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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 28 Mar 2024 at 01:49 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: 2024-03-26

Kim AE, Bennett JC, Luiten K, et al (2024)

Comparative diagnostic utility of SARS-CoV-2 rapid antigen and molecular testing in a community setting.

The Journal of infectious diseases pii:7635471 [Epub ahead of print].

BACKGROUND: SARS-CoV-2 antigen-detection rapid diagnostic tests (Ag-RDTs) have become widely utilized but longitudinal characterization of their community-based performance remains incompletely understood.

METHODS: This prospective longitudinal study at a large public university in Seattle, WA utilized remote enrollment, online surveys, and self-collected nasal swab specimens to evaluate Ag-RDT performance against real-time reverse transcription polymerase chain reaction (rRT-PCR) in the context of SARS-CoV-2 Omicron. Ag-RDT sensitivity and specificity within 1 day of rRT-PCR were evaluated by symptom status throughout the illness episode and Orf1b cycle threshold (Ct).

RESULTS: From February to December 2022, 5,757 participants reported 17,572 Ag-RDT results and completed 12,674 rRT-PCR tests, of which 995 (7.9%) were rRT-PCR-positive. Overall sensitivity and specificity were 53.0% (95% CI: 49.6-56.4%) and 98.8% (98.5-99.0%), respectively. Sensitivity was comparatively higher for Ag-RDTs used 1 day after rRT-PCR (69.0%), 4 to 7 days post-symptom onset (70.1%), and Orf1b Ct ≤20 (82.7%). Serial Ag-RDT sensitivity increased with repeat testing ≥2 (68.5%) and ≥4 (75.8%) days after an initial Ag-RDT-negative result.

CONCLUSION: Ag-RDT performance varied by clinical characteristics and temporal testing patterns. Our findings support recommendations for serial testing following an initial Ag-RDT-negative result, especially among recently symptomatic persons or those at high-risk for SARS-CoV-2 infection.

RevDate: 2024-03-26

Paredes MI, Perofsky AC, Frisbie L, et al (2024)

Local-scale phylodynamics reveal differential community impact of SARS-CoV-2 in a metropolitan US county.

PLoS pathogens, 20(3):e1012117 pii:PPATHOGENS-D-23-01656 [Epub ahead of print].

SARS-CoV-2 transmission is largely driven by heterogeneous dynamics at a local scale, leaving local health departments to design interventions with limited information. We analyzed SARS-CoV-2 genomes sampled between February 2020 and March 2022 jointly with epidemiological and cell phone mobility data to investigate fine scale spatiotemporal SARS-CoV-2 transmission dynamics in King County, Washington, a diverse, metropolitan US county. We applied an approximate structured coalescent approach to model transmission within and between North King County and South King County alongside the rate of outside introductions into the county. Our phylodynamic analyses reveal that following stay-at-home orders, the epidemic trajectories of North and South King County began to diverge. We find that South King County consistently had more reported and estimated cases, COVID-19 hospitalizations, and longer persistence of local viral transmission when compared to North King County, where viral importations from outside drove a larger proportion of new cases. Using mobility and demographic data, we also find that South King County experienced a more modest and less sustained reduction in mobility following stay-at-home orders than North King County, while also bearing more socioeconomic inequities that might contribute to a disproportionate burden of SARS-CoV-2 transmission. Overall, our findings suggest a role for local-scale phylodynamics in understanding the heterogeneous transmission landscape.

RevDate: 2024-03-26

Dalal PJ, Giro P, Rasmussen-Torvik LJ, et al (2024)

Heart Failure Risk Among African-American Women With an ICAM1 Missense Variant.

JACC. Heart failure pii:S2213-1779(24)00145-8 [Epub ahead of print].

BACKGROUND: A common genetic variant of ICAM1 among African-American individuals (rs5491; p.K56M) is associated with heart failure (HF) hospitalization, but whether this risk is specific to heart failure with preserved ejection fraction (HFpEF) remains unclear. Older women are at high risk for HFpEF, and the relationship between rs5491 and HFpEF across the age spectrum is unknown.

OBJECTIVES: This study assessed risk of HF and its subtypes conferred by ICAM1 p.K56M (rs5491).

METHODS: Associations of rs5491 with risk of HF and its subtypes were estimated among African American individuals in WHI (Women's Health Initiative). The study evaluated whether the association between rs5491 and HF hospitalizations was modified by baseline age. Subsequently, African-American women in WHI and MESA (Multi-Ethnic Study of Atherosclerosis) were pooled and analyses were repeated.

RESULTS: Among 8,401 women in WHI, the minor allele frequency of rs5491 was 20.7%, and 731 HF hospitalizations occurred over 19.2 years. The rs5491 variant was not associated with HF or its subtypes across WHI. Interaction analyses suggested that age as a continuous variable modified the association of rs5491 with HFpEF hospitalization (interaction P = 0.04). Upon categorizing women into age decades, rs5491 conferred increased risk of HFpEF among women ≥70 years (HR per additional rs5491 allele: 1.82 [95% CI: 1.25-2.65]; P = 0.002) but was not associated with HFpEF risk among women <70 years. Pooling African-American women in WHI (n = 8,401) and MESA (n = 856) demonstrated that the effect modification by age on the association of rs5491 with HFpEF became more significant (interaction P = 0.009), with consistent HFpEF risk effect estimates among women ≥70 years.

CONCLUSIONS: ICAM1 p.K56M (rs5491) is associated with HFpEF among African-American women ≥70 years.

RevDate: 2024-03-26

Ekwe AP, Au R, Zhang P, et al (2024)

Clinical grade multiparametric cell sorting and gene-marking of regulatory T cells.

Cytotherapy pii:S1465-3249(24)00066-5 [Epub ahead of print].

BACKGROUND AIMS: Regulatory T cells (Tregs) are the main mediators of peripheral tolerance. Treg-directed therapy has shown promising results in preclinical studies of diverse immunopathologies. At present, the clinical applicability of adoptive Treg transfer is limited by difficulties in generating Tregs at sufficient cell dose and purity.

METHODS: We developed a Good Manufacturing Practice (GMP) compliant method based on closed-system multiparametric Fluorescence-Activated Cell Sorting (FACS) to purify Tregs, which are then expanded in vitro and gene-marked with a clinical grade retroviral vector to enable in vivo fate tracking. Following small-scale optimization, we conducted four clinical-scale processing runs.

RESULTS: We showed that Tregs could be enriched to 87- 92% purity following FACS-sorting, and expanded and transduced to yield clinically relevant cell dose of 136-732×10[6] gene-marked cells, sufficient for a cell dose of at least 2 × 10[6] cells/kg. The expanded Tregs were highly demethylated in the FOXP3 Treg-specific demethylated region (TSDR), consistent with bona fide natural Tregs. They were suppressive in vitro, but a small percentage could secrete proinflammatory cytokines, including interferon-γ and interleukin-17A.

CONCLUSIONS: This study demonstrated the feasibility of isolating, expanding and gene-marking Tregs in clinical scale, thus paving the way for future phase I trials that will advance knowledge about the in vivo fate of transferred Tregs and its relationship with concomitant Treg-directed pharmacotherapy and clinical response.

RevDate: 2024-03-26

Ball A, Hadland S, Rodean J, et al (2024)

Trends in Substance-Related Visits Among Youth to US Children's Hospitals, 2016-2021: An Analysis of the Pediatric Health Information System Database.

The Journal of adolescent health : official publication of the Society for Adolescent Medicine pii:S1054-139X(24)00106-X [Epub ahead of print].

PURPOSE: This study evaluates recent trends in substance-related visits among youth visiting children's hospitals.

METHODS: We conducted a cross-sectional study of substance-related visits to pediatric hospitals within the Pediatric Health Information System database of youth aged 12-21 years from 2016 through 2021. Substance-related visits were defined as acute visits for International Classification of Diseases, 10th Revision Clinical Modification codes related to substance 'use', dependence, or overdoses for alcohol, cannabis, nicotine, opioids, sedatives, stimulants, hallucinogens, or other substances. Cumulative growth rate and stratified substance-related trends were calculated using generalized estimating equations. Predicted number of visits during the COVID-19 pandemic was generated using an auto-regressive time series analysis.

RESULTS: There were 106,793 substance-related visits involving 84,632 youth. From 2016 to 2021, substance-related visits increased by 47.9% and increased across all ages, demographics, regions, and payors. Visits of Hispanic youth experienced the greatest percentage growth (63.3%, p < .05) when compared to Non-Hispanic (NH) White (46.2%) or NH Black (49.8%) youth. All substances except sedatives experienced an increase in growth in visits. Cannabis accounted for the largest percentage of visits (52.2%) and experienced the greatest percentage growth during the study period (82.4%, p < .001). During the pandemic, publicly insured, female, NH Black, and Hispanic youth experienced a greater-than-predicted number of substance-related visits.

DISCUSSION: Substance-related visits to children's hospitals are increasing for all demographics and nearly all substances. There were substantial increases in visits for most minoritized youth with a disproportionate rise among Hispanic youth. Visits over the pandemic were concentrated among publicly insured, female, NH Black, and Hispanic youth. Equitable large-scale investment is needed to address the rising morbidity of substance use among adolescents.

RevDate: 2024-03-27
CmpDate: 2024-03-27

Larsen EL, Nilius H, Studt JD, et al (2024)

Accuracy of Diagnosing Heparin-Induced Thrombocytopenia.

JAMA network open, 7(3):e243786 pii:2816742.

IMPORTANCE: Heparin-induced thrombocytopenia (HIT) is a life-threatening condition that requires urgent diagnostic clarification. However, knowledge of the diagnostic utility of the recommended diagnostic tests is limited in clinical practice.

OBJECTIVE: To evaluate the current diagnostic practice for managing the suspicion of HIT.

This prospective diagnostic study was conducted from January 2018 to May 2021 among consecutive patients with suspected HIT from 11 study centers in Switzerland, Germany, and the United States. Detailed clinical data and laboratory information were recorded. Platelet factor 4/heparin antibodies were quantified using an automated chemiluminescent immunoassay (CLIA). A washed-platelet heparin-induced platelet activation (HIPA) test was used as a reference standard to define HIT.

