence of cholangitis occurred in 40 of 207 patients (19.3%). Multivariate analysis revealed that internal stent (external, RR: 2.16, P = 0.026; none, RR: 4.76, P = 0.011), firm pancreas (RR: 2.61, P = 0.021), constipation (RR: 3.49, P = 0.008), and postoperative total bilirubin>1.7 mg/dL (RR: 2.94, P = 0.006) were risk factors of recurrence of cholangitis. Among patients with internal stents (n = 54), those with remnant stents beyond 5 months had more frequent recurrence of cholangitis (≥5 months, 75%; <5 months, 30%). CONCLUSIONS: Internal stents, firm pancreas, constipation, and postoperative high bilirubin levels are risk factors for cholangitis recurrence after pancreaticoduodenectomy. In addition, the long-term implantation of internal stents may trigger cholangitis recurrence.

Transarterial chemoembolization for liver metastases of a pancreatic neuroendocrine neoplasm: a single-center experience.

Transarterial chemoembolization (TACE) is performed for pancreatic neuroendocrine tumor (PanNEN) liver metastases; however, the safety and efficacy of TACE procedures, especially for patients who have undergone previous pancreatic surgery, have not been established. We reviewed 48 TACE procedures (1-6 procedures/patient) performed on 11 patients with PanNEN liver metastases, including 16 TACE procedures (4-6 procedures/patient) for 3 patients with a history of biliary-enteric anastomosis. The overall tumor objective response rate was 94%. The incidence of Clavien‒Dindo grade ≥ 2 complications was 1/16 (6%) and 1/32 (3%), and the median time to untreatable progression was 31 (14-41) and 27 (2-60) months among patients with and without a history of biliary-enteric anastomosis, respectively. Although validation is needed in future studies, our experiences have shown that TACE treatment is a viable treatment option for PanNEN liver metastases, even after biliary-enteric anastomosis with experienced teams and careful patient follow-up.

Standardization of laparoscopic anatomic liver resection of segment 2 by the Glissonean approach.

BACKGROUND: Anatomic liver resection (ALR) has been established to eliminate the tumor-bearing hepatic region with preservation of the remnant liver volume for liver malignancies. Recently, laparoscopic ALR has been widely applied; however, there are few reports on laparoscopic segmentectomy 2. This study aimed to present the standardization of laparoscopic segmentectomy 2 with surgical outcomes. METHODS: This study included seven patients who underwent pure laparoscopic segmentectomy 2 by the Glissonean approach from January 2020 to December 2021. Four of them had hepatocellular carcinoma, two had colorectal liver metastasis, and one had hepatic angiomyolipoma, which was preoperatively diagnosed with hepatocellular carcinoma. In all patients, preoperative three-dimensional (3D) simulation images from dynamic CT were reconstructed using a 3D workstation. The layer between the hepatic parenchyma and the Glissonean pedicle of segment 2 (G2) was dissected to encircle the root of G2. After clamping or ligation of the G2, 2.5 mg of indocyanine green was injected intravenously to identify the boundaries between segments 2 and 3 with a negative staining method under near-infrared light. Parenchymal transection was performed from the caudal side to the cranial side according to the demarcation on the liver surface, and the left hepatic vein was exposed on the cut surface if possible. RESULTS: The mean operative time for all patients was 281 min. The mean blood loss was 37 mL, and no transfusion was necessary. Estimated liver resection volumes significantly correlated with actual liver resection volumes (r = 0.61, P = 0.035). After the operation, one patient presented with asymptomatic deep venous and pulmonary thrombosis, which was treated with anticoagulant therapy. The mean length of hospital stay was 8.9 days. CONCLUSION: Laparoscopic segmentectomy 2 by the Glissonean approach is a feasible and safe procedure with the preservation of the nontumor-bearing segment 3 for liver tumors in segment 2.

Space-Making Particle Therapy for Unresectable Hilar Cholangiocarcinoma.

