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Bibliography on: Publications by FHCRC Researchers

RJR-3x

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 21 Jun 2024 at 01:48 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®)

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RevDate: 2024-06-20

Waters AR, Meehan K, Atkins DL, et al (2024)

How pharmacists would design and implement a community pharmacy-based colorectal cancer screening program.

Preventive oncology & epidemiology, 2(1):.

BACKGROUND: Distributing CRC screening through pharmacies, a highly accessible health service, may create opportunities for more equitable access to CRC screening. However, providing CRC screening in a new context introduces a substantial implementation challenge.

METHODS: We conducted 23 semi-structured interviews with community pharmacists practicing in Washington state and North Carolina about distributing fecal immunochemical tests (FIT) to patients in the pharmacy. The Consolidated Framework for Implementation Research (CFIR) was used to guide analysis.

RESULTS: Pharmacists believed that delivering FITs was highly compatible with their environment, workflow, and scope of practice. While knowledge about FIT eligibility criteria varied, pharmacists felt comfortable screening patients. They identified standardized eligibility criteria, patient-facing educational materials, and continuing education as essential design features. Pharmacists proposed adapting existing pharmacy electronic health record systems for patient reminders/prompts to facilitate FIT completion. While pharmacists felt confident that they could discuss test results with patients, they also expressed a need for stronger communication and care coordination with primary care providers.

DISCUSSION: When designing a pharmacy-based CRC screening program, pharmacists desired programmatic procedures to fit their current knowledge and context. Findings indicate that if proper attention is given to multi-level factors, FIT delivery can be extended to pharmacies.

RevDate: 2024-06-16

Pishgar F, CI Lee (2024)

Improving Patient Understanding of Prostate Cancer Risks Associated with PI-RADS Lexicon.

Journal of the American College of Radiology : JACR pii:S1546-1440(24)00519-2 [Epub ahead of print].

RevDate: 2024-06-15

Sala-Torra O, Beppu L, Wu Q, et al (2024)

Point-of-care BCR::ABL1 transcript monitoring using capillary dried blood in chronic myeloid leukemia patients.

Leukemia [Epub ahead of print].

RevDate: 2024-06-19

Hart TM, Sonnert ND, Tang X, et al (2024)

An atlas of human vector-borne microbe interactions reveals pathogenicity mechanisms.

Cell pii:S0092-8674(24)00532-4 [Epub ahead of print].

Vector-borne diseases are a leading cause of death worldwide and pose a substantial unmet medical need. Pathogens binding to host extracellular proteins (the "exoproteome") represents a crucial interface in the etiology of vector-borne disease. Here, we used bacterial selection to elucidate host-microbe interactions in high throughput (BASEHIT)-a technique enabling interrogation of microbial interactions with 3,324 human exoproteins-to profile the interactomes of 82 human-pathogen samples, including 30 strains of arthropod-borne pathogens and 8 strains of related non-vector-borne pathogens. The resulting atlas revealed 1,303 putative interactions, including hundreds of pairings with potential roles in pathogenesis, including cell invasion, tissue colonization, immune evasion, and host sensing. Subsequent functional investigations uncovered that Lyme disease spirochetes recognize epidermal growth factor as an environmental cue of transcriptional regulation and that conserved interactions between intracellular pathogens and thioredoxins facilitate cell invasion. In summary, this interactome atlas provides molecular-level insights into microbial pathogenesis and reveals potential host-directed targets for next-generation therapeutics.

RevDate: 2024-06-19

Yeh AC, Koyama M, Waltner OG, et al (2024)

Microbiota dictate T cell clonal selection to augment graft-versus-host disease after stem cell transplantation.

Immunity pii:S1074-7613(24)00273-5 [Epub ahead of print].

Allogeneic T cell expansion is the primary determinant of graft-versus-host disease (GVHD), and current dogma dictates that this is driven by histocompatibility antigen disparities between donor and recipient. This paradigm represents a closed genetic system within which donor T cells interact with peptide-major histocompatibility complexes (MHCs), though clonal interrogation remains challenging due to the sparseness of the T cell repertoire. We developed a Bayesian model using donor and recipient T cell receptor (TCR) frequencies in murine stem cell transplant systems to define limited common expansion of T cell clones across genetically identical donor-recipient pairs. A subset of donor CD4[+] T cell clonotypes differentially expanded in identical recipients and were microbiota dependent. Microbiota-specific T cells augmented GVHD lethality and could target microbial antigens presented by gastrointestinal epithelium during an alloreactive response. The microbiota serves as a source of cognate antigens that contribute to clonotypic T cell expansion and the induction of GVHD independent of donor-recipient genetics.

RevDate: 2024-06-14

Halabi S, Guo S, Roy A, et al (2024)

Reply to J.A. Garcia et al.

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

RevDate: 2024-06-14

Nakamura M, SM Parkhurst (2024)

Calcium influx rapidly establishes distinct spatial recruitments of Annexins to cell wounds.

Genetics pii:7693402 [Epub ahead of print].

To survive daily damage, the formation of actomyosin ring at the wound edge is required to rapidly close cell wounds. Calcium influx is one of the start signals for these cell wound repair events. Here, we find that rapid recruitment of all three Drosophila calcium responding and phospholipid binding Annexin proteins (AnxB9, AnxB10, AnxB11) to distinct regions around the wound is regulated by the quantity of calcium influx rather than their binding to specific phospholipids. The distinct recruitment patterns of these Annexins regulate the subsequent recruitment of RhoGEF2 and RhoGEF3 through actin stabilization to form a robust actomyosin ring. Surprisingly, while the wound does not close in the absence of calcium influx, we find that reduced calcium influx can still initiate repair processes, albeit leading to severe repair phenotypes. Thus, our results suggest that, in addition to initiating repair events, the quantity of calcium influx is important for precise Annexin spatiotemporal protein recruitment to cell wounds and efficient wound repair.

RevDate: 2024-06-15

Yanagi KS, N Lehrbach (2024)

Streamlined single shot safe harbor transgene integration in C. elegans using unc-119 rescue.

microPublication biology, 2024:.

Transgenic animals are an invaluable tool in model organism genetics. The ease of modifying the C. elegans genome through high-copy integration of transgenes facilitates the investigation of diverse and fundamental biological processes. However, generation of new multicopy integrated transgenes is limited by the time and labor cost. Further, many transgenes are integrated using non-specific DNA damaging agents. These DNA damaging agents cause unwanted mutations during the integration process and may have deleterious effects. A recently described method for CRISPR/Cas9-based integration of multicopy transgenes at safe harbor loci using Fluorescent Landmark Interference (FLInt) greatly increases the efficiency of multicopy transgene integration and mitigates issues related to off-target mutagenesis during integration. unc-119 rescue is a simple and widely used phenotypic marker in C. elegans transgenesis and genome engineering. To streamline generation of multicopy transgenes via FLInt, we have generated a set of strains suitable for FLInt-mediated integration of transgenes using rescue of the unc-119 mutant phenotype to select transgenic animals. We demonstrate the utility of this approach and outline a protocol that uses unc-119 rescue as a selection marker for streamlined integration of multicopy transgenes at safe harbor loci.

RevDate: 2024-06-14
CmpDate: 2024-06-14

Dima D, Goel U, Sannareddy A, et al (2024)

Outcomes of therapeutic plasma exchange for the treatment of patients with multiple myeloma cast nephropathy.

Hematological oncology, 42(4):e3293.

Current treatment guidelines of myeloma cast nephropathy (MCN) recommend the institution of plasma cell-directed therapy and consideration of therapeutic plasma exchange (TPE), with the goal of rapid reduction of the serum free light chain (sFLC). However, the role of TPE continues to remain a subject of debate. The goal of this retrospective bi-institutional study was to evaluate the clinical outcomes of TPE in combination with systemic therapy. Eighty patients were included in this analysis, of whom 72.5% had ≥50% drop in their initial involved sFLC. At 3 months from TPE initiation, the overall hematologic response rate (ORR) was 67.5% with a very good partial response or better (≥VGPR) rate of 40%. At 6 months, ORR was 57.5%, with ≥VGPR rate of 49%. The renal response rate at 3 and 6 months was 47.5% and 43.75%, respectively; the overall renal response rate was 48.75%. On multivariable analysis, every one unit increase in baseline creatinine (odds ratio [OR] 0.76, p = 0.006), and achievement of ≥VGPR (OR 21.7 p < 0.0001) were significantly associated with renal response. Also, a ≥50% drop in sFLC was favorably associated with renal response (OR 3.39, p = 0.09). With a median follow-up of 36.4 months, the median overall survival (OS) was 11 months. On multivariable analysis, achievement of renal response (hazard ratio [HR] 0.3, p < 0.0001) and newly diagnosed disease (NDMM; HR 0.43, p = 0.0055) were associated with improved OS. Among NDMM patients, those treated with daratumumab-based regimens had a trend for better OS (p = 0.15), compared to other regimens, but the difference was not significant. At the end of follow-up, an estimated 40.4% of patients who were on dialysis were able to become dialysis independent. In conclusion, our study highlights the poor survival of patients with MCN. Achievement of early renal response is crucial for prolonged OS, with daratumumab-based therapies showing promise.

RevDate: 2024-06-14

Zhu Q, Yuan C, Wang D, et al (2024)

The TRIM28/miR133a/CD47 axis acts as a potential therapeutic target in pancreatic necrosis by impairing efferocytosis.

Molecular therapy : the journal of the American Society of Gene Therapy pii:S1525-0016(24)00387-3 [Epub ahead of print].

Efferocytosis, the clearance of apoptotic cells by macrophages, plays a crucial role in inflammatory responses and effectively prevents secondary necrosis. However, the mechanisms underlying efferocytosis in acute pancreatitis remain unclear. In this study, we demonstrated the presence of efferocytosis in injured human and mouse pancreatic tissues. We also observed significant upregulation of CD47, an efferocytosis-related "do not eat me" molecule, in injured acinar cells. Subsequently, we used CRISPR/Cas9 gene editing, anti-adeno-associated virus gene modification, and anti-CD47 antibody to investigate the potential therapeutic role of acute pancreatitis. CD47 expression was negatively regulated by upstream miR133a, which is controlled by the transcription factor TRIM28. To further investigate the regulation of efferocytosis and reduction of pancreatic necrosis in acute pancreatitis, we used miR-133a-agomir and pancreas-specific AAV-shTRIM28 to modulate CD47 expression. Our findings confirmed that CD47-mediated efferocytosis is critical for preventing pancreatic necrosis and suggest that targeting the TRIM28-miR133a-CD47 axis is clinically relevant for the treatment of acute pancreatitis.

RevDate: 2024-06-19
CmpDate: 2024-06-13

Fleurence RL, Kent S, Adamson B, et al (2024)

Assessing Real-World Data From Electronic Health Records for Health Technology Assessment: The SUITABILITY Checklist: A Good Practices Report of an ISPOR Task Force.

Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research, 27(6):692-701.

This ISPOR Good Practices report provides a framework for assessing the suitability of electronic health records data for use in health technology assessments (HTAs). Although electronic health record (EHR) data can fill evidence gaps and improve decisions, several important limitations can affect its validity and relevance. The ISPOR framework includes 2 components: data delineation and data fitness for purpose. Data delineation provides a complete understanding of the data and an assessment of its trustworthiness by describing (1) data characteristics; (2) data provenance; and (3) data governance. Fitness for purpose comprises (1) data reliability items, ie, how accurate and complete the estimates are for answering the question at hand and (2) data relevance items, which assess how well the data are suited to answer the particular question from a decision-making perspective. The report includes a checklist specific to EHR data reporting: the ISPOR SUITABILITY Checklist. It also provides recommendations for HTA agencies and policy makers to improve the use of EHR-derived data over time. The report concludes with a discussion of limitations and future directions in the field, including the potential impact from the substantial and rapid advances in the diffusion and capabilities of large language models and generative artificial intelligence. The report's immediate audiences are HTA evidence developers and users. We anticipate that it will also be useful to other stakeholders, particularly regulators and manufacturers, in the future.

RevDate: 2024-06-13

Bolon YT, Atshan R, Allbee-Johnson M, et al (2024)

Leveraging Hematopoietic Cell Transplant Data and Biorepository Resources at the Center for International Blood and Marrow Transplant Research to Improve Patient Outcomes.

Transplantation and cellular therapy pii:S2666-6367(24)00466-4 [Epub ahead of print].

BACKGROUND: Hematopoietic cell transplantation (HCT) has undergone many advances over the decades. Trends in HCT utilization have been impacted by research based on the data and samples collected by the Center for International Blood and Marrow Transplant Research (CIBMTR).

OBJECTIVE: Here, we provide a summary report of the CIBMTR Biorepository resource and describe the biospecimen inventory along with collection and request procedures.

STUDY DESIGN: The diversity captured in this inventory reflects transplant activity, and these samples can be leveraged for secondary analyses to generate more data and insights to advance the field.

RESULTS: We describe how our resources have already impacted HCT practice and elaborate on possibilities for further collaboration and utilization to maximize capabilities and research opportunities.

CONCLUSION: Hematopoietic cell transplant data and Biorepository resources at the Center for International Blood and Marrow Transplant Research have been and continue to be leveraged to improve patient outcomes.

RevDate: 2024-06-16
CmpDate: 2024-06-13

Wahid KA, Sahin O, Kundu S, et al (2024)

Associations Between Radiation Oncologist Demographic Factors and Segmentation Similarity Benchmarks: Insights From a Crowd-Sourced Challenge Using Bayesian Estimation.

JCO clinical cancer informatics, 8:e2300174.

PURPOSE: The quality of radiotherapy auto-segmentation training data, primarily derived from clinician observers, is of utmost importance. However, the factors influencing the quality of clinician-derived segmentations are poorly understood; our study aims to quantify these factors.

METHODS: Organ at risk (OAR) and tumor-related segmentations provided by radiation oncologists from the Contouring Collaborative for Consensus in Radiation Oncology data set were used. Segmentations were derived from five disease sites: breast, sarcoma, head and neck (H&N), gynecologic (GYN), and GI. Segmentation quality was determined on a structure-by-structure basis by comparing the observer segmentations with an expert-derived consensus, which served as a reference standard benchmark. The Dice similarity coefficient (DSC) was primarily used as a metric for the comparisons. DSC was stratified into binary groups on the basis of structure-specific expert-derived interobserver variability (IOV) cutoffs. Generalized linear mixed-effects models using Bayesian estimation were used to investigate the association between demographic variables and the binarized DSC for each disease site. Variables with a highest density interval excluding zero were considered to substantially affect the outcome measure.

RESULTS: Five hundred seventy-four, 110, 452, 112, and 48 segmentations were used for the breast, sarcoma, H&N, GYN, and GI cases, respectively. The median percentage of segmentations that crossed the expert DSC IOV cutoff when stratified by structure type was 55% and 31% for OARs and tumors, respectively. Regression analysis revealed that the structure being tumor-related had a substantial negative impact on binarized DSC for the breast, sarcoma, H&N, and GI cases. There were no recurring relationships between segmentation quality and demographic variables across the cases, with most variables demonstrating large standard deviations.

CONCLUSION: Our study highlights substantial uncertainty surrounding conventionally presumed factors influencing segmentation quality relative to benchmarks.

RevDate: 2024-06-13
CmpDate: 2024-06-13

Steinman L, Chadwick K, Chavez Santos E, et al (2024)

Remote Evidence-Based Programs for Health Promotion to Support Older Adults During the COVID-19 Pandemic and Beyond: Mixed Methods Outcome Evaluation.

JMIR aging, 7:e52069 pii:v7i1e52069.

BACKGROUND: Evidence-based programs (EBPs) for health promotion were developed to reach older adults where they live, work, pray, and play. When the COVID-19 pandemic placed a disproportionate burden on older adults living with chronic conditions and the community-based organizations that support them, these in-person programs shifted to remote delivery. While EBPs have demonstrated effectiveness when delivered in person, less is known about outcomes when delivered remotely.

OBJECTIVE: This study evaluated changes in remote EBP participants' health and well-being in a national mixed methods outcome evaluation in January 1, 2021, to March 31, 2022.

METHODS: We used the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) for equity framework to guide the evaluation. We purposively sampled for diverse remote EBP delivery modes and delivery organizations, staff, and traditionally underserved older adults, including people of color and rural dwellers. We included 5 EBPs for self-management, falls prevention, and physical activity: videoconferencing (Chronic Disease Self-Management Program, Diabetes Self-Management Program, and EnhanceFitness), telephone plus mailed materials (Chronic Pain Self-Management Program), and enhanced self-directed mailed materials (Walk With Ease). Participant and provider data included validated surveys, in-depth interviews, and open-ended survey questions. We used descriptive statistics to characterize the sample and the magnitude of change and paired t tests (2-tailed) and the Fisher exact test to test for change in outcomes between enrollment and 6-month follow-up. Thematic analysis was used to identify similarities and differences in outcomes within and across programs. Joint display tables facilitated the integration of quantitative and qualitative findings.

RESULTS: A total of 586 older adults, 198 providers, and 37 organizations providing EBPs participated in the evaluation. Of the 586 older adults, 289 (49.3%) provided follow-up outcome data. The mean age of the EBP participants was 65.4 (SD 12.0) years. Of the 289 EBP participants, 241 (83.4%) were female, 108 (37.3%) were people of color, 113 (39.1%) lived alone, and 99 (34.3%) were experiencing financial hardship. In addition, the participants reported a mean of 2.5 (SD 1.7) chronic conditions. Overall, the remote EBP participants showed statistically significant improvements in health, energy, sleep quality, loneliness, depressive symptoms, and technology anxiety. Qualitatively, participants shared improvements in knowledge, attitudes, and skills for healthier living; reduced their social isolation and loneliness; and gained better access to programs. Three-fourths of the providers (149/198, 75.2%) felt that effectiveness was maintained when switching from in-person to remote delivery.

CONCLUSIONS: The findings suggest that participating in remote EBPs can improve health, social, and technological outcomes of interest for older adults and providers, with benefits extending to policy makers. Future policy and practice can better support remote EBP delivery as one model for health promotion, improving access for all older adults.

RevDate: 2024-06-13

Ni Z, Kundu P, McKean DF, et al (2024)

Genome-wide analysis to assess if heavy alcohol consumption modifies the association between SNPs and pancreatic cancer risk.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:745921 [Epub ahead of print].

BACKGROUND: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk.

METHODS: We conducted a genome-wide interaction analysis of single nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than 3 drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies (GWAS). Our analysis included 3,707 cases and 4,167 controls from case-control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed effect meta-analyses were conducted.