EXPOSURES: Suspicion of HIT.

MAIN OUTCOMES AND MEASURES: The primary outcome was the diagnostic accuracy of the 4Ts score, the CLIA, and the recommended algorithm serially combining both tests.

RESULTS: Of 1448 patients included between 2018 and 2021, 1318 were available for the current analysis (median [IQR] age, 67 [57-75] years; 849 [64.6%] male). HIPA was positive in 111 patients (prevalence, 8.4%). The most frequent setting was intensive care unit (487 [37.0%]) or cardiovascular surgery (434 [33.0%]). The 4Ts score was low risk in 625 patients (46.8%). By 2 × 2 table, the numbers of patients with false-negative results were 10 (9.0%; 4Ts score), 5 (4.5%; CLIA), and 15 (13.5%; recommended diagnostic algorithm). The numbers of patients with false-positive results were 592 (49.0%; 4Ts score), 73 (6.0%; CLIA), and 50 (4.1%; recommended diagnostic algorithm), respectively.

CONCLUSIONS AND RELEVANCE: In this diagnostic study of patients suspected of having HIT, when the recommended diagnostic algorithm was used in clinical practice, antibody testing was required in half the patients. A substantial number of patients were, however, still misclassified, which could lead to delayed diagnosis or overtreatment. Development of improved diagnostic algorithms for HIT diagnosis should be pursued.

RevDate: 2024-03-27
CmpDate: 2024-03-27

Uechi L, Vasudevan S, Vilenski D, et al (2024)

Transcriptome free energy can serve as a dynamic patient-specific biomarker in acute myeloid leukemia.

NPJ systems biology and applications, 10(1):32.

Acute myeloid leukemia (AML) is prevalent in both adult and pediatric patients. Despite advances in patient categorization, the heterogeneity of AML remains a challenge. Recent studies have explored the use of gene expression data to enhance AML diagnosis and prognosis, however, alternative approaches rooted in physics and chemistry may provide another level of insight into AML transformation. Utilizing publicly available databases, we analyze 884 human and mouse blood and bone marrow samples. We employ a personalized medicine strategy, combining state-transition theory and surprisal analysis, to assess the RNA transcriptome of individual patients. The transcriptome is transformed into physical parameters that represent each sample's steady state and the free energy change (FEC) from that steady state, which is the state with the lowest free energy.We found the transcriptome steady state was invariant across normal and AML samples. FEC, representing active molecular processes, varied significantly between samples and was used to create patient-specific barcodes to characterize the biology of the disease. We discovered that AML samples that were in a transition state had the highest FEC. This disease state may be characterized as the most unstable and hence the most therapeutically targetable since a change in free energy is a thermodynamic requirement for disease progression. We also found that distinct sets of ongoing processes may be at the root of otherwise similar clinical phenotypes, implying that our integrated analysis of transcriptome profiles may facilitate a personalized medicine approach to cure AML and restore a steady state in each patient.

RevDate: 2024-03-27

Wang M, Krueger JB, Gilkey AK, et al (2024)

Precision Enhancement of CAR-NK Cells through Non-Viral Engineering and Highly Multiplexed Base Editing.

bioRxiv : the preprint server for biology.

Natural killer (NK) cells' unique ability to kill transformed cells expressing stress ligands or lacking major histocompatibility complexes (MHC) has prompted their development for immunotherapy. However, NK cells have demonstrated only moderate responses against cancer in clinical trials and likely require advanced genome engineering to reach their full potential as a cancer therapeutic. Multiplex genome editing with CRISPR/Cas9 base editors (BE) has been used to enhance T cell function and has already entered clinical trials but has not been reported in human NK cells. Here, we report the first application of BE in primary NK cells to achieve both loss-of-function and gain-of-function mutations. We observed highly efficient single and multiplex base editing, resulting in significantly enhanced NK cell function. Next, we combined multiplex BE with non-viral TcBuster transposon-based integration to generate IL-15 armored CD19 CAR-NK cells with significantly improved functionality in a highly suppressive model of Burkitt's lymphoma both in vitro and in vivo. The use of concomitant non-viral transposon engineering with multiplex base editing thus represents a highly versatile and efficient platform to generate CAR-NK products for cell-based immunotherapy and affords the flexibility to tailor multiple gene edits to maximize the effectiveness of the therapy for the cancer type being treated.

RevDate: 2024-03-24

Parikh M, Tangen C, Hussain MHA, et al (2024)

Three- and Seven-month Prostate-specific Antigen Levels as Prognostic Markers for Overall Survival in Metastatic Hormone-sensitive Prostate Cancer: Results from SWOG S1216, a Phase 3 Randomized Trial of Androgen Deprivation Plus Orteronel or Bicalutamide.

European urology oncology pii:S2588-9311(24)00054-3 [Epub ahead of print].

BACKGROUND: A robust decrease in prostate-specific antigen (PSA) in response to androgen deprivation therapy (ADT) has been evaluated as a prognostic factor in patients with metastatic hormone-sensitive prostate cancer (mHSPC) since 2006, but the treatment of mHSPC has since evolved to include intensified therapy.

OBJECTIVE: We assessed the association of PSA levels at 3 (PSA-3mo) and 7 (PSA-7mo) mo with overall survival (OS) in patients with mHSPC treated with ADT combined with either bicalutamide or orteronel in the S1216 phase 3 clinical trial.

PSA responses to treatment of patients in the S1216 trial were categorized as: complete response (CR) if PSA was ≤0.2 ng/ml, partial response if PSA was >0.2 and ≤4 ng/ml, and no response (NR) if PSA was >4 ng/ml.

A Cox analysis (adjusted for treatment arm and three stratification factors: performance status, severity of disease, and early vs late induction) was used for OS association. While PSA-7mo association was a prespecified objective, PSA-3mo association was also evaluated.

RESULTS AND LIMITATIONS: A total of 1251 and 1231 patients from the S1216 study were evaluable for PSA-3mo and PSA-7mo, respectively. A PSA-7mo CR was associated with improved OS compared with NR (HR: 0.20; p < 0.0001). A PSA-3mo CR showed a similar association to NR (HR: 0.34; p < 0.0001). The association of a PSA response with survival did not differ by treatment arm at either time point.

CONCLUSIONS: The PSA-3mo and PSA-7mo responses were strongly associated with OS; taken with other emerging prognostic biomarkers, these markers may allow for early identification of patients at the highest risk of death, aid with counseling in clinical practice, and permit design of future clinical trials targeting these patients.

PATIENT SUMMARY: A low prostate-specific antigen level at 3 or 7 mo after starting treatment for metastatic hormone-sensitive prostate cancer predicts longer survival regardless of the first treatment given with androgen deprivation therapy.

RevDate: 2024-03-23

Tomasin R, CM Ghajar (2024)

Poised epigenetic states dictate metastatic fitness.

Trends in cancer pii:S2405-8033(24)00050-5 [Epub ahead of print].

Seeking to define early events that regulate disseminated tumor cell (DTC) fate upon their arrival to the lung, Jakab et al. reach the surprising conclusion that dormancy is determined by a cell autonomous poised epigenetic state that renders DTCs responsive to angiocrine Wnt signaling.

RevDate: 2024-03-23

Banerjee R, Cowan AJ, Ortega M, et al (2024)

Financial Toxicity, Time Toxicity, and Quality of Life in Multiple Myeloma.

Clinical lymphoma, myeloma & leukemia pii:S2152-2650(24)00090-9 [Epub ahead of print].

BACKGROUND: Patients with multiple myeloma (MM) may be on therapy for years, which can lead to financial toxicity (FinTox) or time toxicity (TimeTox). The prevalence, predictors, and quality of life (QOL) impacts of FinTox and TimeTox during different phases of MM treatment have not been characterized.

PATIENTS AND METHODS: We conducted a single-center cross-sectional survey of patients with MM who had undergone transplantation. FinTox+ was defined as a COST-FACIT score <23, TimeTox+ as MM-related interactions (including phone calls) ≥1x weekly or ≥1x monthly in-person among far-residing patients, QOL using PROMIS Global Health, and functional status using patient-reported Karnofsky performance status (KPS).

RESULTS: Of 252 patients, 22% and 40% met FinTox+ and TimeTox+ criteria respectively. Respective FinTox+ and TimeTox+ proportions were 22%/37% for patients on maintenance, 22%/82% with active therapy, and 20%/14% with observation. FinTox+ predictors included annual income (P < .01) and out-of-pocket costs (P < .01). TimeTox+ predictors included disease status (P < .001), caregiver status (P = .01), far-residing status (P < .001), and out-of-pocket costs (P = .03). FinTox+ was associated with a clinically meaningful decrease in mental QOL, while TimeTox+ patients were more likely to have KPS ≤ 80.

CONCLUSIONS: In our large study, monetary status but not disease status predicted FinTox. Over a third of patients on maintenance reported TimeTox. FinTox+ was associated with decreased mental health, while TimeTox+ was associated with worse performance status. These two toxicities may negatively impact patient wellbeing, and studies of strategies to mitigate their impact are in development.

RevDate: 2024-03-23

Ho CC, Naresh K, Liu Y, et al (2024)

Assessment for 11q and other chromosomal aberrations in large B-cell/high-grade B cell lymphomas of germinal center phenotype lacking BCL2 expression.

Cancer genetics, 284-285:30-33 pii:S2210-7762(24)00002-4 [Epub ahead of print].

The WHO classifications of hematolymphoid malignancies have recognized several distinct entities within the large B cell lymphomas, including the more recently described high-grade B cell lymphoma with 11q aberration (HGBCL-11q). We utilized genomic array to assess for chromosome 11q abnormalities in a broad set of aggressive B cell lymphomas from 27 patients with a focus on younger adults. The findings suggest more frequent alterations of 11q in diffuse large B cell lymphoma (DLBCL)/HGBCL-GC BCL2-, in comparison to cases of Burkitt lymphoma (BL) or DLBCL-GC BCL2+, and confirm a low genomic complexity score of BL. Variability identified in patterns of 11q alterations suggests genomic array studies may afford value over FISH testing as we continue to understand HGBCL-11q as a distinct entity, and interrogate cases of DLBCL/HGBCL-GC BCL2-.

