Citations

Abstract Background: Aromatase inhibitors are a mainstay hormone receptor-positive breast cancer treatment. AIA occur in up to 50% of patients (pts), adversely affecting quality of life and treatment compliance. A small phase II clinical trial of oral testosterone unedeconate appeared to improve AIA over placebo (P), with no significant androgenic side effects. The current study was performed to confirm these findings. Methods: This randomized P-controlled trial enrolled postmenopausal women on adjuvant anastrozole or letrozole and experiencing moderate-to-severe AIA (≥5 on 0-10 scale). Pts were initially randomized to receive a subcutaneous pellet containing T 120 mg + anastrozole 8 mg (T+AIpellet) or P at the end of the first week on study (after obtaining baseline hot flash data) and at 3 months (mo). Due to slow accrual, the protocol was amended to change the route of delivery to topical T or P applied to the skin once daily for 6 mo. Baseline and monthly questionnaires were administered, including: Modified Brief Pain Inventory for aromatase arthralgia (BPI-AIA), prolife of mood states (POMS), the menopause specific quality of life questionnaire (MENQOL), a hot flash diary, the hot flash related daily interference scale (HFRDIS) and a symptom experience questionnaire. The primary endpoint was intra-patient change in joint pain at 3 mo, compared using a two-sample t-test. Results: 227 pts were accrued between 9/1/2013-11/29/2017. 55 pts were randomized prior to the protocol amendment and received T+AIpellet or P. Baseline characteristics were balanced between arms, with the exceptions of median weight, BMI, hemoglobin (all higher in T arm), and breast tenderness, dissatisfaction with personal life/depression, and skin changes (all higher in P arm). Compared to baseline, there were no significant differences between T and P in average pain or joint stiffness at 3 (p=0.483) or 6 mo (p=0.573). Average pain was significantly lower each month compared to baseline, irrespective of treatment arm. There were no significant differences in any other items evaluated by BPI-AIA, POMS, MENQOL, hot flash diary or HFRDIS. Similarly, there were no substantial differences in toxicity. A subset analysis of the 55 pts randomized to receive T+AIpellet or P identified significant reductions in average pain scores with T+AIpellet during the first month (p=0.038), but not thereafter. T+AIpellet pts had significantly more reduction in reported % of baseline hot flash frequency (p=0.034) and score (p=0.031), nausea (p=0.019), fatigue (p=0.042), mood swings (p=0.026), hand/feet swelling (p=0.009), stress urinary incontinence (p=0.039) and changes in appearance, texture or tone of their skin (p=0.0083), than pts on P. Conclusions: Overall, T did not improve AIA or menopausal symptoms compared to P. While there was significant improvement in AIA over the study period, T did not facilitate this process. However, T+AIpellet was associated with improvement in short-term AIA and several menopausal symptoms compared to P, suggesting that subcutaneous T combined with anastrozole may be superior to transdermal T alone. Support: UG1CA189823, U10CA180820, U10CA189809; ClinicalTrials.gov Identifier: NCT01573442 Citation Format: Leon-Ferre RA, Le-Rademacher J, Terstriep S, Glaser R, Novotni P, Giuliano A, Copur MS, Jones C, Page S, Mitchell W, Birrell SN, Loprinzi CL. A randomized, double-blind, placebo-controlled trial of testosterone (T) for aromatase inhibitor-induced arthralgias (AIA) in postmenopausal women: Alliance A221102 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-01.

AbstractAn association between genetic variants in the vitamin D receptor (VDR) gene and epithelial ovarian cancer (EOC) was previously reported in women of African ancestry (AA). We sought to examine associations between genetic variants in VDR and additional genes from vitamin D biosynthesis and pathway targets (EGFR, UGT1A, UGT2A1/2, UGT2B, CYP3A4/5, CYP2R1, CYP27B1, CYP24A1, CYP11A1, and GC). Genotyping was performed using the custom‐designed 533,631 SNP Illumina OncoArray with imputation to the 1,000 Genomes Phase 3 v5 reference set in 755 EOC cases, including 537 high‐grade serous (HGSOC), and 1,235 controls. All subjects are of African ancestry (AA). Logistic regression was performed to estimate odds ratios (OR) and 95% confidence intervals (CI). We further evaluated statistical significance of selected SNPs using the Bayesian False Discovery Probability (BFDP). A significant association with EOC was identified in the UGT2A1/2 region for the SNP rs10017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 1.2 × 10−6, BFDP = 0.02); and an association with HGSOC was identified in the EGFR region for the SNP rs114972508 (per allele OR = 2.3, 95% CI = 1.6‐3.4, P = 1.6 × 10−5, BFDP = 0.29) and in the UGT2A1/2 region again for rs1017134 (per allele OR = 1.4, 95% CI = 1.2‐1.7, P = 2.3 × 10−5, BFDP = 0.23). Genetic variants in the EGFR and UGT2A1/2 may increase susceptibility of EOC in AA women. Future studies to validate these findings are warranted. Alterations in EGFR and UGT2A1/2 could perturb enzyme efficacy, proliferation in ovaries, impact and mark susceptibility to EOC.

