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ObjectiveCholestatic liver diseases in humans as well as bile acid (BA)-feeding and common bile duct ligation (CBDL) in rodents trigger hyperplasia of cholangiocytes within the portal fields. Furthermore, elevation of BA levels enhances proliferation and invasiveness of cholangiocarcinoma (CCA) cells in animal models, thus promoting tumour progression. TGR5 is a G-protein coupled BA receptor, which is highly expressed in cholangiocytes and postulated to mediate the proliferative effects of BA.DesignBA-dependent cholangiocyte proliferation was examined in TGR5-knockout and wild type mice following cholic acid (CA)-feeding and CBDL. TGR5-dependent proliferation and protection from apoptosis was studied in isolated cholangiocytes and CCA cell lines following stimulation with TGR5 ligands and kinase inhibitors. TGR5 expression was analysed in human CCA tissue.ResultsCholangiocyte proliferation was significantly reduced in TGR5-knockout mice in response to CA-feeding and CBDL. Taurolithocholic acid and TGR5-selective agonists induced cholangiocyte proliferation through elevation of reactive oxygen species and cSrc mediated epidermal growth factor receptor transactivation and subsequent Erk1/2 phosphorylation only in wild type but not in TGR5-knockout-derived cells. In human CCA tissue TGR5 was overexpressed and the pathway of TGR5-dependent proliferation via epidermal growth factor receptor and extracellular signal-regulated kinase (ERK)1/2 activation also translated to CCA cell lines. Furthermore, apoptosis was inhibited by TGR5-dependent CD95 receptor serine phosphorylation.ConclusionsTGR5 is an important mediator of BA-induced cholangiocyte proliferation in vivo and in vitro. Furthermore, TGR5 protects cholangiocytes from death receptor-mediated apoptosis. These mechanisms may protect cholangiocytes from BA toxicity under cholestatic conditions, however, they may trigger proliferation and apoptosis resistance in malignantly transformed cholangiocytes, thus promoting CCA progression.

Inflammation-based prognostic scores are proven prognostic biomarkers in various cancers. This study aimed to identify a useful prognostic score for patients with biliary tract cancer (BTC) after surgical resection. This retrospective study recruited 115 patients with BTC during 2010-2020. The relationship between clinicopathological variables, including various prognostic scores and overall survival (OS), was investigated using univariate and multivariate analyses. BTC included 58 cholangiocarcinoma, 29 gallbladder carcinoma, 16 ampullary carcinoma, and 12 perihilar cholangiocarcinoma cases. A significant difference was detected in OS of patients with a Japanese modified Glasgow prognostic score (JmGPS) 0 (n=62) and JmGPS 1 or 2 (high JmGPS) (n=53). In the multivariate analysis, tumour differentiation (p=0.014) and a high JmGPS (p=0.047) were independent prognostic factors. The high JmGPS was an independent prognostic predictor after surgical resection and was superior to other prognostic scores.

Background Ampullary adenocarcinoma (AA) originates from either intestinal (INT) or pancreaticobiliary (PB) epithelium. Different prognostic factors of recurrence have been identified in previous studies. Methods In 91 AA patients of the AGEO retrospective multicentre cohort, we evaluated the centrally reviewed morphological classification, panel markers of Ang et al. including CK7, CK20, MUC1, MUC2 and CDX2, the 50-gene panel mutational analysis, and the clinicopathological AGEO prognostic score. Results Forty-three (47%) of the 91 tumours were Ang-INT, 29 (32%) were Ang-PB, 18 (20%) were ambiguous (Ang-AMB) and one could not be classified. Among these 90 tumours, 68.7% of INT tumours were Ang-INT and 78.2% of PB tumours were Ang-PB. MUC5AC expression was detected in 32.5% of the 86 evaluable cases. Among 71 tumours, KRAS, TP53, APC and PIK3CA were the most frequently mutated genes. The KRAS mutation was significantly more frequent in the PB subtype. In multivariate analysis, only AGEO prognostic score and tumour subtype were associated with relapse-free survival. Only AGEO prognostic score was associated with overall survival. Conclusions Mutational analysis and MUC5AC expression provide no additional value in the prognostic evaluation of AA patients. Ang et al. classification and the AGEO prognostic score were confirmed as a strong prognosticator for disease recurrence.