INTRODUCTION: Although the primary treatment option for hilar cholangiocarcinoma (HC) has been surgical resection, most patients present with unresectable advanced tumors at the time of diagnosis. Particle therapy (PT) holds great potential for HC, even though the anatomical proximity to the gastrointestinal tract prevents delivering a radical dose to the tumor. Space-making PT (SMPT), consisting of spacer placement surgery and subsequent PT, has been developed to minimize complications and maximize the therapeutic benefit of dose escalation for HC. This study aimed to conduct a dosimetric evaluation and examine the effectiveness of SMPT for the treatment of HC. METHODS: Between 2007 and 2018, 12 patients with unresectable HC treated with SMPT were enrolled. The treatment outcomes and effectiveness of spacer placement surgery were evaluated through analyses of pre- and post-surgical parameters of dose-volume histograms. RESULTS: All patients completed the planned SMPT protocol. The median survival time was 29.6 months, and the 1- and 3-year overall survival rates were 82.5% and 45.8%, respectively. The mean V95% value (volume irradiated with 95% of the planned treatment dose) of the gross tumor volume and clinical target volume after spacer placement surgery improved to 98.5% and 96.6% from preoperative values of 85.6% and 78.1%, respectively (p = 0.0196 and p = 0.0053, respectively). Grade 3 or higher adverse events after SMPT were seen in 6 patients. DISCUSSION/CONCLUSION: SMPT led to improvements in dosimetric parameters and showed good feasibility and excellent outcomes. SMPT can be a promising novel alternative for unresectable HC.

Prognostic Impact of Inflammation-Based Scores for Extrahepatic Cholangiocarcinoma.

INTRODUCTION: Although the relationship between systemic inflammatory responses and prognosis has been known in various cancers, it remains unclear which scores are most valuable for determining the prognosis of extrahepatic cholangiocarcinoma. We aimed to verify the usefulness of various inflammation-based scores as prognostic factors in patients with resected extrahepatic cholangiocarcinoma. METHODS: We analyzed consecutive patients undergoing surgical resection for extrahepatic cholangiocarcinoma at our institution between January 2000 and December 2019. The usefulness of the following inflammation-based scores as prognostic factor was investigated: glasgow prognostic score (GPS), modified GPS, neutrophil-to-lymphocyte ratio, platelet to lymphocyte ratio, lymphocyte-to-monocyte ratio, prognostic nutrition index, C-reactive protein to albumin ratio (CAR), controlling nutritional status (CONUT), and prognostic index. RESULTS: A total of 169 patients were enrolled in this study. Of the nine scores, CAR and CONUT indicated prognostic value. Furthermore, multivariate analysis for overall survival revealed that high CAR (>0.23) was an independent prognostic factor (hazard ratio: 1.816, 95% confidence interval: 1.135-2.906, p = 0.0129), along with lymph node metastasis and curability. There was no difference in tumor staging and short-term outcomes between the low CAR (≤0.23) and high CAR groups. CONCLUSIONS: CAR was the most valuable prognostic score in patients with resected extrahepatic cholangiocarcinoma.

[Laparoscopic Distal Pancreatectomy for Pancreatic Metastasis of Undifferentiated Pleomorphic Sarcoma-A Case Report].

Undifferentiated pleomorphic sarcoma(UPS)is a non-epithelial malignant tumor with a high rate of recurrence and metastasis. The frequent metastasis site is lung, lymph node, liver and bone. Pancreatic metastasis is rare. 71-year-old woman whose course after right foot UPS resection had been followed up at our hospital. But multiple bone and muscle metastasis occurred 1 year after operation. She had resection or radiation for the recurrence. 3 years after the first operation, PET-CT and EUS-FNA revealed pancreatic tail metastasis. The tumor grew up in 6 months, so we performed laparoscopic distal pancreatectomy. The patient recovered uneventfully and was discharged on post-operative day 14. Currently 5 years and 6 months have passed since the first surgery and she is alive. Function-preserving and minimally invasive surgery for UPS pancreatic metastasis is considered to be essential.

