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30 Mar 2023 at 01:45
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Bibliography on: Publications by FHCRC Researchers


Robert J. Robbins is a biologist, an educator, a science administrator, a publisher, an information technologist, and an IT leader and manager who specializes in advancing biomedical knowledge and supporting education through the application of information technology. More About:  RJR | OUR TEAM | OUR SERVICES | THIS WEBSITE

RJR: Recommended Bibliography 30 Mar 2023 at 01:45 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: ( fhcrc[Affiliation] OR "fred hutchinson"[Affiliation] OR "Fred Hutchinson Cancer Research"[Affiliation] OR "Fred Hutch"[affiliation] ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2023-03-27

Persad S, Choo ZN, Dien C, et al (2023)

SEACells infers transcriptional and epigenomic cellular states from single-cell genomics data.

Nature biotechnology [Epub ahead of print].

Metacells are cell groupings derived from single-cell sequencing data that represent highly granular, distinct cell states. Here we present single-cell aggregation of cell states (SEACells), an algorithm for identifying metacells that overcome the sparsity of single-cell data while retaining heterogeneity obscured by traditional cell clustering. SEACells outperforms existing algorithms in identifying comprehensive, compact and well-separated metacells in both RNA and assay for transposase-accessible chromatin (ATAC) modalities across datasets with discrete cell types and continuous trajectories. We demonstrate the use of SEACells to improve gene-peak associations, compute ATAC gene scores and infer the activities of critical regulators during differentiation. Metacell-level analysis scales to large datasets and is particularly well suited for patient cohorts, where per-patient aggregation provides more robust units for data integration. We use our metacells to reveal expression dynamics and gradual reconfiguration of the chromatin landscape during hematopoietic differentiation and to uniquely identify CD4 T cell differentiation and activation states associated with disease onset and severity in a Coronavirus Disease 2019 (COVID-19) patient cohort.

RevDate: 2023-03-27

Siebert R, Schuh A, Ott G, et al (2023)

Response to the Comments from the Groupe Francophone de Cytogénétique Hématologique (GFCH) on the 5th edition of the World Health Organization classification of haematolymphoid tumors.

Leukemia [Epub ahead of print].

RevDate: 2023-03-27

Ehler ED, Turcotte LM, Skamene S, et al (2023)

Idiopathic Pneumonitis Syndrome After Total Body Irradiation in Pediatric Patients Undergoing Myeloablative Hematopoietic Stem Cell Transplantation: A PENTEC Comprehensive Review.

International journal of radiation oncology, biology, physics pii:S0360-3016(23)00183-9 [Epub ahead of print].

PURPOSE: Pulmonary complications, especially idiopathic pneumonitis syndrome (IPS), are potentially life altering or fatal sequelae of hematopoietic cell transplantation (HCT). Total body irradiation (TBI) as part of the conditioning regimen has been implicated in IPS. A comprehensive PENTEC (Pediatric Normal Tissues in the Clinic) review was performed to increase our understanding of the role of TBI in the development of acute, noninfectious IPS.

METHODS AND MATERIALS: A systematic literature search was conducted using the MEDLINE, PubMed, and Cochrane library databases for articles describing pulmonary toxicity in children treated with HCT. Data pertaining to TBI and pulmonary endpoints were extracted. Risk of IPS was analyzed in relation to patient age, TBI dose, fractionation, dose rate, lung shielding, timing, and type of transplant, with the goal to better understand factors associated with this complication in children undergoing HCT. A logistic regression model was developed using a subset of studies with comparable transplant regimens and sufficient TBI data.

RESULTS: Six studies met criteria for modeling of the correlation of TBI parameters with IPS; all consisted of pediatric patients undergoing allogeneic HCT with a cyclophosphamide-based chemotherapy regimen. IPS was variably defined, but all studies that reported IPS were included in this analysis. The mean incidence of post-HCT IPS was 16% (range, 4%-41%). Mortality from IPS, when it occurred, was high (median, 50%; range, 45%-100%). Fractionated TBI prescription doses encompassed a narrow range of 9 to 14 Gy. Many differing TBI methods were reported, and there was an absence of 3-dimensional dose analysis of lung blocking techniques. Thus, a univariate correlation between IPS and total TBI dose, dose fractionation, dose rate, or TBI technique could not be made. However, a model, built from these studies based on prescribed dose using a normalized dose parameter of equivalent dose in 2-Gy fractions (EQD2), adjusted for dose rate, suggested correlation with the development of IPS (P = .0004). The model-predicted odds ratio for IPS was 24.3 Gy[-1] (95% confidence interval, 7.0-84.3). Use of TBI lung dose metrics (eg, midlung point dose) could not be successfully modeled, potentially because of dosimetric uncertainties in the actual delivered volumetric lung dose and imperfections in our modeling process.

CONCLUSIONS: This PENTEC report is a comprehensive review of IPS in pediatric patients receiving fractionated TBI regimens for allogenic HCT. IPS was not clearly associated with 1 single TBI factor. Modeling using dose-rate adjusted EQD2 showed a response with IPS for allogeneic HCT using a cyclophosphamide-based chemotherapy regimen. Therefore, this model suggests IPS mitigation strategies can focus on not just the dose and dose per fraction but also the dose rate used in TBI. More data are needed to confirm this model and to determine the influence of chemotherapy regimens and contribution from graft-versus-host disease. The presence of confounding variables (eg, systemic chemotherapies) that affect risk, the narrow range of fractionated TBI doses found in the literature, and limitations of other reported data (eg, lung point dose) may have prevented a more straightforward link between IPS and total dose from being observed.

RevDate: 2023-03-27

Ahmed A, Hippe DS, Snidarich M, et al (2023)

Delays in Recommended Follow-up after Positive Findings in Lung Cancer Screening .

Annals of the American Thoracic Society [Epub ahead of print].

RATIONALE: Lung cancer screening (LCS) is an effective tool to reduce mortality; However, barriers along the LCS care continuum including delay in follow-up care may reduce effectiveness. Objectives: The primary goals of this study were to evaluate delays in follow-up in patients with positive findings on LCS, and examine the impact of delay on lung cancer staging. Methods: This was a retrospective cohort study of patients enrolled in a multisite LCS program with positive LCS findings, defined as Lung-RADS 3, 4A, 4B or 4X. Time-to-first-follow-up was evaluated with delay considered >30 days beyond standardized Lung-RADS recommendation. Multivariable Cox models were used to evaluate the likelihood of delay by Lung-RADS category. Participants with resultant non-small cell lung cancer (NSCLC) were evaluated to determine if delay in follow-up was associated with clinical upstaging.

RESULTS: Three-hundred sixty-nine patients with 434 exams had positive findings; 16% of findings were ultimately diagnosed as lung cancer. In 47% of positive exams, there was a delay in follow-up (median delay: 104 days); 59% (210 days) of Lung-RADS 3 exams, 35% (64 days) of Lung-RADS 4A exams, and 40% (34 days) of Lung-RADS 4B/4X exams (p<0.001). In the 54 patients diagnosed with NSCLC through LCS, delay was associated with increased likelihood of clinical upstaging (p<0.001).

CONCLUSION: In this study of delay in follow-up after positive LCS findings, we found that nearly half of patients had delays in follow-up and that delay was associated with clinical upstaging in patients whose positive findings represent lung cancer. Further targeted interventions to ensure timely follow-up after positive LCS exam are critical.

RevDate: 2023-03-27

Bhimani J, O'Connell K, Kuk D, et al (2023)

Glucosamine and Chondroitin Use and Mortality Among Adults in the United States from 1999 to 2014.

Journal of integrative and complementary medicine [Epub ahead of print].

Introduction: Glucosamine and chondroitin are supplements that are often, but not always, used in combination for arthritis and joint pain. Multiple studies have suggested that glucosamine and chondroitin may be associated with reduced risk of several diseases, as well as all-cause, cancer- and respiratory disease-specific mortality. Methods: Nationally representative data from the National Health and Nutrition Examination Survey (NHANES) were used to further evaluate the association between glucosamine and chondroitin with mortality. Participants include 38,021 adults, ages 20+ years and older, who completed the detailed NHANES between 1999 and 2014. Participants were followed for death through linkage with the National Death Index through the end of 2015, over which time 4905 deaths occurred. Adjusted hazard ratios (HRs) for overall and cause-specific mortality were estimated using Cox regression models. Results: Despite glucosamine and chondroitin use appearing to be inversely associated with mortality in the minimally adjusted models, no association was observed in multivariable models (glucosamine: HR = 1.02; 95% confidence interval [CI]: 0.86-1.21, chondroitin: HR = 1.04, 95% CI: 0.87-1.25). No association with cancer mortality or other mortality rate was observed after multivariable adjustment. There was a suggestive, nonsignificant inverse association for cardiovascular-specific mortality (glucosamine HR = 0.72; 95% CI: 0.46-1.15, chondroitin: HR = 0.76; 95% CI: 0.47-1.21). Conclusion: The lack of significant relationship between glucosamine and chondroitin use and all-cause or cause-specific mortality after adjusting extensively for multiple covariates in this nationally representative adult population was in contrast to prior literature. Given the limited power to explore the cause-specific mortality, future well-powered studies will be needed to better understand the potential association with cardiovascular-specific mortality.

RevDate: 2023-03-27

Kher G, Sabin C, Lun JH, et al (2023)

Direct Blockade of the Norovirus Histo-Blood Group Antigen Binding Pocket by Nanobodies.

Journal of virology [Epub ahead of print].

Noroviruses are the leading cause of outbreaks of acute gastroenteritis. These viruses usually interact with histo-blood group antigens (HBGAs), which are considered essential cofactors for norovirus infection. This study structurally characterizes nanobodies developed against the clinically important GII.4 and GII.17 noroviruses with a focus on the identification of novel nanobodies that efficiently block the HBGA binding site. Using X-ray crystallography, we have characterized nine different nanobodies that bound to the top, side, or bottom of the P domain. The eight nanobodies that bound to the top or side of the P domain were mainly genotype specific, while one nanobody that bound to the bottom cross-reacted against several genotypes and showed HBGA blocking potential. The four nanobodies that bound to the top of the P domain also inhibited HBGA binding, and structural analysis revealed that these nanobodies interacted with several GII.4 and GII.17 P domain residues that commonly engaged HBGAs. Moreover, these nanobody complementarity-determining regions (CDRs) extended completely into the cofactor pockets and would likely impede HBGA engagement. The atomic level information for these nanobodies and their corresponding binding sites provide a valuable template for the discovery of additional "designer" nanobodies. These next-generation nanobodies would be designed to target other important genotypes and variants, while maintaining cofactor interference. Finally, our results clearly demonstrate for the first time that nanobodies directly targeting the HBGA binding site can function as potent norovirus inhibitors. IMPORTANCE Human noroviruses are highly contagious and a major problem in closed institutions, such as schools, hospitals, and cruise ships. Reducing norovirus infections is challenging on multiple levels and includes the frequent emergence of antigenic variants, which complicates designing effective, broadly reactive capsid therapeutics. We successfully developed and characterized four norovirus nanobodies that bound at the HBGA pockets. Compared with previously developed norovirus nanobodies that inhibited HBGA through disrupted particle stability, these four novel nanobodies directly inhibited HBGA engagement and interacted with HBGA binding residues. Importantly, these new nanobodies specifically target two genotypes that have caused the majority of outbreaks worldwide and consequently would have an enormous benefit if they could be further developed as norovirus therapeutics. To date, we have structurally characterized 16 different GII nanobody complexes, a number of which block HBGA binding. These structural data could be used to design multivalent nanobody constructs with improved inhibition properties.

RevDate: 2023-03-28
CmpDate: 2023-03-28

Martinez-Sanz P, Laurent ARG, Slot E, et al (2023)

Humanized MISTRG as a preclinical in vivo model to study human neutrophil-mediated immune processes.

Frontiers in immunology, 14:1105103.

INTRODUCTION: MISTRG mice have been genetically modified to allow development of a human myeloid compartment from engrafted human CD34+ haemopoietic stem cells, making them particularly suited to study the human innate immune system in vivo. Here, we characterized the human neutrophil population in these mice to establish a model that can be used to study the biology and contribution in immune processes of these cells in vivo.

METHODS AND RESULTS: We could isolate human bone marrow neutrophils from humanized MISTRG mice and confirmed that all neutrophil maturation stages from promyelocytes (CD11b-CD16-) to end-stage segmented cells (CD11b+CD16+) were present. We documented that these cells possessed normal functional properties, including degranulation, reactive oxygen species production, adhesion, and antibody-dependent cellular cytotoxicity towards antibody-opsonized tumor cells ex vivo. The acquisition of functional capacities positively correlated with the maturation state of the cell. We found that human neutrophils were retained in the bone marrow of humanized MISTRG mice during steady state. However, the mature segmented CD11b+CD16+ human neutrophils were released from the bone marrow in response to two well-established neutrophil-mobilizing agents (i.e., G-CSF and/or CXCR4 antagonist Plerixafor). Moreover, the neutrophil population in the humanized MISTRG mice actively reacted to thioglycolate-induced peritonitis and could infiltrate implanted human tumors, as shown by flow cytometry and fluorescent microscopy.

DISCUSSION: These results show that functional human neutrophils are generated and can be studied in vivo using the humanized MISTRG mice, providing a model to study the various functions of neutrophils in inflammation and in tumors.

RevDate: 2023-03-28
CmpDate: 2023-03-28

Prentice RL, Pettinger M, Zheng C, et al (2022)

Biomarkers for Components of Dietary Protein and Carbohydrate with Application to Chronic Disease Risk in Postmenopausal Women.

The Journal of nutrition, 152(4):1107-1117.

BACKGROUND: We recently developed protein and carbohydrate intake biomarkers using metabolomics profiles in serum and urine, and used them to correct self-reported dietary data for measurement error. Biomarker-calibrated carbohydrate density was inversely associated with chronic disease risk, whereas protein density associations were mixed.

OBJECTIVES: To elucidate and extend this earlier work through biomarker development for protein and carbohydrate components, including animal protein and fiber.

METHODS: Prospective disease association analyses were undertaken in Women's Health Initiative (WHI) cohorts of postmenopausal US women, aged 50-79 y when enrolled at 40 US clinical centers. Biomarkers were developed using an embedded human feeding study (n = 153). Calibration equations for protein and carbohydrate components were developed using a WHI nutritional biomarker study (n = 436). Calibrated intakes were associated with chronic disease incidence in WHI cohorts (n = 81,954) over a 20-y (median) follow-up period, using HR regression methods.

RESULTS: Previously reported elevations in cardiovascular disease (CVD) with higher-protein diets tended to be explained by animal protein density. For example, for coronary heart disease a 20% increment in animal protein density had an HR of 1.20 (95% CI: 1.02, 1.42) relative to the HR for total protein density. In comparison, cancer and diabetes risk showed little association with animal protein density beyond that attributable to total protein density. Inverse carbohydrate density associations with total CVD were mostly attributable to fiber density, with a 20% increment HR factor of 0.89 (95% CI: 0.83, 0.94). Cancer risk showed little association with fiber density, whereas diabetes risk had a 20% increment HR of 0.93 (95% CI: 0.88, 0.98) relative to the HRs for total carbohydrate density.

CONCLUSIONS: In a population of postmenopausal US women, CVD risk was associated with high-animal-protein and low-fiber diets, cancer risk was associated with low-carbohydrate diets, and diabetes risk was associated with low-fiber/low-carbohydrate diets.

RevDate: 2023-03-28
CmpDate: 2023-03-28

Cheng TD, Ilozumba MN, Balavarca Y, et al (2022)

Associations between Genetic Variants and Blood Biomarkers of One-Carbon Metabolism in Postmenopausal Women from the Women's Health Initiative Observational Study.

The Journal of nutrition, 152(4):1099-1106.

BACKGROUND: Genetic variation in one-carbon metabolism may affect nutrient concentrations and biological functions. However, data on genetic variants associated with blood biomarkers of one-carbon metabolism in US postmenopausal women are limited, and whether these associations were affected by the nationwide folic acid (FA) fortification program is unclear.

OBJECTIVES: We investigated associations between genetic variants and biomarkers of one-carbon metabolism using data from the Women's Health Initiative Observational Study.

METHODS: In 1573 non-Hispanic White (NHW) and 282 Black/African American, American Indian/Alaska Native, Asian/Pacific Islander, and Hispanic/Latino women aged 50-79 y, 288 nonsynonymous and tagging single-nucleotide variants (SNVs) were genotyped. RBC folate, plasma folate, pyridoxal-5'-phosphate (PLP), vitamin B-12, homocysteine, and cysteine concentrations were determined in 12-h fasting blood. Multivariable linear regression tested associations per variant allele and for an aggregated genetic risk score. Effect modifications before, during, and after nationwide FA fortification were examined.

RESULTS: After correction for multiple comparisons, among NHW women, 5,10-methylenetetrahydrofolate reductase (MTHFR) rs1801133 (677C→T) variant T was associated with lower plasma folate (-13.0%; 95% CI: -17.3%, -8.6%) and higher plasma homocysteine (3.5%; 95% CI: 1.7%, 5.3%) concentrations. Other associations for nonsynonymous SNVs included DNMT3A rs11695471 (T→A) with plasma PLP; EHMT2 rs535586 (G→A), TCN2 rs1131603 (L349S A→G), and TCN2 rs35838082 (R188W G→A) with plasma vitamin B-12; CBS rs2851391 (G→A) with plasma homocysteine; and MTHFD1 rs2236224 (G→A) and rs2236225 (R653Q G→A) with plasma cysteine. The influence of FA fortification on the associations was limited. Highest compared with lowest quartiles of aggregated genetic risk scores from SNVs in MTHFR and MTRR were associated with 14.8% to 18.9% lower RBC folate concentrations. Gene-biomarker associations were similar in women of other races/ethnicities.

CONCLUSIONS: Our findings on genetic variants associated with several one-carbon metabolism biomarkers may help elucidate mechanisms of maintaining B vitamin status in postmenopausal women.

RevDate: 2023-03-26

Hall AG, Winestone LE, Sullivan EM, et al (2023)

Access to CAR T-cell Clinical Trials in Underrepresented Populations: a Multicenter Cohort Study of Pediatric and Young Adult ALL Patients.

Transplantation and cellular therapy pii:S2666-6367(23)01198-3 [Epub ahead of print].

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy is a promising approach to improve survival for children and adults with relapsed/refractory (r/r) B-ALL, but these clinical trials may not be equally accessible to patients with low socioeconomic status or to patients from racial or ethnic minority groups.

OBJECTIVE: We sought to describe the sociodemographic characteristics of pediatric and AYA patients enrolled in CAR T-cell clinical trials and to compare these characteristics to other patients with r/r B-ALL.

STUDY DESIGN: We conducted a multicenter retrospective cohort study at five pediatric consortium sites to compare the sociodemographic characteristics of patients treated and enrolled in CAR T-cell trials at their home institution, other patients with r/r B-ALL treated at these sites, and patients referred from an external hospital for CAR T-cell trials. Patients were age 0-27 years with r/r B-ALL treated at one of the consortium sites between 2012-2018. Clinical and demographic data were collected from the electronic health record. We calculated distance from home to treating institution and assigned socioeconomic status scores based on census tract.

RESULTS: Among 337 patients treated for r/r B-ALL, 112 were referred from an external hospital to a consortium site and enrolled in a CAR T-cell trial; 225 were treated primarily at a consortium site, with 34% enrolled in a CAR T-cell trial. Patients treated primarily at a consortium site had similar characteristics, regardless of trial enrollment. A lower proportion of Hispanic patients (37% vs. 56%, p=0.03), patients whose preferred language was Spanish (8% vs. 22%, p=0.006), and publicly insured patients (38% vs. 65%, p=0.001) were referred from an external hospital compared to patients treated primarily at a consortium site and enrolled in a CAR T-cell trial.

CONCLUSIONS: Patients who are Hispanic, Spanish-speaking, or publicly insured are underrepresented in referrals from external hospitals to CAR T-cell centers. External provider implicit bias may also influence referral of these patients. Establishing partnerships between CAR T-cell centers and external hospital sites may improve provider familiarity, patient referral, and patient access to CAR T-cell clinical trials.

RevDate: 2023-03-25

Moolgavkar SH, Chang ET, EG Luebeck (2022)

Multistage carcinogenesis: Impact of age, genetic, and environmental factors on the incidence of malignant mesothelioma.

Environmental research pii:S0013-9351(22)01909-0 [Epub ahead of print].

