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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 25 Oct 2021 at 01:43 Created: 

Publications by FHCRC Researchers

The Fred Hutchinson Cancer Research Center began in 1975, with critical help from Washington State's U.S. Senator Warren Magnuson. Fred Hutch quickly became the permanent home to Dr. E. Donnall Thomas, who had spent decades developing an innovative treatment for leukemia and other blood cancers. Thomas and his colleagues were working to cure cancer by transplanting human bone marrow after otherwise lethal doses of chemotherapy and radiation. At the Hutch, Thomas improved this treatment and readied it for widespread use. Since then, the pioneering procedure has saved hundreds of thousands of lives worldwide. While improving bone marrow transplantation remains central to Fred Hutch's research, it is now only part of its efforts. The Hutch is home to five scientific divisions, three Nobel laureates and more than 2,700 faculty, who collectively have published more than 10,000 scientific papers, presented here as a full bibliography.

NOTE: From 1995 to 2009 I served as the Hutch's vice president for information technology — hence my interest in the organization. Although my role was in the admin division, if you dig through this bibliography, you will find a couple of papers with me as an author.

Created with PubMed® Query: "Fred Hutchinson Cancer Research"[AFFL] or FHCRC[AFFL] or "Fred Hutch"[AFFL] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

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RevDate: 2021-10-22

Johnson AM, Baker KS, Haviland MJ, et al (2021)

A Pilot Randomized Controlled Trial of a Fitbit- and Facebook-Based Physical Activity Intervention for Young Adult Cancer Survivors.

Journal of adolescent and young adult oncology [Epub ahead of print].

Purpose: Most young adult cancer survivors (YACS) do not meet physical activity (PA) guidelines. Although PA can improve health and quality of life (QOL), few randomized controlled trials (RCTs) of PA interventions for YACS exist. We conducted a pilot RCT to test feasibility of a PA intervention among YACS. Methods: We recruited 18-39-year-olds (≥1 and <5 years postcancer therapy) from Seattle Cancer Care Alliance. The 12-week intervention involved a wrist-worn PA-tracking device (Fitbit), a peer-based Facebook support group, step count goal setting, and a self-selected support "buddy." Controls received Fitbit only. Baseline assessments occurred before randomization; follow-up assessments occurred during intervention weeks 10-12. Feasibility criteria are listed below. Exploratory outcomes included PA, sedentary time (ST), QOL measures (e.g., fatigue), and self-determination theory (SDT) construct measures. Results: All feasibility criteria were met: We recruited 50 YACS, intervention participants wore the Fitbit on the majority of intervention days (82.9%), ≥75% of participants completed questionnaires at baseline (100%) and follow-up (93.9%). Exploratory analyses, adjusted for wave, accelerometer wear time, race, and income, showed significant group differences for change in ST (-52.4 vs. 2.5 minutes/day; p = 0.002) but no change in moderate-to-vigorous intensity PA (0.0 vs. -0.2 minutes/day; p = 0.40), comparing intervention participants to controls. The intervention (vs. control) group had a greater increase in fatigue interference (p = 0.03). No other significant differences in SDT or QOL measures were found. Conclusion: This Fitbit and Facebook-based PA intervention was feasible to YACS, with promising effects on reducing ST, and warrants a fully powered RCT. Clinical Trial Registration no.: NCT03233581.

RevDate: 2021-10-22

Giannakis M, U Peters (2021)

Esophageal cancer mutational signatures around the world.

Nature genetics [Epub ahead of print].

RevDate: 2021-10-21

Hamadani M, Gopal AK, Pasquini MC, et al (2021)

Allogeneic Transplant and CAR-T Therapy After Autologous Transplant Failure in DLBCL: A Noncomparative Cohort Analysis.

Blood advances pii:477424 [Epub ahead of print].

Allogeneic transplant (alloHCT) and chimeric antigen receptor modified (CAR) T-cell therapy are potentially cuarative options of diffuse large B-cell lymphoma (DLBCL) relapsing after an autologous (auto) HCT. While the Center for International Blood and Marrow Transplant Research (CIBMTR) prognostic model can predict outcomes of alloHCT in DLBCL after autoHCT failure, corresponding models of CAR-T treatment in similar patient populations are not available. In this noncomparative registry analysis we report outcomes of DLBCL patients (≥18 years), undergoing a reduced intensity alloHCT or CAR-T therapy during 2012-2019, after a prior auto-HCT failure, and apply CIBMTR prognostic model to CAR-T recipients. 584 patients were included. The 1-year relapse, non-relapse mortality, overall survival (OS) and progression-free survival (PFS) for CAR-T treatment after autoHCT failure were were 39.5%, 4.8%, 73.4% and 55.7%, respectively. The corresponding rates in alloHCT cohort were 26.2%, 20.0%, 65.6% and 53.8%, respectively. The 1-year OS of alloHCT recipients classified as low-, intermediate- and high/very high-risk groups according to the CIBMTR prognostic score was 73.3%, 59.9%, and 46.3, respectively (p=0.002). The corresponding rates for low-, intermediate- and high/very high-risk CAR-T patients were 88.4%, 76.4%, and 52.8%, respectively (p<0.001). This registry analysis shows that both CAR-T and alloHCT can provide durable remissions in subset of DLBCL patients relapsing after a prior autoHCT. The simple, CIBMTR prognostic score can be used to identify patients at high risk of treatment failure after either procedure. Evaluation of novel relapse mitigations strategies after cellular immunotherapies are warranted in these high risk patients.

RevDate: 2021-10-21

Yadav S, Hu C, Nathanson KL, et al (2021)

Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast.

MATERIALS AND METHODS: The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC).

RESULTS: The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC.

CONCLUSION: The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

RevDate: 2021-10-21

Boehmer U, Ozonoff A, Winter M, et al (2021)

Anxiety and Depression in Colorectal Cancer Survivors: Are there differences by sexual orientation?.

Psycho-oncology [Epub ahead of print].

OBJECTIVE: To examine sexual minority compared to heterosexual survivors' health-related anxiety, anxiety, and depression.

METHODS: Four-hundred-eighty eligible survivors participated in a telephone survey, which measured their anxiety and depression. These survivors were diagnosed with stage I, II, or III colorectal cancer an average of three years prior to the survey and were recruited from four cancer registries. As explanatory factors, we considered individual, social and contextual characteristics, prior psychological factors, psychological responses to cancer, and characteristics of cancer and its treatments. Using forward selection with generalized linear models or logistic regression models, we identified significant correlates for each outcome.

RESULTS: Prior to adjusting for covariates, depression was similar for all survivors, while sexual minority survivors had worse health-related anxiety and anxiety compared to heterosexual survivors. After adjustment, these differences were no longer statistically significant. Individual, social and contextual characteristics, characteristics of cancer, and psychological responses to cancer explained 44% of the variance in anxiety and 60% of the variance in depression.

CONCLUSION: There are modifiable factors associated with health-related and generalized anxiety as well as depression that can be changed to improve cancer survivorship among diverse survivors. This article is protected by copyright. All rights reserved.

RevDate: 2021-10-21

Streiff MB, Holmstrom B, Angelini D, et al (2021)

Cancer-Associated Venous Thromboembolic Disease, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Journal of the National Comprehensive Cancer Network : JNCCN, 19(10):1181-1201 pii:jnccngls1910.

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cancer-Associated Venous Thromboembolic Disease focus on the prevention, diagnosis, and treatment of patients with cancer who have developed or who are at risk for developing venous thromboembolism (VTE). VTE is a significant concern among cancer patients, who are at heightened risks for developing as well as dying from the disease. The management of patients with cancer with VTE often requires multidisciplinary efforts at treating institutions. The NCCN panel comprises specialists from various fields: cardiology, hematology/hematologic oncology, internal medicine, interventional radiology, medical oncology, pharmacology/pharmacy, and surgery/surgical oncology. This article focuses on VTE prophylaxis for medical and surgical oncology inpatients and outpatients, and discusses risk factors for VTE development, risk assessment tools, as well as management methods, including pharmacological and mechanical prophylactics. Contraindications to therapeutic interventions and special dosing, when required, are also discussed.

RevDate: 2021-10-21

Weiss JM, Gupta S, Burke CA, et al (2021)

NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 1.2021.

Journal of the National Comprehensive Cancer Network : JNCCN, 19(10):1122-1132 pii:jnccnglins1910.

Identifying individuals with hereditary syndromes allows for timely cancer surveillance, opportunities for risk reduction, and syndrome-specific management. Establishing criteria for hereditary cancer risk assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provides recommendations for the assessment and management of patients at risk for or diagnosed with high-risk colorectal cancer syndromes. The NCCN Genetic/Familial High-Risk Assessment: Colorectal panel meets annually to evaluate and update their recommendations based on their clinical expertise and new scientific data. These NCCN Guidelines Insights focus on familial adenomatous polyposis (FAP)/attenuated familial adenomatous polyposis (AFAP) syndrome and considerations for management of duodenal neoplasia.

RevDate: 2021-10-01

Nutt WS, S Srivastava (2021)

Special delivery! CAR-T cells transport RN7SL1 to the tumor microenvironment.

Trends in molecular medicine pii:S1471-4914(21)00250-1 [Epub ahead of print].

In a recent Cell publication, Johnson et al. demonstrate that engineering chimeric antigen receptor (CAR)-T cells to produce RN7SL1, a novel RNA adjuvant that activates the viral sensors RIG-I and MDA5, improves intrinsic CAR-T cell function, activates tumor-infiltrating myeloid cells, and enhances endogenous tumor-specific T cell responses, resulting in improved tumor control despite CAR antigen loss in multiple mouse models.

RevDate: 2021-10-23

Brem EA, Li H, Beaven AW, et al (2021)

SWOG 1918: A phase II/III randomized study of R-miniCHOP with or without oral azacitidine (CC-486) in participants age 75 years or older with newly diagnosed aggressive non-Hodgkin lymphomas - Aiming to improve therapy, outcomes, and validate a prospective frailty tool.

Journal of geriatric oncology pii:S1879-4068(21)00235-6 [Epub ahead of print].

Diffuse large B cell lymphoma (DLBCL) is an aggressive but potentially curable malignancy; however, cure is highly dependent on the ability to deliver intensive, anthracycline-based chemoimmunotherapy. Nearly one third of cases of DLBCL occur in patients over age 75 years, and advanced age is an important adverse feature in prognostic models. Despite this incidence in older patients, there is no clear accepted standard of care due to under-representation of this group in large randomized clinical trials. Furthermore, insufficient assessments of baseline frailty and prediction of toxicity hamper clinical decision-making. Here, we present an ongoing randomized study of R-miniCHOP chemoimmunotherapy with or without oral azacitidine (CC-486, Onureg) for patients age 75 and older with newly diagnosed DLBCL and associated aggressive lymphomas. The incorporation of an oral hypomethylating agent is based on increased tumor methylation as a biologic feature of older patients with DLBCL and a desire to minimize the injection burden for this population. This is the first randomized study in this population conducted in North America by the National Clinical Trials Network (NCTN) and will enroll up to 422 patients including 40 patients in a safety run-in phase. This study incorporates an objective assessment of baseline frailty (the FIL Tool) and a serial comprehensive geriatric assessment (CGA). Key correlative tests will include circulating tumor DNA (ctDNA) assays at pre-specified timepoints to explore if ctDNA quantity and methylation patterns correlate with response. S1918 has the potential to impact future trial design and to change the standard of care for patients 75 years and older with aggressive lymphoma given its randomized design, prospective incorporation of geriatric assessments, and exploration of ctDNA correlatives. Trial registration: The trial is registered with ClinicalTrial.gov Identifier NCT04799275.

RevDate: 2021-10-23

Jobava R, Mao Y, Guan BJ, et al (2021)

Adaptive translational pausing is a hallmark of the cellular response to severe environmental stress.

Molecular cell, 81(20):4191-4208.e8.

To survive, mammalian cells must adapt to environmental challenges. While the cellular response to mild stress has been widely studied, how cells respond to severe stress remains unclear. We show here that under severe hyperosmotic stress, cells enter a transient hibernation-like state in anticipation of recovery. We demonstrate this adaptive pausing response (APR) is a coordinated cellular response that limits ATP supply and consumption through mitochondrial fragmentation and widespread pausing of mRNA translation. This pausing is accomplished by ribosome stalling at translation initiation codons, which keeps mRNAs poised to resume translation upon recovery. We further show that recovery from severe stress involves ISR (integrated stress response) signaling that permits cell cycle progression, resumption of growth, and reversal of mitochondria fragmentation. Our findings indicate that cells can respond to severe stress via a hibernation-like mechanism that preserves vital elements of cellular function under harsh environmental conditions.

RevDate: 2021-10-23

Connerty P, Moles E, de Bock CE, et al (2021)

Development of siRNA-Loaded Lipid Nanoparticles Targeting Long Non-Coding RNA LINC01257 as a Novel and Safe Therapeutic Approach for t(8;21) Pediatric Acute Myeloid Leukemia.

Pharmaceutics, 13(10): pii:pharmaceutics13101681.

Standard of care therapies for children with acute myeloid leukemia (AML) cause potent off-target toxicity to healthy cells, highlighting the need to develop new therapeutic approaches that are safe and specific for leukemia cells. Long non-coding RNAs (lncRNAs) are an emerging and highly attractive therapeutic target in the treatment of cancer due to their oncogenic functions and selective expression in cancer cells. However, lncRNAs have historically been considered 'undruggable' targets because they do not encode for a protein product. Here, we describe the development of a new siRNA-loaded lipid nanoparticle for the therapeutic silencing of the novel oncogenic lncRNA LINC01257. Transcriptomic analysis of children with AML identified LINC01257 as specifically expressed in t(8;21) AML and absent in healthy patients. Using NxGen microfluidic technology, we efficiently and reproducibly packaged anti-LINC01257 siRNA (LNP-si-LINC01257) into lipid nanoparticles based on the FDA-approved Patisiran (Onpattro®) formulation. LNP-si-LINC01257 size and ζ-potential were determined by dynamic light scattering using a Malvern Zetasizer Ultra. LNP-si-LINC01257 internalization and siRNA delivery were verified by fluorescence microscopy and flow cytometry analysis. lncRNA knockdown was determined by RT-qPCR and cell viability was characterized by flow cytometry-based apoptosis assay. LNP-siRNA production yielded a mean LNP size of ~65 nm with PDI ≤ 0.22 along with a >85% siRNA encapsulation rate. LNP-siRNAs were efficiently taken up by Kasumi-1 cells (>95% of cells) and LNP-si-LINC01257 treatment was able to successfully ablate LINC01257 expression which was accompanied by a significant 55% reduction in total cell count following 48 h of treatment. In contrast, healthy peripheral blood mononuclear cells (PBMCs), which do not express LINC01257, were unaffected by LNP-si-LINC01257 treatment despite comparable levels of LNP-siRNA uptake. This is the first report demonstrating the use of LNP-assisted RNA interference modalities for the silencing of cancer-driving lncRNAs as a therapeutically viable and non-toxic approach in the management of AML.

RevDate: 2021-10-23

Esfandiari Nazzaro E, Sabei FY, Vogel WK, et al (2021)

Discovery and Validation of a Compound to Target Ewing's Sarcoma.

Pharmaceutics, 13(10): pii:pharmaceutics13101553.

Ewing's sarcoma, characterized by pathognomonic t (11; 22) (q24; q12) and related chromosomal ETS family translocations, is a rare aggressive cancer of bone and soft tissue. Current protocols that include cytotoxic chemotherapeutic agents effectively treat localized disease; however, these aggressive therapies may result in treatment-related morbidities including second-site cancers in survivors. Moreover, the five-year survival rate in patients with relapsed, recurrent, or metastatic disease is less than 30%, despite intensive therapy with these cytotoxic agents. By using high-throughput phenotypic screening of small molecule libraries, we identified a previously uncharacterized compound (ML111) that inhibited in vitro proliferation of six established Ewing's sarcoma cell lines with nanomolar potency. Proteomic studies show that ML111 treatment induced prometaphase arrest followed by rapid caspase-dependent apoptotic cell death in Ewing's sarcoma cell lines. ML111, delivered via methoxypoly(ethylene glycol)-polycaprolactone copolymer nanoparticles, induced dose-dependent inhibition of Ewing's sarcoma tumor growth in a murine xenograft model and invoked prometaphase arrest in vivo, consistent with in vitro data. These results suggest that ML111 represents a promising new drug lead for further preclinical studies and is a potential clinical development for the treatment of Ewing's sarcoma.

RevDate: 2021-10-23

Hanna DB, Hua S, Gonzalez F, et al (2021)

Higher Neighborhood Population Density Is Associated with Lower Potassium Intake in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

International journal of environmental research and public health, 18(20): pii:ijerph182010716.

Current U.S. dietary guidelines recommend a daily potassium intake of 3400 mg/day for men and 2600 mg/day for women. Sub-optimal access to nutrient-rich foods may limit potassium intake and increase cardiometabolic risk. We examined the association of neighborhood characteristics related to food availability with potassium intake in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). 13,835 participants completed a 24-h dietary recall assessment and had complete covariates. Self-reported potassium intake was calibrated with an objective 24-h urinary potassium biomarker, using equations developed in the SOL Nutrition & Physical Activity Assessment Study (SOLNAS, N = 440). Neighborhood population density, median household income, Hispanic/Latino diversity, and a retail food environment index by census tract were obtained. Linear regression assessed associations with 24-h potassium intake, adjusting for individual-level and neighborhood confounders. Mean 24-h potassium was 2629 mg/day based on the SOLNAS biomarker and 2702 mg/day using multiple imputation and HCHS/SOL biomarker calibration. Compared with the lowest quartile of neighborhood population density, living in the highest quartile was associated with a 26% lower potassium intake in SOLNAS (adjusted fold-change 0.74, 95% CI 0.59-0.94) and a 39% lower intake in HCHS/SOL (adjusted fold-change 0.61 95% CI 0.45-0.84). Results were only partially explained by the retail food environment. The mechanisms by which population density affects potassium intake should be further studied.

RevDate: 2021-10-23

Cargill M, Venkataraman R, S Lee (2021)

DEAD-Box RNA Helicases and Genome Stability.

Genes, 12(10): pii:genes12101471.

DEAD-box RNA helicases are important regulators of RNA metabolism and have been implicated in the development of cancer. Interestingly, these helicases constitute a major recurring family of RNA-binding proteins important for protecting the genome. Current studies have provided insight into the connection between genomic stability and several DEAD-box RNA helicase family proteins including DDX1, DDX3X, DDX5, DDX19, DDX21, DDX39B, and DDX41. For each helicase, we have reviewed evidence supporting their role in protecting the genome and their suggested mechanisms. Such helicases regulate the expression of factors promoting genomic stability, prevent DNA damage, and can participate directly in the response and repair of DNA damage. Finally, we summarized the pathological and therapeutic relationship between DEAD-box RNA helicases and cancer with respect to their novel role in genome stability.

