Citations

Purpose No standard treatment exists for patients with cholangiocarcinoma for whom first-line gemcitabine-based therapy fails. Fibroblast growth factor receptor 2 ( FGFR2) fusions/translocations are present in 13% to 17% of intrahepatic cholangiocarcinomas. BGJ398, an orally bioavailable, selective pan-FGFR kinase inhibitor, has shown preliminary clinical activity against tumors with FGFR alterations. Methods A multicenter, open-label, phase II study ( ClinicalTrials.gov identifier: NCT02150967) evaluated BGJ398 antitumor activity in patients age ≥ 18 years with advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR alterations whose disease had progressed while receiving prior therapy. Patients received BGJ398 125 mg once daily for 21 days, then 7 days off (28-day cycles). The primary end point was investigator-assessed overall response rate. Results Sixty-one patients (35 women; median age, 57 years) with FGFR2 fusion (n = 48), mutation (n = 8), or amplification (n = 3) participated. At the prespecified data cutoff (June 30, 2016), 50 patients had discontinued treatment. All responsive tumors contained FGFR2 fusions. The overall response rate was 14.8% (18.8% FGFR2 fusions only), disease control rate was 75.4% (83.3% FGFR2 fusions only), and estimated median progression-free survival was 5.8 months (95% CI, 4.3 to 7.6 months). Adverse events included hyperphosphatemia (72.1% all grade), fatigue (36.1%), stomatitis (29.5%), and alopecia (26.2%). Grade 3 or 4 treatment-related adverse events occurred in 25 patients (41%) and included hyperphosphatemia (16.4%), stomatitis (6.6%), and palmar-plantar erythrodysesthesia (4.9%). Conclusion BGJ398 is a first-in-class FGFR kinase inhibitor with manageable toxicities that shows meaningful clinical activity against chemotherapy-refractory cholangiocarcinoma containing FGFR2 fusions. This promising antitumor activity supports continued development of BGJ398 in this highly selected patient population.

Background— Diabetes mellitus (DM) adversely affects morbidity and mortality for cardiovascular diseases and procedures. Data evaluating the outcomes of transcatheter aortic valve replacement (TAVR) in diabetic patients are limited by small sample size and contradictory results. We aimed to establish the magnitude of risk and the incremental influence of insulin dependency by examining short- and long-term adverse outcomes according to DM status and therapy in the world’s largest TAVR registry. Methods and Results— We analyzed data from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapy Registry. In-hospital mortality, 30-day mortality, and 1-year mortality after TAVR in patients with and without DM were evaluated using multivariate modeling. Among 47 643 patients treated with TAVR from November 2011 through September 2015 at 394 US hospitals, there were 17 849 (37.5%) patients with DM. Overall, 6600 of the diabetic patients were insulin treated (IT). Thirty-day mortality was 5.0% in patients with DM (6.1% in IT DM and 4.4% in non-IT DM; P <0.001) versus 5.9% in patients without DM ( P <0.001). Overall, 1-year mortality was 21.8% in patients with DM (24.8% in IT DM and 20.1% in non-IT DM; P <0.001) versus 21.2% in patients without DM ( P =0.274). In a multivariable model, DM was associated with increased 1-year mortality (hazard ratio, 1.30; 95% confidence interval, 1.13–1.49; P <0.001). Subgroup multivariable analysis showed stronger mortality association in IT diabetics (hazard ratio, 1.57; 95% confidence interval, 1.28–1.91; P <0.001) than in non-IT diabetics (hazard ratio, 1.17; 95% confidence interval, 1.00–1.38; P =0.052). Conclusions— Our data establish the magnitude of short- and long-term risk conferred by DM and the incremental risk conferred by insulin dependency in the performance of TAVR. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT01737528.

ObjectiveThe relationship between inflammation, obesity, and adverse metabolic conditions is associated with adipose tissue macrophages (ATM). This study compared the measurements of human ATM using flow cytometry, immunohistochemistry (IHC), and real‐time polymerase chain reaction (RT‐PCR) of ATM markers.MethodsA new software program (AMCounter) was evaluated to help measure ATM using IHC, and this was compared to flow cytometry and RT‐PCR.ResultsIHC had good intraindividual reproducibility for total (CD68), proinflammatory (CD14), and anti‐inflammatory (CD206) ATM. The AMCounter improved interreader agreement and was more time efficient. Flow cytometry had acceptable intraindividual reproducibility for the percentage of CD68+ cells that were CD14+ or CD206+, but not for ATMs per gram of tissue. ATMs per gram of tissue was much greater using IHC than flow cytometry. The flow cytometry and IHC measures of ATM from the same biopsies were not correlated. There were statistically significant correlations between RT‐PCR CD68 and IHC CD68, CD14, and CD206 ATMs per 100 adipocytes. Also of interest were statistically significant correlations between RT‐PCR CD68 and IHC CD68, CD14, and adipose flow cytometry measures of CD68+, CD68+/CD14+, and CD68+/CD206+ ATMs per gram of tissue.ConclusionsThe AMCounter software helps provide reproducible and efficient measures of IHC ATMs. Flow cytometry, IHC, and RT‐PCR measures of adipose inflammation provide somewhat different information.

Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.

Abstract Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between individual concurrent comorbidities and prognosis in ovarian cancer patients. Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes. Results: None of the comorbidities were associated with ovarian cancer outcome in the overall sample nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced). Conclusions: Histories of endometriosis; asthma; depression; osteoporosis; and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival. Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev; 26(9); 1470–3. ©2017 AACR.