The current paradigm of carcinogenesis as a cellular evolutionary process driven by mutations of a few critical driver genes has immediate logical implications for the epidemiology of cancer. These include the impact of age on cancer risk, the role played by inherited tumor predisposition syndromes, and the interaction of genetics and environmental exposures on cancer risk. In this paper, we explore the following logical epidemiological consequences of carcinogenesis as a clonal process of mutation accumulation, with special emphasis on asbestos-related cancers, specifically malignant mesothelioma.

RevDate: 2023-03-25

Dec E, Clement J, Cheng K, et al (2023)

Centenarian clocks: epigenetic clocks for validating claims of exceptional longevity.

GeroScience [Epub ahead of print].

Claims surrounding exceptional longevity are sometimes disputed or dismissed for lack of credible evidence. Here, we present three DNA methylation-based age estimators (epigenetic clocks) for verifying age claims of centenarians. The three centenarian clocks were developed based on n = 7039 blood and saliva samples from individuals older than 40, including n = 184 samples from centenarians, 122 samples from semi-supercentenarians (aged 105 +), and 25 samples from supercentenarians (aged 110 +). The oldest individual was 115 years old. Our most accurate centenarian clock resulted from applying a neural network model to a training set composed of individuals older than 40. An epigenome-wide association study of age in different age groups revealed that age effects in young individuals (age < 40) are correlated (r = 0.55) with age effects in old individuals (age > 90). We present a chromatin state analysis of age effects in centenarians. The centenarian clocks are expected to be useful for validating claims surrounding exceptional old age.

RevDate: 2023-03-24

Guo C, Figueiredo I, Gurel B, et al (2023)

Erratum to "B7-H3 as a Therapeutic Target in Advanced Prostate Cancer" [Eur Urol 2023;83(3):224-38].

RevDate: 2023-03-24

Dotan E, Catalano P, Lenchik L, et al (2023)

The GIANT trial (ECOG-ACRIN EA2186) methods paper: A randomized phase II study of gemcitabine and nab-paclitaxel compared with 5-fluorouracil, leucovorin, and liposomal irinotecan in older patients with treatment-naïve metastatic pancreatic cancer - defining a new treatment option for older vulnerable patients.

Journal of geriatric oncology, 14(3):101474 pii:S1879-4068(23)00071-1 [Epub ahead of print].

INTRODUCTION: Pancreatic cancer is the fourth leading cause of cancer-related death in the US with an increasing incidence in older adults (OA) over age 70. There are currently no treatment guidelines for OA with metastatic pancreatic cancer (mPCA) and selecting a chemotherapy regimen for these patients is subjective, based largely on chronologic age and performance status (PS). Geriatric screening tools provide a more objective and accurate evaluation of a patient's overall health but have not yet been validated in patient selection for mPCA treatment. This study aims to elucidate the optimal chemotherapy treatment of vulnerable OA with mPCA and understand the geriatric factors that affect outcomes in this population.

METHODS/DESIGN: The GIANT (ECOG-ACRIN EA2186) study is multicenter, randomized phase II trial enrolling patients over age 70 with newly diagnosed mPCA. This study utilizes a screening geriatric assessment (GA) which characterizes patients as fit, vulnerable, or frail. Patients with mild abnormalities in functional status and/or cognition, moderate comorbidities, or over age 80 are considered vulnerable. Enrolled patients are randomized to one of two dose-reduced treatment regimens (gemcitabine/nab-paclitaxel every other week, or dose-reduced 5-fluoruracil (5FU)/ liposomal irinotecan (nal-IRI) every other week). GA and quality of life (QoL) evaluations are completed prior to treatment initiation and at each disease evaluation. Overall survival (OS) is the primary endpoint, with secondary endpoints including progression free survival (PFS) and objective response rate (ORR). Enrolled patients will be stratified by age (70-74 vs ≥75) and ECOG PS (0-1 vs 2). Additional endpoints of interest for OA include evaluation of risk factors identified through GA, QoL evaluation, and toxicities of interest for older adults. Correlative studies include assessment of pro-inflammatory biomarkers of aging in the blood (IL-6, CRP) and imaging evaluation of sarcopenia as predictors of treatment tolerance.

DISCUSSION: The GIANT study is the first randomized, prospective national trial evaluating vulnerable OA with mPCA aimed at developing a tailored treatment approach for this patient population. This trial has the potential to establish a new way of objectively selecting vulnerable OA with mPCA for modified treatment and to establish a new standard of care in this growing patient population.

TRIAL REGISTRATION: This trial is registered with ClinicalTrial.gov Identifier NCT04233866.

RevDate: 2023-03-27

Cyrus E, Lama JR, Sanchez J, et al (2023)

Substance use and other correlates of HIV infection among transwomen and men who have sex with men in Perú: Implications for targeted HIV prevention strategies for transwomen.

PLOS global public health, 3(1):e0001464.

Characterization of HIV risk factors among transwomen and men who have sex with men (MSM) should be assessed separately and independently. However, due to several constraints, these populations continue to be conflated in clinical research and data. There are limited datasets globally powered to make such comparisons. The study aimed to use one of the largest surveys of transwomen and MSM in Latin America to determine differences in HIV risk and related correlates between the two populations. Secondary data analysis was completed using a cross-sectional biobehavioral survey of 4413 MSM and 714 transwomen living in Perú. Chi Square analysis of selected HIV correlates was conducted to examine differences between transwomen and MSM. Additionally, stratified binary logistic regression was used to split data for further comparative analyses of correlates associated with transwomen and MSM separately. HIV prevalence among transwomen was two-fold greater than among MSM (14.9% vs. 7.0%, p<0.001). Transwomen had a higher prevalence of most HIV risk factors assessed, including presence of alcohol dependence (16.4% vs. 19.0%; p < .001) and drug use in the past 3 months (17.0% vs. 14.9%). MSM were more likely to use marijuana (68.0% vs. 50.0%, p < .001), and transwomen were more likely to engage in inhaled cocaine use (70.0% vs. 51.1%, p < .001). The regression exposed differences in correlates driving sub-epidemics in transwomen vs. MSM, with a trend of substance use increasing HIV risk for transwomen only. Transwomen were more likely to be HIV-infected and had different risk factors from MSM. Targeted prevention strategies are needed for transwomen that are at highest risk. Additionally, further research is needed to determine if these observations in Perú regarding substance use patterns and the role of substance use in HIV risk relate to other trans populations globally.

RevDate: 2023-03-27

Mesic A, Jackson EK, Lalika M, et al (2022)

Interferon-based agents for current and future viral respiratory infections: A scoping literature review of human studies.

PLOS global public health, 2(4):e0000231.

The interferon (IFN) system is a potent line of defense against viral infections. IFN-based agents already tested may be of use in COVID-19 or future viral respiratory outbreaks. Here we review the comparative efficacy, safety/tolerability, and future potential of IFN-based therapeutics. We reviewed human studies in which IFN or IFN pathway-interacting agents were used for viral respiratory infections. We identified 977 articles, of which 194 were included for full-text review. Of these, we deemed 35 articles to be relevant. The use of IFN-based agents for pre-exposure prophylaxis (n = 19) and treatment (n = 15) were most common, with intranasal (n = 22) as the most common route. We found IFN-α (n = 23) was used most often, and rhinovirus (n = 14) was the most common causative agent. Studies demonstrated mixed efficacy but generally positive safety and tolerability. Host-directed therapies, such as IFN or IFN inducers, are worthy of additional research to target viral respiratory infections lacking direct-acting antivirals.

RevDate: 2023-03-27
CmpDate: 2023-03-27

Peehl DM, Badea CT, Chenevert TL, et al (2023)

Animal Models and Their Role in Imaging-Assisted Co-Clinical Trials.

Tomography (Ann Arbor, Mich.), 9(2):657-680.

The availability of high-fidelity animal models for oncology research has grown enormously in recent years, enabling preclinical studies relevant to prevention, diagnosis, and treatment of cancer to be undertaken. This has led to increased opportunities to conduct co-clinical trials, which are studies on patients that are carried out parallel to or sequentially with animal models of cancer that mirror the biology of the patients' tumors. Patient-derived xenografts (PDX) and genetically engineered mouse models (GEMM) are considered to be the models that best represent human disease and have high translational value. Notably, one element of co-clinical trials that still needs significant optimization is quantitative imaging. The National Cancer Institute has organized a Co-Clinical Imaging Resource Program (CIRP) network to establish best practices for co-clinical imaging and to optimize translational quantitative imaging methodologies. This overview describes the ten co-clinical trials of investigators from eleven institutions who are currently supported by the CIRP initiative and are members of the Animal Models and Co-clinical Trials (AMCT) Working Group. Each team describes their corresponding clinical trial, type of cancer targeted, rationale for choice of animal models, therapy, and imaging modalities. The strengths and weaknesses of the co-clinical trial design and the challenges encountered are considered. The rich research resources generated by the members of the AMCT Working Group will benefit the broad research community and improve the quality and translational impact of imaging in co-clinical trials.

RevDate: 2023-03-24

Ameen R, Titus R, Geo JA, et al (2023)

KIR genotype and haplotype repertoire in Kuwaiti healthy donors, hematopoietic cell transplant recipients and healthy family members.

HLA [Epub ahead of print].

The gene complex located on chromosome 19q13.4 encodes the Killer-cell Immunoglobulin-like Receptors (KIRs), which exhibit remarkable polymorphism in both gene content and sequences. Further, the repertoire of KIR genes varies within and between populations, creating a diverse pool of KIR genotypes. This study was carried out to characterize KIR genotypes and haplotypes among 379 Arab Kuwaiti individuals including 60 subjects from 20 trio families, 49 hematopoietic cell transplantation (HCT) recipients and 270 healthy Kuwaiti volunteer HCT donors. KIR Genotyping was performed by a combination of reverse sequence specific oligonucleotide probes (rSSO) and/or Real Time PCR. The frequencies of KIR genes in 270 healthy Kuwaiti volunteer donors were compared to previously reported frequencies in other populations. In addition, we compared the differences in KIR repertoire of patients and healthy donors to investigate the reproducibility of previously reported significant differences between patients with hematological malignancies and healthy donors. The observed frequencies in our cohort volunteer HCT donors was comparable to those reported in neighboring Arab populations. The activating genes KIR2DS1, KIR2DS5 and KIR3DS1 and the inhibitory gene KIR2DL5 were significantly more frequent in patients compared to healthy donors, however, none of the previously reported differences were reproducible in our Kuwaiti cohort. This report is the first description of KIR gene carrier frequency and haplotype characterization in a fairly large cohort of the Kuwaiti population, which may have implications in KIR based HCT donor selection strategies.

RevDate: 2023-03-24

Seyerle AA, Laurie CA, Coombes BJ, et al (2023)

Whole Genome Analysis of Venous Thromboembolism: the Trans-Omics for Precision Medicine Program.

Circulation. Genomic and precision medicine [Epub ahead of print].

Background Risk for venous thromboembolism has a strong genetic component. Whole genome sequencingfrom the Trans-Omics for Precision Medicine program allowed us to look for new associations, particularly rare variants missed by standard genome-wide association studies. Methods The 3793 cases and 7834 controls (11.6% of cases were Black, Hispanic/Latino, or Asian American) were analyzed using a single variant approach and an aggregate gene-based approach using our primary filter (included only loss-of-function and missense variants predicted to be deleterious) and our secondary filter (included all missense variants). Results Single variant analyses identified associations at 5 known loci. Aggregate gene-based analyses identified only PROC (odds ratio, 6.2 for carriers of rare variants; P=7.4×10[-14]) when using our primary filter. Employing our secondary variant filter led to a smaller effect size at PROC (odds ratio, 3.8; P=1.6×10[-14]), while excluding variants found only in rare isoforms led to a larger one (odds ratio, 7.5). Different filtering strategies improved the signal for 2 other known genes: PROS1 became significant (minimum P=1.8×10[-6] with the secondary filter), while SERPINC1 did not (minimum P=4.4×10[-5] with minor allele frequency <0.0005). Results were largely the same when restricting the analyses to include only unprovoked cases; however, one novel gene, MS4A1, became significant (P=4.4×10[-7] using all missense variants with minor allele frequency <0.0005). Conclusions Here, we have demonstrated the importance of using multiple variant filtering strategies, as we detected additional genes when filtering variants based on their predicted deleteriousness, frequency, and presence on the most expressed isoforms. Our primary analyses did not identify new candidate loci; thus larger follow-up studies are needed to replicate the novel MS4A1 locus and to identify additional rare variation associated with venous thromboembolism.

RevDate: 2023-03-26

Nakamura M, Hui J, Stjepić V, et al (2023)

Scar/WAVE has Rac GTPase-independent functions during cell wound repair.

Scientific reports, 13(1):4763.

Rho family GTPases regulate both linear and branched actin dynamics by activating downstream effectors to facilitate the assembly and function of complex cellular structures such as lamellipodia and contractile actomyosin rings. Wiskott-Aldrich Syndrome (WAS) family proteins are downstream effectors of Rho family GTPases that usually function in a one-to-one correspondence to regulate branched actin nucleation. In particular, the WAS protein Scar/WAVE has been shown to exhibit one-to-one correspondence with Rac GTPase. Here we show that Rac and SCAR are recruited to cell wounds in the Drosophila repair model and are required for the proper formation and maintenance of the dynamic actomyosin ring formed at the wound periphery. Interestingly, we find that SCAR is recruited to wounds earlier than Rac and is still recruited to the wound periphery in the presence of a potent Rac inhibitor. We also show that while Rac is important for actin recruitment to the actomyosin ring, SCAR serves to organize the actomyosin ring and facilitate its anchoring to the overlying plasma membrane. These differing spatiotemporal recruitment patterns and wound repair phenotypes highlight the Rac-independent functions of SCAR and provide an exciting new context in which to investigate these newly uncovered SCAR functions.

RevDate: 2023-03-23

Goodsell KE, Sharib JM, Pillarisetty VG, et al (2023)

Leiomyosarcoma of the inferior vena cava: An uncommon malignancy requiring unique reconstructive approaches.

Surgery is considered for patients without metastatic disease and with resectable primary tumor. Pre-operatively, high quality imaging is reviewed to determine the likely extent of resection, specifically including the need for potential en-bloc resection of adjacent organs. In cases where up-front surgical approach would expose the patient to excessive morbidity (such as bilateral nephrectomy, multi-visceral resection, or prohibitively high risk of positive margins), neoadjuvant chemotherapy and/or chemoradiotherapy is considered. Though data are sparse in LMS, a neoadjuvant regimen of doxorubicin and dacarbazine is typically considered for borderline resectable tumors at our institution; patients may be treated for up to 4 months with interval imaging every 2 months to evaluate for tumor response. Postoperatively, adjuvant systemic therapy or radiation may be considered for patients with positive surgical margins or high-grade tumors.

RevDate: 2023-03-23

Arkatkar T, Davé VA, Cruz Talavera I, et al (2023)

Memory T cells possess an innate-like function in local protection from mucosal infection.

The Journal of clinical investigation pii:162800 [Epub ahead of print].

Mucosal infections pose a significant global health burden. Antigen-specific tissue resident T cells are critical to maintaining barrier immunity. Previous studies in the context of systemic infection suggest that memory CD8 T cells may also provide innate-like protection against antigenically unrelated pathogens independent of TCR engagement. Whether "bystander T cell activation" is also an important defense mechanism in the mucosa is poorly understood. Here, we investigated if innate-like memory CD8 T cells could protect against a model mucosal virus infection, herpes simplex virus 2 (HSV-2). We found that immunization with an irrelevant antigen delayed disease progression from lethal HSV-2 challenge, suggesting that memory CD8 T cells may mediate protection despite the lack of antigen-specificity. Upon HSV-2 infection, we observed an early infiltration, rather than substantial local proliferation, of antigen-non-specific CD8 T cells, which became bystander-activated only within the infected mucosal tissue. Critically, we show that bystander-activated CD8 T cells are sufficient to reduce early viral burden after HSV-2 infection. Finally, local cytokine cues within the tissue microenvironment after infection were sufficient for bystander activation of mucosal tissue memory CD8 T cells from mice and humans. Altogether, our findings suggest that local bystander-activation of CD8 memory T cells contribute a fast and effective innate-like response to infection in mucosal tissue.

RevDate: 2023-03-23

Disis MLN (2023)

JAMA Oncology-The Year in Review, 2022.

JAMA oncology pii:2802832 [Epub ahead of print].

RevDate: 2023-03-24

Babu TM, Srinivasan S, Magaret A, et al (2023)

Genital Herpes Simplex Virus Type 2 Suppression With Valacyclovir Is Not Associated With Changes in Nugent Score or Absolute Abundance of Key Vaginal Bacteria.

Open forum infectious diseases, 10(3):ofad099.

BACKGROUND: In women, genital herpes simplex virus type 2 (HSV-2) infection is associated with increased risk for recurrent bacterial vaginosis (BV), but causal relationships are unclear.

METHODS: Women with a self-reported history of BV and HSV-2 seropositivity self-collected vaginal and anogenital swabs for 2 nonconsecutive 28-day periods, in the absence or presence of valacyclovir suppressive therapy (500 mg daily). HSV polymerase chain reaction was performed on anogenital swabs; vaginal swabs were used for assessment of BV by Nugent score and quantification of vaginal microbiota. Days with BV, defined by Nugent score ≥7, were compared during the observational period and valacyclovir treatment.

RESULTS: Forty-one women collected swabs for a median of 28 days (range, 20-32 days) each study period. The HSV-2 shedding rate decreased from 109 of 1126 days (9.7%) presuppression to 6 of 1125 days (0.05%) during valacyclovir (rate ratio [RR], 0.06 [95% confidence interval {CI}, .02-.13]). BV occurred on 343 of 1103 days (31.1%) during observation and 302 of 1091 days (27.7%) during valacyclovir (RR, 0.90 [95% CI, .68-1.20]). The median per-person Nugent score was 3.8 during observation and 4.0 during valacyclovir. Average log10 concentrations of vaginal bacterial species did not change significantly during valacyclovir treatment.

CONCLUSIONS: Short-term HSV-2 suppression with valacyclovir did not significantly affect the Nugent score or the vaginal microbiome despite potent suppression of HSV-2 shedding.

RevDate: 2023-03-25
CmpDate: 2023-03-24

Johnson DB, Atkins MB, Hennessy C, et al (2023)

Impact of COVID-19 in patients on active melanoma therapy and with history of melanoma.

BMC cancer, 23(1):265.

INTRODUCTION: COVID-19 particularly impacted patients with co-morbid conditions, including cancer. Patients with melanoma have not been specifically studied in large numbers. Here, we sought to identify factors that associated with COVID-19 severity among patients with melanoma, particularly assessing outcomes of patients on active targeted or immune therapy.

METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, we identified 307 patients with melanoma diagnosed with COVID-19. We used multivariable models to assess demographic, cancer-related, and treatment-related factors associated with COVID-19 severity on a 6-level ordinal severity scale. We assessed whether treatment was associated with increased cardiac or pulmonary dysfunction among hospitalized patients and assessed mortality among patients with a history of melanoma compared with other cancer survivors.

RESULTS: Of 307 patients, 52 received immunotherapy (17%), and 32 targeted therapy (10%) in the previous 3 months. Using multivariable analyses, these treatments were not associated with COVID-19 severity (immunotherapy OR 0.51, 95% CI 0.19 - 1.39; targeted therapy OR 1.89, 95% CI 0.64 - 5.55). Among hospitalized patients, no signals of increased cardiac or pulmonary organ dysfunction, as measured by troponin, brain natriuretic peptide, and oxygenation were noted. Patients with a history of melanoma had similar 90-day mortality compared with other cancer survivors (OR 1.21, 95% CI 0.62 - 2.35).

CONCLUSIONS: Melanoma therapies did not appear to be associated with increased severity of COVID-19 or worsening organ dysfunction. Patients with history of melanoma had similar 90-day survival following COVID-19 compared with other cancer survivors.

RevDate: 2023-03-23

Goffredo P, Hart AA, Tran CG, et al (2023)

Patterns of Care and Outcomes of Rectal Cancer Patients from the Iowa Cancer Registry: Role of Hospital Volume and Tumor Location.

Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract [Epub ahead of print].

BACKGROUND: Centralization of rectal cancer surgery has been associated with high-quality oncologic care. However, several patient, disease and system-related factors can impact where patients receive care. We hypothesized that patients with low rectal tumors would undergo treatment at high-volume centers and would be more likely to receive guideline-based multidisciplinary treatment.