BACKGROUNDTransfusion‐related acute lung injury (TRALI) is a serious complication of blood transfusion and is among the leading causes of transfusion‐related morbidity and mortality in most developed countries. In the past decade, the pathophysiology of this potentially life‐threatening syndrome has been increasingly elucidated, large cohort studies have identified associated patient conditions and transfusion risk factors, and preventive strategies have been successfully implemented. These new insights provide a rationale for updating the 2004 consensus definition of TRALI.STUDY DESIGN AND METHODSAn international expert panel used the Delphi methodology to develop a redefinition of TRALI by modifying and updating the 2004 definition. Additionally, the panel reviewed issues related to TRALI nomenclature, patient conditions associated with acute respiratory distress syndrome (ARDS) and TRALI, TRALI pathophysiology, and standardization of reporting of TRALI cases.RESULTSIn the redefinition, the term “possible TRALI” has been dropped. The terminology of TRALI Type I (without an ARDS risk factor) and TRALI Type II (with an ARDS risk factor or with mild existing ARDS) is proposed. Cases with an ARDS risk factor that meet ARDS diagnostic criteria and where respiratory deterioration over the 12 hours before transfusion implicates the risk factor as causative should be classified as ARDS. TRALI remains a clinical diagnosis and does not require detection of cognate white blood cell antibodies.CONCLUSIONSClinicians should report all cases of posttransfusion pulmonary edema to the transfusion service so that further investigation can allow for classification of such cases as TRALI (Type I or Type II), ARDS, transfusion‐associated circulatory overload (TACO), or TRALI or TACO cannot distinguish or an alternate diagnosis.

PURPOSE To provide evidence-based recommendations on the treatment of multiple myeloma to practicing physicians and others. METHODS ASCO and Cancer Care Ontario convened an Expert Panel of medical oncology, surgery, radiation oncology, and advocacy experts to conduct a literature search, which included systematic reviews, meta-analyses, randomized controlled trials, and some phase II studies published from 2005 through 2018. Outcomes of interest included survival, progression-free survival, response rate, and quality of life. Expert Panel members used available evidence and informal consensus to develop evidence-based guideline recommendations. RESULTS The literature search identified 124 relevant studies to inform the evidence base for this guideline. RECOMMENDATIONS Evidence-based recommendations were developed for patients with multiple myeloma who are transplantation eligible and those who are ineligible and for patients with relapsed or refractory disease.

Abstract Cardiovascular disease is the leading cause of death in individuals over 60 years old. Aging is associated with an increased prevalence of coronary artery disease and a poorer prognosis following acute myocardial infarction (MI). With age, senescent cells accumulate in tissues, including the heart, and contribute to age‐related pathologies. However, the role of senescence in recovery following MI has not been investigated. In this study, we demonstrate that treatment of aged mice with the senolytic drug, navitoclax, eliminates senescent cardiomyocytes and attenuates profibrotic protein expression in aged mice. Importantly, clearance of senescent cells improved myocardial remodelling and diastolic function as well as overall survival following MI. These data provide proof‐of‐concept evidence that senescent cells are major contributors to impaired function and increased mortality following MI and that senolytics are a potential new therapeutic avenue for MI.

BackgroundThe optimal anticoagulation strategy for patients with atrial fibrillation (AF) and bioprosthetic valve (BPV) replacement or native valve repair remains uncertain.HypothesisWe evaluated the safety and efficacy of apixaban vs warfarin in patients with AF and a history of BPV replacement or native valve repair.MethodsUsing data from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) (n = 18 201), a randomized trial comparing apixaban with warfarin in patients with AF, we analyzed the subgroup of patients (n = 251) with prior valve surgery. We contacted sites by telephone to obtain additional data about prior valve surgery. Full data were available for 156 patients. The primary efficacy endpoint was stroke/systemic embolism. The primary safety endpoint was major bleeding. Treatment groups were compared using a Cox regression model.ResultsIn ARISTOTLE, 104 (0.6%) patients had a history of BPV replacement (n = 73 [aortic], n = 26 [mitral], n = 5 [mitral and aortic]) and 52 (0.3%) had a history of valve repair (n = 50 [mitral], n = 2 [aortic]). Among patients with BPVs, 55 were randomized to apixaban and 49 to warfarin. Among those with a history of native valve repair, 32 were randomized to apixaban and 20 to warfarin. Overall clinical event rates were low, with no significant differences between apixaban and warfarin for any outcomes.ConclusionsIn patients with AF and a history of BPV replacement or repair, the safety and efficacy of apixaban compared with warfarin was consistent with results from ARISTOTLE. These data suggest that apixaban may be reasonable for patients with BPVs or prior valve repair, though future larger randomized trials are needed.ClinicalTrials.govNCT00412984.

Abstract Aims We aimed to evaluate the frequency, clinical features, and prognostic implications of cardiac arrest (CA) in takotsubo syndrome (TTS). Methods and results We reviewed the records of patients with CA and known heart rhythm from the International Takotsubo Registry. The main outcomes were 60-day and 5-year mortality. In addition, predictors of mortality and predictors of CA during the acute TTS phase were assessed. Of 2098 patients, 103 patients with CA and known heart rhythm during CA were included. Compared with patients without CA, CA patients were more likely to be younger, male, and have apical TTS, atrial fibrillation (AF), neurologic comorbidities, physical triggers, and longer corrected QT-interval and lower left ventricular ejection fraction on admission. In all, 57.1% of patients with CA at admission had ventricular fibrillation/tachycardia, while 73.7% of patients with CA in the acute phase had asystole/pulseless electrical activity. Patients with CA showed higher 60-day (40.3% vs. 4.0%, P < 0.001) and 5-year mortality (68.9% vs. 16.7%, P < 0.001) than patients without CA. T-wave inversion and intracranial haemorrhage were independently associated with higher 60-day mortality after CA, whereas female gender was associated with lower 60-day mortality. In the acute phase, CA occurred less frequently in females and more frequently in patients with AF, ST-segment elevation, and higher C-reactive protein on admission. Conclusions Cardiac arrest is relatively frequent in TTS and is associated with higher short- and long-term mortality. Clinical and electrocardiographic parameters independently predicted mortality after CA.