ISL2 is a putative tumor suppressor whose epigenetic silencing reprograms the metabolism of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) cells reprogram their transcriptional and metabolic programs to survive the nutrient-poor tumor microenvironment. Through in vivo CRISPR screening, we discovered islet-2 (ISL2) as a candidate tumor suppressor that modulates aggressive PDA growth. Notably, ISL2, a nuclear and chromatin-associated transcription factor, is epigenetically silenced in PDA tumors and high promoter DNA methylation or its reduced expression correlates with poor patient survival. The exogenous ISL2 expression or CRISPR-mediated upregulation of the endogenous loci reduces cell proliferation. Mechanistically, ISL2 regulates the expression of metabolic genes, and its depletion increases oxidative phosphorylation (OXPHOS). As such, ISL2-depleted human PDA cells are sensitive to the inhibitors of mitochondrial complex I in vitro and in vivo. Spatial transcriptomic analysis shows heterogeneous intratumoral ISL2 expression, which correlates with the expression of critical metabolic genes. These findings nominate ISL2 as a putative tumor suppressor whose inactivation leads to increased mitochondrial metabolism that may be exploitable therapeutically.

Adding Supra-Aortic Trunk Surgical Reconstruction to Carotid Endarterectomy: Implications on Risk of Stroke and Death.

BACKGROUND: Additive risks of combining supra-aortic trunk surgical reconstruction (SAT) with carotid endarterectomy (CEA) for associated carotid bifurcation and great vessel disease management are not well defined. This study sought to define risk of combining SAT with CEA. STUDY DESIGN: Isolated CEA (ICEA) and CEA+SAT (from 2005 to 2015) were identified from NSQIP, excluding nonocclusive indications. CEA+SAT were compared with ICEA as well as a propensity-matched ICEA cohort. Primary outcomes included 30-day stroke, death, and composite (SD). Outcomes were then weighted by symptomatic status. Univariate and logistic regression analyses were performed. RESULTS: Patients included 79,477 ICEA and 270 CEA+SAT. SAT reconstructions included 19 (7%) aorto-carotid bypasses, 21 (8%) carotid-subclavian transpositions, 85 (31%) carotid-carotid bypasses, and 145 (54%) carotid-subclavian bypasses. There was no difference in 30-day mortality (vs CEA+SAT 1.5% vs ICEA 0.7% p = 0.12). CEA+SAT had higher rates of stroke (3.7% vs 1.6%, p = 0.005) and stroke and death (SD) (4.8% vs 2.1%, p = 0.001). Predictors of SD included CEA+SAT (odds ratio [OR] 5.2, 95% CI 1.03-26.3, p = 0.046) and symptomatic status (OR 1.9, 95% CI 1.1-3.2, p = 0.02). After propensity matching, CEA+SAT continued to have higher rates of stroke (3.4% vs 0.4%, p = 0.01) and SD (4.5% vs 1.5%, p = 0.04), with similar mortality (1.5% vs 1.1%, p = 0.70). No differences were noted in primary endpoints in asymptomatic patients. In symptomatic patients, CEA+SAT carried significantly higher stroke (5.6% vs 2.1%, p = 0.04) and SD risk (7.0% vs 2.8%, p = 0.03). CONCLUSIONS: CEA+SAT confers increased risk of stroke and SD over ICEA. Symptomatic status and concomitant procedure contribute to this risk. Management should be considered within the context of lesion characteristics, patient longevity, and individual operative risk profile.

Traumatic Aortic and Celiac Pseudoaneurysm with Aortocaval Fistula Managed with Endovascular Aortic Cuff Deployment and Open Hepatic Revascularization.

We present the case of a young patient who sustained a gunshot wound to the abdomen initially treated with laparotomy and repair of small bowel, splenic vein and diaphragmatic injuries. Subsequent computed tomography (CT) performed for hemodynamic instability demonstrated a pseudoaneurysm involving the aorta and proximal celiac artery, with an associated aortocaval fistula. An attempt at transperitoneal repair of these injuries was aborted due to extensive inflammatory changes in the region encountered during exposure. Subsequently, a hybrid repair was performed. This consisted of exclusion of the aortic and celiac artery pseudoaneurysm using an endovascular aortic cuff (22 × 39 mm, Cook Medical) via infrarenal aortic access, surgical ligation of the celiac artery branches, and revascularization via bypass from the infrarenal aortic access site arteriotomy to the common hepatic artery.

Impact of the Timing of Foot Tissue Resection on Outcomes in Patients Undergoing Revascularization for Chronic Limb-Threatening Ischemia.

