Citations

Purpose Less than 20% of patients with melanoma who undergo sentinel lymph node (SLN) biopsy based on American Society of Clinical Oncology/Society of Surgical Oncology recommendations are SLN positive. We present a multi-institutional study to discover new molecular risk factors associated with SLN positivity in thin and intermediate-thickness melanoma. Patients and Methods Gene clusters with functional roles in melanoma metastasis were discovered by next-generation sequencing and validated by quantitative polymerase chain reaction using a discovery set of 73 benign nevi, 76 primary cutaneous melanoma, and 11 in-transit melanoma metastases. We then used polymerase chain reaction to quantify gene expression in a model development cohort of 360 consecutive thin and intermediate-thickness melanomas and a validation cohort of 146 melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. Logic and logistic regression analyses were used to develop a model for the likelihood of SLN metastasis from molecular, clinical, and histologic variables. Results ITGB3, LAMB1, PLAT, and TP53 expression were associated with SLN metastasis. The predictive ability of a model that included these molecular variables in combination with clinicopathologic variables (patient age, Breslow depth, and tumor ulceration) was significantly greater than a model that only considered clinicopathologic variables and also performed well in the validation cohort (area under the curve, 0.93; 95% CI, 0.87 to 0.97; false-positive and false-negative rates of 22% and 0%, respectively, using a 10% cutoff for predicted SLN metastasis risk). Conclusion The addition of cell adhesion–linked gene expression variables to clinicopathologic variables improves the identification of patients with SLN metastases within 90 days of melanoma diagnosis.

Background— Apixaban is approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. However, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial included a substantial number of patients with valvular heart disease and only excluded patients with clinically significant mitral stenosis or mechanical prosthetic heart valves. Methods and Results— We compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major bleeding, and death in patients with and without moderate or severe valvular heart disease using Cox proportional hazards modeling. Of the 18 201 patients enrolled in ARISTOTLE, 4808 (26.4%) had a history of moderate or severe valvular heart disease or previous valve surgery. Patients with valvular heart disease had higher rates of stroke or systemic embolism and bleeding than patients without valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.51–0.97 and HR, 0.84; 95%, CI 0.67–1.04; interaction P =0.38), causing less major bleeding (HR, 0.79; 95% CI, 0.61–1.04 and HR, 0.65; 95% CI, 0.55–0.77; interaction P =0.23), and reducing mortality (HR, 1.01; 95% CI, 0.84–1.22 and HR, 0.84; 95% CI, 0.73–0.96; interaction P =0.10). Conclusions— More than a quarter of the patients in ARISTOTLE with nonvalvular atrial fibrillation had moderate or severe valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in reducing stroke or systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00412984.

Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression‐free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2‐negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre‐planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF‐A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49–3.75), 1.20 (95% CI, 0.88–1.64) and 0.61 (95% CI, 0.34–1.12). Notably, some SNPs in VEGF‐A exhibited a more pronounced effect in the triple‐negative subgroup. Several SNPs in VEGF‐A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.

Background and Purpose— The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations. Methods— Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P <10 −6 for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations. Results— The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P =3.9×10 −8 ) in African Americans. Nominal associations ( P <10 −6 ) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing ( PTPRG , CDC5L ), platelet function ( HPS4 ), blood–brain barrier permeability ( CLDN17 ), immune response ( ELTD1, WDFY4 , and IL1F10-IL1RN ), and histone modification ( HDAC9 ). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 ( P =0.03), and 1p31.1 ( P =0.018). Four of 7 previously reported ischemic stroke loci ( PITX2, HDAC9, CDKN2A/CDKN2B , and ZFHX3 ) were nominally associated ( P <0.05) with stroke in COMPASS. Conclusions— We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations.

Background: The purpose of this study is to compare the outcome of the conical fully threaded headless screw to that of a smooth shaft headless screw in a series of scaphoid nonunions requiring screw fixation to determine if screw design had an influence on union rates.Methods: We retrospectively reviewed 104 cases of surgically treated scaphoid nonunions. After eliminating cases with our exclusion criteria, the study cohort had 40 cases for analysis. A comparison and analysis of union rates was undertaken between the fully threaded Acutrak 2 mini screw and the smooth shaft Herbert screw.Results: Overall union rate for screw fixation was 88%. The fully threaded conical screw fixation had a significantly lower union rate of 50% compared to 97% for the smooth shaft screws.Conclusions: Our data revealed that the fully threaded conical screws were associated with significantly lower union rate compared to the smooth shaft Herbert type screws.

