Citations

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.

222 Background: Current approaches to measuring the quality of cancer care may not produce sufficient information to enable providers to structure care that aligns closely with their patients’ preferences. To close this gap, we developed the Consumer-based Cancer Care Value Index (CCCVI) survey, which assesses the aspects of cancer care that patients value the most and how their values align with their experience in receiving cancer care. Methods: The CCCVI field test included 721 adults who received cancer care in the last 12 months from 4 geographically diverse cancer care centers, including patients with varying stages of cancer, types of cancer, types of treatment (e.g., surgery, radiation, medical oncology), and demographic characteristics. The survey included items that asked patients to directly rate the “importance” of 24 aspects of cancer care, along with 24 corresponding items that measured the “frequency” with which they received each aspect of care. We evaluated the reliability and validity of the survey items, and developed “value grids” plots which visually depicted the “importance” scores against the “frequency” scores. We conducted subgroup analysis to examine income and racial/ethnic disparities in the extent of misalignment between patients’ values and experiences. Results: The survey demonstrated good internal consistency reliability (Cronbach’s alpha = 0.91) and acceptable-to-good construct and criterion validity. Value grids identified potential areas of improvement in the areas of how doctors communicate and how quickly patients get care. The subgroup analysis showed the most misalignments between patients’ values and experiences in the aspects of doctor communication for lower-income patients and in the aspects of getting care quickly for patients from racial/ethnic minority groups. Conclusions: The CCCVI survey is a reliable and valid tool for cancer care providers to identify top priority areas (i.e., high-importance but low-frequency areas) to facilitate their quality improvement efforts. It also recognizes subgroup variations in the misalignment between patients’ values and care experiences.

Poly(GP) proteins are a promising pharmacodynamic marker for developing and testing therapeutics for treating C9ORF72 -associated amyotrophic lateral sclerosis.

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.

Fibrosis of the subsynovial connective tissue (SSCT) in carpal tunnel syndrome (CTS) patients is increasingly recognized as an important aspect of CTS pathophysiology. In this study, we evaluated the effect of blocking profibrotic pathways in fibroblasts from the SSCT in CTS patients. Fibroblasts were stimulated with transforming growth factor β1 (TGF‐β1), and then treated either with a specific fibrosis pathway inhibitor targeting TGF‐β receptor type 1 (TβRI), platelet‐derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), or vascular endothelial growth factor receptor (VEGFR). Fibrosis array and quantitative real‐time polymerase chain reaction of fibrotic genes were evaluated. Array gene expression analysis revealed significant down‐regulation of multiple fibrotic genes after treatment with TβRI, PDGFR, and VEGFR inhibitors. No array fibrotic genes were significantly down‐regulated with EGFR inhibition. Further gene expression analysis of known CTS fibrosis markers collagen type I A2 (Col1), collagen type III A1 (Col3), connective tissue growth factor (CTGF), and SERPINE1 showed significantly down‐regulation after TβRI inhibition. In contrast, VEGFR inhibition significantly down‐regulated CTGF and SERPINE1, whereas, PDGFR and EGFR inhibition significantly down‐regulated Col3. Taken together the inhibition of TβRI appears to be the primary mediator of fibrotic gene expression in fibroblasts from CTS patients. TGF‐β/Smad activity was further evaluated, and as expected inhibition of Smad activity was significantly down‐regulated after inhibition of TβRI, but not with PDGFR, VEGFR, or EGFR inhibition. These results indicate that local therapies specifically targeting TGF‐β signaling alone or in combination offer the potential of a novel local antifibrosis therapy for patients with CTS.