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Neoadjuvant therapy (NT) for borderline resectable pancreatic cancer (BRPC) has evolved to include multi-agent regimens and chemoradiation. We report our experience and compare outcomes of initially resectable pancreatic cancer (IRPC) vs BRPC receiving NT across two eras of chemotherapy regimens.Data were collected retrospectively on pancreaticoduodenectomy patients between January 2008 and October 2015. Outcomes and survival were compared based on patient, laboratory and treatment factors.195 patients were included and 133 had IRPC and 62 BRPC. IRPC operations were shorter (449 min vs 520 min, p = 0.003), had less blood loss (663 ml vs 954 ml, p = 0.002) and involved fewer vascular resections (29% vs 76%, p = 0.002). The rate of R0 resection was identical (82%, p = 1) and the IRPC group had higher node-positive ratio (19.3% vs 7.2% p 0.0001). 15 patients received a single agent regimen while 47 received multi-agent regimens with 90% receiving radiation.Survival was similar between BRPC and IRPC (log-rank p = 0.7). Histopathologic response (CAP grade 0 or 1) was not associated with survival (p = 0.13), but completion of ≥4 cycles of multi-agent pre-operative chemotherapy (p = 0.001) and complete response to NT (p = 0.04) were significant predictors of survival.BRPC patients treated with NT have similar morbidity and survival to their IRPC counterparts. Pathologic response and modern NT are associated with improved survival.

Importance Despite a large rural US population, there are potential differences between rural and urban regions in the processes and outcomes following trauma. Objectives To describe and evaluate rural vs urban processes of care, injury severity, and mortality among injured patients served by 9-1-1 emergency medical services (EMS). Design, Setting, and Participants This was a preplanned secondary analysis of a prospective cohort enrolled from January 1 through December 31, 2011, and followed up through hospitalization. The study included 44 EMS agencies transporting to 28 hospitals in 2 rural and 5 urban counties in Oregon and Washington. A population-based, consecutive sample of 67 047 injured children and adults served by EMS (1971 rural and 65 076 urban) was enrolled. Among the 53 487 patients transported by EMS, a stratified probability sample of 17 633 patients (1438 rural and 16 195 urban) was created to track hospital outcomes (78.9% with in-hospital follow-up). Data analysis was performed from June 12, 2015, to May 20, 2016. Exposures Rural was defined at the county level by 60 minutes or more driving proximity to the nearest level I or II trauma center and/or rural designation in the Centers for Medicare & Medicaid Services ambulance fee schedule by zip code. Main Outcomes and Measures Mortality (out-of-hospital and in-hospital), need for early critical resources, and transfer rates. Results Of the 53 487 injured patients transported by EMS (17 633 patients in the probability sample), 27 535 were women (51.5%); mean (SD) age was 51.6 (26.1) years. Rural vs urban sensitivity of field triage for identifying patients requiring early critical resources was 65.2% vs 80.5%, and only 29.4% of rural patients needing critical resources were initially transported to major trauma centers vs 88.7% of urban patients. After accounting for transfers, 39.8% of rural patients requiring critical resources were cared for in major trauma centers vs 88.7% of urban patients. Overall mortality did not differ between rural and urban regions (1.44% vs 0.89%; P = .09); however, 89.6% of rural deaths occurred within 24 hours compared with 64% of urban deaths. Rural regions had higher transfer rates (3.2% vs 2.7%) and longer transfer distances (median, 97.4 km; interquartile range [IQR], 51.7-394.5 km; range, 47.8-398.6 km vs 22.5 km; IQR, 11.6-24.6 km; range, 3.5-97.4 km). Conclusions and Relevance Most high-risk trauma patients injured in rural areas were cared for outside of major trauma centers and most rural trauma deaths occurred early, although overall mortality did not differ between regions. There are opportunities for improved timeliness and access to major trauma care among patients injured in rural regions.

SummaryPancreatic ductal adenocarcinoma (PDAC) harbors the worst prognosis of any common solid tumor, and multiple failed clinical trials indicate therapeutic recalcitrance. Here, we use exome sequencing of patient tumors and find multiple conserved genetic alterations. However, the majority of tumors exhibit no clearly defined therapeutic target. High-throughput drug screens using patient-derived cell lines found rare examples of sensitivity to monotherapy, with most models requiring combination therapy. Using PDX models, we confirmed the effectiveness and selectivity of the identified treatment responses. Out of more than 500 single and combination drug regimens tested, no single treatment was effective for the majority of PDAC tumors, and each case had unique sensitivity profiles that could not be predicted using genetic analyses. These data indicate a shortcoming of reliance on genetic analysis to predict efficacy of currently available agents against PDAC and suggest that sensitivity profiling of patient-derived models could inform personalized therapy design for PDAC.