METHODS: Adults who underwent proctectomy for stage II/III rectal cancer were included from the Iowa Cancer Registry and supplemented with tumor location data. Multinomial logistic regression was employed to analyze factors associated with receiving care in high-volume hospital, while logistic regression for those associated with ≥ 12 lymph node yield, pre-operative chemoradiation and sphincter-preserving surgery.

RESULTS: Of 414 patients, 38%, 39%, and 22% had low, mid, and high rectal cancers, respectively. Thirty-two percent were > 65 years, 38% female, and 68% had stage III tumors. Older age and rural residence, but not tumor location, were associated with surgical treatment in low-volume hospitals. Higher tumor location, high-volume, and NCI-designated hospitals had higher nodal yield (≥ 12). Hospital-volume was not associated with neoadjuvant chemoradiation rates or circumferential resection margin status. Sphincter-sparing surgery was independently associated with high tumor location, female sex, and stage III cancer, but not hospital volume.

CONCLUSIONS: Low tumor location was not associated with care in high-volume hospitals. High-volume and NCI-designated hospitals had higher nodal yields, but not significantly higher neoadjuvant chemoradiation, negative circumferential margin, or sphincter preservation rates. Therefore, providing educational/quality improvement support in lower volume centers may be more pragmatic than attempting to centralize rectal cancer care among high-volume centers.

RevDate: 2023-03-23

Berghuijs KMVT, Kaddas HK, Trujillo G, et al (2023)

Age-related differences in employment, insurance, and financial hardship among colorectal cancer patients: a report from the ColoCare Study.

Journal of cancer survivorship : research and practice [Epub ahead of print].

PURPOSE: Employment and financial hardships are common issues for working-age colorectal cancer patients. We surveyed colorectal cancer survivors to investigate employment, insurance, and financial outcomes by age at diagnosis.

METHODS: Cross-sectional survey of six ColoCare Study sites regarding employment, insurance, and financial hardship outcomes. Eligible participants were 1 to 5 years from colorectal cancer diagnosis. Diagnosis age (18-49, 50-64, 65+ years) with outcomes of interest were compared using chi-square and t-tests. Multivariable logistic and Poisson regressions were fit to examine association of demographic factors with any material/psychological hardship (yes/no) and the count of hardships.

RESULTS: N = 202 participants completed the survey (age: 18-49 (n = 42, 20.8%), 50-64 (n = 79, 39.1%), 65+ (n = 81, 40.1%)). Most diagnosed age < 65 worked at diagnosis (18-49: 83%; 50-64: 64%; 65+ : 14%, p < 0.001) and continued working after diagnosis (18-49: 76%; 50-64: 59%; 65+ : 13%; p < 0.001). Participants age 18-49 reported cancer-related difficulties with mental (81.3%) and physical (89%) tasks at work more than those working in the older age groups (45%-61%). In regression models, among those reporting any hardship, the rates of material and psychological hardships were higher among those age 18-64 (Incidence Rate Ratios (IRR) range 1.5-2.3 vs. age 65+) and for those with < college (IRR range 1.3-1.6 vs. college +).

CONCLUSIONS: Younger colorectal cancer patients are more likely to work after a cancer diagnosis and during cancer treatment, but report higher levels of financial hardship than older patients.

Younger colorectal cancer patients may encounter financial hardship, thus may feel a need to work during and after treatment.

RevDate: 2023-03-24
CmpDate: 2023-03-24

Wahid KA, Lin D, Sahin O, et al (2023)

Large scale crowdsourced radiotherapy segmentations across a variety of cancer anatomic sites.

Scientific data, 10(1):161.

Clinician generated segmentation of tumor and healthy tissue regions of interest (ROIs) on medical images is crucial for radiotherapy. However, interobserver segmentation variability has long been considered a significant detriment to the implementation of high-quality and consistent radiotherapy dose delivery. This has prompted the increasing development of automated segmentation approaches. However, extant segmentation datasets typically only provide segmentations generated by a limited number of annotators with varying, and often unspecified, levels of expertise. In this data descriptor, numerous clinician annotators manually generated segmentations for ROIs on computed tomography images across a variety of cancer sites (breast, sarcoma, head and neck, gynecologic, gastrointestinal; one patient per cancer site) for the Contouring Collaborative for Consensus in Radiation Oncology challenge. In total, over 200 annotators (experts and non-experts) contributed using a standardized annotation platform (ProKnow). Subsequently, we converted Digital Imaging and Communications in Medicine data into Neuroimaging Informatics Technology Initiative format with standardized nomenclature for ease of use. In addition, we generated consensus segmentations for experts and non-experts using the Simultaneous Truth and Performance Level Estimation method. These standardized, structured, and easily accessible data are a valuable resource for systematically studying variability in segmentation applications.

RevDate: 2023-03-24

Fong Y, Huang Y, Benkeser D, et al (2023)

Publisher Correction: Immune correlates analysis of the PREVENT-19 COVID-19 vaccine efficacy clinical trial.

Nature communications, 14(1):1581 pii:10.1038/s41467-023-37367-2.

RevDate: 2023-03-22

Lim EA, Schweizer MT, Chi KN, et al (2023)

Phase 1 Study of Safety and Preliminary Clinical Activity of JNJ-63898081, a PSMA and CD3 Bispecific Antibody, for Metastatic Castration-Resistant Prostate Cancer.

Clinical genitourinary cancer pii:S1558-7673(23)00043-5 [Epub ahead of print].

INTRODUCTION: Cancer immunotherapies have limited efficacy in prostate cancer due to the immunosuppressive prostate microenvironment. Prostate specific membrane antigen (PSMA) expression is prevalent in prostate cancer, preserved during malignant transformation, and increases in response to anti-androgen therapies, making it a commonly targeted tumor associated antigen for prostate cancer. JNJ-63898081 (JNJ-081) is a bispecific antibody targeting PSMA-expressing tumor cells and CD3-expressing T cells, aiming to overcome immunosuppression and promoting antitumor activity.

PATIENTS AND METHODS: We conducted a phase 1 dose escalation study of JNJ-081 in patients with metastatic castration-resistance prostate cancer (mCRPC). Eligible patients included those receiving ≥1 prior line treatment with either novel androgen receptor targeted therapy or taxane for mCRPC. Safety, pharmacokinetics, and pharmacodynamics of JNJ-081, and preliminary antitumor response to treatment were evaluated. JNJ-081 was administered initially by intravenous (IV) then by subcutaneous (SC) route.

RESULTS: Thirty-nine patients in 10 dosing cohorts received JNJ-081 ranging from 0.3 µg/kg to 3.0 µg/kg IV and 3.0 µg/kg to 60 µg/kg SC (with step-up priming used at higher SC doses). All 39 patients experienced ≥1 treatment-emergent AE, and no treatment-related deaths were reported. Dose-limiting toxicities were observed in 4 patients. Cytokine release syndrome (CRS) was observed at higher doses with JNJ-081 IV or SC; however, CRS and infusion-related reaction (IRR) were reduced with SC dosing and step-up priming at higher doses. Treatment doses >30 µg/kg SC led to transient PSA decreases. No radiographic responses were observed. Anti-drug antibody responses were observed in 19 patients receiving JNJ-081 IV or SC.

CONCLUSION: JNJ-081 dosing led to transient declines in PSA in patients with mCRPC. CRS and IRR could be partially mitigated by SC dosing, step-up priming, and a combination of both strategies. T cell redirection for prostate cancer is feasible and PSMA is a potential therapeutic target for T cell redirection in prostate cancer.

RevDate: 2023-03-22

Köbel M, Kang EY, Weir A, et al (2023)

p53 and ovarian carcinoma survival: an Ovarian Tumor Tissue Analysis consortium study.

The journal of pathology. Clinical research [Epub ahead of print].

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36-3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11-2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.

RevDate: 2023-03-22

Autio KA, Higano CS, Nordquist L, et al (2023)

First-in-human, phase 1 study of PF-06753512, a vaccine-based immunotherapy regimen (VBIR), in non-metastatic hormone-sensitive biochemical recurrence and metastatic castration-resistant prostate cancer (mCRPC).

Journal for immunotherapy of cancer, 11(3):.

BACKGROUND: This phase 1 study evaluated PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in two clinical states of prostate cancer (PC), metastatic castration-resistant PC (mCRPC) and biochemical recurrence (BCR).

METHODS: For dose escalation, patients with mCRPC received intramuscular PrCa VBIR (adenovirus vector and plasmid DNA expressing prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostate stem cell antigen (PSCA)) with or without immune checkpoint inhibitors (ICIs, tremelimumab 40 or 80 mg with or without sasanlimab 130 or 300 mg, both subcutaneous). For dose expansion, patients with mCRPC received recommended phase 2 dose (RP2D) of PrCa VBIR plus tremelimumab 80 mg and sasanlimab 300 mg; patients with BCR received PrCa VBIR plus tremelimumab 80 mg (Cohort 1B-BCR) or tremelimumab 80 mg plus sasanlimab 130 mg (Cohort 5B-BCR) without androgen deprivation therapy (ADT). The primary endpoint was safety.

RESULTS: Ninety-one patients were treated in dose escalation (mCRPC=38) and expansion (BCR=35, mCRPC=18). Overall, treatment-related and immune-related adverse events occurred in 64 (70.3%) and 39 (42.9%) patients, with fatigue (40.7%), influenza-like illness (30.8%), diarrhea (23.1%), and immune-related thyroid dysfunction (19.8%) and rash (15.4%), as the most common. In patients with mCRPC, the objective response rate (ORR, 95% CI) was 5.6% (1.2% to 15.4%) and the median radiographic progression-free survival (rPFS) was 5.6 (3.5 to not estimable) months for all; the ORR was 16.7% (3.6% to 41.4%) and 6-month rPFS rate was 45.5% (24.9% to 64.1%) for those who received RP2D with measurable disease (n=18). 7.4% of patients with mCRPC achieved a ≥50% decline in baseline PSA (PSA-50), with a median duration of 4.6 (1.2-45.2) months. In patients with BCR, 9 (25.7%) achieved PSA-50; the median duration of PSA response was 3.9 (1.9-4.2) and 10.1 (6.9-28.8) months for Cohorts 5B-BCR and 1B-BCR. Overall, antigen specific T-cell response was 88.0% to PSMA, 84.0% to PSA, and 80.0% to PSCA.

CONCLUSIONS: PrCa VBIR overall demonstrated safety signals similar to other ICI combination trials; significant side effects were seen in some patients with BCR. It stimulated antigen-specific immunity across all cohorts and resulted in modest antitumor activity in patients with BCR without using ADT.


RevDate: 2023-03-22

Zauber AG, Winawer SJ, O'Brien MJ, et al (2023)

Randomized Trial of Facilitated Adherence to Screening-Colonoscopy Versus Sequential Fecal-Based Blood Test.

Gastroenterology pii:S0016-5085(23)00505-X [Epub ahead of print].

BACKGROUND AND AIMS: Colorectal cancer (CRC) screening guidelines include screening-colonoscopy and sequential high sensitivity fecal occult blood testing (HSgFOBT), with expectation of similar effectiveness based on the assumption of similar high adherence. However, adherence to screening-colonoscopy compared to sequential HSgFOBT has not been reported. In this randomized clinical trial, we assessed adherence and pathology findings for a single screening-colonoscopy versus sequential and non-sequential HSgFOBT.

METHODS: Participants aged 40-69 were enrolled in three centers, which represented different clinical settings. Participants were randomized into a single screening-colonoscopy arm versus sequential HSgFOBT arm comprised of 4-7 rounds. Initial adherence to screening-colonoscopy and sequential adherence to HSgFOBT, follow-up colonoscopy for positive HSgFOBT tests, crossover to colonoscopy, and detection of advanced neoplasia or large serrated lesions (ADN-SER) were measured.

RESULTS: 3,523 participants were included in the trial with 1761 and 1762 participants randomized to the screening-colonoscopy and HSgFOBT arms, respectively. Adherence was 1473 (83.6%) for the screening-colonoscopy arm versus 1288 (73.1%) for the HSgFOBT arm after one round (RR=1.14, [95% CI 1.10-1.19] P ≤0.001), but only 674 (38.3%) over four sequential HSgFOBT rounds (RR=2.19, [95% CI 2.05-2.33]). Overall adherence to any screening increased to 1558 (88.5%) in the screening-colonoscopy arm during the entire study period and 1493 in the HSgFOBT arm (84.7%) (RR=1.04, [95% CI 1.02-1.07]). 436 (24.7%) participants crossed over to screening-colonoscopy over the first four rounds. ADN-SER were detected in 121 (8.2%) of the 1473 participants in the colonoscopy arm who were adherent to protocol in the first 12 months of the study, whereas the detection of ADN-SER among those who were not sequentially adherent (N=709) to HSgFOBT was subpar (0.6%) (RR=14.72, [95% CI 5.46-39.67]) when compared to those who were sequentially adherent (3.3%) (N=647) (RR=2.52, [95% CI 1.61-3.98]) to HSgFOBT in the first four rounds. When including colonoscopies from HSgFOBT patients who were never positive yet crossed over (N=1483), 5.5% of ADN-SER were detected (RR=1.50, [95% CI 1.15-1.96]) in the first four rounds.

CONCLUSIONS: Observed adherence to sequential rounds of HSgFOBT was suboptimal when compared to a single screening-colonoscopy. The detection of ADN-SER was inferior when non-sequential HSgFOBT adherence was compared to sequential adherence. However, the greatest number of ADN-SER was detected among those who crossed over to colonoscopy and opted to receive a colonoscopy. The effectiveness of a HSgFOBT screening program may be enhanced if crossover to screening-colonoscopy is permitted.

RevDate: 2023-03-22

Zhang Z, Hong W, Wu Q, et al (2023)

Pathway-driven rare germline variants associated with transplant-associated thrombotic microangiopathy (TA-TMA).

Thrombosis research, 225:39-46 pii:S0049-3848(23)00066-X [Epub ahead of print].

The significance of rare germline mutations in transplant-associated thrombotic microangiopathy (TA-TMA) is not well studied. We performed a genetic association study in 100 adult TA-TMA patients vs. 98 post-transplant controls after matching by race, sex, and year. We focused on 5 pathways in complement, von Willebrand factor (VWF) function and related proteins, VWF clearance, ADAMTS13 function and related proteins, and endothelial activation (3641variants in 52 genes). In the primary analysis focused on 189 functional rare variants, no differential variant enrichment was observed in any of the pathways; specifically, 29 % TA-TMA and 33 % controls had at least 1 rare complement mutation. In the secondary analysis focused on 37 rare variants predicted to be pathogenic or likely pathogenic by ClinVar, Complement Database, or REVEL in-silico prediction tool, rare variants in the VWF clearance pathway were found to be significantly associated with TA-TMA (p = 0.008). On the gene level, LRP1 was the only one with significantly increased variants in TA-TMA in both analyses (p = 0.025 and 0.015). In conclusion, we did not find a significant association between rare variants in the complement pathway and TA-TMA; however, we discovered a new signal in the VWF clearance pathway driven by the gene LRP1 among likely pathogenic variants.

RevDate: 2023-03-22

DeZern AE, Goll JB, Lindsley RC, et al (2023)

Utility of Targeted Gene Sequencing to Differentiate Myeloid Malignancies from other Cytopenic Conditions.

Blood advances pii:495027 [Epub ahead of print].

The National Heart, Lung, and Blood Institute National MDS Natural History Study (NCT02775383) is a prospective cohort study enrolling cytopenic patients with suspected myelodysplastic syndromes (MDS) to evaluate factors associated with disease. Here, we sequenced 53 genes in bone marrow samples harvested from 1,298 patients diagnosed with myeloid malignancy, including MDS and non-MDS myeloid malignancy, or alternative marrow conditions with cytopenia based on concordance between independent histopathologic reviews (local, centralized, and tertiary to adjudicate disagreements when needed). We developed a novel two-stage diagnostic classifier based on mutational profiles in 18 of 53 sequenced genes that were sufficient to best (1) predict a diagnosis of myeloid malignancy and (2) within those with a predicted myeloid malignancy, predict whether they had MDS. The classifier achieved a PPV of 0.84 and NPV of 0.8 with an AUROC of 0.85 when classifying patients as myeloid vs. no myeloid malignancy based on VAFs in 17 genes and a PPV of 0.71 and NPV of 0.64 with an AUROC of 0.73 when classifying patients as MDS vs. non-MDS malignancy based on VAFs in 10 genes. We next assessed how this approach could complement histopathology to improve diagnostic accuracy. For 99 of 139 (71%) patients (PPV of 0.83 and NPV of 0.65) with local and centralized histopathologic disagreement in myeloid vs. no myeloid malignancy, the classifier-predicted diagnosis agreed with the tertiary pathology review (considered the internal gold standard). An online version of the classifier that can be used with either VAFs or binary mutation profiles is available at https://thenationalmdsstudy.net.

RevDate: 2023-03-22

Lu W, Fan M, Ji W, et al (2023)

Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors.

Journal of medicinal chemistry [Epub ahead of print].

Transcriptional enhanced associate domain (TEAD) proteins together with their transcriptional coactivator yes-associated protein (YAP) and transcriptional coactivator with the PDZ-binding motif (TAZ) are important transcription factors and cofactors that regulate gene expression in the Hippo pathway. In mammals, the TEAD families have four homologues: TEAD1 (TEF-1), TEAD2 (TEF-4), TEAD3 (TEF-5), and TEAD4 (TEF-3). Aberrant expression and hyperactivation of TEAD/YAP signaling have been implicated in a variety of malignancies. Recently, TEADs were recognized as being palmitoylated in cells, and the lipophilic palmitate pocket has been successfully targeted by both covalent and noncovalent ligands. In this report, we present the medicinal chemistry effort to develop MYF-03-176 (compound 22) as a selective, cysteine-covalent TEAD inhibitor. MYF-03-176 (compound 22) significantly inhibits TEAD-regulated gene expression and proliferation of the cell lines with TEAD dependence including those derived from mesothelioma and liposarcoma.

RevDate: 2023-03-22

Unger JM, Till C, Hwang JP, et al (2023)

Risk Prediction of Hepatitis B or C or HIV Among Newly Diagnosed Cancer Patients.

Journal of the National Cancer Institute pii:7083441 [Epub ahead of print].

BACKGROUND: Screening for viral infection in cancer patients is inconsistent. A mechanism to readily identify cancer patients at increased risk of existing or prior viral infection could enhance screening efforts while reducing costs.

METHODS: We identified factors associated with increased risk of past or chronic HBV, HCV, or HIV infection prior to initiation of systemic cancer therapy. Data were from a multicenter prospective cohort study of 3,051 patients with newly diagnosed cancer (SWOG-S1204) enrolled between 2013-2017. Patients completed a survey with questions pertaining to personal history, behavioral, socioeconomic, and demographic risk factors for viral hepatitis or HIV. We derived a risk model to predict the presence of viral infection in a random set of 60% of participants using best subset selection. The derived model was validated in the remaining 40% of participants. Logistic regression was used.

RESULTS: A model with 7 risk factors was identified, and a risk score with 4 levels was constructed. In the validation cohort, each increase in risk level was associated with nearly a threefold increased risk of viral positivity (OR = 2.85, 95%-CI, 2.26-3.60, p<0.001). Consistent findings were observed for individual viruses. Participants in the highest risk group (with ≥3 risk factors), comprised of 13.4% of participants, were 18 times more likely to be viral positive compared to participants with no risk factors (OR = 18.18, 95%-CI, 8.00-41.3, p<0.001).

CONCLUSIONS AND RELEVANCE: A risk-stratified screening approach using a limited set of questions could serve as an effective strategy to streamline screening for individuals at increased risk of viral infection.

RevDate: 2023-03-22

Ausenhus C, Gold JM, Perry CK, et al (2023)

Publisher Correction: Factors impacting implementation of nutrition and physical activity policies in rural schools.

BMC public health, 23(1):538 pii:10.1186/s12889-023-15401-8.

RevDate: 2023-03-23
CmpDate: 2023-03-23

Wagner AD, Njuguna IN, Neary J, et al (2023)

Demand creation for HIV testing services: A systematic review and meta-analysis.

PLoS medicine, 20(3):e1004169.

BACKGROUND: HIV testing services (HTS) are the first steps in reaching the UNAIDS 95-95-95 goals to achieve and maintain low HIV incidence. Evaluating the effectiveness of different demand creation interventions to increase uptake of efficient and effective HTS is useful to prioritize limited programmatic resources. This review was undertaken to inform World Health Organization (WHO) 2019 HIV testing guidelines and assessed the research question, "Which demand creation strategies are effective for enhancing uptake of HTS?" focused on populations globally.