Influence of the Retrocolic Versus Antecolic Route for Alimentary Tract Reconstruction on Delayed Gastric Emptying After Pancreatoduodenectomy: A Multicenter, Noninferiority Randomized Controlled Trial.

OBJECTIVE: This study aimed to determine whether retrocolic alimentary tract reconstruction is noninferior to antecolic reconstruction in terms of DGE incidence after pancreatoduodenectomy (PD) and investigated patients' postoperative nutritional status. SUMMARY OF BACKGROUND DATA: The influence of the route of alimentary tract reconstruction on DGE after PD is controversial. METHODS: Patients from 9 participating institutions scheduled for PD were randomly allocated to the retrocolic or antecolic reconstruction groups. The primary outcome was incidence of DGE, defined according to the 2007 version of the International Study Group for Pancreatic Surgery definition. Noninferiority would be indicated if the incidence of DGE in the retrocolic group did not exceed that in the antecolic group by a margin of 10%. Patients' postoperative nutrition data were compared as secondary outcomes. RESULTS: Total, 109 and 103 patients were allocated to the retrocolic and antecolic reconstruction group, respectively (n = 212). Baseline characteristics were similar between both groups. DGE occurred in 17 (15.6%) and 13 (12.6%) patients in the retrocolic and antecolic group, respectively (risk difference; 2.97%, 95% confidence interval; -6.3% to 12.6%, which exceeded the specified margin of 10%). There were no differences in the incidence of other postoperative complications and in the duration of hospitalization. Postoperative nutritional indices were similar between both groups. CONCLUSIONS: This trial could not demonstrate the noninferiority of retrocolic to antecolic alimentary tract reconstruction in terms of DGE incidence. The alimentary tract should not be reconstructed via the retrocolic route after PD, to prevent DGE.

[A Patient with Ascending Jejunal Mesentery Metastasis of Pancreatic Cancer after a Subtotal Stomach-Preserving Pancreaticoduodenectomy].

A 73-year-old woman underwent a subtotal stomach-preserving pancreaticoduodenectomy, wedge resection of the portal vein, and partial resection of the transverse colon for pancreatic cancer at the age of 71. After 18 months, a computed tomography image showed an 8 mm tumor in the ascending jejunal mesentery. Six months later, the tumor grew to 20 mm and had an increased FDG uptake. The tumor was diagnosed as metastasis of pancreatic cancer to the ascending jejunal mesentery. Since no metastasis was found in the other organs, resection was performed. The pathological results showed adenocarcinoma with proximal lymph node metastasis. The patient was diagnosed with ascending jejunal mesentery metastasis of pancreatic cancer. The patient has remained healthy without recurrent disease 1 year 6 months after the resection. Ascending jejunal mesentery metastasis of pancreatic cancer is a type of distant metastasis. In the absence of metastasis to other organs, it is tolerable and radical resection is possible.

[A Case of Pancreatic Cancer with Gastric Wall Recurrence after Laparoscopic Distal Pancreatectomy Due to Needle Tract Seeding following EUS-FNA].

A woman in her 80s was diagnosed with pancreatic tail cancer by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). We performed laparoscopic distal pancreatectomy followed by adjuvant chemotherapy with S-1 for 6 months. One year after surgery, contrast-enhanced computed tomography revealed a 15 mm mass in the posterior wall of the gastric body. EUS showed a hypoechoic mass in the muscular layer in the gastric wall, which was diagnosed as adenocarcinoma by FNA. We diagnosed gastric wall recurrence due to needle tract seeding(NTS)following EUS-FNA and performed partial gastrectomy. Histopathological diagnosis was gastric wall recurrence of pancreatic cancer. Since NTS following EUS-FNA can be proven only by the presence of gastric wall recurrence after surgery for pancreatic body or tail cancer, the actual risk of NTS including peritoneal dissemination is not clear and may have been underestimated. In case of resectable pancreatic body or tail cancer, indication for EUS-FNA should be carefully considered.