Focal nodular hyperplasia (FNH) is the second most common benign lesion of the liver and a common differential in the workup of solid liver lesions. With increasing use of modern imaging modalities FNH is becoming clinically more relevant. We present a case of pedunculated FNH presenting as a pericholecystic mass. This was resected laparoscopically due to persistent symptoms and uncertainty in diagnosis. We summarize the current literature with regard to the diagnosis, etiology, and management of FNH lesions.

Iatrogenic tumor cell implantation within surgical wounds can compromise curative cancer surgery. Adhesion of cancer cells, in particular colon cancer cells, is stimulated by exposure to increased extracellular pressure through a cytoskeleton-dependent signaling mechanism requiring FAK, Src, Akt, and paxillin. Mechanical stimuli during tumor resection may therefore negatively impact patient outcome. We hypothesized that perioperative administration of colchicine, which prevents microtubule polymerization, could disrupt pressure-stimulated tumor cell adhesion to surgical wounds and enhance tumor-free survival. Ex vivo treatment of Co26 and Co51 colon cancer cells with colchicine inhibited pressure-stimulated cell adhesion to murine surgical wounds and blocked pressure-induced FAK and Akt phosphorylation. Surgical wound contamination with pressure-activated Co26 and Co51 cells significantly reduced tumor-free survival compared with contamination with tumor cells under ambient pressure. Mice treated with pressure-activated Co26 and Co51 cells from tumors preoperatively treated with colchicine in vivo displayed reduced surgical site implantation and significantly increased tumor-free survival compared with mice exposed to pressure-activated cells from tumors not pretreated with colchicine. Our data suggest that pressure activation of malignant cells promotes tumor development and impairs tumor-free survival and that perioperative colchicine administration or similar interventions may inhibit this effect.

Metastasizing colon cancer cells bind target tissues primarily via integrins. Extracellular pressure or shear stress stimulates integrin-mediated adhesion to matrix proteins or endothelial cells by activating the focal adhesion proteins FAK and Src. Because this effect is blocked by cytoskeletal perturbation and paxillin may link the cytoskeleton to the focal adhesion complex, we evaluated the role of paxillin in pressure-induced malignant colonocyte adhesion. We studied SW620 colon cancer cells and confirmed key results in Caco-2 colon cancer cells, primary human colon cancer cells, and a murine colonic adenocarcinoma. We evaluated adhesion to collagen at ambient and 15 mmHg increased pressure after 30 minutes, and paxillin, FAK, and Src phosphorylation in suspended cells prior to adhesion. Some cells were treated with siRNA to paxillin or FAK, or the Src inhibitor PP2. We also compared pressure-induced signals in suspended cells with adhesion-induced signals after adhesion to collagen. Pressure stimulated adhesion and paxillin phosphorylation in SW620 and Caco-2 cells and human primary colon cancer cells. Pressure also increased paxillin phosphorylation in murine carcinoma cells. SiRNA to paxillin decreased SW620 and Caco-2 paxillin without altering basal levels of phosphorylated paxillin. Paxillin reduction decreased basal adhesion to collagen, and inhibited pressure-stimulated adhesion, as well as paxillin, FAK397, FAK576, and Src476 phosphorylation. Neither PP2 nor siRNA to FAK inhibited induction of paxillin phosphorylation by pressure. In contrast, adhesion stimulated FAK, Src, and paxillin phosphorylation regardless of paxillin reduction. In summary, pressure induced paxillin phosphorylation in colon cancer cells. Paxillin reduction inhibited basal adhesion and blocked the pressure-mediated increase in adhesion, as well as pressure-induced FAK and Src signals, while adhesion-induced signals were preserved. Paxillin may be an upstream mediator of pressure-stimulated adhesion, important in metastasis.