METHODS AND FINDINGS: The following electronic databases were searched through September 28, 2021: PubMed, PsycInfo, Cochrane CENTRAL, CINAHL Complete, Web of Science Core Collection, EMBASE, and Global Health Database; we searched IAS and AIDS conferences. We systematically searched for randomized controlled trials (RCTs) that compared any demand creation intervention (incentives, mobilization, counseling, tailoring, and digital interventions) to either a control or other demand creation intervention and reported HTS uptake. We pooled trials to evaluate categories of demand creation interventions using random-effects models for meta-analysis and assessed study quality with Cochrane's risk of bias 1 tool. This study was funded by the WHO and registered in Prospero with ID CRD42022296947. We screened 10,583 records and 507 conference abstracts, reviewed 952 full texts, and included 124 RCTs for data extraction. The majority of studies were from the African (N = 53) and Americas (N = 54) regions. We found that mobilization (relative risk [RR]: 2.01, 95% confidence interval [CI]: [1.30, 3.09], p < 0.05; risk difference [RD]: 0.29, 95% CI [0.16, 0.43], p < 0.05, N = 4 RCTs), couple-oriented counseling (RR: 1.98, 95% CI [1.02, 3.86], p < 0.05; RD: 0.12, 95% CI [0.03, 0.21], p < 0.05, N = 4 RCTs), peer-led interventions (RR: 1.57, 95% CI [1.15, 2.15], p < 0.05; RD: 0.18, 95% CI [0.06, 0.31], p < 0.05, N = 10 RCTs), motivation-oriented counseling (RR: 1.53, 95% CI [1.07, 2.20], p < 0.05; RD: 0.17, 95% CI [0.00, 0.34], p < 0.05, N = 4 RCTs), short message service (SMS) (RR: 1.53, 95% CI [1.09, 2.16], p < 0.05; RD: 0.11, 95% CI [0.03, 0.19], p < 0.05, N = 5 RCTs), and conditional fixed value incentives (RR: 1.52, 95% CI [1.21, 1.91], p < 0.05; RD: 0.15, 95% CI [0.07, 0.22], p < 0.05, N = 11 RCTs) all significantly and importantly (≥50% relative increase) increased HTS uptake and had medium risk of bias. Lottery-based incentives and audio-based interventions less importantly (25% to 49% increase) but not significantly increased HTS uptake (medium risk of bias). Personal invitation letters and personalized message content significantly but not importantly (<25% increase) increased HTS uptake (medium risk of bias). Reduced duration counseling had comparable performance to standard duration counseling (low risk of bias) and video-based interventions were comparable or better than in-person counseling (medium risk of bias). Heterogeneity of effect among pooled studies was high. This study was limited in that we restricted to randomized trials, which may be systematically less readily available for key populations; additionally, we compare only pooled estimates for interventions with multiple studies rather than single study estimates, and there was evidence of publication bias for several interventions.

CONCLUSIONS: Mobilization, couple- and motivation-oriented counseling, peer-led interventions, conditional fixed value incentives, and SMS are high-impact demand creation interventions and should be prioritized for programmatic consideration. Reduced duration counseling and video-based interventions are an efficient and effective alternative to address staffing shortages. Investment in demand creation activities should prioritize those with undiagnosed HIV or ongoing HIV exposure. Selection of demand creation interventions must consider risks and benefits, context-specific factors, feasibility and sustainability, country ownership, and universal health coverage across disease areas.

RevDate: 2023-03-23
CmpDate: 2023-03-23

Chlebowski RT, AK Aragaki (2023)

Hormone Therapy for the Prevention of Chronic Conditions in Postmenopausal Persons.

JAMA, 329(11):942.

RevDate: 2023-03-23

Arora S, Szulzewsky F, Jensen M, et al (2023)

An RNA seq-based reference landscape of human normal and neoplastic brain.

Research square.

In order to better understand the relationship between normal and neoplastic brain, we combined five publicly available large-scale datasets, correcting for batch effects and applying Uniform Manifold Approximation and Projection (UMAP) to RNA-seq data. We assembled a reference Brain-UMAP including 702 adult gliomas, 802 pediatric tumors and 1409 healthy normal brain samples, which can be utilized to investigate the wealth of information obtained from combining several publicly available datasets to study a single organ site. Normal brain regions and tumor types create distinct clusters and because the landscape is generated by RNA seq, comparative gene expression profiles and gene ontology patterns are readily evident. To our knowledge, this is the first meta-analysis that allows for comparison of gene expression and pathways of interest across adult gliomas, pediatric brain tumors, and normal brain regions. We provide access to this resource via the open source, interactive online tool Oncoscape, where the scientific community can readily visualize clinical metadata, gene expression patterns, gene fusions, mutations, and copy number patterns for individual genes and pathway over this reference landscape.

RevDate: 2023-03-23

Arora S, Szulzewsky F, Jensen M, et al (2023)

An RNA seq-based reference landscape of human normal and neoplastic brain.

bioRxiv : the preprint server for biology.

In order to better understand the relationship between normal and neoplastic brain, we combined five publicly available large-scale datasets, correcting for batch effects and applying Uniform Manifold Approximation and Projection (UMAP) to RNA-seq data. We assembled a reference Brain-UMAP including 702 adult gliomas, 802 pediatric tumors and 1409 healthy normal brain samples, which can be utilized to investigate the wealth of information obtained from combining several publicly available datasets to study a single organ site. Normal brain regions and tumor types create distinct clusters and because the landscape is generated by RNA seq, comparative gene expression profiles and gene ontology patterns are readily evident. To our knowledge, this is the first meta-analysis that allows for comparison of gene expression and pathways of interest across adult gliomas, pediatric brain tumors, and normal brain regions. We provide access to this resource via the open source, interactive online tool Oncoscape, where the scientific community can readily visualize clinical metadata, gene expression patterns, gene fusions, mutations, and copy number patterns for individual genes and pathway over this reference landscape.

RevDate: 2023-03-23

Kopmar NE, RD Cassaday (2023)

How I prevent and treat central nervous system disease in adults with acute lymphoblastic leukemia.

Blood, 141(12):1379-1388.

The central nervous system (CNS) is the most important site of extramedullary disease in adults with acute lymphoblastic leukemia (ALL). Although CNS disease is identified only in a minority of patients at the time of diagnosis, subsequent CNS relapses (either isolated or concurrent with other sites) occur in some patients even after the delivery of prophylactic therapy targeted to the CNS. Historically, prophylaxis against CNS disease has included intrathecal (IT) chemotherapy and radiotherapy (RT), although the latter is being used with decreasing frequency. Treatment of a CNS relapse usually involves intensive systemic therapy and cranial or craniospinal RT along with IT therapy and consideration of allogeneic hematopoietic cell transplant. However, short- and long-term toxicities can make these interventions prohibitively risky, particularly for older adults. As new antibody-based immunotherapy agents have been approved for relapsed/refractory B-cell ALL, their use specifically for patients with CNS disease is an area of keen interest not only because of the potential for efficacy but also concerns of unique toxicity to the CNS. In this review, we discuss data-driven approaches for these common and challenging clinical scenarios as well as highlight how recent findings potentially support the use of novel immunotherapeutic strategies for CNS disease.

RevDate: 2023-03-22

Anderson GL (2023)

Hormone Therapy for the Prevention of Chronic Conditions in Postmenopausal Persons.

JAMA, 329(11):941.

RevDate: 2023-03-22

Shadman M (2023)

Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Review.

JAMA, 329(11):918-932.

IMPORTANCE: Chronic lymphocytic leukemia (CLL), defined by a minimum of 5 × 109/L monoclonal B cells in the blood, affects more than 200 000 people and is associated with approximately 4410 deaths in the US annually. CLL is associated with an immunocompromised state and an increased rate of complications from infections.

OBSERVATIONS: At the time of diagnosis, the median age of patients with CLL is 70 years, and an estimated 95% of patients have at least 1 medical comorbidity. Approximately 70% to 80% of patients with CLL are asymptomatic at the time of diagnosis, and one-third will never require treatment for CLL. Prognostic models have been developed to estimate the time to first treatment and the overall survival, but for patients who are asymptomatic, irrespective of disease risk category, clinical observation is the standard of care. Patients with symptomatic disease who have bulky or progressive lymphadenopathy or hepatosplenomegaly and those with a low neutrophil count, anemia, or thrombocytopenia and/or symptoms of fever, drenching night sweats, and weight loss (B symptoms) should be offered treatment. For these patients, first-line treatment consists of a regimen containing either a covalent Bruton tyrosine kinase (BTK) inhibitor (acalabrutinib, zanubrutinib, or ibrutinib) or a B-cell leukemia/lymphoma 2 (BCL2) inhibitor (venetoclax). There is no evidence that starting either class before the other improves outcomes. The covalent BTK inhibitors are typically used indefinitely. Survival rates are approximately 88% at 4 years for acalabrutinib, 94% at 2 years for zanubrutinib, and 78% at 7 years for ibrutinib. Venetoclax is prescribed in combination with obinutuzumab, a monoclonal anti-CD20 antibody, in first-line treatment for 1 year (overall survival, 82% at 5-year follow-up). A noncovalent BTK inhibitor, pitobrutinib, has shown an overall response rate of more than 70% after failure of covalent BTK inhibitors and venetoclax. Phosphoinositide 3'-kinase (PI3K) inhibitors (idelalisib and duvelisib) can be prescribed for disease that progresses with BTK inhibitors and venetoclax, but patients require close monitoring for adverse events such as autoimmune conditions and infections. In patients with multiple relapses, chimeric antigen receptor T-cell (CAR-T) therapy with lisocabtagene maraleucel was associated with a 45% complete response rate. The only potential cure for CLL is allogeneic hematopoietic cell transplant, which remains an option after use of targeted agents.

CONCLUSIONS AND RELEVANCE: More than 200 000 people in the US are living with a CLL diagnosis, and CLL causes approximately 4410 deaths each year in the US. Approximately two-thirds of patients eventually need treatment. Highly effective novel targeted agents include BTK inhibitors such as acalabrutinib, zanubrutinib, ibrutinib, and pirtobrutinib or BCL2 inhibitors such as venetoclax.

RevDate: 2023-03-21

Oishi K, Blanco-Melo D, Kurland AP, et al (2023)

Archaeal Kink-Turn Binding Protein Mediates Inhibition of Orthomyxovirus Splicing Biology.

Journal of virology [Epub ahead of print].

Despite lacking a DNA intermediate, orthomyxoviruses complete their replication cycle in the nucleus and generate multiple transcripts by usurping the host splicing machinery. This biology results in dynamic changes of relative viral transcripts over time and dictates the replicative phase of the infection. Here, we demonstrate that the family of archaeal L7Ae proteins uniquely inhibit the splicing biology of influenza A virus, influenza B virus, and Salmon isavirus, revealing a common strategy utilized by Orthomyxoviridae members to achieve this dynamic. L7Ae-mediated inhibition of virus biology was lost with the generation of a splicing-independent strain of influenza A virus and attempts to select for an escape mutant resulted in variants that conformed to host splicing biology at significant cost to their overall fitness. As L7Ae recognizes conventional kink turns in various RNAs, these data implicate the formation of a similar structure as a shared strategy adopted by this virus family to coordinate their replication cycle. IMPORTANCE Here, we demonstrate that a family of proteins from archaea specifically inhibit this splicing biology of all tested members of the Orthomyxoviridae family. We show that this inhibition extends to influenza A virus, influenza B virus, and isavirus genera, while having no significant impact on the mammalian transcriptome or proteome. Attempts to generate an escape mutant against L7Ae-mediated inhibition resulted in mutations surrounding the viral splice sites and a significant loss of viral fitness. Together, these findings reveal a unique biology shared among diverse members of the Orthomyxoviridae family that may serve as a means to generate future universal therapeutics.

RevDate: 2023-03-22

Lopedote P, M Shadman (2023)

Targeted Treatment of Relapsed or Refractory Follicular Lymphoma: Focus on the Therapeutic Potential of Mosunetuzumab.

Cancer management and research, 15:257-264.

Follicular lymphoma is the most common indolent non-Hodgkin's lymphoma, and because of the incurable nature of this disorder, new therapies are constantly needed. The recently approved T-cell-dependent bispecific antibody mosunetuzumab showed promising results and manageable toxicities for patients with relapsed or refractory follicular lymphoma. Namely, as opposed to cellular immunotherapy options, this agent has the potential of being effective in patients with unfavorable features with a tolerable rate and severity of cytokine release syndrome, immune effector cell-associated neurotoxicity, and infectious complications. Given the recent withdrawal from the market of PI3K inhibitors and the practical challenges in utilizing with chimeric antigen receptor T-cells (CAR-T) for some patients, mosunetuzumab represents a "breath of fresh air" for both patients and hemato-oncologists. More data are required to better define the real potential of this molecule, either alone or in combination with other agents, including antibody drug conjugates, immunomodulators, and checkpoint inhibitors. Future studies will also shed light on the efficacy of mosunetuzumab compared with CAR-T, in well-designed registries or ideally in randomized controlled trials.

RevDate: 2023-03-21

Hou K, Ding Y, Xu Z, et al (2023)

Causal effects on complex traits are similar for common variants across segments of different continental ancestries within admixed individuals.

Nature genetics [Epub ahead of print].

Individuals of admixed ancestries (for example, African Americans) inherit a mosaic of ancestry segments (local ancestry) originating from multiple continental ancestral populations. This offers the unique opportunity of investigating the similarity of genetic effects on traits across ancestries within the same population. Here we introduce an approach to estimate correlation of causal genetic effects (radmix) across local ancestries and analyze 38 complex traits in African-European admixed individuals (N = 53,001) to observe very high correlations (meta-analysis radmix = 0.95, 95% credible interval 0.93-0.97), much higher than correlation of causal effects across continental ancestries. We replicate our results using regression-based methods from marginal genome-wide association study summary statistics. We also report realistic scenarios where regression-based methods yield inflated heterogeneity-by-ancestry due to ancestry-specific tagging of causal effects, and/or polygenicity. Our results motivate genetic analyses that assume minimal heterogeneity in causal effects by ancestry, with implications for the inclusion of ancestry-diverse individuals in studies.

RevDate: 2023-03-21

Watanabe K, Wilmanski T, Diener C, et al (2023)

Multiomic signatures of body mass index identify heterogeneous health phenotypes and responses to a lifestyle intervention.

Nature medicine [Epub ahead of print].

Multiomic profiling can reveal population heterogeneity for both health and disease states. Obesity drives a myriad of metabolic perturbations and is a risk factor for multiple chronic diseases. Here we report an atlas of cross-sectional and longitudinal changes in 1,111 blood analytes associated with variation in body mass index (BMI), as well as multiomic associations with host polygenic risk scores and gut microbiome composition, from a cohort of 1,277 individuals enrolled in a wellness program (Arivale). Machine learning model predictions of BMI from blood multiomics captured heterogeneous phenotypic states of host metabolism and gut microbiome composition better than BMI, which was also validated in an external cohort (TwinsUK). Moreover, longitudinal analyses identified variable BMI trajectories for different omics measures in response to a healthy lifestyle intervention; metabolomics-inferred BMI decreased to a greater extent than actual BMI, whereas proteomics-inferred BMI exhibited greater resistance to change. Our analyses further identified blood analyte-analyte associations that were modified by metabolomics-inferred BMI and partially reversed in individuals with metabolic obesity during the intervention. Taken together, our findings provide a blood atlas of the molecular perturbations associated with changes in obesity status, serving as a resource to quantify metabolic health for predictive and preventive medicine.

RevDate: 2023-03-20

Gagelmann N, Badbaran A, Salit RB, et al (2023)

Impact of TP53 on outcome of patients with myelofibrosis undergoing hematopoietic stem cell transplantation.

Blood pii:495000 [Epub ahead of print].

TP53 mutations (TP53MT) have been associated with poor outcomes in various hematologic malignancies, but no data exist on its role in patients with myelofibrosis undergoing hematopoietic stem cell transplantation (HSCT). Here, we took advantage of a large international multicenter cohort to evaluate the role of TP53MTin this setting. Among 349 included patients, 49 (13%) had detectable TP53MT, of whom 30 showed a multi-hit configuration. Median variant allele frequency was 20.3%. Cytogenetic risk was favorable (71%), unfavorable (23%), and very high (6%), with complex karyotype present in 36 patients (10%). Median survival of TP53MT patients was 1.5 years vs 13.5 years for the TP53WT group (P<0.001). Outcome was driven by multi-hit TP53MT constellation (P<0.001), showing 6-year survival of 56% for single-hit vs 25% for multi-hit TP53MT carriers vs 64% for TP53WT. Outcome was independent of current transplant-specific risk factors and conditioning intensity. Similarly, cumulative incidence of relapse was 17% for single-hit vs 52% for multi-hit vs 21% for TP53WT. Ten patients with TP53MT (20%) presented as leukemic transformation vs only 7 (2%) in the TP53WT group (P<0.001). Out of the 10 patients with TP53MT, 8 showed multi-hit constellation. Median time to leukemic transformation was shorter for multi-and single-hit TP53MT (0.7 and 0.5 years, respectively) vs 2.5 years for TP53WT. In summary, multi-hit TP53MT represents a very high-risk group in myelofibrosis patients undergoing HSCT, whereas single-hit TP53MTalone showed similar outcome to non-mutated patients, informing prognostication for survival and relapse together with current transplant-specific tools.

RevDate: 2023-03-20

Miller SJ, Sly JR, Alcaraz KI, et al (2023)

Equity and behavioral digital health interventions: Strategies to improve benefit and reach.

Translational behavioral medicine pii:7081265 [Epub ahead of print].

BACKGROUND: Behavioral digital health interventions (e.g., mobile apps, websites, wearables) have been applied widely to improve health outcomes. However, many groups (e.g., people with low income levels, people who are geographically isolated, older adults) may face obstacles to technology access and use. In addition, research has found that biases and stereotypes can be embedded within digital health interventions. As such, behavioral digital health interventions that intend to improve overall population health may unintentionally widen health-related inequities.

PURPOSE: This commentary offers guidance and strategies to mitigate these risks when using technology as a means for delivering a behavioral health intervention.

METHODS: A collaborative working group from Society of Behavioral Medicine's Health Equity Special Interest Group developed a framework to center equity in the development, testing and dissemination of behavioral digital health interventions.

RESULTS: We introduce Partner, Identify, Demonstrate, Access, Report (PIDAR), a 5-point framework to avoid the creation, perpetuation, and/or widening of health inequities in behavioral digital health work.

CONCLUSIONS: It is critically important to prioritize equity when conducting digital health research. The PIDAR framework can serve as a guide for behavioral scientists, clinicians and developers.

RevDate: 2023-03-20

Romeis E, Lieberman NAP, Molini B, et al (2023)

Treponema pallidum subsp. pallidum with an Artificially impaired TprK antigenic variation system is attenuated in the Rabbit model of syphilis.

PLoS pathogens, 19(3):e1011259 pii:PPATHOGENS-D-22-02156 [Epub ahead of print].

BACKGROUND: The TprK protein of the syphilis agent, Treponema pallidum subsp. pallidum (T. pallidum), undergoes antigenic variation in seven discrete variable (V) regions via non-reciprocal segmental gene conversion. These recombination events transfer information from a repertoire of 53 silent chromosomal donor cassettes (DCs) into the single tprK expression site to continually generate TprK variants. Several lines of research developed over the last two decades support the theory that this mechanism is central to T. pallidum's ability for immune avoidance and persistence in the host. Structural and modeling data, for example, identify TprK as an integral outer membrane porin with the V regions exposed on the pathogen's surface. Furthermore, infection-induced antibodies preferentially target the V regions rather than the predicted β-barrel scaffolding, and sequence variation abrogates the binding of antibodies elicited by antigenically different V regions. Here, we engineered a T. pallidum strain to impair its ability to vary TprK and assessed its virulence in the rabbit model of syphilis.

PRINCIPAL FINDINGS: A suicide vector was transformed into the wild-type (WT) SS14 T. pallidum isolate to eliminate 96% of its tprK DCs. The resulting SS14-DCKO strain exhibited an in vitro growth rate identical to the untransformed strain, supporting that the elimination of the DCs did not affect strain viability in absence of immune pressure. In rabbits injected intradermally with the SS14-DCKO strain, generation of new TprK sequences was impaired, and the animals developed attenuated lesions with a significantly reduced treponemal burden compared to control animals. During infection, clearance of V region variants originally in the inoculum mirrored the generation of antibodies to these variants, although no new variants were generated in the SS14-DCKO strain to overcome immune pressure. Naïve rabbits that received lymph node extracts from animals infected with the SS14-DCKO strain remained uninfected.