Literature on non-ampullary–duodenal carcinomas is limited. We analyzed 47 resected non-ampullary–duodenal carcinomas. Histologically, 78% were tubular-type adenocarcinomas mostly gastro-pancreatobiliary type and only 19% pure intestinal. Immunohistochemistry ( n =38) revealed commonness of ‘gastro-pancreatobiliary markers’ (CK7 55, MUC1 50, MUC5AC 50, and MUC6 34%), whereas ‘intestinal markers’ were relatively less common (MUC2 36, CK20 42, and CDX2 44%). Squamous and mucinous differentiation were rare (in five each); previously, unrecognized adenocarcinoma patterns were noted (three microcystic/vacuolated, two cribriform, one of comedo-like, oncocytic papillary, and goblet-cell-carcinoid-like). An adenoma component common in ampullary–duodenal cancers was noted in only about a third. Most had plaque-like or ulcerating growth. Mismatch repair protein alterations were detected in 13% (all with plaque-like growth and pushing-border infiltration). When compared with ampullary ( n =355) and pancreatic ductal ( n =227) carcinomas, non-ampullary–duodenal carcinomas had intermediary pathologic features with mean invasive size of 2.9 cm ( vs 1.9, and 3.3) and 59% nodal metastasis ( vs 45, and 77%). Its survival (3-, 5-year rates of 57 and 57%) was similar to that of ampullary–duodenal carcinomas (59 and 52%; P =0.78), but was significantly better than the ampullary ductal (41 and 29%, P <0.001) and pancreatic (28 and 18%, P <0.001) carcinomas. In conclusion, non-ampullary–duodenal carcinomas are more histologically heterogeneous than previously appreciated. Their morphologic versatility (commonly showing gastro-pancreatobiliary lineage and hitherto unrecognized patterns), frequent plaque-like growth minus an adenoma component, and frequent expression of gastro-pancreatobiliary markers suggest that many non-ampullary–duodenal carcinomas may arise from Brunner glands or gastric metaplasia or heterotopic pancreatobiliary epithelium. The clinical behavior of non-ampullary–duodenal carcinoma is closer to that of ampullary–duodenal subset of ampullary carcinomas, but is significantly better than that of ampullary ductal and pancreatic cancers. The frequency of mismatch repair protein alterations suggest that routine testing should be considered, especially in the non-ampullary-duodenal carcinomas with plaque-like growth and pushing-border infiltration.

MicroRNAs have potential as diagnostic cancer biomarkers. The aim of this study was (1) to define microRNA expression patterns in formalin-fixed parafin-embedded tissue from pancreatic ductal adenocarcinoma, ampullary adenocarcinoma, normal pancreas and chronic pancreatitis without using micro-dissection and (2) to discover new diagnostic microRNAs and combinations of microRNAs in cancer tissue. The expression of 664 microRNAs in tissue from 170 pancreatic adenocarcinomas and 107 ampullary adenocarcinomas were analyzed using a commercial microRNA assay. Results were compared with chronic pancreatitis, normal pancreas and duodenal adenocarcinoma. In all, 43 microRNAs had higher and 41 microRNAs reduced expression in pancreatic cancer compared with normal pancreas. In all, 32 microRNAs were differently expressed in pancreatic adenocarcinoma compared with chronic pancreatitis (17 higher; 15 reduced). Several of these microRNAs have not before been related to diagnosis of pancreatic cancer (eg, miR-492, miR-614, miR-622). MiR-614, miR-492, miR-622, miR-135b* and miR-196 were most differently expressed. MicroRNA profiles of pancreatic and ampullary adenocarcinomas were correlated (0.990). MicroRNA expression profiles for pancreatic cancer described in the literature were consistent with our findings, and the microRNA profile for pancreatic adenocarcinoma (miR-196b–miR-217) was validated. We identified a more significant expression profile, the difference between miR-411 and miR-198 (P=2.06 × 10−54) and a diagnostic LASSO classifier using 19 microRNAs (sensitivity 98.5%; positive predictive value 97.8%; accuracy 97.0%). We also identified microRNA profiles to subclassify ampullary adenocarcinomas into pancreatobiliary or intestinal type. In conclusion, we found that combinations of two microRNAs could roughly separate neoplastic from non-neoplastic samples. A diagnostic 19 microRNA classifier was constructed which without micro-dissection could discriminate pancreatic and ampullary adenocarcinomas from chronic pancreatitis and normal pancreas with high sensitivity and accuracy. Ongoing prospective studies will evaluate if these microRNA profiles are useful on fine-needle biopsies for early diagnosis of pancreatic cancer.