RESULTS: A potential novel region of association on 10p11.22, lead SNP rs7898449 (Pinteraction = 5.1 x 10-8 in the meta-analysis, Pinteraction = 2.1x10-9 in the case-control studies, Pinteraction = 0.91 cohort studies) was identified. A SNP correlated with this lead SNP is an eQTL for the NRP1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004).

CONCLUSIONS: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an eQTL for the NRP1, a protein that plays an important role in the development and progression of pancreatic cancer Impact: This work can provide insight into the etiology of pancreatic cancer particularly in heavy drinkers.

RevDate: 2024-06-14

Smith MA, Cheng G, Phelan R, et al (2024)

Pulmonary hypertension in the intensive care unit after pediatric allogeneic hematopoietic stem cell transplant: incidence, risk factors, and outcomes.

Frontiers in oncology, 14:1415984.

OBJECTIVE: To determine the incidence, risk factors, and outcomes of pulmonary hypertension (PH) in the pediatric intensive care unit (PICU) after pediatric hematopoietic stem cell transplant (HCT).

METHODS: This was a retrospective study of pediatric patients who underwent allogeneic HCT between January 2008-December 2014 at a center contributing to the Center for International Blood and Marrow Transplant Research data registry. Incidence of PH was assessed from PICU diagnostic codes from records merged from the Virtual Pediatric Systems database. Regression and survival analyses identified factors associated with post-HCT PH. Additional post-HCT morbidities and survival after PH were also assessed.

RESULTS: Among 6,995 HCT recipients, there were 29 cases of PH, a cumulative incidence of 0.42% (95% CI 0.27%-0.57%) at 60 months post-HCT. In the sub-cohort of 1,067 patients requiring intensive care after HCT, this accounted for a PH prevalence of 2.72% (95% CI 1.74-3.69%). There was an increased risk of developing PH associated with Black/African American race, metabolic disorders, partially HLA-matched or cord blood allografts, graft-versus-host prophylaxis regimen, and lower pre-HCT functional status. Patients who developed PH had significant PICU comorbidities including heart failure, pulmonary hemorrhage, respiratory failure, renal failure, and infections. Survival at 6 months after diagnosis of post-HCT PH was 51.7% (95% CI 32.5%-67.9%).

CONCLUSIONS: PH is a rare but serious complication in the pediatric post-HCT population. A significant burden of additional comorbidities, procedural interventions, and risk of mortality is associated with its development. Close monitoring and prompt intervention for this severe complication are necessary in this vulnerable population.

RevDate: 2024-06-15
CmpDate: 2024-06-13

Tordoff DM, Restar A, Minalga B, et al (2024)

Including transgender populations in mathematical models for HIV treatment and prevention: current barriers and policy implications.

Journal of the International AIDS Society, 27(6):e26304.

INTRODUCTION: Mathematical models of HIV have been uniquely important in directing and evaluating HIV policy. Transgender and nonbinary people are disproportionately impacted by HIV; however, few mathematical models of HIV transmission have been published that are inclusive of transgender and nonbinary populations. This commentary discusses current structural challenges to developing robust and accurate trans-inclusive models and identifies opportunities for future research and policy, with a focus on examples from the United States.

DISCUSSION: As of April 2024, only seven published mathematical models of HIV transmission include transgender people. Existing models have several notable limitations and biases that limit their utility for informing public health intervention. Notably, no models include transgender men or nonbinary individuals, despite these populations being disproportionately impacted by HIV relative to cisgender populations. In addition, existing mathematical models of HIV transmission do not accurately represent the sexual network of transgender people. Data availability and quality remain a significant barrier to the development of accurate trans-inclusive mathematical models of HIV. Using a community-engaged approach, we developed a modelling framework that addresses the limitations of existing model and to highlight how data availability and quality limit the utility of mathematical models for transgender populations.

CONCLUSIONS: Modelling is an important tool for HIV prevention planning and a key step towards informing public health interventions, programming and policies for transgender populations. Our modelling framework underscores the importance of accurate trans-inclusive data collection methodologies, since the relevance of these analyses for informing public health decision-making is strongly dependent on the validity of the model parameterization and calibration targets. Adopting gender-inclusive and gender-specific approaches starting from the development and data collection stages of research can provide insights into how interventions, programming and policies can distinguish unique health needs across all gender groups. Moreover, in light of the data structure limitations, designing longitudinal surveillance data systems and probability samples will be critical to fill key research gaps, highlight progress and provide additional rigour to the current evidence. Investments and initiatives like Ending the HIV Epidemic in the United States can be further expanded and are highly needed to prioritize and value transgender populations across funding structures, goals and outcome measures.

RevDate: 2024-06-12
CmpDate: 2024-06-12

Satyal U, Valentine H, Liu D, et al (2024)

Urine Biopsy as Dynamic Biomarker to Enhance Clinical Staging of Bladder Cancer in Radical Cystectomy Candidates.

JCO precision oncology, 8:e2300362.

PURPOSE: There is significant interest in identifying complete responders to neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) to potentially avoid removal of a pathologically benign bladder. However, clinical restaging after NAC is highly inaccurate. The objective of this study was to develop a next-generation sequencing-based molecular assay using urine to enhance clinical staging of patients with bladder cancer.

METHODS: Urine samples from 20 and 44 patients with bladder cancer undergoing RC were prospectively collected for retrospective analysis for molecular correlate analysis from two clinical trials, respectively. The first cohort was used to benchmark the assay, and the second was used to determine the performance characteristics of the test as it correlates to responder status as measured by pathologic examination.

RESULTS: First, to benchmark the assay, known mutations identified in the tissue (MT) of patients from the Accelerated Methotrexate, Vinblastine, Doxorubicin, Cisplatin trial (ClinicalTrials.gov identifier: NCT01611662, n = 16) and a cohort from University of California-San Francisco (n = 4) were cross referenced against mutation profiles from urine (MU). We then determined the correlation between MU persistence and residual disease in pre-RC urine samples from a second prospective clinical trial (The pT0 trial; ClinicalTrials.gov identifier: NCT02968732). Residual MU status correlated strongly with residual disease status (pT0 trial; n = 44; P = .0092) when MU from urine supernatant and urine pellet were assessed separately and analyzed in tandem. The sensitivity, specificity, PPV, and NPV were 91%, 50%, 86%, and 63% respectively, with an overall accuracy of 82% for this second cohort.

CONCLUSION: MU are representative of MT and thus can be used to enhance clinical staging of urothelial carcinoma. Urine biopsy may be used as a reliable tool that can be further developed to identify complete response to NAC in anticipation of safe RC avoidance.

RevDate: 2024-06-11
CmpDate: 2024-06-11

Amonoo HL, Daskalakis E, Wolfe ED, et al (2024)

A Positive Psychology Intervention in Allogeneic Hematopoietic Stem Cell Transplantation Survivors (PATH): A Pilot Randomized Clinical Trial.

Journal of the National Comprehensive Cancer Network : JNCCN, 22(2D):.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (HSCT) survivors experience significant psychological distress and low levels of positive psychological well-being, which can undermine patient-reported outcomes (PROs), such as quality of life (QoL). Hence, we conducted a pilot randomized clinical trial to assess the feasibility and preliminary efficacy of a telephone-delivered positive psychology intervention (Positive Affect for the Transplantation of Hematopoietic stem cells intervention [PATH]) for improving well-being in HSCT survivors.

METHODS: HSCT survivors who were 100 days post-HSCT for hematologic malignancy at an academic institution were randomly assigned to either PATH or usual care. PATH, delivered by a behavioral health expert, entailed 9 weekly phone sessions on gratitude, personal strengths, and meaning. We defined feasibility a priori as >60% of eligible participants enrolling in the study and >75% of PATH participants completing ≥6 of 9 sessions. At baseline and 9 and 18 weeks, patients self-reported gratitude, positive affect, life satisfaction, optimism, anxiety, depression, posttraumatic stress disorder (PTSD), QoL, physical function, and fatigue. We used repeated measures regression models and estimates of effect size (Cohen's d) to explore the preliminary effects of PATH on outcomes.

RESULTS: We enrolled 68.6% (72/105) of eligible patients (mean age, 57 years; 50% female). Of those randomized to PATH, 91% completed all sessions and reported positive psychology exercises as easy to complete and subjectively useful. Compared with usual care, PATH participants reported greater improvements in gratitude (β = 1.38; d = 0.32), anxiety (β = -1.43; d = -0.40), and physical function (β = 2.15; d = 0.23) at 9 weeks and gratitude (β = 0.97; d = 0.22), positive affect (β = 2.02; d = 0.27), life satisfaction (β = 1.82; d = 0.24), optimism (β = 2.70; d = 0.49), anxiety (β = -1.62; d = -0.46), depression (β = -1.04; d = -0.33), PTSD (β = -2.50; d = -0.29), QoL (β = 7.70; d = 0.41), physical function (β = 5.21; d = 0.56), and fatigue (β = -2.54; d = -0.33) at 18 weeks.

CONCLUSIONS: PATH is feasible, with promising signals for improving psychological well-being, QoL, physical function, and fatigue in HSCT survivors. Future multisite trials that investigate PATH's efficacy are needed to establish its effects on PROs in this population.

RevDate: 2024-06-12
CmpDate: 2024-06-11

Benson AB, Venook AP, Adam M, et al (2024)

Colon Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Journal of the National Comprehensive Cancer Network : JNCCN, 22(2 D):.

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.

RevDate: 2024-06-11

Nicolai CJ, Parker M, Qin J, et al (2024)

In vivo CAR T-cell generation in non-human primates using lentiviral vectors displaying a multi-domain fusion ligand.

Blood pii:516468 [Epub ahead of print].

Chimeric antigen receptor (CAR) T-cell therapies have demonstrated transformative efficacy in treating B-cell malignancies. However, high cost and manufacturing complexities hinder their widespread use. To overcome these hurdles, we have developed the VivoVecTM platform, a lentiviral vector capable of generating CAR T-cells in vivo. Here we describe the incorporation of T cell activation and costimulatory signals onto the surface of VivoVecTM particles (VVPs) in the form of a multi-domain fusion protein and show enhanced in vivo transduction and improved CAR-T cell antitumor functionality. Furthermore, in the absence of lymphodepleting chemotherapy, administration of VVPs into non-human primates resulted in the robust generation of anti-CD20 CAR T-cells and the complete depletion of B cells for more than 10 weeks. These data validate the VivoVecTM platform in a translationally relevant model and support its transition into human clinical testing, offering a paradigm shift in the field of CAR T-cell therapies.

RevDate: 2024-06-12

Wu L, Saina M, Brown C, et al (2024)

Establishing adherence-concentration-efficacy thresholds of TDF-FTC pre-exposure prophylaxis for HIV prevention in African women: a protocol for the Women TDF-FTC Benchmark Study.

Frontiers in reproductive health, 6:1325257.

BACKGROUND: Oral pre-exposure prophylaxis (PrEP) using co-formulated emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) is a potent HIV prevention method for men and women, with its efficacy highly dependent on adherence. A pivotal HIV efficacy study combined with a directly observed pharmacological study defined the thresholds for HIV protection in men who have sex with men (MSM), which are the keys to PrEP promotion and development of new PrEP agents. For African women at risk for HIV and belonging to a priority group considered due to disproportionately high incident HIV infections, the variable adherence in PrEP clinical trials and the limited pharmacologic data have resulted in a lack of clarity about the PrEP adherence required for HIV protection. We propose a study to quantify the adherence-concentration-efficacy thresholds of TDF/FTC PrEP among African cisgender women to inform decisions about optimal PrEP dosing and adherence for HIV protection.

METHODS: We randomized 45 low-risk HIV-uninfected African women, aged 18-30 years old, to directly observe the TDF/FTC PrEP of two, four, or seven doses per week for 8 weeks. A complementary age-matched pregnant women cohort at high risk of HIV, who will receive seven doses per week, was recruited (N = 15) with the primary aim of establishing benchmark concentrations in dried blood spots and peripheral blood mononuclear cells. Plasma, whole blood (WB), urine, hair, vaginal fluid, and vaginal tissue (non-pregnant women only) were archived for future testing. Drug concentrations were measured using methods validated for each biological matrix. Pharmacokinetic models were fitted to drug concentrations to quantify concentration-adherence thresholds. To define the drug concentrations associated with HIV protection, we applied the newly defined thresholds from the primary pharmacologic trial to the subset of women randomized to TDF/FTC or TDF in the Partners PrEP Study with the drug concentration assessed in plasma and WB samples. Multiple imputation was used to construct a data set with drug concentrations at each visit when an HIV test was performed for the entire cohort, replicating the work for MSM.

DISCUSSION: The proposed study generated the first African women-specific TDF-PrEP adherence-concentration-efficacy thresholds essential for guiding the accurate interpretation of TDF/FTC PrEP programs and clinical trials of novel HIV prevention products using TDF/FTC as an active control.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, identifier (NCT05057858).

RevDate: 2024-06-12

Pineda-Antunez C, Seguin C, van Duuren LA, et al (2024)

Emulator-Based Bayesian Calibration of the CISNET Colorectal Cancer Models.

Medical decision making : an international journal of the Society for Medical Decision Making [Epub ahead of print].

PURPOSE: To calibrate Cancer Intervention and Surveillance Modeling Network (CISNET)'s SimCRC, MISCAN-Colon, and CRC-SPIN simulation models of the natural history colorectal cancer (CRC) with an emulator-based Bayesian algorithm and internally validate the model-predicted outcomes to calibration targets.

METHODS: We used Latin hypercube sampling to sample up to 50,000 parameter sets for each CISNET-CRC model and generated the corresponding outputs. We trained multilayer perceptron artificial neural networks (ANNs) as emulators using the input and output samples for each CISNET-CRC model. We selected ANN structures with corresponding hyperparameters (i.e., number of hidden layers, nodes, activation functions, epochs, and optimizer) that minimize the predicted mean square error on the validation sample. We implemented the ANN emulators in a probabilistic programming language and calibrated the input parameters with Hamiltonian Monte Carlo-based algorithms to obtain the joint posterior distributions of the CISNET-CRC models' parameters. We internally validated each calibrated emulator by comparing the model-predicted posterior outputs against the calibration targets.

RESULTS: The optimal ANN for SimCRC had 4 hidden layers and 360 hidden nodes, MISCAN-Colon had 4 hidden layers and 114 hidden nodes, and CRC-SPIN had 1 hidden layer and 140 hidden nodes. The total time for training and calibrating the emulators was 7.3, 4.0, and 0.66 h for SimCRC, MISCAN-Colon, and CRC-SPIN, respectively. The mean of the model-predicted outputs fell within the 95% confidence intervals of the calibration targets in 98 of 110 for SimCRC, 65 of 93 for MISCAN, and 31 of 41 targets for CRC-SPIN.

CONCLUSIONS: Using ANN emulators is a practical solution to reduce the computational burden and complexity for Bayesian calibration of individual-level simulation models used for policy analysis, such as the CISNET CRC models. In this work, we present a step-by-step guide to constructing emulators for calibrating 3 realistic CRC individual-level models using a Bayesian approach.

HIGHLIGHTS: We use artificial neural networks (ANNs) to build emulators that surrogate complex individual-based models to reduce the computational burden in the Bayesian calibration process.ANNs showed good performance in emulating the CISNET-CRC microsimulation models, despite having many input parameters and outputs.Using ANN emulators is a practical solution to reduce the computational burden and complexity for Bayesian calibration of individual-level simulation models used for policy analysis.This work aims to support health decision scientists who want to quantify the uncertainty of calibrated parameters of computationally intensive simulation models under a Bayesian framework.

RevDate: 2024-06-10

Sarchi M, Clough CA, Crosse EI, et al (2024)

Mis-splicing of mitotic regulators sensitizes SF3B1-mutated human HSCs to CHK1 inhibition.

Blood cancer discovery pii:745817 [Epub ahead of print].

Splicing factor SF3B1 mutations are frequent somatic lesions in myeloid neoplasms that transform hematopoietic stem cells (HSCs) by inducing mis-splicing of target genes. However, the molecular and functional consequences of SF3B1 mutations in human HSCs remain unclear. Here, we identify the mis-splicing program in human HSCs as a targetable vulnerability by precise gene editing of SF3B1 K700E mutations in primary CD34+ cells. Mutant SF3B1 induced pervasive mis-splicing and reduced expression of genes regulating mitosis and genome maintenance leading to altered differentiation, delayed G2/M progression, and profound sensitivity to CHK1 inhibition (CHK1i). Mis-splicing or reduced expression of mitotic regulators BUBR1 and CDC27 delayed G2/M transit and promoted CHK1i sensitivity. Clinical CHK1i prexasertib selectively targeted SF3B1-mutant HSCs and abrogated engraftment in vivo. These findings identify mis-splicing of mitotic regulators in SF3B1-mutant HSCs as a targetable vulnerability engaged by pharmacological CHK1 inhibition.

RevDate: 2024-06-11
CmpDate: 2024-06-10

Barnett DJ, Sundermeir SM, Reznar MM, et al (2024)

Protocol for the Support Application for Food PAntrieS trial: design, implementation, and evaluation plan for a digital application to promote healthy food access and support food pantry operations.

Frontiers in public health, 12:1340707.

INTRODUCTION: Food-insecure households commonly rely on food pantries to supplement their nutritional needs, a challenge that was underscored during the COVID-19 pandemic. Food pantries, and the food banks that supply them, face common challenges in meeting variable client volume and dietary needs under normal and emergency (e.g., pandemic, natural disaster) conditions. A scalable digital strategy that has the capacity to streamline the emergency food distribution system, while promoting healthy food options, managing volunteer recruitment and training, and connecting to emergency management systems in times of need, is urgently required. To address this gap, we are developing a working mobile application (app) called the Support Application for Food PAntrieS (SAFPAS) and will evaluate its feasibility and impact on food pantry staff preparedness, stocking, and client uptake of healthful foods and beverages in two urban United States settings.

METHODS: This paper describes the protocol for a randomized controlled trial of the SAFPAS mobile application. We will conduct formative research in Baltimore, Maryland and Detroit, Michigan to develop and refine the SAFPAS app and increase scalability potential to other urban settings. Then we will test the app in 20 food pantries in Baltimore randomized to intervention or comparison. The impact of the app will be evaluated at several levels of the emergency food system, including food pantry clients (n = 360), food pantry staff and volunteers (n = 100), food pantry stock, and city agencies such as the local food bank and Office of Emergency Management. The primary outcome of the SAFPAS trial is to improve the healthfulness of the foods received by food pantry clients, measured using the Food Assessment Scoring Tool (FAST). Post-trial, we will conduct additional formative research in Detroit to prepare the app for scale-up.