CONCLUSION: These data further support the critical role of TprK in T. pallidum virulence and persistence during infection.

RevDate: 2023-03-21

Smith JW, O'Meally RN, Burke SM, et al (2023)

Global Discovery and Temporal Changes of Human Albumin Modifications by Pan-Protein Adductomics: Initial Application to Air Pollution Exposure.

Journal of the American Society for Mass Spectrometry [Epub ahead of print].

Assessing personal exposure to environmental toxicants is a critical challenge for predicting disease risk. Previously, using human serum albumin (HSA)-based biomonitoring, we reported dosimetric relationships between adducts at HSA Cys[34] and ambient air pollutant levels (Smith et al., Chem. Res. Toxicol. 2021, 34, 1183). These results provided the foundation to explore modifications at other sites in HSA to reveal novel adducts of complex exposures. Thus, the Pan-Protein Adductomics (PPA) technology reported here is the next step toward an unbiased, comprehensive characterization of the HSA adductome. The PPA workflow requires <2 μL serum/plasma and uses nanoflow-liquid chromatography, gas-phase fractionation, and overlapping-window data-independent acquisition high-resolution tandem mass spectrometry. PPA analysis of albumin from nonsmoking women exposed to high levels of air pollution uncovered 68 unique location-specific modifications (LSMs) across 21 HSA residues. While nearly half were located at Cys[34] (33 LSMs), 35 were detected on other residues, including Lys, His, Tyr, Ser, Met, and Arg. HSA adduct relative abundances spanned a ∼400 000-fold range and included putative products of exogenous (SO2, benzene, phycoerythrobilin) and endogenous (oxidation, lipid peroxidation, glycation, carbamylation) origin, as well as 24 modifications without annotations. PPA quantification revealed statistically significant changes in LSM levels across the 84 days of monitoring (∼3 HSA lifetimes) in the following putative adducts: Cys[34] trioxidation, β-methylthiolation, benzaldehyde, and benzene diol epoxide; Met[329] oxidation; Arg[145] dioxidation; and unannotated Cys[34] and His[146] adducts. Notably, the PPA workflow can be extended to any protein. Pan-Protein Adductomics is a novel and powerful strategy for untargeted global exploration of protein modifications.

RevDate: 2023-03-20

Cassaday RD, Zarling LC, Garcia KA, et al (2023)

Phase II study of dose-adjusted EPOCH as initial therapy for adults with high-risk acute lymphoblastic leukemia.

Leukemia & lymphoma [Epub ahead of print].

Treatments for adults with newly-diagnosed acute lymphoblastic leukemia (ALL) may be prohibitively toxic and/or resource-intense. To address this, we performed a phase II study of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH). Imatinib or dasatinib was added for Ph + disease; rituximab was added when CD20+. Fifty-three patients were evaluable: 28 with Ph + disease, and 25 with Ph-. All patients had ≥1 high-risk clinical feature. Measurable residual disease-negativity by multiparameter flow cytometry within 4 cycles was achieved in 71% in patients with Ph + ALL and 64% in Ph - ALL. Median overall survival (OS) was 49 months, with a 2-year OS of 71%. Median relapse-free survival (RFS) in the 47 patients that attained morphologic remission was 24 months, with a 2-year RFS of 57%. Early mortality was 2%. In summary, DA-EPOCH yields deep and durable remissions in adults with ALL comparable to some resource-intense strategies but with a low rate of treatment-related death.

RevDate: 2023-03-21

Sun Y, Heng F, Lee U, et al (2023)

Estimation of conditional cumulative incidence functions under generalized semiparametric regression models with missing covariates, with application to analysis of biomarker correlates in vaccine trials.

The Canadian journal of statistics = Revue canadienne de statistique, 51(1):235-257.

This article studies generalized semiparametric regression models for conditional cumulative incidence functions with competing risks data when covariates are missing by sampling design or happenstance. A doubly-robust augmented inverse probability weighted complete-case (AIPW) approach to estimation and inference is investigated. This approach modifies IPW complete-case estimating equations by exploiting the key features in the relationship between the missing covariates and the phase-one data to improve efficiency. An iterative numerical procedure is derived to solve the nonlinear estimating equations. The asymptotic properties of the proposed estimators are established. A simulation study examining the finite-sample performances of the proposed estimators shows that the AIPW estimators are more efficient than the IPW estimators. The developed method is applied to the RV144 HIV-1 vaccine efficacy trial to investigate vaccine-induced IgG binding antibodies to HIV-1 as correlates of acquisition of HIV-1 infection while taking account of whether the HIV-1 sequences are near or far from the HIV-1 sequences represented in the vaccine construct.

RevDate: 2023-03-21

Whitehouse JP, Hii H, Mayoh C, et al (2023)

In vivo loss of tumorigenicity in a patient-derived orthotopic xenograft mouse model of ependymoma.

Frontiers in oncology, 13:1123492.

INTRODUCTION: Ependymomas (EPN) are the third most common malignant brain cancer in children. Treatment strategies for pediatric EPN have remained unchanged over recent decades, with 10-year survival rates stagnating at just 67% for children aged 0-14 years. Moreover, a proportion of patients who survive treatment often suffer long-term neurological side effects as a result of therapy. It is evident that there is a need for safer, more effective treatments for pediatric EPN patients. There are ten distinct subgroups of EPN, each with their own molecular and prognostic features. To identify and facilitate the testing of new treatments for EPN, in vivo laboratory models representative of the diverse molecular subtypes are required. Here, we describe the establishment of a patient-derived orthotopic xenograft (PDOX) model of posterior fossa A (PFA) EPN, derived from a metastatic cranial lesion.

METHODS: Patient and PDOX tumors were analyzed using immunohistochemistry, DNA methylation profiling, whole genome sequencing (WGS) and RNA sequencing.

RESULTS: Both patient and PDOX tumors classified as PFA EPN by methylation profiling, and shared similar histological features consistent with this molecular subgroup. RNA sequencing revealed that gene expression patterns were maintained across the primary and metastatic tumors, as well as the PDOX. Copy number profiling revealed gains of chromosomes 7, 8 and 19, and loss of chromosomes 2q and 6q in the PDOX and matched patient tumor. No clinically significant single nucleotide variants were identified, consistent with the low mutation rates observed in PFA EPN. Overexpression of EZHIP RNA and protein, a common feature of PFA EPN, was also observed. Despite the aggressive nature of the tumor in the patient, this PDOX was unable to be maintained past two passages in vivo.

DISCUSSION: Others who have successfully developed PDOX models report some of the lowest success rates for EPN compared to other pediatric brain cancer types attempted, with loss of tumorigenicity not uncommon, highlighting the challenges of propagating these tumors in the laboratory. Here, we discuss our collective experiences with PFA EPN PDOX model generation and propose potential approaches to improve future success in establishing preclinical EPN models.

RevDate: 2023-03-19

Ma J, Shao L, Fuksenko T, et al (2023)

Reference gene selection for clinical chimeric antigen receptor T-cell product vector copy number assays.

Cytotherapy pii:S1465-3249(23)00062-2 [Epub ahead of print].

BACKGROUND AIMS: Reference genes are an essential part of clinical assays such as droplet digital polymerase chain reaction (ddPCR), which measure the number of copies of vector integrated into genetically engineered cells and the loss of plasmids in reprogrammed cells used in clinical cell therapies. Care should be taken to select reference genes, because it has been discovered that there may be thousands of variations in copy number from genomic segments among different individuals. In addition, within the same person in the context of cancer and other proliferative disorders, substantial parts of the genome also can differ in copy number between cells from diseased and healthy people. The purpose of this study was to identify reference genes that could be used for copy number variation analysis of transduced chimeric antigen receptor T cells and for plasmid loss analysis in induced pluripotent stem cells using ddPCR.

METHODS: We used The Cancer Genome Atlas (TCGA) to evaluate candidate reference genes. If TCGA found a candidate gene to have low copy number variance in cancer, ddPCR was used to measure the copy numbers of the potential reference gene in cells from healthy subjects, cancer cell lines and patients with acute lymphocytic leukemia, lymphoma, multiple myeloma and human papillomavirus-associated cancers.

RESULTS: In addition to the rPP30 gene, which we have has been using in our copy number assays, three other candidate reference genes were evaluated using TCGA, and this analysis found that none of the four gene regions (AGO1, AP3B1, MKL2 and rPP30) were amplified or deleted in all of the cancer cell types that are currently being treated with cellular therapies by our facility. The number of copies of the genes AP3B1, AGO1, rPP30 and MKL2 measured by ddPCR was similar among cells from healthy subjects. We found that AGO1 had copy number alteration in some of the clinical samples, and the number of copies of the genes AP3B1, MKL2 and rPP30 measured by ddPCR was similar among cells from patients with the cancer cell types that are currently being treated with genetically engineered T-cell therapies by our facility.

CONCLUSIONS: Based on our current results, the three genes, AP3B1, MKL2 and rPP30, are suitable for use as reference genes for assays measuring vector copy number in chimeric antigen receptor T cells produced from patients with acute leukemia, lymphoma, multiple myeloma and human papillomavirus-associated cancers. We will continue to evaluate AGO1 on our future samples.

RevDate: 2023-03-19

Wilson GJ, Rodriguez B, Li SS, et al (2023)

Cellular and humoral responses to an HIV DNA prime by electroporation boosted with recombinant vesicular stomatitis virus expressing HIV subtype C Env in a randomized controlled clinical trial.

Vaccine pii:S0264-410X(23)00262-1 [Epub ahead of print].

BACKGROUND: HIV subtypes B and C together account for around 60% of HIV-1 cases worldwide. We evaluated the safety and immunogenicity of a subtype B DNA vaccine prime followed by a subtype C viral vector boost.

METHODS: Fourteen healthy adults received DNA plasmid encoding HIV-1 subtype B nef/tat/vif and env (n = 11) or placebo (n = 3) intramuscularly (IM) via electroporation (EP) at 0, 1, and 3 months, followed by IM injection of recombinant vesicular stomatitis virus encoding subtype C Env or placebo at 6 and 9 months. Participants were assessed for safety, tolerability of EP, and Env-specific T-cell and antibody responses.

RESULTS: EP was generally well tolerated, although some device-related adverse events did occur, and vaccine reactogenicity was mild to moderate. The vaccine stimulated Env-specific CD4 + T-cell responses in greater than 80% of recipients, and CD8 + T-cell responses in 30%. Subtype C Env-specific IgG binding antibodies (bAb) were elicited in all vaccine recipients, and antibody-dependent cell-mediated cytotoxicity (ADCC) responses to vaccine-matched subtype C targets in 80%. Negligible V1/V2 and neutralizing antibody (nAb) responses were detected.

CONCLUSIONS: This prime/boost regimen was safe and tolerable, with some device-related events, and immunogenic. Although immunogenicity missed targets for an HIV vaccine, the DNA/rVSV platform may be useful for other applications.


RevDate: 2023-03-21

Janes H, Zhu Y, ER Brown (2020)

Designing HIV Vaccine Efficacy Trials in the Context of Highly Effective Non-vaccine Prevention Modalities.

Statistics in biosciences, 12(3):468-494.

The evolving HIV prevention landscape poses challenges to the statistical design of future trials of candidate HIV vaccines. Study designs must address the anticipated reduction in HIV incidence due to adding new prevention modalities to the standard prevention package provided to trial participants, and must also accommodate individual choices of participants with regard to the use of these modalities. We explore four potential trial designs that address these challenges, with a focus on accommodating the newest addition to the prevention package-antiretroviral-based oral pre-exposure prophylaxis (PrEP). The designs differ with respect to how individuals who take up oral PrEP at screening are handled. An All-Comers Design enrolls and randomizes all eligible individuals, a Decliners Design enrolls and randomizes only those who decline PrEP at screening, and Single and Multi-Stage Run-In Designs enroll all but randomize only those who decline PrEP or show inadequate adherence to PrEP after one or multiple run-in periods. We compare these designs with respect to required sample sizes, study duration, and resource requirements, using a simulation model that incorporates data on HIV risk and PrEP uptake and adherence among men who have sex with men (MSM) in the Americas. We advocate considering Run-In Designs for some future contexts, and identify their advantages and tradeoffs relative to the other designs. The design concepts apply beyond HIV vaccines to other prevention modalities being developed with the aim to achieve further reductions in HIV incidence.

RevDate: 2023-03-19

Banerjee R, Kelkar AH, Durani U, et al (2023)

Demographics, motivations, and experiences of participants in transplantation or cellular therapy fellowships.

Transplantation and cellular therapy pii:S2666-6367(23)01169-7 [Epub ahead of print].

BACKGROUND: Recent ASTCT guidelines have sought to establish clinical and research expectations for participants in blood and marrow transplantation (BMT) and cellular therapy (CT) fellowships. However, little is known about participants in BMT/CT fellowships and the value they find from this additional training.

OBJECTIVES: To characterize the demographics, motivations, and experiences of recent participants in BMT/CT fellowships.

METHODS: We developed a 27-item online survey addressing backgrounds, application processes, training experiences, and perceived benefits among physicians who had started a clinical US-based BMT/CT fellowship between 2012-2021. Anonymous responses were solicited through program director outreach, society website postings, targeted emails, and social media.

RESULTS: Of 105 respondents (44% pediatric trainees), 4% were underrepresented minorities (URM) and 39% were non-US international medical graduates (IMGs). The most important motivations for applying were comfort with allogeneic BMT, improved career prospects, and opportunities for research and publication. Almost all respondents (92%) attended donor selection meetings, while smaller proportions visited cell processing facilities (65%), HLA labs (57%), or GMP facilities (22%). Most respondents reported ≥1 publication (26% reported 4+) based on research or experiences during their fellowship. Respondents reported improved post-fellowship comfort with all queried BMT/CT-related competencies. Seventy percent of respondents stated that they would recommend their fellowship highly to others; this corresponded to a Net Promoter Score of +65%, consistent with a strongly positive experience. Most respondents reported currently being in clinical practice (89% at academic centers), with a median of 70% of time currently spent caring for BMT/CT recipients.

CONCLUSIONS: While limited by recruitment methods and recall bias, our study demonstrated that BMT/CT fellowships are effective at increasing comfort with BMT/CT management and that most participants would highly recommend this BMT/CT training to others. Nevertheless, our study identified substantial heterogeneity in clinical responsibilities and BMT/CT-related laboratory exposure. The high representation of non-US IMGs underscores the distinct role of BMT/CT fellowships for this group, while improved URM recruitment remains an important future direction for the field. Whether advanced fellowships will ever become required for the future BMT/CT workforce, analogous to the additional training required for solid organ transplantation in other medical and pediatric subspecialties, remains uncertain.

RevDate: 2023-03-20

Brasky TM, Hade EM, Cohn DE, et al (2023)

Dietary omega-3 fatty acids and endometrial cancer risk in the Epidemiology of Endometrial Cancer Consortium: An individual-participant meta-analysis.

Gynecologic oncology, 169:137-146.

BACKGROUND: Limited data from prospective studies suggest that higher dietary intake of long-chain omega-3 polyunsaturated fatty acids (LCn3PUFA), which hold anti-inflammatory properties, may reduce endometrial cancer risk; particularly among certain subgroups characterized by body mass and tumor pathology.

MATERIALS AND METHODS: Data from 12 prospective cohort studies participating in the Epidemiology of Endometrial Cancer Consortium were harmonized as nested case-control studies, including 7268 endometrial cancer cases and 26,133 controls. Habitual diet was assessed by food frequency questionnaire, from which fatty acid intakes were estimated. Two-stage individual-participant data mixed effects meta-analysis estimated adjusted odds ratios (OR) and 95% confidence intervals (CI) through logistic regression for associations between study-specific energy-adjusted quartiles of LCn3PUFA and endometrial cancer risk.

RESULTS: Women with the highest versus lowest estimated dietary intakes of docosahexaenoic acid, the most abundant LCn3PUFA in diet, had a 9% increased endometrial cancer risk (Quartile 4 vs. Quartile 1: OR 1.09, 95% CI: 1.01-1.19; P trend = 0.04). Similar elevated risks were observed for the summary measure of total LCn3PUFA (OR 1.07, 95% CI: 0.99-1.16; P trend = 0.06). Stratified by body mass index, higher intakes of LCn3PUFA were associated with 12-19% increased endometrial cancer risk among overweight/obese women and no increased risk among normal-weight women. Higher associations appeared restricted to White women. The results did not differ by cancer grade.

CONCLUSION: Higher dietary intakes of LCn3PUFA are unlikely to reduce endometrial cancer incidence; rather, they may be associated with small to moderate increases in risk in some subgroups of women, particularly overweight/obese women.

RevDate: 2023-03-18

Reyes KR, Huang CY, Lo M, et al (2023)

Safety and efficacy of BCMA CAR-T cell therapy in older patients with multiple myeloma.

Transplantation and cellular therapy pii:S2666-6367(23)01171-5 [Epub ahead of print].

BACKGROUND: Risks of B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) therapy for patients with multiple myeloma (MM) include cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, and infections. The efficacy and safety of BCMA CAR-T therapy in the geriatric setting, including complications such as falls and delirium which may be more prevalent in older patients, have not been fully analyzed.

OBJECTIVES: To analyze the efficacy and safety of BCMA CAR-T therapy among older patients (age ≥70 at infusion) versus younger patients with MM.

STUDY DESIGN: We analyzed all patients with MM who received any autologous BCMA CAR-T therapy over a 5-year period at our institution. Key endpoints included CRS, ICANS incidence, days to absolute neutrophil count (ANC) recovery, incidence of hypogammaglobulinemia (IgG < 400 mg/dL), infections within 6 months, progression-free survival (PFS), and overall survival (OS).

RESULTS: Of 83 analyzed patients (age range 33-77), 22 (27%) were aged ≥70 at infusion. The older cohort had lower creatinine clearances (median 67.3 vs 91.9 mL/min, p<0.001) and a higher proportion of patients with performance status ≥1 (59% vs 30%, p=0.02) but were otherwise similar. Rates of any-grade CRS, any-grade ICANS, and days to ANC recovery were similar between groups. Rates of baseline hypogammaglobulinemia were 36% in older patients and 30% in younger patients (p=0.60), while post-infusion hypogammaglobulinemia occurred in 82% vs 72% respectively (p=0.57). Infections occurred in 36% (n=8) of the older cohort versus 52% (n=32) of the younger cohort (p=0.22). There were no statistically significant differences between the older and younger cohorts in terms of documented falls (9% vs 15%, p=0.72) or non-ICANS delirium (5% vs 7%, p=1.0). Median PFS was 13.1 months in older patients (95% CI 9.2-not reached [NR]) vs 12.5 months in younger patients (95% CI 11.3-22.5, p=0.42. Median OS was not reached in the older cohort (95% CI: NR-NR) vs 31.4 months in the younger cohort (95% CI 24.8-NR) with p=0.04. However, age ≥70 was not a significant predictor of OS after adjusting for high-risk cytogenetics, triple-class refractoriness, extramedullary disease, and bone marrow plasma cell burden.

CONCLUSIONS: While limited by small sample size and unmeasured confounders, our retrospective analysis did not demonstrate significant increases in CAR-T toxicity among older patients. This included toxicities associated with geriatric populations such as falls and delirium. Our paradoxical finding of borderline better OS among patients aged ≥70, which was not significant in regression modeling, may have been due to selection bias in favor of disproportionately healthy CAR-T candidates in the geriatric population. Overall, BCMA CAR-T remains a safe and effective option for older patients with MM.

RevDate: 2023-03-18

Fjeldstad HE, Jacobsen DP, Johnsen GM, et al (2023)

Markers of placental function correlate with prevalence and quantity of nucleated fetal cells in maternal circulation in normotensive term pregnancies.

Acta obstetricia et gynecologica Scandinavica [Epub ahead of print].

INTRODUCTION: Transplacental fetal cell transfer results in the engraftment of fetal-origin cells in the pregnant woman's body, a phenomenon termed fetal microchimerism. Increased fetal microchimerism measured decades postpartum is implicated in maternal inflammatory disease. Understanding which factors cause increased fetal microchimerism is therefore important. During pregnancy, circulating fetal microchimerism and placental dysfunction increase with increasing gestational age, particularly towards term. Placental dysfunction is reflected by changes in circulating placenta-associated markers, specifically placental growth factor (PlGF), decreased by several 100 pg/mL, soluble fms-like tyrosine kinase-1 (sFlt-1), increased by several 1000 pg/mL, and the sFlt-1/PlGF ratio, increased by several 10 (pg/mL)/(pg/mL). We investigated whether such alterations in placenta-associated markers correlate with an increase in circulating fetal-origin cells.

