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Background: Light chain (AL) amyloidosis is a rare disease in which deposits of insoluble amyloid derived from immunoglobulin light chains accumulate and cause dysfunction of organs including the heart and kidneys. In order to reverse organ damage and improve overall survival, treatment must provide rapid, deep, and sustained hematologic responses. Although therapies approved for the treatment of multiple myeloma have demonstrated some efficacy, there are currently no health authority-approved treatments for AL amyloidosis. A retrospective observational study was undertaken to characterize patients and describe treatment patterns in patients with AL amyloidosis from real-world data in the US. Methods: Data were extracted from Optum Electronic Health Records (EHR) and Optum Clinformatics Data Mart (claims) databases. Eligible patients had (1) a diagnosis of AL amyloidosis (ICD-10 code E85.81) on or after January 1, 2008 or (2) a diagnosis of amyloidosis (ICD-9 codes 277.30, 277.39; ICD-10 codes E85.89, E85.9) on or after January 1, 2008 and at least one line of therapy (LOT) comprising one or more of the following treatments: bendamustine bortezomib, carfilzomib, cyclophosphamide, daratumumab, dexamethasone, doxorubicin, elotuzumab, etoposide, interferon alfa-2a, interferon alfa-2b, ixazomib, lenalidomide, melphalan, panobinostat, pomalidomide, prednisone/prednisolone, thalidomide, vincristine, or autologous stem cell transplant. Patients were required to have continuous medical enrollment during the 365 days prior to the index amyloidosis diagnosis date (claims data) or have first active date at least 365 days prior to index amyloidosis date (EHR data), must not have had prior cancer in the 365-day period prior to the index amyloidosis diagnosis date, and must have been age ≥18 years at time of amyloidosis diagnosis. Patients treated with dexamethasone only or dexamethasone and prednisolone only for ≤90 days and those treated with prednisone/prednisolone only irrespective of duration were excluded. LOTs were defined by a start date, an end date, and a distinct regimen made up of ≥1 drugs. Patients may have multiple sequential LOTs during the available follow-up period. Comorbidities were scored according to the Charlson Comorbidity Index (CCI). A score of 0 reflects no comorbidities; higher scores reflect increased mortality risk and the maximum score is 24. Descriptive statistics are provided for patient characteristics at index diagnosis date for patients who had ≥1 LOT, distribution of regimens in each LOT, treatment attrition, and duration of treatment in each line of therapy and by regimen. Results: Data from 1688 patients (Optum claims, n=624; Optum EHR, n=1064) were included in the analysis (Figure). Median age at diagnosis was 67 years and 55.7% of patients were male. Almost 70% of patients had an index diagnosis date between 2013 and 2019. The median CCI score at index diagnosis date (based on comorbidities in the 365-day pre-index diagnosis period) was 1 and 10.9% of patients had a stem cell transplant on or after the index diagnosis date. The three most common comorbidities were hypertension (50.8%), renal failure (26.2%), and congestive heart failure (24.6%). Median follow-up period was 28 months. Treatment information for regimens used by ≥5% of patients for LOT1 is summarized in the Table. The most common treatment regimen for LOT1 was a proteasome inhibitor (PI), an alkylating agent, and a steroid (n=392, 23.2%); this combination was used for an average of 111 days. Of patients treated with this combination, the most common regimen was bortezomib, cyclophosphamide, and dexamethasone (VCd), used by 358 patients. Steroid only (dexamethasone for ≥90 days) regimens accounted for 16.4% and a PI ± steroid for 13.2% of LOT1. A limitation of the study is that assumptions were used to classify AL amyloidosis vs other types of amyloidosis. Conclusions: VCd is the most commonly used regimen in patients with newly-diagnosed AL amyloidosis. This is consistent with clinical guidelines and real world data from Europe (Palladini et al, EHA 2020), supporting this regimen as the current standard of care for treatment of patients with newly-diagnosed AL amyloidosis. Disclosures Dispenzieri: Celgene: Research Funding; Pfizer: Research Funding; Alnylam: Research Funding; Intellia: Research Funding; Janssen: Research Funding; Takeda: Research Funding. Zonder:Intellia, Amgen, Takeda, Janssen, Regeneron, Alnylam, Caelum, Oncopeptides: Consultancy; BMS, Celgene: Research Funding. Hoffman:Loxo: Current equity holder in publicly-traded company; Celgene: Honoraria, Speakers Bureau. Wong:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Fortis: Research Funding; Roche: Research Funding; GSK: Research Funding; Amgen: Consultancy; Bristol Myers Squibb: Research Funding. Liedtke:Adaptive: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Abonour:BMS: Consultancy, Research Funding; Takeda: Consultancy; Janssen: Honoraria, Research Funding; Celgene: Consultancy. D'Souza:Amgen, Merck, TenoBio: Research Funding; Akcea, Imbrium, Janssen, Pfizer: Consultancy. Lee:Janssen: Current Employment. Nair:Janssen: Current Employment. Potluri:SmartAnalyst Inc.: Current Employment. Weiss:Janssen: Current Employment, Current equity holder in publicly-traded company. Vermeulen:Janssen: Current Employment, Current equity holder in publicly-traded company. Lam:Janssen: Current Employment. Mehra:Janssen: Current Employment.