RevDate: 2021-10-23

Whiteaker JR, Sharma K, Hoffman MA, et al (2021)

Targeted mass spectrometry-based assays enable multiplex quantification of receptor tyrosine kinase, MAP Kinase, and AKT signaling.

Cell reports methods, 1(3):.

Summary: A primary goal of the US National Cancer Institute's Ras initiative at the Frederick National Laboratory for Cancer Research is to develop methods to quantify RAS signaling to facilitate development of novel cancer therapeutics. We use targeted proteomics technologies to develop a community resource consisting of 256 validated multiple reaction monitoring (MRM)-based, multiplexed assays for quantifying protein expression and phosphorylation through the receptor tyrosine kinase, MAPK, and AKT signaling networks. As proof of concept, we quantify the response of melanoma (A375 and SK-MEL-2) and colorectal cancer (HCT-116 and HT-29) cell lines to BRAF inhibition by PLX-4720. These assays replace over 60 Western blots with quantitative mass spectrometry-based assays of high molecular specificity and quantitative precision, showing the value of these methods for pharmacodynamic measurements and mechanism of action studies. Methods, fit-for-purpose validation, and results are publicly available as a resource for the community at assays.cancer.gov.

Motivation: A lack of quantitative, multiplexable assays for phosphosignaling limits comprehensive investigation of aberrant signaling in cancer and evaluation of novel treatments. To alleviate this limitation, we sought to develop assays using targeted mass spectrometry for quantifying protein expression and phosphorylation through the receptor tyrosine kinase, MAPK, and AKT signaling networks. The resulting assays provide a resource for replacing over 60 Western blots in examining cancer signaling and tumor biology with high molecular specificity and quantitative rigor.

RevDate: 2021-10-23

Hudson MF, Strassels SA, Durham DD, et al (2021)

Examining pain among non-Hispanic Black and non-Hispanic White patients with cancer visiting emergency departments: CONCERN (Comprehensive Oncologic Emergencies Research Network).

RevDate: 2021-10-20

Dávila Saldaña BJ, John TD, Bonifant CL, et al (2021)

High risk of relapsed disease in patients with NK/T cell chronic active Epstein-Barr virus disease outside of Asia.

Blood advances pii:477394 [Epub ahead of print].

Chronic active Epstein-Barr virus (EBV) disease (CAEBV) is characterized by high levels of EBV predominantly in T and/or NK cells with lymphoproliferation, organ failure due to infiltration of tissues with virus-infected cells, hemophagocytic lymphohistiocytosis (HLH) and/or lymphoma. The disease is more common in Asia than in the United States and Europe. While allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only curative therapy for CAEBV, its efficacy and the best treatment modality to reduce disease severity prior to HSCT is unknown. Here, we retrospectively assessed an international cohort of 57 patients outside of Asia. Treatment for the disease varied widely, although most patients ultimately proceeded to HSCT. Though patients undergoing HSCT had better survival than those who did not (55% v 25%, p<0.01), there was still a high rate of death in both groups. Mortality was largely not affected by age, ethnicity, cell type involvement, or disease complications, but development of lymphoma showed a trend with increased mortality (56% v 35%, p=0.1). The overwhelming majority (75%) of patients who died after HSCT succumbed to relapsed disease. CAEBV remains challenging to treat when advanced disease is present. Outcomes would likely improve with better disease control strategies, earlier referral for HSCT, and close follow-up after HSCT including aggressive management of rising EBV DNA levels in the blood.

RevDate: 2021-10-20

Carroll PA, Freie BW, Cheng PF, et al (2021)

The glucose-sensing transcription factor MLX balances metabolism and stress to suppress apoptosis and maintain spermatogenesis.

PLoS biology, 19(10):e3001085 pii:PBIOLOGY-D-20-03723.

Male germ cell (GC) production is a metabolically driven and apoptosis-prone process. Here, we show that the glucose-sensing transcription factor (TF) MAX-Like protein X (MLX) and its binding partner MondoA are both required for male fertility in the mouse, as well as survival of human tumor cells derived from the male germ line. Loss of Mlx results in altered metabolism as well as activation of multiple stress pathways and GC apoptosis in the testes. This is concomitant with dysregulation of the expression of male-specific GC transcripts and proteins. Our genomic and functional analyses identify loci directly bound by MLX involved in these processes, including metabolic targets, obligate components of male-specific GC development, and apoptotic effectors. These in vivo and in vitro studies implicate MLX and other members of the proximal MYC network, such as MNT, in regulation of metabolism and differentiation, as well as in suppression of intrinsic and extrinsic death signaling pathways in both spermatogenesis and male germ cell tumors (MGCTs).

RevDate: 2021-10-20

Sokolova A, H Cheng (2021)

Germline Testing in Prostate Cancer: When and Who to Test.

Oncology (Williston Park, N.Y.), 35(10):645-653.

The results of multiple studies have shown that a substantial proportion of men with advanced prostate cancer carry germline DNA repair mutations. Germline testing in prostate cancer may inform treatment decisions and consideration for clinical trials. There are 2 FDA approved PARP inhibitors (PARPi), olaparib (Lynparza) and rucaparib (Rubraca), for the treatment of advanced prostate cancer with DNA repair deficiency. Increasing demand for germline testing in prostate cancer and a shortage of genetic counselors have created a need for alternative care models and encouraged oncologists to take a more active role in performing germline testing. This article summarizes recommendations for germline testing in prostate cancer and describes care models for providing counseling and testing.

RevDate: 2021-10-20

Itell HL, Weight H, Fish CS, et al (2021)

SARS-CoV-2 Antibody Binding and Neutralization in Dried Blood Spot Eluates and Paired Plasma.

Microbiology spectrum [Epub ahead of print].

Wide-scale assessment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibodies is critical to understanding population seroprevalence, correlates of protection, and the longevity of vaccine-elicited responses. Most SARS-CoV-2 studies characterize antibody responses in plasma/sera. While reliable and broadly used, these samples pose several logistical restrictions, such as requiring venipuncture for collection and a cold chain for transportation and storage. Dried blood spots (DBS) overcome these barriers as they can be self-collected by fingerstick and mailed and stored at ambient temperature. Here, we evaluate the suitability of DBS for SARS-CoV-2 antibody assays by comparing several antibody responses between paired plasma and DBS from SARS-CoV-2 convalescent and vaccinated individuals. We found that DBS not only reflected plasma antibody binding by enzyme-linked immunosorbent assay (ELISA) and epitope profiles using phage display, but also yielded SARS-CoV-2 neutralization titers that highly correlated with paired plasma. Neutralization measurement was further streamlined by adapting assays to a high-throughput 384-well format. This study supports the adoption of DBS for numerous SARS-CoV-2 binding and neutralization assays. IMPORTANCE Plasma and sera isolated from venous blood represent conventional sample types used for the evaluation of SARS-CoV-2 antibody responses after infection or vaccination. However, collection of these samples is invasive and requires trained personnel and equipment for immediate processing. Once collected, plasma and sera must be stored and shipped at cold temperatures. To define the risk of emerging SARS-CoV-2 variants and the longevity of immune responses to natural infection and vaccination, it will be necessary to measure various antibody features in populations around the world, including in resource-limited areas. A sampling method that is compatible with these settings and is suitable for a variety of SARS-CoV-2 antibody assays is therefore needed to continue to understand and curb the COVID-19 pandemic.

RevDate: 2021-10-20

Cai LM, Hippe DS, Zamora DA, et al (2021)

A Method for Reducing Variability Across Dual-Energy CT Manufacturers in Quantification of Low Iodine Content Levels.

AJR. American journal of roentgenology [Epub ahead of print].

Background: Clinical use of the dual-energy CT (DECT) iodine quantification technique is hindered by between-platform (i.e., across different manufacturers) variability in iodine concentration (IC), particularly at low iodine levels. Objective: To develop in an anthropomorphic phantom a method for reducing between-platform variability in quantification of low iodine content levels using DECT and to evaluate the method's performance in patients undergoing serial clinical DECT examinations on different platforms. Methods: An anthropomorphic phantom in three body sizes, incorporating varied lesion types and scanning conditions, was imaged with three distinct DECT implementations from different manufacturers at varying radiation exposures. A cross-platform iodine quantification model for correcting between-platform variability at low iodine content was developed using the phantom data. The model was tested in a retrospective series of 30 patients (20 men, 10 women; median age, 62 years) who each underwent three serial contrast-enhanced DECT examinations of the abdomen and pelvis (90 scans total) for routine oncology surveillance, using the same three DECT platforms as in the phantom. Estimated accuracy of phantom IC values was summarized using rootmean-squared error (RMSE) relative to known IC. Between-platform variability in patients was summarized using root-mean-square-deviation (RMSD). RMSE and RMSD were compared between platform-based IC (ICPB) and cross-platform IC (ICCP). ICPB was normalized to aorta and portal vein. Results: In the phantom study, mean RMSE of ICPB across platforms and other experimental conditions was 0.65 ± 0.18 mgI/mL compared with 0.40 ± 0.075 mgI/mL for ICCP (38% decrease in mean RMSE; P<.05). Intra-patient between-platform variability across serial DECT examinations was lower for ICPB than ICCP (RMSD: 97% vs 88%; P<.001). Between-platform variability was not reduced by normalization of ICPB to aorta (RMSD: 97% vs 101%; P=.12) or portal vein (RMSD: 97% vs 97%; P=.81). Conclusion: The developed cross-platform method significantly decreased between-platform variability occurring at low iodine content with platform-based DECT iodine quantification. Clinical Impact: With further validation, the cross-platform method, which has been implemented as a webbased app, may expand clinical use of DECT iodine quantification, yielding meaningful IC values that reflect tissue biologic viability or treatment response in patients who undergo serial examinations on different platforms.

RevDate: 2021-10-19

Simon S, SR Riddell (2020)

Dual Targeting with CAR T Cells to Limit Antigen Escape in Multiple Myeloma.

Blood cancer discovery, 1(2):130-133 pii:BCD-20-0122.

Adoptive T-cell therapy targeting a single tumor antigen can induce remissions of hematologic cancers but relapses often occur due to the outgrowth of tumor cells with absent or low expression of the antigen. Strategies to simultaneousy target multiple antigens are needed to fully capitalize on the promise of this therapeutic strategy. In this issue of Blood Cancer Discovery, Fernández de Larrea and colleagues demonstrate in preclinical models of multiple myeloma that targeting BCMA and GPRC5D simultaneously with T cells engineered to express chimeric antigen receptors specific for these antigens may prevent tumor cell escape. See related article by Fernández de Larrea et al., p. 146.

RevDate: 2021-10-19

Juluri KR, Wu V, Voutsinas JM, et al (2021)

Severe cytokine release syndrome is associated with hematologic toxicity following CD19 CAR T-cell therapy.

Blood advances pii:477390 [Epub ahead of print].

CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable efficacy in patients with relapsed/refractory B-cell malignancies, however, is associated with toxicities including cytokine release syndrome (CRS), neurotoxicity, and impaired hematopoietic recovery. The latter is associated with high grade cytopenias requiring extended growth factor or transfusional support, potentially leading to additional complications such as infection or hemorrhage. To date, the factors independently associated with hematologic toxicity have not been well characterized. To address this, we retrospectively analyzed 173 patients who received defined-composition CD19 CAR T-cell therapy on a phase I/II clinical trial (NCT01865617), with primary endpoints of absolute neutrophil count (ANC) and platelet count at day-28 following CAR T-cell infusion. We observed cumulative incidences of neutrophil and platelet recovery of 81% and 75% respectively, at 28 days post-CAR T-cell infusion. Hematologic toxicity was noted in a significant subset of patients with persistent neutropenia in 9% and thrombocytopenia in 14% at last follow-up. Utilizing debiased LASSO regression analysis for high-dimensional modeling and considering patient-, disease-, and treatment-related variables, we identified increased CRS severity as an independent predictor for decreased platelet count and lower pre-lymphodepletion platelet count as independent predictors for both decreased neutrophil and platelet counts following CD19 CAR T-cell infusion. Furthermore, multivariable models including CRS-related cytokines identified associations between higher peak serum concentrations of IL-6 and lower day-28 counts; in contrast, higher serum concentrations of TGF-β were associated with higher counts. Our findings suggest that patient selection and improved CRS management may improve hematopoietic recovery following CD19 CAR T-cell therapy.

RevDate: 2021-10-19

Gaba A, Hix MA, Suhail S, et al (2021)

Divergence in dimerization and activity of primate APOBEC3C.

Journal of molecular biology pii:S0022-2836(21)00543-X [Epub ahead of print].

The APOBEC3 (A3) family of single-stranded DNA cytidine deaminases are host restriction factors that inhibit lentiviruses, such as HIV-1, in the absence of the Vif protein that causes their degradation. Deamination of cytidine in HIV-1 (-)DNA forms uracil that causes inactivating mutations when uracil is used as a template for (+)DNA synthesis. For APOBEC3C (A3C), the chimpanzee and gorilla orthologues are more active than human A3C, and we determined that Old World Monkey A3C from rhesus macaque (rh) is not active against HIV-1. Biochemical, virological, and coevolutionary analyses combined with molecular dynamics simulations showed that the key amino acids needed to promote rhA3C antiviral activity, 44, 45, and 144, also promoted dimerization and changes to the dynamics of loop 1, near the enzyme active site. Although forced evolution of rhA3C resulted in a similar dimer interface with hominid A3C, the key amino acid contacts were different. Overall, our results determine the basis for why rhA3C is less active than human A3C and establish the amino acid network for dimerization and increased activity. Based on identification of the key amino acids determining Old World Monkey antiviral activity we predict that other Old World Monkey A3Cs did not impart anti-lentiviral activity, despite fixation of a key residue needed for hominid A3C activity. Overall, the coevolutionary analysis of the A3C dimerization interface presented also provides a basis from which to analyze dimerization interfaces of other A3 family members.

RevDate: 2021-10-19

Lynch KL, Dillon MR, Bat-Erdene M, et al (2021)

A viral histone-like protein exploits antagonism between linker histones and HMGB proteins to obstruct the cell cycle.

Current biology : CB pii:S0960-9822(21)01290-2 [Epub ahead of print].

Virus infection necessarily requires redirecting cellular resources toward viral progeny production. Adenovirus encodes the histone-like protein VII, which causes catastrophic global reorganization of host chromatin to promote virus infection. Protein VII recruits the family of high mobility group box (HMGB) proteins to chromatin along with the histone chaperone SET. As a consequence of this recruitment, we find that protein VII causes chromatin depletion of several linker histone H1 isoforms. The relationship between linker histone H1 and the functionally opposite HMGB proteins is critical for higher-order chromatin structure. However, the physiological consequences of perturbing this relationship are largely unknown. Here, we employ complementary systems in Saccharomyces cerevisiae and human cells to demonstrate that adenovirus protein VII disrupts the H1-HMGB balance to obstruct the cell cycle. We find that protein VII causes an accumulation of G2/M cells both in yeast and human systems, underscoring the high conservation of this chromatin vulnerability. In contrast, adenovirus E1A and E1B proteins are well established to override cell cycle regulation and promote transformation of human cells. Strikingly, we find that protein VII obstructs the cell cycle, even in the presence of E1A and E1B. We further show that, in a protein-VII-deleted infection, several cell cycle markers are regulated differently compared to wild-type infection, supporting our model that protein VII plays an integral role in hijacking cell cycle regulation during infection. Together, our results demonstrate that protein VII targets H1-HMGB1 antagonism to obstruct cell cycle progression, revealing an unexpected chromatin vulnerability exploited for viral benefit.

RevDate: 2021-10-19

Andrasik MP, Broder GB, Wallace SE, et al (2021)

Increasing Black, Indigenous and People of Color participation in clinical trials through community engagement and recruitment goal establishment.

PloS one, 16(10):e0258858 pii:PONE-D-21-14138.

Longstanding social and economic inequities elevate health risks and vulnerabilities for Black, Indigenous and People of Color (BIPOC) communities. Engagement of BIPOC communities in infectious disease research is a critical component in efforts to increase vaccine confidence, acceptability, and uptake of future approved products. Recent data highlight the relative absence of BIPOC communities in vaccine clinical trials. Intentional and effective community engagement methods are needed to improve BIPOC inclusion. We describe the methods utilized for the successful enrollment of BIPOC participants in the U.S. Government (USG)-funded COVID-19 Prevention Network (CoVPN)-sponsored vaccine efficacy trials and analyze the demographic and enrollment data across the efficacy trials to inform future efforts to ensure inclusive participation. Across the four USG-funded COVID-19 vaccine clinical trials for which data are available, 47% of participants enrolled at CoVPN sites in the US were BIPOC. White enrollment outpaced enrollment of BIPOC participants throughout the accrual period, requiring the implementation of strategies to increase diverse and inclusive enrollment. Trials opening later benefitted considerably from strengthened community engagement efforts, and greater and more diverse volunteer registry records. Despite robust fiscal resources and a longstanding collaborative and collective effort, enrollment of White persons outpaced that of BIPOC communities. With appropriate resources, commitment and community engagement expertise, the equitable enrollment of BIPOC individuals can be achieved. To ensure this goal, intentional efforts are needed, including an emphasis on diversity of enrollment in clinical trials, establishment of enrollment goals, ongoing robust community engagement, conducting population-specific trials, and research to inform best practices.

RevDate: 2021-10-19

Roberts ST, Hawley I, Luecke E, et al (2021)

Acceptability and Preference for 3-Month Versus 1-Month Vaginal Rings for HIV-1 Risk Reduction Among Participants in a Phase 1 Trial.

Journal of women's health (2002) [Epub ahead of print].

Background: The monthly dapivirine vaginal ring provides partial protection against HIV, and a longer duration ring may reduce user burden and improve adherence. We examined acceptability and preference for 3-month versus 1-month rings for HIV-1 risk reduction in a phase 1 clinical trial. Materials and Methods: In Microbicide Trials Network-036/International Partnership for Microbicides 047, 49 HIV-negative participants aged 18-45 were randomized to one of two 3-month rings or the 1-month ring. Acceptability ratings were collected at enrollment, week 4, and study exit (week 13). At exit, ring preference was assessed quantitatively among all participants and a randomly selected subset of 24 participants completed in-depth interviews. Quantitative and qualitative findings were integrated to explore factors influencing acceptability and preference. Results: Acceptability of each ring was initially moderate and increased during the trial. Ratings were lower in the 3-month ring arms than the 1-month arm at each time point, including baseline. Most participants (34/47; 72%) preferred a 3-month ring at exit; however, this proportion was significantly lower within some subgroups characterized by site, education, race/ethnicity, and experiences with ring use. Qualitative interviews revealed reservations about hygiene and safety of the 3-month ring, including discomfort with use during menses, but these were usually outweighed by its increased convenience. Conclusions: Both ring durations were highly acceptable at study exit. Although most participants preferred a 3-month ring, preference was more divided in certain subgroups, highlighting the benefit of offering different duration options. Providing additional support to address concerns about hygiene and safety may improve acceptability of a 3-month vaginal ring.