RevDate: 2024-03-23

Konecny AJ, Huang Y, Setty M, et al (2024)

Signals that control MAIT cell function in healthy and inflamed human tissues.

Immunological reviews [Epub ahead of print].

Mucosal-associated invariant T (MAIT) cells have a semi-invariant T-cell receptor that allows recognition of antigen in the context of the MHC class I-related (MR1) protein. Metabolic intermediates of the riboflavin synthesis pathway have been identified as MR1-restricted antigens with agonist properties. As riboflavin synthesis occurs in many bacterial species, but not human cells, it has been proposed that the main purpose of MAIT cells is antibacterial surveillance and protection. The majority of human MAIT cells secrete interferon-gamma (IFNg) upon activation, while some MAIT cells in tissues can also express IL-17. Given that MAIT cells are present in human barrier tissues colonized by a microbiome, MAIT cells must somehow be able to distinguish colonization from infection to ensure effector functions are only elicited when necessary. Importantly, MAIT cells have additional functional properties, including the potential to contribute to restoring tissue homeostasis by expression of CTLA-4 and secretion of the cytokine IL-22. A recent study provided compelling data indicating that the range of human MAIT cell functional properties is explained by plasticity rather than distinct lineages. This further underscores the necessity to better understand how different signals regulate MAIT cell function. In this review, we highlight what is known in regards to activating and inhibitory signals for MAIT cells with a specific focus on signals relevant to healthy and inflamed tissues. We consider the quantity, quality, and the temporal order of these signals on MAIT cell function and discuss the current limitations of computational tools to extrapolate which signals are received by MAIT cells in human tissues. Using lessons learned from conventional CD8 T cells, we also discuss how TCR signals may integrate with cytokine signals in MAIT cells to elicit distinct functional states.

RevDate: 2024-03-23

Ton M, Newcomb PA, Jones S, et al (2024)

Cannabis use after a cancer diagnosis in a population-based sample of cancer survivors.

Cancer causes & control : CCC [Epub ahead of print].

PURPOSE: This study aimed to characterize the prevalence and correlates of cannabis use and the methods and reasons for use among recently diagnosed cancer survivors in a population sample within Washington state.

METHODS: We identified individuals diagnosed with invasive cancers in the prior 6 to 17 months from April 2020 to December 2020 using the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) cancer registry. Participants (n = 1,515) completed a questionnaire, including demographics, medical history, cannabis use, and other substance use. Cancer characteristics and date of diagnosis were obtained from SEER registry data. We calculated weighted prevalence estimates and logistic regression models to evaluate correlates of cannabis use.

RESULTS: Overall, 41.3% of survivors reported cannabis use at any time after diagnosis, most commonly via edibles (60.5%) and smoking (43.8%). The most frequently reported reasons for use were sleep (54.5%), mood, stress, anxiety, and depression (44.3%), pain (42.3%), and recreation (42.3%). Cannabis use was associated with younger age, race (White vs. Asian), less education, former or current smoking, consuming more than 2 alcohol-containing drinks per day, having late-stage cancer, and cancer site.

CONCLUSION: In this first evaluation of cannabis use in a registry-linked, population-based sample of survivors of all cancer types, based in a state where recreational and medical cannabis have been legal for a decade, approximately 2 in 5 survivors reported post-diagnosis use. Given how common cannabis use is among cancer survivors, there is a great need to understand its impact on cancer treatment outcomes and the overall health of cancer survivors.

RevDate: 2024-03-25
CmpDate: 2024-03-25

Hoff FW, Banerjee R, Khan AM, et al (2024)

Once-weekly versus twice-weekly bortezomib in newly diagnosed multiple myeloma: a real-world analysis.

Blood cancer journal, 14(1):52.

Induction regimens for multiple myeloma (MM) commonly include bortezomib, which has typically been administered twice weekly despite studies demonstrating comparable efficacy and less peripheral neuropathy (PN) with once-weekly bortezomib. We aimed to analyze the real-world prevalence and efficacy of once-weekly versus twice-weekly bortezomib regimens in newly diagnosed MM. We analyzed 2497 US patients aged 18-70 years treated with commercial first-line bortezomib using nationwide Flatiron Health electronic health record-derived data, including 910 (36.4%) patients who received twice-weekly and 1522 (63.2%) who received once-weekly bortezomib. Once-weekly bortezomib use increased over time, from 57.7% in 2017 to 73.1% in 2022. Multivariate analysis identified worsened performance status and more recent year of diagnosis with higher odds of receiving once-weekly bortezomib. Real-world progression-free survival (median 37.2 months with once-weekly versus 39.6 months with twice-weekly, p = 0.906) and overall survival (medians not reached in either cohort, p = 0.800) were comparable. PN rates were higher in patients receiving twice-weekly bortezomib (34.7% versus 18.5%, p < 0.001). In conclusion, once-weekly bortezomib is clearly associated with similar efficacy and fewer toxicities compared to twice-weekly bortezomib. Our findings support once-weekly bortezomib as a standard-of-care regimen for newly diagnosed patients with MM.

RevDate: 2024-03-25

Lin L, Huang Y, McIntyre J, et al (2024)

Prevalent fast evolution of genes involved in heterochromatin functions.

bioRxiv : the preprint server for biology.

Heterochromatin is a gene-poor and repeat-rich genomic compartment ubiquitously found in eukaryotes. Despite its low transcriptional activity, heterochromatin plays important roles in maintaining genome stability, organizing chromosomes, and suppressing transposable elements (TEs). Given the importance of these functions, it is expected that the genes involved in heterochromatin regulation would be highly conserved. Yet, a handful of these genes have been found to evolve rapidly. To investigate whether these previous findings are anecdotal or general to genes modulating heterochromatin, we compiled an exhaustive list of 106 candidate genes involved in heterochromatin functions and investigated their evolution over both short and long evolutionary time scales in Drosophila. Our analyses found that these genes exhibit significantly more frequent evolutionary changes, both in the forms of amino acid substitutions and gene copy number variation, when compared to genes involved in Polycomb-based repressive chromatin. While positive selection drives amino acid changes within both structured domains with diverse functions and irregular disordered regions (IDRs), purifying selection may have maintained the proportions of IDRs. Together with the observed negative associations between rates of protein evolution of these genes and genomic TE abundance, we propose an evolutionary model where the fast evolution of genes involved in heterochromatin functions is an inevitable outcome of the unique molecular features of the heterochromatin environment, while the rapid evolution of TEs may be an effect rather than cause. Our study provides an important global view of the evolution of genes involved in this critical cellular domain and provides insights into the factors driving the distinctive evolution of heterochromatin.

RevDate: 2024-03-25

Müller NF, Bouckaert RR, Wu CH, et al (2024)

MASCOT-Skyline integrates population and migration dynamics to enhance phylogeographic reconstructions.

bioRxiv : the preprint server for biology.

The spread of infectious diseases is shaped by spatial and temporal aspects, such as host population structure or changes in the transmission rate or number of infected individuals over time. These spatiotemporal dynamics are imprinted in the genome of pathogens and can be recovered from those genomes using phylodynamics methods. However, phylodynamic methods typically quantify either the temporal or spatial transmission dynamics, which leads to unclear biases, as one can potentially not be inferred without the other. Here, we address this challenge by introducing a structured coalescent skyline approach, MASCOT-Skyline that allows us to jointly infer spatial and temporal transmission dynamics of infectious diseases using Markov chain Monte Carlo inference. To do so, we model the effective population size dynamics in different locations using a non-parametric function, allowing us to approximate a range of population size dynamics. We show, using a range of different viral outbreak datasets, potential issues with phylogeographic methods. We then use these viral datasets to motivate simulations of outbreaks that illuminate the nature of biases present in the different phylogeographic methods. We show that spatial and temporal dynamics should be modeled jointly even if one seeks to recover just one of the two. Further, we showcase conditions under which we can expect phylogeographic analyses to be biased, particularly different subsampling approaches, as well as provide recommendations of when we can expect them to perform well. We implemented MASCOT-Skyline as part of the open-source software package MASCOT for the Bayesian phylodynamics platform BEAST2.

RevDate: 2024-03-23

Reeves DB, Mayer BT, deCamp AC, et al (2024)

Author Correction: High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials.

Nature communications, 15(1):2575 pii:10.1038/s41467-024-46805-8.

RevDate: 2024-03-22

Jones SMW, BJ Weiner (2024)

Reliability and validity of intervention characteristic measures for assessing barriers to evidence-based practice use.

Translational behavioral medicine pii:7633896 [Epub ahead of print].

Assessing barriers before implementing an evidence-based practice can increase the chances of successful implementation. This project evaluated measures of intervention characteristics that could affect implementation: evidence strength and quality; relative advantage; adaptability; trialability; complexity; design quality and packaging; perceived cost; compatibility; observability; risk; and burden. Measures (109 items total) for each intervention characteristic were developed in a previous study, using prior measures, and expert feedback. Measures were scored such that higher scores meant a more positive view. Healthcare personnel implementing a new practice (n = 175) completed two surveys, 1 month apart. Participants completed the intervention characteristic item banks and questions on the use of the evidence-based practice. Reliability and validity were assessed for each item bank. All measures had Cronbach's alphas over 0.7 (range: 0.700-0.932) indicating good reliability. Frequent users of the practice reported better levels of each determinant at the first (Cohen's d range: -0.239 to -0.687) and second surveys (Cohen's d range: -0.043 to -1.081) except for costs (0.096) with use on the second survey. This preliminary test of measures to assess determinants of implementing evidence-based practice supports the validity and reliability of these tools. Additional studies are needed to further test the psychometric properties of the measures and develop short forms of each intervention characteristic measure.

RevDate: 2024-03-22

Roche SD, Were D, Crawford ND, et al (2024)

Getting HIV Pre-exposure Prophylaxis (PrEP) into Private Pharmacies: Global Delivery Models and Research Directions.

Current HIV/AIDS reports [Epub ahead of print].

