Coordinate transcriptional regulation of ErbB2/3 by C-terminal binding protein 2 signals sensitivity to ErbB2 inhibition in pancreatic adenocarcinoma.

There is a critical need to identify new therapeutic vulnerabilities in pancreatic ductal adenocarcinoma (PDAC). Transcriptional co-regulators C-terminal binding proteins (CtBP) 1 and 2 are highly overexpressed in human PDAC, and CRISPR-based homozygous deletion of Ctbp2 in a mouse PDAC cell line (CKP) dramatically decreased tumor growth, reduced metastasis, and prolonged survival in orthotopic mouse allografts. Transcriptomic profiling of tumors derived from CKP vs. Ctbp2-deleted CKP cells (CKP/KO) revealed significant downregulation of the EGFR-superfamily receptor Erbb3, the heterodimeric signaling partner for both EGFR and ErbB2. Compared with CKP cells, CKP/KO cells also demonstrated reduced Erbb2 expression and did not activate downstream Akt signaling after stimulation of Erbb3 by its ligand neuregulin-1. ErbB3 expression in human PDAC cell lines was similarly dependent on CtBP2 and depletion of ErbB3 in a human PDAC cell line severely attenuated growth, demonstrating the critical role of ErbB3 signaling in maintaining PDAC cell growth. Sensitivity to the ErbB2-targeted tyrosine kinase inhibitor lapatinib, but not the EGFR-targeted agent erlotinib, varied in proportion to the level of ErbB3 expression in mouse and human PDAC cells, suggesting that an ErBb2 inhibitor can effectively leverage CtBP2-driven transcriptional activation of physiologic ErbB2/3 expression and signaling in PDAC cells for therapeutic benefit.

Age-related risks of complications after distal pancreatectomy for neuroendocrine and cystic neoplasms.

BACKGROUND: Distal pancreatic neuroendocrine tumors (PNET) and pancreatic cystic neoplasms (PCN) are often incidentally found in older adults, requiring careful consideration between operative management and watchful waiting. This study analyzes the short-term complications associated with distal pancreatectomy (DP) for PNET and PCN in older adults to inform clinical decision-making. METHODS: Patients undergoing DP for PNET and PCN were analyzed using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database and the pancreatectomy procedure-targeted dataset. Associations between decade of age and 30-day outcomes were evaluated. RESULTS: 1626 patients were analyzed from 2014 to 2015. 692 (42.6%) were younger than 60 years, 507 (31.2%) were sexagenarians, 342 (21.0%) were septuagenarians, and 85 (5.2%) were octogenarians. Minimally invasive approaches were used in 62.7%. While septuagenarians and octogenarians constituted 26.3% of the cohort, they were affected by 55.6% of reintubations, 66.7% of failures to wean, 82.4% of myocardial infarctions, and 57.1% of septic shock. Septuagenarians and octogenarians had longer hospital stays, as compared to those younger than 60 years. CONCLUSION: Septuagenarians and octogenarians are disproportionately affected by perioperative complications after DP for PNET and PCN. Careful patient selection and thorough counseling should be provided when surgery is considered.

Decision Making Influences Tibial Impact Accelerations During Lateral Cutting.

Lower-extremity musculoskeletal injuries are common in sports such as basketball and soccer. Athletes competing in sports of this nature must maneuver in response to the actions of their teammates, opponents, etc. This limits their ability to preplan movements. The purpose of this study was to compare impact accelerations during preplanned versus unplanned lateral cutting. A total of 30 subjects (15 males and 15 females) performed preplanned and unplanned cuts while the authors analyzed impact accelerations using an accelerometer secured to their tibia. For the preplanned condition, subjects were aware of the movement to perform before initiating a trial. For the unplanned condition, subjects initiated their movement and then reacted to the illumination of one of 3 visual stimuli which dictated whether they would cut, land, or land-and-jump. A mixed-model analysis of variance with a between factor of sex (male and female) and a within factor of condition (preplanned and unplanned) was used to analyze the magnitude and variability of the impact accelerations for the cutting trials. Both males and females demonstrated higher impact accelerations (P = .01) and a trend toward greater intertrial variability (P = .07) for the unplanned cutting trials (vs preplanned cuts). Unplanned cutting may place greater demands on the musculoskeletal system.

Predictors of Short-Term Readmission After Pancreaticoduodenectomy.

