Citations

AbstractBackgroundCyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo‐ovarian high‐grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large‐scale, histotype‐specific validation has been performed. The hypothesis was that high‐level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC.MethodsWithin the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated.ResultsHigh‐level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high‐level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08‐1.47, p = .034, and HR, 1.18; 95% CI, 1.05‐1.32, p = .015, respectively). This was also true for cases with combined high‐level amplification/overexpression (HR, 1.26; 95% CI, 1.09‐1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1‐SD increase; 95% CI, 0.94‐1.06; p = .58). CCNE1 high‐level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss.ConclusionThis study provides large‐scale validation that CCNE1 high‐level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.

Abstract Background Financial toxicity is emerging as an important patient-centered outcome and is understudied in prostate cancer patients. We sought to understand the association between financial burden and treatment regret in men with localized prostate cancer to better evaluate the role of financial discussions in patient counseling. Methods Utilizing the Comparative Effectiveness Analysis of Surgery and Radiation dataset, we identified all men accrued between 2011 and 2012 who underwent surgery, radiation, or active surveillance for localized prostate cancer. Financial burden and treatment regret were assessed at 3- and 5-year follow-up. The association between financial burden and regret was assessed using multivariable longitudinal logistic regression controlling for demographic and disease characteristics, treatment, functional outcomes, and patient expectations. Results Of the 2924 eligible patients, regret and financial burden assessments for 3- and/or 5-year follow-up were available for 81% (n = 2359). After adjustment for relevant covariates, financial burden from “finances in general” was associated with treatment regret at 3 years (odds ratio [OR] = 2.47, 95% confidence interval [CI] = 1.33 to 4.57; P = .004); however, this association was no longer statistically significant at 5-year follow-up (OR = 1.19, 95% CI = 0.56 to 2.54; P = .7). Conclusions In this population-based sample of men with localized prostate cancer, we observed associations between financial burden and treatment regret. Our findings suggest indirect treatment costs, especially during the first 3 years after diagnosis, may impact patients more profoundly than direct costs and are important for inclusion in shared decision making.

AbstractBackgroundKnown risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort.MethodsSingle nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer–related cell types.ResultsWe identified statistically significant risk associations with CNVs at known EOC risk genes; BRCA1 (PEOC = 1.60E-21; OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4; odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4; ORHGSOC = 3.31 deletion). Four suggestive associations (P < .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P < .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types.ConclusionsCNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.

AbstractOver the last half‐century, left ventricular assist device (LVAD) technology has progressed from conceptual therapy for failed cardiopulmonary bypass weaning to an accepted destination therapy for advanced heart failure. The history of LVAD engineering is defined by an initial development phase, which demonstrated the feasibility of such an approach, to the more recent three major generations of commercial devices. In this review, we explore the engineering challenges of LVADs, how they were addressed over time, and the clinical outcomes that resulted from each major technological development. The first generation of commercial LVADs were pulsatile devices, which lacked the appropriate durability due to their number of moving components and hemocompatibility. The second generation of LVADs was defined by replacement of complex, pulsatile pumps with primarily axial, continuous‐flow systems with an impeller in the blood passageway. These devices experienced significant commercial success, but the presence of excessive trauma to the blood and in‐situ bearing resulted in an unacceptable burden of adverse events. Third generation centrifugal‐flow pumps use magnetically suspended rotors within the pump chamber. Superior outcomes with this newest generation of devices have been observed, particularly with respect to hemocompatibility‐related adverse events including pump thrombosis, with fully magnetically levitated devices. The future of LVAD engineering includes wireless charging foregoing percutaneous drivelines and more advanced pump control mechanisms, including synchronization of the pump flow with the native cardiac cycle, and varying pump output based on degree of physical exertion using sensor or advanced device‐level data triggers.

Objective To develop updated guidelines for the perioperative management of disease‐modifying medications for patients with rheumatic diseases, specifically those with inflammatory arthritis (IA) and those with systemic lupus erythematosus (SLE), undergoing elective total hip arthroplasty (THA) or elective total knee arthroplasty (TKA). Methods We convened a panel of rheumatologists, orthopedic surgeons, and infectious disease specialists, updated the systematic literature review, and included currently available medications for the clinically relevant population, intervention, comparator, and outcomes (PICO) questions. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence and the strength of recommendations using a group consensus process. Results This guideline updates the 2017 recommendations for perioperative use of disease‐modifying antirheumatic therapy, including traditional disease‐modifying antirheumatic drugs, biologic agents, targeted synthetic small‐molecule drugs, and glucocorticoids used for adults with rheumatic diseases, specifically for the treatment of patients with IA, including rheumatoid arthritis and spondyloarthritis, those with juvenile idiopathic arthritis, or those with SLE who are undergoing elective THA or TKA. It updates recommendations regarding when to continue, when to withhold, and when to restart these medications and the optimal perioperative dosing of glucocorticoids. Conclusion This updated guideline includes recently introduced immunosuppressive medications to help decision‐making by clinicians and patients regarding perioperative disease‐modifying medication management for patients with IA and SLE at the time of elective THA or TKA.