The objective of this study is to describe utilization of revascularization and tissue resection in patients with chronic limb-threatening ischemia (CLTI) and determine whether the timing of resection impacts outcomes. Revascularizations for CLTI were queried (ACS-NSQIP 2011-2015). Outcomes included 30-day major adverse limb events (MALE), major adverse cardiac events (MACE), length of stay (LOS), operative time, 30-day readmissions, and wound infections. Groups included revascularization alone, revascularization/tissue resection during the same procedure (concurrent), or revascularization/delayed tissue resection (delayed). Resections were debridement or transmetatarsal amputations. Multivariate logistic regression determined risk-adjusted effects of tissue resection on outcomes. There was no difference in overall 30-day MACE or MALE between groups (P = .70 and P = .35, respectively). Length of stay (6.1 days revascularization alone vs 7.8 days concurrent vs 8.7 days delayed, P < .0001) was longer in patients who underwent any tissue resection. Highest 30-day readmission and operative time was the concurrent group (P = .02 and P < .0001, respectively). Wound infection was highest in the delayed group (1.4% revascularization alone vs 1.3% concurrent vs 6.2% delayed, P < .0001). After risk adjustment, timing of resection did not impact LOS for concurrent and delayed groups compared to revascularization alone (both P < .0001). Debridement and minor amputations can be done concurrently in patients undergoing revascularization for CLTI.

Comparison of 30 Day Stroke and Death in Hybrid Intervention and Open Surgical Reconstruction for the Treatment of Tandem Carotid Bifurcation and Supra-aortic Trunk Disease.

OBJECTIVE: The optimal approach for the treatment of tandem carotid bifurcation and supra-aortic trunk (SAT) disease remains controversial. The hybrid technique of carotid endarterectomy (CEA) with ipsilateral proximal endovascular intervention (IPE) has provided an attractive alternative to CEA with open SAT reconstruction (SATr). However, no studies have compared cohorts treated by these two approaches. METHODS: Using the National Surgical Quality Improvement Program (2005-2017), patients who underwent CEA + IPE and CEA + SATr were identified. Non-occlusive indications were excluded. Primary outcomes included 30 day stroke, death, and their composite (stroke and/or death [SD]). Univariable and logistic regression analyses were performed. RESULTS: In total, 372 patients were identified: 319 CEA + SATr and 53 CEA + IPE. SATr included 19 (5.9%) aorta to carotid bypasses, 22 (6.9%) carotid subclavian transpositions, 96 (30.1%) carotid carotid bypasses, 179 (56.1%) carotid subclavian bypasses, and three (0.9%) SAT endarterectomies. The mean age was 69 ± 10 years. The majority were men (53%), white (85%), and had a history of hypertension (84%). There were no demographic differences between the operative cohorts except that those having CEA + SATr were more likely to have hypertension (86% vs. 74%; p = .031). CEA + SATr had longer operative times and longer hospital length of stay. There were no differences in outcomes between the cohorts: stroke (CEA + SATr 4.1% vs. CEA + IPE 3.8%; p = .92), death (1.6% vs. 0%; p = .36), or SD (5.3% vs. 3.8%; p = .63). After risk adjustment, predictors of SD included symptomatic status (odds ratio [OR] 3.9, 95% confidence interval [CI] 1.1-13.5; p = .034), congestive heart failure (OR 16.5, 95% CI 2.0-136; p = .011), and return to the operating room (OR 8.5, 95% CI 2.3-30.8; p = .001). Operative method was not predictive (p = .63). CONCLUSION: Outcomes following CEA + SATr and CEA + IPE are similar. Although proposed as a safer, less invasive alternative, the hybrid approach did not reduce the risk of operative stroke or death relative to open reconstruction for the treatment of occlusive, tandem carotid/SAT disease. Based upon lesion and patient factors, both may be considered management options in select patients.

Impact of Adding Carotid Endarterectomy to Supra-aortic Trunk Surgical Reconstruction.