Biliary intraductal tubule-forming neoplasm: a whole exome sequencing study of MUC5AC-positive and -negative cases.

AIMS: Biliary intraductal tubular neoplasms that are non-mucinous and negative for mucin 5AC (MUC5AC) are called intraductal tubulopapillary neoplasms (ITPNs). Intraductal tubular neoplasms with mucinous cytoplasm and MUC5AC positivity also occur and their nature remains unclear, although some pathologists may classify these as 'intraductal papillary neoplasms of the bile duct (IPNBs) of gastric type'. This study aimed to elucidate genetic features of biliary intraductal tubular neoplasms. METHODS AND RESULTS: Six resected cases of biliary intraductal neoplasm with >70% tubular configuration were characterised by clinicopathological examination and whole exome sequencing, and the findings obtained were compared between MUC5AC-negative (n = 2) and -positive cases (n = 4). The intraductal tumours consisted of the pancreatobiliary-type epithelium with high-grade dysplasia arranged in back-to-back tubules. Both of the two MUC5AC-negative cases were non-invasive neoplasms and developed in the liver, whereas all MUC5AC-positive cases had invasive carcinoma and were present in the intrahepatic (n = 2), perihilar (n = 1) and distal bile ducts (n = 1). In an exome-sequencing study, MUC5AC-negative cases harboured mutations in CTNNB1, SF3B1, BAP1 and BRCA1 (one case each). KRAS mutations were observed in three of four MUC5AC-positive cases (75%) but none of the MUC5AC-negative neoplasms. Compared to published data, known driver genes of other intraductal neoplasms of the pancreatobiliary system (e.g. APC, CTNNB1, STK11, GNAS and PIK3CA) were wild-type in all but one MUC5AC-negative case with CTNNB1 mutation. Chromatin modifiers (ARID1A, BAP1 and KMT2C) were also altered in MUC5AC-positive cases, similar to usual cholangiocarcinomas. CONCLUSIONS: This exome-sequencing study suggested that MUC5AC-negative biliary ITPNs are genetically distinct from pancreatic ITPNs and IPNBs. They may also biologically differ from MUC5AC-positive tubular neoplasms despite morphological resemblance.

Predictors of postoperative early recurrence of extrahepatic bile duct cancer.

PURPOSES: Resected bile duct cancers often relapse during postoperative follow-up. The aim of this study was to detect predictors of early recurrence in patients with extrahepatic bile duct cancer. METHODS: Consecutive cases (n = 162) of extrahepatic bile duct cancer in which R0 or R1 resection was achieved in Kobe University Hospital between 2000 and 2016 were divided into three groups [early recurrence (ER), within 6 months of surgery, late recurrence (LR), and no recurrence (NR)] and their clinicopathological features were compared. RESULTS: Twenty-two patients (14%) developed ER and 69 (43%) developed LR after surgery. The rates of lymph node metastasis and residual cancer status were similar in all three groups. Liver metastasis was more common in the ER group than in the LR group (59% vs. 32%, p = 0.02). ER had a significantly worse prognosis than LR and NR (7% vs. 44% vs. 85% at 1 year, p < 0.01, respectively). Multivariate analysis showed that age > 75 years, serum CA19-9 > 1008 U/ml and perineural invasion were independent predictors of early recurrence. CONCLUSIONS: High serum CA19-9 values (> 1008 U/ml) were an independent predictor of early recurrence. Neoadjuvant therapy and aggressive adjuvant therapy may be beneficial for patients who show highly elevated CA19-9 values before surgery.

Benefits and limitations of middle bile duct segmental resection for extrahepatic cholangiocarcinoma.

