Search

Frequencies of mutations in genes previously reported6-8,10 as observed in our panel of bladder carcinoma patients.

Genes calculated to be significantly mutated by Genome MuSic algorithm (p

Pathologic specifications of analyzed tumor specimens (formal pathologist review).

Clinical characteristics of the 81 patients, according to recurrence status.

Genes calculated to be significantly mutated by MutSigCV algorithm (p

Purpose: Because of suboptimal outcomes in muscle-invasive bladder cancer even with multimodality therapy, determination of potential genetic drivers offers the possibility of improving therapeutic approaches and discovering novel prognostic indicators.Experimental Design: Using pTN staging, we case-matched 81 patients with resected ≥pT2 bladder cancers for whom perioperative chemotherapy use and disease recurrence status were known. Whole-exome sequencing was conducted in 43 cases to identify recurrent somatic mutations and targeted sequencing of 10 genes selected from the initial screening in an additional 38 cases was completed. Mutational profiles along with clinicopathologic information were correlated with recurrence-free survival (RFS) in the patients.Results: We identified recurrent novel somatic mutations in the gene UNC5C (9.9%), in addition to TP53 (40.7%), KDM6A (21.0%), and TSC1 (12.3%). Patients who were carriers of somatic mutations in DNA repair genes (one or more of ATM, ERCC2, FANCD2, PALB2, BRCA1, or BRCA2) had a higher overall number of somatic mutations (P = 0.011). Importantly, after a median follow-up of 40.4 months, carriers of somatic mutations (n = 25) in any of these six DNA repair genes had significantly enhanced RFS compared with noncarriers [median, 32.4 vs. 14.8 months; hazard ratio of 0.46, 95% confidence interval (CI), 0.22–0.98; P = 0.0435], after adjustment for pathologic pTN staging and independent of adjuvant chemotherapy usage.Conclusion: Better prognostic outcomes of individuals carrying somatic mutations in DNA repair genes suggest these mutations as favorable prognostic events in muscle-invasive bladder cancer. Additional mechanistic investigation into the previously undiscovered role of UNC5C in bladder cancer is warranted. Clin Cancer Res; 20(24); 6605–17. ©2014 AACR.

Normal adjacent bladder tissue specimens (formal pathologist review).

Author(s): McKillip, Ryan P.; Gopalsami, Anand; Montoya, Magdeline; Kim, Gene; Walter, James J.; Juricek, Colleen; Shappell, Eric | Abstract: Introduction: Left ventricular assist device (LVAD) insertion is an increasingly common intervention for patients with advanced heart failure; however, published literature on the emergency department (ED) presentation of this population is limited. The objective of this study was to characterize ED presentations of patients with LVADs with a focus on device-specific complications to inform provider education and preparation initiatives. Methods: This was a retrospective chart review of all patients with LVADs followed at an urban academic medical center presenting to the ED over a five-year period (July 1, 2009, to June 30, 2014). Two abstractors reviewed 45 randomly selected charts to standardize the abstraction process and establish a priori categories for reason for presentation to the ED. Remaining charts were then divided evenly for review by one of the two abstractors. Primary outcomes for this study were (1) frequency of and (2) reason for presentation to the ED by patients with LVADs. Results: Of 349 patients with LVADs identified, 143 (41.0%) had ED encounters during the study period. There were 620 total ED encounters, (range 1 to 32 encounters per patient, median=3, standard deviation=5.3). Among the encounters, 431 (69.5%) resulted in admission. The most common reasons for presentation were bleeding (e.g., gastrointestinal, epistaxis) (182, 29.4%); infection (127, 20.5%); heart failure exacerbation (68, 11.0%); pain (56, 9.0%); other (45, 7.3%); and arrhythmias (40, 6.5%). Fifty-two encounters (8.4%) were device-specific; these patients frequently presented with abnormal device readings (37, 6.0%). Interventions for device-specific presentations included anticoagulation regimen adjustment (16/52, 30.8%), pump exchange (9, 17.3%), and hardware repair (6, 11.5%). Pump thrombosis occurred in 23 cases (3.7% of all encounters). No patients required cardiopulmonary resuscitation or died in the ED. Conclusion: This is the largest study known to the investigators to report the rate of ED presentations of patients with LVADs and provide analysis of device-specific presentations. In patients who do have device-specific ED presentations, pump thrombosis is a common diagnosis and can present without device alarms. Specialized LVAD education and preparation initiatives for ED providers should emphasize the recognition and management of the most common and critical conditions for this patient population, which have been identified in this study as bleeding, infection, heart failure, and pump thrombosis.