BACKGROUND: Up to 20% of patients requiring open supra-aortic trunk (SAT) reconstruction have significant carotid artery stenosis. The addition of carotid endarterectomy (CEA) to SAT has been described. Yet, additive risks are not well defined and controversy remains as to whether concomitant CEA increases stroke risk. This study assessed the perioperative effects of adding CEA to SAT. METHODS: Using the National Surgical Quality Improvement Program (NSQIP), patients who underwent SAT from 2005 to 2015 were evaluated. SAT + CEA were identified. An isolated SAT (ISAT) cohort was created by removing patients who underwent concurrent secondary procedures. Nonocclusive indications were excluded. SAT + CEA were compared with ISAT as well as a propensity-matched ISAT cohort. Primary outcomes were 30-day stroke, death, and composite stroke/death/myocardial infarction (SDM). Univariate and logistic regression analyses were performed. RESULTS: After review, 1,515 patients were identified: 1,245 ISAT (82%) and 270 SAT + CEA (18%). Most were women (56%), 86% were Caucasian, and 24% were symptomatic. Average age was 65 ± 12 years and SAT + CEA were older (69 vs. 64 years, P < 0.001). CEA + SAT were more likely to be men (53% vs. 42%, P < 0.001), have hypertension (86% vs. 75%, P < 0.001) and diabetes (26% vs. 20%, P = 0.04). SAT procedures included the following: carotid-subclavian bypass (68%), carotid-carotid bypass (16%), aorta-great vessel bypass (9%), and carotid-subclavian transposition (7%). ISAT were more likely to undergo carotid-subclavian bypass than SAT + CEA (71% vs. 54%, P < 0.001). Overall stroke was 2.3%, death 1.4%, and SDM 4.6%. There were no differences in 30-day stroke (ISAT 2.0% vs. SAT + CEA 3.7%, P = 0.09) or mortality (1.4% vs. 1.5%, P = 0.88). SAT + CEA had higher rates of SDM (7% vs. 4%, P = 0.03). On logistic regression, urgency was a predictor of SDM (operating room [OR] 3.6, 95% confidence interval [CI] 1.5-8.4, P = 0.003); addition of CEA was not predictive of stroke (OR 1.4, 95% CI 0.5-4.2, P = 0.52) or SDM (OR 1.5, 95% CI 0.6-3.6, P = 0.40). After propensity matching, there were no longer differences in demographics or primary end points between the 2 cohorts. CONCLUSIONS: Addition of CEA does not confer increased perioperative stroke or SDM risk over ISAT. Perioperative outcomes appear to be more affected by disseminated disease risk factors than the addition of CEA. In patients undergoing SAT, it is reasonable to consider performing combined CEA in populations with tandem carotid bifurcation disease and appropriate operative risk profile.

Compliance with the Accreditation Council for Graduate Medical Education duty hours in a general surgery residency program: Challenges and solutions in a teaching hospital.

BACKGROUND: The inception of work hour restrictions for resident physicians in 2003 created controversial changes within surgery training programs. On a recent Accreditation Council for Graduate Medical Education survey at our institution, we noted a discrepancy between low recorded violations of the duty hour restrictions and the surgery resident's perception of poor duty hour compliance. We sought to identify factors that lead to duty hour violations and to encourage accurate reporting among surgery trainees. METHODS: The A3/Lean methodology, an industry-derived, systematic, problem-solving approach, was used to investigate barriers to accurate reporting of duty hours by residents within the Department of Surgery at our academic institution. In partnership with our office of Graduate Medical Education, we encouraged a 6-month period where residents were asked to record duty hour accurately and to provide honest, descriptive explanations of violations without punitive effects on residents or the program. We performed a 6-month before-and-after analysis of duty hours violations after the A3/Lean implementation. Quantitative analysis was used to elucidate trends in violations by post graduate year and rotation. Qualitative evaluation by key thematic areas revealed resident attitudes and opinions about duty hour violations. RESULTS: Residents reported concern for personal and programmatic, punitive measures, desire to retain control of their education, and frustration with the administrative burden after violations as deterrents to honest duty hour reporting. The intervention was successful in changing logging behavior with 10 total violations prior to A3 meeting and 179 violations afterward (P = .003). This change was driven largely from an increase in short break violations (4 vs 134, P = .021). Analysis of violations revealed trends by post-graduate year, rotation, and weekend cross-coverage. Key findings including less than anticipated violations of the 80-hour work week despite high rates of short break violations. The ability to participate in procedures voluntarily and a sense of professional responsibility emerged as the prevailing themes among surgery residents describing violations. CONCLUSION: Systematic evaluation of duty hour reporting within a surgery training program can identify structural and cultural barriers to accurate reporting of duty hours. Accurate reporting can identify program-specific trends in duty hour violations that can be addressed though programmatic intervention.

Academic or community practice? What is driving decision-making and career choices.