PURPOSE OF REVIEW: To provide an overview of the current state of HIV pre-exposure prophylaxis (PrEP) delivery via private sector pharmacies globally, to discuss the context-specific factors that have influenced the design and implementation of different pharmacy-based PrEP delivery models in three example settings, and to identify future research directions.

RECENT FINDINGS: Multiple high- and low-income countries are implementing or pilot testing PrEP delivery via private pharmacies using a variety of delivery models, tailored to the context. Current evidence indicates that pharmacy-based PrEP services are in demand and generally acceptable to clients and pharmacy providers. Additionally, the evidence suggests that with proper training and oversight, pharmacy providers are capable of safely initiating and managing clients on PrEP. The delivery of PrEP services at private pharmacies also achieves similar levels of PrEP initiation and continuation as traditional health clinics, but additionally reach individuals underserved by such clinics (e.g., young men; minorities), making pharmacies well-positioned to increase overall PrEP coverage. Implementation of pharmacy-based PrEP services will look different in each context and depend not only on the state of the private pharmacy sector, but also on the extent to which key needs related to governance, financing, and regulation are addressed. Private pharmacies are a promising delivery channel for PrEP in diverse settings. Countries with robust private pharmacy sectors and populations at HIV risk should focus on aligning key areas related to governance, financing, and regulation that have proven critical to pharmacy-based PrEP delivery while pursuing an ambitious research agenda to generate information for decision-making. Additionally, the nascency of pharmacy-based PrEP delivery in both high- and low-and-middle-income settings presents a prime opportunity for shared learning and innovation.

RevDate: 2024-03-21

Ma RK, Tsai PY, Farghli AR, et al (2024)

DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma.

PLoS genetics, 20(3):e1011216 pii:PGENETICS-D-23-01036 [Epub ahead of print].

Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long noncoding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells. We show by loss- and gain-of-function studies that LINC00473 suppresses apoptosis, increases the expression of FLC marker genes, and promotes FLC growth in cell-based and in vivo disease models. Mechanistically, LINC00473 plays an important role in promoting glycolysis and altering mitochondrial activity. Specifically, LINC00473 knockdown leads to increased spare respiratory capacity, which indicates mitochondrial fitness. Overall, we propose that LINC00473 could be a viable target for this devastating disease. Schematic was created with BioRender.com.

RevDate: 2024-03-22
CmpDate: 2024-03-22

Zhang J (2024)

How Can a Global Experience Enkindle a Passion for Oncology Nursing?.

Clinical journal of oncology nursing, 28(2):232.

I have had a broad global life experience. I was born in China and at the age of 11 years, my family decided that going to live with relatives in the United States was the best thing for me. I had to learn a new culture and l.

RevDate: 2024-03-22
CmpDate: 2024-03-22

Eisenberg S, Walton A, TH Connor (2024)

The Occupational and Environmental Hazards of Uncovered Toilets.

The American journal of nursing, 124(4):55-60.

Substantial evidence demonstrates that plumes from uncovered toilets potentially expose nurses and other health care workers to aerosols containing infectious agents and hazardous drugs, including antineoplastic drugs. Most hospitals in the United States utilize flushometer-type toilets, which operate under high pressure and do not have a permanently attached closure or lid, which is known to reduce the aerosols generated by flushing. This article aims to raise awareness among nurses of the potential exposure risks associated with toilet plume aerosols, so they can educate other health care workers and take part in initiatives to address these risks.

RevDate: 2024-03-22

Hammoud RA, Mulrooney DA, Rhea IB, et al (2024)

Modifiable Cardiometabolic Risk Factors in Survivors of Childhood Cancer: JACC: CardioOncology State-of-the-Art Review.

JACC. CardioOncology, 6(1):16-32.

The growing community of childhood cancer survivors faces a heavy burden of late onset morbidities and mortality, with cardiovascular diseases being the leading noncancer cause. In addition to demographics and cancer treatment exposures, which cannot be altered, cardiometabolic risk factors (obesity, hypertension, diabetes, and dyslipidemia) and frailty potentiate the risk of morbidity and mortality associated with chronic health conditions. Important opportunities exist to target these risk factors and improve late health outcomes for survivors. Unfortunately, limited evidence exists on the optimal methods to prevent, screen, and treat cardiometabolic risk factors among survivors, resulting in significant underdiagnosis and undertreatment. In this review, we discuss the prevalence of, risk factors for, current survivor-specific recommendations, and gaps in knowledge to mitigate potentially modifiable cardiometabolic risk factors and frailty among survivors of childhood cancer.

RevDate: 2024-03-21

Zepeda-Rivera M, Minot SS, Bouzek H, et al (2024)

A distinct Fusobacterium nucleatum clade dominates the colorectal cancer niche.

Nature [Epub ahead of print].

Fusobacterium nucleatum (Fn), a bacterium present in the human oral cavity and rarely found in the lower gastrointestinal tract of healthy individuals[1], is enriched in human colorectal cancer (CRC) tumours[2-5]. High intratumoural Fn loads are associated with recurrence, metastases and poorer patient prognosis[5-8]. Here, to delineate Fn genetic factors facilitating tumour colonization, we generated closed genomes for 135 Fn strains; 80 oral strains from individuals without cancer and 55 unique cancer strains cultured from tumours from 51 patients with CRC. Pangenomic analyses identified 483 CRC-enriched genetic factors. Tumour-isolated strains predominantly belong to Fn subspecies animalis (Fna). However, genomic analyses reveal that Fna, considered a single subspecies, is instead composed of two distinct clades (Fna C1 and Fna C2). Of these, only Fna C2 dominates the CRC tumour niche. Inter-Fna analyses identified 195 Fna C2-associated genetic factors consistent with increased metabolic potential and colonization of the gastrointestinal tract. In support of this, Fna C2-treated mice had an increased number of intestinal adenomas and altered metabolites. Microbiome analysis of human tumour tissue from 116 patients with CRC demonstrated Fna C2 enrichment. Comparison of 62 paired specimens showed that only Fna C2 is tumour enriched compared to normal adjacent tissue. This was further supported by metagenomic analysis of stool samples from 627 patients with CRC and 619 healthy individuals. Collectively, our results identify the Fna clade bifurcation, show that specifically Fna C2 drives the reported Fn enrichment in human CRC and reveal the genetic underpinnings of pathoadaptation of Fna C2 to the CRC niche.

RevDate: 2024-03-22
CmpDate: 2024-03-22

Slamon D, Lipatov O, Nowecki Z, et al (2024)

Ribociclib plus Endocrine Therapy in Early Breast Cancer.

The New England journal of medicine, 390(12):1080-1091.

BACKGROUND: Ribociclib has been shown to have a significant overall survival benefit in patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. Whether this benefit in advanced breast cancer extends to early breast cancer is unclear.

METHODS: In this international, open-label, randomized, phase 3 trial, we randomly assigned patients with HR-positive, HER2-negative early breast cancer in a 1:1 ratio to receive ribociclib (at a dose of 400 mg per day for 3 weeks, followed by 1 week off, for 3 years) plus a nonsteroidal aromatase inhibitor (NSAI; letrozole at a dose of 2.5 mg per day or anastrozole at a dose of 1 mg per day for ≥5 years) or an NSAI alone. Premenopausal women and men also received goserelin every 28 days. Eligible patients had anatomical stage II or III breast cancer. Here we report the results of a prespecified interim analysis of invasive disease-free survival, the primary end point; other efficacy and safety results are also reported. Invasive disease-free survival was evaluated with the use of the Kaplan-Meier method. The statistical comparison was made with the use of a stratified log-rank test, with a protocol-specified stopping boundary of a one-sided P-value threshold of 0.0128 for superior efficacy.

RESULTS: As of the data-cutoff date for this prespecified interim analysis (January 11, 2023), a total of 426 patients had had invasive disease, recurrence, or death. A significant invasive disease-free survival benefit was seen with ribociclib plus an NSAI as compared with an NSAI alone. At 3 years, invasive disease-free survival was 90.4% with ribociclib plus an NSAI and 87.1% with an NSAI alone (hazard ratio for invasive disease, recurrence, or death, 0.75; 95% confidence interval, 0.62 to 0.91; P = 0.003). Secondary end points - distant disease-free survival and recurrence-free survival - also favored ribociclib plus an NSAI. The 3-year regimen of ribociclib at a 400-mg starting dose plus an NSAI was not associated with any new safety signals.

CONCLUSIONS: Ribociclib plus an NSAI significantly improved invasive disease-free survival among patients with HR-positive, HER2-negative stage II or III early breast cancer. (Funded by Novartis; NATALEE ClinicalTrials.gov number, NCT03701334.).

RevDate: 2024-03-20

Uo T, Ojo KK, Sprenger CCT, et al (2024)

A Compound that Inhibits Glycolysis in Prostate Cancer Controls Growth of Advanced Prostate Cancer.

Molecular cancer therapeutics pii:741918 [Epub ahead of print].

Metastatic castration-resistant prostate cancer remains incurable regardless of recent therapeutic advances. Prostate cancer tumors display highly glycolytic phenotypes as the cancer progresses. Non-specific inhibitors of glycolysis have not been utilized successfully for chemotherapy, because of their penchant to cause systemic toxicity. This study reports the preclinical activity, safety, and pharmacokinetics of a novel small molecule preclinical candidate, BKIDC-1553, with antiglycolytic activity. We tested a large battery of prostate cancer cell lines for inhibition of cell proliferation, in vitro. Cell cycle, metabolic and enzymatic assays were used to demonstrate their mechanism of action. A human PDX model implanted in mice and a human organoid were studied for sensitivity to our BKIDC preclinical candidate. A battery of pharmacokinetic experiments, absorption, distribution, metabolism, and excretion experiments, and in vitro and in vivo toxicology experiments were carried out to assess readiness for clinical trials. We demonstrate a new class of small molecule inhibitors where antiglycolytic activity in prostate cancer cell lines is mediated through inhibition of hexokinase 2. These compounds display selective growth inhibition across multiple prostate cancer models. We describe a lead BKIDC-1553 that demonstrates promising activity in a preclinical xenograft model of advanced prostate cancer, equivalent to that of enzalutamide. BKIDC-1553 demonstrates safety and pharmacologic properties consistent with a compound that can be taken into human studies with expectations of a good safety margin and predicted dosing for efficacy. This work supports testing BKIDC-1553 and its derivatives in clinical trials for patients with advanced prostate cancer.

