Citations

Abstract Background: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer. Methods: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history. Results: The prostate cancer risk for men in the top 1% of the PRS distribution was 30.6 (95% CI, 16.4–57.3) fold compared with men in the bottom 1%, and 4.2 (95% CI, 3.2–5.5) fold compared with the median risk. The absolute risk of prostate cancer by age of 85 years was 65.8% for a man with family history in the top 1% of the PRS distribution, compared with 3.7% for a man in the bottom 1%. The PRS was only weakly correlated with serum PSA level (correlation = 0.09). Conclusions: Risk profiling can identify men at substantially increased or reduced risk of prostate cancer. The effect size, measured by OR per unit PRS, was higher in men at younger ages and in men with family history of prostate cancer. Incorporating additional newly identified loci into a PRS should improve the predictive value of risk profiles. Impact: We demonstrate that the risk profiling based on SNPs can identify men at substantially increased or reduced risk that could have useful implications for targeted prevention and screening programs. Cancer Epidemiol Biomarkers Prev; 24(7); 1121–9. ©2015 AACR.

Proximal claudication is secondary to ischemia caused by peripheral artery disease (PAD), whereas proximal pseudo-claudication is secondary to other disease processes such as hip arthritis, spinal stenosis, neuropathy, and so forth. The differentiation between the two can be challenging. Exercise transcutaneous oxygen pressure measurement (exercise-TcPO 2 ) allows noninvasive detection of flow-reducing lesions in the proximal arteries and tributaries of the lower extremity arterial tree. We present the first case report in the United States using an exercise-TcPO 2 algorithm. A 71-year-old diabetic patient with proximal left-sided and right-calf claudication with indeterminate ankle-brachial indices underwent an exercise-TcPO 2 study before and after endovascular intervention. Four TcPO 2 probes were placed: one at chest level (reference probe), one on each buttock, and one on the symptomatic calf. The Delta from Resting Oxygen Pressure (DROP) index was calculated at each probe site using a previously validated protocol. Proximal left- and right-calf ischemia were confirmed by the initial exercise-TcPO 2 , and, after endovascular treatment of the left iliac artery lesion, improvements in proximal exercise-TcPO 2 values were found. These data suggest that exercise-TcPO 2 can be useful in PAD evaluation in patients with non-compressible arteries and/or proximal claudication.

AbstractBackgroundAllogeneic hematopoietic stem cell transplant (allo‐HSCT) recipients have multiple risk factors for coccidioidomycosis, and previous reports of coccidioidomycosis in this patient population describe severe infections with poor outcomes.MethodsWe performed a retrospective chart review of allo‐HSCT recipients with active coccidioidomycosis to characterize the utility of diagnostic tests for coccidioidomycosis and to determine treatment outcomes.ResultsEleven of 426 (2.6%) allo‐HSCT recipients experienced active coccidioidomycosis after transplantation. Of these 11 patients, 1 (9%) had extrapulmonary infection, 9 (82%) patients were hospitalized, and 5 (45%) died. Culture or histology was positive in 33% (3/9) of the patients tested. Most (64% [7/11]) had at least 1 positive serologic test result, and the enzyme immunoassay immunoglobulin G test was positive most often (overall 55% [6/11]). Chest radiographs and chest computed tomography scans showed miliary or multifocal nodular infiltrates or consolidations, consistent with coccidioidomycosis, in 80% (8/10) and 100% (9/9), respectively, of patients tested throughout the course of active illness. Rapid polymerase chain reaction testing was positive in 71% (5/7) of the patients tested. Peripheral eosinophilia was present in 18% (2/11) of patients.ConclusionCoccidioidomycosis is associated with high morbidity and mortality in allo‐HSCT recipients in an area endemic for Coccidioides. Diagnosis of this infection can be difficult and often requires multiple and frequently invasive tests. Antifungal prophylaxis should be considered for patients at highest risk.

Abstract Myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN) are hematologically diverse stem cell malignancies sharing phenotypic features of both myelodysplastic syndromes and myeloproliferative neoplasms. There are currently no standard treatment recommendations for most adult patients with MDS/MPN. To optimize efforts to improve the management and disease outcomes, it is essential to identify meaningful clinical and biologic end points and standardized response criteria for clinical trials. The dual dysplastic and proliferative features in these stem cell malignancies define their uniqueness and challenges. We propose response assessment guidelines to harmonize future clinical trials with the principal objective of establishing suitable treatment algorithms. An international panel comprising laboratory and clinical experts in MDS/MPN was established involving 3 independent academic MDS/MPN workshops (March 2013, December 2013, and June 2014). These recommendations are the result of this collaborative project sponsored by the MDS Foundation.