BACKGROUND: Readmissions are a common complication after pancreaticoduodenectomy and are increasingly being used as a performance metric affecting quality assessment, public reporting, and reimbursement. This study aims to identify general and pancreatectomy-specific factors contributing to 30-day readmission after pancreaticoduodenectomy, and determine the additive value of incorporating pancreatectomy-specific factors into a large national dataset. METHODS: Prospective American College of Surgeons-National Surgical Quality Improvement Project (ACS-NSQIP) data were retrospectively analyzed for patients who underwent pancreaticoduodenectomy (PD) between 2011 and 2015. Additionally, a subset of patients with pancreatectomy-targeted data between 2014 and 2015 were analyzed. RESULTS: Outcomes of 18,440 pancreaticoduodenectomies were analyzed, and found to have an 18.7% overall readmission rate. Multivariable modeling with pancreatectomy-specific variables increased the predictive value of the model (area under receiver operator characteristic 0.66 to 0.73). Statistically significant independent contributors to readmission included renal insufficiency, sepsis, septic shock, organ space infection, dehiscence, venous thromboembolism, pancreatic fistula, delayed gastric emptying, need for percutaneous drainage, and reoperation. CONCLUSIONS: Large registry analyses of pancreatectomy outcomes are markedly improved by the incorporation of granular procedure-specific data. These data emphasize the need for prevention and careful management of perioperative infectious complications, fluid management, thromboprophylaxis, and pancreatic fistulae.

Clinical assessment and management of general surgery patients via synchronous telehealth.

Objective This paper describes how a clinical team at Landstuhl Regional Medical Center (LRMC) successfully integrated synchronous telehealth (TH) into their routine clinical practice. Methods and materials Synchronous TH encounters were performed using Polycom® software on surgeons' computers with high-definition (HD) cameras on monitors at distant sites and PolyCom HDX9000® Telehealth Practitioner Carts at originating sites. Patients provided consented and were presented to general surgeons by nurses and medical technicians at Army health clinics throughout the European Theater. Results In calendar year (CY) 2014, five general surgeons and two surgical physician assistants (PAs) at Landstuhl Regional Medical Center along with registered nurses (RNs) at six originating clinic sites throughout Europe completed 130 synchronous TH encounters for 101 general surgery patients resulting in 73 completed and 16 recommended surgeries. Eighty-eight percent of patients had a completed or recommended surgery. No surgeries or procedures planned after initial TH evaluation were cancelled. Originating site clinics ranged in distance from 68 miles to 517 miles. Acceptance by providers, patients and clinic staff was high. Conclusion Synchronous TH was effective and safe in evaluating common general surgical conditions. We excluded sensitive and complex conditions requiring a nuanced physical examination. The TH efforts of the general surgery staff have resulted in high-quality, seamless and predictable TH activities that continue to expand into other surgical and medical specialties beyond general surgery. Seven surgeons and two PAs use synchronous TH regularly serving patients over a broad geographic area.

Management of suspected pancreatic cystic neoplasms based on cyst size.

BACKGROUND: Evaluation and management of cystic pancreatic neoplasms remain problematic. International consensus guidelines have advised resection for lesions greater than 3 cm. METHODS: We reviewed our prospective pancreatic cystic neoplasm database for outcomes based on a cyst size of 3 cm. RESULTS: Five hundred patients have been managed from 1999 to 2006. There were 349 patients (70%) with cysts less than or equal to 3 cm: 293 (84%) were not operated, including 243 nonmucinous cysts: 2 failed observation (0.8%, mean follow-up of 24 months). Fifty-six patients with cysts less than or equal to 3 cm were initially operated (16%), including 23 asymptomatic patients. Histopathology showed intraductal papillary mucinous neoplasm (IPMN) in 20, mucinous cystic neoplasm (MCN) in 18, and serous cystadenoma in 5. Twelve had carcinoma (21%). A total of 151 patients (30%) had cysts greater than cm: 87 (50%) were not operated, including 68 that were nonmucinous: 2 failed observation (2.9%, mean follow-up of 47 months). Sixty-four patients with cysts greater than 3 cm (42%) were initially operated, and final pathology showed MCN in 27, serous cystadenoma in 11, IPMN in 7, and pseudocyst in 7. Twelve had carcinoma (19%). Patients with cysts less than or equal to 3 cm were less likely to be operated (16 vs 42%; P < .001), less often symptomatic (39 vs 50%; P = .017), while older (mean age, 65 vs 61 years; P = .03). Had patients been managed by size alone, up to 20% would have received inappropriate treatment. Management based on aspiration was significantly better in predicting mucinous neoplasms compared with size (75% vs 57%; P < .001), including asymptomatic patients less than or equal to 3 cm (78% vs 65%; P = .003). CONCLUSION: Size of pancreatic cystic lesions alone is not a reasonable basis for determining management.