Project DRIVE: A Compendium of Cancer Dependencies and Synthetic Lethal Relationships Uncovered by Large-Scale, Deep RNAi Screening.

Elucidation of the mutational landscape of human cancer has progressed rapidly and been accompanied by the development of therapeutics targeting mutant oncogenes. However, a comprehensive mapping of cancer dependencies has lagged behind and the discovery of therapeutic targets for counteracting tumor suppressor gene loss is needed. To identify vulnerabilities relevant to specific cancer subtypes, we conducted a large-scale RNAi screen in which viability effects of mRNA knockdown were assessed for 7,837 genes using an average of 20 shRNAs per gene in 398 cancer cell lines. We describe findings of this screen, outlining the classes of cancer dependency genes and their relationships to genetic, expression, and lineage features. In addition, we describe robust gene-interaction networks recapitulating both protein complexes and functional cooperation among complexes and pathways. This dataset along with a web portal is provided to the community to assist in the discovery and translation of new therapeutic approaches for cancer.

Increased Mortality in Octogenarians Undergoing Endovascular Aortic Aneurysm Repair for Smaller Aneurysms Warrants Caution.

BACKGROUND: Geriatric patients constitute a growing portion of the general population, with particular increase in the prevalence of octogenarians. The incidence and prevalence of abdominal aortic aneurysms (AAAs) have been clearly shown to be associated with advancing age. The effect of advanced age in outcomes from endovascular aneurysm repair (EVAR) is unclear. We study the effect of advanced age, as an independent risk factor for mortality in octogenarian geriatric patients (OGPs) compared to nonoctogenarian geriatric patients (NOGPs) undergoing EVAR. METHODS: The 2011-2017 American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) Procedure-Targeted Vascular database was queried for geriatric patients (>65 years) undergoing EVAR for symptomatic and asymptomatic indications. A multivariable logistic regression analysis was performed comparing outcomes between OGPs and NOGPs. RESULTS: Of the 10,490 geriatric patients who underwent EVAR, 7,508 (71.6%) were NOGPs and 2,982 (28.4%) were OGPs. Octogenarians were more often female (82.3% vs. 76.7%). In comparison to NOGPs, fewer OGPs were treated for AAA <5.5 cm (46.7% vs. 54.9%, P < 0.001) and AAA <5.0 cm (19.2% vs. 24.0%, P < 0.001). Nearly 90% of male and over 80% of female NOGPs and OGPs treated for AAA <5.0 cm were asymptomatic. Octogenarian geriatric patients (OGPs) had less dyspnea (15.3% vs. 17.3%, P = 0.01), chronic obstructive pulmonary disease (16.1% vs. 20.5%, P < 0.001), diabetes (12.7% vs. 17.8%, P < 0.001), and smoking (13.2% vs. 36.3%, P < 0.001) compared to NOGPs. Octogenarian geriatric patients (OGPs) were found to have a greater length of stay (2 days vs. 1 day, P < 0.001), as well as rate of mortality (3.4% vs. 1.7%, P < 0.001). Both symptomatic and asymptomatic OGPs had a higher rate of mortality than their NOGP counterparts (symptomatic 16% vs. 9.5%, P < 0.001; asymptomatic 1.3% vs. 0.5%, P < 0.001). Multivariate logistic regression analysis showed OGPs to have increased overall associated risk of mortality compared to NOGPs (odds ratio (OR) 1.88, confidence interval (CI) 1.39-2.54, P < 0.001), as well as in the symptomatic (OR 1.54, CI 1.06-2.23, P < 0.001) and asymptomatic cohorts (OR 2.66, CI 1.59-4.45, P < 0.001). CONCLUSIONS: Octogenarian geriatric patients (OGPs) accounted for over a quarter of geriatric patients undergoing EVAR. This elderly group was associated with an increased rate and risk of mortality compared to NOGPs, even when controlling for known risk factors for mortality. Given this increased risk of mortality in OGPs undergoing EVAR, elective treatment of AAAs in this advanced age group should be performed with caution, particularly in those with diameters in which the risk of rupture may not warrant repair.

Intraoperative Anastomotic Evaluation Methods: Rigid Proctoscopy Versus Flexible Endoscopy.

