ObjectiveDNA-based testing of pancreatic cyst fluid (PCF) is a useful adjunct to the evaluation of pancreatic cysts (PCs). Mutations in KRAS/GNAS are highly specific for intraductal papillary mucinous neoplasms (IPMNs) and mucinous cystic neoplasms (MCNs), while TP53/PIK3CA/PTEN alterations are associated with advanced neoplasia. A prospective study was performed to evaluate preoperative PCF DNA testing.DesignOver 43-months, 626 PCF specimens from 595 patients were obtained by endoscopic ultrasound (EUS)-fine needle aspiration and assessed by targeted next-generation sequencing (NGS). Molecular results were correlated with EUS findings, ancillary studies and follow-up. A separate cohort of 159 PCF specimens was also evaluated for KRAS/GNAS mutations by Sanger sequencing.ResultsKRAS/GNAS mutations were identified in 308 (49%) PCs, while alterations in TP53/PIK3CA/PTEN were present in 35 (6%) cases. Based on 102 (17%) patients with surgical follow-up, KRAS/GNAS mutations were detected in 56 (100%) IPMNs and 3 (30%) MCNs, and associated with 89% sensitivity and 100% specificity for a mucinous PC. In comparison, KRAS/GNAS mutations by Sanger sequencing had a 65% sensitivity and 100% specificity. By NGS, the combination of KRAS/GNAS mutations and alterations in TP53/PIK3CA/PTEN had an 89% sensitivity and 100% specificity for advanced neoplasia. Ductal dilatation, a mural nodule and malignant cytopathology had lower sensitivities (42%, 32% and 32%, respectively) and specificities (74%, 94% and 98%, respectively).ConclusionsIn contrast to Sanger sequencing, preoperative NGS of PCF for KRAS/GNAS mutations is highly sensitive for IPMNs and specific for mucinous PCs. In addition, the combination of TP53/PIK3CA/PTEN alterations is a useful preoperative marker for advanced neoplasia.

Continuous assessment of quality metrics allows for safe implementation of RPD. We identified several inflexion points corresponding to optimization of performance metrics for RPD that can be used as benchmarks for surgeons who are adopting this technology.

ALT and DAXX/ATRX loss in PanNETs was associated with shorter DFS and DSS and likely plays a significant role in driving metastatic disease. Clin Cancer Res; 23(2); 600-9. ©2016 AACR.

Postlearning curve RPD can be performed with similar perioperative outcomes achieved with OPD. Further studies of cost, quality of life, and long-term oncologic outcomes are needed.

Purpose Autophagy is a cell survival mechanism that plays a critical role in pancreatic carcinogenesis. Murine studies have previously demonstrated that treatment with the late-autophagy inhibitor chloroquine in combination with chemotherapy limited tumor growth. Methods In this Phase I/II trial we examined treatment with hydroxychloroquine (HCQ) with gemcitabine for patients with pancreatic adenocarcinoma. The primary endpoints were the safety and tolerability, evaluated with Storer's dose escalation design. Secondary endpoints were CA 19-9 biomarker response, R0 resection rates, survival and correlative studies of autophagy. Results Thirty-five patients were enrolled. There were no dose-limiting toxicities and no Grade 4/5 events related to treatment. 19 patients (61%) had a decrease in CA19-9 following treatment. 29 patients (94%) underwent surgical resection as scheduled with a 77% R0 resection rate. Median overall survival was 34.8 months (95% CI: (11.57 months, not reached)). Patients who had more than a 51% increase in the autophagy marker LC3-II in circulating peripheral blood mononuclear cells had improvement in disease-free (15.03 vs. 6.9 months, p<0.05) and overall survival (34.83 vs. 10.83 months, p<0.05). No outcome differences were demonstrated in the 81% of patients with abnormal p53 expression assessed by immunohistochemistry in the resected specimens. Conclusion Pre-operative autophagy inhibition with HCQ plus gemcitabine is safe and well-tolerated. Surrogate biomarker responses (CA19-9) and surgical oncologic outcomes were enouraging. p53 status was not associated with adverse outcomes.

Purpose: We hypothesized that autophagy inhibition would increase response to chemotherapy in the preoperative setting for patients with pancreatic adenocarcinoma. We performed a randomized controlled trial to assess the autophagy inhibitor hydroxychloroquine in combination with gemcitabine and nab-paclitaxel. Experimental Design: Participants with potentially resectable tumors were randomized to two cycles of nab-paclitaxel and gemcitabine (PG) alone or with hydroxychloroquine (PGH), followed by resection. The primary endpoint was histopathologic response in the resected specimen. Secondary clinical endpoints included CA 19-9 serum biomarker response and margin negative R0 resection. Exploratory endpoints included markers of autophagy, immune infiltrate, and serum cytokines. Results: Thirty-four patients in the PGH arm and 30 in the PG arm were evaluable for the primary endpoint. The PGH arm demonstrated statistically improved Evans grade histopathologic responses (P = 0.00016), compared to control. In patients with elevated CA 19-9, a return to normal was associated with improved overall and recurrence-free survival (P < 0.0001). There were no differences in serious adverse events between arms and chemotherapy dose number was equivalent. The PGH arm had greater evidence of autophagy inhibition in their resected specimens (increased SQSTM1, P = 0.027, as well as increased immune cell tumor infiltration, P = 0.033). OS (P = 0.59) and RFS (P = 0.55) did not differ between the two arms. Conclusions: The addition of hydroxychloroquine to preoperative gemcitabine and nabpaclitaxel chemotherapy in patients with resectable pancreatic adenocarcinoma resulted in greater pathological tumor response, improved serum biomarker response, and evidence of autophagy inhibition and immune activity. Research.

No abstract

The scenarios identified by the high-risk FRS zone represent challenging anastomoses associated with markedly elevated rates of fistula. Externalized stents and omission of prophylactic octreotide, in the setting of intraperitoneal drainage and pancreaticojejunostomy reconstruction, provides optimal outcomes.