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Background The influence of bile microflora, particularly with broad antimicrobial resistance patterns, on postoperative outcomes after pancreatoduodenectomy (PD), is poorly understood. The aim of this study was to determine the influence of the microbiology of bactibilia on postoperative outcomes following PD. Methods Intraoperative bile cultures were obtained in 162 patients undergoing PD between 2015 and 2017. Intraoperative bile cultures were analyzed and correlated with short-term outcomes after PD. Independent groups t test, Pearson’s correlation, or Fisher’s exact tests were performed. Hazard ratios (HR) are reported with 95% confidence intervals (CI). Statistical significance was defined as P value of < 0.05. Results Intraoperative bile cultures were positive in 89/162 patients (55%). The most common bacteria were Enterococcus spp. ( n = 48, 54%), Klebsiella spp. ( n = 24, 27%), and Enterobacter spp. ( n = 17, 19%). Bactibilia was not associated with increased infectious complications, postoperative pancreatic fistula (POPF), or mortality. Enterococcus and Enterobacter were associated with higher rates of incisional (HR, 6.5; 95% CI, 1.2–34.8; P = 0.03) and organ-space surgical site infection (HR, 4.9; 95% CI, 1.1–22.0; P = 0.03), respectively. No single bacterium was associated with POPF, bile leak, cholangitis, 30- or 90-day mortality. Conclusion Bactibilia, in general, does not increase the risk of developing a postoperative complication following pancreatoduodenectomy; however, Enterococcus and Enterobacter increase the likelihood of developing incisional and organ-space surgical infections, respectively.

More than 2% of adults harbor a pancreatic cyst, a subset of which progresses to invasive lesions with lethal consequences. To assess the genomic landscapes of neoplastic cysts of the pancreas, we determined the exomic sequences of DNA from the neoplastic epithelium of eight surgically resected cysts of each of the major neoplastic cyst types: serous cystadenomas (SCAs), intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCNs), and solid pseudopapillary neoplasms (SPNs). SPNs are low-grade malignancies, and IPMNs and MCNs, but not SCAs, have the capacity to progress to cancer. We found that SCAs, IPMNs, MCNs, and SPNs contained 10 ± 4.6, 27 ± 12, 16 ± 7.6, and 2.9 ± 2.1 somatic mutations per tumor, respectively. Among the mutations identified, E3 ubiquitin ligase components were of particular note. Four of the eight SCAs contained mutations of the von Hippel–Lindau gene (VHL), a key component of the VHL ubiquitin ligase complex that has previously been associated with renal cell carcinomas, SCAs, and other neoplasms. Six of the eight IPMNs and three of the eight MCNs harbored mutations of RNF43, a gene coding for a protein with intrinsic E3 ubiquitin ligase activity that has not previously been found to be genetically altered in any human cancer. The preponderance of inactivating mutations in RNF43 unequivocally establish it as a suppressor of both IPMNs and MCNs. SPNs contained remarkably few genetic alterations but always contained mutations of CTNNB1, previously demonstrated to inhibit degradation of the encoded protein (β-catenin) by E3 ubiquitin ligases. These results highlight the essential role of ubiquitin ligases in these neoplasms and have important implications for the diagnosis and treatment of patients with cystic tumors.

BackgroundWe conducted an integrated cross-species spatial assessment of transcriptomic and metabolomic alterations associated with progression of intraductal papillary mucinous neoplasms (IPMNs), which are bona fide cystic precursors of pancreatic ductal adenocarcinoma (PDAC).ObjectiveWe aimed to uncover biochemical and molecular drivers that underlie malignant progression of IPMNs to PDAC.DesignMatrix-assisted laser desorption/ionisation (MALDI) mass spectrometry (MS)-based spatial imaging and Visium spatial transcriptomics (ST) was performed on human resected IPMN/PDAC tissues (n=23) as well as pancreata from a mutant Kras;Gnas mouse model of IPMN/PDAC. Functional studies in murine IPMN/PDAC-derived Kras;Gnas cells were performed using CRISPR/cas9 technology, small interfering RNAs, and pharmacological inhibition.ResultsMALDI-MS analyses of patient tissues revealed long-chain hydroxylated sulfatides to be selectively enriched in the neoplastic epithelium of IPMN/PDAC. Integrated ST analyses showed cognate transcripts involved in sulfatide biosynthesis, including UGT8, Gal3St1, and FA2H, to co-localise with areas of sulfatide enrichment. Genetic knockout or pharmacological inhibition of UGT8 in Kras;Gnas IPMN/PDAC cells decreased protein expression of FA2H and Gal3ST1 with consequent alterations in mitochondrial morphology and reduced mitochondrial respiration. Small molecule inhibition of UGT8 elicited anticancer effects via ceramide-mediated compensatory mitophagy and activation of intrinsic apoptosis pathways. In vivo, UGT8 inhibition suppressed tumour growth in allograft models of murine IPMN/PDAC cells derived from Kras;Gnas and Kras;Tp53;Gnas mice.ConclusionOur work identifies enhanced sulfatide metabolism as an early metabolic alteration in cystic precancerous lesions of the pancreas that persists through invasive neoplasia and a potential actionable vulnerability in IPMN-derived PDAC.