Background: Cancer cells adhere principally by integrins, matrix receptors that may be influenced by divalent cations. Surgical wound fluid is high in Mg2+ and low in Ca2+. We hypothesized that Mg+ and Mn2+ promote perioperative adhesion of shed cancer cells to surgical sites and that washing surgical wounds with Ca2+ inhibits implantation.Methods: We tested our hypothesis in a murine colon 26 adenocarcinoma model. We added 10 mmol/L CaCl2, 0.25 mmol/L MgCl2, or 0.5 mmol/L MnCl2 to suspended murine colon 26 cancer cells and placed these suspensions into wounds in anesthetized mice. After 30 minutes, we washed away nonadherent cells. In some studies, we Cr-51-labeled the cells and assayed tumor adhesion by wound radioactivity. In parallel studies, we closed the wounds and observed the mice for 90 days.Results: Mg2+ increased adhesion to 188% +/- 15% of control (n = 10, P

Cervical anastomotic leak rates are high after esophagectomy. We examined the effect of a purposeful delay in institution of oral diet after esophagectomy on the leak rate and hospital length of stay. A retrospective analysis of 120 patients submitted to esophagectomy with cervical esophagogastric anastomosis was conducted. Eighty-seven resumed diet within 7 days of surgery (early eaters), and 33 had delayed diet until a mean of 12 days after surgery (late eaters). Mean age was 62.3 years; 98 patients were male. One hundred one resections were for cancer, and 49 % of cancer patients received neoadjuvant therapy. The overall leak rate was 17.5 %, and hospital length of stay was 10.9 days. Anastomotic leak rate was 3 % for late eaters versus 23 % for early eaters (OR of 9.57, p = 0.010). Hospital length of stay was 6 days for late eaters versus 11.8 days for early eaters (p < 0.001). Anastomotic leak was significantly associated with increased length of stay (p < 0.001), adding an average of 7.6 days to hospital stay. Respiratory complications (p < 0.001) and delayed gastric emptying (p = 0.014) were also independent predictors of increased length of stay, but early eater status was not. Delayed resumption of oral diet after esophagectomy significantly reduces cervical anastomotic leak rate and avoids the increased length of stay associated with leak.

Importance Although consensus statements support the preoperative treatment of borderline resectable pancreatic cancer, no prospective, quality-controlled, multicenter studies of this strategy have been conducted. Existing studies are retrospective and confounded by heterogeneity in patients studied, therapeutic algorithms used, and outcomes reported. Objective To determine the feasibility of conducting studies of multimodality therapy for borderline resectable pancreatic cancer in the cooperative group setting. Design, Setting, and Participants A prospective, multicenter, single-arm trial of a multimodality treatment regimen administered within a study framework using centralized quality control with the cooperation of 14 member institutions of the National Clinical Trials Network. Twenty-nine patients with biopsy-confirmed pancreatic cancer preregistered, and 23 patients with tumors who met centrally reviewed radiographic criteria registered. Twenty-two patients initiated therapy (median age, 64 years [range, 50-76 years]; 55% female). Patients registered between May 29, 2013, and February 7, 2014. Interventions Patients received modified FOLFIRINOX treatment (85 mg/m2 of oxaliplatin, 180 mg/m2of irinotecan hydrochloride, 400 mg/m2of leucovorin calcium, and then 2400 mg/m2of 5-fluorouracil for 4 cycles) followed by 5.5 weeks of external-beam radiation (50.4 Gy delivered in 28 daily fractions) with capecitabine (825 mg/m2orally twice daily) prior to pancreatectomy. Main Outcomes and Measures Feasibility, defined by the accrual rate, the safety of the preoperative regimen, and the pancreatectomy rate. Results The accrual rate of 2.6 patients per month was superior to the anticipated rate. Although 14 of the 22 patients (64% [95% CI, 41%-83%]) had grade 3 or higher adverse events, 15 of the 22 patients (68% [95% CI, 49%-88%]) underwent pancreatectomy. Of these 15 patients, 12 (80%) required vascular resection, 14 (93%) had microscopically negative margins, 5 (33%) had specimens that had less than 5% residual cancer cells, and 2 (13%) had specimens that had pathologic complete responses. The median overall survival of all patients was 21.7 months (95% CI, 15.7 to not reached) from registration. Conclusions and Relevance The successful completion of this collaborative study demonstrates the feasibility of conducting quality-controlled trials for this disease stage in the multi-institutional setting. The data generated by this study and the logistical elements that facilitated the trial’s completion are currently being used to develop cooperative group trials with the goal of improving outcomes for this subset of patients. Trial Registration clinicaltrials.gov Identifier:NCT01821612

Focal nodular hyperplasia (FNH) is the second most common benign lesion of the liver and a common differential in the workup of solid liver lesions. With increasing use of modern imaging modalities FNH is becoming clinically more relevant. We present a case of pedunculated FNH presenting as a pericholecystic mass. This was resected laparoscopically due to persistent symptoms and uncertainty in diagnosis. We summarize the current literature with regard to the diagnosis, etiology, and management of FNH lesions.

