Faculty Bibliography

BACKGROUND:Periampullary neuroendocrine tumors (NETs) arise from the duodenum, ampulla, and periampullary pancreas. Duodenal and ampullary NETs are rare and may have distinct biologic behavior from pancreatic NETs (P-NETs). We examined the outcomes of these entities. METHODS:An institutional database was queried for patients undergoing resection for pancreatic head, duodenal, or ampullary NETs from 2000 to 2018. Patients with MEN1 syndrome or follow up less than 12 months were excluded. RESULTS:Three hundred and ten patients were identified. Tumor locations were ampulla (n = 15), duodenum (n = 35) and pancreas (n = 260). Median follow-up and recurrence-free survival (RFS) were 60.9 (interquartile range [IQR]: 34.8-99.3) and 171.7 (IQR: 84.0-NR) months. Clinicopathologic data and survival outcomes were similar for duodenal and ampullary NETs (RFS: p = .347 and overall survival [OS]: p = .246) and were combined into an intestinal subtype (IS) group. There were no differences in OS or RFS when comparing IS-NET and P-NET. On multivariate analysis, tissue of origin was not associated with risk of recurrence. The current American Joint Committee on Cancer staging guidelines, which account for origin tissue, were predictive of outcomes for all subtypes. CONCLUSION/CONCLUSIONS:Tissue of origin does not appear to impact long-term outcomes when comparing IS-NETs and P-NETs. The AJCC staging system offers good discriminatory capacity in the context of the tissue type.

Recent research on genomic profiling of pancreatic ductal adenocarcinoma (PDAC) has identified many potentially actionable alterations. However, the feasibility of using genomic profiling to guide routine clinical decision making for PDAC patients remains unclear. We retrospectively reviewed PDAC patients between October 2013 and December 2017, who underwent treatment at the Johns Hopkins Hospital and had clinical tumor next-generation sequencing (NGS) through commercial resources. Ninety-two patients with 93 tumors tested were included. Forty-eight (52%) patients had potentially curative surgeries. The median time from the tissue available to the NGS testing ordered was 229 days (interquartile range 62-415). A total of three (3%) patients had matched targeted therapies based on genomic profiling results. Genomic profiling guided personalized treatment for PDAC patients is feasible, but the percentage of patients who receive targeted therapy is low. The main challenges are ordering NGS testing early in the clinical course of the disease and the limited evidence of using a targeted approach in these patients. A real-time department level genomic testing ordering system in combination with an evidence-based flagging system for potentially actionable alterations could help address these shortcomings.

PURPOSE/OBJECTIVE:We assessed the feasibility and safety of placing a radiopaque hydrogel in the pancreaticoduodenal groove via endoscopic ultrasound guidance in patients with borderline resectable/locally advanced pancreatic cancer (BR/LAPC). METHODS AND MATERIALS/METHODS:Hydrogel injections were done at time of fiducial placement to form blebs in the pancreaticoduodenal groove. Patients subsequently underwent simulation computed tomography (sim-CT) followed by hypofractionated stereotactic body radiotherapy (SBRT; 33 Gy in 5 fractions). Four to 8 weeks after SBRT, patients underwent CT re-evaluation for surgical candidacy and assessment of hydrogel location and size. Hydrogel placement was considered successful if identified in the pancreaticoduodenal groove on sim-CT scan. Stability was evaluated using equivalence testing analyses, with a null hypothesis of the presence of a ≥20% mean percentage change in volume and ≥2 mm change in the median and mean interbleb surface distance with a P value <.05 required to reject the null hypothesis and conclude equivalence. For patients undergoing pancreaticoduodenectomy, hydrogel sites were histologically examined for location and local inflammatory reactions. RESULTS:Hydrogel placement was successful in 6 of the 6 evaluable patients. The average changes in median and mean interbleb distances were -0.43 mm and -0.35 mm, respectively, with P < .05. The average change in volume from sim-CT to post-SBRT CT was -1.0%, with P < .05. One patient experienced grade 3 nausea after fiducial/hydrogel placement, with no other adverse events to date. CONCLUSIONS:These data demonstrate feasibility and safety of injecting a hydrogel marker in the pancreaticoduodenal groove in patients with BR/LAPC and set the stage for a follow-up clinical trial to place hydrogel as a spacer between the pancreatic tumor and dose-limiting, radiosensitive duodenum.

BACKGROUND:The objective of this study was to validate and update the Amsterdam prediction model including tumor grade, lymph node ratio, margin status and adjuvant therapy, for prediction of overall survival (OS) after pancreatoduodenectomy for pancreatic cancer. METHODS:We included consecutive patients who underwent pancreatoduodenectomy for pancreatic cancer between 2000 and 2017 at 11 tertiary centers in 8 countries (USA, UK, Germany, Italy, Sweden, the Netherlands, Korea, Australia). Model performance for prediction of OS was evaluated by calibration statistics and Uno's C-statistic for discrimination. Validation followed the TRIPOD statement. RESULTS:Overall, 3081 patients (53% male, median age 66 years) were included with a median OS of 24 months, of whom 38% had N2 disease and 77% received adjuvant chemotherapy. Predictions of 3-year OS were fairly similar to observed OS with a calibration slope of 0.72. Statistical updating of the model resulted in an increase of the C-statistic from 0.63 to 0.65 (95% CI 0.64-0.65), ranging from 0.62 to 0.67 across different countries. The area under the curve for the prediction of 3-year OS was 0.71 after updating. Median OS was 36, 25 and 15 months for the low, intermediate and high risk group, respectively (P < 0.001). CONCLUSIONS:This large international study validated and updated the Amsterdam model for survival prediction after pancreatoduodenectomy for pancreatic cancer. The model incorporates readily available variables with a fairly accurate model performance and robustness across different countries, while novel markers may be added in the future. The risk groups and web-based calculator www.pancreascalculator.com may facilitate use in daily practice and future trials.