BACKGROUND: Pancreaticoduodenectomy (PD) is a standardized strategy for patients with middle and distal bile duct cancers. The aim of this study was to compare clinicopathological features of bile duct segmental resection (BDR) with PD in patients with extrahepatic cholangiocarcinoma. METHODS: Consecutive cases with extrahepatic cholangiocarcinoma who underwent BDR (n = 21) or PD (n = 84) with achievement of R0 or R1 resection in Kobe University Hospital between January 2000 and December 2016 were enrolled in the present study. RESULTS: Patients who underwent PD were significantly younger than those receiving BDR. The frequency of preoperative jaundice, biliary drainage and cholangitis was not significantly different between the two groups. The duration of surgery was longer and there was more intraoperative bleeding in the PD than in the BDR group (553 vs. 421 min, and 770 vs. 402 mL; both P<0.01). More major complications (>Clavien-Dindo IIIa) were observed in the PD group (46% vs. 10%, P<0.01). Postoperative hospital stay was also longer in that group (30 vs. 19 days, P = 0.02). Pathological assessment revealed that tumors were less advanced in the BDR group but the rate of lymph node metastasis was similar in both groups (33% in BDR and 48% in PD, P = 0.24). The rate of R0 resection was significantly higher in the PD group (80% vs. 38%, P<0.01). Adjuvant chemotherapy was more frequently administered to patients in the BDR group (62% vs. 38%, P = 0.04). Although 5-year overall survival rates were similar in both groups (44% for BDR and 51% for PD, P = 0.72), in patients with T1 and T2, the BDR group tended to have poorer prognosis (44% vs. 68% at 5-year, P = 0.09). CONCLUSIONS: BDR was comparable in prognosis to PD in middle bile duct cancer. Less invasiveness and lower morbidity of BDR justified this technique for selected patients in a poor general condition.

A Prospective, Randomized Phase II Study of Adjuvant Gemcitabine Versus S-1 After Major Hepatectomy for Biliary Tract Cancer (KHBO 1208): Kansai Hepato-Biliary Oncology Group.

OBJECTIVE: To evaluate each arm independently and compare adjuvant gemcitabine (GEM) and S-1 chemotherapy after major hepatectomy (hemihepatectomy or trisectionectomy) for biliary tract cancer (BTC). BACKGROUND: Standardized adjuvant therapy is not performed after major hepatectomy for BTC, and we determined the recommended dose in the former study (KHBO1003). METHODS: We performed a multicenter, randomized phase II study. The primary measure was 1-year recurrence-free survival (RFS); the secondary measures were other RFS, overall survival (OS), and others. The following 6-month adjuvant chemotherapy was administered within 12 weeks of R0/1: GEM (1000 mg/m) every 2 weeks; or S-1 (80 mg/m/d) for 28 days every 6 weeks. Thirty-five patients were assigned to each arm (alpha error, 10%; beta error, 20%). RESULTS: No patients were excluded for the per-protocol analysis. There were no statistically significant differences in the patient characteristics of the 2 arms. The 1-year RFS and 1-year OS rates of the GEM arm were 51.4% and 80.0%, respectively, whereas those of the S-1 group were 62.9% and 97.1%. The comparison of the 2 arms revealed that 2-year RFS rate, 1 and 2-year OS rates, and OS curve of the S-1 arm were superior to GEM. With regard to OS, the hazard ratio of the S-1 group was 0.477 (90% confidence interval 0.245-0.927). CONCLUSION: The comparison of the survival of the 2 groups revealed that adjuvant S-1 therapy may be superior to adjuvant GEM therapy after major hepatectomy for BTC.

Keratin 19-expressing hepatocellular carcinoma and small-duct type intrahepatic cholangiocarcinoma show a similar postoperative clinical course but have distinct genetic features.

