Citations

Abstract Background: The lack of consensus on whether bilateral oophorectomy impacts risk of developing breast cancer among BRCA1 mutation carriers might be attributed to various biases, specifically, cancer-induced testing bias due to inclusion of prevalent cases. We conducted two complementary matched case–control analyses to evaluate the association of oophorectomy and BRCA1 breast cancer. Methods: A research questionnaire was administered every two years to collect information on exposures and disease. In the first analysis, we limited the study to prevalent breast cancer cases (diagnosed prior to study entry; n = 2,962) who were matched to controls on year of birth and country of residence (n = 4,358). In the second approach, we limited to 330 incident cases (diagnosed in the follow-up period) and 1,548 matched controls. Conditional logistic regression was used to estimate the adjusted odds ratios (OR) and 95% confidence intervals (CI) of invasive breast cancer. Results: In the first approach, there was a significant inverse association between oophorectomy and the risk of developing breast cancer [OR = 0.43; 95% confidence interval (CI), 0.34–0.55; P < 00001]. In the second approach, there was no association between oophorectomy and risk (OR = 1.21; 95% CI, 0.87–1.70; P = 0.26). Conclusions: The inclusion of women with a personal history of breast cancer prior to ascertainment likely impacts upon the association of oophorectomy and BRCA1 breast cancer risk. Impact: Oophorectomy is unlikely a determinant of breast cancer risk in BRCA1 mutation carriers but should be offered at age 35 to reduce the risk of ovarian and fallopian tube cancer.

AbstractProsthetic valve endocarditis (PVE) remains a serious condition with a high mortality rate. Precise identification of the PVE-associated pathogen/s and their virulence is essential for successful therapy and patient survival. The commonly described PVE-associated pathogens are staphylococci, streptococci, and enterococci, with Staphylococcus aureus being the most frequently diagnosed species. Furthermore, multi-drug resistance pathogens are increasing in prevalence and continue to pose new challenges mandating a personalized approach. Blood cultures in combination with echocardiography are the most common methods to diagnose PVE, often being the only indication, it exists. In many cases, the diagnostic strategy recommended in the clinical guidelines does not identify the precise microbial agent, and frequently, false-negative blood cultures are reported. Despite the fact that blood culture findings are not always a good indicator of the actual PVE agent in the valve tissue, only a minority of re-operated prostheses are subjected to microbiological diagnostic evaluation. In this review, we focus on the diversity and the complete spectrum of PVE-associated bacterial, fungal, and viral pathogens in blood and prosthetic heart valve, their possible virulence potential, and their challenges in making a microbial diagnosis. We are curious to understand if the unacceptable high mortality of PVE is associated with the high number of negative microbial findings in connection with a possible PVE. Herein, we discuss the possibilities and limits of the diagnostic methods conventionally used and make recommendations for enhanced pathogen identification. We also show possible virulence factors of the most common PVE-associated pathogens and their clinical effects. Based on blood culture, molecular biological diagnostics, and specific valve examination, better derivations for the antibiotic therapy as well as possible preventive intervention can be established in the future.

Background The American Association for the Surgery of Trauma (AAST) has developed a grading system for emergency general surgery (EGS) conditions. We sought to validate the AAST EGS grades for patients undergoing urgent/emergent colorectal resection. Methods Patients enrolled in the “Eastern Association for the Surgery of Trauma Multicenter Colorectal Resection in EGS—to anastomose or not to anastomose” study undergoing urgent/emergent surgery for obstruction, ischemia, or diverticulitis were included. Baseline demographics, comorbidity severity as defined by Charlson comorbidity index (CCI), procedure type, and AAST grade were prospectively collected. Outcomes included length of stay (LOS) in-hospital mortality, and surgical complications (superficial/deep/organ-space surgical site infection, anastomotic leak, stoma complication, fascial dehiscence, and need for further intervention). Multivariable logistic regression models were used to describe outcomes and risk factors for surgical complication or mortality. Results There were 367 patients, with a mean (± SD) age of 62 ± 15 years. 39% were women. The median interquartile range (IQR) CCI was 4 (2-6). Overall, the pathologies encompassed the following AAST EGS grades: I (17, 5%), II (54, 15%), III (115, 31%), IV (95, 26%), and V (86, 23%). Management included laparoscopic (24, 7%), open (319, 87%), and laparoscopy converted to laparotomy (24, 6%). Higher AAST grade was associated with laparotomy ( P = .01). The median LOS was 13 days (8-22). At least 1 surgical complication occurred in 33% of patients and the mortality rate was 14%. Development of at least 1 surgical complication, need for unplanned intervention, mortality, and increased LOS were associated with increasing AAST severity grade. On multivariable analysis, factors predictive of in-hospital mortality included AAST organ grade, CCI, and preoperative vasopressor use (odds ratio (OR) 1.9, 1.6, 3.1, respectively). The American Association for the Surgery of Trauma emergency general surgery grade was also associated with the development of at least 1 surgical complication (OR 2.5), while CCI, preoperative vasopressor use, respiratory failure, and pneumoperitoneum were not. Conclusion The American Association for the Surgery of Trauma emergency general surgery grading systems display construct validity for mortality and surgical complications after urgent/emergent colorectal resection. These results support incorporation of AAST EGS grades for quality benchmarking and surgical outcomes research.