MATERIAL AND METHODS: We included 118 normotensive, clinically uncomplicated pregnancies (gestational age 37+1 up to 42+2 weeks' gestation) pre-delivery. PlGF and sFlt-1 (pg/mL) were measured by Elecsys® Immunoassays. We extracted DNA from maternal and fetal samples and genotyped four human leukocyte antigen loci and 17 other autosomal loci. Paternally inherited, unique fetal alleles served as polymerase chain reaction (PCR) targets for detecting fetal-origin cells in maternal buffy coat. Fetal-origin cell prevalence was assessed by logistic regression, and quantity by negative binomial regression. Statistical exposures included gestational age (weeks), PlGF (100 pg/mL), sFlt-1 (1000 pg/mL) and the sFlt-1/PlGF ratio (10 (pg/mL)/(pg/mL)). Regression models were adjusted for clinical confounders and PCR-related competing exposures.

RESULTS: Gestational age was positively correlated with fetal-origin cell quantity (DRR = 2.2, P = 0.003) and PlGF was negatively correlated with fetal-origin cell prevalence (odds ratio [OR]100 = 0.6, P = 0.003) and quantity (DRR100 = 0.7, P = 0.001). The sFlt-1 and the sFlt-1/PlGF ratios were positively correlated with fetal-origin cell prevalence (OR1000 = 1.3, P = 0.014 and OR10 = 1.2, P = 0.038, respectively), but not quantity (DRR1000 = 1.1, P = 0.600; DRR10 = 1.1, P = 0.112, respectively).

CONCLUSIONS: Our results suggest that placental dysfunction as evidenced by placenta-associated marker changes, may increase fetal cell transfer. The magnitudes of change tested were based on ranges in PlGF, sFlt-1 and the sFlt-1/PlGF ratio previously demonstrated in pregnancies near and post-term, lending clinical significance to our findings. Our results were statistically significant after adjusting for confounders including gestational age, supporting our novel hypothesis that underlying placental dysfunction potentially is a driver of increased fetal microchimerism.

RevDate: 2023-03-18

Crisp AM, Halloran ME, Longini IM, et al (2023)

Covariate-constrained randomization with cluster selection and substitution.

Clinical trials (London, England) [Epub ahead of print].

BACKGROUND: An ongoing cluster-randomized trial for the prevention of arboviral diseases utilizes covariate-constrained randomization to balance two treatment arms across four specified covariates and geographic sector. Each cluster is within a census tract of the city of Mérida, Mexico, and there were 133 eligible tracts from which to select 50. As some selected clusters may have been subsequently found unsuitable in the field, we desired a strategy to substitute new clusters while maintaining covariate balance.

METHODS: We developed an algorithm that successfully identified a subset of clusters that maximized the average minimum pairwise distance between clusters in order to reduce contamination and balanced the specified covariates both before and after substitutions were made.

SIMULATIONS: Simulations were performed to explore some limitations of this algorithm. The number of selected clusters and eligible clusters were varied along with the method of selecting the final allocation pattern.

CONCLUSION: The algorithm is presented here as a series of optional steps that can be added to the standard covariate-constrained randomization process in order to achieve spatial dispersion, cluster subsampling, and cluster substitution. Simulation results indicate that these extensions can be used without loss of statistical validity, given a sufficient number of clusters included in the trial.

RevDate: 2023-03-17

Diamantopoulos LN, Makrakis D, Korentzelos D, et al (2023)

Development and validation of a prognostic nomogram for overall and disease-specific survival in patients with sarcomatoid urothelial carcinoma.

Urologic oncology pii:S1078-1439(23)00046-7 [Epub ahead of print].

INTRODUCTION: Sarcomatoid urothelial carcinoma (SUC) is a rare and aggressive variant of bladder cancer with limited data guiding prognosis. In this study, we present the first prognostic nomograms in the literature for 3- and 5-year overall survival (OS) and disease-specific survival (DSS), for patients with SUC derived from the surveillance, epidemiology and end results database (SEER).

MATERIALS AND METHODS: Patients with SUC were identified by using the ICD-10 topography codes C67.0-C67.9 (bladder cancer), and the morphologic code 8122 (SUC). Patients were randomly divided into a training cohort (TC) and a validation cohort (VC) (7:3 ratio). Variables significantly associated with OS and DSS were identified with multivariate Cox regression and were used to build the nomograms. Harrel's C-statistic with bootstrap resampling and calibration curves were used for internal (TC) and external (VC) validation. Clinical utility of the nomograms was assessed with the decision curve analysis (DCA). Goodness of fit between the nomograms and the AJCC 8th edition staging system was compared with the likelihood ratio test.

RESULTS: A total of 741 patients with SUC were included (507 TC, 234 VC). No statistically significant differences in baseline characteristics were identified between the 2 cohorts. Sex, SEER stage, radical cystectomy and chemotherapy were common variables for the OS and the DSS nomograms with the addition of age in the former. Optimism-corrected C-statistic for the nomograms was 0.68 and 0.67 for OS and DSS respectively. In comparison, C-statistic for AJCC was 0.59 for OS and 0.60 for DSS (P < 0.001). Calibration curves constructed for the nomograms showed appropriate consistency between predicted and actual survival. The nomograms demonstrated optimal clinical utility in the DCA, outperforming the AJCC staging system, by maintaining a higher clinical net benefits than treat all, treat none and AJCC curves, across threshold probabilities.

CONCLUSION: We present the first prognostic nomograms developed in patients with SUC. Our models demonstrated superior prognostic performance to the AJCC system, by utilizing a set of variables readily available in daily practice and may serve as useful tools for the individualized risk assessment of these patients.

RevDate: 2023-03-17

Tripathi P, Bender MF, Lei H, et al (2023)

Cryo-EM structures of anti-malarial antibody L9 with circumsporozoite protein reveal trimeric L9 association and complete 27-residue epitope.

Structure (London, England : 1993) pii:S0969-2126(23)00043-6 [Epub ahead of print].

Monoclonal antibody L9 recognizes the Plasmodium falciparum circumsporozoite protein (PfCSP) and is highly protective following controlled human malaria challenge. To gain insight into its function, we determined cryoelectron microscopy (cryo-EM) structures of L9 in complex with full-length PfCSP and assessed how this recognition influenced protection by wild-type and mutant L9s. Cryo-EM reconstructions at 3.6- and 3.7-Å resolution revealed L9 to recognize PfCSP as an atypical trimer. Each of the three L9s in the trimer directly recognized an Asn-Pro-Asn-Val (NPNV) tetrapeptide on PfCSP and interacted homotypically to facilitate L9-trimer assembly. We analyzed peptides containing different repeat tetrapeptides for binding to wild-type and mutant L9s to delineate epitope and homotypic components of L9 recognition; we found both components necessary for potent malaria protection. Last, we found the 27-residue stretch recognized by L9 to be highly conserved in P. falciparum isolates, suggesting the newly revealed complete L9 epitope to be an attractive vaccine target.

RevDate: 2023-03-17

Haring B, Hunt RP, Shadyab AH, et al (2023)

Cardiovascular Disease and Mortality in Black Women Carrying the Amyloidogenic V122I Transthyretin Gene Variant.

JACC. Heart failure pii:S2213-1779(23)00087-2 [Epub ahead of print].

BACKGROUND: Long-term data on cardiovascular disease (CVD) and mortality in female carriers of the transthyretin (TTR) V122I (pV142I) variant, one of the most common variants of hereditary transthyretin cardiac amyloidosis, are sparse and the effects of blood pressure, heart rate, body mass index, and physical activity on CVD outcomes remain largely unknown.

OBJECTIVES: The aim was to first examine the relationship of TTR V122I (pV142I) carrier status with CVD and mortality and second to investigate the effects of blood pressure, heart rate, body mass index, and physical activity in a large cohort of postmenopausal women.

METHODS: The study population consisted of 9,862 non-Hispanic Black/African American women, 9,529 noncarriers and 333 TTR V122I carriers, enrolled in the Women's Health Initiative at 40 centers in the United States. Women were generally healthy and postmenopausal at the time of enrollment (1993-1998). CVD was defined as a composite endpoint consisting of coronary heart disease, stroke, acute heart failure or CVD death, and all-cause mortality. CVD cases were based on self-reported annual mailed health updates. All information was centrally adjudicated by trained physicians. HRs and 95% CIs were obtained from adjusted Cox proportional hazards models.

RESULTS: Among 9,862 Black female participants (mean age: 62 years [IQR: 56-67 years]), the population frequency of the TTR V122I variant was 3.4% (333 variant carriers and 9,529 noncarriers). During a mean follow-up of 16.1 years (IQR: 9.7-22.2 years), incident CVD occurred in 2,229 noncarriers and 96 carriers, whereas 2,689 noncarriers and 108 carriers died. In adjusted models including demographic, lifestyle, and medical history covariates, TTR V122I carriers were at higher risk of the composite endpoint CVD (HR: 1.52; 95% CI: 1.22-1.88), acute heart failure (HR: 2.21; 95% CI: 1.53-3.18), coronary heart disease (HR: 1.80; 95% CI: 1.30-2.47), CVD death (HR: 1.70; 95% CI: 1.26-2.30), and all-cause mortality (HR: 1.28; 95% CI: 1.04-1.56). The authors found a significant interaction by age but not by blood pressure, heart rate, body mass index, or physical activity.

CONCLUSIONS: Black female TTR V122I (pV142I) carriers have a higher CVD and all-cause mortality risk compared to noncarriers. In case of clinical suspicion of amyloidosis, they should be screened for TTR V122I (pV142I) carrier status to ensure early treatment onset.

RevDate: 2023-03-17

Lindström S, Wang L, Feng H, et al (2023)

Genome-Wide Analyses Characterize Shared Heritability Among Cancers and Identify Novel Cancer Susceptibility Regions.

Journal of the National Cancer Institute pii:7079819 [Epub ahead of print].

BACKGROUND: The shared inherited genetic contribution to risk of different cancers is not fully known. In this study, we leverage results from twelve cancer genome-wide association studies (GWAS) to quantify pair-wise genome-wide genetic correlations across cancers and identify novel cancer susceptibility loci.

METHODS: We collected GWAS summary statistics for twelve solid cancers based on 376,759 cancer cases and 532,864 controls of European ancestry. The included cancer types were breast, colorectal, endometrial, esophageal, glioma, head and neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancers. We conducted cross-cancer GWAS and transcriptome-wide association studies (TWAS) to discover novel cancer susceptibility loci. Finally, we assessed the extent of variant-specific pleiotropy among cancers at known and newly identified cancer susceptibility loci.

RESULTS: We observed wide-spread but modest genome-wide genetic correlations across cancers. In cross-cancer GWAS and TWAS, we identified 15 novel cancer susceptibility loci. Additionally, we identified multiple variants at 77 distinct loci with strong evidence of being associated with at least two cancer types by testing for pleiotropy at known cancer susceptibility loci.

CONCLUSIONS: Overall, these results suggest that some genetic risk variants are shared among cancers, though much of cancer heritability is cancer- and thus tissue-specific. The increase in statistical power associated with larger sample sizes in cross-disease analysis allows for the identification of novel susceptibility regions. Future studies incorporating data on multiple cancer types are likely to identify additional regions associated with the risk of multiple cancer types.

RevDate: 2023-03-17

Malahleha M, Laher F, Dilraj A, et al (2023)

Risk Factors Associated with HIV Acquisition in Males Participating in HIV Vaccine Efficacy Trials in South Africa.

AIDS and behavior [Epub ahead of print].

In South Africa, HIV acquisition risk has been studied less in people assigned male at birth. We studied the associations between risk behaviors, clinical features and HIV incidence amongst males in two South African HIV preventive vaccine efficacy trials. We used Cox proportional hazards models to test for associations between demographics, sexual behaviors, clinical variables and HIV acquisition among males followed in the HVTN 503 (n = 219) and HVTN 702 (n = 1611) trials. Most males reported no male sexual partners (99.09% in HVTN 503) or identified as heterosexual (88.08% in HVTN 702). Annual HIV incidence was 1.39% in HVTN 503 (95% CI 0.76-2.32%) and 1.33% in HVTN 702 (95% CI 0.80-2.07%). Increased HIV acquisition was significantly associated with anal sex (HR 6.32, 95% CI 3.44-11.62), transactional sex (HR 3.42, 95% CI 1.80-6.50), and non-heterosexual identity (HR 16.23, 95%CI 8.13-32.41) in univariate analyses and non-heterosexual identity (HR 14.99, 95% CI 4.99-45.04; p < 0.01) in multivariate analysis. It is appropriate that prevention efforts in South Africa, although focused on the severe epidemic in young women, also encompass key male populations, including men who have sex with men, but also men who engage in anal or transactional sex.

RevDate: 2023-03-17

Jiao B, Johnson KM, Ramsey SD, et al (2023)

Long-Term Survival with Sickle Cell Disease: A Nationwide Cohort Study of Medicare and Medicaid Beneficiaries.

Blood advances pii:494890 [Epub ahead of print].

We report the first population-based period life table, the expected lifetime survival for Medicare and Medicaid beneficiaries with Sickle Cell Disease (SCD), and the disparities in survival by insurance types in the United States. We constructed a retrospective cohort of individuals with diagnosed SCD receiving Common Care (any real-world patterns of care except transplant) based on nationwide Medicare and Medicaid claims data (2008-2016), covering beneficiaries in all 50 states. We analyzed lifetime survival probabilities using Kaplan-Meier curves and projected life expectancies at various ages for all and stratified by sex and insurance types. Our analysis included 94,616 individuals with SCD that have not undergone any transplant. Life expectancy at birth was 52.6 years (95% CI: 51.9, 53.4). Compared to the adults covered by Medicaid only, those covered by Medicare for disabilities or end-stage renal disease and those dually insured by Medicare and Medicaid had significantly worse life expectancy. Similarly, for beneficiaries aged ≥65 years, these two insurance types were associated with significantly shorter life expectancy than those enrolled in Medicare old age and survivor's insurance. Our study underscores the persistent life expectancy shortfall for SCD patients, the burden of premature mortality during adulthood, and survival disparities by insurance status.

RevDate: 2023-03-17

Balgansuren G, Sprague M, Peterson P, et al (2023)

HLA-B leader genotypes in a clinical population.

HLA [Epub ahead of print].

The -21 dimorphism in the leader sequences of HLA-B exon 1 is associated with risk of graft-versus-host disease (GVHD), relapse and overall survival after unrelated donor hematopoietic cell transplantation (HCT), haploidentical HCT and cord blood transplantation. Consideration of the leader dimorphism in the prospective selection of allogeneic donors for HCT may help to lower risks for patients, but requires understanding of the frequencies of the leader in patients and candidate transplant donors. We defined the frequencies of the HLA-B leader, and its association to HLA-B Bw4/Bw6 and C1/C2 KIR epitopes. Sequence variants of rs1050458 of exon 1 position -21 for 11,126 haplotypes were analyzed from high resolution HLA typing of over 5500 study subjects. HLA typing was performed by TruSight/AlloSeq NGS and analyzed using TruSight/AlloSeq Assign software. HLA-B Bw4/Bw6 and C1/C2 KIR epitopes were defined based on established sequence alignments and nomenclature. Alleles at rs1050458 of HLA-B exon 1 were validated as dimorphic: rs1050458-C or -T variants encoding threonine (T) or methionine (M) at anchor position 2 (P2) of nonameric HLA-B leader peptides, respectfully. No additional variants were observed. Among study subjects, 70% of HLA-B haplotypes encoded T-leader and 30% encoded M-leader sequences. The genotype frequencies of TT, MT, and MM were consistent among patient, related, and unrelated donor groups. The associations of M/T leader, Bw4/Bw6, and C1/C2 enhanced understanding of the Class I features involved in the innate immune response. A population of patients and transplant donors confirms the rs1050458 leader dimorphism and its association with HLA-B Bw4/Bw6 and C1/C2 KIR features.

RevDate: 2023-03-18

Goswami H, Alsumali A, Jiang Y, et al (2023)

Correction to: Cost-Effectiveness Analysis of Molnupiravir Versus Best Supportive Care for the Treatment of Outpatient COVID-19 in Adults in the US.

RevDate: 2023-03-17

Pogosova-Agadjanyan EL, Hua X, Othus M, et al (2023)

Verification of prognostic expression biomarkers is improved by examining enriched leukemic blasts rather than mononuclear cells from acute myeloid leukemia patients.

Biomarker research, 11(1):31.

BACKGROUND: Studies have not systematically compared the ability to verify performance of prognostic transcripts in paired bulk mononuclear cells versus viable CD34-expressing leukemic blasts from patients with acute myeloid leukemia. We hypothesized that examining the homogenous leukemic blasts will yield different biological information and may improve prognostic performance of expression biomarkers.

METHODS: To assess the impact of cellular heterogeneity on expression biomarkers in acute myeloid leukemia, we systematically examined paired mononuclear cells and viable CD34-expressing leukemic blasts from SWOG diagnostic specimens. After enrichment, patients were assigned into discovery and validation cohorts based on availability of extracted RNA. Analyses of RNA sequencing data examined how enrichment impacted differentially expressed genes associated with pre-analytic variables, patient characteristics, and clinical outcomes.

RESULTS: Blast enrichment yielded significantly different expression profiles and biological pathways associated with clinical characteristics (e.g., cytogenetics). Although numerous differentially expressed genes were associated with clinical outcomes, most lost their prognostic significance in the mononuclear cells and blasts after adjusting for age and ELN risk, with only 11 genes remaining significant for overall survival in both cell populations (CEP70, COMMD7, DNMT3B, ECE1, LNX2, NEGR1, PIK3C2B, SEMA4D, SMAD2, TAF8, ZNF444). To examine the impact of enrichment on biomarker verification, these 11 candidate biomarkers were examined by quantitative RT/PCR in the validation cohort. After adjusting for ELN risk and age, expression of 4 genes (CEP70, DNMT3B, ECE1, and PIK3CB) remained significantly associated with overall survival in the blasts, while none met statistical significance in mononuclear cells.

CONCLUSIONS: This study provides insights into biological information gained/lost by examining viable CD34-expressing leukemic blasts versus mononuclear cells from the same patient and shows an improved verification rate for expression biomarkers in blasts.

RevDate: 2023-03-16

Auletta JJ, Kou J, Chen M, et al (2023)

Real-world data showing trends and outcomes by race and ethnicity in allogeneic hematopoietic cell transplantation: a report from the Center for International Blood and Marrow Transplant Research.

Transplantation and cellular therapy pii:S2666-6367(23)01165-X [Epub ahead of print].

BACKGROUND: Use of human leukocyte antigen (HLA)-mismatched donors could enable more patients with ethnically diverse backgrounds to receive allogeneic hematopoietic cell transplantation (HCT) in the United States. However, real-world trends and outcomes following mismatched donor HCT for diverse patients remain largely undefined.

OBJECTIVE: To determine whether mismatched donor platforms have increased access to allogeneic HCT for ethnically diverse patients, particularly through the application of novel graft-versus-host disease (GvHD) prophylaxis regimens, and if outcomes for diverse patients were comparable to those of non-Hispanic White patients.

DESIGN: Observational cross-sectional study using real-world data from the Center for International Blood and Marrow Transplant Research (CIBMTR) registry. All patients receiving their first allogeneic HCT in the U.S. from 2009-2020 with focus on transplants performed in 2020 were included. Data from patients receiving allogeneic HCT using bone marrow, peripheral blood or cord blood from HLA-matched or mismatched related and unrelated donors was analyzed. Specifically, relative proportions of allogeneic HCT were generated as percent of total for donor type and for patient age, disease indication, GvHD prophylaxis, and race and ethnicity. Causes of death were summarized using frequencies, and the Kaplan-Meier estimator was used for estimating overall survival.

RESULTS: Compared to matched related donor and matched unrelated donor HCT, more ethnically diverse patients received mismatched unrelated donor, haploidentical donor, and cord blood HCT. Matched unrelated donor remains the most common donor type, but use of haploidentical donors has increased significantly over the last 5 years. Paralleling the increase in haploidentical HCT is the increased use of post-transplant cyclophosphamide (PTCy) as GvHD prophylaxis. Relative to older transplant eras, the most contemporary transplant era associates with the highest survival rates following allogeneic HCT irrespective of patient race and ethnicity. However, disease relapse remains the primary cause of death for both adult and pediatric allogeneic HCT recipients by donor type and across all patient race and ethnicity groups.