Pancreatic cancer has a poor prognosis with complete surgical resection being the only therapy to offer a realistic chance for long-term survival. The aim of this study is to identify surgery-related variables that influence long-term survival. Between 1990 and 2002, 226 consecutive patients (mean age of 64 ± 11 years) had resection for pancreatic adenocarcinoma. Prognostic variables in these patients were analyzed using univariate and multivariate analysis. Two hundred four patients (90%) had pancreaticoduodenectomy, 13 patients (6%) had distal pancreatectomy, and 9 patients (4%) had a TP. Stage I disease was present in 50 (22%), stage II disease in 170 (75%), and stage III disease in 6 (3%). R0 resections were achieved in 70%. Operative morbidity was 36% and 30-day mortality was 6%. Actual 1-year, 3-year, and 5-year survival rates were 49% (n = 111), 14% (n = 31), and 4% (n = 9). Using multivariate analysis: tumor size, tumor differentiation, obtaining an R0 resection, and lack of postoperative complications were variables associated with long-term survival. Long-term survival in patients with pancreatic cancer after resection remains poor. Achieving a margin negative resection (R0) with no postoperative complications are prognostic variables that can be affected by the surgeon.

Introduction Hepaticojejunostomy leaks are less frequent than pancreatic leaks after pancreatoduodenectomy, and the current literature suggests comparable outcomes. The purpose of this study was to determine if the hepaticojejunostomy leak adversely affected patient outcomes. Methods Consecutive cases of pancreatoduodenectomy ( n  = 924) were reviewed at a single high-volume institution over an 8-year period (2006–2014). Results Pancreaticojejunostomy leaks were identified in 217 (23%) patients and hepaticojejunostomy leaks were identified in 24 patients (3%); combined hepaticojejunostomy/pancreaticojejunostomy leaks were identified in 31 patients (3%). Those with hepaticojejunostomy leaks or combined leaks had a significantly increased risk of morbidity when compared to pancreaticojejunostomy leaks or no leak (54 and 58 vs. 34 and 24%, respectively, p  < 0.05). The median length of stay was significantly greater for hepaticojejunostomy leaks or combined leaks when compared to pancreatojejunostomy leaks (17 or 14 vs. 9 days, p  = 0.001) and those with no leak (17 or 14 vs. 7 days, p  = 0.001). Ninety-day mortality for all patients was 3.6%. Hepaticojejunostomy leaks and combined leaks significantly increased 90-day mortality rate (17 and 32%, respectively, p  < 0.05). Conclusions Hepaticojejunostomy and combined leaks after pancreatoduodenectomy are rarer than pancreaticojejunostomy leaks; these patients are at a significantly increased risk of major morbidity and mortality.

Background and AimThe natural history of KRAS mutations in mucinous pancreatic cysts (MPCs) over time remains to be fully understood. The aim of this study was to examine the performance of DNA markers and assess changes of KRAS mutations over time.MethodsPatients who underwent EUS-FNA of pancreatic cysts with at least two separate molecular analysis results were included in the study. We assessed the baseline patient and cyst characteristics, and DNA fluid analysis. The presence of either a KRAS mutation, or a CEA > 192 ng/ml was used as the diagnostic standard for mucinous cysts when surgical pathology was not available.ResultsA total of 933 pancreatic cyst fluid samples were collected, including 117 with ≥ 2 FNAs. Examinations were performed over a median of 30 months (range 1–115 months). Forty-three (36%) had a mutant KRAS on the index analysis out of which 26 had a change in their KRAS status to the wild-type. Eighty-one (64%) had a wild-type KRAS on the index analysis out of which 18 had change in their KRAS status to mutant type. There was no significant difference in the index cyst characteristics, presence of symptoms, or main duct involvement based on KRAS status change. Increasing age was associated with a changing KRAS mutation status (p = 0.023).ConclusionKRAS mutations gain and loss in pancreatic cyst fluid appears to occur frequently during long-term surveillance of MPCs. Age appears to be the only predictor for KRAS change over time.