Abstract Background We evaluated the time to progression (TTP) and survival outcomes of second-line therapy for metastatic colorectal cancer among adults aged 70 years and older compared with younger adults following progression on first-line clinical trials. Methods Associations between clinical and disease characteristics, time to initial progression, and rate of receipt of second-line therapy were evaluated. TTP and overall survival (OS) were compared between older and younger adults in first- and second-line trials by Cox regression, adjusting for age, sex, Eastern Cooperative Oncology Group Performance Status, number of metastatic sites and presence of metastasis in the lung, liver, or peritoneum. All statistical tests were 2-sided. Results Older adults comprised 16.4% of patients on first-line trials (870 total older adults aged >70 years; 4419 total younger adults aged ≤70 years, on first-line trials). Older adults and those with Eastern Cooperative Oncology Group Performance Status >0 were less likely to receive second-line therapy than younger adults. Odds of receiving second-line therapy decreased by 11% for each additional decade of life in multivariable analysis (odds ratio = 1.11, 95% confidence interval = 1.02 to 1.21, P = .01). Older and younger adults enrolled in second-line trials experienced similar median TTP and median OS (median TTP = 5.1 vs 5.2 months, respectively; median OS = 11.6 vs 12.4 months, respectively). Conclusions Older adults were less likely to receive second-line therapy for metastatic colorectal cancer, though we did not observe a statistical difference in survival outcomes vs younger adults following second-line therapy. Further study should examine factors affecting decisions to treat older adults with second-line therapy. Inclusion of geriatric assessment may provide better criteria regarding the risks and benefits of second-line therapy.

AbstractBackgroundFrontotemporal lobar degeneration (FTLD) refers to a group of neurodegenerative conditions, affecting the frontal and/or temporal lobes. Ongoing research has provided insight into developing clinical trials for FTLD and key clinical measures such as structural MRI. To inform clinical trial design and optimize participation, it is imperative to explore facilitators and barriers for potential candidates.ObjectiveThe objective of this study is to explore facilitators and barriers to participating in future clinical trials for FTLD.MethodsAdvancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) are observational studies focused on characterizing FTLD syndromes in preparation for clinical trials. The 584 participants enrolled across 18 research sites in the United States and Canada completed a survey assessing interest in clinical trial participation.Results29% of respondents self‐reported as patients (63±10 years), 26% self‐reported as caregivers answering on behalf of patients (65±10 years), and 45% self‐reported as healthy but at risk for FTLD (48±14 years). Travel reimbursement was the most common factor reported to positively influence participation (≧66%), with the healthy but at risk group showing the strongest endorsement (83%). Cost and time involved in travel were possible barriers for about half of the patients (48%) and healthy but at risk respondents (53%). The respondents value receiving feedback on the study findings (≧80%) and being informed of their individual disease progression (≧75%). Particularly, keeping participation confidential was very important for the healthy but at risk group (62%). In regard to research assessments, most participants demonstrated a high interest in physical and neurological exams at a research center (≧87%) whereas only half were interested in doing more invasive procedures such as the lumbar puncture (≧52%). Overall, respondents showed a positive attitude and support for research participation (≧77%) and trusted that their health information would remain confidential in a clinical trial (≧53%).ConclusionsFavorable attitudes and interest towards medical research exist among participants. To optimize participation, clinical trials should allocate funding for travel and involve participants in feedback about study results and their disease progression. Alternatives to invasive assessments may increase participation.