Purpose: Because of suboptimal outcomes in muscle-invasive bladder cancer even with multimodality therapy, determination of potential genetic drivers offers the possibility of improving therapeutic approaches and discovering novel prognostic indicators. Experimental Design: Using pTN staging, we case-matched 81 patients with resected ≥pT2 bladder cancers for whom perioperative chemotherapy use and disease recurrence status were known. Whole-exome sequencing was conducted in 43 cases to identify recurrent somatic mutations and targeted sequencing of 10 genes selected from the initial screening in an additional 38 cases was completed. Mutational profiles along with clinicopathologic information were correlated with recurrence-free survival (RFS) in the patients. Results: We identified recurrent novel somatic mutations in the gene UNC5C (9.9%), in addition to TP53 (40.7%), KDM6A (21.0%), and TSC1 (12.3%). Patients who were carriers of somatic mutations in DNA repair genes (one or more of ATM, ERCC2, FANCD2, PALB2, BRCA1, or BRCA2) had a higher overall number of somatic mutations (P = 0.011). Importantly, after a median follow-up of 40.4 months, carriers of somatic mutations (n = 25) in any of these six DNA repair genes had significantly enhanced RFS compared with noncarriers [median, 32.4 vs. 14.8 months; hazard ratio of 0.46, 95% confidence interval (CI), 0.22–0.98; P = 0.0435], after adjustment for pathologic pTN staging and independent of adjuvant chemotherapy usage. Conclusion: Better prognostic outcomes of individuals carrying somatic mutations in DNA repair genes suggest these mutations as favorable prognostic events in muscle-invasive bladder cancer. Additional mechanistic investigation into the previously undiscovered role of UNC5C in bladder cancer is warranted. Clin Cancer Res; 20(24); 6605–17. ©2014 AACR.

The immune microenvironment in follicular lymphoma (FL) plays an important role in controlling disease characteristics. To characterize the T-cell receptor (TCR) repertoire in follicular lymphoma (FL) tissues, we applied a next-generation sequencing platform and deeply sequenced TCR cDNAs of T-cell subset populations present in pretreatment FL biopsy specimens. T regulatory cell (Treg) TCRs in FL tissues revealed a highly oligoclonal expansion compared to those in control lymph nodes. Furthermore, an inverse correlation was observed between the diversity of Treg and CD8+ TCRs in FL specimens. Interestingly, a tumor from an FL patient, who had not received anticancer treatment for more than 10 years, was found to have missense mutations in the peptide-binding domain of both human leukocyte antigen (HLA) class I and II molecules, which might have presented tumor-specific antigens and enhanced host immune responses. Although further verification is required, our data suggest that the T-cell repertoire is skewed and restricted in FL and support the evolving understanding of the microenvironment in this disease.

Bladder cancer is the fourth most common cancer type in males and approximately 72,500 individuals were diagnosed in the United States in 2012. Patients with superficial (low-grade papillary) tumors generally have a good prognosis with a 5-year survival rate exceeding 90%, but those with muscle-invasive or locally advanced disease at surgical resection have a significant risk of recurrence with 5-year survival rates of 30-60%. The systemic chemotherapy options for bladder cancer are very limited, and no new drugs have been approved in the United States for metastatic bladder cancer in over 20 years. Although a number of newer, molecularly targeting drugs have been developed and approved for multiple cancer types in the last two decades, no such drug has been developed for the treatment of bladder cancer. This is likely due, in part, to the relatively limited molecular understanding of invasive bladder cancers and lack of knowledge about potential genetic drivers of invasive forms of the disease. Hence, it is of priority to discover novel genetic pathways involved in the carcinogenesis of muscle-invasive bladder cancer for the assessment of risk stratification and for the development of novel drugs. We analyzed exomes of 43 muscle-invasive bladder carcinomas and identified two novel significantly mutated genes, NOS3 (18.6%) and UNC5C (16.3%), in addition to previously reported frequently mutated genes like TP53 (37.2%) and KDM6A (18.6%). Both NOS3 and UNC5C are known to be involved in the apoptotic pathways, with NOS3 encoding for endothelial nitric oxide synthase (eNOS), and UNC5C for netrin receptor, a member of the dependence receptor family. When we correlated the mutational profiles with clinicopathological outcomes by stratifying patients according to disease recurrence status and observing for specific clustering of genetic mutations, we found that somatic mutations in six DNA repair genes (ATM, ERCC2, FANCD2, RAD51AP1, PALB2, BRCA2) were significantly associated with enhanced recurrence-free survival (hazard ratio of 0.091 with 95% CI of 0.018 to 0.45; P=0.0034) even after adjustment for pathologic TN staging, suggestive of their mutations as favorable prognostic events in bladder cancer. Citation Format: Kai Lee Yap, Kazuma Kiyotani, Kenji Tamura, Miran Jang, Magdeline Montoya, Cory Ganshert, Tomoaki Fujioka, Gary Steinberg, Peter O'Donnell, Yusuke Nakamura. Recurrent somatic mutations of nitric oxide synthase NOS3, netrin receptor UNC5C and DNA repair genes in muscle-invasive bladder carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3430. doi:10.1158/1538-7445.AM2014-3430