CONCLUSIONS: Ethnically diverse patients are undergoing allogeneic HCTs at higher rates largely through the use of alternative donor platforms incorporating PTCy. Maintaining access to potential life-saving allogeneic HCT using alternative donors and novel GvHD prophylaxis strategies and improving HCT outcomes, particularly disease relapse, are urgent clinical needs.

RevDate: 2023-03-16

Andtbacka RHI, Wang Y, Pierce RH, et al (2022)

Mavorixafor, an Orally Bioavailable CXCR4 Antagonist, Increases Immune Cell Infiltration and Inflammatory Status of Tumor Microenvironment in Patients with Melanoma.

Cancer research communications, 2(8):904-913.

PURPOSE: Mavorixafor is an oral, selective inhibitor of the CXCR4 chemokine receptor that modulates immune cell trafficking. A biomarker-driven phase Ib study (NCT02823405) was conducted in 16 patients with melanoma to investigate the hypothesis that mavorixafor favorably modulates immune cell profiles in the tumor microenvironment (TME) and to evaluate the safety of mavorixafor alone and in combination with pembrolizumab.

EXPERIMENTAL DESIGN: Serial biopsies of melanoma lesions were assessed after 3 weeks of mavorixafor monotherapy and after 6 weeks of combination treatment for immune cell markers by NanoString analysis for gene expression and by multiplexed immunofluorescent staining for in situ protein expression. Serum samples taken at biopsy timepoints were evaluated for key chemokine and cytokine alterations using the Myriad Rules Based Medicine multiplex immunoassays.

RESULTS: Within the TME, mavorixafor alone increased CD8[+] T-cell infiltration, granzyme B signal, antigen presentation machinery, and both tumor inflammatory signature (TIS) and IFNγ gene expression signature scores. Increases in the key serum cytokines CXCL9 and CXCL10 were further enhanced when mavorixafor was combined with pembrolizumab. Adverse events (AE), as assessed by the investigator according to NCI Common Terminology Criteria for Adverse Events (v4.03), related to either mavorixafor or pembrolizumab (≥15%) were diarrhea, fatigue, maculopapular rash, and dry eye. Reported AEs were all ≤ grade 3.

CONCLUSION/DISCUSSION: Treatment with single-agent mavorixafor resulted in enhanced immune cell infiltration and activation in the TME, leading to increases in TIS and IFNγ gene signatures. Mavorixafor as a single agent, and in combination with pembrolizumab, has an acceptable safety profile. These data support further investigation of the use of mavorixafor for patients unresponsive to checkpoint inhibitors.

SIGNIFICANCE: Despite survival improvements in patients with melanoma treated with checkpoint inhibitor therapy, a significant unmet medical need exists for therapies that enhance effectiveness. We propose that mavorixafor sensitizes the melanoma tumor microenvironment and enhances the activity of checkpoint inhibitors, and thereby may translate to a promising treatment for broader patient populations.

RevDate: 2023-03-16

Sager JE, El-Zailik A, Passarell J, et al (2023)

Population pharmacokinetics and exposure-response analysis of a single dose of sotrovimab in the early treatment of patients with mild to moderate COVID-19.

CPT: pharmacometrics & systems pharmacology [Epub ahead of print].

Sotrovimab is a recombinant human monoclonal antibody that has been shown to prevent progression to hospitalization or death in non-hospitalized high-risk patients with mild-to-moderate COVID-19 following either intravenous (IV) or intramuscular (IM) administration. Population pharmacokinetic (popPK) and exposure-response (ER) analyses were performed to characterize single dose sotrovimab PK and the relationship between exposure and response (probability of progression), as well as covariates that may contribute to between-participant variability in sotrovimab PK and efficacy following IV or IM administration. Sotrovimab PK was described by a two-compartment model with linear elimination; IM absorption was characterized by a sigmoid absorption model. PopPK covariate analysis led to the addition of the effect of body weight on systemic clearance and peripheral volume of distribution, sex on IM bioavailability and first-order absorption rate (KA), and body mass index on KA. However, the magnitude of covariate effect was not pronounced and was therefore not expected to be clinically relevant based on available data to date. For ER analysis, sotrovimab exposure measures were predicted using the final popPK model. An ER model was developed using the exposure measure of sotrovimab concentration at 168 hours that described the relationship between exposure and probability of progression within the ER dataset for COMET-TAIL. The number of risk factors (≤1 vs >1) was incorporated as an additive shift on the model-estimated placebo response but had no impact on overall drug response. Limitations in the ER model may prevent generalization of these results to describe the sotrovimab exposure-progression relationship across SARS-COV-2 variants.

RevDate: 2023-03-15

Okamoto S, Iida M, Hamad N, et al (2023)

American Society of Transplantation and Cellular Therapy International Affair Committee: Report of 3[rd] Workshop on Global Perspective to Access to Transplantation at the 2022 Tandem Meeting.

Transplantation and cellular therapy pii:S2666-6367(23)01134-X [Epub ahead of print].

RevDate: 2023-03-15

Rashid N, Arora M, Jurdi NE, et al (2023)

Frailty in Patients with Chronic Graft-versus-Host Disease.

Transplantation and cellular therapy pii:S2666-6367(23)01168-5 [Epub ahead of print].

BACKGROUND: Frailty is an increasingly recognized clinical diagnosis associated with high risk of disability and mortality. Frailty in patients after hematopoietic cell transplantation (HCT) is associated with increased non-relapse mortality (NRM) and decreased overall survival (OS). Frailty has not been extensively studied in patients with chronic graft-versus-host disease (cGVHD).

OBJECTIVES: The objectives of this study were to assess the prevalence and clinical correlates of frailty and the association of frailty with NRM and OS in patients enrolled in the Chronic GVHD Consortium. Patients were characterized as frail if they met Fried's definition: ≥3 of the following criteria at enrollment: unintentional weight loss, exhaustion, slow walking speed, low physical activity, and weakness. Frailty was assessed retrospectively and used surrogate measures for the 5 domains of frailty. Frailty, chronic GVHD organ scores, and patient-reported outcomes were measured at the time of enrollment.

RESULTS: This study included 399 patients from 9 centers in the United States with 32% characterized as frail and 68% as not frail. The median follow-up time from enrollment was 9 years (interquartile range 7 - 11 years). Frail patients were more likely to be older (p=0.004), have lower Karnofsky performance score (p<0.001), have severe cGVHD (p<0.001), and have GI (p<0.001), liver (p=0.04), or lung cGVHD (p=0.002). In a multivariable analysis, older age, increased cGVHD global severity, and thrombocytopenia were statically associated with frailty when cGVHD organ involvement was excluded. A separate analysis excluding cGVHD severity and including organ involvement showed that lung and liver cGVHD, and older age were associated with frailty. Neither corticosteroid usage at the time of enrollment nor the maximum recorded dose of corticosteroids prior to enrollment were associated with frailty. Frail patients had higher NRM than not frail patients (p<0.001) with 10-year cumulative incidences of 41% (95% CI 32-49%) vs 22% (95% CI 17-28%), respectively. Reciprocally, frailty was also associated with a significantly lower OS (p<0.001) with 10-year OS of 43% (95% CI 35-53%) in frail patients vs 63% (95% CI 57-69%) in not frail patients. In multivariable analysis that included the individual domains of frailty, weakness, low physical activity, and slow walking speed were associated with survival. Frail patients also had worse scores on various measures of patient reported outcomes including SF-36, Lee Symptom Scale, and the trial outcome of the FACT-BMT index score.

CONCLUSIONS: Frail patients with cGVHD have significantly worse outcomes compared to not frail patients. Clinical features such as older age and lung and liver cGVHD are associated with frailty. Earlier clinical recognition of frailty in cGVHD patients may prompt interventions to counteract frailty that could be beneficial to this population.

RevDate: 2023-03-15

Peterson LM, Lee H, Huybrechts I, et al (2023)

Reliability estimates for assessing meal timing derived from longitudinal repeated 24-hour dietary recalls.

The American journal of clinical nutrition pii:S0002-9165(23)46259-4 [Epub ahead of print].

BACKGROUND: Regulating meal timing may have efficacy for improving metabolic health for preventing or managing chronic disease. However, the reliability of measuring meal timing with commonly used dietary assessment tools needs characterization prior to investigating meal timing and health outcomes in epidemiologic studies.

OBJECTIVE: To evaluate the reliability of estimating meal timing parameters including overnight fasting duration, midpoint of overnight fasting time, number of daily eating episodes, period with largest percentage of daily caloric intake, and late last eating episode (>9pm) from repeated 24-hour dietary recalls (24HR).

DESIGN: Intraclass correlation coefficients, Light's kappa estimates and 95% confidence intervals (CIs) were calculated from repeated 24HR administered in three epidemiologic studies: United States-based IDATA study (n=996, six 24HR collected over 12-months), German EPIC-Potsdam Validation Study (n=134, twelve 24HR collected over 12-months) and EPIC-Potsdam BMBF-II Study (n=725, four 24HR collected over 36-months).

RESULTS: Measurement reliability of overnight fasting duration based on a single 24HR was "poor" in all studies (ICC range 0.27, 95% CI 0.23, 0.32 to 0.46, 95% CI 0.43, 0.50). Reliability was "moderate" with three 24HR (ICC range: 0.53, 95% CI 0.47, 0.58 in IDATA, 0.62, 95% CI 0.52, 0.69 in the EPIC-Potsdam Validation Study, and 0.72, 95% CI 0.70-0.75 in the EPIC-Potsdam BMBF-II Study). Results were similar for midpoint of overnight fasting time and number of eating episodes. Reliability of measuring late eating was "fair" in IDATA (Light's Kappa 0.30, 95% CI 0.21, 0.39) and "slight" in the EPIC-Potsdam Validation study and the EPIC-Potsdam BMBF-II study (Light's Kappa 0.19, 95% CI 0.15, 0.25 and 0.09, 95% CI 0.06, 0.12, respectively). Reliability estimates differed by sex, body mass index, and weekday and season of 24HR administration in some studies.

CONCLUSIONS: Our result show that at least three 24HR over a 1-3-year period are required for reliable estimates of meal timing variables.

RevDate: 2023-03-15

Du M, Gu D, Xin J, et al (2023)

Integrated multi-omics approach to distinct molecular characterization and classification of early-onset colorectal cancer.

Cell reports. Medicine pii:S2666-3791(23)00080-0 [Epub ahead of print].

Incidence of early-onset colorectal cancer (EOCRC), defined by a diagnosed age under 50 years, is increasing, but its heterogeneous etiologies that differ from general CRC remain undetermined. We initially characterize the genome, epigenome, transcriptome, and proteome of tumors from 79 patients in a Chinese CRC cohort. Data for an additional 126 EOCRC subjects are obtained from the International Cancer Genome Consortium Chinese cohort and The Cancer Genome Atlas European cohort. We observe that early-onset tumors have a high tumor mutation burden; increased DNA repair features by mutational signature 3 and multi-layer pathway enrichments; strong perturbations at effects of DNA methylation and somatic copy-number alteration on gene expression; and upregulated immune infiltration as hot tumors underlying immunophenotypes. Notably, LMTK3 exhibits ancestral mutation disparity, potentially being a functional modulator and biomarker that drives molecular alterations in EOCRC development and immunotherapies. This integrative omics study provides valuable knowledge for precision oncology of CRC.

RevDate: 2023-03-15

Hulverson MA, Choi R, Schaefer DA, et al (2023)

Comparison of Toxicities among Different Bumped Kinase Inhibitor Analogs for Treatment of Cryptosporidiosis.

Antimicrobial agents and chemotherapy [Epub ahead of print].

Recent advances on the development of bumped kinase inhibitors for treatment of cryptosporidiosis have focused on the 5-aminopyrazole-4-carboxamide scaffold, due to analogs that have less hERG inhibition, superior efficacy, and strong in vitro safety profiles. Three compounds, BKI-1770, -1841, and -1708, showed strong efficacy in C. parvum infected mice. Both BKI-1770 and BKI-1841 had efficacy in the C. parvum newborn calf model, reducing diarrhea and oocyst excretion. However, both compounds caused hyperflexion of the limbs seen as dropped pasterns. Toxicity experiments in rats and calves dosed with BKI-1770 showed enlargement of the epiphyseal growth plate at doses only slightly higher than the efficacious dose. Mice were used as a screen to check for bone toxicity, by changes to the tibia epiphyseal growth plate, or neurological causes, by use of a locomotor activity box. These results showed neurological effects from both BKI-1770 and BKI-1841 and bone toxicity in mice from BKI-1770, indicating one or both effects may be contributing to toxicity. However, BKI-1708 remains a viable treatment candidate for further evaluation as it showed no signs of bone toxicity or neurological effects in mice.

RevDate: 2023-03-16
CmpDate: 2023-03-16

Arora S, Szulzewsky F, Jensen M, et al (2023)

Visualizing genomic characteristics across an RNA-Seq based reference landscape of normal and neoplastic brain.

Scientific reports, 13(1):4228.

In order to better understand the relationship between normal and neoplastic brain, we combined five publicly available large-scale datasets, correcting for batch effects and applying Uniform Manifold Approximation and Projection (UMAP) to RNA-Seq data. We assembled a reference Brain-UMAP including 702 adult gliomas, 802 pediatric tumors and 1409 healthy normal brain samples, which can be utilized to investigate the wealth of information obtained from combining several publicly available datasets to study a single organ site. Normal brain regions and tumor types create distinct clusters and because the landscape is generated by RNA-Seq, comparative gene expression profiles and gene ontology patterns are readily evident. To our knowledge, this is the first meta-analysis that allows for comparison of gene expression and pathways of interest across adult gliomas, pediatric brain tumors, and normal brain regions. We provide access to this resource via the open source, interactive online tool Oncoscape, where the scientific community can readily visualize clinical metadata, gene expression patterns, gene fusions, mutations, and copy number patterns for individual genes and pathway over this reference landscape.

RevDate: 2023-03-17
CmpDate: 2023-03-16

Young WJ, Haessler J, Benjamins JW, et al (2023)

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease.

Nature communications, 14(1):1411.

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction.

RevDate: 2023-03-17
CmpDate: 2023-03-14

Shields PG, Bierut L, Arenberg D, et al (2023)

Smoking Cessation, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology.

Journal of the National Comprehensive Cancer Network : JNCCN, 21(3):297-322.

Although the harmful effects of smoking after a cancer diagnosis have been clearly demonstrated, many patients continue to smoke cigarettes during treatment and beyond. The NCCN Guidelines for Smoking Cessation emphasize the importance of smoking cessation in all patients with cancer and seek to establish evidence-based recommendations tailored to the unique needs and concerns of patients with cancer. The recommendations contained herein describe interventions for cessation of all combustible tobacco products (eg, cigarettes, cigars, hookah), including smokeless tobacco products. However, recommendations are based on studies of cigarette smoking. The NCCN Smoking Cessation Panel recommends that treatment plans for all patients with cancer who smoke include the following 3 tenets that should be done concurrently: (1) evidence-based motivational strategies and behavior therapy (counseling), which can be brief; (2) evidence-based pharmacotherapy; and (3) close follow-up with retreatment as needed.

RevDate: 2023-03-17
CmpDate: 2023-03-14

Moses KA, Sprenkle PC, Bahler C, et al (2023)

NCCN Guidelines® Insights: Prostate Cancer Early Detection, Version 1.2023.

Journal of the National Comprehensive Cancer Network : JNCCN, 21(3):236-246.

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for individuals with a prostate who opt to participate in an early detection program after receiving the appropriate counseling on the pros and cons. These NCCN Guidelines Insights provide a summary of recent updates to the NCCN Guidelines with regard to the testing protocol, use of multiparametric MRI, and management of negative biopsy results to optimize the detection of clinically significant prostate cancer and minimize the detection of indolent disease.

RevDate: 2023-03-15
CmpDate: 2023-03-15

Rahmioglu N, Mortlock S, Ghiasi M, et al (2023)

The genetic basis of endometriosis and comorbidity with other pain and inflammatory conditions.

Nature genetics, 55(3):423-436.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention.

RevDate: 2023-03-15

Drain PK, Dalmat RR, Hao L, et al (2023)

Duration of viral infectiousness and correlation with symptoms and diagnostic testing in non-hospitalized adults during acute SARS-CoV-2 infection: A longitudinal cohort study.

Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology, 161:105420 [Epub ahead of print].

BACKGROUND: Guidelines for SARS-CoV-2 have relied on limited data on duration of viral infectiousness and correlation with COVID-19 symptoms and diagnostic testing.

METHODS: We enrolled ambulatory adults with acute SARS-CoV-2 infection and performed serial measurements of COVID-19 symptoms, nasal swab viral RNA, nucleocapsid (N) and spike (S) antigens, and replication-competent SARS-CoV-2 by viral growth in culture. We determined average time from symptom onset to a first negative test result and estimated risk of infectiousness, as defined by positive viral growth in culture.

RESULTS: Among 95 adults, median [interquartile range] time from symptom onset to first negative test result was 9 [5] days, 13 [6] days, 11 [4] days, and >19 days for S antigen, N antigen, culture growth, and viral RNA by RT-PCR, respectively. Beyond two weeks, virus growth and N antigen titers were rarely positive, while viral RNA remained detectable among half (26/51) of participants tested 21-30 days after symptom onset. Between 6-10 days from symptom onset, N antigen was strongly associated with culture positivity (relative risk=7.61, 95% CI: 3.01-19.22), whereas neither viral RNA nor symptoms were associated with culture positivity. During the 14 days following symptom onset, the presence of N antigen remained strongly associated (adjusted relative risk=7.66, 95% CI: 3.96-14.82) with culture positivity, regardless of COVID-19 symptoms.

CONCLUSIONS: Most adults have replication-competent SARS-CoV-2 for 10-14 after symptom onset. N antigen testing is a strong predictor of viral infectiousness and may be a more suitable biomarker, rather than absence of symptoms or viral RNA, to discontinue isolation within two weeks from symptom onset.

RevDate: 2023-03-13

Lynch RC, Ujjani CS, Poh C, et al (2023)

Concurrent pembrolizumab with AVD for untreated classical Hodgkin lymphoma.

Blood pii:494889 [Epub ahead of print].

Concurrent administration pembrolizumab with chemotherapy in untreated classical Hodgkin lymphoma (CHL) has not previously been studied. To investigate this combination, we conducted a single arm study of concurrent pembrolizumab with AVD (APVD) for untreated CHL. We enrolled 30 patients (6 early favorable, 6 early unfavorable, and 18 advanced stage, median age 33 years (range 18-69 years)) and met the primary safety endpoint with no observed significant treatment delays in the first two cycles. Twelve patients experienced grade 3-4 non-hematologic adverse events (AEs) most commonly febrile neutropenia (5, 17%) and infection/sepsis (3, 10%). Grade 3-4 immune-related AEs were seen in 3 patients, including ALT elevation (3, 10%) and AST elevation (1, 3%). One patient experienced an episode of grade 2 colitis and arthritis. Six (20%) patients missed at least one dose of pembrolizumab due to adverse events, primarily grade 2 or higher transaminitis (5, 17%). Among 29 response-evaluable patients, the best overall response rate was 100% and CR rate of 90%. With median follow up of 2.1 years, 2-year progression-free survival (PFS) and overall survival were 97% and 100%, respectively. To date, no patient who withheld or discontinued pembrolizumab due to toxicity has progressed. Clearance of ctDNA was associated with superior PFS when measured after cycle 2 (p=0.025) and at end of treatment (EOT, p=0.0016). None of the 4 patients with persistent disease by FDG-PET at EOT yet negative ctDNA have relapsed to date. Concurrent APVD shows promising safety and efficacy, but may yield spurious PET findings in some patients. Trial Registration Number: NCT03331341.

RevDate: 2023-03-13

Nguyen HT, Tang W, Webster ALH, et al (2023)

Fanconi anemia-isogenic head and neck cancer cell line pairs - a basic and translational science resource.

International journal of cancer [Epub ahead of print].