Abstract Objective In the wake of the COVID-19 pandemic, psychologists were pushed to look beyond traditional in-person models of neurodevelopmental assessment to maintain continuity of care. A wealth of data demonstrates that telehealth is efficacious for pediatric behavioral intervention; however, best practices for incorporating telehealth into neurodevelopmental assessment are yet to be developed. In this topical review, we propose a conceptual model to demonstrate how telehealth can be incorporated into various components of neurodevelopmental assessment. Methods Harnessing existing literature and expertise from a multidisciplinary task force comprised of clinicians, researchers, and patient/parent representatives from the subspecialty of cardiac neurodevelopmental care, a conceptual framework for telehealth neurodevelopmental assessment was developed. Considerations for health equity and access to care are discussed, as well as general guidelines for clinical implementation and gaps in existing literature. Results There are opportunities to integrate telehealth within each stage of neurodevelopmental assessment, from intake to testing, through to follow-up care. Further research is needed to determine whether telehealth mitigates or exacerbates disparities in access to care for vulnerable populations as well as to provide evidence of validity for a wider range of neurodevelopmental measures to be administered via telehealth. Conclusions While many practices are returning to traditional, face-to-face neurodevelopmental assessment services, psychologists have a unique opportunity to harness the momentum for telehealth care initiated during the pandemic to optimize the use of clinical resources, broaden service delivery, and increase access to care for pediatric neurodevelopmental assessment.

AbstractBackgroundThere is sparse clinical information on the racial and ethnic distribution of results of multigene panel testing among individuals at high risk for hereditary cancer.MethodsWe evaluated the results of multigene panel testing across eight clinical sites across the state of Michigan for individuals seen for genetic counseling from May 13, 2013 to October 31, 2019 at the Karmanos Cancer Institute's cancer genetics clinic. We estimated the prevalence of pathogenic variants and variants of uncertain significance (VUS) from genes other than BRCA1/2 among individuals of non‐Hispanic White (NHW), Black or African American (AA), Ashkenazi Jewish (AJ), Arab, Hispanic, and other ancestry.ResultsThe racial and ethnic distribution of 2419 individuals who had panel testing included 68.8% NHW, 22.1% AA, 2.3% Arab, 2.2% AJ, 1.0% Hispanic, and 3.6% other. Of these, 11.2% had pathogenic variants and 17.5% had VUS. After multivariable analyses, compared to NHW, AA were less likely to have pathogenic variants (OR 95% CI, 0.38, 0.24–0.59, p < 0.001). Both AA and Arabs were more likely to have VUS (OR 95% CI, 1.53, 1.18–1.98, p = 0.001 and OR 95% CI, 2.28, 1.17–4.43, p = 0.015, respectively). There were no significant differences for other groups. The most common pathogenic variants were CHEK2 (n = 65), MUTYH (n = 45), ATM (n = 28), and MSH2 (n = 22); the most common pathogenic variants by race and ethnicity were CHEK2 (NHW), MSH2 and MUTYH (AA), MSH2 (Arab), MSH6 and CHEK2 (AJ), and MLH1 (Hispanic); the most common pathogenic variants by primary cancer site were CHEK2 (breast), MSH2 (colon), BRIP1 and MUTYH (ovarian), and MSH2 and MSH6 (endometrial).ConclusionsUnderstanding the racial and ethnic distribution of pathogenic variants in multi‐gene panels has the potential to lead to better identification of individuals at risk for hereditary cancer.

Cholangiocarcinoma (CCA) is a heterogenous group of malignancies originating in the biliary tree, and associated with poor prognosis. Until recently, treatment options have been limited to surgical resection, liver-directed therapies, and chemotherapy. Identification of actionable genomic alterations with biomarker testing has revolutionized the treatment paradigm for these patients. However, several challenges exist to the seamless adoption of precision medicine in patients with CCA, relating to a lack of awareness of the importance of biomarker testing, hurdles in tissue acquisition, and ineffective collaboration among the multidisciplinary team (MDT). To identify gaps in standard practices and define best practices, multidisciplinary hepatobiliary teams from the University of California (UC) Davis and UC Irvine were convened; discussions of the meeting, including optimal approaches to tissue acquisition for diagnosis and biomarker testing, communication among academic and community healthcare teams, and physician education regarding biomarker testing, are summarized in this review.

