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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.

Predicting the response and identifying additional targets that will improve the efficacy of chemotherapy is a major goal in cancer research. Through large-scale in vivo and in vitro CRISPR knockout screens in pancreatic ductal adenocarcinoma cells, we identified genes whose genetic deletion or pharmacologic inhibition synergistically increase the cytotoxicity of MEK signaling inhibitors. Furthermore, we show that CRISPR viability scores combined with basal gene expression levels could model global cellular responses to the drug treatment. We develop drug response evaluation by in vivo CRISPR screening (DREBIC) method and validated its efficacy using large-scale experimental data from independent experiments. Comparative analyses demonstrate that DREBIC predicts drug response in cancer cells from a wide range of tissues with high accuracy and identifies therapeutic vulnerabilities of cancer-causing mutations to MEK inhibitors in various cancer types., Predicting the response to chemotherapy is a major goal of cancer research. Here the authors use CRISPR knockout screens in pancreatic ductal adenocarcinoma cells to identify deletions synergistic with MEK inhibitors.

Adequate lymphadenectomy is associated with improved survival in patients who undergo oncologic resection of colorectal cancer and has been identified as a quality metric. Neoadjuvant chemotherapy has been found to be associated with collection of 12 lymph nodes. Of 9077 patients with a diagnosis of colon cancer who underwent colectomy, a minimum of 12 lymph nodes was harvested in 7897 (87%). Significant factors independently associated with inadequate lymphadenectomy included preoperative chemotherapy, emergent surgery, and T1 tumors (all P < 0.05). A large majority of patients who undergo colectomy for colon cancer have at least 12 lymph nodes collected. Preoperative chemotherapy is a major risk factor for inadequate lymph node retrieval. Recognition of factors associated with inadequate lymphadenectomy may improve colectomy lymph node yield and survival in patients with colon cancer.

BACKGROUND: Surgical site infection is a frequent cause of morbidity after colorectal resection, and is a quality measure for hospitals and surgeons. In an effort to reduce the risk of postoperative infections, many wounds are left open at the time of surgery for secondary or delayed primary wound closure. OBJECTIVE: Evaluate the impact of delayed wound closure on the rate of surgical infections and resource utilization. DESIGN: This retrospective propensity matched study compared colorectal surgery patients with wounds left open with a cohort of patients with primary skin closure. SETTINGS: The American College of Surgeons National Quality Improvement Program Participant Use file for 2014 was queried. PATIENTS: 50,212 patients who underwent elective or emergent colectomy, proctectomy, and stoma creation were included. MAIN OUTCOME MEASURES: Rates of postoperative infections and discharge to medical facilities. RESULTS: Surgical wounds were left open in 2.9% of colorectal cases (n=1,466). Patients with skin left open were broadly higher-risk, as evident by a significantly higher median estimated probability of 30-day mortality (3.4% vs 0.45%, p0.05). Resource utilization was higher for patients with incisions left open including longer length of stay (11 vs 10 days, p=0.006) and higher rates of discharge to a facility (34% vs 27%, p

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.

Ureteral stents are commonly placed before colorectal resection to assist in identification of ureters and prevent injury. Acute kidney injury (AKI) is a common cause of morbidity and increased cost following colorectal surgery. Although previously associated with reflex anuria, prophylactic stents have not been found to increase AKI. We sought to determine the impact of ureteral stents on the incidence of AKI following colorectal surgery. All patients undergoing colon or rectal resection at a single institution between 2005 and 2015 were reviewed using American College of Surgeons National Surgical Quality Improvement Program dataset. AKI was defined as a rise in serum creatinine to ≥ 1.5 times the preoperative value. Univariate and multivariate regression analyses were performed to identify independent predictors of AKI. 2910 patients underwent colorectal resection. Prophylactic ureteral stents were placed in 129 patients (4.6%). Postoperative AKI occurred in 335 (11.5%) patients during their hospitalization. The stent group demonstrated increased AKI incidence (32.6% vs. 10.5%; p