RevDate: 2021-10-20

Newcomb PA, Ton M, Malen RC, et al (2021)

Correction to: Cannabis use is associated with patient and clinical factors in a population-based sample of colorectal cancer survivors.

RevDate: 2021-10-20

Zifodya JS, Triplette M, Shahrir S, et al (2021)

A cross-sectional analysis of diagnosis and management of chronic obstructive pulmonary disease in people living with HIV: Opportunities for improvement.

Medicine, 100(37):e27124.

ABSTRACT: Chronic obstructive pulmonary disease (COPD) is common in people living with HIV (PLWH). We sought to evaluate the appropriateness of COPD diagnosis and management in PLWH, comparing results to HIV-uninfected persons.We conducted a cross-sectional analysis of Veterans enrolled in the Examinations of HIV-Associated Lung Emphysema study, in which all participants underwent spirometry at enrollment and reported respiratory symptoms on self-completed surveys. Primary outcomes were misdiagnosis and under-diagnosis of COPD, and the frequency and appropriateness of inhaler prescriptions. Misdiagnosis was defined as having an International Classification of Diseases (ICD)-9 diagnosis of COPD without spirometric airflow limitation (post-bronchodilator forced expiratory volume in 1-second [FEV1]/Forced vital capacity [FVC] < 0.7). Under-diagnosis was defined as having spirometry-defined COPD without a prior ICD-9 diagnosis.The analytic cohort included 183 PLWH and 152 HIV-uninfected participants. Of 25 PLWH with an ICD-9 diagnosis of COPD, 56% were misdiagnosed. Of 38 PLWH with spirometry-defined COPD, 71% were under-diagnosed. In PLWH under-diagnosed with COPD, 85% reported respiratory symptoms. Among PLWH with an ICD-9 COPD diagnosis as well as in those with spirometry-defined COPD, long-acting inhalers, particularly long-acting bronchodilators (both beta-agonists and muscarinic antagonists) were prescribed infrequently even in symptomatic individuals. Inhaled corticosteroids were the most frequently prescribed long-acting inhaler in PLWH (28%). Results were overall similar amongst the HIV-uninfected.COPD was frequently misdiagnosed and under-diagnosed in PLWH, similar to uninfected-veterans. Among PLWH with COPD and a likely indication for therapy, long-acting inhalers were prescribed infrequently, particularly guideline-concordant, first-line long-acting bronchodilators. Although not a first-line controller therapy for COPD, inhaled corticosteroids were prescribed more often.

RevDate: 2021-10-19

Janssens DH, Meers MP, Wu SJ, et al (2021)

Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia.

Nature genetics [Epub ahead of print].

Acute myeloid and lymphoid leukemias often harbor chromosomal translocations involving the KMT2A gene, encoding the KMT2A lysine methyltransferase (also known as mixed-lineage leukemia-1), and produce in-frame fusions of KMT2A to other chromatin-regulatory proteins. Here we map fusion-specific targets across the genome for diverse KMT2A oncofusion proteins in cell lines and patient samples. By modifying CUT&Tag chromatin profiling for full automation, we identify common and tumor-subtype-specific sites of aberrant chromatin regulation induced by KMT2A oncofusion proteins. A subset of KMT2A oncofusion-binding sites are marked by bivalent (H3K4me3 and H3K27me3) chromatin signatures, and single-cell CUT&Tag profiling reveals that these sites display cell-to-cell heterogeneity suggestive of lineage plasticity. In addition, we find that aberrant enrichment of H3K4me3 in gene bodies is sensitive to Menin inhibitors, demonstrating the utility of automated chromatin profiling for identifying therapeutic vulnerabilities. Thus, integration of automated and single-cell CUT&Tag can uncover epigenomic heterogeneity within patient samples and predict sensitivity to therapeutic agents.

RevDate: 2021-10-19

Oh H, Saquib N, Ochs-Balcom HM, et al (2021)

Recreational physical activity, sitting, and androgen metabolism among postmenopausal women in the Women's Health Initiative Observational Study.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-21-0809 [Epub ahead of print].

BACKGROUND: Prolonged sitting and physical inactivity are associated with higher circulating levels of estrogens. It is unknown whether these risk factors are associated with circulating androgens/androgen metabolites, another set of hormones implicated in the etiology of cancers in postmenopausal women.

METHODS: We conducted a cross-sectional analysis of 1,782 postmenopausal women in the Women's Health Initiative Observational Study. Serum concentrations of 12 androgens/androgen metabolites were quantified using liquid chromatography-tandem mass spectrometry. Physical activity and sitting time were self-reported at baseline. We performed linear regression to estimate geometric means(GMs) of androgen/androgen metabolite concentrations(pmol/L) according to physical activity and sitting time, adjusting for potential confounders and stratified by menopausal hormone therapy(MHT) use.

RESULTS: Physical activity (>15 vs. 0 MET-hour/week) was inversely associated with estrogen-to-androgen ratios among never/former MHT users (adj-GM=37.5 vs. 49.6 unconjugated estrone:androstenedione; 20.2 vs. 30.3 unconjugated estradiol:testosterone; all p-trend<0.03) but was not associated among current MHT users. Prolonged sitting(>10 vs. <5 hours/day) was positively associated with these ratios among both never/former (adj-GM=44.2 vs. 38.3, p-trend=0.10; adj-GM=23.4 vs. 20.2, p-trend=0.17; respectively) and current MHT users (adj-GM=197 vs. 147; 105 vs. 75.5; respectively; all p-trend<0.02) but the associations were statistically significant among current MHT users only. The associations persisted after adjustment for BMI. After adjustment for adrenal androgens, physical activity and sitting were not associated with androgen metabolites.

CONCLUSIONS: Physical activity and sitting were associated with serum estrogen-to-androgen ratios but not androgen metabolites.

IMPACT: This study contributes to our understanding of the link between physical activity, sitting, and cancer risk in postmenopausal women.

RevDate: 2021-10-20
CmpDate: 2021-10-20

Makarov DV, Ciprut S, Kelly M, et al (2021)

Protocol: A multi-modal, physician-centered intervention to improve guideline-concordant prostate cancer imaging.

Trials, 22(1):711.

BACKGROUND: Almost half of Veterans with localized prostate cancer receive inappropriate, wasteful staging imaging. Our team has explored the barriers and facilitators of guideline-concordant prostate cancer imaging and found that (1) patients with newly diagnosed prostate cancer have little concern for radiographic staging but rather focus on treatment and (2) physicians trust imaging guidelines but are apt to follow their own intuition, fear medico-legal consequences, and succumb to influence from imaging-avid colleagues. We used a theory-based approach to design a multi-level intervention strategy to promote guideline-concordant imaging to stage incident prostate cancer.

METHODS: We designed the Prostate Cancer Imaging Stewardship (PCIS) intervention: a multi-site, stepped wedge, cluster-randomized trial to determine the effect of a physician-focused behavioral intervention on Veterans Health Administration (VHA) prostate cancer imaging use. The multi-level intervention, developed according to the Theoretical Domains Framework (TDF) and Behavior Change Wheel, combines traditional physician behavior change methods with novel methods of communication and data collection. The intervention consists of three components: (1) a system of audit and feedback to clinicians informing individual clinicians and their sites about how their behavior compares to their peers' and to published guidelines, (2) a program of academic detailing with the goal to educate providers about prostate cancer imaging, and (3) a CPRS Clinical Order Check for potentially guideline-discordant imaging orders. The intervention will be introduced to 10 participating geographically distributed study sites.

DISCUSSION: This study is a significant contribution to implementation science, providing VHA an opportunity to ensure delivery of high-quality care at the lowest cost using a theory-based approach. The study is ongoing. Preliminary data collection and recruitment have started; analysis has yet to be performed.

TRIAL REGISTRATION: CliniclTrials.gov NCT03445559. Prospectively registered on February 26, 2018.

RevDate: 2021-10-19

Wu X, RN Eisenman (2021)

MYC and TFEB Control DNA Methylation and Differentiation in AML.

Blood cancer discovery, 2(2):116-118 pii:BCD-20-0230.

Although the MYC transcription factor has been consistently implicated in acute myeloid leukemia (AML), its gene targets and precise role in leukemogenesis remain unknown. In this issue of Blood Cancer Discovery, Yun and colleagues provide evidence that MYC directly suppresses the expression of TFEB, an mTORC1-regulated transcription factor. They show that, in the context of the myelocytic/granulocytic lineage, TFEB acts as a tumor suppressor by inducing the IDH1/2-TET pathway, which in turn, leads to altered DNA methylation and increased expression of genes involved in myeloid differentiation and apoptosis. Therefore, high levels of MYC suppress an epigenetic pathway that should normally act to attenuate leukemic progression. Identification of the components of this pathway is likely to inform new therapeutic tactics for AML and possibly other cancers. See related article by Yun et al., p. 162.

RevDate: 2021-10-18

Yue K, Ma J, Thornton T, et al (2021)

REHE: Fast variance components estimation for linear mixed models.

Genetic epidemiology [Epub ahead of print].

Linear mixed models are widely used in ecological and biological applications, especially in genetic studies. Reliable estimation of variance components is crucial for using linear mixed models. However, standard methods, such as the restricted maximum likelihood (REML), are computationally inefficient in large samples and may be unstable with small samples. Other commonly used methods, such as the Haseman-Elston (HE) regression, may yield negative estimates of variances. Utilizing regularized estimation strategies, we propose the restricted Haseman-Elston (REHE) regression and REHE with resampling (reREHE) estimators, along with an inference framework for REHE, as fast and robust alternatives that provide nonnegative estimates with comparable accuracy to REML. The merits of REHE are illustrated using real data and benchmark simulation studies.

RevDate: 2021-10-17

Bauermeister JA, Tingler RC, Dominguez C, et al (2021)

Acceptability of a Dapivirine/Placebo Gel Administered Rectally to HIV-1 Seronegative Adults (MTN-026).

AIDS and behavior [Epub ahead of print].

This study describes the acceptability of a rectal microbicide gel formulation using dapivirine (DPV) among men and women from two countries (United States and Thailand) participating in the Microbicide Trials Network-026 trial. We evaluated participants' acceptability of a rectal DPV/placebo gel as part of a Phase I trial (N = 26; 18 male, 8 female). Participants reported favorable acceptability of the study gel, with most participants reporting that they liked the gel the same (n = 14; 53.8%) or more (n = 11; 42.4%) than when they started the trial. Over half of participants noted that they would prefer the gel over condoms (n = 13; 50%) or that they liked condoms and the gel equally (n = 8; 30.8%). Side effects across products included leakage (n = 8; 30.8%), diarrhea (n = 4; 15.4%), or soiling (n = 1; 3.8%). The high acceptability of a rectal gel underscores its promise as a short-acting biomedical prevention, warranting future research for HIV prevention.Trial Registration: NCT03239483.

RevDate: 2021-10-17

Vo P, Onstad L, Flowers ME, et al (2021)

Cancers after HLA-matched related bone marrow transplantation for aplastic anemia.

Bone marrow transplantation [Epub ahead of print].

We analyzed subsequent cancers in 329 patients with aplastic anemia given HLA-matched related marrow grafts. Median follow-up: 26 (range 1-47) years. Conditioning: cyclophosphamide ± antithymocyte globulin; graft-vs.-host disease (GVHD) prevention: methotrexate ± cyclosporine. The long follow-up and homogeneous treatment allowed definitive analyses of incidence, nature, time of onset, and potential causes of cancers. Fifty-three cancers occurred in 46 patients, 42 had solid tumors and 4 blood cancers. Of the 42, 22 had non-melanoma skin and 7 oropharyngeal cancers. The remainder had a spectrum of other cancers including two liver cancers from pre-transplant hepatitis C. The 26-year cumulative incidence (CI) of cancer was 11% and mortality 5%. Excluding non-melanoma skin cancers, the 26-year CI of cancer was 7%. Cancers were 2.03-fold more than expected from SEER data; that number was 1.89-fold after excluding liver cancers. Nearly all cancers developed between 14 and 34 years. Skin and oropharyngeal cancers showed significant association with chronic GVHD, whereby GVHD had resolved in most patients within 7 years of transplantation. Thus, tumors evolved after a lag time of 7-27 years. Other cancers showed no clear associations with chronic GVHD or drugs used for transplantation. Results reemphasize the importance of preventing chronic GVHD.

RevDate: 2021-10-17

Cicconi L, Testi AM, Montesinos P, et al (2021)

Characteristics and outcome of acute myeloid leukemia with uncommon retinoic acid receptor-alpha (RARA) fusion variants.

Blood cancer journal, 11(10):167.

RevDate: 2021-10-16

Snow SM, Matkowskyj KA, Maresh M, et al (2021)

Validation of genetic classifiers derived from mouse and human tumors to identify molecular subtypes of colorectal cancer.

Human pathology pii:S0046-8177(21)00180-5 [Epub ahead of print].

Colorectal cancer (CRC) is a leading cause of cancer death in the United States. Standard treatment for advanced stage CRC for decades has included 5-fluorouracil based chemotherapy. More recently, targeted therapies for metastatic CRC are being used based on the individual cancer's molecular profile. In the past few years, several different molecular subtype schemes for human CRC have been developed. The molecular subtypes can be distinguished by gene expression signatures and have the potential to be used to guide treatment decisions. However, many subtyping classification methods were developed using mRNA expression levels of hundreds to thousands of genes, making them impractical for clinical use. In this study, we assessed whether an immunohistochemical approach could be used for molecular subtyping of colorectal cancers. We validated two previously published, independent sets of immunohistochemistry classifiers and modified the published methods to improve the accuracy of the scoring methods. In addition, we evaluated whether protein and genetic signatures identified originally in the mouse were linked to clinical outcomes of patients with CRC. We found that low DDAH1 or low GAL3ST2 protein levels in human CRCs correlate with poor patient outcome. The results of this study have the potential to impact methods for determining the prognosis and therapy selection for CRC patients.

RevDate: 2021-10-20

Petermann V, Zahnd WE, Vanderpool RC, et al (2021)

How cancer programs identify and address the financial burdens of rural cancer patients.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer [Epub ahead of print].

PURPOSE: Financial toxicity is associated with negative patient outcomes, and rural populations are disproportionately affected by the high costs of cancer care compared to urban populations. Our objective was to (1) understand cancer programs' perceptions of rural-urban differences in cancer patients' experiences of financial hardship, (2) evaluate the resources available to cancer patients across the rural-urban continuum, and (3) determine how rural and urban health care teams assess and address financial distress in cancer patients.

METHODS: Seven research teams within the Cancer Prevention and Research Control Network conducted semi-structured interviews with cancer program staff who have a role in connecting cancer patients with financial assistance services in both rural and urban counties. Interviews were audio-recorded and transcribed. We identified themes using descriptive content and thematic analysis.

RESULTS: We interviewed 35 staffs across 29 cancer care programs in seven states, with roughly half of respondents from programs in rural counties. Participants identified differences in rural and urban patients' experiences of financial hardship related to distance required to travel for treatment, underinsurance, and low socioeconomic status. Insufficient staffing was an identified barrier to addressing rural and urban patients' financial concerns.

CONCLUSIONS: Improved financial navigation services could mitigate the effects of financial toxicity experienced by cancer patients, particularly rural patients, throughout treatment and survivorship. Future research is needed to improve how cancer programs assess financial hardship in patients and to expand financial navigation services to better serve rural cancer patients.

RevDate: 2021-10-13

Lotan Y, de Jong J, Liu VYT, et al (2021)

Patients With Muscle Invasive Bladder Cancer with Non-luminal Subtype Derive Greatest Benefit from Platinum Based Neoadjuvant Chemotherapy.

The Journal of urology [Epub ahead of print].

PURPOSE: Neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) in patients with non-metastatic muscle-invasive bladder cancer (MIBC) confers an absolute survival benefit of 5-10%. There is evidence that molecular differences between tumors may impact response to therapy, highlighting a need for clinically validated biomarkers to predict response to NAC.

MATERIALS AND METHODS: Four bladder cancer cohorts were included. Inverse probability weighting was used to make baseline characteristics (age, sex, and clinical tumor stage) between NAC-treated and untreated groups more comparable. Molecular subtypes were determined using a commercial genomic subtyping classifier. Survival rates were estimated using weighted Kaplan Meier (KM) curves. Cox proportional hazards (PH) models were used to evaluate the primary and secondary study endpoints of overall survival (OS) and cancer-specific survival (CSS), respectively.

RESULTS: A total of 601 patients with MIBC were included, where 247 had been treated with NAC and RC and 354 underwent RC without NAC. With NAC, the overall net benefit to OS and CSS at three years was 7% and 5%, respectively. After controlling for clinicopathologic variables, non-luminal tumors had greatest benefit from NAC with 10% greater OS at 3 years (71% vs 61%) while luminal tumors had minimal benefit (63% vs 65%) for NAC vs. non-NAC, respectively.

CONCLUSIONS: In patients with MIBC, a commercially available molecular subtyping assay revealed non-luminal tumors received the greatest benefit from NAC, while patients with luminal tumors experienced a minimal survival benefit. A genomic classifier may help identify patients with MIBC who would benefit most from NAC.

RevDate: 2021-10-05

Sato S, Li N, Dixon SB, et al (2021)

Functional Outcomes and Social Attainment in Asian/Pacific Islander Childhood Cancer Survivors in the United States: A Report from the Childhood Cancer Survivor Study.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-21-0628 [Epub ahead of print].

BACKGROUND: Given the relatively small population of Asians or Pacific Islanders (API) in the United States, studies describing long-term outcomes in API survivors of childhood cancer are limited. This study compared functional outcomes between API versus non-Hispanic White (NHW) survivors.

METHODS: This study included 203 API five-year survivors (age at follow-up: 29.2 [SD=6.3] years) and 12,186 NHW survivors (age at follow-up 31.5[SD=7.3] years) from the Childhood Cancer Survivor Study. Self-reported functional outcomes of neurocognitive function, emotional distress, quality of life, and social attainment were compared between the two groups using multivariable regression, adjusted for sex, age at diagnosis and evaluation, cancer diagnosis, and neurotoxic treatment.

RESULTS: No statistically significant race/ethnicity-based differences were identified in neurocognitive and emotional measures. API survivors reported, on average, less bodily pain than NHW survivors (mean 54.11 [SD=8.98] vs. 51.32 [SD=10.12]; P<.001). NHW survivors were less likely to have attained at least a college degree than API survivors (odds ratio[OR]=0.50; 95% confidence interval[CI]=0.34, 0.73). API survivors were more likely than NHW survivors to be never-married (OR=2.83, 95% CI=1.93, 4.13) and to live dependently (OR=3.10; 95% CI=2.02, 4.74). Older age (>45 years), brain tumor diagnosis, and higher cranial radiation dose were associated with poorer functional outcomes in API survivors (all, P's<0.05).

