Microvessel area as a predictor of sorafenib response in metastatic renal cell carcinoma.

BACKGROUND: Sorafenib was the first Food and Drug Administration approved anti-angiogenic therapy for renal cell carcinoma (RCC). Currently, there are no validated predictive biomarkers for sorafenib. Our purpose was to determine if sorafenib target expression is predictive of sorafenib sensitivity. METHODS: We used an automated, quantitative immunofluorescence-based method to determine expression levels of sorafenib targets VEGF, VEGF-R1, VEGF-R2, VEGF-R3, c-RAF, B-RAF, c-Kit, and PDGFR-ß in a cohort of 96 patients treated with sorafenib. To measure vasculature in the tumor samples, we measured microvessel area (MVA) by CD-34 staining. RESULTS: Of the markers studied, only high MVA was predictive of response (p = 0.005). High MVA was associated with smaller primary tumors (p = 0.005). None of the biomarkers studied was predictive of overall or progression-free survival. Using the Bonferroni adjustment correcting for 9 variables with an alpha of 0.05, MVA remained significantly associated with sorafenib response. CONCLUSIONS: Our results suggest that high MVA in tumor specimens might be associated with a greater likelihood of response to therapy. Further studies are needed to confirm these results in additional patients and in patients receiving other VEGF-R2 inhibitors, as MVA might be useful to improve patient selection for VEGF-R2 inhibitors.

Expression of drug targets in primary and matched metastatic renal cell carcinoma tumors.

BACKGROUND: Targeted therapies in renal cell carcinoma can have different effects on primary and metastatic tumors. To pave the way for predictive biomarker development, we assessed differences in expression of targets of currently approved drugs in matched primary and metastatic specimens from 34 patients. METHODS: Four cores from each site were embedded in tissue microarray blocks. Expression of B-Raf, C-Raf, cKIT, FGF-R1, HIF-2α, mTOR, PDGF-Rß, VEGF-R1, VEGF-R2, VEGF-R3, VEGF, VEGF-B, VEGF-C, VEGF-D, MEK1, and ERK1/2 was studied using a quantitative immunofluorescence method. RESULTS: No significant differences were observed in global expression levels in primary and metastatic renal cell carcinoma tumors, with the exception of MEK, which had higher expression in metastatic than primary specimens. Similarly, more ki67 positive cells were seen in metastatic specimens. Correlations between marker expression in primary and metastatic specimens were variable, with the lowest correlation seen for FGF-R1 and VEGF-D. There were no significant differences in the degree of heterogeneity in primary versus metastatic tumors. CONCLUSIONS: Expression of most of the studied markers was similar in primary and metastatic renal cell carcinoma tumors, suggesting that predictive biomarker testing for these markers can be conducted on either the primary or metastatic tumors for most markers.

Routine post-operative labs and healthcare system burden in acute appendicitis.

BACKGROUND: Data from the National Health Expenditure Accounts have shown a steady increase in healthcare cost paralleled by availability of laboratory tests. Resource utilization is a top priority for reducing health care costs. We hypothesized that routine post-operative laboratory utilization unnecessarily increases costs and healthcare system burden in acute appendicitis (AA) management. METHODS: A retrospective cohort of patients with uncomplicated AA 2016-2020 were identified. Clinical variables, demographics, lab usage, interventions, and costs were collected. RESULTS: A total of 3711 patients with uncomplicated AA were identified. Total costs of labs ($289,505, 99.56%) and repletions ($1287.63, 0.44%) were $290,792.63. Increased LOS was associated with lab utilization in multivariable modeling, increasing costs by $837,602 or 472.12 per patient. CONCLUSIONS: In our patient population, post-operative labs resulted in increased costs without discernible impact on clinical course. Routine post-operative laboratory testing should be re-evaluated in patients with minimal comorbidities as this likely increases cost without adding value.

Etiology of fatal thoracic aortic injuries: Secondary data analysis.

