Mitochondria undergo fission and fusion to maintain homeostasis, and tumors exhibit the dysregulation of mitochondrial dynamics. We recently demonstrated that ectopic HRasG12V promotes mitochondrial ...fragmentation and tumor growth through Erk phosphorylation of the mitochondrial fission GTPase Dynamin-related protein 1 (Drp1). However, the role of Drp1 in the setting of endogenous oncogenic KRas remains unknown. Here, we show that Drp1 is required for KRas-driven anchorage-independent growth in fibroblasts and patient-derived pancreatic cancer cell lines, and it promotes glycolytic flux, in part through the regulation of hexokinase 2 (HK2). Furthermore, Drp1 deletion imparts a significant survival advantage in a model of KRas-driven pancreatic cancer, and tumors exhibit a strong selective pressure against complete Drp1 deletion. Rare tumors that arise in the absence of Drp1 have restored glycolysis but exhibit defective mitochondrial metabolism. This work demonstrates that Drp1 plays dual roles in KRas-driven tumor growth: supporting both glycolysis and mitochondrial function through independent mechanisms.
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•Drp1 is required for oncogenic KRas-driven transformation•Drp1 promotes KRas-driven glycolysis•Loss of Drp1 inhibits pancreatic tumorigenesis•Loss of Drp1 impairs mitochondrial metabolism in tumor cells
Nagdas et al. find that the mitochondrial fission GTPase Drp1 is required for KRas-driven transformation and pancreatic tumor growth. The inhibition of Drp1 in cells expressing oncogenic KRas leads to impaired glycolytic flux and the eventual loss of mitochondrial metabolic function.
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.
There is a strong association between socioeconomic status and surgical outcomes; however, the optimal method for socioeconomic risk-stratification remains elusive. We aimed to compare 2 metrics of ...socioeconomic ranking by ZIP code, the Distressed Communities Index, and the Area Deprivation Index and their association with surgical outcomes.
This retrospective study included all general surgery cases performed at a single institution from 2005 to 2015. Each patient was assigned Distressed Communities Index and Area Deprivation Index scores based on ZIP code. Both indices are normalized composite measures of socioeconomic status derived from census data. Primary outcome was 30-day morbidity; secondary outcomes included long-term mortality and cost, stratified by socioeconomic status. The utility of the addition of each metric to the American College of Surgeons National Surgical Quality Improvement Program risk calculator was assessed.
The 9,843 patients had normally distributed Distressed Communities Index (47.3 ± 22.4) and Area Deprivation Index (35.4 ± 19.0). Patients who experienced any complication or readmission had significantly higher Distressed Communities Index (48.6 vs 47.1, P = .04) and Area Deprivation Index (37.2 vs 35.1, P = .002). Risk-adjusted models demonstrated that only Area Deprivation Index independently predicted postoperative complications (odds ratio 1.11, P = .02), improved the discrimination of risk-stratification when added to the American College of Surgeons National Surgical Quality Improvement Program risk calculator (area under curve 0.758−0.790, P = .02), and was associated with hospitalization cost ($1,811 ± 856/quartile, P = .03).
Area Deprivation Index provides improved socioeconomic risk-adjustment in this surgical population. The addition of Area Deprivation Index to risk-stratification tools would allow us to better inform our patients of their expected postoperative courses, more accurately account for the increased cost of providing their care, and identify patients and regions that are most in need of improvements in health and healthcare.
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.
Abstract 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 2,260 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 (+$1,124) 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.
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.
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-
-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.
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.
clodronate depletion experiments and NOD-
-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
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.
These findings suggest that following surgical resection of PDAC, adjuvant immunotherapy with anti-CD47 antibody could lead to substantially improved outcomes for patients.
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Background
Obesity and obesity-related comorbidities are associated with increased risk of coronary artery disease (CAD). Bariatric surgery results in durable weight loss and improvement in numerous ...CAD risk factors, yet limited data exist on CAD-related outcomes. We hypothesized that bariatric surgery would lead to decreased risk of CAD and reduced rates of coronary revascularization procedures.
Methods
All patients who underwent bariatric surgery at a single medical center from 1985 to 2015 were identified. A control population of morbidly obese patients who did not undergo bariatric surgery was identified using an institutional clinical data repository over the same study period, propensity score matched 1:1 on patient demographics and comorbidities including cardiac history. Univariate analyses were performed to compare outcomes in the surgery and non-surgery groups.