RevDate: 2024-03-22

Loes AN, Tarabi RAL, Huddleston J, et al (2024)

High-throughput sequencing-based neutralization assay reveals how repeated vaccinations impact titers to recent human H1N1 influenza strains.

bioRxiv : the preprint server for biology.

The high genetic diversity of influenza viruses means that traditional serological assays have too low throughput to measure serum antibody neutralization titers against all relevant strains. To overcome this challenge, we have developed a sequencing-based neutralization assay that simultaneously measures titers against many viral strains using small serum volumes via a workflow similar to traditional neutralization assays. The key innovation is to incorporate unique nucleotide barcodes into the hemagglutinin (HA) genomic segment, and then pool viruses with numerous different barcoded HA variants and quantify infectivity of all of them simultaneously using next-generation sequencing. With this approach, a single researcher performed the equivalent of 2,880 traditional neutralization assays (80 serum samples against 36 viral strains) in approximately one month. We applied the sequencing-based assay to quantify the impact of influenza vaccination on neutralization titers against recent human H1N1 strains for individuals who had or had not also received a vaccine in the previous year. We found that the viral strain specificities of the neutralizing antibodies elicited by vaccination vary among individuals, and that vaccination induced a smaller increase in titers for individuals who had also received a vaccine the previous year-although the titers six months after vaccination were similar in individuals with and without the previous-year vaccination. We also identified a subset of individuals with low titers to a subclade of recent H1N1 even after vaccination. This study demonstrates the utility of high-throughput sequencing-based neutralization assays that enable titers to be simultaneously measured against many different viral strains. We provide a detailed experimental protocol (DOI: https://dx.doi.org/10.17504/protocols.io.kqdg3xdmpg25/v1) and a computational pipeline (https://github.com/jbloomlab/seqneut-pipeline) for the sequencing-based neutralization assays to facilitate the use of this method by others.

RevDate: 2024-03-22

Barnes DR, Tyrer JP, Dennis J, et al (2024)

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk.

medRxiv : the preprint server for health sciences.

BACKGROUND: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS).

METHODS: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan.

RESULTS: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10[-9]). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62).

CONCLUSIONS: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

RevDate: 2024-03-20

Henriques WS, Young JM, Nemudryi A, et al (2024)

The diverse evolutionary histories of domesticated metaviral capsid genes in mammals.

Molecular biology and evolution pii:7632644 [Epub ahead of print].

Selfish genetic elements comprise significant fractions of mammalian genomes. In rare instances, host genomes domesticate segments of these elements for function. Using a complete human genome assembly and 25 additional vertebrate genomes, we re-analyzed the evolutionary trajectories and functional potential of capsid genes domesticated from Metaviridae, a lineage of retrovirus-like retrotransposons. Our study expands on previous analyses to unearth several new insights about the evolutionary histories of these ancient genes. We find that at least five independent domestication events occurred from diverse Metaviridae, giving rise to three universally-retained single-copy genes evolving under purifying selection and two gene families unique to placental mammals with multiple members showing evidence of rapid evolution. In the SIRH/RTL family, we find diverse amino-terminal domains, widespread loss of protein-coding capacity in RTL10 despite its retention in several mammalian lineages, and differential utilization of an ancient programmed ribosomal frameshift in RTL3 between the domesticated capsid and protease domains. Our analyses also reveal that most members of the PNMA family in mammalian genomes encode a conserved putative amino-terminal RNA-binding domain both adjoining and independent from domesticated capsid domains. Our analyses lead to a significant correction of previous annotations of the essential CCDC8 gene. We show that this putative RNA-binding domain is also present in several extant Metaviridae, revealing a novel protein domain configuration in retrotransposons. Collectively, our study reveals the divergent outcomes of multiple domestication events from diverse Metaviridae in the common ancestor of placental mammals.

RevDate: 2024-03-21
CmpDate: 2024-03-21

He Y, Kouabenan YR, Assoa PH, et al (2024)

Laboratory Data Timeliness and Completeness Improves Following Implementation of an Electronic Laboratory Information System in Côte d'Ivoire: Quasi-Experimental Study on 21 Clinical Laboratories From 2014 to 2020.

JMIR public health and surveillance, 10:e50407 pii:v10i1e50407.

BACKGROUND: The Ministry of Health in Côte d'Ivoire and the International Training and Education Center for Health at the University of Washington, funded by the United States President's Emergency Plan for AIDS Relief, have been collaborating to develop and implement the Open-Source Enterprise-Level Laboratory Information System (OpenELIS). The system is designed to improve HIV-related laboratory data management and strengthen quality management and capacity at clinical laboratories across the nation.

OBJECTIVE: This evaluation aimed to quantify the effects of implementing OpenELIS on data quality for laboratory tests related to HIV care and treatment.

METHODS: This evaluation used a quasi-experimental design to perform an interrupted time-series analysis to estimate the changes in the level and slope of 3 data quality indicators (timeliness, completeness, and validity) after OpenELIS implementation. We collected paper and electronic records on clusters of differentiation 4 (CD4) testing for 48 weeks before OpenELIS adoption until 72 weeks after. Data collection took place at 21 laboratories in 13 health regions that started using OpenELIS between 2014 and 2020. We analyzed the data at the laboratory level. We estimated odds ratios (ORs) by comparing the observed outcomes with modeled counterfactual ones when the laboratories did not adopt OpenELIS.

RESULTS: There was an immediate 5-fold increase in timeliness (OR 5.27, 95% CI 4.33-6.41; P<.001) and an immediate 3.6-fold increase in completeness (OR 3.59, 95% CI 2.40-5.37; P<.001). These immediate improvements were observed starting after OpenELIS installation and then maintained until 72 weeks after OpenELIS adoption. The weekly improvement in the postimplementation trend of completeness was significant (OR 1.03, 95% CI 1.02-1.05; P<.001). The improvement in validity was not statistically significant (OR 1.34, 95% CI 0.69-2.60; P=.38), but validity did not fall below pre-OpenELIS levels.

CONCLUSIONS: These results demonstrate the value of electronic laboratory information systems in improving laboratory data quality and supporting evidence-based decision-making in health care. These findings highlight the importance of OpenELIS in Côte d'Ivoire and the potential for adoption in other low- and middle-income countries with similar health systems.

RevDate: 2024-03-20

Lange JM, Gogebakan KC, Gulati R, et al (2024)

Projecting the impact of multi-cancer early detection on late-stage incidence using multi-state disease modeling.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:741914 [Epub ahead of print].

BACKGROUND: Downstaging- reduction in late-stage incidence-has been proposed as an endpoint in randomized trials of multi-cancer early detection (MCED) tests. How downstaging depends on test performance and follow-up has been studied for some cancers but is understudied for cancers without existing screening and for MCED tests that include these cancer types.

METHODS: We develop a model for cancer natural history that can be fit to registry incidence patterns under minimal inputs and can be estimated for solid cancers without existing screening. Fitted models are combined to project downstaging in MCED trials given sensitivity for early- and late-stage cancers. We fit models for 12 cancers using incidence data from the Surveillance, Epidemiology, and End Results program and project downstaging in a simulated trial under variable preclinical latencies and test sensitivities.

RESULTS: A proof-of-principle lung cancer model approximated downstaging in the National Lung Screening Trial. Given published stage-specific sensitivities for 12 cancers, we projected downstaging ranging 21%-43% across plausible preclinical latencies in a hypothetical 3-screen MCED trial. Late-stage incidence reductions manifest soon after screening begins. Downstaging increases with longer early-stage latency or higher early-stage test sensitivity.

CONCLUSION: Even short-term MCED trials could produce substantial downstaging given adequate early-stage test sensitivity.

IMPACT: Modeling the natural histories of cancers without existing screening facilitates analysis of novel MCED products and trial designs. The framework informs expectations of MCED impact on disease stage at diagnosis and could serve as a building block for designing trials with late-stage incidence as the primary endpoint.

RevDate: 2024-03-21
CmpDate: 2024-03-21

Pothuri VS, Hogg GD, Conant L, et al (2024)

Intratumoral T-cell receptor repertoire composition predicts overall survival in patients with pancreatic ductal adenocarcinoma.

Oncoimmunology, 13(1):2320411.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is refractory to immune checkpoint inhibitor therapy. However, intratumoral T-cell infiltration correlates with improved overall survival (OS). Herein, we characterized the diversity and antigen specificity of the PDAC T-cell receptor (TCR) repertoire to identify novel immune-relevant biomarkers. Demographic, clinical, and TCR-beta sequencing data were collated from 353 patients across three cohorts that underwent surgical resection for PDAC. TCR diversity was calculated using Shannon Wiener index, Inverse Simpson index, and "True entropy." Patients were clustered by shared repertoire specificity. TCRs predictive of OS were identified and their associated transcriptional states were characterized by single-cell RNAseq. In multivariate Cox regression models controlling for relevant covariates, high intratumoral TCR diversity predicted OS across multiple cohorts. Conversely, in peripheral blood, high abundance of T-cells, but not high diversity, predicted OS. Clustering patients based on TCR specificity revealed a subset of TCRs that predicts OS. Interestingly, these TCR sequences were more likely to encode CD8[+] effector memory and CD4[+] T-regulatory (Tregs) T-cells, all with the capacity to recognize beta islet-derived autoantigens. As opposed to T-cell abundance, intratumoral TCR diversity was predictive of OS in multiple PDAC cohorts, and a subset of TCRs enriched in high-diversity patients independently correlated with OS. These findings emphasize the importance of evaluating peripheral and intratumoral TCR repertoires as distinct and relevant biomarkers in PDAC.

RevDate: 2024-03-21
CmpDate: 2024-03-21

Strausz S, Abner E, Blacker G, et al (2024)

SCGB1D2 inhibits growth of Borrelia burgdorferi and affects susceptibility to Lyme disease.