Objectives To determine event‐free survival after transcatheter closure of ventricular septal defect (VSD), and to identify predictors of adverse events (AE) in post myocardial infarction VSD (post‐MI VSD) subgroup. Background There are limited data on mid‐term follow‐up after transcatheter VSD closure. Methods Retrospective review of 27 cases of transcatheter VSD closure (post‐MI = 18 and non‐ischemic = 9) performed from 1999 to 2013. We defined AE as death, device embolization, hemolysis requiring blood transfusion, heart block and reintervention. Results In the post‐MI VSD subgroup, mean age and follow‐up was 69 ± 11 and 7.3 ± 7 years, respectively. AE occurred in 8 (44%) patients (death‐3, device embolization‐1, hemolysis‐1, surgical VSD closure‐2, reintervention‐1). Event‐free survival was 56% at 1 month and 5 years, and all AE occurred in the periprocedural period. Cardiogenic shock (HR: 3.21, CI: 1.82–5.41, P = 0.002), and VSD closure in acute phase (HR: 2.14, CI: 1.12–4.31, P = 0.004) were independent predictors of AE. In the non‐ischemic VSD subgroup, mean age and follow‐up was 49 ± 15 and 8.7 ± 8 years, respectively. AE occurred in 3 (33%) patients (late death‐1, surgical VSD closure‐2). For the entire cohort, freedom from death was 89% and 85% at 1 month and 5 years, and event‐free survival was 70% and 61% at 1 month and 5 years. Conclusions Transcatheter closure of post‐MI VSD carries a moderate risk of periprocedural complications but low event rates afterwards. By comparison, device closure of non‐ischemic VSD has lower periprocedural morbidity but some patients continued to experience AE during follow‐up. © 2015 Wiley Periodicals, Inc.

The objective of this analysis of 4500 inpatients was to identify the experience and expectations of 18–35 year olds regarding chaplain visitation and to compare results with data from older adults. 71% of young adults reported wanting to be visited by a chaplain; 45.5% were visited; 68% indicated that this was important. Young adults value chaplains' role as a sign of God's care and presence (77.4%), in providing support for family (73.6%), being present during times of anxiety (66.0%), and praying/reading scripture with them (62.3%). Results were similar to older respondents, but young adults were more likely to value ethical counsel from chaplains (58.5% vs. 38.2%). This study provides clinically relevant information and suggestions for further research.

Introduction Symptomatic metastatic epidural spinal cord compression (MESCC) afflicts up to 10% of all cancer patients. MESCC is associated with shortened survival and worsened quality of life; thus, early diagnosis and management is crucial. In a multidisciplinary setting, life expectancy must be considered along with other factors, such as patient's symptoms and overall medical condition, to select the optimal patient-specific treatment plan. This study aims to identify and compare key survival prognostic factors in surgically treated symptomatic MESCC patients with a 12-month postoperative follow-up. Materials and Methods Over a 5-year period, 145 patients surgically treated for a single symptomatic MESCC lesion were enrolled in a prospective North American multicenter study. Univariate analyses, Kaplan–Meier methods, and log-rank tests were used to evaluate the prognostic value of various clinical predictors. Preoperative prognostic factors evaluated: age, gender, comorbidities, history of smoking, metastases outside the spine, site of primary tumor, previous systemic treatment for the primary tumor, MESCC location, number of vertebral body involved, previous MESCC treatment, ASIA score, motor deficits, bladder dysfunction, Oswestry Disability Index (ODI), EQ-5D, SF-36v2 mental and physical components, and ability to walk four steps. Predictors with p < 0.2 in univariate analyses were included into the final Cox proportional hazards model. Results The overall median survival was 7.7 months (235 days). Lung and breast cancer had the shortest and longest median survival, respectively (4.5 vs. 12.1 months). Nine patients (6%), whose primary cancer were lung (3), kidney (3), melanoma (1), prostate (1), and breast (1), died within 30 days after surgery; 46 (32%), 61 (42%), 74 (51%), and 86 (59%) patients died at 3, 6, 9, and 12 months, respectively. The site of primary tumor, number of vertebrae involved, ODI, EQ-5D, ASIA score, metastases outside the spine, bladder dysfunction, and ability to walk four steps were significant predictors on the univariate analyses. However, the multivariate Cox-regression analysis demonstrated that only spinal metastasis involving four or more vertebral bodies had a negative impact on survival ( p = 0.002, HR: 25). Conclusion The extent of spinal metastasis, which is regarded as an indicator of the severity of patient's metastasis burden, and the site of the primary tumor, although not statistically significant in our regression model but well recognized in the literature as an important clinical predictor, are considered as independent predictors of poor prognosis in patients with a single-level symptomatic MESCC lesion. MESCC patients are a challenging and vulnerable heterogenous population. It is essential to identify factors predicting survival, functional and clinical outcomes in this population to guide patient-centered management to optimize quality of life.