ObjectiveTo develop updated guidelines for the perioperative management of disease‐modifying medications for patients with rheumatic diseases, specifically those with inflammatory arthritis (IA) and those with systemic lupus erythematosus (SLE), undergoing elective total hip arthroplasty (THA) or elective total knee arthroplasty (TKA).MethodsWe convened a panel of rheumatologists, orthopedic surgeons, and infectious disease specialists, updated the systematic literature review, and included currently available medications for the clinically relevant population, intervention, comparator, and outcomes (PICO) questions. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology to rate the quality of evidence and the strength of recommendations using a group consensus process.ResultsThis guideline updates the 2017 recommendations for perioperative use of disease‐modifying antirheumatic therapy, including traditional disease‐modifying antirheumatic drugs, biologic agents, targeted synthetic small‐molecule drugs, and glucocorticoids used for adults with rheumatic diseases, specifically for the treatment of patients with IA, including rheumatoid arthritis and spondyloarthritis, those with juvenile idiopathic arthritis, or those with SLE who are undergoing elective THA or TKA. It updates recommendations regarding when to continue, when to withhold, and when to restart these medications and the optimal perioperative dosing of glucocorticoids.ConclusionThis updated guideline includes recently introduced immunosuppressive medications to help decision‐making by clinicians and patients regarding perioperative disease‐modifying medication management for patients with IA and SLE at the time of elective THA or TKA.

Abstract Background: Ovarian cancer is the deadliest gynecologic cancer. Standard treatments for advanced stage high-grade serous ovarian cancer, the most common type, include (1) primary cytoreductive surgery (PCS) followed by adjuvant chemotherapy or (2) neoadjuvant chemotherapy (NACT) with interval debulking surgery. Patients in whom PCS is unlikely to yield optimal cytoreduction to no visible residual disease (R0) or who have medical contraindications to PCS are recommended to undergo NACT. Previous studies on associations between environmental factors and risk of any macroscopic residual disease have yielded inconsistent results. We aimed to (1) comprehensively examine the associations between demographic, lifestyle and reproductive factors and risk of residual disease after PCS; and (2) develop and internally validate a risk prediction model based on these factors. Methods: We used pooled data on 3,492 women who had PCS following a diagnosis with advanced stage high-grade serous ovarian, fallopian tube or primary peritoneal cancers from the Ovarian Cancer Association Consortium. Fifteen exposures of interest included age at diagnosis, menopausal status, race/ethnicity, education level, first-degree family history of ovarian cancer, endometriosis, smoking, body mass index, parity, incomplete pregnancy, tubal ligation, use of combined oral contraceptives, depot-medroxyprogesterone acetate, estrogen (ET), and combined estrogen-progestin therapy. We fit logistic regression models to examine each exposure-residual disease association in 80% of the data (n=2,794; random selection of participants). We developed a risk prediction model including the factors with p-values ≤0.2. Area under the receiver operating characteristic curve (AUC) was used to assess the model’s discrimination in the remaining 20% of the data (n=698). Results: Of the 3,492 participants, 2,003 (57%) had residual disease following PCS. Older age at diagnosis was associated with an increased risk of residual disease (OR=1.07 per five years, 95% CI 1.03-1.11). In contrast, a family history of ovarian cancer (OR=0.63, 95% CI 0.42-0.95) or ET use for 5+ years (OR=0.61, 95% CI 0.39-0.96) were associated with achieving R0. These above factors were included in the risk prediction model as were race/ethnicity, personal history of endometriosis, and smoking, whose p-values ≤0.2. The model showed modest performance in the validation set (AUC=0.64). Conclusions: Younger age at diagnosis, family history of ovarian cancer, and long-term ET use were associated with achieving R0 following PCS. Future studies incorporating genetic and clinical factors to improve the risk prediction for residual disease following PCS are warranted. Citation Format: Minh Tung Phung, Andrew Berchuck, Ellen L. Goode, Marc T. Goodman, Gillian E. Hanley, Jean Richardson, Bronwyn Grout, Anne Chase, Cindy McKinnon Deurloo, Beth Y. Karlan, Toon Van Gorp, Keitaro Matsuo, Karen McLean, Malcolm C. Pike, Joellen M. Schildkraut, Kathryn L. Terry, Anna DeFazio, Penelope M. Webb, Paul D. P. Pharoah, Susan J. Ramus, Celeste Leigh Pearce. Environmental factors associated with residual disease after ovarian cancer primary cytoreduction surgery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2248.