CONCLUSION: We observed differences in social attainment between API and NHW survivors, though statistically significant differences in neurocognitive and emotional outcomes were not identified.

IMPACT: Future studies should evaluate whether racial/ethnic differences in environmental and sociocultural factors may have differential effects on health and functional outcomes.

RevDate: 2021-10-15

Duggan C, Trapani D, Ilbawi AM, et al (2021)

National health system characteristics, breast cancer stage at diagnosis, and breast cancer mortality: a population-based analysis.

The Lancet. Oncology pii:S1470-2045(21)00462-9 [Epub ahead of print].

BACKGROUND: In some countries, breast cancer age-standardised mortality rates have decreased by 2-4% per year since the 1990s, but others have yet to achieve this outcome. In this study, we aimed to characterise the associations between national health system characteristics and breast cancer age-standardised mortality rate, and the degree of breast cancer downstaging correlating with national age-standardised mortality rate reductions.

METHODS: In this population-based study, national age-standardised mortality rate estimates for women aged 69 years or younger obtained from GLOBOCAN 2020 were correlated with a broad panel of standardised national health system data as reported in the WHO Cancer Country Profiles 2020. These health system characteristics include health expenditure, the Universal Health Coverage Service Coverage Index (UHC Index), dedicated funding for early detection programmes, breast cancer early detection guidelines, referral systems, cancer plans, number of dedicated public and private cancer centres per 10 000 patients with cancer, and pathology services. We tested for differences between continuous variables using the non-parametric Kruskal-Wallis test, and for categorical variables using the Pearson χ2 test. Simple and multiple linear regression analyses were fitted to identify associations between health system characteristics and age-standardised breast cancer mortality rates. Data on TNM stage at diagnosis were obtained from national or subnational cancer registries, supplemented by a literature review of PubMed from 2010 to 2020. Mortality trends from 1950 to 2016 were assessed using the WHO Cancer Mortality Database. The threshold for significance was set at a p value of 0·05 or less.

FINDINGS: 148 countries had complete health system data. The following variables were significantly higher in high-income countries than in low-income countries in unadjusted analyses: health expenditure (p=0·0002), UHC Index (p<0·0001), dedicated funding for early detection programmes (p=0·0020), breast cancer early detection guidelines (p<0·0001), breast cancer referral systems (p=0·0030), national cancer plans (p=0·014), cervical cancer early detection programmes (p=0·0010), number of dedicated public (p<0·0001) and private (p=0·027) cancer centres per 10 000 patients with cancer, and pathology services (p<0·0001). In adjusted multivariable regression analyses in 141 countries, two health system characteristics were significantly associated with lower age-standardised mortality rates: higher UHC Index levels (β=-0·12, 95% CI -0·16 to -0·08) and increasing numbers of public cancer centres (β=-0·23, -0·36 to -0·10). These findings indicate that each unit increase in the UHC Index was associated with a 0·12-unit decline in age-standardised mortality rates, and each additional public cancer centre per 10 000 patients with cancer was associated with a 0·23-unit decline in age-standardised mortality rate. Among 35 countries with available breast cancer TNM staging data, all 20 that achieved sustained mean reductions in age-standardised mortality rate of 2% or more per year for at least 3 consecutive years since 1990 had at least 60% of patients with invasive breast cancer presenting as stage I or II disease. Some countries achieved this reduction without most women having access to population-based mammographic screening.

INTERPRETATION: Countries with low breast cancer mortality rates are characterised by increased levels of coverage of essential health services and higher numbers of public cancer centres. Among countries achieving sustained mortality reductions, the majority of breast cancers are diagnosed at an early stage, reinforcing the value of clinical early diagnosis programmes for improving breast cancer outcomes.

FUNDING: None.

RevDate: 2021-10-15

Docampo MD, Burgos da Silva M, Lazrak A, et al (2021)

Alloreactive T cells deficient of the short-chain fatty acid receptor GPR109A induce less graft-versus-host disease.

Blood pii:477329 [Epub ahead of print].

The intestinal microbiota is essential for the fermentation of dietary fiber into short-chain fatty acids (SCFA) such as butyrate, acetate, and propionate. SCFAs can bind to the G-protein-coupled receptors GPR43 and GPR109A (HCAR2), with varying affinities to promote cellular effects in metabolism or changes in immune function. We explored the role of GPR109A as the main receptor for butyrate in mouse models of allogeneic hematopoietic cell transplantation (allo-HCT) and graft-versus-host disease (GVHD). Deletion of GPR109A in allo-HCT recipients did not affect GVHD, but transplantation of T cells from GPR109A knockout (Gpr109a-/-) mice into allo-HCT recipient mice significantly reduced GVHD morbidity and mortality compared to recipients of wild type T cells. Recipients of Gpr109a-/- T cells exhibited less GVHD-associated target organ pathology and decreased proliferation and homing of alloreactive T cells to target tissues. Although Gpr109a-/- T cells did not exhibit immune deficits at steady state, following allo-activation Gpr109a-/- T cells underwent increased apoptosis and had impaired mitochondrial oxidative phosphorylation, which was reversible through antioxidant treatment with N-acetyl cysteine (NAC). In conclusion, we found that GPR109A expression by allo-activated T cells is essential for metabolic homeostasis and expansion, which are necessary features to induce GVHD after allo-HCT.

RevDate: 2021-10-15

Townsend MK, Trabert B, Fortner RT, et al (2021)

Cohort Profile: The Ovarian Cancer Cohort Consortium (OC3).

International journal of epidemiology pii:6398054 [Epub ahead of print].

RevDate: 2021-10-15

Lorona NC, Malone KE, CI Li (2021)

Racial/ethnic disparities in risk of breast cancer mortality by molecular subtype and stage at diagnosis.

Breast cancer research and treatment [Epub ahead of print].

PURPOSE: Previous research has found significant survival disparities between Black and White women among select stages and subtypes of breast cancer, however other racial/ethnic groups have been less well-studied. This study expands on previous research, examining differences in breast cancer-specific mortality across multiple racial and ethnic groups.

METHODS: Women diagnosed with a first primary invasive breast cancer between 2010 and 2016 who were 20-85 years of age at diagnosis were identified from 18 Surveillance, Epidemiology, and End Results (SEER) registries. Subtypes were defined by joint hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status. Cox proportional hazards models for each stage and subtype were fit, with non-Hispanic white women as the reference group. Effect modification by age at diagnosis (< 50, ≥ 50) was found and thus analyses were age-stratified.

RESULTS: After multivariable adjustment, younger Black women had greater risks of breast cancer-specific death for all stages of HR+/HER2-, and certain stages of HR+/HER2+ , TN, and HR-/HER2 + breast cancer. Asian/Pacific Islander women generally had a lower hazard of breast cancer-specific death. Older Hispanic White women had a lower hazard of breast cancer-specific death for stages I-III HR + /HER2- and stage II TN breast cancer.

CONCLUSIONS: These findings demonstrate that different racial/ethnic groups experience different risks of breast cancer-specific mortality by stage and subtype. Efforts to address survival disparities should place additional focus on young Black women, as they experience meaningful disparities in breast cancer-specific mortality.

RevDate: 2021-10-16

Martin NA, Tepper JE, Giri VN, et al (2021)

Adopting Consensus Terms for Testing in Precision Medicine.

JCO precision oncology, 5:.

Despite the well-understood benefits of biomarker and genetic testing in precision medicine, uptake remains low, particularly for patients with low socioeconomic status and minority ethnic backgrounds. Patients report having limited familiarity with testing terminology and may not be able to accurately explain testing's role in treatment decisions. Patient confusion and lack of understanding is exacerbated by a multiplicity of overlapping terms used in communicating about testing. A LUNGevity Foundation-led working group composed of five professional societies, 23 patient advocacy groups, and 19 industry members assessed and recommended specific terms for communicating with patients on testing for tumor characteristics and germline mutations.

METHODS: Members completed a precision oncology testing framework analysis (biomarkers, germline variants, testing modalities, biospecimen, and commonly used testing terms) for nine solid tumors and blood cancers. The evaluation was segmented into terms that distinguish between somatic and germline testing. Additional data were captured in a comprehensive survey (1,650 respondents) led by FORCE (Facing Our Risk of Cancer Empowered) on patient preferences on germline testing terms.

RESULTS: Thirty-three terms were noted in patient education related to biomarker, genetic, and genomic testing. Biomarker testing was selected as the preferred term for testing for somatic (acquired) alterations and other biomarkers. Genetic testing for an inherited mutation and genetic testing for inherited cancer risk were selected as the preferred terms for testing for germline variants.

CONCLUSION: Democratizing comprehension about precision oncology testing through intentional use of plain language and common umbrella terminology by oncology health care providers and others in the oncology ecosystem may help improve understanding and communication, and facilitate shared decision making about the role of appropriate testing in treatment decisions and other aspects of oncology care.

RevDate: 2021-10-16

Hasanov M, Milton DR, Sharfman WH, et al (2021)

An Open-Label, Randomized, Multi-Center Study Comparing the Sequence of High Dose Aldesleukin (Interleukin-2) and Ipilimumab (Yervoy) in Patients with Metastatic Melanoma.

Oncoimmunology, 10(1):1984059.

Combination immunotherapy with sequential administration may enhance metastatic melanoma (MM) patients with long-term disease control. High Dose Aldesleukin/Recombinant Interleukin-2 (HD rIL-2) and ipilimumab (IPI) offer complementary mechanisms against MM. This phase IV study assessed the sequenced use of HD rIL-2 and IPI in MM patients. Eligible Stage IV MM patients were randomized to treatment with either two courses of HD rIL-2(600,000 IU/kg) followed by four doses of IPI 3 mg/kg or vice-versa. The primary objective was to compare one-year overall survival (OS) with historical control (46%, Hodi et al., NEJM 2010). Secondary objectives were 1-year progression-free survival (PFS), objective response rate (ORR), and adverse events (AEs) profile. Evaluable Population (EP) included patients who received at least 50% of planned treatment with each drug. Thirteen and 16 patients were randomized to receive HD rIL-2 first, and IPI first, respectively. One-year OS rate was 75% for intention to treat population. Eighteen patients were included in EP, 8 in HD rIL-2, 10 in IPI first arm. In EP, 1-year OS, PFS and ORR rates were 87%, 68%, and 50%, respectively. The frequency of AEs was similar in both arms with 13 patients experiencing Grade 3 or higher AEs, 3 resulting in the end of study participation. There was one HD rIL-2-related death, from cerebral hemorrhage due to thrombocytopenia. In this study with small sample size, HD rIL-2 and IPI were safe to administer sequentially in MM patients and showed more than additive effects. 1-year OS was superior to that of IPI alone from historical studies.

RevDate: 2021-10-15

Bastani R, Glenn BA, Singhal R, et al (2021)

Increasing HPV Vaccination among Low-income, Ethnic Minority Adolescents: Effects of a Multicomponent System Intervention through a County Health Department Hotline.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:1055-9965.EPI-20-1578 [Epub ahead of print].

BACKGROUND: Introduction of the human papillomavirus (HPV) vaccine in 2006 was a game-changing advance in cancer control. Despite the vaccine's potential cancer prevention benefits, uptake remains low. We utilized a randomized design to evaluate a multicomponent intervention to improve HPV vaccine uptake among low-income, ethnic minority adolescents seeking services through a county health department telephone hotline.

METHODS: Hotline callers who were caregivers of never-vaccinated adolescents (11-17 years) were randomized by call-week to intervention or control conditions. The intervention included brief telephone and print education, delivered in multiple languages, and personalized referral to a low-cost/free vaccine provider. Participants completed baseline (n=238), 3-month (n=215), and 9-month (n=204) telephone follow-up surveys.

RESULTS: HPV vaccine initiation rates increased substantially by 9-month follow-up overall, though no differences were observed between intervention and control groups (45% vs. 42%, respectively, p>0.05). We also observed significant improvements in perceived HPV risk, barriers to vaccination, and perceived knowledge in both study conditions (p<0.05).

CONCLUSIONS: A low-intensity county hotline intervention did not produce a greater increase in HPV vaccination rates than routine practice. However, 44% of unvaccinated adolescents in both conditions received at least one dose of the vaccine, which can be viewed as a successful public health outcome. Future studies should evaluate more intensive interventions that address accessing and utilizing services in complex safety net settings.

IMPACT: Study results suggest the need for investigators to be aware of the potential priming effects of study participation, which may obscure the effect of low-intensity interventions.

RevDate: 2021-10-14

Lazaryan A, Lee SJ, Arora M, et al (2021)

Phase 2 multicenter trial of ofatumumab and prednisone as initial therapy of chronic graft-vs-host disease.

Blood advances pii:477315 [Epub ahead of print].

Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal and transient responses in a significant number of patients. Safety and feasibility of anti-CD20 directed B-cell therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n=12). We now report the mature results of the phase II expansion of the trial (n=38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The combined therapy was generally well tolerated, with some anticipated infusion reactions to ofatumumab, and common toxicities of glucocorticoids. Total B-cell depletion following therapy was profound, with marginal recovery within first 12 months from initial therapy. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR=complete + partial response[CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial IS agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial is registered at www.clinicaltrials.gov as NCT01680965.

RevDate: 2021-10-14

Chow VA, Cassaday RD, Gooley TA, et al (2021)

Mega-dose 90Y-Ibritumomab tiuxetan prior to allogeneic transplantation is effective for aggressive large B-cell lymphoma.

Blood advances pii:477313 [Epub ahead of print].

Allogeneic hematopoietic cell transplantation (allo-HCT) can be curative for relapsed or refractory B-cell lymphomas (BCL), though outcomes are worse in aggressive disease and most patients will still experience relapse. Radioimmunotherapy (RIT) using 90Y-Ibritumomab tiuxetan can induce disease control across lymphoma subtypes in a dose-dependent fashion. We hypothesized that mega-doses of 90Y-Ibritumomab tiuxetan with reduced-intensity conditioning (RIC) could safely produce deeper remissions in aggressive BCL further maintained with the immunologic effect of allo-HCT. In this phase 2 study, CD20+ BCL patients received outpatient 90Y-Ibritumomab tiuxetan (1.5mCi/kg, maximum 120mCi), fludarabine, then 2Gy total body irradiation (TBI) prior to HLA-matched allo-HCT. Twenty patients were enrolled after a median of 4.5 prior lines of therapy including 14 with prior autologous transplant and 4 with prior anti-CD19 chimeric T-cellular therapy. A median 90Y activity of 113.6 mCi (range 71.2-129.2) was administered delivering a median of 552cGy to liver (range 499-2411cGy). The estimated 1 and 5-year PFS was 55% (95% CI, 31-73%) and 50% (95% CI, 27-69%) with a median PFS of 1.57 years. The estimated 1- and 5-year overall survival (OS) was 80% (95% CI, 54-92%) and 63% (95% CI, 38-81%) with a median OS of 6.45 years. Sixteen patients (80%) experienced grade ≥3 toxicities, although nonrelapse mortality was 10% at 1-year. No patients developed secondary AML/MDS. Mega-dose 90Y-Ibritumomab tiuxetan, fludarabine, and low-dose TBI followed by an HLA-matched allo-HCT was feasible, safe, and effective in treating aggressive BCL, exceeding the prespecified endpoint while producing nonhematologic toxicities comparable to standard RIC regimens. (Registered at ClinicalTrials.gov as NCT01434472).

RevDate: 2021-10-14

Zarnitsyna VI, Akondy RS, Ahmed H, et al (2021)

Dynamics and turnover of memory CD8 T cell responses following yellow fever vaccination.

PLoS computational biology, 17(10):e1009468 pii:PCOMPBIOL-D-20-02212 [Epub ahead of print].

Understanding how immunological memory lasts a lifetime requires quantifying changes in the number of memory cells as well as how their division and death rates change over time. We address these questions by using a statistically powerful mixed-effects differential equations framework to analyze data from two human studies that follow CD8 T cell responses to the yellow fever vaccine (YFV-17D). Models were first fit to the frequency of YFV-specific memory CD8 T cells and deuterium enrichment in those cells 42 days to 1 year post-vaccination. A different dataset, on the loss of YFV-specific CD8 T cells over three decades, was used to assess out of sample predictions of our models. The commonly used exponential and bi-exponential decline models performed relatively poorly. Models with the cell loss following a power law (exactly or approximately) were most predictive. Notably, using only the first year of data, these models accurately predicted T cell frequencies up to 30 years post-vaccination. Our analyses suggest that division rates of these cells drop and plateau at a low level (0.1% per day, ∼ double the estimated values for naive T cells) within one year following vaccination, whereas death rates continue to decline for much longer. Our results show that power laws can be predictive for T cell memory, a finding that may be useful for vaccine evaluation and epidemiological modeling. Moreover, since power laws asymptotically decline more slowly than any exponential decline, our results help explain the longevity of immune memory phenomenologically.

RevDate: 2021-10-14

Cranmer LD, Chau B, Mantilla JG, et al (2021)

Is Chemotherapy Associated with Improved Overall Survival in Patients with Dedifferentiated Chondrosarcoma? A SEER Database Analysis.

Clinical orthopaedics and related research pii:00003086-990000000-00509 [Epub ahead of print].

BACKGROUND: Dedifferentiated chondrosarcoma is a chondrosarcoma subtype associated with high rates of recurrence and a poor prognosis. Others have proposed treatment of dedifferentiated chondrosarcoma using osteosarcoma protocols, including perioperative chemotherapy. However, the rarity of this condition poses difficulties in undertaking single- institution studies of sufficient sample size.

QUESTION/PURPOSE: Is perioperative chemotherapy associated with improved overall survival in patients with dedifferentiated chondrosarcoma?

METHODS: We queried the Surveillance, Epidemiology, and End Results (SEER) 1973 to 2016 database for patients with a diagnosis of dedifferentiated chondrosarcoma (n = 308). As dedifferentiated chondrosarcoma was only classified as a distinct entity in SEER starting in 2000, only patients treated in 2000 and later were included. We excluded from our analyses those patients with distant disease at diagnosis, a primary site of disease other than bone or joints, and those who did not receive cancer-directed surgery. These criteria yielded 185 dedifferentiated chondrosarcoma patients for inclusion. We used Kaplan-Meier analyses and Cox proportional hazards models to assess the association of clinical, demographic, and treatment characteristics on overall survival (OS).

RESULTS: After controlling for confounding variables, including age, sex, tumor size, stage, grade, location, and radiation treatment status, and after adjusting for missing data, no overall survival benefit was associated with receipt of chemotherapy in patients with dedifferentiated chondrosarcoma (hazard ratio 0.75 [95% confidence interval 0.49 to 1.12]; p = 0.16).