Nature communications, 15(1):2041.

Lyme disease is a tick-borne disease caused by bacteria of the genus Borrelia. The host factors that modulate susceptibility for Lyme disease have remained mostly unknown. Using epidemiological and genetic data from FinnGen and Estonian Biobank, we identify two previously known variants and an unknown common missense variant at the gene encoding for Secretoglobin family 1D member 2 (SCGB1D2) protein that increases the susceptibility for Lyme disease. Using live Borrelia burgdorferi (Bb) we find that recombinant reference SCGB1D2 protein inhibits the growth of Bb in vitro more efficiently than the recombinant protein with SCGB1D2 P53L deleterious missense variant. Finally, using an in vivo murine infection model we show that recombinant SCGB1D2 prevents infection by Borrelia in vivo. Together, these data suggest that SCGB1D2 is a host defense factor present in the skin, sweat, and other secretions which protects against Bb infection and opens an exciting therapeutic avenue for Lyme disease.

RevDate: 2024-03-19

Porter J, Ward LC, Nguo K, et al (2024)

Development and validation of age-specific predictive equations for total energy expenditure and physical activity levels for older adults.

The American journal of clinical nutrition pii:S0002-9165(24)00072-8 [Epub ahead of print].

BACKGROUND: Predicting energy requirements for older adults is compromised by the underpinning data being extrapolated from younger adults.

OBJECTIVES: To generate and validate new total energy expenditure (TEE) predictive equations specifically for older adults using readily available measures (age, weight, height) and to generate and test new physical activity level (PAL) values derived from 1) reference method of indirect calorimetry and 2) predictive equations in adults aged ≥65 y.

METHODS: TEE derived from "gold standard" methods from n = 1657 (n = 1019 females, age range 65-90 y), was used to generate PAL values. PAL ranged 1.28-2.05 for males and 1.26-2.06 for females. Physical activity (PA) coefficients were also estimated and categorized (inactive to very active) from population means. Nonlinear regression was used to develop prediction equations for estimating TEE. Double cross-validation in a randomized, sex-stratified, age-matched 50:50 split, and leave one out cross-validation were performed. Comparisons were made with existing equations.

RESULTS: Equations predicting TEE using the Institute of Medicine method are as follows: For males, TEE = -5680.17 - 17.50 × age (years) + PA coefficient × (6.96 × weight [kilograms] + 44.21 × height [centimeters]) + 1.13 × resting metabolic rate (RMR) (kilojoule/day). For females, TEE = -5290.72 - 8.38 × age (years) + PA coefficient × (9.77 × weight [kilograms] + 41.51 × height [centimeters]) + 1.05 × RMR (kilojoule/day), where PA coefficient values range from 1 (inactive) to 1.51 (highly active) in males and 1 to 1.44 in females respectively. Predictive performance for TEE from anthropometric variables and population mean PA was moderate with limits of agreement approximately ±30%. This improved to ±20% if PA was adjusted for activity category (inactive, low active, active, and very active). Where RMR was included as a predictor variable, the performance improved further to ±10% with a median absolute prediction error of approximately 4%.

CONCLUSIONS: These new TEE prediction equations require only simple anthropometric data and are accurate and reproducible at a group level while performing better than existing equations. Substantial individual variability in PAL in older adults is the major source of variation when applied at an individual level.

RevDate: 2024-03-21
CmpDate: 2024-03-21

Abu-Rustum NR, Yashar CM, Arend R, et al (2024)

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

Journal of the National Comprehensive Cancer Network : JNCCN, 22(2):117-135.

Vulvar cancer is annually diagnosed in an estimated 6,470 individuals and the vast majority are histologically squamous cell carcinomas. Vulvar cancer accounts for 5% to 8% of gynecologic malignancies. Known risk factors for vulvar cancer include increasing age, infection with human papillomavirus, cigarette smoking, inflammatory conditions affecting the vulva, and immunodeficiency. Most vulvar neoplasias are diagnosed at early stages. Rarer histologies exist and include melanoma, extramammary Paget's disease, Bartholin gland adenocarcinoma, verrucous carcinoma, basal cell carcinoma, and sarcoma. This manuscript discusses recommendations outlined in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for treatments, surveillance, systemic therapy options, and gynecologic survivorship.

RevDate: 2024-03-21
CmpDate: 2024-03-21

Stevenson J, Ettinger DS, Wood DE, et al (2024)

Mesothelioma: Pleural, Version 1.2024.

Journal of the National Comprehensive Cancer Network : JNCCN, 22(2):72-81.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of the pleura and other sites, and is estimated to occur in approximately 3,500 people in the United States annually. Pleural mesothelioma is the most common type and represents approximately 85% of these cases. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pleural mesothelioma. These NCCN Guidelines Insights highlight significant updates to the NCCN Guidelines for Mesothelioma: Pleural, including revised guidance on disease classification and systemic therapy options.

RevDate: 2024-03-19

Moodie Z, Andersen-Nissen E, Grunenberg N, et al (2024)

Safety and immunogenicity of a subtype C ALVAC-HIV (vCP2438) vaccine prime plus bivalent subtype C gp120 vaccine boost adjuvanted with MF59 or alum in healthy adults without HIV (HVTN 107): A phase 1/2a randomized trial.

PLoS medicine, 21(3):e1004360 pii:PMEDICINE-D-23-03685 [Epub ahead of print].

BACKGROUND: Adjuvants are widely used to enhance and/or direct vaccine-induced immune responses yet rarely evaluated head-to-head. Our trial directly compared immune responses elicited by MF59 versus alum adjuvants in the RV144-like HIV vaccine regimen modified for the Southern African region. The RV144 trial of a recombinant canarypox vaccine vector expressing HIV env subtype B (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost adjuvanted with alum is the only trial to have shown modest HIV vaccine efficacy. Data generated after RV144 suggested that use of MF59 adjuvant might allow lower protein doses to be used while maintaining robust immune responses. We evaluated safety and immunogenicity of an HIV recombinant canarypox vaccine vector expressing HIV env subtype C (ALVAC-HIV) prime followed by ALVAC-HIV plus a bivalent gp120 protein vaccine boost (gp120) adjuvanted with alum (ALVAC-HIV+gp120/alum) or MF59 (ALVAC-HIV+gp120/MF59) or unadjuvanted (ALVAC-HIV+gp120/no-adjuvant) and a regimen where ALVAC-HIV+gp120 adjuvanted with MF59 was used for the prime and boost (ALVAC-HIV+gp120/MF59 coadministration).

METHODS AND FINDINGS: Between June 19, 2017 and June 14, 2018, 132 healthy adults without HIV in South Africa, Zimbabwe, and Mozambique were randomized to receive intramuscularly: (1) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/MF59 (months 3, 6, and 12), n = 36; (2) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/alum (months 3, 6, and 12), n = 36; (3) 4 doses of ALVAC-HIV+gp120/MF59 coadministered (months 0, 1, 6, and 12), n = 36; or (4) 2 priming doses of ALVAC-HIV (months 0 and 1) followed by 3 booster doses of ALVAC-HIV+gp120/no adjuvant (months 3, 6, and 12), n = 24. Primary outcomes were safety and occurrence and mean fluorescence intensity (MFI) of vaccine-induced gp120-specific IgG and IgA binding antibodies at month 6.5. All vaccinations were safe and well-tolerated; increased alanine aminotransferase was the most frequent related adverse event, occurring in 2 (1.5%) participants (1 severe, 1 mild). At month 6.5, vaccine-specific gp120 IgG binding antibodies were detected in 100% of vaccinees for all 4 vaccine groups. No significant differences were seen in the occurrence and net MFI of vaccine-specific IgA responses between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/alum-prime-boost groups or between the ALVAC-HIV+gp120/MF59-prime-boost and ALVAC-HIV+gp120/MF59 coadministration groups. Limitations were the relatively small sample size per group and lack of evaluation of higher gp120 doses.

CONCLUSIONS: Although MF59 was expected to enhance immune responses, alum induced similar responses to MF59, suggesting that the choice between these adjuvants may not be critical for the ALVAC+gp120 regimen.

TRIAL REGISTRATION: HVTN 107 was registered with the South African National Clinical Trials Registry (DOH-27-0715-4894) and ClinicalTrials.gov (NCT03284710).

RevDate: 2024-03-18

Zhao LP, Papadopoulos GK, Skyler JS, et al (2024)

HLA Class II (DR, DQ, DP) Genes Were Separately Associated With the Progression From Seroconversion to Onset of Type 1 Diabetes Among Participants in Two Diabetes Prevention Trials (DPT-1 and TN07).

Diabetes care pii:154294 [Epub ahead of print].

OBJECTIVE: To explore associations of HLA class II genes (HLAII) with the progression of islet autoimmunity from asymptomatic to symptomatic type 1 diabetes (T1D).

RESEARCH DESIGN AND METHODS: Next-generation targeted sequencing was used to genotype eight HLAII genes (DQA1, DQB1, DRB1, DRB3, DRB4, DRB5, DPA1, DPB1) in 1,216 participants from the Diabetes Prevention Trial-1 and Randomized Diabetes Prevention Trial with Oral Insulin sponsored by TrialNet. By the linkage disequilibrium, DQA1 and DQB1 are haplotyped to form DQ haplotypes; DP and DR haplotypes are similarly constructed. Together with available clinical covariables, we applied the Cox regression model to assess HLAII immunogenic associations with the disease progression.

RESULTS: 1) The current investigation updated the previously reported genetic associations of DQA1*03:01-DQB1*03:02 (hazard ratio [HR] = 1.25, P = 3.50*10-3) and DQA1*03:03-DQB1*03:01 (HR = 0.56, P = 1.16*10-3), and also uncovered a risk association with DQA1*05:01-DQB1*02:01 (HR = 1.19, P = 0.041). 2) After adjusting for DQ, DPA1*02:01-DPB1*11:01 and DPA1*01:03-DPB1*03:01 were found to have opposite associations with progression (HR = 1.98 and 0.70, P = 0.021 and 6.16*10-3, respectively). 3) DRB1*03:01-DRB3*01:01 and DRB1*03:01-DRB3*02:02, sharing the DRB1*03:01, had opposite associations (HR = 0.73 and 1.44, P = 0.04 and 0.019, respectively), indicating a role of DRB3. Meanwhile, DRB1*12:01-DRB3*02:02 and DRB1*01:03 alone were found to associate with progression (HR = 2.6 and 2.32, P = 0.018 and 0.039, respectively). 4) Through enumerating all heterodimers, it was found that both DQ and DP could exhibit associations with disease progression.