Prior studies have demonstrated a reoperation rate ranging from 5.8 to 7.6% following colorectal surgery. However, the indications for reoperation have not been extensively evaluated. We aimed to describe the indications for reoperation and associated procedures following colorectal resection. This is a retrospective cohort study of all patients undergoing colorectal resection at a single institution from 2003 to 2013. For patients who returned to the operating room, the primary indication was categorized into mutually exclusive categories and all procedures performed within 30 days of the initial operation were indexed. Univariate and multivariate analyses were performed. We identified 2793 patients who underwent colorectal operations, of which 407 (14.6%) were emergent. A total of 178 (6.7%) patients returned to the operating room. On multivariate analysis, emergent operation, malnutrition, corticosteroid use, and operative duration were independently associated with reoperation; independent functional status was protective. The most common indications for reoperation were anastomotic leak and bowel obstruction. The most common procedures performed were ostomy creation, bowel resection, and adhesiolysis. Reoperation after colorectal surgery is a relatively common occurrence for which we have identified the risk factors, most common indications, and specific procedures performed. This knowledge will help identify areas for improvement.

Following weight-loss surgery, patients who failed to achieve or sustain weight loss have nevertheless reported high satisfaction with their long-term bariatric experience. Understanding this phenomenon better will likely improve patients' experiences.The purpose of this study was to explore patients' long-term experiences following bariatric surgery.A 604-bed academic health system in the USA.Participants rated satisfaction and shared spontaneous comments regarding their gastric bypass experience. A phenomenological mode of inquiry explored participants' experiences. Transcribed phrases were categorized and themes identified.In a 2004 surgical cohort, with 55% (155/281) participation, 99% of participants rated bariatric experience satisfaction (mean score 8.4) and 74% (115/155) shared comments regarding experiences. Responses were categorized as positive (63% 72/115), neutral (25% 29/115), or negative (12% 14/115). Satisfaction, Appreciation, and Gratefulness emerged as themes from positive comments, with 8% (6/72) explicitly acknowledging amount of weight loss achieved. Twenty-five percent (18/72) spontaneously mentioned undergoing surgery again or recommending the procedure to others. Neutral comments contained the themes of Reflection, Acknowledgment, and Wistfulness. Themes of Dissatisfaction, Disappointment, and Regret emerged from negative comments. Forty-three percent (6/14) of negative comments remarked on regaining weight or not reaching goal weight. Twenty-one percent (3/14) of negative comments explicitly stated regret at having undergone surgery.Participants readily shared comments regarding their gastric bypass experience. Exploring themes provided insight into patients' satisfaction with bariatric surgery even when weight-loss goals were not met and conversely substantial dissatisfaction even when weight loss occurred. This study underscores the importance of understanding the patients' long-term experience following bariatric surgery.

Duodenal neuroendocrine tumors (NETs) are rare neoplasms with poorly defined management. We sought to evaluate the outcomes of patients undergoing resection of duodenal NETs.Using a multi-institutional database, 146 patients who underwent resection for duodenal NETs between 1993 and 2015 were identified. Data on clinicopathologic characteristics and outcomes were collected and analyzed.Local surgical resection (LR) was performed in 57 (39.0 %) patients, while 50 (34.3 %) patients underwent pancreaticoduodenectomy (PD) and 39 (26.7 %) patients an endoscopic resection (ER). Factors associated with worse RFS included advanced tumor grade and metastasis at diagnosis (both P 0.05) but not procedure type (P 0.05). Among patients who had at least one lymph node examined (n = 85), 50 (58.8 %) had a metastatic lymph node; lymph node metastasis (P = 0.04) and advanced tumor grade (P = 0.04) were more common among patients with tumors1.5 cm. Median length-of-stay was longer for PD versus LR (P 0.001). PD patients were at increased risk for severe postoperative complications (P = 0.01).Recurrence of duodenal NETs was dependent on tumor biology rather than procedure type. PD was associated with a longer hospital stay and higher risk of perioperative complications. For patients with tumors ≤1.5 cm, LR or ER may be appropriate with PD reserved for larger lesions and those not amenable to a more local approach.