CONCLUSION: Chemotherapy treatment of dedifferentiated chondrosarcoma was not associated with improved OS. These results must be viewed cautiously, given the limited granularity of information on chemotherapy treatment, the concerns regarding chemotherapy misclassification in SEER data, and the small sample of patients with dedifferentiated chondrosarcoma, all of which limit the power to detect a difference. Our findings are nevertheless consistent with those of prior reports in which no benefit of chemotherapy could be detected. Lack of clear benefit from perioperative chemotherapy in dedifferentiated chondrosarcoma argues that it should be used only after careful consideration, and ideally in the context of a clinical trial.

LEVEL OF EVIDENCE: Level III, therapeutic study.

RevDate: 2021-10-14

Knoerl R, Giobbie-Hurder A, Sannes TS, et al (2021)

Exploring the impact of exercise and mind-body prehabilitation interventions on physical and psychological outcomes in women undergoing breast cancer surgery.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer [Epub ahead of print].

PURPOSE: To compare the impact of exercise and mind-body prehabilitation interventions on changes in quality of life and cancer treatment-related symptoms in women with newly diagnosed breast cancer.

METHODS: The following describes a secondary analysis of a randomized window of opportunity trial (The Pre-Operative Health and Body Study). Forty-nine women were randomized to participate in either an exercise prehabilitation intervention or a mind-body prehabilitation intervention from the time of enrollment to surgery. Participants (N = 47) completed measures of quality of life, anxiety, depression, and stress at the time of enrollment (T1), post-intervention/surgery (T2), and one-month post-surgery (T3). Changes in outcome measures between groups were compared over time using longitudinal models.

RESULTS: Mind-body group participants experienced significant improvements in cognitive functioning in comparison to exercise group participants between T1 and T3 (difference in average change: -9.61, p = 0.04, d = 0.31), otherwise, there were no significant differences between groups. Within group comparisons demonstrated that both groups experienced improvements in anxiety (exercise: average change = -1.18, p = 0.03, d = 0.34; mind-body: average change = -1.69, p = 0.006, d = 0.43) and stress (exercise: average change = -2.33, p = 0.04, d = 0.30; mind-body: average change = -2.59, p = 0.05, d = 0.29), while mind-body group participants experienced improvements in insomnia (average change = -10.03, p = 0.04, d = 0.30) and cognitive functioning (average change = 13.16, p = 0.0003, d = 0.67).

CONCLUSIONS: Both prehabilitation interventions impacted cancer treatment-related symptoms. Further work in larger groups of patients is needed to evaluate the efficacy of prehabilitation interventions on quality of life in women with breast cancer. Pre-operative exercise and mind-body interventions may impact physical and/or psychological effects of cancer diagnosis and treatment in women with breast cancer.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01516190. Registered January 24, 2012.

RevDate: 2021-10-14

Sarangapani KK, Koch LB, Nelson CR, et al (2021)

Kinetochore-bound Mps1 regulates kinetochore-microtubule attachments via Ndc80 phosphorylation.

The Journal of cell biology, 220(12):.

Dividing cells detect and correct erroneous kinetochore-microtubule attachments during mitosis, thereby avoiding chromosome missegregation. The Aurora B kinase phosphorylates microtubule-binding elements specifically at incorrectly attached kinetochores, promoting their release and providing another chance for proper attachments to form. However, growing evidence suggests that the Mps1 kinase is also required for error correction. Here we directly examine how Mps1 activity affects kinetochore-microtubule attachments using a reconstitution-based approach that allows us to separate its effects from Aurora B activity. When endogenous Mps1 that copurifies with kinetochores is activated in vitro, it weakens their attachments to microtubules via phosphorylation of Ndc80, a major microtubule-binding protein. This phosphorylation contributes to error correction because phospho-deficient Ndc80 mutants exhibit genetic interactions and segregation defects when combined with mutants in other error correction pathways. In addition, Mps1 phosphorylation of Ndc80 is stimulated on kinetochores lacking tension. These data suggest that Mps1 provides an additional mechanism for correcting erroneous kinetochore-microtubule attachments, complementing the well-known activity of Aurora B.

RevDate: 2021-10-14

Huang D, Savage SR, Calinawan AP, et al (2021)

A highly annotated database of genes associated with platinum resistance in cancer.

Oncogene [Epub ahead of print].

Platinum-based chemotherapy, including cisplatin, carboplatin, and oxaliplatin, is prescribed to 10-20% of all cancer patients. Unfortunately, platinum resistance develops in a significant number of patients and is a determinant of clinical outcome. Extensive research has been conducted to understand and overcome platinum resistance, and mechanisms of resistance can be categorized into several broad biological processes, including (1) regulation of drug entry, exit, accumulation, sequestration, and detoxification, (2) enhanced repair and tolerance of platinum-induced DNA damage, (3) alterations in cell survival pathways, (4) alterations in pleiotropic processes and pathways, and (5) changes in the tumor microenvironment. As a resource to the cancer research community, we provide a comprehensive overview accompanied by a manually curated database of the >900 genes/proteins that have been associated with platinum resistance over the last 30 years of literature. The database is annotated with possible pathways through which the curated genes are related to platinum resistance, types of evidence, and hyperlinks to literature sources. The searchable, downloadable database is available online at http://ptrc-ddr.cptac-data-view.org .

RevDate: 2021-10-14

Finn OJ, Bhardwaj N, Fling SP, et al (2021)

Martin A. "Mac" Cheever, MD: In Memoriam (1944-2021).

Cancer immunology research pii:2326-6066.CIR-21-0823 [Epub ahead of print].

RevDate: 2021-10-13

Summers C, Wu QV, Annesley C, et al (2021)

Hematopoietic cell transplantation after CD19 CAR T cell-induced ALL remission confers leukemia-free survival advantage.

Transplantation and cellular therapy pii:S2666-6367(21)01295-1 [Epub ahead of print].

BACKGROUND: Consolidative hematopoietic cell transplantation (HCT) after CD19 chimeric antigen receptor (CAR) T cell therapy is frequently performed for patients with refractory/relapsed B cell acute lymphoblastic leukemia (B-ALL). However, there is controversy regarding the role of HCT following remission attainment.

OBJECTIVES: We evaluated the effect of consolidative HCT on leukemia-free survival (LFS) in pediatric and young adult subjects following CD19 CAR T cell induced remission.

STUDY DESIGN: We evaluated the effect of consolidative HCT on leukemia-free survival (LFS) in pediatric and young adult subjects treated with a 41BB-CD19 CAR T cell product on a Phase 1/2 trial, Pediatric and Young Adult Leukemia Adoptive Therapy (PLAT)-02 (NCT02028455), using a time-dependent Cox proportional hazards statistical model. Fifty of 64 subjects enrolled onto PLAT-02 Phase 1 and early Phase 2 were evaluated, excluding 14 subjects who did not achieve remission, relapsed or died prior to day 63 post-CAR T cell therapy.

RESULTS: An improved LFS (P=0.01) was observed in subjects who underwent consolidative HCT after CAR T cell therapy versus watchful waiting. Consolidative HCT improved LFS specifically in subjects who had no prior history of HCT, with a trend towards significance (P=0.09). This benefit was not evident when restricted to the cohort of 34 subjects with a history of a prior HCT (P=0.45). However, for subjects who had CAR T cell functional persistence of 63 days or less, inclusive of those with a history of prior HCT, HCT significantly improved LFS outcomes (P=0.01).

CONCLUSIONS: These data support consolidative HCT following CD19 CAR T cell-induced remission for patients with no prior history of HCT or for those with short functional CAR T cell persistence.

RevDate: 2021-10-13

Chow EJ, Aplenc R, Vrooman LM, et al (2021)

Late health outcomes after dexrazoxane treatment: A report from the Children's Oncology Group.

Cancer [Epub ahead of print].

BACKGROUND: The objective of this study was to examine long-term outcomes among children newly diagnosed with cancer who were treated in dexrazoxane-containing clinical trials.

METHODS: P9404 (acute lymphoblastic leukemia/lymphoma [ALL]), P9425 and P9426 (Hodgkin lymphoma), P9754 (osteosarcoma), and Dana-Farber Cancer Institute 95-01 (ALL) enrolled 1308 patients between 1996 and 2001: 1066 were randomized (1:1) to doxorubicin with or without dexrazoxane, and 242 (from P9754) were nonrandomly assigned to receive dexrazoxane. Trial data were linked with the National Death Index, the Organ Procurement and Transplantation Network, the Pediatric Health Information System (PHIS), and Medicaid. Osteosarcoma survivors from the Childhood Cancer Survivor Study (CCSS; n = 495; no dexrazoxane) served as comparators in subanalyses. Follow-up events were assessed with cumulative incidence, Cox regression, and Fine-Gray methods.

RESULTS: In randomized trials (cumulative prescribed doxorubicin dose, 100-360 mg/m2 ; median follow-up, 18.6 years), dexrazoxane was not associated with relapse (hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63-1.13), second cancers (HR, 1.19; 95% CI, 0.62-2.30), all-cause mortality (HR, 1.07; 95% CI, 0.78-1.47), or cardiovascular mortality (HR, 1.45; 95% CI, 0.41-5.16). Among P9754 patients (all exposed to dexrazoxane; cumulative doxorubicin, 450-600 mg/m2 ; median follow-up, 16.6-18.4 years), no cardiovascular deaths or heart transplantation occurred. The 20-year heart transplantation rate among CCSS osteosarcoma survivors (mean doxorubicin, 377 ± 145 mg/m2) was 1.6% (vs 0% in P9754; P = .13). Among randomized patients, serious cardiovascular outcomes (cardiomyopathy, ischemic heart disease, and stroke) ascertained by PHIS/Medicaid occurred less commonly with dexrazoxane (5.6%) than without it (17.6%; P = .02), although cardiomyopathy rates alone did not differ (4.4% vs 8.1%; P = .35).

CONCLUSIONS: Dexrazoxane did not appear to adversely affect long-term mortality, event-free survival, or second cancer risk.

RevDate: 2021-10-13

Santiago-Torres M, Mull KE, Sullivan BM, et al (2021)

Efficacy and Utilization of Smartphone Applications for Smoking Cessation among American Indians and Alaska Natives: Results from the iCanQuit Trial.

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco pii:6395852 [Epub ahead of print].

INTRODUCTION: There is tremendous need for efficacious and accessible interventions for smoking cessation among American Indians and Alaska Natives. We tested the efficacy of an Acceptance and Commitment Therapy (ACT)-based smartphone application (iCanQuit) vs. US Clinical Practice Guidelines based smartphone application (QuitGuide) for smoking cessation among American Indians and Alaska Natives.

METHODS: We compared cessation, changes in ACT-based processes, engagement and satisfaction between American Indians and Alaska Natives iCanQuit (n=89) and QuitGuide (n=80) trial participants enrolled in the iCanQuit trial. The primary outcome was self-reported, complete-case, 30-day point-prevalence abstinence (PPA). Follow-up timepoints were 12, 6, and 3-months.

RESULTS: Randomized American Indians and Alaska Natives from 31 US states (70% urban, 30% rural, with 25% of participants residing on tribal land). The outcome data retention rates were 93%, 92%, and 90% at the 12, 6, and 3-month follow-ups, respectively, with no differential retention between arms. The 30-day PPA for iCanQuit vs. QuitGuide was 30% vs. 18% at 12-months (OR=1.96; 95% CI: 0.90, 4.26) 25% vs. 11% at 6-months (OR=2.62; 95% CI: 1.06, 6.45), and 15% vs. 6% at 3-months (OR=2.93; 95% CI: 0.90, 9.59). Increases in acceptance of internal cues to smoke mediated the effect of treatment on smoking cessation at 12-months. iCanQuit arm participants were also significantly more engaged and satisfied with their assigned application.

CONCLUSIONS: In a nationwide sample with high data retention and participant engagement, this is the first study to show that a digital intervention may be efficacious for helping American Indians and Alaska Natives quit smoking.

IMPLICATONS: This is the first study to provide evidence of an efficacious, accessible, and engaging treatment for helping American Indians and Alaska Natives quit smoking. Compared to a USCPG-based smartphone application (QuitGuide), an ACT-based smartphone application (iCanQuit) was more efficacious, engaging, and satisfactory among American Indians and Alaska Natives nationwide. Our results will inform the tailoring of the iCanQuit smartphone application for American Indian and Alaska Native tribal communities and organizations with potential for broad dissemination and high impact.

RevDate: 2021-10-13

Forsberg KJ, Schmidtke DT, Werther R, et al (2021)

The novel anti-CRISPR AcrIIA22 relieves DNA torsion in target plasmids and impairs SpyCas9 activity.

PLoS biology, 19(10):e3001428 pii:PBIOLOGY-D-21-00143 [Epub ahead of print].

To overcome CRISPR-Cas defense systems, many phages and mobile genetic elements (MGEs) encode CRISPR-Cas inhibitors called anti-CRISPRs (Acrs). Nearly all characterized Acrs directly bind Cas proteins to inactivate CRISPR immunity. Here, using functional metagenomic selection, we describe AcrIIA22, an unconventional Acr found in hypervariable genomic regions of clostridial bacteria and their prophages from human gut microbiomes. AcrIIA22 does not bind strongly to SpyCas9 but nonetheless potently inhibits its activity against plasmids. To gain insight into its mechanism, we obtained an X-ray crystal structure of AcrIIA22, which revealed homology to PC4-like nucleic acid-binding proteins. Based on mutational analyses and functional assays, we deduced that acrIIA22 encodes a DNA nickase that relieves torsional stress in supercoiled plasmids. This may render them less susceptible to SpyCas9, which uses free energy from negative supercoils to form stable R-loops. Modifying DNA topology may provide an additional route to CRISPR-Cas resistance in phages and MGEs.

RevDate: 2021-10-13

Kalia V, Yuzefpolskiy Y, Vegaraju A, et al (2021)

Metabolic regulation by PD-1 signaling promotes long-lived quiescent CD8 T cell memory in mice.

Science translational medicine, 13(615):eaba6006.

[Figure: see text].

RevDate: 2021-10-12

Bhatt VR, Wang T, Chen K, et al (2021)

Chronic Graft-Versus-Host Disease, Non-Relapse Mortality and Disease Relapse in Older versus Younger Adults Undergoing Matched Allogeneic Peripheral Blood Hematopoietic Cell Transplantation: A CIBMTR Analysis.

Transplantation and cellular therapy pii:S2666-6367(21)01293-8 [Epub ahead of print].

BACKGROUND: The effect of chronic graft-versus-host disease (cGVHD) on the risk of non-relapse mortality (NRM) and relapse has not been specifically studied in older adults, who are increasingly undergoing allogeneic hematopoietic cell transplantation (alloHCT) and surviving long-term to develop cGVHD. In this Center for International Blood and Marrow Transplant Research analysis, we tested our hypothesis that the risk of NRM was higher with the development of cGVHD, particularly among older adults (≥60 years).

METHODS: We included 4429 adults ≥40 years who received first HLA-matched peripheral blood alloHCT for acute myeloid leukemia or myelodysplastic syndrome between the years 2008-2017. We compared outcomes of 4 groups: older adults (≥60 years) and younger adults (40-59 years) with or without cGVHD to determine the effect of older age and cGVHD on various outcomes. We used Cox proportional hazard models to determine the risk of NRM, relapse and overall survival (OS). We treated cGVHD as a time-dependent covariate. Severity of cGVHD was based on the CIBMTR clinical definitions.

RESULTS: cGVHD was significantly associated with a higher risk of NRM and lower risk of relapse regardless of age. The risk of NRM was higher among older versus younger adults. Adults who developed cGVHD as a group had longer OS, compared to age-matched cohorts without cGVHD. Older adults had worse OS regardless of cGVHD. Among adults with cGVHD, clinically moderate or severe cGVHD was associated with a significantly higher risk of NRM and lower risk of relapse; severe cGVHD was associated with shorter OS, whereas mild and moderate cGVHD were associated with longer OS.

CONCLUSIONS: Among both younger and older adults, the development of cGVHD was associated with a higher risk of NRM, lower risk of relapse and longer OS. Older adults had a higher risk of NRM but the increased risk of NRM associated with cGVHD did not differ based on age. Development of mild-moderate cGVHD offered the most favorable balance between minimizing NRM and decreasing relapses. The relapse risk was lowest for adults with severe cGVHD, but high NRM resulted in shorter OS. Developing strategies to avoid clinically severe cGVHD is critically important.

RevDate: 2021-10-12

Inoue T, Koyama M, Kaida K, et al (2021)

Peri-transplant glucocorticoids redistribute donor T-cells to the bone marrow and prevent relapse after haploidentical SCT.

JCI insight pii:153551 [Epub ahead of print].

Patients with acute leukemia who are unable to achieve complete remission prior to allogeneic hematopoietic stem cell transplantation (SCT) have dismal outcomes with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities but typically requires intensive immune-suppression with post-transplant cyclophosphamide (PT-Cy) to prevent lethal graft-versus-host disease (GVHD). Here we demonstrate in preclinical models that glucocorticoid administration from day -1 to +5 inhibits alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T-cell priming and subsequent expansion therein. In contrast, direct glucocorticoid signaling of donor T-cells promotes chemokine and integrin signatures permissive of preferential circulation and migration into the bone marrow, promoting donor T-cell residency. This results in significant reductions in GVHD whilst promoting potent GVL effects (relapse in recipients receiving glucocorticoids, vehicle or PT-Cy was 12%, 56% and 100% respectively). Intriguingly, patients with acute myeloid leukemia not in remission that received unmanipulated haplo-SCT and peri-transplant glucocorticoids also had an unexpectedly low relapse rate at 1 year (32%: 95% CI, 18%-47%) with high overall survival at 3 years (58%: 95% CI, 38-74%). These data highlight a potentially simple and effective approach to prevent relapse in patients with otherwise incurable leukemia that could be studied in prospective randomized trials.

RevDate: 2021-10-12

Wagner AJ, Ravi V, Riedel RF, et al (2021)

nab-Sirolimus for Patients With Malignant Perivascular Epithelioid Cell Tumors.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: Malignant perivascular epithelioid cell tumor (PEComa) is a rare aggressive sarcoma, with no approved treatment. To our knowledge, this phase II, single-arm, registration trial is the first prospective clinical trial in this disease, investigating the safety and efficacy of the mammalian target of rapamycin inhibitor nab-sirolimus (AMPECT, NCT02494570).

PATIENTS AND METHODS: Patients with malignant PEComa were treated with nab-sirolimus 100 mg/m2 intravenously once weekly for 2 weeks in 3-week cycles. The primary end point was objective response rate evaluated by independent radiology review. Key secondary end points included duration of response, progression-free survival, and safety. A key exploratory end point was tumor biomarker analysis.

