Citations

Purpose Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E, an antimicrotubule agent, into CD30-expressing cells. In phase I studies, brentuximab vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory CD30-positive lymphomas. Patients and Methods In this multinational, open-label, phase II study, the efficacy and safety of brentuximab vedotin were evaluated in patients with relapsed or refractory Hodgkin's lymphoma (HL) after autologous stem-cell transplantation (auto-SCT). Patients had histologically documented CD30-positive HL by central pathology review. A total of 102 patients were treated with brentuximab vedotin 1.8 mg/kg by intravenous infusion every 3 weeks. In the absence of disease progression or prohibitive toxicity, patients received a maximum of 16 cycles. The primary end point was the overall objective response rate (ORR) determined by an independent radiology review facility. Results The ORR was 75% with complete remission (CR) in 34% of patients. The median progression-free survival time for all patients was 5.6 months, and the median duration of response for those in CR was 20.5 months. After a median observation time of more than 1.5 years, 31 patients were alive and free of documented progressive disease. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Conclusion The ADC brentuximab vedotin was associated with manageable toxicity and induced objective responses in 75% of patients with relapsed or refractory HL after auto-SCT. Durable CRs approaching 2 years were observed, supporting study in earlier lines of therapy.

Abstract Background: Genome-wide association studies (GWAS) for epithelial ovarian cancer (EOC), the most lethal gynecologic malignancy, have identified novel susceptibility loci. GWAS for survival after EOC have had more limited success. The association of each single-nucleotide polymorphism (SNP) individually may not be well suited to detect small effects of multiple SNPs, such as those operating within the same biologic pathway. Gene set analysis (GSA) overcomes this limitation by assessing overall evidence for association of a phenotype with all measured variation in a set of genes. Methods: To determine gene sets associated with EOC overall survival, we conducted GSA using data from two large GWAS (N cases = 2,813, N deaths = 1,116), with a novel Principal Component-Gamma GSA method. Analysis was completed for all cases and then separately for high-grade serous histologic subtype. Results: Analysis of the high-grade serous subjects resulted in 43 gene sets with P < 0.005 (1.7%); of these, 21 gene sets had P < 0.10 in both GWAS, including intracellular signaling pathway (P = 7.3 × 10−5) and macrolide binding (P = 6.2 × 10−4) gene sets. The top gene sets in analysis of all cases were meiotic mismatch repair (P = 6.3 × 10−4) and macrolide binding (P = 1.0 × 10−3). Of 18 gene sets with P < 0.005 (0.7%), eight had P < 0.10 in both GWAS. Conclusion: This research detected novel gene sets associated with EOC survival. Impact: Novel gene sets associated with EOC survival might lead to new insights and avenues for development of novel therapies for EOC and pharmacogenomic studies. Cancer Epidemiol Biomarkers Prev; 21(3); 529–36. ©2012 AACR.

Objective Sudden hearing loss (SHL) is a frightening symptom that often prompts an urgent or emergent visit to a physician. This guideline provides evidence‐based recommendations for the diagnosis, management, and follow‐up of patients who present with SHL. The guideline primarily focuses on sudden sensorineural hearing loss (SSNHL) in adult patients (aged 18 and older). Prompt recognition and management of SSNHL may improve hearing recovery and patient quality of life (QOL). Sudden sensorineural hearing loss affects 5 to 20 per 100,000 population, with about 4000 new cases per year in the United States. This guideline is intended for all clinicians who diagnose or manage adult patients who present with SHL. Purpose The purpose of this guideline is to provide clinicians with evidence‐based recommendations in evaluating patients with SHL, with particular emphasis on managing SSNHL. The panel recognized that patients enter the health care system with SHL as a nonspecific, primary complaint. Therefore, the initial recommendations of the guideline deal with efficiently distinguishing SSNHL from other causes of SHL at the time of presentation. By focusing on opportunities for quality improvement, the guideline should improve diagnostic accuracy, facilitate prompt intervention, decrease variations in management, reduce unnecessary tests and imaging procedures, and improve hearing and rehabilitative outcomes for affected patients. Results The panel made strong recommendations that clinicians should (1) distinguish sensorineural hearing loss from conductive hearing loss in a patient presenting with SHL; (2) educate patients with idiopathic sudden sensorineural hearing loss (ISSNHL) about the natural history of the condition, the benefits and risks of medical interventions, and the limitations of existing evidence regarding efficacy; and (3) counsel patients with incomplete recovery of hearing about the possible benefits of amplification and hearing‐assistive technology and other supportive measures. The panel made recommendations that clinicians should (1) assess patients with presumptive SSNHL for bilateral SHL, recurrent episodes of SHL, or focal neurologic findings; (2) diagnose presumptive ISSNHL if audiometry confirms a 30‐dB hearing loss at 3 consecutive frequencies and an underlying condition cannot be identified by history and physical examination; (3) evaluate patients with ISSNHL for retrocochlear pathology by obtaining magnetic resonance imaging, auditory brainstem response, or audiometric follow‐up; (4) offer intratympanic steroid perfusion when patients have incomplete recovery from ISSNHL after failure of initial management; and (5) obtain follow‐up audiometric evaluation within 6 months of diagnosis for patients with ISSNHL. The panel offered as options that clinicians may offer (1) corticosteroids as initial therapy to patients with ISSNHL and (2) hyperbaric oxygen therapy within 3 months of diagnosis of ISSNHL. The panel made a recommendation against clinicians routinely prescribing antivirals, thrombolytics, vasodilators, vasoactive substances, or antioxidants to patients with ISSNHL. The panel made strong recommendations against clinicians (1) ordering computerized tomography of the head/brain in the initial evaluation of a patient with presumptive SSNHL and (2) obtaining routine laboratory tests in patients with ISSNHL.

Abstract The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05–1.15; P = 3.49 × 10−5] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13–1.31; P = 2.22 × 10−7). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89–1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18–1.33; P = 3.31 × 10−13]. Thus, 19p13.1 is the first triple-negative–specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. Cancer Res; 72(7); 1795–803. ©2012 AACR.

Background— The HeartMate II (HMII) destination therapy (DT) trial demonstrated significant improvements in outcomes in continuous-flow left ventricular assist devices compared with patients implanted with the pulsatile-flow HeartMate XVE. The primary hypothesis of the current study is that trial patients enrolled after the initial data cohort would have better clinical outcomes. Methods and Results— Two hundred eighty-one patients who underwent HMII for DT from May 2007 to March 2009 (Mid Trial [MT] group) were compared with the initial 133 HMII patients from March 2005 to May 2007 (Early Trial [ET] group). Patient entry criteria were the same during the 2 time periods. Survival, adverse events, and quality of life were compared between the 2 groups. Baseline characteristics were similar between the groups. Compared with the ET group, patients in the MT group had reduced adverse event rates for bleeding requiring transfusions (1.66 versus 1.13 events per patient-year, P <0.001), sepsis (0.38 versus 0.27, P =0.025), device-related infections (0.47 versus 0.27, P <0.001), and hemorrhagic stroke (0.07 versus 0.03, P =0.01). Other event rates were similar between groups including ischemic stroke (0.06 versus 0.05 events per patient-year, P =0.57). Survival at 1 year in the MT group was 73% versus 68% in the ET group ( P =0.21). Additionally, there was a significant reduction in deaths caused by hemorrhagic stroke ( P =0.01). Quality of life improvements were significant in both the groups ( P <0.001). Conclusions— The benefit of DT therapy with the HMII is confirmed in subsequent trial patients, with improved adverse event rates and a strong trend for improvements in survival. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00121485.