Adequate lymphadenectomy is associated with improved survival in patients who undergo oncologic resection of colorectal cancer and has been identified as a quality metric. Neoadjuvant chemotherapy has been found to be associated with collection of12 lymph nodes in patients with rectal cancer. The purpose of this study was to evaluate patient and operative risk factors for inadequate lymph node retrieval during oncologic colectomy. The 2014 American College of Surgeons National Surgical Quality Improvement Program Participant Use File data set for oncologic colectomy (n = 9077) was analyzed. Patient- and operation-related factors were assessed by univariate and multivariate regression analyses to determine factors associated with the number of lymph nodes collected. Adequate lymphadenectomy was defined by collection of12 lymph nodes. Of 9077 patients with a diagnosis of colon cancer who underwent colectomy, a minimum of 12 lymph nodes was harvested in 7897 (87%). Significant factors independently associated with inadequate lymphadenectomy included preoperative chemotherapy, emergent surgery, and T1 tumors (all P0.05). A large majority of patients who undergo colectomy for colon cancer have at least 12 lymph nodes collected. Preoperative chemotherapy is a major risk factor for inadequate lymph node retrieval. Recognition of factors associated with inadequate lymphadenectomy may improve colectomy lymph node yield and survival in patients with colon cancer.

The 30-day readmission rate is a quality metric under the Affordable Care Act. Readmission rates after thyroidectomy and parathyroidectomy and associated factors remain ill-defined. We evaluated patient and perioperative factors for association with readmission after thyroidectomy and parathyroidectomy.The American College of Surgeons National Surgical Quality Improvement Program Participant Use File (2011) data for thyroid (n = 3,711) and parathyroid (n = 3,358) resections were analyzed. Patient- and operation-related factors were assessed by univariate and multivariate analyses.Among 7,069 patients, 30-day readmission rate was 4.0%: 4.1% after thyroidectomy and 3.8% after parathyroidectomy. Significant associations for 30-day readmission included declining functional status (odds ratio [OR], 6.4-10.1), preoperative hemodialysis (OR, 2.6; 95% CI, 1.5-4.7), malnutrition (OR, 3.4; 95% CI, 1.2-10.1), increasing American Society of Anesthesiologists class (OR 1.3-4.7), unplanned reoperation (OR, 61.6), and length of stay (LOS)24 hours (OR, 0.61; 95% CI, 0.45-0.85; all P.05). Readmission was associated with greater total and postoperative LOS and major postoperative complications, including renal insufficiency (all P.01).Thirty-day readmission after cervical endocrine resection occurs in 4% of patients. Discharge within 24 hours of operation does not affect the likelihood of readmission. Risk factors for readmission are multifactorial and driven by preoperative conditions. Decreasing the index hospital stay and preventing major postoperative complications may decrease readmissions and improve quality metrics.

What will the future hold for minimally invasive colorectal surgery? Colorectal surgeons have been at the forefront of technological progress of this field dating back to the development of endoscopic polypectomy. Progress in laparoscopic and natural orifice transluminal endoscopic surgeries has pointed toward the path to the future. Endoluminal surgery—operating within the lumen of the colon and rectum—exists in the transanal endoscopic microsurgery experience. Transluminal surgery—operating in the abdomen through the wall of another organ—is ideally suited to the colorectum, where the organ of access is also the target organ for surgery. Herein, developments in transluminal surgery are presented along with an outline of challenges and developing solutions, including needlescopic surgery, miniaturized robotics, and the role of magnets. These advancements follow a natural progress of development and are in an early stage but promise an exciting future for colorectal surgery.

Background Robotic technology is increasingly being utilized by general surgeons. However, the impact of introducing robotics to surgical residency has not been examined. This study aims to assess the financial costs and training impact of introducing robotics at an academic general surgery residency program. Methods All patients who underwent laparoscopic or robotic cholecystectomy, ventral hernia repair (VHR), and inguinal hernia repair (IHR) at our institution from 2011-2015 were identified. The effect of robotic surgery on laparoscopic case volume was assessed with linear regression analysis. Resident participation, operative time, hospital costs, and patient charges were also evaluated. Results We identified 2260 laparoscopic and 139 robotic operations. As the volume of robotic cases increased, the number of laparoscopic cases steadily decreased. Residents participated in all laparoscopic cases and 70% of robotic cases but operated from the robot console in only 21% of cases. Mean operative time was increased for robotic cholecystectomy (+22%), IHR (+55%), and VHR (+61%). Financial analysis revealed higher median hospital costs per case for robotic cholecystectomy (+$411), IHR (+$887), and VHR (+$1124) as well as substantial associated fixed costs. Conclusions Introduction of robotic surgery had considerable negative impact on laparoscopic case volume and significantly decreased resident participation. Increased operative time and hospital costs are substantial. An institution must be cognizant of these effects when considering implementing robotics in departments with a general surgery residency program.