DISCUSSION: We anticipate that SAFPAS will improve alignment in the supply and demand for healthy foods among food pantry clients, food pantries, and city agencies which supply food in Baltimore. Real-time, bidirectional communication between entities across the system allows for increased situational awareness at all levels during normal and emergency operations. By conducting formative research in Detroit, we hope to increase the scalability of the SAFPAS app to additional settings nationwide.

CLINICAL TRIAL REGISTRATION: NCT87654321. https://classic.clinicaltrials.gov/ct2/show/NCT05880004.

RevDate: 2024-06-14

Yeung CC, Eacker SM, Sala-Torra O, et al (2024)

Evaluation of Acute Myeloid Leukemia Genomes using Genomic Proximity Mapping.

medRxiv : the preprint server for health sciences.

BACKGROUND: Cytogenetic analysis encompasses a suite of standard-of-care diagnostic testing methods that is routinely applied in cases of acute myeloid leukemia (AML) to assess chromosomal changes that are clinically relevant for risk classification and treatment decisions.

OBJECTIVE: In this study, we assess the use of Genomic Proximity Mapping (GPM) for cytogenomic analysis of AML diagnostic specimens for detection of cytogenetic risk variants included in the European Leukemia Network (ELN) risk stratification guidelines.

METHODS: Archival patient samples (N=48) from the Fred Hutchinson Cancer Center leukemia bank with historical clinical cytogenetic data were processed for GPM and analyzed with the CytoTerra[®] cloud-based analysis platform.

RESULTS: GPM showed 100% concordance for all specific variants that have associated impacts on risk stratification as defined by ELN 2022 criteria, and a 72% concordance rate when considering all variants reported by the FH cytogenetic lab. GPM identified 39 additional variants, including variants of known clinical impact, not observed by cytogenetics.

CONCLUSIONS: GPM is an effective solution for the evaluation of known AML-associated risk variants and a source for biomarker discovery.

RevDate: 2024-06-14
CmpDate: 2024-06-14

Zhao Y, Laird AD, Roberts KG, et al (2024)

Association of leukemic molecular profile with efficacy of inotuzumab ozogamicin in adults with relapsed/refractory ALL.

Blood advances, 8(12):3226-3236.

The phase 3 INO-VATE trial demonstrated higher rates of remission, measurable residual disease negativity, and improved overall survival for patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) who received inotuzumab ozogamicin (InO) vs standard-of-care chemotherapy (SC). Here, we examined associations between genomic alterations and the efficacy of InO. Of 326 randomized patients, 91 (InO, n = 43; SC, n = 48) had samples evaluable for genomic analysis. The spectrum of gene fusions and other genomic alterations observed was comparable with prior studies of adult ALL. Responses to InO were observed in all leukemic subtypes, genomic alterations, and risk groups. Significantly higher rates of complete remission (CR)/CR with incomplete count recovery were observed with InO vs SC in patients with BCR::ABL1-like ALL (85.7% [6/7] vs 0% [0/5]; P = .0076), with TP53 alterations (100% [5/5] vs 12.5% [1/8]; P = .0047), and in the high-risk BCR::ABL1- (BCR::ABL1-like, low-hypodiploid, KMT2A-rearranged) group (83.3% [10/12] vs 10.5% [2/19]; P < .0001). This retrospective, exploratory analysis of the INO-VATE trial demonstrated potential for benefit with InO for patients with R/R ALL across leukemic subtypes, including BCR::ABL1-like ALL, and for those bearing diverse genomic alterations. Further confirmation of the efficacy of InO in patients with R/R ALL exhibiting the BCR::ABL1-like subtype or harboring TP53 alterations is warranted. This trial was registered at www.ClinicalTrials.gov as #NCT01564784.

RevDate: 2024-06-11

Kelly SP, McEwen LM, Isaksson M, et al (2024)

Viral SARS-CoV-2 Rebound Rates in Linked Commercial Pharmacy-Based Testing and Health Care Claims.

Open forum infectious diseases, 11(6):ofae243.

BACKGROUND: Viral SARS-CoV-2 rebound (viral RNA rebound) is challenging to characterize in large cohorts due to the logistics of collecting frequent and regular diagnostic test results. Pharmacy-based testing data provide an opportunity to study the phenomenon in a large population, also enabling subgroup analyses. The current real-world evidence approach complements approaches focused on smaller, prospective study designs.

METHODS: We linked real-time reverse transcription quantitative polymerase chain reaction test data from national pharmacy-based testing to health care claims data via tokenization to calculate the cumulative incidence of viral RNA rebound within 28 days following positive test results in nirmatrelvir/ritonavir (NMV-r)-treated and untreated individuals during the Omicron era (December 2021-November 2022) and prior to the Omicron era (October 2020-November 2021).

RESULTS: Among 30 646 patients, the rate of viral RNA rebound was 3.5% (95% CI, 2.0%-5.7%) in NMV-r-treated infections as compared with 1.5% (95% CI, 1.3%-1.7%) in untreated infections during the Omicron era and 1.9% (95% CI, 1.7%-2.1%) prior to the Omicron era. Viral RNA rebound in patients who were vaccinated (n = 8151), high risk (n = 4411), or older (≥65 years, n = 4411) occurred at comparable rates to the overall cohort (range, 1.1%-4.8%). Viral rebounds to high RNA levels in NMV-r-treated infections occurred in 8% of viral rebounds as compared with 5% to 11% in untreated infections. Rates of hospitalization were comparable between patients with NMV-r-treated infections with viral RNA rebound (0%) and untreated patients with viral RNA rebound (0%-1.2%).

CONCLUSIONS: Our findings suggest viral RNA rebound is rare (< 5%), with rates that were consistent with those from the EPIC-HR trial (Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients). Most occurrences of viral RNA rebound were associated with low viral RNA levels, and viral RNA rebound progression to severe disease was not observed.

RevDate: 2024-06-13

Parrish AG, Arora S, Thirimanne HN, et al (2024)

Aggressive high-grade NF2 mutant meningiomas downregulate oncogenic YAP signaling via the upregulation of VGLL4 and FAT3/4.

bioRxiv : the preprint server for biology.

Meningiomas are the most common primary brain tumors in adults. Although generally benign, a subset of meningiomas is of higher grade, shows aggressive growth behavior and recurs even after multiple surgeries. Around half of all meningiomas harbor inactivating mutations in NF2. While benign low-grade NF2 mutant meningiomas exhibit few genetic events in addition to NF2 inactivation, aggressive high-grade NF2 mutant meningiomas frequently harbor a highly aberrant genome. We and others have previously shown that NF2 inactivation leads to YAP1 activation and that YAP1 acts as the pivotal oncogenic driver in benign NF2 mutant meningiomas. Using bulk and single-cell RNA-Seq data from a large cohort of human meningiomas, we show that aggressive NF2 mutant meningiomas harbor decreased levels YAP1 activity compared to their benign counterparts. Decreased expression levels of YAP target genes are significantly associated with an increased risk of recurrence. We then identify the increased expression of the YAP1 competitor VGLL4 as well as the YAP1 upstream regulators FAT3/4 as a potential mechanism for the downregulation of YAP activity in aggressive NF2 mutant meningiomas. High expression of these genes is significantly associated with an increased risk of recurrence. In vitro, overexpression of VGLL4 resulted in the downregulation of YAP activity in benign NF2 mutant meningioma cells, confirming the direct link between VGLL4 expression and decreased levels of YAP activity observed in aggressive NF2 mutant meningiomas. Our results shed new insight on the biology of benign and aggressive NF2 mutant meningiomas and may have important implications for the efficacy of therapies targeting oncogenic YAP1 activity in NF2 mutant meningiomas.

RevDate: 2024-06-09

Park C, Azhideh A, Pooyan A, et al (2024)

Diagnostic performance and inter-reader reliability of bone reporting and data system (Bone-RADS) on computed tomography.

Skeletal radiology [Epub ahead of print].

OBJECTIVE: To evaluate the diagnostic performance and inter-reader reliability of the Bone Reporting and Data System (Bone-RADS) for solitary bone lesions on CT.

MATERIALS AND METHODS: This retrospective analysis included 179 patients (mean age, 56 ± 18 years; 94 men) who underwent bone biopsies between March 2005 and September 2021. Patients with solitary bone lesions on CT and sufficient histopathology results were included. Two radiologists categorized the bone lesions using the Bone-RADS (1, benign; 4, malignant). The diagnostic performance of the Bone-RADS was calculated using histopathology results as a standard reference. Inter-reader reliability was calculated.

RESULTS: Bone lesions were categorized into two groups: 103 lucent (pathology: 34 benign, 12 intermediate, 54 malignant, and 3 osteomyelitis) and 76 sclerotic/mixed (pathology: 46 benign, 2 intermediate, 26 malignant, and 2 osteomyelitis) lesions. The Bone-RADS for lucent lesions had sensitivities of 95% and 82%, specificities of 11% and 11%, and accuracies of 57% and 50% for readers 1 and 2, respectively. The Bone-RADS for sclerotic/mixed lesions had sensitivities of 75% and 68%, specificities of 27% and 27%, and accuracies of 45% and 42% for readers 1 and 2, respectively. Inter-reader reliability was moderate to very good (κ = 0.744, overall; 0.565, lucent lesions; and 0.851, sclerotic/mixed lesions).

CONCLUSION: Bone-RADS has a high sensitivity for evaluating malignancy in lucent bone lesions and good inter-reader reliability. However, it has poor specificity and accuracy for both lucent and sclerotic/mixed lesions. A possible explanation is that proposed algorithms heavily depend on clinical features such as pain and history of malignancy.

RevDate: 2024-06-07

Duerr A, C Beyrer (2024)

Reducing HIV transmission in British Columbia, Canada.

The lancet. HIV pii:S2352-3018(24)00117-6 [Epub ahead of print].

RevDate: 2024-06-10
CmpDate: 2024-06-07

Hyrien O, NM Yanev (2024)

A branching stochastic evolutionary model of the B-cell repertoire.

Journal of mathematical biology, 89(1):10.

We propose a stochastic framework to describe the evolution of the B-cell repertoire during germinal center (GC) reactions. Our model is formulated as a multitype age-dependent branching process with time-varying immigration. The immigration process captures the mechanism by which founder B cells initiate clones by gradually seeding GC over time, while the branching process describes the temporal evolution of the composition of these clones. The model assigns a type to each cell to represent attributes of interest. Examples of attributes include the binding affinity class of the B cells, their clonal family, or the nucleotide sequence of the heavy and light chains of their receptors. The process is generally non-Markovian. We present its properties, including as t → ∞ when the process is supercritical, the most relevant case to study expansion of GC B cells. We introduce temporal alpha and beta diversity indices for multitype branching processes. We focus on the dynamics of clonal dominance, highlighting its non-stationarity, and the accumulation of somatic hypermutations in the context of sequential immunization. We evaluate the impact of the ongoing seeding of GC by founder B cells on the dynamics of the B-cell repertoire, and quantify the effect of precursor frequency and antigen availability on the timing of GC entry. An application of the model illustrates how it may help with interpretation of BCR sequencing data.

RevDate: 2024-06-07

Stone D, Wang X, M Abou-El-Enein (2024)

Biomanufacturing in gene and cell therapy.

Molecular therapy. Methods & clinical development, 32(2):101261.

RevDate: 2024-06-07

Heffner JL, Serfozo E, Baker K, et al (2024)

Behavioral Activation mHealth Application for Smoking Cessation: A Randomized Controlled Pilot Trial.

Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco pii:7689250 [Epub ahead of print].

BACKGROUND: Behavioral activation (BA) is an effective intervention for both depression and substance use disorders. Combining BA with a standard smoking cessation intervention may improve quit rates by addressing depressive symptoms, a key barrier to quitting. This study preliminarily evaluated the acceptability and efficacy of the BA-based Actify! mobile health application (mHealth app) for smoking cessation.

METHODS: We conducted a pilot randomized controlled trial (n=242) comparing Actify! with the National Cancer Institute's (NCI) app for smoking cessation (QuitGuide) on acceptability (user satisfaction, app openings), smoking abstinence, and mechanisms of change (behavioral activation and depressive symptoms) at 8 weeks and 6 months post-randomization. Participants were US adults recruited online who smoked daily.

RESULTS: Treatment satisfaction was uniformly higher in the Actify! arm. Number of app openings was similar across arms (M=34.3 openings over 8 weeks in both arms). Self-reported 30-day point prevalence abstinence (PPA) at 8 weeks was 12.6% for Actify! vs. 7.3% for QuitGuide. Differences in 30-day PPA continued through 6 months (18.5% for Actify! vs. 12.2% for QuitGuide). Changes between baseline and 8 weeks in depressive symptoms and behavioral activation favored Actify!. Planned subgroup analyses suggested greater benefit of Actify! among participants with pre-treatment mild to moderate depression symptom severity compared to those with no depression symptoms.

CONCLUSIONS: Actify! showed considerable promise as a novel mHealth treatment, as evidenced by high usage and higher user satisfaction and quit rates than QuitGuide at both short- and long-term follow-up. The next step is to evaluate Actify! in a fully-powered efficacy trial.

IMPLICATIONS: Study findings demonstrate the promise of a behavioral activation (BA)-based mobile health app (Actify!) for smoking cessation as a population-level intervention that can effectively address depressive symptoms as a risk factor for worse smoking treatment outcomes. The Actify! app is the first standalone BA-based app to demonstrate potential for improved acceptability and efficacy relative to a standard care comparison app, with user satisfaction and smoking quit rates descriptively exceeding those of the National Cancer Institute's QuitGuide app.

RevDate: 2024-06-12

Nascimento De Lima P, Van Den Puttelaar R, Knudsen AB, et al (2024)

Characteristics of a cost-effective blood test for colorectal cancer screening.

Journal of the National Cancer Institute pii:7689164 [Epub ahead of print].

BACKGROUND: Blood-based biomarker tests can potentially change the landscape of colorectal cancer (CRC) screening. We characterize the conditions under which blood test screening would be as effective and cost-effective as annual fecal immunochemical testing (FIT) or decennial colonoscopy.

METHODS: We used the three CISNET-Colon models to compare scenarios of no screening, annual FIT, decennial colonoscopy, and a blood test meeting CMS coverage criteria (74% CRC sensitivity and 90% specificity). We varied the sensitivity to detect CRC (74%-92%), advanced adenomas (AAs, 10%-50%), screening interval (1-3 years), and test cost ($25-$500). Primary outcomes included quality-adjusted life-years gained (QALYG) from screening and costs for an US average-risk 45-year-old cohort.

RESULTS: Annual FIT yielded 125-163 QALYG per 1,000 at a cost of $3,811-5,384 per person, whereas colonoscopy yielded 132-177 QALYG at a cost of $5,375-7,031 per person. A blood test with 92% CRC sensitivity and 50% AA sensitivity yielded 117-162 QALYG if used every three years and 133-173 QALYG if used every year but would not be cost-effective if priced above $125 per test. If used every three years, a $500 blood test only meeting CMS coverage criteria yielded 83-116 QALYG, at a cost of $8,559-9,413 per person.

CONCLUSION: Blood tests that only meet CMS coverage requirements should not be recommended to patients who would otherwise undergo screening by colonoscopy or FIT due to lower benefit. Blood tests need higher AA sensitivity (above 40%) and lower costs (below $125) to be cost-effective.

RevDate: 2024-06-06

Camidge DR, Bar J, Horinouchi H, et al (2024)

Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein-Overexpressing Advanced Non-Squamous EGFR-Wildtype NSCLC in the Phase 2 LUMINOSITY Trial.

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

PURPOSE: Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase 2 LUMINOSITY trial (NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage 1) and expand the selected group for efficacy evaluation (stage 2). Stage 2 enrolled patients with non-squamous epidermal growth factor receptor (EGFR)-wildtype NSCLC.

METHODS: Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and ≤2 prior lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in non-squamous EGFR-wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%-<50%]). Teliso-V was administered at 1.9 mg/kg every 2 weeks. Primary endpoint was overall response rate (ORR) by independent central review.

RESULTS: In total, 172 patients with non-squamous EGFR-wildtype NSCLC received Teliso-V in stages 1 and 2. ORR was 28.6% (95% CI, 21.7-36.2; c-Met high, 34.6% [24.2-46.2]; c-Met intermediate, 22.9% [14.4-33.4]). Median duration of response was 8.3 months (95% CI, 5.6-11.3; c-Met high, 9.0 [4.2-13.0]; c-Met intermediate: 7.2 [5.3-11.5]). Median overall survival was 14.5 months (95% CI, 9.9-16.6; c-Met high, 14.6 [9.2-25.6]; c-Met intermediate, 14.2 [9.6-16.6]). Median progression-free survival was 5.7 months (95% CI, 4.6-6.9; c-Met high, 5.5 [4.1-8.3]; c-Met intermediate: 6.0 [4.5-8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 was peripheral sensory neuropathy (7%).

CONCLUSION: Teliso-V was associated with durable responses in c-Met protein-overexpressing non-squamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

RevDate: 2024-06-06

Li C, Anderson AK, Ruminski PG, et al (2024)

A simplified, G-CSF-free procedure allows for in vivo HSC gene therapy of sickle cell disease in a mouse model.

Blood advances pii:516369 [Epub ahead of print].

We have reported direct repair of the sickle cell mutation in vivo in a disease model using vectorized prime editors after hematopoietic stem cell (HSC) mobilization with G-CSF/AMD3100. The use of G-CSF for HSC mobilization would be a hurdle for the clinical translation of the approach. Here, we tested a G-CSF-free mobilization regimen using WU-106, a PEG-conjugated inhibitor of integrin VLA-4 ((?)4β1), plus AMD3100 for in vivo HSC prime editing in sickle cell disease (SCD) mice (CD46/Townes). Mobilization with WU-106+AMD3100 in CD46/Townes mice was rapid and efficient. In contrast to the G-CSF/AMD3100 approach, mobilization of activated granulocytes and elevation of the key pro-inflammatory cytokine IL-6 in serum were minimal. The combination of WU-106+AMD3100 mobilization and intravenous injection of an HDAd-PE5 vector together with in vivo selection resulted in a SCD mutation editing (T>A correction) rate of ~23% in bone marrow and peripheral blood cells of CD46/Townes mice. The treated mice demonstrated phenotypic correction, reflected by normalized blood parameters and spleen size. Editing rates were significantly increased (29%) in secondary recipients indicating preferential mobilization/transduction of long-term repopulating HSCs. Using this approach, we found <1% of undesired indels and no detectable off-target editing at top-scored potential sites. Our study shows that in vivo transduction to treat SCD (including HSC mobilization and HDAd injection) can now be done within 2 hours involving only simple intravenous injections with a good safety profile. The same-day mobilization regimen makes in vivo HSC gene therapy more attractive for the resource-poor settings where SCD does the most damage.