RESULTS: Thirty-four patients were treated (safety evaluable), and 31 were evaluable for efficacy. The overall response rate was 39% (12 of 31; 95% CI, 22 to 58) with one complete and 11 partial responses, 52% (16 of 31) of patients had stable disease, and 10% (3 of 31) had progressive disease. Responses were of rapid onset (67% by week 6) and durable. Median duration of response was not reached after a median follow-up for response of 2.5 years, with 7 of 12 responders with treatment ongoing (range 5.6-47.2+ months). Twenty-five of 31 patients had tumor mutation profiling: 8 of 9 (89%) patients with a TSC2 mutation achieved a confirmed response versus 2 of 16 (13%) without TSC2 mutation (P < .001). The median progression-free survival was 10.6 months (95% CI, 5.5 months to not reached), and the median overall survival was 40.8 months (95% CI, 22.2 months to not reached). Most treatment-related adverse events were grade 1 or 2 and were manageable for long-term treatment. No grade ≥ 4 treatment-related events occurred.

CONCLUSION: nab-Sirolimus is active in patients with malignant PEComa. The response rate, durability of response, disease control rate, and safety profile support that nab-sirolimus represents an important new treatment option for this disease.

RevDate: 2021-10-12

Huang AS, Ramos V, Oliveira TY, et al (2021)

Integration features of intact latent HIV-1 in CD4+ T cell clones contribute to viral persistence.

The Journal of experimental medicine, 218(12):.

Latent intact HIV-1 proviruses persist in a small subset of long-lived CD4+ T cells that can undergo clonal expansion in vivo. Expanded clones of CD4+ T cells dominate latent reservoirs in individuals on long-term antiretroviral therapy (ART) and represent a major barrier to HIV-1 cure. To determine how integration landscape might contribute to latency, we analyzed integration sites of near full length HIV-1 genomes from individuals on long-term ART, focusing on individuals whose reservoirs are highly clonal. We find that intact proviruses in expanded CD4+ T cell clones are preferentially integrated within Krüppel-associated box (KRAB) domain-containing zinc finger (ZNF) genes. ZNF genes are associated with heterochromatin in memory CD4+ T cells; nevertheless, they are expressed in these cells under steady-state conditions. In contrast to genes carrying unique integrations, ZNF genes carrying clonal intact integrations are down-regulated upon cellular activation. Together, the data suggest selected genomic sites, including ZNF genes, can be especially permissive for maintaining HIV-1 latency during memory CD4+ T cell expansion.

RevDate: 2021-10-12

Sartor O, George D, Tombal B, et al (2021)

Real-world outcomes of second novel hormonal therapy or radium-223 following first novel hormonal therapy for mCRPC.

Future oncology (London, England) [Epub ahead of print].

Aim: To evaluate real-world clinical outcomes of radium-223 or alternative novel hormonal therapy (NHT) following first-line NHT for metastatic castration-resistant prostate cancer (mCRPC). Patients & methods: Retrospective analysis of the US Flatiron database (ClinicalTrials.gov identifier: NCT03896984). Results: In the radium-223 cohort (n = 120) versus the alternative NHT cohort (n = 226), proportionally more patients had prior symptomatic skeletal events and bone-only metastases, and first-line NHT duration was shorter. Following second-line therapy, 49 versus 39% of patients received subsequent life-prolonging therapy; of these, 47 versus 76% received taxane. Median overall survival was 10.8 versus 11.2 months. Conclusion: Real-world patients with mCRPC had similar median overall survival following second-line radium-223 or alternative NHT after first-line NHT. Many patients received subsequent therapy, with less taxane use after radium-223.

RevDate: 2021-10-12

Thomas R, Chansinghakul D, Limkittikul K, et al (2021)

Associations of human leukocyte antigen with neutralizing antibody titers in a tetravalent dengue vaccine phase 2 efficacy trial in Thailand.

Human immunology pii:S0198-8859(21)00236-6 [Epub ahead of print].

The recombinant, live, attenuated, tetravalent dengue vaccine CYD-TDV has shown efficacy against all four dengue serotypes. In this exploratory study (CYD59, NCT02827162), we evaluated potential associations of host human leukocyte antigen (HLA) alleles with dengue antibody responses, CYD-TDV vaccine efficacy, and virologically-confirmed dengue (VCD) cases. Children 4-11 years old, who previously completed a phase 2b efficacy study of CYD-TDV in a single center in Thailand, were included in the study. Genotyping of HLA class I and II loci was performed by next-generation sequencing from DNA obtained from 335 saliva samples. Dengue neutralizing antibody titers (NAb) were assessed as a correlate of risk and protection. Regression analyses were used to assess associations between HLA alleles and NAb responses, vaccine efficacy, and dengue outcomes. Month 13 NAb log geometric mean titers (GMTs) were associated with decreased risk of VCD. In the vaccine group, HLA-DRB1*11 was significantly associated with higher NAb log GMT levels (beta: 0.76; p = 0.002, q = 0.13). Additionally, in the absence of vaccination, HLA associations were observed between the presence of DPB1*03:01 and increased NAb log GMT levels (beta: 1.24; p = 0.005, q = 0.17), and between DPB1*05:01 and reduced NAb log GMT levels (beta: -1.1; p = 0.001, q = 0.07). This study suggests associations of HLA alleles with NAb titers in the context of dengue outcomes. This study was registered with clinicaltrials.gov: NCT02827162.

RevDate: 2021-10-11

Basu P, Malvi SG, Joshi S, et al (2021)

Vaccine efficacy against persistent human papillomavirus (HPV) 16/18 infection at 10 years after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre, prospective, cohort study.

The Lancet. Oncology pii:S1470-2045(21)00453-8 [Epub ahead of print].

BACKGROUND: A randomised trial designed to compare three and two doses of quadrivalent human papillomavirus (HPV) vaccine in adolescent girls in India was converted to a cohort study after suspension of HPV vaccination in trials by the Indian Government. In this Article, the revised aim of the cohort study was to compare vaccine efficacy of single dose to that of three and two doses in protecting against persistent HPV 16 and 18 infection at 10 years post vaccination.

METHODS: In the randomised trial, unmarried girls aged 10-18 years were recruited from nine centres across India and randomly assigned to either two doses or three doses of the quadrivalent HPV vaccine (Gardasil [Merck Sharp & Dohme, Whitehouse Station, NJ, USA]; 0·5 mL administered intramuscularly). After suspension of recruitment and vaccination, the study became a longitudinal, prospective cohort study by default, and participants were allocated to four cohorts on the basis of the number vaccine doses received per protocol: the two-dose cohort (received vaccine on days 1 and 180 or later), three-dose cohort (days 1, 60, and 180 or later), two-dose default cohort (days 1 and 60 or later), and the single-dose default cohort. Participants were followed up yearly. Cervical specimens were collected from participants 18 months after marriage or 6 months after first childbirth, whichever was earlier, to assess incident and persistent HPV infections. Married participants were screened for cervical cancer as they reached 25 years of age. Unvaccinated women age-matched to the married vaccinated participants were recruited to serve as controls. Vaccine efficacy against persistent HPV 16 and 18 infections (the primary endpoint) was analysed for single-dose recipients and compared with that in two-dose and three-dose recipients after adjusting for imbalance in the distribution of potential confounders between the unvaccinated and vaccinated cohorts. This trial is registered with ISRCTN, ISRCTN98283094, and ClinicalTrials.gov, NCT00923702.

FINDINGS: Vaccinated participants were recruited between Sept 1, 2009, and April 8, 2010 (date of vaccination suspension), and followed up over a median duration of 9·0 years (IQR 8·2-9·6). 4348 participants had three doses, 4980 had two doses (0 and 6 months), and 4949 had a single dose. Vaccine efficacy against persistent HPV 16 and 18 infection among participants evaluable for the endpoint was 95·4% (95% CI 85·0-99·9) in the single-dose default cohort (2135 women assessed), 93·1% (77·3-99·8) in the two-dose cohort (1452 women assessed), and 93·3% (77·5-99·7) in three-dose recipients (1460 women assessed).

INTERPRETATION: A single dose of HPV vaccine provides similar protection against persistent infection from HPV 16 and 18, the genotypes responsible for nearly 70% of cervical cancers, to that provided by two or three doses.

FUNDING: Bill & Melinda Gates Foundation.

RevDate: 2021-10-11

Nicholl A, Deering KE, Evelegh K, et al (2021)

Whole-fat dairy products do not adversely affect adiposity or cardiometabolic risk factors in children in the Milky Way Study: a double-blind randomized controlled pilot study.

The American journal of clinical nutrition pii:6388163 [Epub ahead of print].

BACKGROUND: Limited evidence supports the common public health guideline that children >2 y of age should consume dairy with reduced fat content.

OBJECTIVES: We aimed to investigate the effects of whole-fat compared with reduced-fat dairy intake on measures of adiposity and biomarkers of cardiometabolic risk in healthy 4- to 6-y-old children.

METHODS: The Milky Way Study enrolled 49 children (mean ± SD age: 5.2 ± 0.9 y; 47% girls) who were habitual consumers of whole-fat dairy, then randomly assigned them in a double-blind fashion to remain on whole-fat dairy or switch their dairy consumption to reduced-fat products for 3 mo. Primary endpoints included measures of adiposity, body composition, blood pressure, fasting serum lipids, blood glucose, glycated hemoglobin (HbA1c), and C-reactive protein (CRP) and were assessed at baseline and study end. Pre- and postintervention results were compared using linear mixed models, adjusted for growth, age, and sex.

RESULTS: Dairy fat intake was reduced by an adjusted (mean ± SEM) 12.9 ± 4.1 g/d in the reduced-fat compared with the whole-fat dairy group (95% CI: -21.2, -4.6 g/d; P = 0.003), whereas dietary energy intakes remained similar (P = 0.936). We found no significant differential changes between dairy groups in any measure of adiposity, body composition, blood pressure, or fasting serum lipids, glucose, HbA1c, and CRP.

CONCLUSIONS: Our results suggest that although changing from whole-fat to reduced-fat dairy products does reduce dairy fat intake, it does not result in changes to markers of adiposity or cardiometabolic disease risk in healthy children.This trial was registered at www.anzctr.org.au as ACTRN12616001642471.

RevDate: 2021-10-11

Duetz C, Cucchi DGJ, Polak TB, et al (2021)

The wider perspective: twenty years of clinical trials in myelodysplastic syndromes.

British journal of haematology [Epub ahead of print].

Most patients with myelodysplastic syndromes (MDS) require therapeutic intervention. However, there are few approved treatments for MDS. To explore reasons, we searched clinicaltrials.gov and clinicaltrialsregister.eu for MDS trials from 2000 to 2020. We assessed which agents were under investigation and analysed clinical trial characteristics and continuation rates from phase I to II to III to approval. As such, we identified 384 unique agents in 426 phase I, 430 phase II and 48 phase III trials. Success rates for phase III trials and agents were low, and MDS trials took markedly longer to complete than the average clinical trial. Although success rates were higher when MDS-specific phase I trials were conducted, 52% of the agents had not been evaluated in a phase I trial for MDS. MDS trials often failed to include quality of life, an especially important outcome for older MDS patients. Our work identifies factors potentially contributing to the paucity of available agents for MDS. We suggest a framework to improve clinical research in MDS that might ultimately augment the number of available agents.

RevDate: 2021-10-11

Hess JM, Stephensen CB, Kratz M, et al (2021)

Exploring the Links between Diet and Inflammation: Dairy Foods as Case Studies.

Advances in nutrition (Bethesda, Md.), 12(Supplement_1):1S-13S.

Systemic chronic inflammation may be a contributing factor to many noncommunicable diseases, including diabetes, cardiovascular disease, and obesity. With the rapid rise of these conditions, identifying the causes of and treatment for chronic inflammation is an important research priority, especially with regard to modifiable lifestyle factors such as diet. An emerging body of evidence indicates that consuming certain foods, including dairy foods like milk, cheese, and yogurt, may be linked to a decreased risk for inflammation. To discuss both broader research on diet and inflammation as well as research on links between individual foods and inflammation, the National Dairy Council sponsored a satellite session entitled "Exploring the Links between Diet and Inflammation: Dairy Foods as Case Studies" at the American Society for Nutrition's 2020 LIVE ONLINE Conference. This article, a review based on the topics discussed during that session, explores the links between diet and inflammation, focusing most closely on the relations between intake of dairy fat and dairy foods like milk, cheese, and yogurt, and biomarkers of inflammation from clinical trials. While there is currently insufficient evidence to prove an "anti-inflammatory" effect of dairy foods, the substantial body of clinical research discussed in this review indicates that dairy foods do not increase concentrations of biomarkers of chronic systemic inflammation.

RevDate: 2021-10-11

Little P, Jo H, Hoyle A, et al (2021)

UNMASC: tumor-only variant calling with unmatched normal controls.

NAR cancer, 3(4):zcab040 pii:zcab040.

Despite years of progress, mutation detection in cancer samples continues to require significant manual review as a final step. Expert review is particularly challenging in cases where tumors are sequenced without matched normal control DNA. Attempts have been made to call somatic point mutations without a matched normal sample by removing well-known germline variants, utilizing unmatched normal controls, and constructing decision rules to classify sequencing errors and private germline variants. With budgetary constraints related to computational and sequencing costs, finding the appropriate number of controls is a crucial step to identifying somatic variants. Our approach utilizes public databases for canonical somatic variants as well as germline variants and leverages information gathered about nearby positions in the normal controls. Drawing from our cohort of targeted capture panel sequencing of tumor and normal samples with varying tumortypes and demographics, these served as a benchmark for our tumor-only variant calling pipeline to observe the relationship between our ability to correctly classify variants against a number of unmatched normals. With our benchmarked samples, approximately ten normal controls were needed to maintain 94% sensitivity, 99% specificity and 76% positive predictive value, far outperforming comparable methods. Our approach, called UNMASC, also serves as a supplement to traditional tumor with matched normal variant calling workflows and can potentially extend to other concerns arising from analyzing next generation sequencing data.

RevDate: 2021-10-11

Guimarães Alves AC, Sukow NM, Adelman Cipolla G, et al (2021)

Tracing the Distribution of European Lactase Persistence Genotypes Along the Americas.

Frontiers in genetics, 12:671079.

In adulthood, the ability to digest lactose, the main sugar present in milk of mammals, is a phenotype (lactase persistence) observed in historically herder populations, mainly Northern Europeans, Eastern Africans, and Middle Eastern nomads. As the -13910∗T allele in the MCM6 gene is the most well-characterized allele responsible for the lactase persistence phenotype, the -13910C > T (rs4988235) polymorphism is commonly evaluated in lactase persistence studies. Lactase non-persistent adults may develop symptoms of lactose intolerance when consuming dairy products. In the Americas, there is no evidence of the consumption of these products until the arrival of Europeans. However, several American countries' dietary guidelines recommend consuming dairy for adequate human nutrition and health promotion. Considering the extensive use of dairy and the complex ancestry of Pan-American admixed populations, we studied the distribution of -13910C > T lactase persistence genotypes and its flanking haplotypes of European origin in 7,428 individuals from several Pan-American admixed populations. We found that the -13910∗T allele frequency in Pan-American admixed populations is directly correlated with allele frequency of the European sources. Moreover, we did not observe any overrepresentation of European haplotypes in the -13910C > T flanking region, suggesting no selective pressure after admixture in the Americas. Finally, considering the dominant effect of the -13910∗T allele, our results indicate that Pan-American admixed populations are likely to have higher frequency of lactose intolerance, suggesting that general dietary guidelines deserve further evaluation across the continent.

RevDate: 2021-10-11

Prentice RL, S Zhao (2021)

Regression Models and Multivariate Life Tables.

Journal of the American Statistical Association, 116(535):1330-1345.

Semiparametric, multiplicative-form regression models are specified for marginal single and double failure hazard rates for the regression analysis of multivariate failure time data. Cox-type estimating functions are specified for single and double failure hazard ratio parameter estimation, and corresponding Aalen-Breslow estimators are specified for baseline hazard rates. Generalization to allow classification of failure times into a smaller set of failure types, with failures of the same type having common baseline hazard functions, is also included. Asymptotic distribution theory arises by generalization of the marginal single failure hazard rate estimation results of Danyu Lin, L.J. Wei and colleagues. The Péano series representation for the bivariate survival function in terms of corresponding marginal single and double failure hazard rates leads to novel estimators for pairwise bivariate survival functions and pairwise dependency functions, at specified covariate history. Related asymptotic distribution theory follows from that for the marginal single and double failure hazard rates and the continuity, compact differentiability of the Péano series transformation and bootstrap applicability. Simulation evaluation of the proposed estimation procedures are presented, and an application to multiple clinical outcomes in the Women's Health Initiative Dietary Modification Trial is provided. Higher dimensional marginal hazard rate regression modeling is briefly mentioned.

RevDate: 2021-10-11

Longino AA, Paul R, Wang Y, et al (2021)

HIV disease dynamics, markers of inflammation and CNS injury during primary HIV infection and their relationship to cognitive performance.

Journal of acquired immune deficiency syndromes (1999) pii:00126334-900000000-95788 [Epub ahead of print].

INTRODUCTION: Early systemic and central nervous system viral replication and inflammation may impact brain integrity in people with HIV (PWH), leading to chronic cognitive symptoms not fully reversed by antiretroviral therapy (ART). This study examined associations between cognitive performance and markers of CNS injury associated with acute HIV infection and ART.

METHODS: HIV-infected MSM and transgender women (average age: 27 and education: 13 years) enrolled within 100 days from estimated date of detectable infection [EDDI]. A cognitive performance (NP) protocol was administered at enrollment (before ART initiation) and every 24 weeks until week 192. An overall index of cognitive performance (NPZ) was created using local normative data. Blood (n=87) and cerebrospinal fluid (CSF; n=29) biomarkers of inflammation and neuronal injury were examined before ART initiation. Regression analyses assessed relationships between time since EDDI, pre-ART biomarkers, and NPZ.

RESULTS: Adjusting for multiple comparisons, shorter time since EDDI was associated with higher pre-ART VL and multiple biomarkers in plasma and CSF. NPZ scores were within the normative range at baseline (NPZ=.52) and at each follow-up visit, with a modest increase through week 192. Plasma or CSF biomarkers were not correlated with NP scores at baseline or after ART.

CONCLUSIONS: Biomarkers of CNS inflammation, immune activation and neuronal injury peak early and then decline during acute HIV infection, confirming and extending results of other studies. Neither plasma nor CSF biomarkers during acute infection corresponded to NP scores before or after sustained ART in this cohort with few psychosocial risk factors for cognitive impairment.

RevDate: 2021-10-10

Eastment MC, Wanje G, Richardson BA, et al (2021)

Results of a cluster randomized trial testing the systems analysis and improvement approach to increase HIV testing in family planning clinics in Mombasa, Kenya.

AIDS (London, England) pii:00002030-900000000-96295 [Epub ahead of print].

OBJECTIVE: To test an implementation strategy, the Systems Analysis and Improvement Approach (SAIA), to increase rates of HIV testing and counseling (HTC) in family planning (FP) clinics in Mombasa, Kenya.

DESIGN: Cluster randomized trial.