Accountable care organizations (ACOs) attempt to provide the most efficient and effective care to patients within a region. We hypothesized that patients who undergo surgery closer to home have improved survival due to proximity of preoperative and post-discharge care.All (17,582) institutional American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) patients with a documented ZIP code and predicted risk, who underwent surgery at our institution (2005 to 2014), were evaluated. Google Maps calculated travel times, and patients were stratified by 1 hour of travel (local vs regional). Multivariable logistic regression and Cox proportional hazard models were used to evaluate the NSQIP risk-adjusted effects of travel time on operative morbidity, mortality, and long-term survival.Median travel time was 65 minutes, with regional patients demonstrating significantly higher rates of ascites, hypertension, diabetes, disseminated cancer,10% weight loss, higher American Society of Anesthesiologists (ASA) score, higher predicted risk of morbidity and mortality, and lower functional status (all p0.01). After adjusting for ACS NSQIP-predicted risk, travel time was not significantly associated with 30-day mortality (odds ratio [OR] 1.06; p = 0.42) or any major morbidities (all p0.05). However, survival analysis demonstrated that travel time is an independent predictor of long-term mortality (OR 1.24; p0.001).Patients traveling farther for care at a quaternary center had higher rates of comorbidities and predicted risk of complications. Additionally, travel time predicts risk-adjusted long-term mortality, suggesting a major focus of ACOs will need to be integration of care at the periphery of their region.

Background and Objective: Neuroendocrine liver metastasis tumors (NELM) are a heterogeneous group of neoplasms with varied histologic features and a wide range of clinical behaviors. We aimed to identify the fraction of patients cured after liver surgery for NELM. Methods: Cure fraction models were used to analyze 376 patients who underwent hepatectomy with curative intent for NELM. Results: The median and 5-year disease-free survival (DFS) were 4.5 years and 46%, respectively. The probability of being cured from NELM by liver surgery was 44%; the time to cure was 5.1 years. In a multivariable cure model, type of neuroendocrine tumor (NET), grade of tumor differentiation, and rate of liver involvement resulted as independent predictors of cure. The cure fraction for patients with well differentiated NELM from gastrointestinal NET or a functional pancreatic NET, and with < 50% of liver-involvement was 95%. Patients who had moderately/poorly differentiated NELM from a non-functional pancreatic NET, and with < 50% of liver-involvement was 43%. In the presence of all the three unfavorable prognostic factors (nonfunctional PNET, liver involvement > 50%, moderately/poorly differentiation), the cure fraction was 8%. Conclusions: Statistical cure after surgery for NELM is possible, and allow for a more accurate prediction of long-term outcome among patients with NELM undergoing liver resection.

Extramedullary hematopoiesis (EMH) of the lung is a rare clinical phenomenon associated with chronic hemolytic anemias and myeloproliferative diseases. Pulmonary EMH has documented sensitivity to ionizing radiation which translates to an efficacious therapy. The optimal local management of EMH of the lung with radiotherapy is uncertain because of the low incidence of cases. Herein, we describe the case of a 93-year-old gentleman with a 30-year history of essential thrombocythemia who developed extramedullary hematopoiesis of the lung. He was treated with two separate courses of whole lung external beam radiation with a durable response of approximately 4 months on both occasions. We discuss his clinical course, management, and a comparison to the current literature.

Gallstone ileus is a rare cause of small bowel obstruction, classically occurring in patients with recurrent cholecystitis. The incidence of biliary enteric fistula and gallstone ileus in patients with large, asymptomatic gallstones is not known. We report a case of gallstone ileus, which occurred in the setting of a large, asymptomatic gallstone. This case suggests that large gallstones may warrant cholecystectomy, even in asymptomatic patients.