RevDate: 2024-06-06
CmpDate: 2024-06-06

Pullarkat S, Black G, Bleakley M, et al (2024)

qPCR assay for detection of Woodchuck Hepatitis Virus Post-Transcriptional Regulatory Elements from CAR-T and TCR-T cells in fresh and formalin-fixed tissue.

PloS one, 19(6):e0303057.

As adoptive cellular therapies become more commonplace in cancer care, there is a growing need to monitor site-specific localization of engineered cells-such as chimeric antigen receptor T (CAR-T) cells and T-cell receptor T (TCR-T) cells-in patients' tissues to understand treatment effectiveness as well as associated adverse events. Manufacturing CAR-T and TCR-T cells involves transduction with viral vectors commonly containing the WPRE gene sequence to enhance gene expression, providing a viable assay target unique to these engineered cells. Quantitative PCR (qPCR) is currently used clinically in fresh patient tissue samples and blood with target sequences specific to each immunotherapy product. Herein, we developed a WPRE-targeted qPCR assay that is broadly applicable for detection of engineered cell products in both fresh and archival formalin-fixed paraffin embedded (FFPE) tissues. Using both traditional PCR and SYBR Green PCR protocols, we demonstrate the use of this WPRE-targeted assay to successfully detect two CAR-T cell and two TCR-T cell products in FFPE tissue. Standard curve analysis reported a reproducible limit of detection at 100 WPRE copies per 20μL PCR reaction. This novel and inexpensive technique could provide better understanding of tissue abundance of engineered therapeutic T cells in both tumor and second-site toxicity tissues and provide quantitative assessment of immune effector cell trafficking in archival tissue.

RevDate: 2024-06-09
CmpDate: 2024-06-06

Alver SK, Pan S, Mossavar-Rahmani Y, et al (2024)

Physical Activity, Cardiovascular Status, Mortality, and Prediabetes in Hispanic and Non-Hispanic Adults.

JAMA network open, 7(6):e2415094.

IMPORTANCE: Data are limited on the association of physical activity (PA) with incident cardiovascular disease (CVD) and mortality in prediabetes, especially in racial and ethnic minority groups, including Hispanic and Latino populations.

OBJECTIVE: To determine the association of PA with incident CVD and mortality by prediabetes status among Hispanic or Latino and non-Hispanic adults.

This cohort study included data from 2 cohorts of adults with prediabetes or normoglycemia who were free of CVD at baseline visit: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) from baseline examination through 2017, with median (IQR) follow-up of 7.8 (7.2-8.5) years, and the Framingham Heart Study (FHS) with non-Hispanic participants from index examination through 2019, with median (IQR) follow-up of 9.6 (8.1-10.7) years. Analyses were conducted between September 1, 2022, and January 10, 2024.

EXPOSURE: The primary exposure was baseline accelerometry-measured moderate to vigorous PA, insufficient vs sufficient to meet 2018 Physical Activity Guidelines for Americans (PAG) in both cohorts; additional accelerometer-measured exposures in HCHS/SOL were steps per day, sedentary behavior, and counts per min.

MAIN OUTCOMES AND MEASURES: The outcome was a composite of incident CVD or all-cause mortality, whichever came first.

RESULTS: This cohort study included 13 223 participants: from HCHS/SOL, there were 9456 adults (all self-identified Hispanic or Latino ethnicity; survey-adjusted mean [SD] age, 38.3 [13.9] years, unweighted counts 5673 (60.0%) female; 4882 [51.6%] with normoglycemia; 4574 [48.4%] with prediabetes), and from FHS there were 3767 adults (3623 [96.2%] non-Hispanic and 140 [3.7%] Hispanic or Latino ethnicity, with 4 [0.1%] participants missing ethnicity; mean [SD] age, 54.2 [13.6] years; 2128 (56.5%) female; 2739 [72.7%] with normoglycemia; 1028 [27.3%] with prediabetes). Not meeting PAG was associated with higher risk of the composite outcome among participants with normoglycemia (vs PAG met; hazard ratio [HR], 1.85 [95% CI, 1.12-3.06]), but not among participants with prediabetes (HR, 1.07 [95% CI, 0.72-1.58]). For HCHS/SOL, no statistically significant association was found between the composite outcome and other PA metrics, although estimated HRs tended to be higher for lower activity in the normoglycemia group but not for the prediabetes group (eg, for steps less than vs at least 7000 per day, the HR was 1.58 [95% CI, 0.85-2.93] for normoglycemia vs 1.08 [95% CI 0.67-1.74] for prediabetes). While there was also no association in HCHS/SOL between the composite outcome and sedentary behavior, results were similar in the prediabetes group (HR per 30 minutes per day of sedentary behavior, 1.05 [95% CI 0.99-1.12]) and in the normoglycemia group (HR, 1.07 [95% CI 0.98-1.16]).

CONCLUSIONS AND RELEVANCE: In this cohort study of US Hispanic or Latino and non-Hispanic adults, lower moderate to vigorous PA levels were associated with CVD or mortality among participants with normoglycemia but not participants with prediabetes. Adults with prediabetes may benefit from reducing sedentary behavior and improving multiple lifestyle factors beyond improving moderate to vigorous PA alone.

RevDate: 2024-06-09
CmpDate: 2024-06-06

Yanez Hernandez M, Kuo EF, Henriquez Taveras Y, et al (2024)

Mental Health and Well-Being Among Home Health Aides.

JAMA network open, 7(6):e2415234.

IMPORTANCE: Home health aides and attendants (HHAs) provide essential care to older adults and those with chronic conditions in the home. However, some HHAs struggle with poor mood and stress, which may have been exacerbated by the COVID-19 pandemic.

OBJECTIVE: To elicit HHAs' perspectives toward mental health and well-being, including how their job influences both and how to better support the workforce in the future.

For this qualitative study, focus groups and interviews with HHAs were facilitated in English and Spanish from August 17, 2022, to February 9, 2023, in partnership with the 1199SEIU Training and Employment Fund, a benefit fund of the 1199SEIU United Healthcare Workers East and the largest health care union in the US. Included were HHAs at risk for poor mental health and well-being, which were defined as having at least mild or more symptoms on either the 8-item Personal Health Questionnaire depression scale, the 4-item Cohen Perceived Stress Scale, or the University of California, Los Angeles Loneliness Scale.

EXPOSURE: Mental health and well-being of HHAs.

MAIN OUTCOMES AND MEASURES: Focus groups and interviews were audio recorded, professionally transcribed, and translated. A thematic analysis was performed that was informed by Pender's Health Promotion Model and the National Institute for Occupational Safety and Health's Total Worker Health model.

RESULTS: A total of 28 HHAs from 14 different agencies participated (mean [SD] age, 54.3 [10.8] years; 26 female [93%]). Seventeen participants (61%) spoke Spanish at home. Five key themes emerged: (1) HHAs' attitudes toward mental health and well-being were influenced by a variety of personal and cultural factors; (2) HHAs' relationships with their patients impacted their mood in both positive and negative ways; (3) structural and organizational aspects of the job, alongside the COVID-19 pandemic, impacted HHAs' mood and stress levels; (4) HHAs used a variety of strategies to cope with their emotions; and (5) HHAs were eager for interventions that can improve their mood, particularly those that bring them closer to their colleagues.

CONCLUSIONS AND RELEVANCE: These findings suggest that HHAs' mental health and well-being may be influenced by both personal and occupational factors. Interventions and policies to better support their emotional well-being on the job are warranted.

RevDate: 2024-06-06

Gottschalk Z, SA Cohen (2024)

Use of Circulating Tumor DNA to Guide Decision-making in Adjuvant Colon Cancer.

Current oncology reports [Epub ahead of print].

PURPOSE OF REVIEW: The use of circulating tumor DNA (ctDNA) assays to guide clinical decision-making in early-stage colon cancer is an area of rapidly advancing active research. With assays clinically available, clinicians must be informed how to best use this novel tool to treat patients.

RECENT FINDINGS: Recent observational and prospective studies have suggested that ctDNA has potential to guide clinical decision-making in early-stage colon cancer by detecting minimal residual disease (MRD) and predicting recurrence risks. MRD-negative patients may be able to de-escalate or forgo adjuvant chemotherapy (ACT) without compromising disease-free survival or overall survival, while MRD-positive patients may benefit significantly from ACT. Recent and ongoing studies have given reason for optimism about the future of ctDNA as a useful biomarker for clinicians treating early-stage colon cancer. Data thus far are mostly limited to observational studies; inconsistent results highlight the need for caution. As more evidence emerges, ctDNA may become standard of care for colon cancer patients.

RevDate: 2024-06-05

Files MA, Gentles L, Kehoe L, et al (2024)

The kinetics and durability of antibody and T-cell responses to SARS-CoV-2 in children.

The Journal of infectious diseases pii:7688405 [Epub ahead of print].

BACKGROUND: The kinetics and durability of T-cell responses to SARS-CoV-2 in children are not well-characterized. We studied a cohort of children aged 6 months to 20 years with COVID-19 in whom peripheral blood mononuclear cells (PBMC) and sera were archived at approximately 1, 6, and 12 months post-symptom onset.

METHODS: We compared antibody (N = 85) and T-cell responses (N = 26) to nucleocapsid (N) and spike (S) glycoprotein over time across four age strata: 6 months to 5 years, 5-9, 10-14, and 15-20 years.

RESULTS: N-specific antibody responses declined over time, becoming undetectable in 26/32 (81%) children by approximately one year post-infection. Functional breadth of anti-N CD4+ T-cell responses also declined over time and were positively correlated with N-antibody responses (Pearson's r = 0.31, p = 0.008). CD4+ T-cell responses to S displayed greater functional breadth than N in unvaccinated children, and, along with neutralization titers, were stable over time and similar across age strata. Functional profiles of CD4+ T-cell responses against S were not significantly modulated by vaccination.

CONCLUSIONS: Our data reveal durable, age-independent T-cell immunity to SARS-CoV-2 structural proteins in children over time following COVID-19 infection as well as S-Ab responses overall, in comparison to declining antibody responses to N.

RevDate: 2024-06-07
CmpDate: 2024-06-05

Achilles SL, Kelly CW, Hoesley CJ, et al (2024)

Phase 1 randomized trials to assess safety, pharmacokinetics, and vaginal bleeding associated with use of extended duration dapivirine and levonorgestrel vaginal rings.

PloS one, 19(6):e0304552.

BACKGROUND: Vaginal rings formulated to deliver two drugs simultaneously have potential as user-controlled, long-acting methods for dual prevention of HIV and pregnancy.

METHODS: Two phase 1 randomized trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported.

RESULTS: There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs with DPV/LNG ring vs. DPV ring use (p = .22), or with DPV/LNG ring continuous vs. cyclic use (p = .67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (Cmax p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (Cmax p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12).

CONCLUSIONS: The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal.

RevDate: 2024-06-05

Gupta V, Yacoub A, Mesa RA, et al (2024)

Safety and efficacy of fedratinib in patients with myelofibrosis previously treated with ruxolitinib: primary analysis of FREEDOM trial.

Leukemia & lymphoma [Epub ahead of print].

The phase 3b FREEDOM trial (ClinicalTrials.gov: NCT03755518) evaluates efficacy/safety of fedratinib in intermediate- or high-risk myelofibrosis patients with platelet count ≥50 × 10[9]/L, previously treated with ruxolitinib. The trial design included protocol specified strategies to mitigate the risk for gastrointestinal (GI) adverse events (AEs), thiamine supplementation, and encephalopathy surveillance. Due to COVID-19, accrual was cut short with 38 patients enrolled. In the efficacy evaluable population (n = 35), nine (25.7%; 95% confidence interval 12.5-43.3) patients achieved primary endpoint of ≥35% spleen volume reduction (SVR) at end of cycle (EOC) 6; and 22 (62.9%) patients showed best overall response of ≥35% SVR up to end of treatment. Sixteen (44.4%) patients showed ≥50% reduction in total symptom score at EOC6 (n = 36). Compared to previously reported JAKARTA-2 trial, rates of GI AEs were lower, and no patient developed encephalopathy. Overall, FREEDOM study showed clinically relevant spleen and symptom responses with fedratinib, and effective mitigation of GI AEs.

RevDate: 2024-06-05

Saner FAM, Takahashi K, Budden T, et al (2024)

Concurrent RB1 Loss and BRCA-Deficiency Predicts Enhanced Immunological Response and Long-Term Survival in Tubo-Ovarian High-Grade Serous Carcinoma.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:745770 [Epub ahead of print].

PURPOSE: To evaluate RB1 expression and survival across ovarian carcinoma histotypes, and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC).

EXPERIMENTAL DESIGN: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 primary HGSC to characterize tumors with concurrent BRCA-deficiency and RB1 loss.

RESULTS: RB1 loss was associated with longer OS in HGSC, but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared to patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA-deficiency correlated with transcriptional markers of enhanced interferon response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.

CONCLUSIONS: Co-occurrence of RB1 loss and BRCA-deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

RevDate: 2024-06-05

Voldal EC, Kenny A, Xia F, et al (2024)

Robust analysis of stepped wedge trials using composite likelihood models.

Statistics in medicine [Epub ahead of print].

Stepped wedge trials (SWTs) are a type of cluster randomized trial that involve repeated measures on clusters and design-induced confounding between time and treatment. Although mixed models are commonly used to analyze SWTs, they are susceptible to misspecification particularly for cluster-longitudinal designs such as SWTs. Mixed model estimation leverages both "horizontal" or within-cluster information and "vertical" or between-cluster information. To use horizontal information in a mixed model, both the mean model and correlation structure must be correctly specified or accounted for, since time is confounded with treatment and measurements are likely correlated within clusters. Alternative non-parametric methods have been proposed that use only vertical information; these are more robust because between-cluster comparisons in a SWT preserve randomization, but these non-parametric methods are not very efficient. We propose a composite likelihood method that focuses on vertical information, but has the flexibility to recover efficiency by using additional horizontal information. We compare the properties and performance of various methods, using simulations based on COVID-19 data and a demonstration of application to the LIRE trial. We found that a vertical composite likelihood model that leverages baseline data is more robust than traditional methods, and more efficient than methods that use only vertical information. We hope that these results demonstrate the potential value of model-based vertical methods for SWTs with a large number of clusters, and that these new tools are useful to researchers who are concerned about misspecification of traditional models.

RevDate: 2024-06-10

Dadonaite B, Ahn JJ, Ort JT, et al (2024)

Deep mutational scanning of H5 hemagglutinin to inform influenza virus surveillance.

bioRxiv : the preprint server for biology.

H5 influenza is considered a potential pandemic threat. Recently, H5 viruses belonging to clade 2.3.4.4b have caused large outbreaks in avian and multiple non-human mammalian species[1,2]. Previous studies have identified molecular phenotypes of the viral hemagglutinin (HA) protein that contribute to pandemic potential in humans, including cell entry, receptor preference, HA stability, and reduced neutralization by polyclonal sera[3-6]. However, prior experimental work has only measured how these phenotypes are affected by a handful of the >10,000 different possible amino-acid mutations to HA. Here we use pseudovirus deep mutational scanning[7] to measure how all mutations to a 2.3.4.4b H5 HA affect each phenotype. We identify mutations that allow HA to better bind α2-6-linked sialic acids, and show that some viruses already carry mutations that stabilize HA. We also measure how all HA mutations affect neutralization by sera from mice and ferrets vaccinated against or infected with 2.3.4.4b H5 viruses. These antigenic maps enable rapid assessment of when new viral strains have acquired mutations that may create mismatches with candidate vaccine strains. Overall, the systematic nature of deep mutational scanning combined with the safety of pseudoviruses enables comprehensive measurements of the phenotypic effects of mutations that can inform real-time interpretation of viral variation observed during surveillance of H5 influenza.

RevDate: 2024-06-10

Tran-Kiem C, Paredes MI, Perofsky AC, et al (2024)

Fine-scale spatial and social patterns of SARS-CoV-2 transmission from identical pathogen sequences.

medRxiv : the preprint server for health sciences.

Pathogen genomics can provide insights into disease transmission patterns, but new methods are needed to handle modern large-scale pathogen genome datasets. Genetically proximal viruses indicate epidemiological linkage and are informative about transmission events. Here, we leverage pairs of identical sequences using 114,298 SARS-CoV-2 genomes collected via sentinel surveillance from March 2021 to December 2022 in Washington State, USA, with linked age and residence information to characterize fine-scale transmission. The location of pairs of identical sequences is highly consistent with expectations from mobility and social contact data. Outliers in the relationship between genetic and mobility data can be explained by SARS-CoV-2 transmission between postal codes with male prisons, consistent with transmission between prison facilities. Transmission patterns between age groups vary across spatial scales. Finally, we use the timing of sequence collection to understand the age groups driving transmission. This work improves our ability to characterize transmission from large pathogen genome datasets.

RevDate: 2024-06-10

Salisbury NJH, Amonkar S, Vinueza JL, et al (2024)

Polyomavirus ALTOs, but not MTs, downregulate viral early gene expression by activating the NF-κB pathway.

bioRxiv : the preprint server for biology.

Polyomaviruses are small, circular dsDNA viruses that can cause cancer. Alternative splicing of polyomavirus early transcripts generates large and small tumor antigens (LT, ST) that play essential roles in viral replication and tumorigenesis. Some polyomaviruses also express middle tumor antigens (MTs) or Alternate LT ORFs (ALTOs), which are evolutionarily related but have distinct gene structures. MTs are a splice variant of the early transcript whereas ALTOs are overprinted on the second exon of the LT transcript in an alternate reading frame and are translated via an alternative start codon. Merkel cell polyomavirus (MCPyV), the only human polyomavirus that causes cancer, encodes an ALTO but its role in the viral lifecycle and tumorigenesis has remained elusive. Here, we show MCPyV ALTO acts as a tumor suppressor and is silenced in Merkel cell carcinoma (MCC). Rescuing ALTO in MCC cells induces growth arrest and activates NF-κB signaling. ALTO activates NF-κB by binding SQSTM1 and TRAF2&3 via two N-Terminal Activating Regions (NTAR1+2), resembling Epstein-Barr virus (EBV) Latent Membrane Protein 1 (LMP1).. Following activation, NF-κB dimers bind the MCPyV non-coding control region (NCCR) and downregulate early transcription. Beyond MCPyV, NTAR motifs are conserved in other polyomavirus ALTOs, which activate NF-κB signaling, but are lacking in MTs that do not. Furthermore, polyomavirus ALTOs downregulate their respective viral early transcription in an NF-κB and NTAR dependent manner. Our findings suggest that ALTOs evolved to suppress viral replication and promote viral latency and that MCPyV ALTO must be silenced for MCC to develop.