INTRODUCTION: Rigid proctosigmoidoscopy (RP) and flexible sigmoidoscopy (FS) are two modalities commonly used for intraoperative evaluation of colorectal anastomoses. This study seeks to determine whether there is an association between the endoscopic modality used to evaluate colorectal anastomoses and the rate of anastomotic leak (AL), organ space infection, and overall infectious complication. METHODS: The 2012-2018 American College of Surgeons National Surgical Quality Improvement Program database was queried for patients undergoing colorectal anastomoses. Anastomotic evaluation method (RP versus FS) was identified by Current Procedural Terminologycoding and used for group classification. Outcomes measured included AL, organ space infections, and overall infection. Multivariable logistic regression analysis for predicting AL was performed. RESULTS: We identified 7100 patients who underwent a colorectal anastomosis with intraoperative endoscopic evaluation. RP was utilized in 3397 (47.8%) and FS in 3703 (52.2%) patients. RP was used more commonly in diverticulitis (44.5% versus 36.2%, P < 0.01), while FS was used more frequently in malignancy (47.5% versus 36.7%, P < 0.01). Anastomotic evaluation with FS was associated with lower rates of organ space infection (3.8% versus 4.8%, P = 0.025) and AL (2.9% versus 3.8%, P = 0.028) compared to RP. On multivariate logistic regression modeling, anastomotic evaluation with RP was associated with a higher risk of AL (odds ratio 1.403, 95% CI 1.028-1.916, P = 0.033) compared to FS. CONCLUSIONS: Compared to FS, rigid proctosigmoidoscopic evaluation of a colorectal anastomosis was associated with an increased rate of AL and organ space infection.

Intentional Bilateral Renal Artery Coverage During Ruptured Endovascular Paraanastomotic Pseudoaneurysm Repair.

The development of a paraanastomotic pseudoaneurysm is a serious complication after open prosthetic reconstruction of the aorta for occlusive or aneurysmal disease. Open repair of these lesions has previously been associated with high rates of morbidity and mortality. Endovascular repair may provide suitable treatment for proximal paraanastomotic aortic bypass graft pseudoaneurysms in patients who are poor candidates for open surgery. Bilateral renal artery coverage may be necessary to achieve adequate fixation and seal during life-threatening emergency cases of pseudoaneurysm rupture. Due to the infrequency of reported cases, the consequences of bilateral renal artery occlusion during these complex procedures are poorly understood. We present a case of a proximal paraanastomotic aortobifemoral bypass pseudoaneurysm rupture that was managed using endovascular repair with intentional coverage of both renal arteries. We also review the contemporary literature on endovascular management of paraanastomotic aneurysms and discuss the role of bilateral renal artery coverage in treating select patients with complex ruptured aortic pathology.

University Teaching Trauma Centers: Decreased Mortality but Increased Complications.

BACKGROUND: Teaching hospitals are often regarded as excellent institutions with significant resources and prominent academic faculty. However, the involvement of trainees may contribute to higher rates of complications. Conflicting reports exist regarding outcomes between teaching and nonteaching hospitals, and the difference among trauma centers is unknown. We hypothesized that university teaching trauma centers (UTTCs) and nonteaching trauma centers (NTTCs) would have a similar risk of complications and mortality. METHODS: We queried the Trauma Quality Improvement Program (2010-2016) for adults treated at UTTCs or NTTCs. A multivariable logistic regression analysis was performed to evaluate the risk of mortality and in-hospital complications, such as respiratory complications (RCs), venous thromboembolisms (VTEs), and infectious complications (ICs). RESULTS: From 895,896 patients, 765,802 (85%) were treated at UTTCs and 130,094 (15%) at NTTCs. After adjusting for covariates, UTTCs were associated with an increased risk of RCs (odds ratio (OR) 1.33, confidence interval (CI) 1.28-1.37, P < 0.001), VTEs (OR 1.17, CI 1.12-1.23, P < 0.001), and ICs (OR 1.56, CI 1.49-1.64, P < 0.001). However, UTTCs were associated with decreased mortality (OR 0.96, CI 0.93-0.99, P = 0.008) compared with NTTCs. CONCLUSIONS: Our study demonstrates increased associated risks of RCs, VTEs, and ICs, yet a decreased associated risk of in-hospital mortality for UTTCs when compared with NTTCs. Future studies are needed to identify the underlying causative factors behind these differences.