OBJECTIVES: Motor vehicle crashes remain a leading cause of death in the United States (US). Thoracic aortic dissection due to blunt trauma remains a major injury mechanism, and up to 90% of these injuries result in death on the scene. The objective of this study is to understand the modern risk factors and etiology of fatal thoracic aortic injuries in the current US fleet. METHODS: Using a unique, linked, Fatality Analysis Reporting System (FARS) and Multiple Cause of Death (MCOD) database from 2000-2010, 144,169 drivers over 16 years of age who suffered fatal injuries were identified. The merged database provides an unparalleled fidelity for identifying thoracic aortic injuries due to motor vehicle accidents. Thoracic aortic injuries were defined by ICD-10 codes S250. Univariate and multivariate logistic regression models for presence of any thoracic aortic injuries were fitted. Age, gender, BMI weight categories, vehicle class, model year, crash type/direction, severity of crash damage, airbag deployment location, and seatbelt use, fatal injury codes, and location of injury were considered. Odds ratios (OR) and corresponding 95% confidence intervals (95%CI) are calculated. RESULTS: There were 2953 deaths (2.10%) related to thoracic aortic injuries that met the inclusion criteria. Nearside crashes were associated with an increased odds (OR = 1.42, 1.1-1.83), while rollover crashes (OR =.44,.29-.66) were associated with a reduced odds of fatal thoracic aortic injury. Using backward selection on the full multivariate model, the only significant model effects that remained were vehicle type, crash type, body region, and injury type. CONCLUSIONS: The increased prevalence of fatal thoracic aortic injury in nearside crashes, increasing age, and vehicle type provide some insight into the current US fleet. Important factors, including model year, had significantly lower levels of the injury in univariate analysis, demonstrating the effect of safety improvements in newer model vehicles. Further study of this fatal injury is warranted, including comparisons of those who survive the injury.

Association Between American Board of Surgery In-Training Examination Scores and Resident Performance.

IMPORTANCE: The American Board of Surgery In-Training Examination (ABSITE) is designed to measure progress, applied medical knowledge, and clinical management; results may determine promotion and fellowship candidacy for general surgery residents. Evaluations are mandated by the Accreditation Council for Graduate Medical Education but are administered at the discretion of individual institutions and are not standardized. It is unclear whether the ABSITE and evaluations form a reasonable assessment of resident performance. OBJECTIVE: To determine whether favorable evaluations are associated with ABSITE performance. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of preliminary and categorical residents in postgraduate years (PGYs) 1 through 5 training in a single university-based general surgery program from July 1, 2011, through June 30, 2014, who took the ABSITE. EXPOSURES: Evaluation overall performance and subset evaluation performance in the following categories: patient care, technical skills, problem-based learning, interpersonal and communication skills, professionalism, systems-based practice, and medical knowledge. MAIN OUTCOMES AND MEASURES: Passing the ABSITE (≥30th percentile) and ranking in the top 30% of scores at our institution. RESULTS: The study population comprised residents in PGY 1 (n = 44), PGY 2 (n = 31), PGY 3 (n = 26), PGY 4 (n = 25), and PGY 5 (n = 24) during the 4-year study period (N = 150). Evaluations had less variation than the ABSITE percentile (SD = 5.06 vs 28.82, respectively). Neither annual nor subset evaluation scores were significantly associated with passing the ABSITE (n = 102; for annual evaluation, odds ratio = 0.949; 95% CI, 0.884-1.019; P = .15) or receiving a top 30% score (n = 45; for annual evaluation, odds ratio = 1.036; 95% CI, 0.964-1.113; P = .33). There was no difference in mean evaluation score between those who passed vs failed the ABSITE (mean [SD] evaluation score, 91.77 [5.10] vs 93.04 [4.80], respectively; P = .14) or between those who received a top 30% score vs those who did not (mean [SD] evaluation score, 92.78 [4.83] vs 91.92 [5.11], respectively; P = .33). There was no correlation between annual evaluation score and ABSITE percentile (r(2) = 0.014; P = .15), percentage correct unadjusted for PGY level (r(2) = 0.019; P = .09), or percentage correct adjusted for PGY level (r(2) = 0.429; P = .91). CONCLUSIONS AND RELEVANCE: Favorable evaluations do not correlate with ABSITE scores, nor do they predict passing. Evaluations do not show much discriminatory ability. It is unclear whether individual resident evaluations and ABSITE scores fully assess competency in residents or allow comparisons to be made across programs. Creation of a uniform evaluation system that encompasses the necessary subjective feedback from faculty with the objective measure of the ABSITE is warranted.

Studies of NVP-BEZ235 in melanoma.

The PI3k pathway represents an attractive target for drug development in melanoma, as numerous studies have shown that this pathway is active in malignant melanocytes. In addition, previous work has shown that multi-level targeting of this pathway might be more effective than targeting the pathway at a single level. In this review, we discuss targeting different members of this pathway, potential escape mechanisms, classes of specific molecular inhibitors, and development of NVP-BEZ235, a novel dual PI3k/mTOR inhibitor.