Glucose impairment notably affects the postoperative course of gastrointestinal surgeries. However, evidence on its impact on clinically relevant pancreatic fistulas(CR-POPFs) after pancreaticoduodenectomy(PD) is lacking. This study evaluates if and how preoperative glucose metabolism affects the development of CR-POPF after PD. One hundred and ten consecutive PDs were included. Patients underwent preoperative metabolic profiling using the Oral Glucose Tolerance Test(OGTT) and the hyperinsulinemic euglycemic clamp procedure. Accordingly, patients were categorized as normal glucose tolerant (NGT), impaired glucose tolerant (IGT), diabetic (DM), and longstanding-DM. Receiver operating characteristics(ROC) analyses were performed to determine the values of metabolic features in prediction of CR-POPF. The CR-POPF rate was 36.3 ​%(40 patients). NGT patients had a higher CR-POPF rate (51.7 ​%) compared to IGT(45.2 ​%), DM (15.8 ​%), and longstanding-DM (25.8 ​%) (p ​= ​0.03). CR-POPF patients had lower median fasting glucose levels (p ​= ​0.01) and higher c-peptide values at all OGTT time points (p ​< ​0.05). Fasting glucose and c-peptide levels had high diagnostic accuracy for CR-POPF (AUC>0.8) and were independent risk factors for CR-POPF (OR: 24.7[95%CI: 3.7–165.3] for fasting glucose; OR: 19.9[95%CI: 3.2–125.3] for c-peptide). Normoglycemia and normal beta cell function may be risk factors for CR-POPF after PD. Fasting glucose and c-peptide levels effectively predicted CR-POPF development following PD. NCT02175459 [Display omitted] •The impact of glucose metabolism on the post-operative course and clinically relevant pancreatic fistula (CR-POPF) development after pancreaticoduodenectomy (PD) is still a field of investigation.•Patients undergoing PD were prospectively enrolled and underwent a preoperative comprehensive metabolic assessment.•Normoglycemia and normal β-cell function were recognized as risk features for CR-POPF development. fasting glucose and c-peptide levels demonstrated a high accuracy in prediction of CR-POPF.

Ampullary carcinoma (AC) of the intestinal type represents a distinct variant within the broader category of ampullary neoplasms. The scarcity of pertinent cellular models has constrained investigations centered on this particular malignancy. This research effectively generated a cell line (CL) of intestinal-type AC (DPC-X3). This newly developed CL has been continuously cultured for 1 year and has demonstrated stable passaging exceeding 60 generations. Morphologically, DPC-X3 exhibited characteristic attributes of an epithelial tumor. The cell proliferation rate of DPC-X3 exhibited a doubling interval of 79 h. Short tandem repeat (STR) analysis validated the high consistency between DPC-X3 and the patient’s primary tumor. Characteristically, DPC-X3 displayed sub diploid karyotypes, primarily featuring 44, XY inv (9), -18, -20, -22, and + mar. Under suspension culture conditions, DPC-X3 could efficiently form organoids, and DPC-X3 cells inoculated subcutaneously into NXG mice could form transplanted tumors. Drug susceptibility assays demonstrated that DPC-X3 resisted paclitaxel, oxaliplatin, 5-fluorouracil(5-FU), and gemcitabine. Immunohistochemical (IHC) evaluation revealed affirmative reactivity for CK7 and CK20 within DPC-X3 cells, while CDX2 exhibited no detectable expression. E-cadherin and Vimentin demonstrated positive immunoreactivity, whereas CEA and CA19-9 displayed faint positivity. The Ki-67 proliferation index was determined to be approximately 40%. DPC-X3 presents a valuable experimental platform for elucidating the pathogenesis of intestinal-type AC and can serve as a driver for drug development efforts.