Recent studies considered surgery as a treatment option for patients with pancreatic ductal adenocarcinoma (PDAC) and synchronous liver metastases. The aim of this study was to evaluate systematically the literature on the role of surgical resection in this setting as an upfront procedure or following primary chemotherapy. A systematic search was performed of PubMed, Embase and the Cochrane Library in accordance with PRISMA guidelines. Only studies that included patients with synchronous liver metastases published in the era of multiagent chemotherapy (after 2011) were considered, excluding those with lung/peritoneal metastases or metachronous liver metastases. Median overall survival (OS) was the primary outcome. Six studies with 204 patients were analyzed. 63% of patients underwent upfront pancreatic and liver resection, 35% had surgery after primary chemotherapy with strict selection criteria and 2% had an inverse approach (liver surgery first). 38 patients (18.5%) did not undergo any liver resection since metastases disappeared after chemotherapy. Postoperative mortality was low (< 2%). Median OS ranged from 7.6 to 14.5 months after upfront pancreatic/liver resection and from 34 to 56 months in those undergoing preoperative treatment. This systematic review suggests that surgical resection of pancreatic cancer with synchronous liver oligometastases is safe, and it can be associated with improved survival, providing a careful selection of patients after primary chemotherapy.

We report a sensitive PCR-based assay called Repetitive Element AneupLoidy Sequencing System (RealSeqS) that can detect aneuploidy in samples containing as little as 3 pg of DNA. Using a single primer pair, we amplified ∼350,000 amplicons distributed throughout the genome. Aneuploidy was detected in 49% of liquid biopsies from a total of 883 nonmetastatic, clinically detected cancers of the colorectum, esophagus, liver, lung, ovary, pancreas, breast, or stomach. Combining aneuploidy with somatic mutation detection and eight standard protein biomarkers yielded a median sensitivity of 80% in these eight cancer types, while only 1% of 812 healthy controls scored positive.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy characterized by extensive local invasion and systemic spread. In this study, we employed a three-dimensional organoid model of human pancreatic cancer to characterize the molecular alterations critical for invasion. Time-lapse microscopy was used to observe invasion in organoids from 25 surgically resected human PDAC samples in collagen I. Subsequent lentiviral modification and small-molecule inhibitors were used to investigate the molecular programs underlying invasion in PDAC organoids. When cultured in collagen I, PDAC organoids exhibited two distinct, morphologically defined invasive phenotypes, mesenchymal and collective. Each individual PDAC gave rise to organoids with a predominant phenotype, and PDAC that generated organoids with predominantly mesenchymal invasion showed a worse prognosis. Collective invasion predominated in organoids from cancers with somatic mutations in the driver gene SMAD4 (or its signaling partner TGFBR2). Reexpression of SMAD4 abrogated the collective invasion phenotype in SMAD4-mutant PDAC organoids, indicating that SMAD4 loss is required for collective invasion in PDAC organoids. Surprisingly, invasion in passaged SMAD4-mutant PDAC organoids required exogenous TGFβ, suggesting that invasion in SMAD4-mutant organoids is mediated through noncanonical TGFβ signaling. The Rho-like GTPases RAC1 and CDC42 acted as potential mediators of TGFβ-stimulated invasion in SMAD4-mutant PDAC organoids, as inhibition of these GTPases suppressed collective invasion in our model. These data suggest that PDAC utilizes different invasion programs depending on SMAD4 status, with collective invasion uniquely present in PDAC with SMAD4 loss. SIGNIFICANCE: Organoid models of PDAC highlight the importance of SMAD4 loss in invasion, demonstrating that invasion programs in SMAD4-mutant and SMAD4 wild-type tumors are different in both morphology and molecular mechanism.

BACKGROUND:Patients with high body mass index are associated with a higher risk of complications after open pancreatectomy. We aimed to investigate the perioperative outcome for patients with high body mass index after robotic pancreatectomy. METHODS:This is a retrospective, propensity-score matched cohort analysis. From our prospectively maintained database, we identified consecutive patients with body mass index >25 who underwent robotic pancreatectomy between January 2016 and December 2018. Propensity score matching with open pancreatectomy was applied in 1:2 fashion based on age, gender, American Society of Anesthesiologists classification, surgery type, histology, neoadjuvant therapy, and body mass index during the same study period. RESULTS:A total of 127 patients were included. The mean age for all patients was 61.7 ± 12.8 years and 65 (51.2%) were male. Median body mass index was 29.9 (interquartile range, 27.0-31.8) for both groups. Propensity score matching provided equally distributed general demographic and clinicopathological factors. Robotic pancreatectomy was associated with decreased blood loss (100 mL vs 300 mL, P < .001) and shorter hospital stay (7 vs 9 days, P = .019). CONCLUSION:Robotic pancreatectomy is associated with decreased blood loss and shorter length of hospital stay in overweight patients. Robotic approach may help alleviate morbidity in overweight patients undergoing pancreatectomy.