RevDate: 2024-06-05

Shenoy ES, Banach DB, Batshon LJ, et al (2024)

SHEA position statement on pandemic preparedness for policymakers: the role of healthcare epidemiologists in communicating during infectious diseases outbreaks.

Infection control and hospital epidemiology pii:S0899823X24000631 [Epub ahead of print].

RevDate: 2024-06-07

Zou J, Lin T, Di C, et al (2023)

A RIEMANN MANIFOLD MODEL FRAMEWORK FOR LONGITUDINAL CHANGES IN PHYSICAL ACTIVITY PATTERNS.

The annals of applied statistics, 17(4):3216-3240.

Physical activity (PA) is significantly associated with many health outcomes. The wide usage of wearable accelerometer-based activity trackers in recent years has provided a unique opportunity for in-depth research on PA and its relations with health outcomes and interventions. Past analysis of activity tracker data relies heavily on aggregating minute-level PA records into day-level summary statistics in which important information of PA temporal/diurnal patterns is lost. In this paper we propose a novel functional data analysis approach based on Riemann manifolds for modeling PA and its longitudinal changes. We model smoothed minute-level PA of a day as one-dimensional Riemann manifolds and longitudinal changes in PA in different visits as deformations between manifolds. The variability in changes of PA among a cohort of subjects is characterized via variability in the deformation. Functional principal component analysis is further adopted to model the deformations, and PC scores are used as a proxy in modeling the relation between changes in PA and health outcomes and/or interventions. We conduct comprehensive analyses on data from two clinical trials: Reach for Health (RfH) and Metabolism, Exercise and Nutrition at UCSD (MENU), focusing on the effect of interventions on longitudinal changes in PA patterns and how different modes of changes in PA influence weight loss, respectively. The proposed approach reveals unique modes of changes, including overall enhanced PA, boosted morning PA, and shifts of active hours specific to each study cohort. The results bring new insights into the study of longitudinal changes in PA and health and have the potential to facilitate designing of effective health interventions and guidelines.

RevDate: 2024-06-07

Perrone G, Rigacci L, Roviello G, et al (2024)

Validation of single nucleotide polymorphisms potentially related to R-CHOP resistance in diffuse large B-cell lymphoma patients.

Cancer drug resistance (Alhambra, Calif.), 7:21.

Aim: Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma (NHL). Despite the availability of clinical and molecular algorithms applied for the prediction of prognosis, in up to 30%-40% of patients, intrinsic or acquired drug resistance occurs. Constitutional genetics may help to predict R-CHOP resistance. This study aimed to validate previously identified single nucleotide polymorphisms (SNPs) in the literature as potential predictors of R-CHOP resistance in DLBCL patients, SNPs. Methods: Twenty SNPs, involved in R-CHOP pharmacokinetics/pharmacodynamics or other pathobiological processes, were investigated in 185 stage I-IV DLBCL patients included in a multi-institution pharmacogenetic study to validate their previously identified correlations with resistance to R-CHOP. Results: Correlations between rs2010963 (VEGFA gene) and sex (P = 0.046), and rs1625895 (TP53 gene) and stage (P = 0.003) were shown. After multivariate analyses, a concordant effect (i.e., increased risk of disease progression and death) was observed for rs1883112 (NCF4 gene) and rs1800871 (IL10 gene). When patients were grouped according to the revised International Prognostic Index (R-IPI), both these SNPs further discriminated progression-free survival (PFS) and overall survival (OS) of the R-IPI-1-2 subgroup. Overall, patients harboring the rare allele showed shorter PFS and OS compared with wild-type patients. Conclusions: Two out of the 20 study SNPs were validated. Thus, these results support the role of previously identified rs1883112 and rs1800871 in predicting DLBCL resistance to R-CHOP and highlight their ability to further discriminate the prognosis of R-IPI-1-2 patients. These data point to the need to also focus on host genetics for a more comprehensive assessment of DLBCL patient outcomes in future prospective trials.

RevDate: 2024-06-05

Branch-Elliman W, Banach DB, Batshon LJ, et al (2024)

SHEA position statement on pandemic preparedness for policymakers: pandemic data collection, maintenance, and release.

Infection control and hospital epidemiology pii:S0899823X24000655 [Epub ahead of print].

The Society for Healthcare Epidemiology in America (SHEA) strongly supports modernization of data collection processes and the creation of publicly available data repositories that include a wide variety of data elements and mechanisms for securely storing both cleaned and uncleaned data sets that can be curated as clinical and research needs arise. These elements can be used for clinical research and quality monitoring and to evaluate the impacts of different policies on different outcomes. Achieving these goals will require dedicated, sustained and long-term funding to support data science teams and the creation of central data repositories that include data sets that can be "linked" via a variety of different mechanisms and also data sets that include institutional and state and local policies and procedures. A team-based approach to data science is strongly encouraged and supported to achieve the goal of a sustainable, adaptable national shared data resource.

RevDate: 2024-06-05

Weber DJ, Malani AN, Shenoy ES, et al (2024)

Society for Healthcare Epidemiology of America position statement on pandemic preparedness for policymakers: mitigating supply shortages.

Infection control and hospital epidemiology pii:S0899823X24000679 [Epub ahead of print].

The COVID-19 has had major direct (e.g., deaths) and indirect (e.g., social inequities) effects in the United States. While the public health response to the epidemic featured some important successes (e.g., universal masking ,and rapid development and approval of vaccines and therapeutics), there were systemic failures (e.g., inadequate public health infrastructure) that overshadowed these successes. Key deficiency in the U.S. response were shortages of personal protective equipment (PPE) and supply chain deficiencies. Recommendations are provided for mitigating supply shortages and supply chain failures in healthcare settings in future pandemics. Some key recommendations for preventing shortages of essential components of infection control and prevention include increasing the stockpile of PPE in the U.S. National Strategic Stockpile, increased transparency of the Stockpile, invoking the Defense Production Act at an early stage, and rapid review and authorization by FDA/EPA/OSHA of non-U.S. approved products. Recommendations are also provided for mitigating shortages of diagnostic testing, medications and medical equipment.

RevDate: 2024-06-05

Banach DB, Mathew TA, Batshon LJ, et al (2024)

SHEA position statement on pandemic preparedness for policymakers: building a strong and resilient healthcare workforce.

Infection control and hospital epidemiology pii:S0899823X2400062X [Epub ahead of print].

Throughout the COVID-19 pandemic, many areas in the United States experienced healthcare personnel (HCP) shortages tied to a variety of factors. Infection prevention programs, in particular, faced increasing workload demands with little opportunity to delegate tasks to others without specific infectious diseases or infection control expertise. Shortages of clinicians providing inpatient care to critically ill patients during the early phase of the pandemic were multifactorial, largely attributed to increasing demands on hospitals to provide care to patients hospitalized with COVID-19 and furloughs.[1] HCP shortages and challenges during later surges, including the Omicron variant-associated surges, were largely attributed to HCP infections and associated work restrictions during isolation periods and the need to care for family members, particularly children, with COVID-19. Additionally, the detrimental physical and mental health impact of COVID-19 on HCP has led to attrition, which further exacerbates shortages.[2] Demands increased in post-acute and long-term care (PALTC) settings, which already faced critical staffing challenges difficulty with recruitment, and high rates of turnover. Although individual healthcare organizations and state and federal governments have taken actions to mitigate recurring shortages, additional work and innovation are needed to develop longer-term solutions to improve healthcare workforce resiliency. The critical role of those with specialized training in infection prevention, including healthcare epidemiologists, was well-demonstrated in pandemic preparedness and response. The COVID-19 pandemic underscored the need to support growth in these fields.[3] This commentary outlines the need to develop the US healthcare workforce in preparation for future pandemics.

RevDate: 2024-06-05

Hsu VP, Haessler S, Banach DB, et al (2024)

SHEA position statement on pandemic preparedness for policymakers: introduction and overview.

Infection control and hospital epidemiology pii:S0899823X24000667 [Epub ahead of print].

Throughout history, pandemics and their aftereffects have spurred society to make substantial improvements in healthcare. After the Black Death in 14[th] century Europe, changes were made to elevate standards of care and nutrition that resulted in improved life expectancy.[1] The 1918 influenza pandemic spurred a movement that emphasized public health surveillance and detection of future outbreaks and eventually led to the creation of the World Health Organization Global Influenza Surveillance Network.[2] In the present, the COVID-19 pandemic exposed many of the pre-existing problems within the US healthcare system, which included (1) a lack of capacity to manage a large influx of contagious patients while simultaneously maintaining routine and emergency care to non-COVID patients; (2) a "just in time" supply network that led to shortages and competition among hospitals, nursing homes, and other care sites for essential supplies; and (3) longstanding inequities in the distribution of healthcare and the healthcare workforce. The decades-long shift from domestic manufacturing to a reliance on global supply chains has compounded ongoing gaps in preparedness for supplies such as personal protective equipment and ventilators. Inequities in racial and socioeconomic outcomes highlighted during the pandemic have accelerated the call to focus on diversity, equity, and inclusion (DEI) within our communities. The pandemic accelerated cooperation between government entities and the healthcare system, resulting in swift implementation of mitigation measures, new therapies and vaccinations at unprecedented speeds, despite our fragmented healthcare delivery system and political divisions. Still, widespread misinformation or disinformation and political divisions contributed to eroded trust in the public health system and prevented an even uptake of mitigation measures, vaccines and therapeutics, impeding our ability to contain the spread of the virus in this country.[3] Ultimately, the lessons of COVID-19 illustrate the need to better prepare for the next pandemic. Rising microbial resistance, emerging and re-emerging pathogens, increased globalization, an aging population, and climate change are all factors that increase the likelihood of another pandemic.[4].

RevDate: 2024-06-04

Mack TM, Raddatz MA, Pershad Y, et al (2024)

Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate.

Nature aging [Epub ahead of print].

Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion.

RevDate: 2024-06-04
CmpDate: 2024-06-04

Hall E, Davis K, Ohrnberger J, et al (2024)

Associations between HIV stigma and health-related quality-of-life among people living with HIV: cross-sectional analysis of data from HPTN 071 (PopART).

Scientific reports, 14(1):12835.

People living with HIV (PLHIV) report lower health-related quality-of-life (HRQoL) than HIV-negative people. HIV stigma may contribute to this. We explored the association between HIV stigma and HRQoL among PLHIV. We used cross-sectional data from 3991 randomly selected PLHIV who were surveyed in 2017-2018 for HPTN 071 (PopART), a cluster randomised trial in Zambia and South Africa. Participants were 18-44 years, had laboratory-confirmed HIV infection, and knew their status. HRQoL was measured using the EuroQol-5-dimensions-5-levels (EQ-5D-5L) questionnaire. Stigma outcomes included: internalised stigma, stigma experienced in the community, and stigma experienced in healthcare settings. Associations were examined using logistic regression. Participants who had experienced community stigma (n = 693/3991) had higher odds of reporting problems in at least one HRQoL domain, compared to those who had not (adjusted odds ratio, aOR: 1.51, 95% confidence interval, 95% Cl: 1.16-1.98, p = 0.002). Having experienced internalised stigma was also associated with reporting problems in at least one HRQoL domain (n = 552/3991, aOR: 1.98, 95% CI: 1.54-2.54, p < 0.001). However, having experienced stigma in a healthcare setting was less common (n = 158/3991) and not associated with HRQoL (aOR: 1.04, 95% CI: 0.68-1.58, p = 0.850). A stronger focus on interventions for internalised stigma and stigma experienced in the community is required.

RevDate: 2024-06-04

Nimgaonkar I, Flaherty PW, Oshima MU, et al (2024)

Acute Endothelial Complications Post-Allogeneic Hematopoietic Cell Transplant in Patients with Pre-Cellular Therapy SARS-CoV-2 Infection.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:7687709 [Epub ahead of print].

RevDate: 2024-06-04

Joy J, Gervassi AL, Chen L, et al (2024)

Antigen specificities and proviral integration sites differ in HIV-infected cells by timing of antiretroviral treatment initiation.

The Journal of clinical investigation pii:159569 [Epub ahead of print].

Despite effective antiretroviral therapy (ART), persons living with HIV (PWH) harbor reservoirs of persistently infected CD4+ cells, which constitute a barrier to cure. Initiation of ART during acute infection reduces the size of the HIV reservoir, and we hypothesized that in addition, it would favor integration of proviruses in HIV-specific CD4+ T cells, while initiation of ART during chronic HIV infection would favor relatively more proviruses in herpesvirus-specific cells. We further hypothesized that proviruses in acute-ART-initiators would be integrated into antiviral genes, whereas integration sites in chronic-ART-initiators would favor genes associated with cell proliferation and exhaustion. We found the HIV DNA distribution across HIV-specific vs. herpesvirus-specific CD4+ T cells was as hypothesized. HIV integration sites (IS) in acute-ART-initiators were significantly enriched in gene sets controlling lipid metabolism and HIF-1α-mediated hypoxia, both metabolic pathways active in early HIV infection. Persistence of these infected cells during prolonged ART suggests a survival advantage. IS in chronic-ART-initiators were enriched in a gene set controlling EZH2 histone methylation; and methylation has been associated with diminished LTR transcription. These differences we found in antigen specificities and IS distributions within HIV-infected cells might be leveraged in designing cure strategies tailored to the timing of ART initiation.

RevDate: 2024-06-05

Baik C, Cheng ML, Dietrich M, et al (2024)

Correction to: A Practical Review of Encorafenib and Binimetinib Therapy Management in Patients with BRAF V600EMutant Metastatic Non-Small Cell Lung Cancer.

RevDate: 2024-06-04

Sun X, Verma SP, Jia G, et al (2024)

Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants that Confer Risk for Breast Cancer.

Cancer research pii:745717 [Epub ahead of print].

Breast cancer includes several subtypes with distinct characteristic biological, pathological, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate development of improved prevention and treatment approaches. Here, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case GWAS (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared to luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to 2-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case-control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among breast cancer patients. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC.

RevDate: 2024-06-03

Ennist NM, Wang S, Kennedy MA, et al (2024)

De novo design of proteins housing excitonically coupled chlorophyll special pairs.

Nature chemical biology [Epub ahead of print].

Natural photosystems couple light harvesting to charge separation using a 'special pair' of chlorophyll molecules that accepts excitation energy from the antenna and initiates an electron-transfer cascade. To investigate the photophysics of special pairs independently of the complexities of native photosynthetic proteins, and as a first step toward creating synthetic photosystems for new energy conversion technologies, we designed C2-symmetric proteins that hold two chlorophyll molecules in closely juxtaposed arrangements. X-ray crystallography confirmed that one designed protein binds two chlorophylls in the same orientation as native special pairs, whereas a second designed protein positions them in a previously unseen geometry. Spectroscopy revealed that the chlorophylls are excitonically coupled, and fluorescence lifetime imaging demonstrated energy transfer. The cryo-electron microscopy structure of a designed 24-chlorophyll octahedral nanocage with a special pair on each edge closely matched the design model. The results suggest that the de novo design of artificial photosynthetic systems is within reach of current computational methods.

RevDate: 2024-06-03

Zhang MY, Othus M, McMillen K, et al (2024)

Association between class III obesity and overall survival in previously untreated younger patients with acute myeloid leukemia enrolled on SWOG S1203.

Leukemia [Epub ahead of print].

There has been ongoing debate on the association between obesity and outcomes in acute myeloid leukemia (AML). Currently few studies have stratified outcomes by class I obesity, class II obesity, and class III obesity, and a more nuanced understanding is becoming increasingly important with the rising prevalence of obesity. We examined the association between body mass index (BMI) and outcomes in previously untreated AML in younger patients (age ≤60) enrolled in SWOG S1203 (n = 729). Class III obesity was associated with an increased rate of early death (p = 0.004) and worse overall survival (OS) in multivariate analysis (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.62-3.80 versus normal weight). Class III obesity was also associated with worse OS after allogeneic hematopoietic cell transplant (HR 2.37, 95% CI 1.24-4.54 versus normal weight). These findings highlight the unique risk of class III obesity in AML, and the importance of further investigation to better characterize this patient population.

RevDate: 2024-06-03
CmpDate: 2024-06-03

Loacker DE, Shannon-Dorcy K, Rajotte EJ, et al (2024)

Closing the Gaps: Addressing the Unmet Needs of Cancer Survivors.

Clinical journal of oncology nursing, 28(3):241-246.

Moving Beyond Cancer to Wellness is a patient- and caregiver-focused educational outreach event with an inspirational message and lectures that address common concerns among cancer survivors. This event is open to the communi.

RevDate: 2024-06-05

Gulati R, Jiao B, Al-Faouri R, et al (2024)

Lifetime Health and Economic Outcomes of Biparametric Magnetic Resonance Imaging as First-Line Screening for Prostate Cancer : A Decision Model Analysis.

Annals of internal medicine [Epub ahead of print].

BACKGROUND: Contemporary prostate cancer (PCa) screening uses first-line prostate-specific antigen (PSA) testing, possibly followed by multiparametric magnetic resonance imaging (mpMRI) for men with elevated PSA levels. First-line biparametric MRI (bpMRI) screening has been proposed as an alternative.

OBJECTIVE: To evaluate the comparative effectiveness and cost-effectiveness of first-line bpMRI versus PSA-based screening.

DESIGN: Decision analysis using a microsimulation model.

DATA SOURCES: Surveillance, Epidemiology, and End Results database; randomized trials.

TARGET POPULATION: U.S. men aged 55 years with no prior screening or PCa diagnosis.

TIME HORIZON: Lifetime.

PERSPECTIVE: U.S. health care system.

INTERVENTION: Biennial screening to age 69 years using first-line PSA testing (test-positive threshold, 4 µg/L) with or without second-line mpMRI or first-line bpMRI (test-positive threshold, PI-RADS [Prostate Imaging Reporting and Data System] 3 to 5 or 4 to 5), followed by biopsy guided by MRI or MRI plus transrectal ultrasonography.

OUTCOME MEASURES: Screening tests, biopsies, diagnoses, overdiagnoses, treatments, PCa deaths, quality-adjusted and unadjusted life-years saved, and costs.

RESULTS OF BASE-CASE ANALYSIS: For 1000 men, first-line bpMRI versus first-line PSA testing prevented 2 to 3 PCa deaths and added 10 to 30 life-years (4 to 11 days per person) but increased the number of biopsies by 1506 to 4174 and the number of overdiagnoses by 38 to 124 depending on the biopsy imaging scheme. At conventional cost-effectiveness thresholds, first-line PSA testing with mpMRI followed by either biopsy approach for PI-RADS 4 to 5 produced the greatest net monetary benefits.