Fanconi anemia (FA) is a heritable malformation, bone marrow failure and cancer predisposition syndrome that confers an exceptionally high risk of squamous carcinomas. These carcinomas originate in epithelia lining the mouth, proximal esophagus, vulva and anus: their origins are not understood, and no effective ways have been identified to prevent or delay their appearance. Many FA-associated carcinomas are also therapeutically challenging: they may be multi-focal and stage-advanced at diagnosis, and most individuals with FA cannot tolerate standard-of-care systemic therapies such as DNA cross-linking drugs or ionizing radiation due to constitutional DNA damage hypersensitivity. We developed the Fanconi Anemia Cancer Cell Line Resource (FA-CCLR) to foster new work on the origins, treatment and prevention of FA-associated carcinomas. The FA-CCLR consists of Fanconi-isogenic head and neck squamous cell carcinoma (HNSCC) cell line pairs generated from 5 individuals with FA-associated HNSCC, and 5 individuals with sporadic HNSCC. Sporadic, isogenic HNSCC cell line pairs were generated in parallel with FA patient-derived isogenic cell line pairs to provide comparable experimental material to use to identify cell and molecular phenotypes driven by germline or somatic loss of Fanconi pathway function, and the subset of these FA-dependent phenotypes that can be modified, complemented or suppressed. All ten FANC-isogenic cell line pairs are available to academic, non-profit and industry investigators via the 'Fanconi Anemia Research Materials' Resource and Repository at Oregon Health & Sciences University, Portland OR. This article is protected by copyright. All rights reserved.

RevDate: 2023-03-14
CmpDate: 2023-03-14

Kiptinness C, Naik P, Thuo N, et al (2023)

Online HIV prophylaxis delivery: Protocol for the ePrEP Kenya pilot study.

Frontiers in public health, 11:1054559.

BACKGROUND: Online pharmacies in Kenya provide sexual and reproductive health products (e.g., HIV self-testing, contraception) and could be leveraged to increase the reach of HIV pre-exposure and post-exposure prophylaxis (PrEP/PEP) to populations who do not frequently attend health facilities. To date, evidence is limited for operationalizing online PrEP/PEP delivery and the type of populations reached with this differential service delivery model.

METHODS: The ePrEP Kenya Pilot will deliver daily oral PrEP and PEP via MYDAWA, a private online pharmacy retailer, to clients in Nairobi for 18 months. Potential clients will obtain information about PrEP/PEP on MYDAWA's sexual wellness page and self-screen for HIV risk. Individuals ≥18 years, identified as at HIV risk, and willing to pay for a blood-based HIV self-test and PrEP/PEP delivery will be eligible for enrollment. To continue with online PrEP/PEP initiation, eligible clients will purchase a blood-based HIV self-test for 250 KES (~USD 2) [delivered to their setting of choice for 99 KES (~USD 1)], upload an image of their self-test result, and attend a telemedicine visit with a MYDAWA provider. During the telemedicine visit, providers will screen clients for PrEP/PEP eligibility, including clinical concerns (e.g., kidney disease), discuss self-test results, and complete counseling on PrEP/PEP use and safety. Providers will refer clients who self-test HIV positive or report any existing medical conditions to the appropriate services at healthcare facilities that meet their preferences. Eligible clients will be prescribed PrEP (30-day PrEP supply at initiation; 90-day PrEP supply at follow-up visits) or PEP (28-day supply) for free and have it delivered for 99 KES (~USD 1). We will measure PrEP and PEP initiation among eligible clients, PEP-to-PrEP transition, PrEP continuation, and implementation outcomes (e.g., feasibility, acceptability, and costs).

DISCUSSION: Establishing pathways to increase PrEP and PEP access is crucial to help curb new HIV infections in settings with high HIV prevalence. The findings from this study will provide evidence on the implementation of online pharmacy PrEP and PEP service delivery that can help inform guidelines in Kenya and similar settings.

RevDate: 2023-03-12

Takata Y, Yang JJ, Yu D, et al (2023)

Calcium intake and lung cancer risk: a pooled analysis of 12 prospective cohort studies.

The Journal of nutrition pii:S0022-3166(23)35478-6 [Epub ahead of print].

BACKGROUND: Previous studies on calcium intake and lung cancer risk reported inconsistent associations, possibly due to differences in intake amounts and contributing sources of calcium and smoking prevalence.

OBJECTIVE: We investigated associations of lung cancer risk with intakes of calcium from foods and/or supplements and major calcium-rich foods in 12 studies.

METHODS: Data from 12 prospective cohort studies conducted in the US, Europe, and Asia were pooled and harmonized. We applied Dietary Reference Intake to categorize calcium intake based on the recommendations and quintile distribution to categorize calcium-rich food intakes. We ran multivariable Cox regression by each cohort and pooled risk estimates to compute overall hazard ratios (HR) (95% confidence intervals [CI]).

RESULTS: Among 1,624,244 adult men and women, 21,513 incident lung cancer cases were ascertained during a mean follow-up of 9.9 years. Overall, dietary calcium intake was not significantly associated with lung cancer risk; the HRs (95% CI) were 1.08 (0.98-1.18) for higher (>1,500 [men] or >1,800 [women] mg/d) and1.01 (0.95-1.07) for lower intake (≤500 [men] or ≤600 [women] mg/d) comparing with recommended intake (800-1,200 mg/d). Milk and soy food intake was positively or inversely associated with lung cancer risk (HR [95% CI]=1.07 [1.02-1.12] and 0.92 [0.84-1.00]), respectively. The positive association with milk intake was significant only in European and US studies (P-interaction for region=0.04). No significant association was observed for calcium supplements.

CONCLUSIONS: In this largest prospective investigation, overall, calcium intake was not associated with risk of lung cancer, but milk intake was associated with a higher risk. Our findings underscore the importance of considering food sources of calcium in studies of calcium intake.

RevDate: 2023-03-11

Hines MR, Knight TE, McNerney KO, et al (2023)

Immune Effector Cell associated Hemophagocytic Lymphohistiocytosis-like Syndrome (IEC-HS).

Transplantation and cellular therapy pii:S2666-6367(23)01164-8 [Epub ahead of print].

BACKGROUND: T cell mediated hyperinflammatory responses such as cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) are now well-established toxicities of chimeric antigen receptor (CAR) T cells. As the field of CAR T cells advances, however, there is increasing recognition that hemophagocytic lymphohistiocytosis (HLH)-like toxicities following CAR T cell infusions are occurring broadly across patient populations and CAR T cell constructs. Importantly, these HLH-like toxicities are often not as directly associated with CRS and/or its severity as initially described. This emergent toxicity, however ill-defined, is associated with life-threatening complications, creating an urgent need for improved identification and optimal management.

OBJECTIVES: With the goal to improve patient outcomes and formulate a framework to characterize and study this HLH-like syndrome, we established an American Society for Transplantation and Cellular Therapy (ASTCT) panel comprised of experts in primary and secondary HLH, pediatric and adult HLH, infectious disease, rheumatology and hematology, oncology, and cellular therapy.

RESULTS: Through this effort, we provide an overview of the underlying biology of classical primary and secondary HLH, its relationship with similar manifestations following CAR T cell infusions and propose the term "immune effector cell (IEC) associated HLH-like syndrome (IEC-HS)" to describe this emergent toxicity. Further, we delineate a framework for identification of IEC-HS and put forward a grading schema which can be used to assess severity and facilitate cross-trial comparisons. Additionally, given the critical need to optimize outcomes for patients experiencing IEC-HS, we provide insights into potential treatment approaches, strategies to optimize supportive care and delineate alternate etiologies which should be considered in a patient presenting with IEC-HS.

CONCLUSION: By collectively defining IEC-HS as a hyperinflammatory toxicity we can now embark on further study of the pathophysiology underlying this toxicity profile and make strides towards a more comprehensive assessment and treatment approach.

RevDate: 2023-03-11

van den Puttelaar R, Meester RGS, Peterse EEP, et al (2023)

Risk-stratified screening for colorectal cancer using genetic and environmental risk factors: A cost-effectiveness analysis based on real-world data.

Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association pii:S1542-3565(23)00177-5 [Epub ahead of print].

BACKGROUND AND AIMS: Previous studies on the cost-effectiveness of personalized colorectal cancer (CRC) screening were based on hypothetical performance of CRC risk prediction and did not consider the association with competing causes of death. In this study, we estimated the cost-effectiveness of risk-stratified screening using real-world data for CRC risk and competing causes of death.

METHODS: Risk predictions for CRC and competing causes of death, from a large community-based cohort, were used to stratify individuals into risk groups. A microsimulation model was used to optimize colonoscopy screening for each risk group by varying the start age (40-60 years), end age (70-85 years), and screening interval (5-15 years). The outcomes included personalized screening ages and intervals, and cost-effectiveness compared to uniform colonoscopy screening (ages 45-75, every 10 years). Key assumptions were varied in sensitivity analyses.

RESULTS: Risk-stratified screening resulted in substantially different screening recommendations, ranging from a one-time colonoscopy at age 60 for low-risk individuals to a colonoscopy every five years from ages 40-85 for high-risk individuals. Nevertheless, on a population-level, risk-stratified screening would increase net quality adjusted life years gained (QALYG) by only 0.7% at equal costs to uniform screening, or, reduce average costs by 1.2% for equal QALYG. The benefit of risk-stratified screening improved when it was assumed to increase participation or costs less per genetic test.

CONCLUSIONS: Personalized screening for CRC, accounting for competing causes of death risk, could result in highly tailored individual screening programs. However, average improvements across the population in QALYG and cost-effectiveness compared with uniform screening are small.

RevDate: 2023-03-14
CmpDate: 2023-03-14

Murakami K, Furuya H, Hokutan K, et al (2023)

Association of SNPs in the PAI1 Gene with Disease Recurrence and Clinical Outcome in Bladder Cancer.

International journal of molecular sciences, 24(5):.

PURPOSE: Bladder cancer (BCa) is one of the most common cancer types worldwide and is characterized by a high rate of recurrence. In previous studies, we and others have described the functional influence of plasminogen activator inhibitor-1 (PAI1) in bladder cancer development. While polymorphisms in PAI1 have been associated with increased risk and worsened prognosis in some cancers, the mutational status of PAI1 in human bladder tumors has not been well defined.

METHODS: In this study, we evaluated the mutational status of PAI1 in a series of independent cohorts, comprised of a total of 660 subjects.

RESULTS: Sequencing analyses identified two clinically relevant 3' untranslated region (UTR) single nucleotide polymorphisms (SNPs) in PAI1 (rs7242; rs1050813). Somatic SNP rs7242 was present in human BCa cohorts (overall incidence of 72%; 62% in Caucasians and 72% in Asians). In contrast, the overall incidence of germline SNP rs1050813 was 18% (39% in Caucasians and 6% in Asians). Furthermore, Caucasian patients with at least one of the described SNPs had worse recurrence-free survival and overall survival (p = 0.03 and p = 0.03, respectively). In vitro functional studies demonstrated that SNP rs7242 increased the anti-apoptotic effect of PAI1, and SNP rs1050813 was related to a loss of contact inhibition associated with cellular proliferation when compared to wild type.

CONCLUSION: Further investigation of the prevalence and potential downstream influence of these SNPs in bladder cancer is warranted.

RevDate: 2023-03-14
CmpDate: 2023-03-14

Dong J, Buradagunta CS, Zhang T, et al (2023)

Prognostic landscape of mitochondrial genome in myelodysplastic syndrome after stem-cell transplantation.

Journal of hematology & oncology, 16(1):21.

Despite mitochondrial DNA (mtDNA) mutations are common events in cancer, their global frequency and clinical impact have not been comprehensively characterized in patients with myelodysplastic neoplasia (also known as myelodysplastic syndromes, MDS). Here we performed whole-genome sequencing (WGS) on samples obtained before allogenic hematopoietic cell transplantation (allo-HCT) from 494 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research. We evaluated the impact of mtDNA mutations on transplantation outcomes, including overall survival (OS), relapse, relapse-free survival (RFS), and transplant-related mortality (TRM). A random survival forest algorithm was applied to evaluate the prognostic performance of models that include mtDNA mutations alone and combined with MDS- and HCT-related clinical factors. A total of 2666 mtDNA mutations were identified, including 411 potential pathogenic variants. We found that overall, an increased number of mtDNA mutations was associated with inferior transplantation outcomes. Mutations in several frequently mutated mtDNA genes (e.g., MT-CYB and MT-ND5) were identified as independent predictors of OS, RFS, relapse and/or TRM after allo-HCT. Integration of mtDNA mutations into the models based on the Revised International Prognostic Scores (IPSS-R) and clinical factors related to MDS and allo-HCT could capture more prognostic information and significantly improve the prognostic stratification efforts. Our study represents the first WGS effort in MDS receiving allo-HCT and shows that there may be clinical utility of mtDNA variants to predict allo-HCT outcomes in combination with more standard clinical parameters.

RevDate: 2023-03-14

Benkeser D, Fong Y, Janes HE, et al (2023)

Immune correlates analysis of a phase 3 trial of the AZD1222 (ChAdOx1 nCoV-19) vaccine.

NPJ vaccines, 8(1):36.

In the phase 3 trial of the AZD1222 (ChAdOx1 nCoV-19) vaccine conducted in the U.S., Chile, and Peru, anti-spike binding IgG concentration (spike IgG) and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured four weeks after two doses were assessed as correlates of risk and protection against PCR-confirmed symptomatic SARS-CoV-2 infection (COVID-19). These analyses of SARS-CoV-2 negative participants were based on case-cohort sampling of vaccine recipients (33 COVID-19 cases by 4 months post dose two, 463 non-cases). The adjusted hazard ratio of COVID-19 was 0.32 (95% CI: 0.14, 0.76) per 10-fold increase in spike IgG concentration and 0.28 (0.10, 0.77) per 10-fold increase in nAb ID50 titer. At nAb ID50 below the limit of detection (< 2.612 IU50/ml), 10, 100, and 270 IU50/ml, vaccine efficacy was -5.8% (-651%, 75.6%), 64.9% (56.4%, 86.9%), 90.0% (55.8%, 97.6%) and 94.2% (69.4%, 99.1%). These findings provide further evidence towards defining an immune marker correlate of protection to help guide regulatory/approval decisions for COVID-19 vaccines.

RevDate: 2023-03-10

Nava Lauson CB, Tiberti S, Corsetto PA, et al (2023)

Linoleic acid potentiates CD8[+] T cell metabolic fitness and antitumor immunity.

Cell metabolism pii:S1550-4131(23)00049-9 [Epub ahead of print].

The metabolic state represents a major hurdle for an effective adoptive T cell therapy (ACT). Indeed, specific lipids can harm CD8[+] T cell (CTL) mitochondrial integrity, leading to defective antitumor responses. However, the extent to which lipids can affect the CTL functions and fate remains unexplored. Here, we show that linoleic acid (LA) is a major positive regulator of CTL activity by improving metabolic fitness, preventing exhaustion, and stimulating a memory-like phenotype with superior effector functions. We report that LA treatment enhances the formation of ER-mitochondria contacts (MERC), which in turn promotes calcium (Ca[2+]) signaling, mitochondrial energetics, and CTL effector functions. As a direct consequence, the antitumor potency of LA-instructed CD8 T cells is superior in vitro and in vivo. We thus propose LA treatment as an ACT potentiator in tumor therapy.

RevDate: 2023-03-10

Kato I, JC Larson (2023)

Reply to: Comments on "Association of calcium and vitamin D supplementation with cancer incidence and cause-specific mortality in Black women: extended follow-up of the Women's Health Initiative calcium-vitamin D trial".

RevDate: 2023-03-10

Kopmar NE, Gooley T, Curley N, et al (2023)

Results from a phase I study of continuous infusion cladribine, high-dose cytarabine, and mitoxantrone for relapsed/refractory high-grade myeloid neoplasms.

Leukemia & lymphoma [Epub ahead of print].

RevDate: 2023-03-11

Wright CE, Enquobahrie DA, Prager S, et al (2023)

Pregnancy loss and risk of incident CVD within 5 years: Findings from the Women's Health Initiative.

Frontiers in cardiovascular medicine, 10:1108286.

BACKGROUND: Previous studies have demonstrated an increased risk of cardiovascular disease (CVD) in women with a history of pregnancy loss. Less is known about whether pregnancy loss is associated with age at the onset of CVD, but this is a question of interest, as a demonstrated association of pregnancy loss with early-onset CVD may provide clues to the biological basis of the association, as well as having implications for clinical care. We conducted an age-stratified analysis of pregnancy loss history and incident CVD in a large cohort of postmenopausal women aged 50-79 years old.

METHODS: Associations between a history of pregnancy loss and incident CVD were examined among participants in the Women's Health Initiative Observational Study. Exposures were any history of pregnancy loss (miscarriage and/or stillbirth), recurrent (2+) loss, and a history of stillbirth. Logistic regression analyses were used to examine associations between pregnancy loss and incident CVD within 5 years of study entry in three age strata (50-59, 69-69, and 70-79). Outcomes of interest were total CVD, coronary heart disease (CHD), congestive heart failure, and stroke. To assess the risk of early onset CVD, Cox proportional hazard regression was used to examine incident CVD before the age of 60 in a subset of subjects aged 50-59 at study entry.

RESULTS: After adjustment for cardiovascular risk factors, a history of stillbirth was associated with an elevated risk of all cardiovascular outcomes in the study cohort within 5 years of study entry. Interactions between age and pregnancy loss exposures were not significant for any cardiovascular outcome; however, age-stratified analyses demonstrated an association between a history of stillbirth and risk of incident CVD within 5 years in all age groups, with the highest point estimate seen in women aged 50-59 (OR 1.99; 95% CI, 1.16-3.43). Additionally, stillbirth was associated with incident CHD among women aged 50-59 (OR 3.12; 95% CI, 1.33-7.29) and 60-69 (OR 2.06; 95% CI, 1.24-3.43) and with incident heart failure and stroke among women aged 70-79. Among women aged 50-59 with a history of stillbirth, a non-significantly elevated hazard ratio was observed for heart failure before the age of 60 (HR 2.93, 95% CI, 0.96-6.64).

CONCLUSIONS: History of stillbirth was strongly associated with a risk of cardiovascular outcomes within 5 years of baseline in a cohort of postmenopausal women aged 50-79. History of pregnancy loss, and of stillbirth in particular, might be a clinically useful marker of cardiovascular disease risk in women.


RJR Experience and Expertise


Robbins holds BS, MS, and PhD degrees in the life sciences. He served as a tenured faculty member in the Zoology and Biological Science departments at Michigan State University. He is currently exploring the intersection between genomics, microbial ecology, and biodiversity — an area that promises to transform our understanding of the biosphere.


Robbins has extensive experience in college-level education: At MSU he taught introductory biology, genetics, and population genetics. At JHU, he was an instructor for a special course on biological database design. At FHCRC, he team-taught a graduate-level course on the history of genetics. At Bellevue College he taught medical informatics.


Robbins has been involved in science administration at both the federal and the institutional levels. At NSF he was a program officer for database activities in the life sciences, at DOE he was a program officer for information infrastructure in the human genome project. At the Fred Hutchinson Cancer Research Center, he served as a vice president for fifteen years.


Robbins has been involved with information technology since writing his first Fortran program as a college student. At NSF he was the first program officer for database activities in the life sciences. At JHU he held an appointment in the CS department and served as director of the informatics core for the Genome Data Base. At the FHCRC he was VP for Information Technology.


While still at Michigan State, Robbins started his first publishing venture, founding a small company that addressed the short-run publishing needs of instructors in very large undergraduate classes. For more than 20 years, Robbins has been operating The Electronic Scholarly Publishing Project, a web site dedicated to the digital publishing of critical works in science, especially classical genetics.


Robbins is well-known for his speaking abilities and is often called upon to provide keynote or plenary addresses at international meetings. For example, in July, 2012, he gave a well-received keynote address at the Global Biodiversity Informatics Congress, sponsored by GBIF and held in Copenhagen. The slides from that talk can be seen HERE.


Robbins is a skilled meeting facilitator. He prefers a participatory approach, with part of the meeting involving dynamic breakout groups, created by the participants in real time: (1) individuals propose breakout groups; (2) everyone signs up for one (or more) groups; (3) the groups with the most interested parties then meet, with reports from each group presented and discussed in a subsequent plenary session.


Robbins has been engaged with photography and design since the 1960s, when he worked for a professional photography laboratory. He now prefers digital photography and tools for their precision and reproducibility. He designed his first web site more than 20 years ago and he personally designed and implemented this web site. He engages in graphic design as a hobby.

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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

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Collection of publications by R J Robbins

Reprints and preprints of publications, slide presentations, instructional materials, and data compilations written or prepared by Robert Robbins. Most papers deal with computational biology, genome informatics, using information technology to support biomedical research, and related matters.

Research Gate page for R J Robbins

ResearchGate is a social networking site for scientists and researchers to share papers, ask and answer questions, and find collaborators. According to a study by Nature and an article in Times Higher Education , it is the largest academic social network in terms of active users.

Curriculum Vitae for R J Robbins

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Curriculum Vitae for R J Robbins

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