BackgroundThe role of concomitant gastrostomy or jejunostomy feeding tube (FT) placement during pancreatoduodenectomy (PD) and its impact on patient outcomes remain controversial.MethodsNSQIP database was surveyed for patients undergoing PD between 2014 and 2017. FT placement was identified using CPT codes. Propensity scores were used to match the two groups (1:1) on baseline characteristics and intraoperative variables including pancreas specific ones (duct size, gland texture, underlying disease, wound class, use of wound protector, drain placement, type of pancreatic reconstruction and vascular reconstruction). Outcomes were compared. Finally, a subset analyses for patients with delayed gastric emptying (DGE) or postoperative pancreatic fistula (POPF) were performed.ResultsOut of 15,224 PD, 1,104 (7.5%) had FT. POPF and DGE rates were 17% and 18%, respectively, for the entire cohort. Feeding jejunostomy was the most placed FT (88.2%). Patients with FT placement were more likely to be older (mean, 65.8 vs. 64.6 y), smokers (22.6% vs. 17.8%) who had preoperative weight loss (22.5% vs. 15.3%), ASA class ≥ 3 (80.8% vs. 77.5%), preoperative transfusion (1.5% vs. 0.84%), chemotherapy (22.8% vs. 17.5%), and radiation (14.5% vs. 6.8%, p < 0.05). The matched cohort included 880 patients in each group with completely balanced preoperative and intraoperative characteristics. In the matched cohort, patients with FT placement had higher overall morbidity (52.2% vs. 44.3%, p = 0.001), major morbidity (28.4% vs. 22.5%, p = 0.004), organ/space infection (14.4% vs. 10.9%, p = 0.026), re-operation (8.6% vs. 5.1%, p = 0.003), DGE (26.8% vs. 16.4%, p < 0.001), and longer mean hospital length of stay (12.9 vs. 11.2 days, p = 0.001) than those without FT. There was no difference in mortality (1.7% vs. 2.2%, p = 0.488) or readmission rate (20.2% vs. 17.2%, p = 0.099). In patients with DGE and POPF, FT placement was not associated with morbidity, mortality, length of stay, or readmission rate (p > 0.05).ConclusionPatients with FT placement during PD tend to have higher postoperative morbidity and delayed recovery.

Background The most common type of mucinous pancreatic cyst that may progress to pancreatic cancer is intraductal papillary mucinous neoplasm (IPMN). Low-risk IPMN with low-/moderate-grade dysplasia may be safely watched, whereas high-risk IPMN with high-grade dysplasia or invasive components should undergo resection. However, there is currently no reliable means of making this distinction. We hypothesize that blood concentrations of insulin resistance biomarkers may aid in the differentiation of low- and high-risk IPMN. Methods Plasma/serum was collected from consented patients undergoing pancreatic resection. IPMN diagnosis and dysplastic grade were confirmed by surgical pathology. The study included 235 IPMN (166 low/moderate grade, 39 high grade, 30 invasive). Circulating levels of leptin, branched chain amino acids (BCAA), and retinol-binding protein-4 (RBP-4) were measured by enzyme-linked immunoassay and correlated with surgical pathology. Results Circulating leptin levels (mean ± SE) were significantly higher in patients with low/moderate IPMN than in high-grade/invasive IPMN (15,803 ± 1686 vs. 10,275 ± 1228 pg/ml; p  = 0.0086). Leptin levels were positively correlated with BMI ( r  = 0.65, p  < 0.0001) and were higher in females ( p  < 0.0001). Stratified analysis showed that mean leptin levels were significantly different between low/moderate and high/invasive IPMNs only in females (24,383 ± 2748 vs. 16,295 ± 2040 pg/ml; p  = 0.020). Conversely, circulating BCAA levels were lower in low/moderate IPMN than in high-grade/invasive IPMN (0.38 ± 0.007 vs. 0.42 ± 0.01 mM; p  = 0.011). No significant differences in RBP-4 levels were observed. Conclusions Circulating leptin in females and BCAA correlates with IPMN dysplastic grade and, if combined with clinical characteristics, have the potential to improve clinical decision-making.