First-line PSA testing remained more cost-effective even if bpMRI was free, all men with low-risk PCa underwent surveillance, or screening was quadrennial.

LIMITATION: Performance of first-line bpMRI was based on second-line mpMRI data.

CONCLUSION: Decision analysis suggests that comparative effectiveness and cost-effectiveness of PCa screening are driven by false-positive results and overdiagnoses, favoring first-line PSA testing with mpMRI over first-line bpMRI.

PRIMARY FUNDING SOURCE: National Cancer Institute.

RevDate: 2024-06-05
CmpDate: 2024-06-03

Pineda JMB, RK Bradley (2024)

DUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers.

eLife, 12:.

Cancer immune evasion contributes to checkpoint immunotherapy failure in many patients with metastatic cancers. The embryonic transcription factor DUX4 was recently characterized as a suppressor of interferon-γ signaling and antigen presentation that is aberrantly expressed in a small subset of primary tumors. Here, we report that DUX4 expression is a common feature of metastatic tumors, with ~10-50% of advanced bladder, breast, kidney, prostate, and skin cancers expressing DUX4. DUX4 expression is significantly associated with immune cell exclusion and decreased objective response to PD-L1 blockade in a large cohort of urothelial carcinoma patients. DUX4 expression is a significant predictor of survival even after accounting for tumor mutational burden and other molecular and clinical features in this cohort, with DUX4 expression associated with a median reduction in survival of over 1 year. Our data motivate future attempts to develop DUX4 as a biomarker and therapeutic target for checkpoint immunotherapy resistance.

RevDate: 2024-06-03
CmpDate: 2024-06-03

Wang Y, Ullah MA, Waltner OG, et al (2024)

Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD.

The Journal of clinical investigation, 134(11):.

Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.

RevDate: 2024-06-03

Nguyen JK, Harik LR, Klein EA, et al (2024)

Proposal for an optimised definition of adverse pathology (unfavourable histology) that predicts metastatic risk in prostatic adenocarcinoma independent of grade group and pathological stage.

Histopathology [Epub ahead of print].

AIMS: Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential.

METHODS AND RESULTS: Two separate non-overlapping cohorts were identified: a 419-patient post-radical prostatectomy cohort with long term clinical follow-up and a 209-patient post-radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re-reviewed for high-risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord-like growth. For the outcome cohort, Kaplan-Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post-prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post-prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology.

CONCLUSIONS: Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post-prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation.

RevDate: 2024-06-04

Jones SM, Yi J, Henrikson NB, et al (2024)

Financial hardship after cancer: revision of a conceptual model and development of patient-reported outcome measures.

Future science OA, 10(1):FSO983.

Aim: This qualitative study refined a conceptual model of financial hardship and developed measures corresponding to model constructs. Methods: Eighteen women with breast cancer recruited through a comprehensive cancer center completed interviews. A qualitative framework analysis was conducted of the interviews. Results: Participants experienced varying levels of financial hardship. Protective factors included good health insurance, work accommodations and social support. Participants worried about cancer care costs and employment. Programs for alleviating financial hardship had high administrative burdens. Four preliminary financial hardship measures were developed: coping, impacts, depression and worry. Conclusion: Reducing administrative barriers to benefits could reduce financial hardship after cancer. More research is needed on the effects of out-of-network/formulary care and denials of coverage and to validate the measures.

RevDate: 2024-06-04

Lowndes JS, Holder AM, Markowitz EH, et al (2024)

Shifting institutional culture to develop climate solutions with Open Science.

Ecology and evolution, 14(6):e11341.

To address our climate emergency, "we must rapidly, radically reshape society"-Johnson & Wilkinson, All We Can Save. In science, reshaping requires formidable technical (cloud, coding, reproducibility) and cultural shifts (mindsets, hybrid collaboration, inclusion). We are a group of cross-government and academic scientists that are exploring better ways of working and not being too entrenched in our bureaucracies to do better science, support colleagues, and change the culture at our organizations. We share much-needed success stories and action for what we can all do to reshape science as part of the Open Science movement and 2023 Year of Open Science.

RevDate: 2024-06-03

Vilcot M, Faure N, Andrews KR, et al (2024)

Neutral processes and taxonomic scale drive beta species-genetic diversity correlations in a submesophotic tropical reef fish.

Molecular ecology [Epub ahead of print].

If similar evolutionary forces maintain intra- and interspecific diversity, patterns of diversity at both levels of biological organization can be expected to covary across space. Although this prediction of a positive species-genetic diversity correlation (SGDC) has been tested for several taxa in natural landscapes, no study has yet evaluated the influence of the community delineation on these SGDCs. In this study, we focused on tropical fishes of the Indo-Pacific Ocean, using range-wide single nucleotide polymorphism data for a deep-sea fish (Etelis coruscans) and species presence data of 4878 Teleostei species. We investigated whether a diversity continuum occurred, for different community delineations (subfamily, family, order and class) and spatial extents, and which processes explained these diversity patterns. We found no association between genetic diversity and species richness (α-SGDC), regardless of the community and spatial extent. In contrast, we evidenced a positive relationship between genetic and species dissimilarities (β-SGDC) when the community was defined at the subfamily or family level of the species of interest, and when the Western Indian Ocean was excluded. This relationship was related to the imprint of dispersal processes across levels of biological organization in Lutjanidae. However, this positive β-SGDC was lost when considering higher taxonomic communities and at the scale of the entire Indo-Pacific, suggesting different responses of populations and communities to evolutionary processes at these scales. This study provides evidence that the taxonomic scale at which communities are defined and the spatial extent are pivotal to better understand the processes shaping diversity across levels of biological organization.

RevDate: 2024-06-05

Einav T, Khoo Y, A Singer (2023)

Quantitatively Visualizing Bipartite Datasets.

Physical review. X, 13(2):.

As experiments continue to increase in size and scope, a fundamental challenge of subsequent analyses is to recast the wealth of information into an intuitive and readily interpretable form. Often, each measurement conveys only the relationship between a pair of entries, and it is difficult to integrate these local interactions across a dataset to form a cohesive global picture. The classic localization problem tackles this question, transforming local measurements into a global map that reveals the underlying structure of a system. Here, we examine the more challenging bipartite localization problem, where pairwise distances are available only for bipartite data comprising two classes of entries (such as antibody-virus interactions, drug-cell potency, or user-rating profiles). We modify previous algorithms to solve bipartite localization and examine how each method behaves in the presence of noise, outliers, and partially observed data. As a proof of concept, we apply these algorithms to antibody-virus neutralization measurements to create a basis set of antibody behaviors, formalize how potently inhibiting some viruses necessitates weakly inhibiting other viruses, and quantify how often combinations of antibodies exhibit degenerate behavior.

RevDate: 2024-06-03

Boeckh M, Pergam SA, Limaye AP, et al (2024)

How Immunocompromised Hosts Were Left Behind in the Quest to Control the Covid-19 Pandemic.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:7686576 [Epub ahead of print].

The immunocompromised population was disproportionately affected by the SARS-CoV-2 pandemic. However, these individuals were largely excluded from clinical trials of vaccines, monoclonal antibodies, and small molecule antivirals. While the community of scientists, clinical researchers, and funding agencies have proven that these therapeutics can be made and tested in record time, extending this progress to vulnerable and medically complex individuals from the start has been a missed opportunity. Here we advocate that it is paramount to plan for future pandemics by investing in specific clinical trial infrastructure for the immunocompromised population to be prepared when the need arises.

RevDate: 2024-06-02

Cortés J, Hurvitz SA, Im SA, et al (2024)

Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer: long-term survival analysis of the DESTINY-Breast03 trial.

Nature medicine [Epub ahead of print].

Trastuzumab deruxtecan (T-DXd) demonstrated significantly improved efficacy over trastuzumab emtansine (T-DM1) in DESTINY-Breast03 (median follow-up, 28 months). We report updated efficacy and safety analyses, including secondary and exploratory efficacy endpoints (median follow-up, 41 months) of DESTINY-Breast03. Patients with advanced HER2-positive metastatic breast cancer previously treated with taxane and trastuzumab were randomized to T-DXd (5.4 mg per kg (261 patients)) or T-DM1 (3.6 mg per kg (263 patients)). The primary endpoint was progression-free survival (PFS) by blinded independent central review and was previously reported. The key secondary endpoint was overall survival (OS). Other secondary endpoints included objective response rate, duration of response and PFS (all by investigator assessment) and safety. At data cutoff, 20 November 2023, median PFS by investigator assessment was 29.0 versus 7.2 months (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.24-0.38), the 36-month PFS rate was 45.7% versus 12.4% and median OS was 52.6 versus 42.7 months (HR, 0.73; 95% CI, 0.56-0.94) with T-DXd versus T-DM1, respectively. Treatment-emergent adverse events were consistent with the previous analyses. No new instances of grade ≥3 interstitial lung disease or pneumonitis occurred (all grade rate, 16.7% (T-DXd) versus 3.4% (T-DM1)). With longer follow-up, T-DXd continued to demonstrate superior efficacy over T-DM1 with a manageable safety profile. ClinicalTrials.gov registration: NCT03529110 .

RevDate: 2024-06-02

Mehta RS (2024)

SOHO State of the Art Updates and Next Questions | Current Status and Future Directions of Donor Selection.

Clinical lymphoma, myeloma & leukemia pii:S2152-2650(24)00183-6 [Epub ahead of print].

The landscape of HLA matching in hematopoietic cell transplantation (HCT) is continuously advancing, introducing more nuanced criteria beyond traditional 10/10 HLA-A, -B, -C, and -DRB1 allele matching. For 10/10 matched donors, prioritizing a donor with a "core" permissive HLA-DPB1 mismatch is recommended over "noncore" permissive mismatches, with nonpermissive mismatches being the least prefered. In the one-antigen mismatched setting (7/8 HLA-matched), HLA-C matching, particularly avoiding high-expression mismatches at residues 116 or 77/80, is preferred over HLA-A or HLA-B mismatches. HLA B-leader matching is beneficial in both one-antigen mismatched and haploidentical HCT. Additionally, specific HLA mismatches in haploidentical HCT, such as DRB1 mismatches with DQB1 matches and DPB1 nonpermissive mismatches are linked to better outcomes. Among non-HLA factors, evidence consistently underscores the pivotal impact of donor age on overall survival. For HLA-mismatched transplants, including haploidentical HCT, avoidance of donors against whom the recipient has preformed donor-specific antibodies is paramount. Selecting a cytomegalovirus (CMV) seronegative donor is important particularly for CMV-negative recipients; however, more research is needed in the letermovir prophylaxis era. The impact of ABO-matching on transplant outcomes is debatable. Other unanswered questions include defining "younger" donors and establishing hierarchy in donor selection based on factors like CMV status, ABO compatibility, or sex-mismatch, to name a few. Future research addressing these issues will refine donor selection algorithms and improve transplant success. In conclusion, selecting a donor for HCT requires multifaceted considerations, integrating evolving HLA-matching criteria and non-HLA factors, to optimize HCT outcomes in this rapidly advancing field.

RevDate: 2024-06-02

Neefjes J, Gurova K, Sarthy J, et al (2024)

Chromatin as an old and new anticancer target.

Trends in cancer pii:S2405-8033(24)00095-5 [Epub ahead of print].

Recent genome-wide analyses identified chromatin modifiers as one of the most frequently mutated classes of genes across all cancers. However, chemotherapies developed for cancers involving DNA damage remain the standard of care for chromatin-deranged malignancies. In this review we address this conundrum by establishing the concept of 'chromatin damage': the non-genetic damage to protein-DNA interactions induced by certain small molecules. We highlight anthracyclines, a class of chemotherapeutic agents ubiquitously applied in oncology, as an example of overlooked chromatin-targeting agents. We discuss our current understanding of this phenomenon and explore emerging chromatin-damaging agents as a basis for further studies to maximize their impact in modern cancer treatment.

RevDate: 2024-06-01

Powles T, Chang YH, Yamamoto Y, et al (2024)

Pembrolizumab for advanced urothelial carcinoma: exploratory ctDNA biomarker analyses of the KEYNOTE-361 phase 3 trial.

Nature medicine pii:10.1038/s41591-024-03091-7 [Epub ahead of print].

Circulating tumor DNA (ctDNA) is emerging as a potential biomarker in early-stage urothelial cancer but its utility in metastatic disease remains unknown. In the phase 3 KEYNOTE-361 study, pembrolizumab with and without chemotherapy was compared with chemotherapy alone in patients with metastatic urothelial cancer. The study did not meet prespecified efficacy thresholds for statistical significance. To identify potential biomarkers of response, we retrospectively evaluated association of pre- and post-treatment ctDNA with clinical outcomes in a subset of patients who received pembrolizumab (n = 130) or chemotherapy (n = 130) in KEYNOTE-361. Baseline ctDNA were associated with best overall response (BOR;P = 0.009), progression-free survival (PFS;P < 0.001), and overall survival (OS;P < 0.001) for pembrolizumab, but not chemotherapy (all, P > 0.05). Chemotherapy induced larger ctDNA decreases from baseline to treatment cycle 2 than pembrolizumab; however, change with pembrolizumab (n = 87) were more associated with BOR (P = 4.39 × 10[-5]) and OS (P = 7.07 × 10[-5]) versus chemotherapy (n = 102; BOR: P = 1.01 × 10[-4]; OS: P = 0.018). Tumor tissue-informed versions of ctDNA change metrics were most associated with clinical outcomes but did not show statistically significant independent value for explaining OS beyond radiographic change by RECIST v1.1 when jointly modeled (pembrolizumab P = 0.364; chemotherapy P = 0.823). These results suggest distinct patterns in early ctDNA changes with immunotherapy and chemotherapy and differences in their association with long-term outcomes, which provide preliminary insights on the utility of liquid biopsies for treatment monitoring in metastatic urothelial cancer. Clinical trial registration: NCT02853305.

RevDate: 2024-06-01

Oh DY, He AR, Bouattour M, et al (2024)

Durvalumab or placebo plus gemcitabine and cisplatin in participants with advanced biliary tract cancer (TOPAZ-1): updated overall survival from a randomised phase 3 study.

The lancet. Gastroenterology & hepatology pii:S2468-1253(24)00095-5 [Epub ahead of print].

BACKGROUND: In the preplanned interim analysis of the TOPAZ-1 study, durvalumab plus gemcitabine-cisplatin significantly improved overall survival versus placebo plus gemcitabine-cisplatin in participants with advanced biliary tract cancer. We aimed to report updated overall survival and safety data from TOPAZ-1 with additional follow-up and data maturity beyond the interim analysis.

METHODS: TOPAZ-1 was a phase 3, randomised, double-masked, placebo-controlled, global study done at 105 sites in 17 countries. Participants aged 18 years or older with unresectable, locally advanced, or metastatic biliary tract cancer were randomly assigned (1:1) to durvalumab plus gemcitabine-cisplatin or placebo plus gemcitabine-cisplatin using a computer-generated randomisation scheme, stratified by disease status and primary tumour location. Participants received durvalumab (1500 mg) or placebo on day 1 of each cycle every 3 weeks for up to eight cycles, plus gemcitabine (1000 mg/m[2]) and cisplatin (25 mg/m[2]) intravenously on days 1 and 8 of each cycle every 3 weeks for up to eight cycles, followed by durvalumab (1500 mg) or placebo monotherapy every 4 weeks until disease progression or other discontinuation criteria were met. Investigators and participants were masked to study treatment. The primary endpoint was overall survival. TOPAZ-1 met its primary endpoint at the preplanned interim analysis, and the study is active but no longer recruiting participants. Updated overall survival and safety data from TOPAZ-1, with additional follow-up (data cutoff Feb 25, 2022) and data maturity beyond the interim analysis, are reported here. Efficacy was assessed in the full analysis set (all randomly assigned participants). Safety was assessed in the safety analysis set (all participants who received at least one dose of study treatment). The TOPAZ-1 study is registered with ClinicalTrials.gov, NCT03875235.

FINDINGS: From April 16, 2019, to Dec 11, 2020, 914 participants were enrolled, 685 of whom were randomly assigned (341 to the durvalumab plus gemcitabine-cisplatin group and 344 to the placebo plus gemcitabine-cisplatin group). 345 (50%) participants were male and 340 (50%) were female. Median follow-up at the updated data cutoff was 23·4 months (95% CI 20·6-25·2) in the durvalumab plus gemcitabine-cisplatin group and 22·4 months (21·4-23·8) in the placebo plus gemcitabine-cisplatin group. At the updated data cutoff, 248 (73%) participants in the durvalumab plus gemcitabine-cisplatin group and 279 (81%) participants in the placebo plus gemcitabine-cisplatin group had died (median overall survival 12·9 months [95% CI 11·6-14·1] vs 11·3 months [10·1-12·5]; hazard ratio 0·76 [95% CI 0·64-0·91]). Kaplan-Meier-estimated 24-month overall survival rates were 23·6% (95% CI 18·7-28·9) in the durvalumab plus gemcitabine-cisplatin group and 11·5% (7·6-16·2) in the placebo plus gemcitabine-cisplatin group. Maximum grade 3 or 4 adverse events occurred in 250 (74%) of 338 participants in the durvalumab plus gemcitabine-cisplatin group and 257 (75%) of 342 in the placebo plus gemcitabine-cisplatin group. The most common maximum grade 3 or 4 treatment-related adverse events were decreased neutrophil count (70 [21%] vs 86 [25%]), anaemia (64 [19%] vs 64 [19%]), and neutropenia (63 [19%] vs 68 [20%]).

INTERPRETATION: Durvalumab plus gemcitabine-cisplatin showed robust and sustained overall survival benefit with no new safety signals. Findings continue to support the regimen as a standard of care for people with untreated, advanced biliary tract cancer.

FUNDING: AstraZeneca.

RevDate: 2024-06-03
CmpDate: 2024-06-01

John EM, Koo J, Phipps AI, et al (2024)

Reproductive characteristics, menopausal status, race and ethnicity, and risk of breast cancer subtypes defined by ER, PR and HER2 status: the Breast Cancer Etiology in Minorities study.

Breast cancer research : BCR, 26(1):88.

BACKGROUND: Associations between reproductive factors and risk of breast cancer differ by subtype defined by joint estrogen receptor (ER), progesterone receptor (PR), and HER2 expression status. Racial and ethnic differences in the incidence of breast cancer subtypes suggest etiologic heterogeneity, yet data are limited because most studies have included non-Hispanic White women only.