METHODS: Twenty-four FP clinics were randomized 1:1 to implementing SAIA versus usual procedures. Study staff implemented monthly SAIA cycles with FP clinic staff for 12 months. SAIA has five steps. Step 1 uses a "cascade analysis" tool to quantify the number of individuals who complete each step of a process. Step 2 involves sequential process flow mapping to identify modifiable bottlenecks in the system. Step 3 develops and implements workflow modifications to address bottlenecks. Step 4 assesses impact of the modification by recalculating the cascade analysis. Step 5 repeats the cycle. The primary outcome was the proportion of new FP clients tested for HIV during the last quarter of the trial.

RESULTS: During the last three months of the trial, 85% (740/868) of new FP clients were counseled for HIV in intervention clinics compared to 67% (1036/1542) in control clinics (prevalence rate ratio [PRR] 1.27, 95% confidence interval [CI] 1.15-1.30). Forty-two percent (364/859) of FP clients were tested for HIV at intervention clinics compared to 32% (485/1521) at control clinics (PRR 1.33, 95%CI 1.16-1.52).

CONCLUSION: SAIA led to a significant increase in HIV testing in FP clinics in Mombasa. Integrating routine HTC into FP clinics is a promising strategy to achieve the UNAIDS goal of 95% of people living with HIV being aware of their status.

RevDate: 2021-10-10

Poudel B, Desman J, Aihara G, et al (2021)

Adequacy of samples obtained via percutaneous core-needle rebiopsy for EGFR T790M molecular analysis in patients with non-small cell lung cancer following acquired resistance to first-line therapy: A systematic review and meta-analysis.

Cancer treatment and research communications, 29:100470 pii:S2468-2942(21)00166-0 [Epub ahead of print].

MICRO ABSTRACT: Rebiopsies characterizing resistance mutations in patients with non-small cell lung cancer (NSCLC) can guide personalized medicine and improve overall survival rates. In this systematic review, we examine the suitability of percutaneous core-needle biopsy (PT-CNB) to obtain adequate samples for molecular characterization of the acquired resistance mutation T790M. This review provides evidence that PT-CNB can obtain samples with high adequacy, with a mutation detection rate that is in accordance with prior literature.

BACKGROUND: Non-small cell lung cancer (NSCLC) comprises 85% of all lung cancers and has seen improved survival rates with the rise of personalized medicine. Resistance mutations to first-line therapies, such as T790M, however, render first-line therapies ineffective. Rebiopsies characterizing resistance mutations inform therapeutic decisions, which result in prolonged survival. Given the high efficacy of percutaneous core-needle biopsy (PT-CNB), we conducted the first systematic review to analyze the ability of PT-CNB to obtain samples of high adequacy in order to characterize the acquired resistance mutation T790M in patients with NSCLC.

METHODS: We performed a comprehensive literature search across PubMed, Embase, and CENTRAL. Search terms related to "NSCLC," "rebiopsy," and "PT-CNB" were used to obtain results. We included all prospective and retrospective studies that satisfied our inclusion and exclusion criteria. A random effects model was utilized to pool adequacy and detection rates of the chosen articles. We performed a systematic review, meta-analysis, and meta-regression to investigate the adequacy and T790M detection rates of samples obtained via PT-CNB.

RESULTS: Out of the 173 studies initially identified, 5 studies met the inclusion and exclusion criteria and were chosen for our final cohort of 436 patients for meta-analysis. The pooled adequacy rate of samples obtained via PT-CNB was 86.92% (95% CI: [79.31%, 92.0%]) and the pooled T790M detection rate was 46.0% (95% CI: [26.6%, 66.7%]). There was considerable heterogeneity among studies (I2 > 50%) in both adequacy and T790M detection rates.

CONCLUSION: PT-CNB can obtain adequate samples for T790M molecular characterization in NSCLC lung cancer patients. Additional prospective studies are needed to corroborate the results in this review.

RevDate: 2021-10-10

Madewell ZJ, Dean NE, Berlin JA, et al (2021)

Challenges of evaluating and modelling vaccination in emerging infectious diseases.

Epidemics, 37:100506 pii:S1755-4365(21)00055-4 [Epub ahead of print].

Outbreaks of emerging pathogens pose unique methodological and practical challenges for the design, implementation, and evaluation of vaccine efficacy trials. Lessons learned from COVID-19 highlight the need for innovative and flexible study design and application to quickly identify promising candidate vaccines. Trial design strategies should be tailored to the dynamics of the specific pathogen, location of the outbreak, and vaccine prototypes, within the regional socioeconomic constraints. Mathematical and statistical models can assist investigators in designing infectious disease clinical trials. We introduce key challenges for planning, evaluating, and modelling vaccine efficacy trials for emerging pathogens.

RevDate: 2021-10-10

Kim CS, Grady ST, Hart JE, et al (2021)

Long-term aircraft noise exposure and risk of hypertension in the Nurses' Health Studies.

Environmental research pii:S0013-9351(21)01496-1 [Epub ahead of print].

BACKGROUND: Aircraft noise can affect populations living near airports. Chronic exposure to aircraft noise has been associated with cardiovascular disease, including hypertension. However, previous studies have been limited in their ability to characterize noise exposures over time and to adequately control for confounders.

OBJECTIVES: The aim of this study was to examine the association between aircraft noise and incident hypertension in two cohorts of female nurses, using aircraft noise exposure estimates with high spatial resolution over a 20-year period.

METHODS: We obtained contour maps of modeled aircraft noise levels over time for 90 U.S. airports and linked them with geocoded addresses of participants in the Nurses' Health Study (NHS) and Nurses' Health Study II (NHS II) to assign noise exposure for 1994-2014 and 1995-2013, respectively. We used time-varying Cox proportional hazards models to estimate hypertension risk associated with time-varying noise exposure (dichotomized at 45 and 55 dB(A)), adjusting for fixed and time-varying confounders. Results from both cohorts were pooled via random effects meta-analysis.

RESULTS: and Discussion: In meta-analyses of parsimonious and fully-adjusted models with aircraft noise dichotomized at 45 dB(A), hazard ratios (HR) for hypertension incidence were 1.04 (95% CI: 1.00, 1.07) and 1.03 (95% CI: 0.99, 1.07), respectively. When dichotomized at 55 dB(A), HRs were 1.10 (95% CI: 1.01, 1.19) and 1.07 (95% CI: 0.98, 1.15), respectively. After conducting fully-adjusted sensitivity analyses limited to years in which particulate matter (PM) was obtained, we observed similar findings. In NHS, the PM-unadjusted HR was 1.01 (95% CI: 0.90, 1.14) and PM-adjusted HR was 1.01 (95% CI: 0.89, 1.14); in NHS II, the PM-unadjusted HR was 1.08 (95% CI: 0.96, 1.22) and the PM-adjusted HR was 1.08 (95% CI: 0.95, 1.21). Overall, in these cohorts, we found marginally suggestive evidence of a positive association between aircraft noise exposure and hypertension.

RevDate: 2021-10-10

Querfeld C, Thompson JA, Taylor MH, et al (2021)

Intralesional TTI-621, a novel biologic targeting the innate immune checkpoint CD47, in patients with relapsed or refractory mycosis fungoides or Sézary syndrome: a multicentre, phase 1 study.

The Lancet. Haematology pii:S2352-3026(21)00271-4 [Epub ahead of print].

BACKGROUND: Intravenous TTI-621 (SIRPα-IgG1 Fc) was previously shown to have activity in relapsed or refractory haematological malignancies. This phase 1 study evaluated the safety and activity of TTI-621 in patients with percutaneously accessible relapsed or refractory mycosis fungoides, Sézary syndrome, or solid tumours. Here we report the clinical and translational results among patients with mycosis fungoides or Sézary syndrome.

METHODS: This multicentre, open-label, phase 1 study was conducted at five academic health-care and research centres in the USA. Eligible patients were aged 18 years or older; had injectable, histologically or cytologically confirmed relapsed or refractory cutaneous T-cell lymphoma (CTCL) or solid tumours; Eastern Cooperative Oncology Group performance status of 2 or less; and adequate haematological, renal, hepatic, and cardiac function. TTI-621 was injected intralesionally in a sequential dose escalation (cohorts 1-5; single 1 mg, 3 mg, or 10 mg injection or three 10 mg injections weekly for 1 or 2 weeks) and in expansion cohorts (cohorts 6-9; 2 week induction at the maximum tolerated dose; weekly continuation was allowed). In cohort 6, patients were injected with TTI-621 in a single lesion and in cohort 7, they were injected in multiple lesions. In cohort 8, TTI-621 was combined with pembrolizumab 200 mg injections per product labels. In cohort 9, TTI-621 was combined with the standard labelled dose of subcutaneous pegylated interferon alpha-2a 90 μg. The primary endpoint was the incidence and severity of adverse events. The study is registered with ClinicalTrials.gov, NCT02890368, and was closed by the sponsor to focus on intravenous studies with TTI-621.

FINDINGS: Between Jan 30, 2017, and March 31, 2020, 66 patients with mycosis fungoides, Sézary syndrome, other CTCL, or solid tumours were screened, 35 of whom with mycosis fungoides or Sézary syndrome were enrolled and received intralesional TTI-621 (escalation, n=13; expansion, n=22). No dose-limiting toxicities occurred; the maximum tolerated dose was not established. In the dose expansion cohorts, the maximally assessed regimen (10 mg thrice weekly for 2 weeks) was used. 25 (71%) patients had treatment-related adverse events; the most common (occurring in ≥10% of patients) were chills (in ten [29%] patients), injection site pain (nine [26%]), and fatigue (eight [23%]). No treatment-related adverse events were grade 3 or more or serious. There were no treatment-related deaths. Rapid responses (median 45 days, IQR 17-66) occurred independently of disease stage or injection frequency. 26 (90%) of 29 evaluable patients had decreased Composite Assessment of Index Lesion Severity (CAILS) scores; ten (34%) had a decrease in CAILS score of 50% or more (CAILS response). CAILS score reductions occurred in adjacent non-injected lesions in eight (80%) of ten patients with paired assessments and in distal non-injected lesions in one additional patient.

INTERPRETATION: Intralesional TTI-621 was well tolerated and had activity in adjacent or distal non-injected lesions in patients with relapsed or refractory mycosis fungoides or Sézary syndrome, suggesting it has systemic and locoregional abscopal effects and potential as an immunotherapy for these conditions.

FUNDING: Trillium Therapeutics.

RevDate: 2021-10-11

Antia R, ME Halloran (2021)

Transition to endemicity: Understanding COVID-19.

Immunity [Epub ahead of print].

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its associated disease, coronavirus disease 2019 (COVID-19), has caused a devastating pandemic worldwide. Here, we explain basic concepts underlying the transition from an epidemic to an endemic state, where a pathogen is stably maintained in a population. We discuss how the number of infections and the severity of disease change in the transition from the epidemic to the endemic phase and consider the implications of this transition in the context of COVID-19.

RevDate: 2021-10-09

Schumacher BT, Bellettiere J, LaMonte MJ, et al (2021)

Accelerometer-Measured Daily Steps, Physical Function, and Subsequent Fall Risk in Older Women: The Objective Physical Activity and Cardiovascular Disease in Older Women Study.

Journal of aging and physical activity pii:japa.2021-0159 [Epub ahead of print].

Steps per day were measured by accelerometer for 7 days among 5,545 women aged 63-97 years between 2012 and 2014. Incident falls were ascertained from daily fall calendars for 13 months. Median steps per day were 3,216. There were 5,473 falls recorded over 61,564 fall calendar-months. The adjusted incidence rate ratio comparing women in the highest versus lowest step quartiles was 0.71 (95% confidence interval [0.54, 0.95]; ptrend across quartiles = .01). After further adjustment for physical function using the Short Physical Performance Battery, the incidence rate ratio was 0.86 ([0.64, 1.16]; ptrend = .27). Mediation analysis estimated that 63.7% of the association may be mediated by physical function (p = .03). In conclusion, higher steps per day were related to lower incident falls primarily through their beneficial association with physical functioning. Interventions that improve physical function, including those that involve stepping, could reduce falls in older adults.

RevDate: 2021-10-08

Anderson LJ, Migula D, Abay R, et al (2021)

Androgens and estrogens predict sexual function after autologous hematopoietic stem cell transplant in men.

Andrology [Epub ahead of print].

BACKGROUND: Autologous hematopoietic stem cell transplantation (AHSCT) is associated with sexual dysfunction and hypogonadism. Androgens are associated with sexual function in healthy men, but the role of estrogens is less well-known, and the association of these sex steroids with sexual function during AHSCT has not been characterized.

OBJECTIVES: The purpose of this study was to determine the predictive value of sex hormones before and acutely after AHSCT on sexual function recovery.

MATERIALS AND METHODS: We examined sex hormones and self-reported sexual function before (PRE) and one month post-AHSCT (MONTH1; n = 19), and sexual function again one-year post-AHSCT in men (YEAR1; n = 15).

RESULTS: Sexual function decreased from PRE to MONTH1 (p≤0.05) with no differences between PRE and YEAR1. Erectile dysfunction was prevalent at PRE (68.4%) and increased at MONTH1 (100%; p≤0.05) but was not different between PRE and YEAR1 (60.0%). From PRE to MONTH1, total testosterone (TT), dihydrotestosterone (DHT), follicle-stimulating hormone, and sex-hormone binding globulin (SHBG) increased (p≤0.02) while estradiol (p≤0.026) and estrone decreased (p≤0.001). MONTH1 TT and DHT were associated with sexual function at MONTH1, while PRE SHBG, MONTH1 estradiol, and change in estrone predicted sexual function at YEAR1.

DISCUSSION: Sexual dysfunction is very prevalent prior to AHSCT and is transiently and severely worsened acutely after. AHSCT induces acute decreases in total and free estrogens, with SHBG increases leading to increases in total androgens, without changes in free androgens.

CONCLUSION: Androgens and estrogens are both adversely affected by AHSCT but may predict sexual dysfunction in this population. This supports the premise that estrogen impacts sexual function independent from androgens and that steroid hormones are associated with acute changes in sexual function in this setting. Larger, controlled trials with long-term sex hormone assessment will need to confirm the association between early changes in estrogens and long-term sexual function recovery. This article is protected by copyright. All rights reserved.

RevDate: 2021-10-08

Russell HV, Chi YY, Okcu MF, et al (2021)

Rising drug cost impacts on cost-effectiveness of 2 chemotherapy regimens for intermediate-risk rhabdomyosarcoma: A report from the children's oncology group.

Cancer [Epub ahead of print].

BACKGROUND: The Children's Oncology Group clinical trial for intermediate risk rhabdomyosarcoma randomized participants to a combination of vincristine, dactinomycin, and cyclophosphamide (VAC) alone or VAC alternating with vincristine plus irinotecan (VAC/VI). Clinical outcomes were similar, but toxicity profiles differed. This study estimates the cost differences between arms from the health care system's perspective.

METHODS: A decision-analytic model was used to estimate the incremental cost-effectiveness ratio (ICER) of VAC versus VAC/VI. Protocol-required or recommended medications and laboratory studies were included. Costs were obtained from national databases or supporting literature and inflated to 2019 US dollars. Demographic and outcome data were obtained from the clinical trial and directed chart reviews. Life-years (LY) were estimated from life-expectancy tables and discounted by 3% annually. Probabilistic sensitivity analyses and alternative clinical scenarios identified factors driving costs.

RESULTS: Mean direct medical costs of VAC and VAC/VI were $164,757 and $102,303, respectively. VAC was associated with an additional 0.97 LY and an ICER of $64,386/LY compared with VAC/VI. The ICER was sensitive to survival estimations and to alternative clinical scenarios including outpatient cyclophosphamide delivery (ICER $49,037/LY) or substitution of alternative hematopoietic growth factor schedules (ICER $73,191-$91,579/LY). Applying drug prices from 2012 decreased the total costs of VAC by 20% and VAC/VI by 15% because of changes in dactinomycin and pegfilgrastim prices.

CONCLUSIONS: Neither arm was clearly more cost-effective. Pharmaceutical pricing and location of treatment drove costs and may inform future treatment decisions. Rising pharmaceutical costs added $30,000 per patient, a finding important for future drug-pricing policy decisions.

LAY SUMMARY: Two chemotherapy regimens recently tested side-by-side for rhabdomyosarcoma had similar tumor outcomes, but different side effects. The health care costs of each regimen were compared; neither was clearly more cost-effective. However, the costs of each treatment changed dramatically with choices of supportive medicines and location of treatment. Costs of treatment rose by 15% to 20% because of rising US drug costs not associated with the clinical trial.

RevDate: 2021-10-08

Weinberger AH, Steinberg ML, Mills SD, et al (2021)

Assessing sex, gender identity, sexual orientation, race, ethnicity, socioeconomic status, and mental health concerns in tobacco use disorder treatment research: Measurement challenges and recommendations from a Society for Research on Nicotine and Tobacco (SRNT) pre-conference workshop.

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco pii:6384329 [Epub ahead of print].

This paper reports on topics discussed at a Society for Research on Nicotine and Tobacco (SRNT) pre-conference workshop at the 2019 annual SRNT meeting. The goal of the preconference workshop was to help develop a shared understanding of the importance of several tobacco-related priority groups in tobacco use disorder treatment research and to highlight challenges in measurement related to these groups. The workshop focused on persons with minoritized sex, gender identity, and sexual orientation identities; persons with minoritized racial and ethnic backgrounds; persons with lower socioeconomic status (SES); and persons with mental health concerns. In addition to experiencing commercial tobacco-related health disparities, these groups are also underrepresented in tobacco research, including tobacco use disorder (TUD) treatment studies. Importantly, there is wide variation in how and whether researchers are identifying variation within these priority groups. Best practices for measuring and reporting sex, gender identity, sexual orientation, race, ethnicity, SES, and mental health concerns in TUD treatment research are needed. This paper provides information about measurement challenges when including these groups in TUD treatment research and specific recommendations about how to measure these groups and assess potential disparities in outcomes. The goal of this paper is to encourage TUD treatment researchers to use measurement best practices in these priority groups in an effort to conduct meaningful and equity-promoting research. Increasing the inclusion and visibility of these groups in TUD treatment research will help to move the field forward in decreasing tobacco-related health disparities.

IMPLICATIONS: Tobacco-related disparities exist for a number of priority groups including, among others, women, individuals with minoritized sexual and gender identities, individuals with minoritized racial and ethnic backgrounds, individuals with lower socioeconomic status, and individuals with mental health concerns. Research on tobacco use disorder (TUD) treatments for many of these subgroups is lacking. Accurate assessment and consideration of these subgroups will provide needed information about efficacious and effective TUD treatments, about potential mediators and moderators, and for accurately describing study samples, all critical elements for reducing tobacco-related disparities, and improving diversity, equity, and inclusion in TUD treatment research.

RevDate: 2021-10-08

Moore A, Machiela MJ, Machado M, et al (2021)

Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes.

Journal of translational genetics and genomics, 5:200-217.

Aim: Recessive genetic variation is thought to play a role in non-Hodgkin lymphoma (NHL) etiology. Runs of homozygosity (ROH), defined based on long, continuous segments of homozygous SNPs, can be used to estimate both measured and unmeasured recessive genetic variation. We sought to examine genome-wide homozygosity and NHL risk.