Given the current climate of outcomes-driven quality reporting, it is critical to appropriately risk stratify patients using standardized metrics.To elucidate the risk associated with urgent surgery on complications and mortality after general surgical procedures.This retrospective review used the American College of Surgeons National Surgery Quality Improvement Program database to capture all general surgery cases performed at 435 hospitals nationwide between January 1, 2013, and December 31, 2013. Data analysis was performed from November 11, 2015, to February 16, 2017.Any operations coded as both nonelective and nonemergency were designated into a novel category titled urgent.The primary outcome was 30-day mortality; secondary outcomes included 30-day rates of complications, reoperation, and readmission in urgent cases compared with both elective and emergency cases.Of 173 643 patients undergoing general surgery (101 632 females and 72 011 males), 130 235 (75.0%) were categorized as elective, 22 592 (13.0%) as emergency, and 20 816 (12.0%) as nonelective and nonemergency. When controlling for standard American College of Surgeons National Surgery Quality Improvement Program preoperative risk factors, with elective surgery as the reference value, the 3 groups had significantly distinct odds ratios (ORs) of experiencing any complication (urgent surgery: OR, 1.38; 95% CI, 1.30-1.45; P .001; and emergency surgery: OR, 1.65; 95% CI, 1.55-1.76; P .001) and of mortality (urgent surgery: OR, 2.32; 95% CI, 2.00-2.68; P .001; and emergency surgery: OR, 2.91; 95% CI, 2.48-3.41; P .001). Surgical procedures performed urgently had a 12.3% rate of morbidity (n = 2560) and a 2.3% rate of mortality (n = 471).This study highlights the need for improved risk stratification on the basis of urgency because operations performed urgently have distinct rates of morbidity and mortality compared with procedures performed either electively or emergently. Because we tie quality outcomes to reimbursement, such a category should improve predictive models and more accurately reflect the quality and value of care provided by surgeons who do not have traditional elective practices.

Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) allows restoration of continence in select patients with ulcerative colitis but is associated with significant morbidity. Well-known complications following IPAA include pouchitis, anastomotic leak, and small bowel obstruction. Obstruction secondary to ileal pouch volvulus is exceedingly rare. We report a case of ileal pouch volvulus, which occurred secondary to internal hernia. Radiographic and endoscopic identification of volvulus allowed for early operative management and pouch salvage.

Background: Eighty percent of patients with pancreatic ductal adenocarcinoma (PDAC) die from their disease within five years of surgical resection, likely due to presence of occult metastases at diagnosis. We have developed a patient-derived xenograft (PDX) model in mice to investigate the behavior of occult metastatic cells in the liver microenvironment and derive novel adjuvant therapies. Methods: Five PDAC tumors (215, 366, 608, 654 and 738) were resected from patients and implanted orthotopically in mice. Tumors were harvested, cell lines generated and transduced with luciferase, then injected into spleens of mice to generate microscopic liver metastases, then primary tumors removed via splenectomy. Bioluminescence imaging of mice and histologic analysis and flow cytometry of livers were utilized to characterize each tumor's distinct pattern of cell clearance and outgrowth kinetics. Affymetrix gene expression of tumors was performed. Mice were treated with adjuvant therapy following resection of primary tumors in the spleen and time-to-progression (TTP) and overall survival (OS) were measured. Results: Each PDX cell line demonstrated unique and reproducible clearance in the liver and outgrowth kinetics as measured by bioluminescence imaging. Distinct differences in gene expression were identified in tumors exhibiting rapid vs. delayed outgrowth. The MEK inhibitor trametinib (0.3 mg/kg oral daily) prolonged TTP and OS vs. control (OS - Tumor 608: 114 vs. 43 days, p Conclusions: This PDX PDAC model of occult metastasis allows characterization of hepatic clearance of tumor cells and outgrowth kinetics. Metastatic outgrowth appears to be dependent upon distinguishable tumor cell-specific factors. Trametinib effectively inhibits KRAS-MEK-ERK signaling, delays outgrowth of occult metastases and prolongs survival of mice. Utilization of this model will help further define the complex interaction of PDAC cells and the metastatic microenvironment of the liver. Citation Format: Matthew G. Mullen, Timothy E. Newhook, James M. Lindberg, Sara J. Adair, Edik M. Blais, Alex D. Michaels, Edward B. Stelow, Jason A. Papin, J. Thomas Parsons, Todd W. Bauer. A patient-derived xenograft model of pancreatic cancer in mice to develop novel adjuvant therapies. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A47.