Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis and insights into both disease etiology and targeted intervention are needed. A total of 109 micro-dissected PDA cases were subjected to whole-exome sequencing. Microdissection enriches tumour cellularity and enhances mutation calling. Here we show that environmental stress and alterations in DNA repair genes associate with distinct mutation spectra. Copy number alterations target multiple tumour suppressive/oncogenic loci; however, amplification of MYC is uniquely associated with poor outcome and adenosquamous subtype. We identify multiple novel mutated genes in PDA, with select genes harbouring prognostic significance. RBM10 mutations associate with longer survival in spite of histological features of aggressive disease. KRAS mutations are observed in >90% of cases, but codon Q61 alleles are selectively associated with improved survival. Oncogenic BRAF mutations are mutually exclusive with KRAS and define sensitivity to vemurafenib in PDA models. High-frequency alterations in Wnt signalling, chromatin remodelling, Hedgehog signalling, DNA repair and cell cycle processes are observed. Together, these data delineate new genetic diversity of PDA and provide insights into prognostic determinants and therapeutic targets.

An American Hepato-Pancreato-Biliary Association (AHPBA)-sponsored consensus meeting of expert panellists met on 15 January 2014 to review current evidence on the management of hilar cholangiocarcinoma in order to establish practice guidelines and to agree consensus statements. It was established that the treatment of patients with hilar cholangiocarcinoma requires a coordinated, multidisciplinary approach to optimize the chances for both durable survival and effective palliation. An adequate diagnostic and staging work-up includes high-quality cross-sectional imaging; however, pathologic confirmation is not required prior to resection or initiation of a liver transplant trimodal treatment protocol. The ideal treatment for suitable patients with resectable hilar malignancy is resection of the intra- and extrahepatic bile ducts, as well as resection of the involved ipsilateral liver. Preoperative biliary drainage is best achieved with percutaneous transhepatic approaches and may be indicated for patients with cholangitis, malnutrition or hepatic insufficiency. Portal vein embolization is a safe and effective strategy for increasing the future liver remnant (FLR) and is particularly useful for patients with an FLR of <30%. Selected patients with unresectable hilar cholangiocarcinoma should be evaluated for a standard trimodal protocol incorporating external beam and endoluminal radiation therapy, systemic chemotherapy and liver transplantation. Post-resection chemoradiation should be offered to patients who show high-risk features on surgical pathology. Chemoradiation is also recommended for patients with locally advanced, unresectable hilar cancers. For patients with locally recurrent or metastatic hilar cholangiocarcinoma, first-line chemotherapy with gemcitabine and cisplatin is recommended based on multiple Phase II trials and a large randomized controlled trial including a heterogeneous population of patients with biliary cancers.

Background and aim: To compare cancer-specific survival (CSS) between patients who received neoadjuvant radiation followed by resection (NRR) and those who received upfront resection (UR) for locally advanced pancreatic cancer (LAPC). Methods: A total of 772 LAPC patients who underwent curative-intent surgical resection with or without neoadjuvant radiation from 2004 to 2013 were identified from the Surveillance, Epidemiology, and End Result (SEER) database. Propensity score matching (PSM) was conducted to eliminate possible bias. Kaplan-Meier method was used to analyze long-term outcome. Independent risk factors of CSS were predicted by Cox proportional hazards model. Subgroup analyses were done according to 5 variables. Results: The propensity score model matched 196 patients from the whole cohort. Neoadjuvant radiation was an independent predictor of CSS no matter before or after PSM. After PSM, the 1-, 3-, 5-year CSS rates of NRR group were 82.7%, 39.2% and 17.1%, while 64.3%, 19.9% and 12.4% for UR group. The median CSS for NRR group was 25 months, while 17 months for UR group. In subgroup analyses, CSS rates or median CSS of NRR group were still superior to those of UR group in married, unmarried, pancreatic adenocarcinoma, G1+G2, G3+G4, N0 stage, N1 stage and M0 stage subgroups, but no differences were found in other histological types and M1 stage subgroups. Other predictors of CSS included histological type, tumor grade and marital status. Conclusions: Neoadjuvant radiation followed by resection has a significant survival benefit compared with upfront resection in LAPC patients. Therapeutic strategy for LAPC patients should be further explored.

Summary Downregulation of the miR-143/145 microRNA (miRNA) cluster has been repeatedly reported in colon cancer and other epithelial tumors. In addition, overexpression of these miRNAs inhibits tumorigenesis, leading to broad consensus that they function as cell-autonomous epithelial tumor suppressors. We generated mice with deletion of miR-143/145 to investigate the functions of these miRNAs in intestinal physiology and disease in vivo. While intestinal development proceeded normally in the absence of these miRNAs, epithelial regeneration after injury was dramatically impaired. Surprisingly, we found that miR-143/145 are expressed and function exclusively within the mesenchymal compartment of intestine. Defective epithelial regeneration in miR-143/145-deficient mice resulted from dysfunction of smooth muscle and myofibroblasts and was associated with de-repression of the novel miR-143 target Igfbp5, which impaired IGF signaling after epithelial injury. These results provide important insights into the regulation of epithelial wound healing and argue against a cell-autonomous tumor suppressor role for miR-143/145 in colon cancer.