AIMS: The present study aimed to systematically compare clinicopathological and genetic features between keratin 19 (K19)-expressing hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). METHODS AND RESULTS: Consecutive cases of HCC (n = 430) were classified into K19+ and K19- using immunohistochemistry. ICCA cases were also separated into small-(S-iCCA; n = 36) and large-duct types (n = 22) based on recently proposed criteria, with the former being used in the present study. Mutational hot-spots in TERT, CTNNB1, KRAS and IDH1 were sequenced. Twenty-six cases (6%) of HCC expressed K19. K19+ HCC was more strongly associated with chronic hepatitis B than K19- HCC and S-iCCA (46% versus 17% and 6%; both P < 0.001). Lymph node metastasis was observed in K19+ HCC (8%) and S-iCCA (22%), but was exceptional in K19- HCC (1%). K19+ HCC had TERT promoter mutations less frequently than K19- HCC (31% versus 59%; P = 0.022), and lacked alterations in KRAS and IDH1. CTNNB1 mutations were similarly observed in K19+ and K19- HCC (23% and 19%, respectively), but rare in S-iCCA (3%). The postoperative survival curve of K19+ HCC was almost identical to that of S-iCCA in the first 5 years (approximately 50% at 5 years), and significantly worse than that of K19- HCC (P = 0.040). Extrahepatic recurrence was more common in K19+ HCC (50%) and S-iCCA (35%) than in K19- HCC (15%) (P = 0.001). CONCLUSIONS: Although K19+ HCC and S-iCCA showed similar biological behaviours, they did not share any driver gene mutations, suggesting the possible involvement of epigenetic alterations in the iCCA-like features of K19+ HCC.

IL-33 overexpression in gallbladder cancers associated with pancreatobiliary maljunction.

AIMS: To investigate whether genetic or inflammatory pro-oncogenic factors are relevant to the increased risk of gallbladder cancers in patients with pancreaticobiliary maljunction (PBM). METHODS AND RESULTS: Mutations in KRAS exon 2 were examined by a highly sensitive, droplet digital PCR platform using surgically resected specimens of PBM-associated (n = 31) and non-associated gallbladder cancers (n = 49). The tissue expression of IL-6 and IL-33, which are suspected to promote biliary carcinogenesis, was analysed by quantitative real-time PCR and in-situ hybridisation. The incidence of KRAS mutations was similarly low in PBM-associated (five of 32 cases; 16%) and non-associated cancers (four of 49 cases; 8%) (P = 0.272). The tissue expression of IL-33 mRNA, but not IL-6 mRNA, was significantly higher in PBM-associated gallbladder cancers than in gallbladder cancers without PBM (P = 0.004). A similar degree of IL-33 overexpression was also observed in the background non-cancerous mucosa in cases of PBM-associated gallbladder cancers, and was significantly greater than that in PBM cases with cholecystitis alone (P < 0.001). The results of in-situ hybridisation indicated that the source of IL-33 production in PBM-associated carcinomas was the endothelium, cancer cells and non-neoplastic biliary epithelium. In a combined PBM-associated and non-associated cohort, IL-33 overexpression in gallbladder cancers correlated with less aggressive features (e.g. a lower pT stage and longer overall survival), similar to recently reported findings on large-duct cholangiocarcinomas. CONCLUSIONS: KRAS mutations do not appear to be associated with a high risk of malignancy in PBM, while IL-33 overexpression may provide a pro-oncogenic microenvironment in the gallbladder mucosa of patients with PBM.

Histological and molecular characterization of intrahepatic bile duct cancers suggests an expanded definition of perihilar cholangiocarcinoma.