BACKGROUND: Identifying factors that impact progression of surgery trainees into academic versus non-academic practices may permit tailoring residency experiences to promote academic careers in institutions charged with the training of future surgeon scientists. The aim of this study was to identify factors associated with progression of surgery trainees into academic versus non-academic practice. METHODS: A survey was distributed to 135 surgeons graduating from the University of Virginia residency program from 1964-2016, a single academic institution. Questions addressed practice type, research productivity, work/life balance, mentorship, and overall sentiment toward research and academic surgery. A 5-point Likert scale measured career satisfaction and influence of factors in practice setting choice. RESULTS: Of the 135 surveys that were electronically distributed, 69 participants responded (response rate: 51%). Of the 54 with known current practice types, 34 (63%) were academic and 20 (37%) non-academic. Academic surgeons reported more publications by the conclusion of surgery training (56% vs 25% with >10 publications, P = .02). More academic surgeons reported >$100,000 in student debt at graduation (44% vs 25%, P < .05). Factors encouraging an academic career were similar for both types of surgeons, including involvement in education of trainees and access to mentorship. Both groups were discouraged from an academic practice by requirements of grant-writing and funding responsibilities. Surgeons in academic practice were more likely to recommend surgery as a career to a current medical student (100% vs 70%, P = .001). CONCLUSION: This knowledge may help to tailor training experiences to promote academic careers. By supporting funding mechanisms and grant-writing programs, while encouraging mentorship and productive research experiences, current surgical trainees may be more enthusiastic about a career in academic practice.

CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer.

Purpose: Patients with pancreatic ductal adenocarcinoma (PDAC) who undergo surgical resection and adjuvant chemotherapy have an expected survival of only 2 years due to disease recurrence, frequently in the liver. We investigated the role of liver macrophages in progression of PDAC micrometastases to identify adjuvant treatment strategies that could prolong survival.Experimental Design: A murine splenic injection model of hepatic micrometastatic PDAC was used with five patient-derived PDAC tumors. The impact of liver macrophages on tumor growth was assessed by (i) depleting mouse macrophages in nude mice with liposomal clodronate injection, and (ii) injecting tumor cells into nude versus NOD-scid-gamma mice. Immunohistochemistry and flow cytometry were used to measure CD47 ("don't eat me signal") expression on tumor cells and characterize macrophages in the tumor microenvironment. In vitro engulfment assays and mouse experiments were performed with CD47-blocking antibodies to assess macrophage engulfment of tumor cells, progression of micrometastases in the liver and mouse survival.Results:In vivo clodronate depletion experiments and NOD-scid-gamma mouse experiments demonstrated that liver macrophages suppress the progression of PDAC micrometastases. Five patient-derived PDAC cell lines expressed variable levels of CD47. In in vitro engulfment assays, CD47-blocking antibodies increased the efficiency of PDAC cell clearance by macrophages in a manner which correlated with CD47 receptor surface density. Treatment of mice with CD47-blocking antibodies resulted in increased time-to-progression of metastatic tumors and prolonged survival.Conclusions: These findings suggest that following surgical resection of PDAC, adjuvant immunotherapy with anti-CD47 antibody could lead to substantially improved outcomes for patients. Clin Cancer Res; 24(6); 1415-25. ©2017 AACR.

Standardization of care: impact of an enhanced recovery protocol on length of stay, complications, and direct costs after colorectal surgery.

BACKGROUND: Colorectal surgery is associated with considerable morbidity and prolonged length of stay (LOS). Recognizing the need for improvement, we implemented an enhanced recovery (ER) protocol for all patients undergoing elective colorectal surgery at an academic institution. STUDY DESIGN: A multidisciplinary team implemented an ER protocol based on: preoperative counseling with active patient participation, carbohydrate loading, multimodal analgesia with avoidance of intravenous opioids, intraoperative goal-directed fluid resuscitation, immediate postoperative feeding, and ambulation. Discharge requirements remained identical throughout. A before and after study design was undertaken comparing patients before (August 2012 to February 2013) and after implementation of an ER protocol (August 2013 to February 2014). Risk stratification was performed using the NSQIP risk calculator to calculate the predicted LOS for each patient based on 23 variables. RESULTS: One hundred and nine consecutive patients underwent surgery within the ER protocol compared with 98 consecutive historical controls (conventional). The risk-adjusted predicted LOS was similar for each group at 5.1 and 5.2 days. Substantial reductions were seen in LOS, morphine equivalents, intravenous fluids, return of bowel function, and overall complications with the ER group. There was a $7,129/patient reduction in direct cost, corresponding to a cost savings of $777,061 in the ER group. Patient satisfaction as measured by Press Ganey improved considerably during the study period. CONCLUSIONS: Implementation of an ER protocol led to improved patient satisfaction and substantial reduction in LOS, complication rates, and costs for patients undergoing both open and laparoscopic colorectal surgery. These data demonstrate that small investments in the perioperative environment can lead to large returns.