Purpose To evaluate differences in overall survival in patients with hepatocellular carcinoma (HCC) after the establishment of a multidisciplinary clinic (MDC) for HCC. Methods Patient demographic and tumor characteristics of 355 patients diagnosed with HCC were collected between October 2006 and September 2011. Patients diagnosed after the initiation of the HCC MDC on October 1, 2010, were compared to patients diagnosed in the 4 years before. Patient demographics, tumor characteristics, treatment regimens, and overall survival were analyzed between the groups. Results A total of 105 patients were diagnosed in the time period after HCC MDC initiation compared to 250 patients in the previous 4 years. Patients diagnosed with HCC after the HCC MDC had fewer symptoms at presentation (64 vs. 78 %, p = 0.01) and earlier stage of tumor presentation [Barcelona Clinic for Liver Cancer (BCLC) A stage, 44 vs. 26 %, p = 0.0003; tumor, node, metastasis classification system stage 1, 44 vs. 30 %, p = 0.003) compared with patients diagnosed before MDC formation. The median time to treatment after diagnosis in the later period was significantly shorter than in the earlier time period (2.3 vs. 5.3 months, p = 0.002). On multivariate analysis, being seen in the HCC MDC remained independently associated with better overall survival (hazard ratio 2.5, 95 % confidence interval 2–3), after adjusting for BCLC stage and recipient of curative treatment. Patients diagnosed after HCC MDC initiation had a median survival of 13.2 months compared to the 4.8 months observed in patients diagnosed before MDC formation (p = 0.005). Conclusions The implementation of a MDC for the evaluation and treatment of patients with HCC is associated with improved overall survival.

IMPORTANCE Adrenocortical carcinoma (ACC) is a rare but aggressive endocrine tumor, and the prognostic factors associated with long-term outcomes after surgical resection remain poorly defined. OBJECTIVES To define clinicopathological variables associated with recurrence-free survival (RFS) and overall survival (OS) after curative surgical resection of ACC and to propose nomograms for individual risk prediction. DESIGN, SETTING, AND PARTICIPANTS Nomograms to predict RFS and OS after surgical resection of ACC were proposed using a multi-institutional cohort of patients who underwent curative-intent surgery for ACC at 13 major institutions in the United States between March 17, 1994, and December 22, 2014. The dates of our study analysis were April 15, 2015, to May 12, 2015. MAIN OUTCOMES AND MEASURES The discriminative ability and calibration of the nomograms to predict RFS and OS were tested using C statistics, calibration plots, and Kaplan-Meier curves. RESULTS In total, 148 patients who underwent surgery for ACC were included in the study. The median patient age was 53 years, and 65.5% (97 of 148) of the patients were female. One-third of the patients (35.1% [52 of 148]) had a functional tumor, and the median tumor size was 11.2 cm. Most patients (77.7% [115 of 148]) underwent R0 resection, and 8.8% (13 of 148) of the patients had N1 disease. Using backward stepwise selection of clinically important variables with the Akaike information criterion, the following variables were incorporated in the prediction of RFS: tumor size of at least 12 cm (hazard ratio [HR], 3.00; 95% CI, 1.63–5.70; P < .001), positive nodal status (HR, 4.78; 95% CI, 1.47–15.50; P = .01), stage III/IV (HR, 1.80; 95% CI, 0.95–3.39; P = .07), cortisol-secreting tumor (HR, 2.38; 95% CI, 1.27–4.48; P = .01), and capsular invasion (HR, 1.96; 95% CI, 1.02–3.74; P = .04). Factors selected as predicting OS were tumor size of at least 12 cm (HR, 1.78; 95% CI, 1.00–3.17; P = .05), positive nodal status (HR, 5.89; 95% CI, 2.05–16.87; P = .001), and R1 margin (HR, 2.83; 95% CI, 1.51–5.30; P = .001). The discriminative ability and calibration of the nomograms revealed good predictive ability as indicated by the C statistics (0.74 for RFS and 0.70 for OS). CONCLUSIONS AND RELEVANCE Independent predictors of survival and recurrence risk after curative-intent surgery for ACC were selected to create nomograms predicting RFS and OS. The nomograms were able to stratify patients into prognostic groups and performed well on internal validation.

Posttreatment nodal status and perineural or vascular invasion at resection, but not graded histologic response, independently predict DSS after neoadjuvant chemotherapy and surgical resection of gastric cancer.

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