BACKGROUND: Growing evidence has suggested that intrahepatic cholangiocarcinoma (iCCA) can be classified into small- and large-duct types. The present study aimed to elucidate how large-duct iCCA is similar and dissimilar to perihilar cholangiocarcinoma (pCCA). METHODS: The study cohort consisted of iCCA (n = 58) and pCCA (n = 44). After iCCA tumors were separated into small- (n = 36) and large-duct (n = 22) types based on our histologic criteria, genetic statuses of the three types of neoplasms were compared. Locations of iCCA were plotted on a three-dimensional image and their distances from the portal bifurcation were measured. RESULTS: Large-duct iCCA was distinct from small-duct iCCA in terms of frequency of bile duct reconstruction required, perineural infiltration, and survival, with these features more similar to pCCA. Large-duct iCCA and pCCA more frequently had the loss of SMAD4 expression and MDM2 amplifications than small-duct iCCA, whereas the loss of BAP1 expression and IDH1 mutations were mostly restricted to small-duct iCCA. From imaging analysis, most tumors of large-duct iCCA were present around the second branches of the portal vein. CONCLUSION: Large-duct type iCCA shared the molecular features with pCCA, and it may be reasonable to expand the definition of pCCA to include cancers originating from the second bile duct branches.

[Analysis of Surgical Resection for Elderly Patients with Biliary Tract Cancer].

Although surgical resection is the first-line treatment for biliary tract cancer(BTC), elderly patients often have underlying diseases and decreased cardiopulmonary function that place them at a high risk of undergoing surgery. We examined the safety and efficacy of surgical resection in elderly BTC patients. Among the BTC cases that underwent surgical resection at Kobe University Hospital from 2009 to 2015, the safety and prognosis ofthose aged 75 years or older(Group 1)were compared to those younger than 75 years(Group 2)at the time ofsurgery. Fifty-two patients with perihilar cholangiocarcinoma( Bp), 29 patients with intrahepatic cholangiocarcinoma(ICC), and 40 patients with ampulla ofVater cancer(AV) were included. There was no significant difference between the 2 groups with respect to complications of Grade Ⅲor above, while surgery-related death was more common in Bp and ICC ofGroup 1. The median survival ofGroup 1 following hepatectomy for Bp and ICC(22 months)was significantly shorter than that of Group 2(40 months)(p=0.023). There was no significant difference in overall survival of Group 1 and Group 2 patients with AV(p=0.094). Surgical resection for BP and ICC for elderly patients has a higher risk of hepatectomy; therefore, precise assessment of oncologic and patient risk factors should be performed. As we can expect to achieve similar prognoses between non-elderly and elderly patients with AV, aggressive treatments should be considered for elderly patients with AV.

[Analysis of Hepatectomy for Extreme Elderly Patients with Hepatocellular Carcinoma].

Although the first-line treatment for hepatocellular carcinoma(HCC)is hepatectomy, extreme elderly(80 years or older) patients often tend to have a variety of underlying diseases and decreased cardiopulmonary function, which means that surgery involves a high risk. In this case, we examined the safety and efficacy of hepatectomy performed in an extreme elderly patient with HCC. Of the patients with HCC that underwent initial hepatectomy at Kobe University Hospital(n=348)between 2009 and 2015, 23 patients aged 80 years or older at the time of surgery(Group 1, n=23)and those younger than 80 years at the time(Group 2, n=325)were compared, based on parameters related to safety and prognosis. We did not identify differences between the 2 groups with respect to blood loss and operating time. Intraoperative blood transfusion was more common in Group 1. There was no significant difference between the 2 groups with respect to complications of Grade Ⅲ or higher. The median survival of Group 2 patients following hepatectomy(42 months)was better than that of Group 1 patients(34 months), but there was no significant difference between the 2 groups(p=0.429). Furthermore, when the same parameters were compared after adjusting for and matching propensity scores, there were no significant differences in complications, hospitalization periods, and prognosis between the 2 groups. Through proper assessment of oncologic factors and patient risk factors, hepatectomy can be performed safely and effectively even for extreme elderly patients with HCC. If there is no other disease regulating the prognosis, we can expect to achieve similar prognosis in non-extreme elderly patients. Hence, treatments should not be limited solely based on a patient being extremely elderly; rather, proactive treatments should be considered.