METHODS: We analyzed harmonized data for 2,794 breast cancer cases and 4,579 controls, of whom 90% self-identified as African American, Asian American or Hispanic. Questionnaire data were pooled from three population-based studies conducted in California and data on tumor characteristics were obtained from the California Cancer Registry. The study sample included 1,530 luminal A (ER-positive and/or PR-positive, HER2-negative), 442 luminal B (ER-positive and/or PR-positive, HER2-positive), 578 triple-negative (TN; ER-negative, PR-negative, HER2-negative), and 244 HER2-enriched (ER-negative, PR-negative, HER2-positive) cases. We used multivariable unconditional logistic regression models to estimate subtype-specific ORs and 95% confidence intervals associated with parity, breast-feeding, and other reproductive characteristics by menopausal status and race and ethnicity.

RESULTS: Subtype-specific associations with reproductive factors revealed some notable differences by menopausal status and race and ethnicity. Specifically, higher parity without breast-feeding was associated with higher risk of luminal A and TN subtypes among premenopausal African American women. In contrast, among Asian American and Hispanic women, regardless of menopausal status, higher parity with a breast-feeding history was associated with lower risk of luminal A subtype. Among premenopausal women only, luminal A subtype was associated with older age at first full-term pregnancy (FTP), longer interval between menarche and first FTP, and shorter interval since last FTP, with similar OR estimates across the three racial and ethnic groups.

CONCLUSIONS: Subtype-specific associations with reproductive factors overall and by menopausal status, and race and ethnicity, showed some differences, underscoring that understanding etiologic heterogeneity in racially and ethnically diverse study samples is essential. Breast-feeding is likely the only reproductive factor that is potentially modifiable. Targeted efforts to promote and facilitate breast-feeding could help mitigate the adverse effects of higher parity among premenopausal African American women.

RevDate: 2024-05-31
CmpDate: 2024-05-31

Kulac I, Roudier MP, MC Haffner (2024)

Molecular Pathology of Prostate Cancer.

Clinics in laboratory medicine, 44(2):161-180.

Molecular profiling studies have shed new light on the complex biology of prostate cancer. Genomic studies have highlighted that structural rearrangements are among the most common recurrent alterations. In addition, both germline and somatic mutations in DNA repair genes are enriched in patients with advanced disease. Primary prostate cancer has long been known to be multifocal, but recent studies demonstrate that a large fraction of prostate cancer shows evidence of multiclonality, suggesting that genetically distinct, independently arising tumor clones coexist. Metastatic prostate cancer shows a high level of morphologic and molecular diversity, which is associated with resistance to systemic therapies. The resulting high level of intratumoral heterogeneity has important implications for diagnosis and poses major challenges for the implementation of molecular studies. Here we provide a concise review of the molecular pathology of prostate cancer, highlight clinically relevant alterations, and discuss opportunities for molecular testing.

RevDate: 2024-05-31

Smith MR, Jegede O, Martin P, et al (2024)

Randomized Bendamustine-Rituximab(R) + Bortezomib Induction and R + Lenalidomide Maintenance for Mantle Cell Lymphoma.

Blood pii:516345 [Epub ahead of print].

While initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine-rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance following induction is often utilized. Thus, the open-label, randomized phase II ECOG-ACRIN Cancer Research Group E1411 trial was designed to test two questions: 1) Does addition of bortezomib to BR induction (BVR) and/or 2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012-2016, 373 previously untreated patients, 87% ≥ 60 years old, were enrolled in this trial. At a median follow up of 7.5 years, there is no difference in the median PFS of BR compared to BVR (5.5 yrs vs. 6.4 yrs, HR 0.90, 90% CI 0.70, 1.16). There were no unexpected additional toxicities with BVR treatment compared to BR, with no impact on total dose/duration of treatment received. Independent of the induction treatment, addition of lenalidomide to rituximab did not significantly improve PFS, with median PFS in R vs LR (5.9 yrs vs 7.2 yrs, HR 0.84 90% CI 0.62, 1.15). The majority of patients completed the planned 24 cycles of LR at the scheduled dose. In summary, adding bortezomib to BR induction does not prolong PFS in treatment-naïve MCL, and LR maintenance was not associated with longer PFS compared with rituximab alone following BR. Nonetheless, the > 5 year median PFS outcomes in this prospective cooperative group trial indicate the efficacy of BR followed by rituximab maintenance as highly effective initial therapy for older MCL patients. (NCT01415752).

RevDate: 2024-06-03
CmpDate: 2024-05-31

Habtemariam S, Hery CM, Zhang X, et al (2024)

Association between sociodemographics and change in alcohol or tobacco use behaviors during the COVID-19 pandemic.

PloS one, 19(5):e0304111.

OBJECTIVE: To examine the association between various sociodemographic factors with alcohol and tobacco use behaviors during the COVID-19 pandemic.

METHODS: Participants from Ohio and Indiana were asked to participate in the 'Impact of COVID-19 on the Cancer Continuum Consortium' study (N = 32,989) from June-November 2020. Those who completed the survey and responded to key study questions were included (n = 5,374). Participants were asked about the frequency and type of alcohol and tobacco product used. Multivariable logistic regression was conducted to determine factors associated with the impact of COVID-19 on change in alcohol and/or tobacco use.

RESULTS: Mean age was 57 years old, 68% were female, 90% non-Hispanic white, 75% married, and 31% lived in rural counties. Out of 5,374 participants, 53% used alcohol-only (n = 2,833), 5% used tobacco-only (n = 255), 7% used both alcohol and tobacco (n = 395), and 35% used neither alcohol nor tobacco (n = 1,891). Urban county of residence (vs. rural) was associated with an increase in alcohol-use (p = 0.0001), change in alcohol products (p = 0.023), and an increase in tobacco use (p = 0.05). Among alcohol-only users, those who were younger (OR = 0.97), female (OR = 1.58), married (OR = 1.69), of high socioeconomic status (OR = 1.99), residing in urban counties (OR = 1.65), and had elevated financial (OR = 1.06) and employment concerns (OR = 1.28) were significantly more likely to report increased alcohol-use. Similarly, among tobacco users, those who were younger (OR = 0.97), female (OR = 2.79), married (OR = 2.16) or divorced (OR = 2.83), and had higher levels of neighborhood disadvantage (OR = 2.19) were significantly more likely to report increased tobacco-use.

CONCLUSIONS: Findings suggest targeted intervention and prevention strategies for young, female participants with elevated financial and employment concerns during the COVID-19 pandemic are necessary to mitigate risks associated with higher odds of alcohol and tobacco use. Our findings on alcohol and tobacco use may be a result of the unique social and economic influence of the pandemic on women.

RevDate: 2024-06-03
CmpDate: 2024-05-31

Telisinghe L, Floyd S, MacLeod D, et al (2024)

Incidence of self-reported tuberculosis treatment with community-wide universal testing and treatment for HIV and tuberculosis screening in Zambia and South Africa: A planned analysis of the HPTN 071 (PopART) cluster-randomised trial.

PLoS medicine, 21(5):e1004393.

BACKGROUND: HIV is a potent risk factor for tuberculosis (TB). Therefore, community-wide universal testing and treatment for HIV (UTT) could contribute to TB control, but evidence for this is limited. Community-wide TB screening can decrease population-level TB prevalence. Combining UTT with TB screening could therefore significantly impact TB control in sub-Saharan Africa, but to our knowledge there is no evidence for this combined approach.

METHODS AND FINDINGS: HPTN 071 (PopART) was a community-randomised trial conducted between November 2013 to July 2018; 21 Zambian and South African communities (with a total population of approximately 1 million individuals) were randomised to arms A (community-wide UTT and TB screening), B (community-wide universal HIV testing with treatment following national guidelines and TB screening), or C (standard-of-care). In a cohort of randomly selected adults (18 to 44 years) enrolled between 2013 and 2015 from all 21 communities (total size 38,474; 27,139 [71%] female; 8,004 [21%] HIV positive) and followed-up annually for 36 months to measure the population-level impact of the interventions, data on self-reported TB treatment in the previous 12 months (self-reported TB) were collected by trained research assistants and recorded using a structured questionnaire at each study visit. In this prespecified analysis of the trial, self-reported TB incidence rates were measured by calendar year between 2014 and 2017/2018. A p-value ≤0.05 on hypothesis testing was defined as reaching statistical significance. Between January 2014 and July 2018, 38,287 individuals were followed-up: 494 self-reported TB during 104,877 person-years. Overall incidence rates were similar across all arms in 2014 and 2015 (0.33 to 0.46/100 person-years). In 2016 incidence rates were lower in arm A compared to C overall (adjusted rate ratio [aRR] 0.48 [95% confidence interval (95% CI) 0.28 to 0.81; p = 0.01]), with statistical significance reached. In 2017/2018, while incidence rates were lower in arm A compared to C, statistical significance was not reached (aRR 0.58 [95% CI 0.27 to 1.22; p = 0.13]). Among people living with HIV (PLHIV) incidence rates were lower in arm A compared to C in 2016 (RR 0.56 [95% CI 0.29 to 1.08; p = 0.08]) and 2017/2018 (RR 0.50 [95% CI 0.26 to 0.95; p = 0.04]); statistical significance was only reached in 2017/2018. Incidence rates in arms B and C were similar, overall and among PLHIV. Among HIV-negative individuals, there were too few events for cross-arm comparisons. Study limitations include the use of self-report which may have been subject to under-reporting, limited covariate adjustment due to the small number of events, and high losses to follow-up over time.

CONCLUSIONS: In this study, community-wide UTT and TB screening resulted in substantially lower TB incidence among PLHIV at population-level, compared to standard-of-care, with statistical significance reached in the final study year. There was also some evidence this translated to a decrease in self-reported TB incidence overall in the population. Reduction in arm A but not B suggests UTT drove the observed effect. Our data support the role of UTT in TB control, in addition to HIV control, in high TB/HIV burden settings.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT01900977.

RevDate: 2024-06-03
CmpDate: 2024-05-30

Hrytsenko Y, Shea B, Elgart M, et al (2024)

Machine learning models for predicting blood pressure phenotypes by combining multiple polygenic risk scores.

Scientific reports, 14(1):12436.

We construct non-linear machine learning (ML) prediction models for systolic and diastolic blood pressure (SBP, DBP) using demographic and clinical variables and polygenic risk scores (PRSs). We developed a two-model ensemble, consisting of a baseline model, where prediction is based on demographic and clinical variables only, and a genetic model, where we also include PRSs. We evaluate the use of a linear versus a non-linear model at both the baseline and the genetic model levels and assess the improvement in performance when incorporating multiple PRSs. We report the ensemble model's performance as percentage variance explained (PVE) on a held-out test dataset. A non-linear baseline model improved the PVEs from 28.1 to 30.1% (SBP) and 14.3% to 17.4% (DBP) compared with a linear baseline model. Including seven PRSs in the genetic model computed based on the largest available GWAS of SBP/DBP improved the genetic model PVE from 4.8 to 5.1% (SBP) and 4.7 to 5% (DBP) compared to using a single PRS. Adding additional 14 PRSs computed based on two independent GWASs further increased the genetic model PVE to 6.3% (SBP) and 5.7% (DBP). PVE differed across self-reported race/ethnicity groups, with primarily all non-White groups benefitting from the inclusion of additional PRSs. In summary, non-linear ML models improves BP prediction in models incorporating diverse populations.

RevDate: 2024-05-30
CmpDate: 2024-05-30

Salgado M, Gálvez C, Nijhuis M, et al (2024)

Dynamics of virological and immunological markers of HIV persistence after allogeneic haematopoietic stem-cell transplantation in the IciStem cohort: a prospective observational cohort study.

The lancet. HIV, 11(6):e389-e405.

BACKGROUND: Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) markedly reduces HIV reservoirs, but the mechanisms by which this occurs are only partly understood. In this study, we aimed to describe the dynamics of virological and immunological markers of HIV persistence after allo-HSCT.

METHODS: In this prospective observational cohort study, we analysed the viral reservoir and serological dynamics in IciStem cohort participants with HIV who had undergone allo-HSCT and were receiving antiretroviral therapy, ten of whom had received cells from donors with the CCR5Δ32 mutation. Participants from Belgium, Canada, Germany, Italy, the Netherlands, Spain, Switzerland, and the UK were included in the cohort both prospectively and retrospectively between June 1, 2014 and April 30, 2019. In the first 6 months after allo-HSCT, participants had monthly assessments, with annual assessments thereafter, with the protocol tailored to accommodate for the individual health status of each participant. HIV reservoirs were measured in blood and tissues and HIV-specific antibodies were measured in plasma. We used the Wilcoxon signed-rank test to compare data collected before and after allo-HSCT in participants for whom longitudinal data were available. When the paired test was not possible, we used the Mann-Whitney U test. We developed a mathematical model to study the factors influencing HIV reservoir reduction in people with HIV after allo-HSCT.

FINDINGS: We included 30 people with HIV with haematological malignancies who received a transplant between Sept 1, 2009 and April 30, 2019 and were enrolled within the IciStem cohort and included in this analysis. HIV reservoirs in peripheral blood were reduced immediately after full donor chimerism was achieved, generally accompanied by undetectable HIV-DNA in bone marrow, ileum, lymph nodes, and cerebrospinal fluid, regardless of donor CCR5 genotype. HIV-specific antibody levels and functionality values declined more slowly than direct HIV reservoir values, decaying significantly only months after full donor chimerism. Mathematical modelling suggests that allogeneic immunity mediated by donor cells is the main viral reservoir depletion mechanism after massive reservoir reduction during conditioning chemotherapy before allo-HSCT (half-life of latently infected replication-competent cells decreased from 44 months to 1·5 months).

INTERPRETATION: Our work provides, for the first time, data on the effects of allo-HSCT in the context of HIV infection. Additionally, we raise the question of which marker can serve as the last reporter of the residual viraemia, postulating that the absence of T-cell immune responses might be a more reliable marker than antibody decline after allo-HSCT.

FUNDING: amfAR (American Foundation for AIDS Research; ARCHE Program), National Institutes of Health, National Institute of Allergy and Infectious Diseases, and Dutch Aidsfonds.

RevDate: 2024-05-31

Briercheck EL, Ravishankar S, Ahmed EH, et al (2024)

Geographic EBV variants confound disease-specific variant interpretation and predict variable immune therapy responses.

Blood advances pii:516312 [Epub ahead of print].

Epstein-Barr virus (EBV) is a potent carcinogen linked to hematologic and solid malignancies, causing significant global morbidity and mortality. Therapy using allogeneic EBV-specific lymphocytes shows promise in certain populations, but the impact of EBV genome variation on these strategies remains unexplored. To address this, we sequenced 217 EBV genomes, including hematologic malignancies from Guatemala, Peru, Malawi, and Taiwan, and analyzed them alongside 1,307 publicly available EBV genomes from cancer, non-malignant diseases, and healthy individuals across Africa, Asia, Europe, North America, and South America. These included the first NK/T-cell lymphoma (NKTCL) EBV genomes reported outside East Asia. Our findings indicate that previously proposed EBV genome variants specific to certain cancer types are more closely tied to geographic origin than cancer histology. This included variants previously reported to be specific to NKTCL but were prevalent in EBV genomes from other cancer types and healthy individuals in East Asia. After controlling for geographic region, we did identify multiple NKTCL-specific variants associated with a 7.8- to 21.9- fold increased risk. We also observed frequent variations in EBV genomes affecting peptide sequences previously reported to bind common MHC alleles. Finally, we found several non-synonymous variants spanning the coding sequences of current vaccine targets BALF4, BKRF2, BLLF1, BXLF2, BZLF1, and BZLF2. These results highlight the need to consider geographic variation in EBV genomes when devising strategies for exploiting adaptive immune responses against EBV-related cancers, ensuring greater global effectiveness and equity in prevention and treatment.

RevDate: 2024-05-30
CmpDate: 2024-05-30

Elliott MJ, Shen S, Lam DL, et al (2024)

Enhancing Early-Stage Breast Cancer Survivorship: Evidence-Based Strategies, Surveillance Testing, and Imaging Guidelines.

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting, 44(3):e432564.

Addressing the challenges of survivorship necessitates a comprehensive, patient-centered approach, focusing on mitigating risk through lifestyle modification, identifying distant recurrence, and optimization of breast imaging. This article will discuss the current and emerging clinical strategies for the survivorship period, advocating a multidisciplinary and comprehensive approach. In this manner, early-stage breast cancer survivors are empowered to navigate their journey with enhanced knowledge, facilitating a transition to life beyond cancer.

RevDate: 2024-05-30
CmpDate: 2024-05-30

Garraway IP, Carlsson SV, Nyame YA, et al (2024)

Prostate Cancer Foundation Screening Guidelines for Black Men in the United States.

NEJM evidence, 3(5):EVIDoa2300289.

BACKGROUND: In the United States, Black men are at highest risk for being diagnosed with and dying from prostate cancer. Given this disparity, we examined relevant data to establish clinical prostate-specific antigen (PSA) screening guidelines for Black men in the United States.

METHODS: A comprehensive literature search identified 1848 unique publications for screening. Of those screened, 287 studies were selected for full-text review, and 264 were considered relevant and form the basis for these guidelines. The numbers were reported according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.

RESULTS: Three randomized controlled trials provided Level 1 evidence that regular PSA screening of men 50 to 74 years of age of average risk reduced metastasis and prostate cancer death at 16 to 22 years of follow-up. The best available evidence specifically for Black men comes from observational and modeling studies that consider age to obtain a baseline PSA, frequency of testing, and age when screening should end. Cohort studies suggest that discussions about baseline PSA testing between Black men and their clinicians should begin in the early 40s, and data from modeling studies indicate prostate cancer develops 3 to 9 years earlier in Black men compared with non-Black men. Lowering the age for baseline PSA testing to 40 to 45 years of age from 50 to 55 years of age, followed by regular screening until 70 years of age (informed by PSA values and health factors), could reduce prostate cancer mortality in Black men (approximately 30% relative risk reduction) without substantially increasing overdiagnosis.

CONCLUSIONS: These guidelines recommend that Black men should obtain information about PSA screening for prostate cancer. Among Black men who elect screening, baseline PSA testing should occur between ages 40 and 45. Depending on PSA value and health status, annual screening should be strongly considered. (Supported by the Prostate Cancer Foundation.).

RevDate: 2024-06-03

Zhang Y, Spitzer BW, Zhang Y, et al (2024)

Untargeted Metabolome Atlas for Sleep Phenotypes in the Hispanic Community Health Study/Study of Latinos.

medRxiv : the preprint server for health sciences.