Abstract Purpose: We tested whether 18 polymorphisms in 16 genes (GSTP1, COX2, IL10, EGFR, EGF, FGFR4, CCDN1, VEGFR2, VEGF, CXCR2, IL8, MMP3, ICAM1, ERCC1, RAD51, and XRCC3) would predict disease-free survival (DFS), overall survival (OS), and toxicity in the INT0144 trial, which was designed to investigate different postoperative regimens of 5-fluorouracil (5-FU)–based chemoradiation (CRT) in locally advanced rectal cancers: Arm 1 consisted of bolus 5-FU followed by 5-FU protracted venous infusion (PVI) with radiotherapy; arm 2 was induction and concomitant PVI 5-FU with radiotherapy and arm 3 was induction and concomitant bolus 5-FU with radiotherapy. Experimental Design: DNA from 746 stage II/III rectal patients enrolled in the Southwest Oncology Group (SWOG) S9304 phase III trial was analyzed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue. The polymorphisms were analyzed using direct DNA-sequencing or polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: GSTP1-Ile105Val (rs1695) was significantly associated with DFS and OS and its effect did not vary by treatment arm. The five-year DFS and OS were 53% and 58%, respectively, for G/G, 66% and 72% for G/A, and 57% and 66% for A/A patients. In arm 2, IL8-251A/A genotype (rs4073) was associated with a lower risk of toxicities (P = 0.04). The VEGFR2 H472Q Q/Q genotype (rs1870377) was associated with a higher risk of grade 3–5 proximal upper gastrointestinal tract (PUGIT) mucositis (P = 0.04) in arm 2. However, in arm 1, this genotype was associated with a lower risk of PUGIT mucositis (P = 0.004). Conclusion: rs1695 may be prognostic in patients with rectal cancer treated with adjuvant CRT. rs4073 and rs1870377 may exhibit different associations with toxicity, according to the 5-FU schedule. Clin Cancer Res; 21(7); 1583–90. ©2015 AACR.

Abstract Motivation: RNA-seq has been widely used to study the transcriptome. Comparing to microarray, sequencing-based RNA-seq is able to identify splicing variants and single nucleotide variants in one experiment simultaneously. This provides unique opportunity to detect variants that associated with aberrant splicing. Despite the popularity of RNA-seq, no bioinformatics tool has been developed to leverage this advantage to identify variants associated with aberrant splicing. Results: We have developed PVAAS, a tool to identify single nucleotide variants that associated with aberrant alternative splicing from RNA-seq data. PVAAS works in three steps: (i) identify aberrant splicings; (ii) use user-provided variants or perform variant calling; (iii) assess the significance of association between variants and aberrant splicing events. Availability and implementation: PVAAS is written in Python and C. Source code and a comprehensive user’s manual are freely available at: http://pvaas.sourceforge.net/. Contact: wang.liguo@mayo.edu or kocher.jeanpierre@mayo.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Background The Carotid Revascularization Endarterectomy Versus Stenting Trial ( CREST ) is a multicenter randomized trial of stenting versus endarterectomy in patients with symptomatic and asymptomatic carotid disease. This study assesses management of vascular risk factors. Methods and Results Management was provided by the patient's physician, with biannual monitoring results collected by the local site. Therapeutic targets were low‐density lipoprotein, cholesterol <100 mg/dL, systolic blood pressure <140 mm Hg, fasting blood glucose <126 mg/dL, and nonsmoking status. Optimal control was defined as achieving all 4 goals concurrently. Generalized estimating equations were used to compare risk factors at baseline with those observed in scheduled follow‐up visits for up to 48 months. In the analysis cohort of 2210, significant improvements in risk‐factor control were observed across risk factors for all follow‐up visits compared with baseline. At 48 months, achievement of the low‐density lipoprotein cholesterol goal improved from 59.1% to 73.6% ( P <0.001), achievement of the systolic blood pressure goal improved from 51.6% to 65.1% ( P <0.001), achievement of the glucose goal improved from 74.9% to 80.7% ( P =0.0101), and nonsmoking improved from 74.4% to 80.9% ( P <0.0001). The percentage with optimal risk‐factor control also improved significantly, from 16.7% to 36.2% ( P <0.001), but nearly 2 of 3 study participants did not achieve optimal control during the study. Conclusions Site‐based risk‐factor control improved significantly in the first 6 months and over the long term in CREST but was often suboptimal. Intensive medical management should be considered for future trials of carotid revascularization. Clinical Trial Registration URL: ClinicalTrials.gov. Unique identifier: NCT00004732.