AbstractCastleman disease (CD) is a rare lymphoproliferative disease characterized by diverse clinical and pathologic features. Due to its rarity, there are limited studies comparing currently available therapies. The role of autologous stem cell transplantation (ASCT) in CD has not yet been established. In this paper, we describe the clinical characteristics, treatment choices, and outcomes in 34 Mayo Clinic patients diagnosed with multicentric CD from July 1, 2003 to April 30, 2018. Eighteen patients (53%) also met the criteria for POEMS, including 14 with the osteosclerotic variant. The first‐line treatments included: steroid monotherapy (4), cytotoxic chemotherapy (6), rituximab alone (8) or with chemotherapy (2), anti‐IL6 treatment (3), and ASCT (10). The median follow‐up was 4.8 (range: 0.1–15.2) years. The 5‐ and 10‐year overall survival rates were 84% and 71%, respectively. Sixteen patients received high‐dose chemotherapy followed by ASCT during their disease course. Among those, 14 had multicentric CD associated with POEMS. There were no transplant‐related deaths. All patients had at least a partial response to ASCT, most of whom achieved a complete response. The favorable outcomes seen with ASCT in this cohort suggest that transplantation may have a role in multicentric CD, particularly for patients with multicentric CD associated with POEMS.

Abstract Background: MASS-FIX is a screening method for serum and urine monoclonal proteins in multiple myeloma and related plasma cell disorders, which uses immunoglobulin enrichment coupled with matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MALDI-TOF). In addition to superior sensitivity over conventional gel-based techniques, MASS-FIX can distinguish therapeutic monoclonal antibodies (MoAb) from patient's M protein. As the utilization of therapeutic MoAbs increases, it is essential to understand the persistence pattern of these therapeutic antibodies in the serum. We designed this study to evaluate the duration of daratumumab detection by MASS-FIX in the serum of treated patients. Methods: We used a prospectively maintained database at Mayo clinic to identify patients with multiple myeloma and related plasma cell disorders who were treated with a daratumumab-containing regimen anytime during their disease course and had serial MASS-FIX data available after discontinuation of daratumumab. A univariate analysis was performed to assess for factors that may impact the clearance of daratumumab. Results: We included 125 patients with plasma cell disorders who received daratumumab as first or subsequent line of treatment between March 15 th, 2016, and March 4 th, 2020. The median age was 60.2 years and 57% were male. The most common diagnoses were multiple myeloma (70%) and light chain amyloidosis (18%). Daratumumab-based treatments were initiated after a median of 28.8 (IQR: 6.4-76.3) months from initial diagnosis. The most common regimen used was daratumumab, bortezomib and dexamethasone (23%); 26% underwent transplant after daratumumab-based induction. The median duration of treatment with a daratumumab-based regimen was 208 (IQR: 99-479) days. The median follow-up from the time of daratumumab discontinuation was 457 (95% CI: 346-NR) days. By last follow up, daratumumab was not detected by MASS-FIX in 93 (74%) patients but remained detectable in 32 (26%) patients. The median time from daratumumab discontinuation to disappearance of daratumumab by MASS-FIX was 160 (IQR: 107-233) days. On univariate analysis, the presence of ≥0.5 grams of urine protein was associated with earlier disappearance of daratumumab on MASS-FIX [risk ratio (RR): 2.0, P=0.02). The median time from daratumumab discontinuation to disappearance of daratumumab on MASS-FIX was 116 (95%CI: 76-160) days in patients with urine protein ≥0.5 grams and 203 (95%CI: 162-216) days in patients with urine protein &lt;0.5 grams (P=0.02). There was no association between the time to disappearance of daratumumab by MASS-FIX and old age ≥70 (RR: 0.9, P=0.81], male gender (RR: 0.9, P=0.60), eGFR &lt;60 (RR: 1.0, P=0.98), daratumumab schedule (every 1/2 weeks vs &gt;2weeks) (RR: 1.0, P=0.97), treatment duration (&lt;200 days vs ≥200 days) ( RR: 1.0, P=0.95), or transplantation status (RR: 1.0, P=0.98). Conclusion: The therapeutic monoclonal antibody daratumumab remains detectable in the serum of treated patients by MASS-FIX for several months after discontinuation and the duration varies between individual patients. This data has implications for diagnostic and monitoring testing and may provide guidance for reuse of daratumumab in clinical trials and practice. Proteinuria is associated with earlier disappearance of daratumumab by MASS-FIX and may have implications in patients with amyloidosis and monoclonal immunoglobulin deposition disease (MIDD). Further studies are needed to identify additional factors associated with the timing of disappearance. Disclosures Murray: Mayo Clinic: Other: Has received patents for the Mass-Fix technology which has been licensed to the Binding Site with potential royalties.. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; Aurora Biopharma: Other: Stock option; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Dingli: Alexion: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; GSK: Consultancy. Kumar: Antengene: Consultancy, Honoraria; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.