Background Biliary fistula after pancreatoduodenectomy (PD) is associated with significant morbidity and mortality. The aim of this study was to determine the risk of early postoperative biliary fistula for developing biliary anastomotic stricture after PD. Methods Retrospective review of all PD performed for various indications at a single institution between 2013 and 2018. Postoperative biliary fistulae were graded according to the International Study Group of Liver Surgery (ISGLS) as grade A–C. Multivariable analysis was performed for all comparative patient subgroups. Results A total of 843 patients underwent PD for malignant (68%) and benign (32%) indications. Postoperative biliary fistula developed in 66 (8%) patients; ISGLS grade A in 29 (3%), grade B in 32 (4%), and grade C in 5 (0.6%). Ninety-day mortality was 3% (25 patients). The remaining 818 patients were evaluated with a median follow-up of 16 months (IQR, 5–32 months). Biliary anastomotic stricture developed in 41 (5%) patients at a median of 10 months (IQR, 6–18 months) postoperatively. Strictures were managed with percutaneous (27 patients, 66%) or endoscopic (14 patients, 34%) stenting. No biliary stricture required operative anastomotic revision. Postoperative biliary fistula (HR, 4.4; 95% CI, 2.0–9.9; P  = 0.0002) was associated with biliary anastomotic stricture; an increased risk for biliary anastomotic stricture was seen in patients with grade A (HR, 6.4; 95% CI, 2.4–16.9; P  = 0.0002) and grade B (HR, 3.6; 95% CI, 1.2–10.9; P  = 0.02) postoperative biliary fistula. Conclusion Postoperative biliary fistula after pancreatoduodenectomy, including clinically insignificant, transient biliary fistula, is associated with an increased risk of a late biliary anastomotic stricture requiring stenting.

Background Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy partly due to frequent, severe cachexia. Serum activin correlates with cachexia and mortality, while exogenous activin causes cachexia in mice. Methods Isoform‐specific activin expression and activities were queried in human and murine tumours and PDAC models. Activin inhibition was by administration of soluble activin type IIB receptor (ACVR2B/Fc) and by use of skeletal muscle specific dominant negative ACVR2B expressing transgenic mice. Feed‐forward activin expression and muscle wasting activity were tested in vivo and in vitro on myotubes. Results Murine PDAC tumour‐derived cell lines expressed activin‐βA but not activin‐βB. Cachexia severity increased with activin expression. Orthotopic PDAC tumours expressed activins, induced activin expression by distant organs, and produced elevated serum activins. Soluble factors from PDAC elicited activin because conditioned medium from PDAC cells induced activin expression, activation of p38 MAP kinase, and atrophy of myotubes. The activin trap ACVR2B/Fc reduced tumour growth, prevented weight loss and muscle wasting, and prolonged survival in mice with orthotopic tumours made from activin‐low cell lines. ACVR2B/Fc also reduced cachexia in mice with activin‐high tumours. Activin inhibition did not affect activin expression in organs. Hypermuscular mice expressing dominant negative ACVR2B in muscle were protected for weight loss but not mortality when implanted with orthotopic tumours. Human tumours displayed staining for activin, and expression of the gene encoding activin‐βA (INHBA) correlated with mortality in patients with PDAC, while INHBB and other related factors did not. Conclusions Pancreatic adenocarcinoma tumours are a source of activin and elicit a systemic activin response in hosts. Human tumours express activins and related factors, while mortality correlates with tumour activin A expression. PDAC tumours also choreograph a systemic activin response that induces organ‐specific and gene‐specific expression of activin isoforms and muscle wasting. Systemic blockade of activin signalling could preserve muscle and prolong survival, while skeletal muscle‐specific activin blockade was only protective for weight loss. Our findings suggest the potential and need for gene‐specific and organ‐specific interventions. Finally, development of more effective cancer cachexia therapy might require identifying agents that effectively and/or selectively inhibit autocrine vs. paracrine activin signalling.