CONCLUSIONS: These results suggest that HLAII polymorphisms influence progression from islet autoimmunity to T1D among at-risk subjects with islet autoantibodies.

RevDate: 2024-03-18

Twentyman J, Emerman M, M Ohainle (2024)

Capsid-dependent lentiviral restrictions.

Journal of virology [Epub ahead of print].

Host antiviral proteins inhibit primate lentiviruses and other retroviruses by targeting many features of the viral life cycle. The lentiviral capsid protein and the assembled viral core are known to be inhibited through multiple, directly acting antiviral proteins. Several phenotypes, including those known as Lv1 through Lv5, have been described as cell type-specific blocks to infection against some but not all primate lentiviruses. Here we review important features of known capsid-targeting blocks to infection together with several blocks to infection for which the genes responsible for the inhibition still remain to be identified. We outline the features of these blocks as well as how current methodologies are now well suited to find these antiviral genes and solve these long-standing mysteries in the HIV and retrovirology fields.

RevDate: 2024-03-20
CmpDate: 2024-03-19

Bauermeister J, Lin W, Tingler R, et al (2024)

A conjoint experiment of three placebo rectal products used with receptive anal sex: results from MTN-035.

Journal of the International AIDS Society, 27(3):e26219.

INTRODUCTION: End-user perspectives are vital to the design of new biomedical HIV prevention products. Conjoint analysis can support the integration of end-user perspectives by examining their preferences of potential pre-exposure prophylaxis (PrEP) products. The Microbicides Trial Network (MTN) 035 protocol examined three placebo rectal dosage forms (insert, enema and suppository) that could deliver PrEP prior to receptive anal sex (RAS).

METHODS: Between April 2019 and July 2020, we enrolled 217 HIV-negative, cisgender men who have sex with men (MSM; n = 172; 79.3%) and transgender people (n = 47; 20.7%) ages 18-35 into a randomized cross-over trial across Malawi, Peru, South Africa, Thailand and the United States. Participants used each product prior to RAS over 4-week periods. Participants completed a conjoint experiment where they selected between random profiles using seven features (dosage form, timing of use before sex, side effects, duration of protection, effectiveness, frequency of use and need for a prescription).

RESULTS: Effectiveness was the strongest determinant of choice (30.4%), followed by modality (18.0%), potential side effects (17.2%), frequency of use (10.8%), duration of protection (10.4%), timing of use before sex (7.4%) and need for a prescription (5.9%). Relative utility scores indicated that the most desirable combination of attributes was a product with 95% efficacy, used 30 minutes before sex, offering a 3- to 5-day protection window, used weekly, having no side effects, in the form of an enema and available over-the-counter.

CONCLUSIONS: Choice in next-generation PrEP products is highly desired by MSM and transgender people, as no one-size-fits-all approach satisfies all the preferences. MTN-035 participants weighed product features differently, recognizing the need for diverse, behaviourally congruent biomedical options that fit the needs of intended end-users.

RevDate: 2024-03-20

Barrero DJ, Wijeratne SS, Zhao X, et al (2024)

Architecture and flexibility of native kinetochores revealed by structural studies utilizing a thermophilic yeast.

bioRxiv : the preprint server for biology.

Eukaryotic chromosome segregation requires kinetochores, multi-megadalton protein machines that assemble on the centromeres of chromosomes and mediate attachments to dynamic spindle microtubules. Kinetochores are built from numerous complexes, and understanding how they are arranged is key to understanding how kinetochores perform their multiple functions. However, an integrated understanding of kinetochore architecture has not yet been established. To address this, we purified functional, native kinetochores from Kluyveromyces marxianus and examined them by electron microscopy, cryo-electron tomography and atomic force microscopy. The kinetochores are extremely large, flexible assemblies that exhibit features consistent with prior models. We assigned kinetochore polarity by visualizing their interactions with microtubules and locating the microtubule binder Ndc80c. This work shows that isolated kinetochores are more dynamic and complex than what might be anticipated based on the known structures of recombinant subassemblies, and provides the foundation to study the global architecture and functions of kinetochores at a structural level.

RevDate: 2024-03-17

Smith S, Beima-Sofie K, Naveed A, et al (2024)

Impact of the COVID-19 Pandemic on Persons Living with HIV in Western Washington: Examining Lived Experiences of Social Distancing Stress, Personal Buffers, and Mental Health.

AIDS and behavior [Epub ahead of print].

Pandemic-related stressors may disproportionately affect the mental health of people with HIV (PWH). Stratified, purposive sampling was used to recruit 24 PWH who participated in a quantitative survey on COVID-19 experiences for in-depth interviews (IDIs). IDIs were conducted by Zoom, audio recorded and transcribed. Thematic analysis was used to develop an adapted stress-coping model. Participants experienced acute stress following exposure events and symptoms compatible with COVID-19. Social isolation and job loss were longer-term stressors. While adaptive coping strategies helped promote mental health, participants who experienced multiple stressors simultaneously often felt overwhelmed and engaged in maladaptive coping behaviors. Healthcare providers were important sources of social support and provided continuity in care and referrals to mental health and social services. Understanding how PWH experienced stressors and coped during the COVID-19 pandemic can help healthcare providers connect with patients during future public health emergencies, address mental health needs and support adaptive coping strategies.

RevDate: 2024-03-18
CmpDate: 2024-03-18

Yang Z, Heijnsdijk EAM, Newcomb LF, et al (2024)

Exploring the relation of active surveillance schedules and prostate cancer mortality.

Cancer medicine, 13(5):e6977.

BACKGROUND: Active surveillance (AS), where treatment is deferred until cancer progression is detected by a biopsy, is acknowledged as a way to reduce overtreatment in prostate cancer. However, a consensus on the frequency of taking biopsies while in AS is lacking. In former studies to optimize biopsy schedules, the delay in progression detection was taken as an evaluation indicator and believed to be associated with the long-term outcome, prostate cancer mortality. Nevertheless, this relation was never investigated in empirical data. Here, we use simulated data from a microsimulation model to fill this knowledge gap.

METHODS: In this study, the established MIcrosimulation SCreening Analysis model was extended with functionality to simulate the AS procedures. The biopsy sensitivity in the model was calibrated on the Canary Prostate Cancer Active Surveillance Study (PASS) data, and four (tri-yearly, bi-yearly, PASS, and yearly) AS programs were simulated. The relation between detection delay and prostate cancer mortality was investigated by Cox models.

RESULTS: The biopsy sensitivity of progression detection was found to be 50%. The Cox models show a positive relation between a longer detection delay and a higher risk of prostate cancer death. A 2-year delay resulted in a prostate cancer death risk of 2.46%-2.69% 5 years after progression detection and a 10-year risk of 5.75%-5.91%. A 4-year delay led to an approximately 8% greater 5-year risk and an approximately 25% greater 10-year risk.

CONCLUSION: The detection delay is confirmed as a surrogate for prostate cancer mortality. A cut-off for a "safe" detection delay could not be identified.

RevDate: 2024-03-18
CmpDate: 2024-03-18

Ishengoma DS, Mandara CI, Madebe RA, et al (2024)

Microsatellites reveal high polymorphism and high potential for use in anti-malarial efficacy studies in areas with different transmission intensities in mainland Tanzania.

Malaria journal, 23(1):79.

BACKGROUND: Tanzania is currently implementing therapeutic efficacy studies (TES) in areas of varying malaria transmission intensities as per the World Health Organization (WHO) recommendations. In TES, distinguishing reinfection from recrudescence is critical for the determination of anti-malarial efficacy. Recently, the WHO recommended genotyping polymorphic coding genes, merozoite surface proteins 1 and 2 (msp1 and msp2), and replacing the glutamate-rich protein (glurp) gene with one of the highly polymorphic microsatellites in Plasmodium falciparum to adjust the efficacy of antimalarials in TES. This study assessed the polymorphisms of six neutral microsatellite markers and their potential use in TES, which is routinely performed in Tanzania.

METHODS: Plasmodium falciparum samples were obtained from four TES sentinel sites, Kibaha (Pwani), Mkuzi (Tanga), Mlimba (Morogoro) and Ujiji (Kigoma), between April and September 2016. Parasite genomic DNA was extracted from dried blood spots on filter papers using commercial kits. Genotyping was done using six microsatellites (Poly-α, PfPK2, TA1, C3M69, C2M34 and M2490) by capillary method, and the data were analysed to determine the extent of their polymorphisms and genetic diversity at the four sites.

RESULTS: Overall, 83 (88.3%) of the 94 samples were successfully genotyped (with positive results for ≥ 50.0% of the markers), and > 50.0% of the samples (range = 47.6-59.1%) were polyclonal, with a mean multiplicity of infection (MOI) ranging from 1.68 to 1.88 among the four sites. There was high genetic diversity but limited variability among the four sites based on mean allelic richness (RS = 7.48, range = 7.27-8.03, for an adjusted minimum sample size of 18 per site) and mean expected heterozygosity (He = 0.83, range = 0.80-0.85). Cluster analysis of haplotypes using STRUCTURE, principal component analysis, and pairwise genetic differentiation (FST) did not reveal population structure or clustering of parasites according to geographic origin. Of the six markers, Poly-α was the most polymorphic, followed by C2M34, TA1 and C3M69, while M2490 was the least polymorphic.

CONCLUSION: Microsatellite genotyping revealed high polyclonality and genetic diversity but no significant population structure. Poly-α, C2M34, TA1 and C3M69 were the most polymorphic markers, and Poly-α alone or with any of the other three markers could be adopted for use in TES in Tanzania.