An isolated cyst of the cystic duct is an extremely rare lesion. Only single case reports are documented in the literature. The most accepted classification system of biliary cysts, the Todani classification, does not include this lesion. We report a case of isolated cyst of the cystic duct. The initial referral was for evaluation of a gallbladder mass discovered during evaluation of abdominal pain. Preoperative diagnosis was challenging as multiple imaging studies were unable to differentiate this lesion from a choledochal cyst. Surgical planning thus included cyst excision and biliary reconstruction. Operative exploration revealed a type VI biliary cyst and cholecystectomy with cystic duct ligation near the common bile duct was curative.

4008 Background: Infusional 5-FU, oxaliplatin, leucovorin and irinotecan (FOLFIRINOX) is effective for metastatic PDAC. The tolerability and efficacy of neoadjuvant FOLFIRINOX and CRT for BLR PDAC ...

Paxillin is an adapter protein regulating signaling and focal adhesion assembly that has been linked to malignant potential in many malignancies. Overexpression of paxillin has been noted in aggressive tumors. Integrin-mediated binding through the focal adhesion complex is important in metastatic adhesion and is upregulated by extracellular pressure in malignant colonocytes through FAK and Src activation. Neither head and neck cancers nor paxillin have been studied in this regard. We hypothesized that paxillin would play a role in modulating squamous cancer adhesion both at baseline and under conditions of increased extracellular pressure. Using SCC25 tongue squamous cancer cells stably transfected with either an empty selection vector or paxillin expression and selection vectors, we studied adhesion to collagen, paxillin, FAK, and Src expression and phosphorylation in cells maintained for 30 min under ambient or 15 mmHg increased pressure conditions. Paxillin-overexpressing cells exhibited adhesion 121 +/- 2.9% of that observed in vector-only cells (n = 6, P < 0.001) under ambient pressure. Paxillin-overexpression reduced FAK phosphorylation. Pressure stimulated adhesion to 118 +/- 2.3% (n = 6, P < 0.001) of baseline in vector-only cells, similar to its effect in the parental line, and induced paxillin, FAK, and Src phosphorylation. However, increased pressure did not stimulate adhesion or phosphorylate paxillin, FAK, or Src further in paxillin-overexpressing cells. Metastasizing squamous cancer cell adhesiveness may be increased by paxillin-overexpression or by paxillin activation by extracellular pressure during surgical manipulation or growth within a constraining compartment. Targeting paxillin in patients with malignancy and minimal tumor manipulation during surgical resection may be important therapeutic adjuncts.

Peripancreatic collections related to acute pancreatitis can range from simple serous fluid to infected phlegmon. The latter can be associated with significant morbidity and mortality. A patient with striking abdominal computed tomography images of an infected phlegmonous peripancreatic collection was seen at our institution. The clinical picture was much different from what the images predicted. Endoscopic retrograde cholangiopancreatography revealed a fistulous connection between the collection and the stomach, also seen on retrospective abdominal computed tomography scan review, indicating spontaneous decompression, which cured the patient.

S A T A b st ra ct s Six patients (5%) with conversion to OPD were included in LPD group based on intent-totreat. Daily opioid consumption of the LPD group was significantly less than that of OPD group from POD 2 through POD 5, and total opioid consumption of LPD group was also significantly less (LPD: 5.3 ± 6.4 mg/kg, OPD: 7.3 ± 9.4 mg/kg, P = 0.007). Multivariate analysis revealed that younger age (, 65 years old) (HR 1.89, 95% CI 1.29 2.79, P = 0.001), no preoperative diabetes mellitus (HR 1.74, 95% CI 1.10 2.80, P = 0.01), PD for chronic pancreatitis (HR 2.87, 95% CI 1.18 7.51, P = 0.02), OPD (HR 2.01, 95% CI 1.26 3.27, P = 0.003) and postoperative major complication (Grade III-V) (HR 2.30, 95% CI 1.36 3.91, P = 0.001) were independently associated with increased opioid consumption after PD (total opioid consumption . 6mg/kg). Conclusion: Patients undergoing TLPD have lless opioid consumption compared to those with the open approach. Younger age, absence of diabetes, chronic pancreatitis indication and major postoperative complications are independent predictors of increased opioid consumption. These findings warrant further evaluation as to the potential clinical impact of reduced pain and less opioid consumption on patient-specific advantages including early recovery and better quality of life after pancreaticoduodenectomy.