Germ line mutations in H3F3A and H3F3B cause a previously unidentified neurodevelopmental syndrome.

Abstract High intensity interval training (HIIT) improves cardiorespiratory fitness (VO2max), but its impact on metabolism remains unclear. We hypothesized that 12-week HIIT improves insulin sensitivity in people with or without type 2 diabetes (T2D, NDM). However, despite identically improved VO2max, mainly insulin-resistant persons (T2D, IR NDM) responded with improved insulin sensitivity and circulating small extracellular vesicles (SEV), along with reduced myocellular protein kinase Cε activity (T2D) or inflammation (IR NDM). These changes related to the SEV proteome, characterized by downregulated phospholipase C pathway (T2D) and upregulated antioxidant capacity (IR NDM). Thus, SEV cargo likely contributes to modulating exercise responsiveness in humans.

Gastrointestinal bleeding (GIB) especially from arteriovenous malformations (AVM) remains one of the devastating complications following continuous-flow left ventricular device (CF-LVAD) implantation. Blockade of angiotensin II pathway using angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) was reported to mitigate the risk of GIB and AVM-related GIB by suppressing angiogenesis. We performed a systematic review and meta-analysis to evaluate the association between ACEI/ARB treatment and GIB in CF-LVAD population. Comprehensive literature search was performed through December 2019. We included studies reporting risk of GIB and/or AVM-related GIB events in LVAD patients who received ACEI/ARB with those who did not. Data from each study were combined using the random-effects to calculate odd ratios and 95% confidence intervals. Three retrospective cohort studies were included in this meta-analysis involving 619 LVADs patients (467 patients receiving ACEI/ARB). The use of ACEI/ARB was statistically associated with decreased incidence of overall GIB (pooled OR 0.35, 95% CI 0.22–0.56, I 2 = 0.0%, p < 0.001). There was a non-significant trend toward lower risk for AVM-related GIB in patients who received ACEI/ARB (pooled OR 0.46, 95% CI 0.19–1.07, I 2 = 51%, p = 0.07). Larger studies with specific definitions of ACEI/ARB use and GIB are warranted to accurately determine the potential non-hemodynamic benefits of ACEI/ARB in CF-LVAD patients.

AbstractBackgroundMedulloblastoma (MB) is a rare brain tumor occurring more frequently in children in whom research has been primarily focused. Treatment recommendations in adults are mainly based on retrospective data and pediatric experience; however, molecular features and treatment tolerance differ between the 2 age groups. In adults, prognostic tools are suboptimal, late recurrences are typical, and long-term sequelae remain understudied. Treatment has not adapted to molecular classification advances; thus, the survival rate of adult MB has not improved.MethodsIn 2017, the National Cancer Institute (NCI) received support from the Cancer Moonshot℠ to address the challenges and unmet needs of adults with rare central nervous system tumors through NCI-CONNECT, a program that creates partnerships among patients, health care professionals, researchers, and advocacy organizations. On November 25, 2019, NCI-CONNECT convened leading clinicians and scientists in a workshop to review advances in research, share scientific insights, and discuss clinical challenges in adult MB.ResultsWorking groups identified unmet needs in clinical trial design, tissue acquisition and testing, tumor modeling, and measurement of clinical outcomes.ConclusionsParticipants identified opportunities for collaboration; discussed plans to create a working group of clinicians, researchers, and patient advocates; and developed specific action items to expedite progress in adult MB.

Bladder carcinoma (BC) incidence and mortality rates are increasing worldwide. The development of novel therapeutic strategies is required to improve clinical management of this cancer. Aberrant protein expression may lead to cancer initiation and progression. Therefore, the identification of these potential protein targets and limiting their expression levels would provide alternative treatment options. In this study, we utilized a liquid-chromatography tandem mass spectrometry-based global proteomics approach to identify differentially expressed proteins in bladder cancer cell lines. A total of 3913 proteins were identified in this study, of which 479 proteins were overexpressed and 141 proteins were downregulated in 4 out of 6 BC cell lines when compared with normal human urothelial cell line (TERT-NHUC). We evaluated the role of UDP-N-acetylhexosamine pyrophosphorylase (UAP1) in bladder cancer pathogenesis. The silencing of UAP1 led to reduction in proliferation, invasion, colony formation and migration capability of bladder cancer cell lines. Thus, our study reveals UAP1 as a promising therapeutic target for bladder cancer.