Background: Outcomes for ampullary adenocarcinomas are heterogeneous, and numerous methods of categorisation exist. A histomolecular phenotype based on histology, caudal-type homeodomain transcription factor 2 (CDX2) staining and Mucin 1 (MUC1) staining has recently been tested and validated in two cohorts. We attempt to validate this classification in a large patient population. Methods: Tissue samples from 163 patients with resected ampullary adenocarcinoma were classified based on histology and immunohistochemical expression of CDX2 and MUC1. A pancreaticobiliary histomolecular classification (PB) was defined as a sample with pancreaticobiliary histology, positive MUC1 and negative CDX2 expression. Results: There were 82 deaths; median follow-up of 32.4 months; and median overall survival of 87.7 (95% CI 42.9–109.5) months. PB comprised 28.2% of the cases. Factors associated with overall survival were histological subtype ( P =0.0340); T1/2 vs T3/4 ( P =0.001); perineural ( P <0.0001) and lymphovascular ( P =0.0203) invasion; and histomolecular intestinal histomolecular phenotype (INT) vs PB phenotype (106.4 vs 21.2 months, P <0.0001). Neither MUC1 nor CDX2 was statistically significant, although MUC1 positivity defined as ⩾10% staining was significant ( P =0.0023). In multivariate analysis, age (HR 1.03), PB phenotype (HR 2.26) and perineural invasion (PNI; HR 2.26) were associated with poor survival. Conclusions: The prognostic ability of histomolecular phenotype has been validated in an independent cohort of ampullary adenocarcinoma patients.

Objectives To investigate immunohistochemical predictors for intestinal and pancreatobiliary types of adenocarcinoma of ampulla of Vater and identify clinicopathological characteristics associated with the histological types and patient survival. Methods Immunohistochemical markers included MUC1, MUC2, MUC5AC, CDX2, CK7, and CK20. The data were analyzed by univariate and multivariate methods. The two-step cluster method was used to determine the best immunohistochemical markers to discriminate the intestinal from the pancreatobiliary type. Results This study identified 9 (33.3%) intestinal and 21 (66.7%) pancreatobiliary tumors. CK7 and CDX2 achieved the highest value (= 1) as predictor markers, while CK20, MUC1, and MUC2 showed degrees of importance equal to 0.77, 0.71, and 0.68, respectively. MUC5AC did not reach 0.50 of importance. In the univariate analysis, lymph node involvement, staging (TNM), and angiolymphatic and perineural invasions were associated with histological types. The independent clinicopathological variable in the multivariate model to predict the histological type was angiolymphatic invasion ( p  = 0.005), OR = 17 (95% CI 2.33 to 123.83). The final model showed positive nodes (N1) associated with shorter survival (HR = 9.5; p  = 0.006). Overall survival at 12, 36, and 60 months was 88.5, 67.0, and 47.6%, respectively. Conclusions CDX2 and CK7 were the immunohistochemical markers that best discriminated the intestinal from the pancreatobiliary type. Lymph node involvement had a high impact on survival and proved to be more frequent in the pancreatobiliary type.

It is unclear to what extent patients with pancreatic cancer have cachexia and had a dietetic consult for nutritional support. The aim was to assess the prevalence of cachexia, dietitian consultation, and overall survival in these patients. This prospective multicenter cohort study included patients with pancreatic cancer, who participated in the Dutch Pancreatic Cancer Project and completed patient reported outcome measures (2015–2018). Additional data were obtained from the Netherlands Cancer Registry. Cachexia was defined as self‐reported >5% body weight loss, or >2% in patients with a BMI <20 kg/m2over the past half year. The Kaplan–Meier method was used to analyze overall survival. In total, 202 patients were included from 18 centers. Cachexia was present in 144 patients (71%) and 81 of those patients (56%) had dietetic consultation. Cachexia was present in 63% of 94 patients who underwent surgery, 77% of 70 patients who received palliative chemotherapy and 82% of 38 patients who had best supportive care. Dietitian consultation was reported in 53%, 52%, and 71%, respectively. Median overall survival did not differ between patients with and without cachexia, but decreased in those with severe weight loss (12 months (IQR 7–20) vs. 16 months (IQR 8–31), p = 0.02), as compared to those with <10% weight loss during the past half year. Two‐thirds of patients with pancreatic cancer present with cachexia of which nearly half had no dietetic consultation. Survival was comparable in patients with and without cachexia, but decreased in patients with more severe weight loss. The extent of cachexia and dietetic consultation in patients with pancreatic cancer in the real‐world setting is unclear. This prospective multicenter cohort study found that in patients, diagnosed between 2015 and 2018, two‐third presented with cachexia of whom nearly half had no dietetic consultation. Survival was comparable in patients with and without cachexia, but decreased in patients with more severe weight loss.