Results
A total of 3410 bariatric surgery patients and 45,750 non-surgical patients were identified. After 1:1 propensity-score matching, a total of 3242 patients in each group were found to be well balanced in baseline characteristics and risk factors. With a median follow-up of greater than 6 years, the surgery group had significantly lower rates of myocardial infarction (1.8% vs. 10.0%; RR 0.18), coronary catheterization (1.9% vs. 8.8%; RR 0.22), percutaneous coronary intervention (0.4% vs. 7.8%; RR 0.05), and coronary artery bypass grafting (0.6% vs. 2.3%; RR 0.26). Similar benefits were observed for subgroups of patients with and without diabetes.
Conclusions
Bariatric surgery was associated with a significant reduction in the incidence of myocardial infarction as well as lower rates of coronary revascularization in a propensity-matched cohort of morbidly obese patients. Though the retrospective nature of this study may have introduced a degree of selection bias, these outcomes support increased utilization of bariatric surgery for the prevention of heart disease.
Graphic abstract
Increasingly, patients are faced with greater travel distances to undergo bariatric surgery at high-volume centers.
This study sought to evaluate the impact of travel distance on access to care and ...outcomes after bariatric surgery.
Patients who underwent Roux-en-Y gastric bypass at an academic bariatric surgery center from 1985 to 2004 were examined and stratified by patient travel distance.
Univariate analyses were performed for preoperative risk factors, 30-day complications, and long-term (10-yr) weight loss between "local," defined as<1 hour of travel time, and "regional," defined as>1 hour of travel time. Survival analysis was performed with Kaplan-Meier and Cox proportional hazards models.
A total of 650 patients underwent Roux-en-Y gastric bypass, of whom 316 (48.6%) traveled<1 hour to undergo surgery and 334 (51.4%) traveled>1 hour. Median body mass index was equivalent between the groups (local, 52.9 kg/m
; regional, 53.2 kg/m
; P = .76). Patients who traveled longer distances had higher rates of preoperative co-morbidities, including chronic obstructive pulmonary disease, congestive heart failure, diabetes, and sleep apnea (all P<.05). Complications within 30 days of surgery and long-term reduction of excess body mass index were equivalent between groups. Travel time was an independent predictor of risk-adjusted reduced long-term survival (hazard ratio, 1.23, P = .0002).
A majority of patients who underwent bariatric surgery at our center traveled>1 hour. Despite longer travel time for care, 30-day complications and long-term weight loss were equivalent with that of local patients. As expected, patients who lived in close proximity were more likely to adhere to yearly follow-up in surgery clinic. Travel time was an independent predictor of risk-adjusted reduced long-term survival.
Background
Thyroid ultrasounds extend surgeons’ outpatient capabilities and are essential for operative planning. However, most residents are not formally trained in thyroid ultrasound. The purpose ...of this study was to create a novel thyroid ultrasound proficiency metric through a collaborative Delphi approach.
Methods
Clinical faculty experienced in thyroid ultrasound participated on a Delphi panel to design the thyroid Ultrasound Proficiency Scale (UPS-Thyroid). Participants proposed items under the categories of Positioning, Technique, Image Capture, Measurement, and Interpretation. In subsequent rounds, participants voted to retain, revise, or exclude each item. The process continued until all items had greater than 70% consensus for retention. The UPS-Thyroid was pilot tested across 5 surgery residents with moderate ultrasound experience. Learning curves were assessed with cumulative sum.
Results
Three surgeons and 4 radiologists participated on the Delphi panel. Following 3 iterative Delphi rounds, the panel arrived at >70% consensus to retain 14 items without further revisions or additions. The metric included the following items on a 3-point scale for a maximum of 42 points: Positioning (1 item), Technique (4 items), Image Capture (2 items), Measurement (2 items), and Interpretation (5 items). A pilot group of 5 residents was scored against a proficiency threshold of 36 points. Learning curve inflection points were noted at between 4 to 7 repetitions.
Conclusions
A multidisciplinary Delphi approach generated consensus for a thyroid ultrasound proficiency metric (UPS-Thyroid). Among surgery residents with moderate ultrasound experience, basic proficiency at thyroid ultrasound is feasible within 10 repetitions.
Background
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.
Methods
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.
Results
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
< 0.0001) with bilateral having a higher rate than unilateral stents. Hospital costs were higher in the stent group ($23,629 vs. $16,091;
p
< 0.0001), and patients with bilateral stents had the highest costs. Multivariable logistic regression identified predictors of AKI after colorectal surgery including age, procedure duration, and ureteral stent placement.
Conclusions
Prophylactic ureteral stents independently increased AKI risk when placed prior to colorectal surgery. These data demonstrate increased morbidity and hospital costs related to usage of stents in colorectal surgery, indicating that placement should be limited to patients with highest potential benefit.
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