Methods: We used data from eight genome-wide association studies of four common NHL subtypes: 3061 chronic lymphocytic leukemia (CLL), 3814 diffuse large B-cell lymphoma (DLBCL), 2784 follicular lymphoma (FL), and 808 marginal zone lymphoma (MZL) cases, as well as 9374 controls. We examined the effect of homozygous variation on risk by: (1) estimating the fraction of the autosome containing runs of homozygosity (FROH); (2) calculating an inbreeding coefficient derived from the correlation among uniting gametes (F3); and (3) examining specific autosomal regions containing ROH. For each, we calculated beta coefficients and standard errors using logistic regression and combined estimates across studies using random-effects meta-analysis.

Results: We discovered positive associations between FROH and CLL (β = 21.1, SE = 4.41, P = 1.6 × 10-6) and FL (β = 11.4, SE = 5.82, P = 0.02) but not DLBCL (P = 1.0) or MZL (P = 0.91). For F3, we observed an association with CLL (β = 27.5, SE = 6.51, P = 2.4 × 10-5). We did not find evidence of associations with specific ROH, suggesting that the associations observed with FROH and F3 for CLL and FL risk were not driven by a single region of homozygosity.

Conclusion: Our findings support the role of recessive genetic variation in the etiology of CLL and FL; additional research is needed to identify the specific loci associated with NHL risk.

RevDate: 2021-10-08

Stephenson KE, Julg B, Tan CS, et al (2021)

Safety, pharmacokinetics and antiviral activity of PGT121, a broadly neutralizing monoclonal antibody against HIV-1: a randomized, placebo-controlled, phase 1 clinical trial.

Nature medicine [Epub ahead of print].

Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg-1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg-1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.

RevDate: 2021-10-08

Penson DF, Armstrong AJ, Concepcion RS, et al (2021)

Enzalutamide versus bicalutamide in patients with nonmetastatic castration-resistant prostate cancer: a prespecified subgroup analysis of the STRIVE trial.

Prostate cancer and prostatic diseases [Epub ahead of print].

BACKGROUND: In the phase 2, randomized, double-blind STRIVE trial, enzalutamide significantly reduced the risk of prostate cancer progression or death versus bicalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) and nonmetastatic CRPC (nmCRPC). The objective of this protocol-specified subgroup analysis of STRIVE was to investigate the benefit of enzalutamide versus bicalutamide specifically in patients with nmCRPC.

METHODS: Patients (N = 139) were stratified by disease stage and randomized to enzalutamide 160 mg/day plus androgen deprivation therapy (ADT; n = 70) or bicalutamide 50 mg/day plus ADT (n = 69).

RESULTS: Baseline characteristics of patients with nmCRPC were comparable between groups. At a median of 17 months follow-up, enzalutamide reduced the risk of progression or death by 76% versus bicalutamide in patients with nmCRPC (hazard ratio [HR], 0.24; 95% CI 0.14-0.42). Enzalutamide reduced risk of prostate-specific antigen progression by 82% versus bicalutamide in patients with nmCRPC (HR, 0.18; 95% CI 0.10-0.34). The most frequently reported adverse events by patients receiving enzalutamide were fatigue (36.2%), hot flush (20.3%), decreased appetite (17.4%), dizziness (17.4%), and nausea (17.4%).

CONCLUSIONS: This STRIVE subgroup analysis of patients with nmCRPC illustrates the benefit of enzalutamide in reducing the risk of progression or death versus bicalutamide in patients with nmCRPC.

TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01664923.

RevDate: 2021-10-07

Witlox WJA, Ramaekers BLT, Lacas B, et al (2021)

Association of different fractionation schedules for prophylactic cranial irradiation with toxicity and brain metastases-free survival in locally advanced non-small cell lung cancer: a pooled analysis of individual patient data from three randomized trials.

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology pii:S0167-8140(21)08750-8 [Epub ahead of print].

We assessed the impact of different PCI fractionation schedules (30 Gy in 10 versus 15 fractions) on brain metastases-free survival (BMFS) and toxicity. Our results suggest that 30 Gy in 10 fractions is associated with increased toxicity, while no conclusive evidence of improving BMFS was seen with this schedule.

RevDate: 2021-10-07

Walls AC, Miranda MC, Schäfer A, et al (2021)

Elicitation of broadly protective sarbecovirus immunity by receptor-binding domain nanoparticle vaccines.

Cell pii:S0092-8674(21)01062-X [Epub ahead of print].

Understanding vaccine-elicited protection against SARS-CoV-2 variants and other sarbecoviruses is key for guiding public health policies. We show that a clinical stage multivalent SARS-CoV-2 spike receptor-binding domain nanoparticle (RBD-NP) vaccine protects mice from SARS-CoV-2 challenge after a single immunization, indicating a potential dose-sparing strategy. We benchmarked serum neutralizing activity elicited by RBD-NPs in non-human primates against a lead prefusion-stabilized SARS-CoV-2 spike (HexaPro) using a panel of circulating mutants. Polyclonal antibodies elicited by both vaccines are similarly resilient to many RBD residue substitutions tested, although mutations at and surrounding position 484 have negative consequences for neutralization. Mosaic and cocktail nanoparticle immunogens displaying multiple sarbecovirus RBDs elicit broad neutralizing activity in mice and protect mice against SARS-CoV challenge even in the absence of SARS-CoV RBD in the vaccine. This study provides proof of principle that multivalent sarbecovirus RBD-NPs induce heterotypic protection and motivates advancing such broadly protective sarbecovirus vaccines to the clinic.

RevDate: 2021-10-07

Long JE, Montaño M, Sanchez H, et al (2021)

Self-Identity, Beliefs, and Behavior Among Men Who Have Sex with Transgender Women: Implications for HIV Research and Interventions.

Archives of sexual behavior [Epub ahead of print].

While transgender women have been identified as a global priority population for HIV prevention and treatment, little is known about the cisgender male partners of transgender women, including their sexual behavior and HIV prevalence. Previous research has suggested that these male partners have varied identities and sexual behavior, which make identifying and engaging them in research difficult. This paper describes interviews conducted with fifteen cisgender men who reported recent sexual activity with transgender women in Lima, Peru. The purpose of this research was to explore how these men reported their identities and sexual behavior, to better understand how they would interact with HIV outreach, research, and care. The major themes were sexual orientation and identity; view of transgender partners; social ties to transgender women and other men with transgender women partners; disclosure of relationships; HIV knowledge and risk perception; and attitudes toward interventions. We found that language used to assess sexual orientation was problematic in this population, due to lack of consistency between orientation and reported behavior, and unfamiliarity with terms used to describe sexual orientation. In addition, stigma, lack of knowledge of HIV prevention methods, and fear of disclosure of sexual behavior were identified as barriers that could impact engagement in HIV research, prevention, and care. However, participants reported social relationships with both transgender women and other men who have transgender partners, presenting possible avenues for recruitment into HIV research and healthcare services.

RevDate: 2021-10-06

Katzelnick LC, Zambrana JV, Elizondo D, et al (2021)

Dengue and Zika virus infections in children elicit cross-reactive protective and enhancing antibodies that persist long term.

Science translational medicine, 13(614):eabg9478.

[Figure: see text].

RevDate: 2021-10-05

Kinsella S, Evandy CA, Cooper K, et al (2021)

Attenuation of apoptotic cell detection triggers thymic regeneration after damage.

Cell reports, 37(1):109789.

The thymus, which is the primary site of T cell development, is particularly sensitive to insult but also has a remarkable capacity for repair. However, the mechanisms orchestrating regeneration are poorly understood, and delayed repair is common after cytoreductive therapies. Here, we demonstrate a trigger of thymic regeneration, centered on detecting the loss of dying thymocytes that are abundant during steady-state T cell development. Specifically, apoptotic thymocytes suppressed production of the regenerative factors IL-23 and BMP4 via TAM receptor signaling and activation of the Rho-GTPase Rac1, the intracellular pattern recognition receptor NOD2, and micro-RNA-29c. However, after damage, when profound thymocyte depletion occurs, this TAM-Rac1-NOD2-miR29c pathway is attenuated, increasing production of IL-23 and BMP4. Notably, pharmacological inhibition of Rac1-GTPase enhanced thymic function after acute damage. These findings identify a complex trigger of tissue regeneration and offer a regenerative strategy for restoring immune competence in patients whose thymic function has been compromised.

RevDate: 2021-10-05

Dong X, Liu W, Shen Y, et al (2021)

Anticoagulation Targeting Membrane-Bound Anionic Phospholipids Improved Outcomes of Traumatic Brain Injury in Mice.

Blood pii:477167 [Epub ahead of print].

Severe traumatic brain injury (TBI) often causes an acute systemic hypercoagulable state that rapidly develops into consumptive coagulopathy. We have recently demonstrated that TBI-induced coagulopathy (TBI-IC) is initiated and disseminated by brain-derived extracellular vesicles (BDEVs) and propagated by extracellular vesicles (EVs) from endothelial cells and platelets. Here, we present results from a study designed to test the hypothesis that anticoagulation targeting anionic phospholipid-expressing EVs prevents TBI-IC and improves the outcomes of mice subjected to severe TBI. We evaluated the effects of a fusion protein (ANV-6L15) for improving the outcomes of TBI. ANV-6L15 combines the phosphatidylserine (PS)-binding annexin V with a peptide anticoagulant modified to preferentially target extrinsic coagulation. We found that ANV-6L15 reduced intracranial hematoma by 70.2%, improved neurological function, and reduced death by 56.8% in mice subjected to fluid percussion injury at 1.9 atm. It protected the TBI mice by preventing vascular leakage, tissue edema, and the TBI-induced hypercoagulable state. We further showed that the extrinsic tenase complex was formed on the surfaces of circulating EVs, with the highest level found on BDEVs. Phospholipidomic analysis detected the highest levels of PS on BDEVs, as compared to EVs from endothelial cells and platelets (79.1, 15.2, and 3.5 nM/mg of protein, respectively). These findings demonstrate that TBI-IC results from a trauma-induced hypercoagulable state and may be treated by anticoagulation targeting on the anionic phospholipid-expressing membrane of EVs from the brain and other cells.

RevDate: 2021-10-05

Greninger AL, Rybkina K, Lin MJ, et al (2021)

Human parainfluenza virus evolution during lung infection of immunocompromised humans promotes viral persistence.

The Journal of clinical investigation pii:150506 [Epub ahead of print].

The capacity of respiratory viruses to undergo evolution within the respiratory tract raises the possibility of evolution under the selective pressure of the host environment or drug treatment. Long-term infections in immunocompromised hosts are potential drivers of viral evolution and development of infectious variants. We show that intra-host evolution in chronic human parainfluenza virus 3 (HPIV3) infection in immunocompromised individuals elicited mutations that favor viral entry and persistence, suggesting that similar processes may operate across enveloped respiratory viruses. We profiled longitudinal HPIV3 infections from two immunocompromised individuals that persisted for 278 and 98 days. Mutations accrued in the HPIV3 attachment protein hemagglutinin-neuraminidase (HN), including the first in vivo mutation in HN's receptor binding site responsible for activating the viral fusion process. Fixation of this mutation was associated with exposure to a drug that cleaves host cell sialic acid moieties. Longitudinal adaptation of HN was associated with features that promote viral entry and persistence in cells, including greater avidity for sialic acid and more active fusion activity in vitro, but not with antibody escape. Long term infection thus led to mutations promoting viral persistence, suggesting that host-directed therapeutics may support the evolution of viruses that alter their biophysical characteristics to persist in the face of these agents in vivo.

RevDate: 2021-10-05

Manohar PM, NE Davidson (2021)

Updates in endocrine therapy for metastatic breast cancer.

Cancer biology & medicine pii:j.issn.2095-3941.2021.0255 [Epub ahead of print].

Endocrine therapy (ET) remains the mainstay of treatment for steroid hormone receptor-positive, human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC). Tumor resistance to hormone therapy has led to the development of novel endocrine drug combinations, transforming the landscape of MBC management. The options for ET are expanding, with promising agents in the pipeline. Although MBC remains incurable, many patients can enjoy years of survival with good quality of life by cycling through the many available agents. With the plethora of available agents and rapid approvals, clinicians look to evidence-based guidelines to assist in treatment selection to maximize patient well-being. In this review, we provide a contemporary review of the advances in ET and a suggested algorithm to guide clinicians in daily management of patients with hormone receptor-positive, HER2-negative MBC. We will discuss landmark trials and highlight their impact in reshaping treatment approaches. Finally, we will provide a glimpse into advances on the horizon and the promise they bring to improve outcomes in patients with advanced breast cancer.

RevDate: 2021-10-05

Halpern AB, Othus M, Howard NP, et al (2021)

Comparative analysis of infectious complications with outpatient vs. inpatient care for adults with high-risk myeloid neoplasm receiving intensive induction chemotherapy.

Leukemia & lymphoma [Epub ahead of print].

We recently reported an early hospital discharge (EHD) care strategy following intensive acute myeloid leukemia (AML)-like chemotherapy is safe. To evaluate its impact on infectious outcomes, we compared all adults treated from 8/1/2014 to 7/31/2018 discharging within 72 h of completing chemotherapy (EHD) with hospitalized patients (controls) across 354 induction and 259 post-remission cycles. While overall outcomes were similar, gram-positive bacteremias were more common in EHD patients than control (p<.001), although they received fewer days of IV antimicrobials (p< .001). Notably, cumulative infection risks in EHD patients were similar after induction and post-remission therapy. In multivariable analysis, only EHD status was independently associated with risk for gram-positive bacteremia (p= .01), whereas the only independent risk factor for fungal infection was fluconazole (vs. posaconazole) use (p< .001). The observation of increased rates of gram-positive bacteremias with EHD identifies improvements in catheter management as one area to further increase the safety of this care approach.

RevDate: 2021-10-05

Pasvolsky O, Yeshurun M, Fraser R, et al (2021)

Maintenance therapy after second autologous hematopoietic cell transplantation for multiple myeloma. A CIBMTR analysis.

Bone marrow transplantation [Epub ahead of print].

The role of maintenance therapy after high-dose chemotherapy and first autologous transplantation in multiple myeloma (MM) is well established. We explored the effect of maintenance therapy on outcomes after salvage second autologous hematopoietic cell transplant (AHCT2) using the Center for International Blood and Marrow Transplant Research registry. Outcomes of interest included non-relapse mortality (NRM), relapse/progression (REL), progression-free and overall survival (PFS, OS). Of 522 patients who underwent AHCT2 between 2010 and 2018, 342 received maintenance therapy and 180 did not. Maintenance regimens included lenalidomide (42%), pomalidomide (13%), and bortezomib (13%). Median follow up was 58 months in the maintenance group and 61.5 months in the no-maintenance group. Univariate analysis showed superior outcomes at 5 years in maintenance compared to the no-maintenance group: NRM 2 (0.7-3.9)% vs 9.9 (5.9-14.9)%, (p < 0.01), REL 70.2 (64.4-75.8)% vs 80.3 (73.6-86.3)% (p < 0.01), PFS 27.8 (22.4-33.5)% vs. 9.8 (5.5-15.2)% (p < 0.01), and OS 54 (47.5-60.5)% vs 30.9 (23.2-39.2)% (p < 0.01), respectively. Use of maintenance therapy retained its association with improved outcomes in multivariate analysis. There was no difference in second cancers in the two groups (p = 0.39). We conclude that maintenance after AHCT2 is associated with improved 5-year outcomes.

RevDate: 2021-10-04

Deeg HJ (2021)

All patients with AML over 60 years of age should not be offered early allogeneic stem cell transplantation.

Blood advances pii:477148 [Epub ahead of print].

RevDate: 2021-10-04

Fontenele RS, Kraberger S, Hadfield J, et al (2021)

High-throughput sequencing of SARS-CoV-2 in wastewater provides insights into circulating variants.

Water research, 205:117710 pii:S0043-1354(21)00904-0 [Epub ahead of print].

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) likely emerged from a zoonotic spill-over event and has led to a global pandemic. The public health response has been predominantly informed by surveillance of symptomatic individuals and contact tracing, with quarantine, and other preventive measures have then been applied to mitigate further spread. Non-traditional methods of surveillance such as genomic epidemiology and wastewater-based epidemiology (WBE) have also been leveraged during this pandemic. Genomic epidemiology uses high-throughput sequencing of SARS-CoV-2 genomes to inform local and international transmission events, as well as the diversity of circulating variants. WBE uses wastewater to analyse community spread, as it is known that SARS-CoV-2 is shed through bodily excretions. Since both symptomatic and asymptomatic individuals contribute to wastewater inputs, we hypothesized that the resultant pooled sample of population-wide excreta can provide a more comprehensive picture of SARS-CoV-2 genomic diversity circulating in a community than clinical testing and sequencing alone. In this study, we analysed 91 wastewater samples from 11 states in the USA, where the majority of samples represent Maricopa County, Arizona (USA). With the objective of assessing the viral diversity at a population scale, we undertook a single-nucleotide variant (SNV) analysis on data from 52 samples with >90% SARS-CoV-2 genome coverage of sequence reads, and compared these SNVs with those detected in genomes sequenced from clinical patients. We identified 7973 SNVs, of which 548 were "novel" SNVs that had not yet been identified in the global clinical-derived data as of 17th June 2020 (the day after our last wastewater sampling date). However, between 17th of June 2020 and 20th November 2020, almost half of the novel SNVs have since been detected in clinical-derived data. Using the combination of SNVs present in each sample, we identified the more probable lineages present in that sample and compared them to lineages observed in North America prior to our sampling dates. The wastewater-derived SARS-CoV-2 sequence data indicates there were more lineages circulating across the sampled communities than represented in the clinical-derived data. Principal coordinate analyses identified patterns in population structure based on genetic variation within the sequenced samples, with clear trends associated with increased diversity likely due to a higher number of infected individuals relative to the sampling dates. We demonstrate that genetic correlation analysis combined with SNVs analysis using wastewater sampling can provide a comprehensive snapshot of the SARS-CoV-2 genetic population structure circulating within a community, which might not be observed if relying solely on clinical cases.

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ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

ESP Help

Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

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Cancer is the generic name for more than 100 diseases in which cells begin to grow and divide in an uncontrolled manner. Usually, when cells get too old or damaged, they die and new cells take their place. Cancer begins when genetic changes impair this orderly process so that some cells start to grow uncontrollably. The Emperor of All Maladies is a "biography" of cancer — from its first documented appearances thousands of years ago through the epic battles in the twentieth century to cure, control, and conquer it to a radical new understanding of its essence. This is a must read book for anyone with an interest in cancer. R. Robbins

Electronic Scholarly Publishing
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Bellingham, WA 98226

E-mail: RJR8222 @ gmail.com

Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).

Timelines

ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.

Biographies

Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

ESP Picks from Around the Web (updated 07 JUL 2018 )