Analysis of Unintentional Falls in Pediatric Population and Predictors of Morbidity.

INTRODUCTION: Unintentional falls are a leading cause of pediatric traumatic injury. This study evaluates clinical outcomes of fall-related injuries in children under the age of 10. METHODS: The National Trauma Database was queried for children who experienced an unintentional fall. Patients were stratified by age in two groups: 1-5 and 6-10 years old. The primary outcome was post discharge extension of care, defined as transfer to skilled nursing facility or rehabilitation center after discharge from the hospital. Descriptive statistics and a multivariable logistic regression analysis were used to compare the two groups. RESULTS: From 2009 to 2016, a total of 8,277 pediatric patients experienced an unintentional fall, with 93.6% of patients being discharged home. Falls were more common in younger children, with greater odds of post discharge extension of care. Predictors of increased associated risk of extended medical care included intracranial hemorrhage (OR 1.05, 95% CI 1.03-1.06) and thoracic injuries (OR 1.03, 95% CI 1.00-1.1.05) (P< 0.05). Mortality in pediatric patients suffering unintentional falls was a rare event occurring in 0.7% of cases in children 1-5 years old and 0.4% of children 6-10 years old. CONCLUSION: The majority of children experiencing an unintentional fall are discharged home, with mortality being very rare. However, younger age is prone to more severe and serious injury patterns. Intracranial hemorrhage and thoracic injury were a predictor of need for extended medical care.

Evolving Utility of Endovascular Treatment of Juxtarenal, Pararenal, and Suprarenal Abdominal Aortic Aneurysms Associated With Increased Risk of Mortality Over Time.

BACKGROUND: Continued advances in endovascular technologies are resulting in fewer open abdominal aortic aneurysm (AAA) repairs. In addition, more complex juxtarenal, pararenal, and suprarenal (JPS) AAAs are being managed with various endovascular techniques. This study sought to evaluate the evolving trends in endovascular aneurysm repair (EVAR) of AAAs, hypothesizing increased rate of JPS AAA repair by EVAR. We also sought to evaluate the risk for morbidity and mortality for EVAR and open aneurysm repair (OAR) of JPS AAAs over time. METHODS: The 2011-2017 American College of Surgeons National Surgical Quality Improvement Program Procedure-Targeted Vascular database was queried for patients undergoing OAR or EVAR for AAAs. A multivariable logistic regression analysis was performed for both infrarenal and JPS AAA repairs. RESULTS: Of 18,661 patients who underwent AAA repair, 3,941 (21.1%) were OAR and 14,720 (78.9%) were EVAR. The rate of OAR decreased from 29.5% in 2011 to 21.3% in 2017 (P < 0.001) with a geometric-mean-annual decrease of 27.8%. The rate of EVAR increased from 70.5% to 78.7% during the same time period (P < 0.001) with a geometric-mean-annual increase of 11.6%. These trends remained true for both infrarenal and JPS AAAs. After adjusting for covariates, there was no difference in associated risk of 30-day mortality, renal complications, or ischemic colitis for either OAR or EVAR over each incremental year for infrarenal AAAs (P > 0.05). However, in patients undergoing EVAR for JPS AAAs, the associated risk of mortality increased with each incremental year (odds ratio [OR]: 1.30, confidence interval [CI]: 1.01-1.69, P = 0.039), whereas there was no difference in the risk of mortality for OAR of JPS AAAs with each incremental year (OR: 1.11, CI: 0.99-1.23, P = 0.067). CONCLUSIONS: The rate of OAR for AAA has decreased over the past seven years with an increase in EVAR, particularly for more complex JPS AAAs. The associated risk for morbidity and mortality for treatment of infrarenal AAAs was not significantly affected by this increased utility of EVAR. The associated risk of mortality for JPS AAAs treated by EVAR increased over time, whereas this trend for associated risk of mortality was not seen for OAR of JPS AAAs. These findings, especially the increased associated risk of mortality over time with EVAR for JPS AAAs, warrant careful prospective analysis.

Iatrogenic Arteriovenous Fistula Formation after Endovenous Laser Treatment Resulting in High-output Cardiac Failure: A Case Report and Review of the Literature.