Sleep is essential to maintaining health and wellbeing of individuals, influencing a variety of outcomes from mental health to cardiometabolic disease. This study aims to assess the relationships between various sleep phenotypes and blood metabolites. Utilizing data from the Hispanic Community Health Study/Study of Latinos, we performed association analyses between 40 sleep phenotypes, grouped in several domains (i.e., sleep disordered breathing (SDB), sleep duration, timing, insomnia symptoms, and heart rate during sleep), and 768 metabolites measured via untargeted metabolomics profiling. Network analysis was employed to visualize and interpret the associations between sleep phenotypes and metabolites. The patterns of statistically significant associations between sleep phenotypes and metabolites differed by superpathways, and highlighted subpathways of interest for future studies. For example, some xenobiotic metabolites were associated with sleep duration and heart rate phenotypes (e.g. 1H-indole-7-acetic acid, 4-allylphenol sulfate), while ketone bodies and fatty acid metabolism metabolites were associated with sleep timing measures (e.g. 3-hydroxybutyrate (BHBA), 3-hydroxyhexanoylcarnitine (1)). Heart rate phenotypes had the overall largest number of detected metabolite associations. Many of these associations were shared with both SDB and with sleep timing phenotypes, while SDB phenotypes shared relatively few metabolite associations with sleep duration measures. A number of metabolites were associated with multiple sleep phenotypes, from a few domains. The amino acids vanillylmandelate (VMA) and 1-carboxyethylisoleucine were associated with the greatest number of sleep phenotypes, from all domains other than insomnia. This atlas of sleep-metabolite associations will facilitate hypothesis generation and further study of the metabolic underpinnings of sleep health.

RevDate: 2024-06-03

Buteyn NJ, Burke CG, Sartori VJ, et al (2024)

EZH2-driven immune evasion defines high-risk pediatric AML with t(16;21) FUS::ERG gene fusion.

bioRxiv : the preprint server for biology.

Minimal improvement in outcomes for high-risk pediatric acute myeloid leukemia (pAML) patients has been made in the past decades. Nowhere is this more evident than in patients carrying a t(16;21)(p11;q22) FUS::ERG translocation; quick time to relapse and universal failure of hematopoietic stem cell transplant contribute to one of the lowest survival rates in childhood leukemia. Here, we have identified a unique, defining immune-evasion phenotype in FUS::ERG pAML driven by EZH2 and characterized by loss of MHC class I and II molecules and immune co-stimulatory receptors. This loss of immune engagement, present at diagnosis, allows pervasiveness of blasts that prove resistant to standard treatment. We demonstrate that treatment with the FDA-approved EZH2 inhibitor tazemetostat, in combination with IFN-γ, reverses the phenotype, re-expresses MHC receptor expression, and reduces blast viability. EZH2 inhibitors provide a novel therapeutic option for this high-risk population and may prove a beneficial supplemental treatment for FUS::ERG pAML.

RevDate: 2024-06-03

Rubio AA, Baharani VA, Dadonaite B, et al (2024)

Bispecific antibodies with broad neutralization potency against SARS-CoV-2 variants of concern.

bioRxiv : the preprint server for biology.

The ongoing emergence of SARS-CoV-2 variants of concern (VOCs) that reduce the effectiveness of antibody therapeutics necessitates development of next-generation antibody modalities that are resilient to viral evolution. Here, we characterized N-terminal domain (NTD) and receptor binding domain (RBD)-specific monoclonal antibodies previously isolated from COVID-19 convalescent donors for their activity against emergent SARS-CoV-2 VOCs. Among these, the NTD-specific antibody C1596 displayed the greatest breadth of binding to VOCs, with cryo-EM structural analysis revealing recognition of a distinct NTD epitope outside of the site i antigenic supersite. Given C1596's favorable binding profile, we designed a series of bispecific antibodies (bsAbs) termed CoV2-biRNs, that featured both NTD and RBD specificities. Notably, two of the C1596-inclusive bsAbs, CoV2-biRN5 and CoV2-biRN7, retained potent in vitro neutralization activity against all Omicron variants tested, including XBB.1.5, EG.5.1, and BA.2.86, contrasting the diminished potency of parental antibodies delivered as monotherapies or as a cocktail. Furthermore, prophylactic delivery of CoV2-biRN5 significantly reduced the viral load within the lungs of K18-hACE2 mice following challenge with SARS-CoV-2 XBB.1.5. In conclusion, our NTD-RBD bsAbs offer promising potential for the design of resilient, next-generation antibody therapeutics against SARS-CoV-2 VOCs.

RevDate: 2024-06-03
CmpDate: 2024-06-03

Agarwal N, Castellano D, Alonso-Gordoa T, et al (2024)

A Signal-Finding Study of Abemaciclib in Heavily Pretreated Patients with Metastatic Castration-Resistant Prostate Cancer: Results from CYCLONE 1.

Clinical cancer research : an official journal of the American Association for Cancer Research, 30(11):2377-2383.

PURPOSE: Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors radically changed the treatment paradigm for breast cancer. Similar to estrogen receptor in breast cancer, androgen receptor signaling activates cyclin D-CDK4/6, driving proliferation and resistance to hormonal manipulation in prostate cancer. This study was designed to detect signals of clinical activity for abemaciclib in treatment-refractory metastatic castration-resistant prostate cancer (mCRPC).

PATIENTS AND METHODS: Eligible patients had progressive mCRPC, measurable disease, and previously received ≥1 novel hormonal agent(s) and 2 lines of taxane chemotherapy. Abemaciclib 200 mg twice daily was administered on a continuous dosing schedule. Primary endpoint was objective response rate (ORR) without concurrent bone progression. This study was designed to detect a minimum ORR of 12.5%.

RESULTS: At trial entry, 40 (90.9%) of 44 patients had objective radiographic disease progression, 4 (9.1%) had prostate-specific antigen (PSA)-only progression, and 20 (46.5%) had visceral metastases (of these, 60% had liver metastases). Efficacy analyses are as follows: ORR without concurrent bone progression: 6.8%; disease control rate: 45.5%; median time to PSA progression: 6.5 months [95% confidence interval (CI), 3.2-NA]; median radiographic PFS; 2.7 months (95% CI, 1.9-3.7); and median OS, 8.4 months (95% CI, 5.6-12.7). Most frequent grade ≥3 treatment-emergent adverse events (AE) were neutropenia (25.0%), anemia, and fatigue (11.4% each). No grade 4 or 5 AEs were related to abemaciclib.

CONCLUSIONS: Abemaciclib monotherapy was well tolerated and showed clinical activity in this heavily pretreated population, nearly half with visceral metastases. This study is considered preliminary proof-of-concept and designates CDK4/6 as a valid therapeutic target in prostate cancer.

RevDate: 2024-05-30

McGuinness JE, Anderson GL, Mutasa S, et al (2024)

Effects of vitamin D supplementation on a deep learning-based mammographic evaluation in SWOG S0812.

JNCI cancer spectrum pii:7685408 [Epub ahead of print].

Deep learning-based mammographic evaluations could noninvasively assess response to breast cancer (BC) chemoprevention. We evaluated change in a convolutional neural network (CNN)-based BC risk model applied to mammograms among women enrolled in SWOG S0812, which randomized 208 premenopausal high-risk women to receive oral vitamin D3 20,000IU weekly or placebo for 12 months. We applied the CNN model to mammograms collected at baseline (n = 109), 12 months (n = 97) and 24 months (n = 67), and compared changes in CNN risk score between treatment groups. Change in CNN score was neither significantly different between vitamin D and placebo groups at 12 months (0.005 vs. 0.002, p = 0.875) nor at 24 months (0.020 vs. 0.001, p = 0.563). The findings are consistent with the primary analysis of S0812, which did not demonstrate significant changes in MD with vitamin D supplementation compared to placebo. There is an ongoing need to evaluate biomarkers of response to novel BC chemopreventive agents.

RevDate: 2024-06-01

Newcomb LF, Schenk JM, Zheng Y, et al (2024)

Long-Term Outcomes in Patients Using Protocol-Directed Active Surveillance for Prostate Cancer.

JAMA [Epub ahead of print].

IMPORTANCE: Outcomes from protocol-directed active surveillance for favorable-risk prostate cancers are needed to support decision-making.

OBJECTIVE: To characterize the long-term oncological outcomes of patients receiving active surveillance in a multicenter, protocol-directed cohort.

The Canary Prostate Active Surveillance Study (PASS) is a prospective cohort study initiated in 2008. A cohort of 2155 men with favorable-risk prostate cancer and no prior treatment were enrolled at 10 North American centers through August 2022.

EXPOSURE: Active surveillance for prostate cancer.

MAIN OUTCOMES AND MEASURES: Cumulative incidence of biopsy grade reclassification, treatment, metastasis, prostate cancer mortality, overall mortality, and recurrence after treatment in patients treated after the first or subsequent surveillance biopsies.

RESULTS: Among 2155 patients with localized prostate cancer, the median follow-up was 7.2 years, median age was 63 years, 83% were White, 7% were Black, 90% were diagnosed with grade group 1 cancer, and median prostate-specific antigen (PSA) was 5.2 ng/mL. Ten years after diagnosis, the incidence of biopsy grade reclassification and treatment were 43% (95% CI, 40%-45%) and 49% (95% CI, 47%-52%), respectively. There were 425 and 396 patients treated after confirmatory or subsequent surveillance biopsies (median of 1.5 and 4.6 years after diagnosis, respectively) and the 5-year rates of recurrence were 11% (95% CI, 7%-15%) and 8% (95% CI, 5%-11%), respectively. Progression to metastatic cancer occurred in 21 participants and there were 3 prostate cancer-related deaths. The estimated rates of metastasis or prostate cancer-specific mortality at 10 years after diagnosis were 1.4% (95% CI, 0.7%-2%) and 0.1% (95% CI, 0%-0.4%), respectively; overall mortality in the same time period was 5.1% (95% CI, 3.8%-6.4%).

CONCLUSIONS AND RELEVANCE: In this study, 10 years after diagnosis, 49% of men remained free of progression or treatment, less than 2% developed metastatic disease, and less than 1% died of their disease. Later progression and treatment during surveillance were not associated with worse outcomes. These results demonstrate active surveillance as an effective management strategy for patients diagnosed with favorable-risk prostate cancer.

RevDate: 2024-05-31

Ghali F, Holt SK, Koehne EL, et al (2024)

Patterns of chemotherapy use with primary radiotherapy for localized bladder cancer in patients 65 or older.

Frontiers in oncology, 14:1341655.

INTRODUCTION: Bladder preservation with concurrent chemoradiotherapy after maximum transurethral resection of bladder tumor is an alternative to radical cystectomy in select patients with muscle invasive bladder cancer (MIBC). Concurrent administration of radio-sensitizing chemotherapy and radiation therapy (RT) has been shown to have superior disease control compared with RT alone and can often be administered with modest added toxicity. We sought to describe national patterns of chemotherapy use.

METHODS: The linked surveillance, epidemiology, and end results (SEER)-Medicare database was used to identify patients with cT2-4, N0/X, M0/X BC who received radiation between 2004 and 2018. Data on demographics, clinicopathologic factors, therapy and outcomes were extracted. Concurrent utilization of chemotherapy with RT was also identified (CRT). Multivariate logistic regression (MVA) models were used to explore factors associated with receipt of chemotherapy and overall survival (OS).

RESULTS: 2190 patients met inclusion criteria. Of these, 850 (38.8%) received no chemotherapy. Among those receiving chemotherapy, the most frequent regimens were single agent carboplatin, cisplatin, or gemcitabine. Factors that were independently associated with decreased likelihood of chemotherapy use were increasing age (OR 0.93, CI 0.92 - 0.95), Hispanic race (compared with White, OR 0.62, CI 0.39 - 0.99), cT3 or T4 (compared with cT2, OR 0.70, CI 0.55 - 0.90), and lower National Cancer Institute comorbidity index (OR 0.60, CI 0.51 - 0.70) (p < 0.05). Variables independently associated with increased likelihood of receipt of chemotherapy were married status (OR 1.28, CI 1.06 - 1.54), higher socioeconomic status (OR 1.31, CI 1.06 - 1.64), and later year of diagnosis (OR 1.09, CI 1.06 - 1.12). Receipt of concurrent chemotherapy with RT was associated with superior OS compared with RT alone.

CONCLUSION: Over a third of patients >/65 years old receiving curative-intent RT for MIBC do not receive concurrent chemotherapy. Considering the improvement in oncologic outcomes with CRT over RT alone and more options, such as low dose gemcitabine which can be administered with modest toxicity, efforts are needed to identify barriers to utilization and increase the use of radio-sensitizing chemotherapy.

RevDate: 2024-05-29

Rafati M, McReynolds LJ, Wang Y, et al (2024)

Hemophagocytic Lymphohistiocytosis Gene Variants in Severe Aplastic Anemia and Their Impact on Hematopoietic Cell Transplantation Outcomes.

Transplantation and cellular therapy pii:S2666-6367(24)00427-5 [Epub ahead of print].

BACKGROUND: Germline genetic testing for patients with severe aplastic anemia (SAA) is recommended to guide treatment, including the use of immunosuppressive therapy and/or adjustment of hematopoietic cell transplantation (HCT) modalities. Hemophagocytic lymphohistiocytosis (HLH) is a life threatening hyperinflammatory condition often associated with cytopenias with autosomal recessive (AR) or X-linked recessive (XLR) inheritance. HLH is part of the SAA differential diagnosis and genetic testing may identify variants in HLH genes in patients with SAA. The impact of pathogenic/likely pathogenic (P/LP) variants in HLH genes on HCT outcomes in SAA is unclear.

OBJECTIVES: We aimed to determine the frequency of HLH gene variants in a large cohort of patients with acquired SAA and to evaluate their association(s) with HCT outcomes.

STUDY DESIGN: The Transplant Outcomes in Aplastic Anemia project, a collaboration between the National Cancer Institute and the Center for International Blood and Marrow Transplant Research, consists of genomic and clinical data from 824 patients who underwent HCT for SAA between 1989 and 2015. We excluded 140 patients with inherited bone marrow failure syndromes and used exome sequencing data from the remaining 684 patients with acquired SAA to identify P/LP variants in 14 HLH-associated genes (11 AR, 3 XLR) curated using ACMG/AMP criteria. Deleterious variants of uncertain significance (del-VUS) were defined as those not meeting ACMG/AMP P/LP criteria but with damaging predictions in ≥3/5 meta-predictors (BayesDel, REVEL, CADD, MetaSVM and/or EIGEN). Kaplan-Meier estimator was used to calculate the probability of overall survival (OS) after HCT, and cumulative incidence calculator was used for other HCT outcomes accounting for relevant competing risks.

RESULTS: There were 46 HLH variants in 49 patients (7.2%; N total=684). Seventeen variants in 19 patients (2.8%) were P/LP; 8 of these were loss of function variants. Among 19 patients with P/LP HLH variants, 16 (84%) had monoallelic variants in genes with AR inheritance, and three had variants in XLR genes. PRF1 was the most frequently affected gene (8/19 patients). We found no statistically significant differences in transplant-related factors between patients with and without P/LP HLH variants. The 5-year survival probabilities were 89% (95% CI=72-99), and 70% (95% CI=53-85%) in patients with P/LP and del-VUS HLH variants, respectively, as compared with 66% (95% CI=62-70) in those without variants (p-log-rank=0.16). The median time to neutrophil engraftment was 16 days for patients with P/LP HLH variants versus 18 days in those with del-VUS or without variants, combined (p-Gray's test=0.01). No statistically significant associations between P/LP HLH variants and the risk of acute or chronic graft-versus-host disease were noted.

CONCLUSIONS: In this large cohort of acquired SAA, we found that 2.8% of patients harbor a P/LP variant in an HLH gene. No negative effect on post-HCT survival was noted with HLH gene variants. The small number of patients with P/LP HLH variants limit the study ability to provide conclusive evidence. Yet, our data suggest no need for special transplant considerations for patients with SAA carrying P/LP variants.

RevDate: 2024-05-31
CmpDate: 2024-05-29

Drew DA, Kim AE, Lin Y, et al (2024)

Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer.

Science advances, 10(22):eadk3121.

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.

RevDate: 2024-05-31

Gobbo M, Joy J, Guedes H, et al (2024)

Emerging pharmacotherapy trends in preventing and managing oral mucositis induced by chemoradiotherapy and targeted agents.

Expert opinion on pharmacotherapy [Epub ahead of print].

INTRODUCTION: The introduction of targeted therapy and immunotherapy has tremendously changed the clinical outcomes and prognosis of cancer patients. Despite innovative pharmacological therapies and improved radiotherapy (RT) techniques, patients continue to suffer from side effects, of which oral mucositis (OM) is still the most impactful, especially for quality of life.

AREAS COVERED: We provide an overview of current advances in cancer pharmacotherapy and RT, in relation to their potential to cause OM, and of the less explored and more recent literature reports related to the best management of OM. We have analyzed natural/antioxidant agents, probiotics, mucosal protectants and healing coadjuvants, pharmacotherapies, immunomodulatory and anticancer agents, photobiomodulation and the impact of technology.

EXPERT OPINION: The discovery of more precise pathophysiologic mechanisms of CT and RT-induced OM has outlined that OM has a multifactorial origin, including direct effects, oxidative damage, upregulation of immunologic factors, and effects on oral flora. A persistent upregulated immune response, associated with factors related to patients' characteristics, may contribute to more severe and long-lasting OM. The goal is strategies to conjugate individual patient, disease, and therapy-related factors to guide OM prevention or treatment. Despite further high-quality research is warranted, the issue of prevention is paramount in future strategies.

RevDate: 2024-05-31
CmpDate: 2024-05-28

Fitzgerald K, Stephan SB, Ma N, et al (2024)

Liquid foam improves potency and safety of gene therapy vectors.

Nature communications, 15(1):4523.

Interest in gene therapy medicines is intensifying as the first wave of gene-correcting drugs is now reaching patient populations. However, efficacy and safety concerns, laborious manufacturing protocols, and the high cost of the therapeutics are still significant barriers in gene therapy. Here we describe liquid foam as a vehicle for gene delivery. We demonstrate that embedding gene therapy vectors (nonviral or viral) in a methylcellulose/xanthan gum-based foam formulation substantially boosts gene transfection efficiencies in situ, compared to liquid-based gene delivery. We further establish that our gene therapy foam is nontoxic and retained at the intended target tissue, thus minimizing both systemic exposure and targeting of irrelevant cell types. The foam can be applied locally or injected to fill body cavities so the vector is uniformly dispersed over a large surface area. Our technology may provide a safe, facile and broadly applicable option in a variety of clinical settings.

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RJR Experience and Expertise

Researcher

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.

Educator

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.

Administrator

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.

Technologist

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.

Publisher

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.

Speaker

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.

Facilitator

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.

Designer

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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