Citations

AbstractDespite the withdrawal of CB1 antagonists, such as rimonabant, from the market and from active clinical development because of concerns about their side effect profiles, research suggests that the endocannabinoid system may play an important role in modulating nicotine's effects. We report the combined results, using a pooled analysis, of three previously unpublished trials assessing rimonabant as a smoking cessation pharmacotherapy conducted between 2002 and 2004. Smokers (n = 2097) motivated to quit were enrolled in three randomized, double‐blind, placebo‐controlled trials, STRATUS EU, US, and META, which consisted of a 10‐week treatment period with either rimonabant 20 mg (n = 789), 5 mg (n = 518; used in only two of the three studies), or placebo (n = 790), in conjunction with brief counseling. The impact of drug on prolonged abstinence and adverse events was examined at 8 weeks (end‐of‐treatment) and at 48 weeks (available for STRATUS EU and US) after the targeted quit date. Rimonabant 20 mg resulted in significantly higher abstinence at end‐of‐treatment and at 48 weeks post‐targeted quit date compared with placebo, while rimonabant 5 mg and placebo did not differ. Serious AEs did not differ by drug group. The 20 mg rimonabant dose, compared with placebo, produced increased nausea, diarrhea, anxiety symptoms, hyporexia, and vomiting, and decreased headache, constipation, and cough. These results support rimonabant 20 mg as a modestly effective aid for smoking cessation. Although work on CB1 antagonists such as rimonabant has mostly been stopped because of unacceptable adverse events, these results may inform and spur the development of other endocannabinoids for smoking cessation.

Abstract Purpose: Randomized, multicenter, open-label, phase 2/3 trial investigating lenalidomide versus investigator's choice (IC) in relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Experimental Design: Patients with DLBCL who received ≥2 prior therapies were stratified by DLBCL subtype [germinal center B-cell (GCB) vs. non-GCB; determined by immunohistochemistry (IHC)] and then randomized 1:1 to lenalidomide (25 mg/day, 21 days of 28-day cycle) or IC (gemcitabine, rituximab, etoposide, or oxaliplatin). Crossover to lenalidomide was permitted for IC-treated patients with radiologically confirmed progressive disease. The primary endpoint was overall response rate (ORR). Progression-free survival (PFS), overall survival, and subtype analysis [GCB vs. activated B-cell (ABC)] using gene expression profiling (GEP) were exploratory endpoints. Results: Stage 1: 102 DLBCL patients (by IHC: non-GCB, n = 54; GCB, n = 48) received ≥1 dose of lenalidomide or IC. Hematologic treatment-emergent adverse events with lenalidomide versus IC included neutropenia (42.6%; 36.4%), anemia (33.3%; 47.3%), thrombocytopenia (24.1%; 43.6%), and leukopenia (5.6%; 12.7%), respectively. Overall, lenalidomide-treated patients had an ORR of 27.5% versus 11.8% in IC (ORRs were similar regardless of IHC-defined DLBCL subtype). Median PFS was increased in patients receiving lenalidomide (13.6 weeks) versus IC (7.9 weeks; P = 0.041), with greater improvements in non-GCB patients (15.1 vs. 7.1 weeks, respectively; P = 0.021) compared with GCB (10.1 vs. 9.0 weeks, respectively; P = 0.550). Conclusions: The clinical benefit of lenalidomide monotherapy in DLBCL patients was more evident in the non-GCB subtype. Exploratory analyses suggest that this preferential benefit was more pronounced in the GEP-defined ABC population, demonstrating a need for additional studies of lenalidomide in DLBCL using GEP subtyping. Clin Cancer Res; 23(15); 4127–37. ©2017 AACR.

Abstract Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case–control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789–99. ©2017 AACR.

ObjectivesIdiopathic subglottic stenosis (iSGS) is rare, and its cause remains elusive. Treatment options include empiric medical therapy and endoscopic or open surgery. We present our results for open surgical technique.Study DesignCase series with chart review (1978‐2015).SettingTertiary academic center.Subjects/MethodsThirty‐three patients (32 female; median age, 51 years) met inclusion criteria and underwent cricotracheal resection with thyrotracheal anastomosis, tracheal resection with primary anastomosis, or laryngotracheoplasty with rib grafting. Continuous variables were summarized using medians and ranges while categorical features are presented using frequency counts and percentages.ResultsSixteen patients (48%) underwent a single‐stage approach with immediate extubation or temporary intubation following surgery (median, 1 day; range, 1‐3 days). Seventeen patients (52%) underwent a double‐staged approach with a median time to decannulation of 35 days (range, 13‐100 days). Twenty‐four (73%) patients underwent a previous intervention. Median stay in the intensive care unit was 1 day (range, 0‐3 days), with a median hospital stay of 4 days (range, 2‐7 days). Recurrence requiring further surgical intervention was observed in 12 patients (36%). The median time to recurrence was 8 years over an average follow‐up of 9.7 years. The most common complaint following surgery was change in voice quality (fair to poor; n = 10; 30%).ConclusionsOpen surgery should be reserved for refractory cases of iSGS; cricotracheal resection with thyrotracheal anastomosis is the preferred open technique. Recurrence may occur after open treatment, highlighting the importance of long‐term follow‐up. Patients should be counseled about the potential for worsening voice quality with the open approach.

Key Points An international panel established the first ever diagnostic criteria for iMCD based on review of 244 clinical cases and 88 tissue samples. The criteria require multicentric lymphadenopathy with defined histopathology, ≥2 clinical/laboratory changes, and exclusion of iMCD mimics.

Prostate cancer is the most common malignancy of men in the United States. Small-cell carcinoma (SCC), which typically presents as an aggressive lung malignancy, is a rare diagnosis within the setting of prostate cancer pathology. Due to its limited prevalence, little information regarding the treatment and prognosis of this disease in large populations is available. To date our current knowledge base is largely limited to case reports and retrospective case reviews. The mainstay of treatment for this particular histology most often involves a multimodality approach utilizing chemotherapy in conjunction with radiation therapy, androgen deprivation therapy, or prostatectomy. Here we present the case of an elderly 89-year-old Caucasian male who was diagnosed with SCC of the prostate. Despite proceeding with a course of definitive radiotherapy, the patient experienced rapid progression of disease and ultimately elected to discontinue radiation therapy and receive hospice care.

AbstractWe present a case of JC polyomavirus (JCV)‐associated nephropathy (PyVAN) in an asymptomatic deceased‐donor kidney transplant recipient. Despite the presence of viral cytopathic effect in the kidney biopsy and positive BK polyomavirus (BKV) in situ hybridization (ISH), BKV real‐time polymerase chain reaction (PCR) results of plasma and urine were negative. JCV ISH was performed and was found to be positive. JCV real‐time PCR on urine, plasma, and the kidney biopsy tissue was positive. Reduction in immunosuppression resulted in resolution of JCV viremia. This case highlights that JC‐PyVAN is a distinct clinical entity and is likely to have a better clinical outcome than BK‐PyVAN. Concurrent infection with BKV and JCV may occur, but may be difficult to confirm due to the potential for cross‐reactivity between BKV and JCV ISH stains.