Formation of a clinically significant iatrogenic arteriovenous fistula after endovenous laser treatment of the great saphenous vein is an extremely rare complication. Because of the infrequency of reported cases, there is no clear consensus on how to best manage this complication. We present a unique case of an iatrogenic high-output superficial femoral artery-common femoral vein fistula resulting in right heart failure and a distal deep vein thrombosis. Deployment of a covered arterial stent graft resulted in resolution of the arteriovenous fistula and high-output cardiac state. Clinically significant arteriovenous fistulas resulting from inadvertent vessel injury during endovenous laser treatment appear to be amenable to percutaneous endovascular interventions. During these challenging endovascular cases, intravascular ultrasonography can be used to help delineate the morphology of the fistula tract and obtain vessel measurements to ensure accurate endoprosthesis sizing and placement.

Sternotomy for Hemorrhage Control in Trauma.

BACKGROUND: Little is known about the injuries, mechanisms, and outcomes in trauma patients undergoing sternotomy for hemorrhage control (SHC). The purpose of this study was to identify predictors of mortality for SHC and provide a descriptive analysis of the use of SHC in trauma. We hypothesize blunt trauma is associated with higher mortality compared with penetrating trauma among trauma patients requiring SHC. METHODS: The Trauma Quality Improvement Program (2013-2016) database was queried for adult patients undergoing SHC within 24 h of admission. Patients with blunt and penetrating trauma were compared using chi-square and Mann-Whitney U-test. A multivariable logistic regression model was used to determine the risk of mortality. RESULTS: Of 584 patients undergoing SHC, 322 (55.1%) were involved in penetrating trauma, and 69 (11.8%) were involved in blunt. The blunt trauma group had a higher median injury severity score (31.5 versus 25.0; P < 0.001) compared with the penetrating group. The median time to hemorrhage control was longer in those with blunt compared with penetrating trauma (84.6 versus 49.8 min; P < 0.001). The mortality rate was higher in patients with blunt compared with penetrating trauma (29.0% versus 12.7%; P < 0.001). However, after adjusting for covariates, there was no difference in risk of mortality between blunt and penetrating trauma (P = 0.06). CONCLUSIONS: Trauma patients requiring SHC after blunt trauma had a higher mortality rate than those in penetrating trauma. After adjusting for predictors of mortality, there was no difference in risk of mortality despite nearly double the time to hemorrhage control in patients presenting after blunt trauma.

Analysis of Endovascular Aneurysm Repair for Small Abdominal Aortic Aneurysms in Males.

BACKGROUND: Current guidelines recommend repair of abdominal aortic aneurysms (AAAs) when ≥5.5 cm. This study sought to evaluate the incidence of male patients undergoing endovascular aneurysm repair (EVAR) for AAAs of various diameters (small <4 cm; intermediate 4-5.4 cm; standard ≥5.5 cm). We analyzed predictors of mortality, hypothesizing that smaller AAAs (<5.5 cm) have no differences in associated risk of mortality compared to standard AAAs (≥5.5 cm). METHODS: The 2011-2017 American College of Surgeons National Surgical Quality Improvement Program Procedure-Targeted Vascular database was queried for male patients undergoing elective EVAR. Patients were stratified by aneurysm diameter. A multivariable logistic regression analysis for clinical outcomes, adjusting for age, clinical characteristics, and comorbidities, was performed. RESULTS: A total of 8037 male patients underwent EVAR with 3926 (48.9%) performed for AAAs <5.5 cm. There was no difference in mortality, readmission, major complications, myocardial infarction, stroke, or ischemic complications among the 3 groups (P > 0.05). In AAAs <5.5 cm, predictors of mortality included prior abdominal surgery (odds ratio [OR], 5.77; confidence interval [CI], 1.38-24.13; P = 0.016), weight loss (OR, 43.4; CI, 3.78-498.7; P = 0.002), disseminated cancer (OR, 17.9; CI, 1.30-245.97; P = 0.031), and diabetes (OR, 6.09; CI, 1.52-24.36; P = 0.011). CONCLUSIONS: Nearly 50% of male patients undergoing elective EVAR were treated for AAAs <5.5 cm. There was no difference in associated risk of mortality for smaller AAAs compared to standard AAAs. The strongest predictors of mortality for patients with smaller AAAs were prior abdominal surgery, weight loss, disseminated cancer, and diabetes.