RevDate: 2024-03-18

Rickles-Young M, Tinoco G, Tsuji J, et al (2024)

Assay Validation of Cell-Free DNA Shallow Whole Genome Sequencing To Determine Tumor Fraction in Advanced Cancers.

The Journal of molecular diagnostics : JMD pii:S1525-1578(24)00052-7 [Epub ahead of print].

Blood-based 'liquid biopsy' is increasingly utilized in clinical care of cancer patients and fraction of tumor-derived DNA in circulation ('tumor fraction', TFx) has demonstrated clinical validity across multiple cancer types. To determine TFx, shallow whole genome sequencing of cell-free DNA can be performed from a single blood sample, using an established computational pipeline (ichorCNA), without prior knowledge of tumor mutations, in a highly cost effective manner. We describe assay validation of this approach to facilitate broad clinical application, including evaluation of assay sensitivity, precision, repeatability, reproducibility, pre-analytic factors, and DNA quality/quantity. Sensitivity to detect TFx of 3% (lower limit of detection) was 97.2%-100% at 1x and 0.1x mean sequencing depth. Precision was demonstrated on distinct sequencing instruments (Illumina HiSeqX and NovaSeq) with no observable differences. The assay achieved pre-specified 95% agreement of TFx across replicates of the same specimen (repeatability) and duplicate samples in different batches (reproducibility). Comparison of samples collected in EDTA and Streck tubes from single venipuncture in 23 patients demonstrated that EDTA or Streck tubes were comparable if processed within 8 hours. Based on a range of DNA inputs (1ng-50ng), 20ng cfDNA is preferred input, with 5ng minimum acceptable. Overall, this shallow whole genome sequencing of cell-free DNA and ichorCNA approach offers sensitive, precise, reproductible quantitation of TFx, facilitating assay application in clinical cancer care.

RevDate: 2024-03-15

An J, McDougall J, Lin Y, et al (2024)

Randomized trial promoting cancer genetic risk assessment when genetic counseling cost removed: 1-year follow-up.

JNCI cancer spectrum pii:7630178 [Epub ahead of print].

PURPOSE: Cancer Genetic Risk Assessment (CGRA) is recommended for women with ovarian and high-risk breast cancer. However, the underutilization of CGRA has long been documented, and cost has been a major barrier. In this randomized controlled trial, a Tailored Counseling and Navigation (TCN) intervention significantly improved CGRA uptake at 6-month follow-up, compared with Targeted Print (TP) and Usual Care (UC). We aimed to examine the effect of removing genetic counseling costs on CGRA uptake by 12 months.

METHODS: We recruited racially and geographically diverse women with breast and ovarian cancer from cancer registries in Colorado, New Jersey, and New Mexico. Participants assigned to TCN received phone-based psychoeducation and navigation. After 6 months, the trial provided free genetic counseling to participants in all arms.

RESULTS: At 12 months, more women in TCN obtained CGRA (26.6%) than those in TP (11.0%, Odds ratio (OR) = 2.77, 95% Confidence interval (CI) 1.56 to 4.89) and UC (12.2%, OR = 2.46, 95% CI 1.41 to 4.29). There were no significant differences in CGRA uptake between TP and UC. The Kaplan-Meier curve shows that the divergence of cumulative incidence slopes (TCN vs UC, TCN vs TP) appears primarily within the initial 6 months.

CONCLUSION: TCN significantly increased CGRA uptake at the 12-month follow-up. Directly removing the costs of genetic counseling attenuated the effects of TCN, highlighting the critical enabling role played by cost coverage. Future policies and interventions should address multi-level cost-related barriers to expand patients' access to CGRA.

TRIAL REGISTRATION: This trial was registered with the NIH clinical trial registry, clinicaltrials.gov, NCT03326713. https://clinicaltrials.gov/ct2/show/NCT03326713.

RevDate: 2024-03-15

Farland LV, Valenti M, Degnan WJ, et al (2024)

Laparoscopically confirmed endometriosis and anti-Müllerian hormone levels: Findings from the Nurses' Health Study II.

Maturitas, 183:107969 pii:S0378-5122(24)00064-1 [Epub ahead of print].

OBJECTIVE: Anti-Müllerian hormone is a reliable measure of ovarian reserve associated with menopause timing and fertility. Previous studies have observed that individuals with endometriosis have lower anti-Müllerian hormone levels than those without. However, sample sizes have been small and information is limited regarding the long-term influence of endometriosis on anti-Müllerian hormone levels among the general population, which may have important implications for menopause timing and chronic disease risk.

METHODS: Among 1961 premenopausal women in the Nurses' Health Study II who provided a blood sample and had not been pregnant in the last 6 months, we used generalized linear models to determine the association between laparoscopically-confirmed endometriosis and log-transformed plasma anti-Müllerian hormone level, adjusted for age (continuous and squared) and other potential confounding variables.

RESULTS: Participants were on average 40 years old (interquartile range 37-42 years) at blood draw. Women with endometriosis diagnosed prior to blood draw (n = 119) had a lower mean anti-Müllerian hormone level (1.6 ng/mL [SD = 2.3]) than women without known endometriosis (n = 1842) (2.8 ng/mL [SD = 3.0]). In multivariable adjusted models, women with endometriosis had 29.6 % lower anti-Müllerian hormone levels (95 % CI: -45.4, -9.2 %) than women without. This association was greater among women with a body mass index of 25 kg/m[2] or more (percent difference: -44.0 % (-63.7, -13.8)), compared to those with a body mass index of under 25 kg/m[2] (percent difference: -19.8 % (-41.7, 10.4)), but did not vary by parity or infertility history.

CONCLUSIONS: Lower anti-Müllerian hormone levels in women with endometriosis may be one mechanism through which endometriosis influences risk of infertility, younger age at menopause, and cardiovascular disease.

RevDate: 2024-03-15

Madan RA, Yu EY, Posadas EM, et al (2024)

Restaging With Prostate-Specific Membrane Antigen Imaging in Metastatic Castration-Resistant Prostate Cancer: When Seeing More Is Detrimental to Care.

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

#PSMA is amazing new tech but is using it to expedite the call of disease progression helping #ProstateCancer patients?

RevDate: 2024-03-15

Zainal NH, Bossarte RM, Gildea SM, et al (2024)

Developing an individualized treatment rule for Veterans with major depressive disorder using electronic health records.

Molecular psychiatry [Epub ahead of print].

Efforts to develop an individualized treatment rule (ITR) to optimize major depressive disorder (MDD) treatment with antidepressant medication (ADM), psychotherapy, or combined ADM-psychotherapy have been hampered by small samples, small predictor sets, and suboptimal analysis methods. Analyses of large administrative databases designed to approximate experiments followed iteratively by pragmatic trials hold promise for resolving these problems. The current report presents a proof-of-concept study using electronic health records (EHR) of n = 43,470 outpatients beginning MDD treatment in Veterans Health Administration Primary Care Mental Health Integration (PC-MHI) clinics, which offer access not only to ADMs but also psychotherapy and combined ADM-psychotherapy. EHR and geospatial databases were used to generate an extensive baseline predictor set (5,865 variables). The outcome was a composite measure of at least one serious negative event (suicide attempt, psychiatric emergency department visit, psychiatric hospitalization, suicide death) over the next 12 months. Best-practices methods were used to adjust for nonrandom treatment assignment and to estimate a preliminary ITR in a 70% training sample and to evaluate the ITR in the 30% test sample. Statistically significant aggregate variation was found in overall probability of the outcome related to baseline predictors (AU-ROC = 0.68, S.E. = 0.01), with test sample outcome prevalence of 32.6% among the 5% of patients having highest predicted risk compared to 7.1% in the remainder of the test sample. The ITR found that psychotherapy-only was the optimal treatment for 56.0% of patients (roughly 20% lower risk of the outcome than if receiving one of the other treatments) and that treatment type was unrelated to outcome risk among other patients. Change in aggregate treatment costs of implementing this ITR would be negligible, as 16.1% fewer patients would be prescribed ADMs and 2.9% more would receive psychotherapy. A pragmatic trial would be needed to confirm the accuracy of the ITR.

RevDate: 2024-03-15

Maciel M, Amara RR, Bar KJ, et al (2024)

Author Correction: Exploring synergies between B- and T-cell vaccine approaches to optimize immune responses against HIV-workshop report.

NPJ vaccines, 9(1):61 pii:10.1038/s41541-024-00852-w.

RevDate: 2024-03-14

Marks F, Im J, Park SE, et al (2024)

Incidence of typhoid fever in Burkina Faso, Democratic Republic of the Congo, Ethiopia, Ghana, Madagascar, and Nigeria (the Severe Typhoid in Africa programme): a population-based study.

The Lancet. Global health, 12(4):e599-e610.

BACKGROUND: Typhoid Fever remains a major cause of morbidity and mortality in low-income settings. The Severe Typhoid in Africa programme was designed to address regional gaps in typhoid burden data and identify populations eligible for interventions using novel typhoid conjugate vaccines.

METHODS: A hybrid design, hospital-based prospective surveillance with population-based health-care utilisation surveys, was implemented in six countries in sub-Saharan Africa. Patients presenting with fever (≥37·5°C axillary or ≥38·0°C tympanic) or reporting fever for three consecutive days within the previous 7 days were invited to participate. Typhoid fever was ascertained by culture of blood collected upon enrolment. Disease incidence at the population level was estimated using a Bayesian mixture model.

FINDINGS: 27 866 (33·8%) of 82 491 participants who met inclusion criteria were recruited. Blood cultures were performed for 27 544 (98·8%) of enrolled participants. Clinically significant organisms were detected in 2136 (7·7%) of these cultures, and 346 (16·2%) Salmonella enterica serovar Typhi were isolated. The overall adjusted incidence per 100 000 person-years of observation was highest in Kavuaya and Nkandu 1, Democratic Republic of the Congo (315, 95% credible interval 254-390). Overall, 46 (16·4%) of 280 tested isolates showed ciprofloxacin non-susceptibility.

INTERPRETATION: High disease incidence (ie, >100 per 100 000 person-years of observation) recorded in four countries, the prevalence of typhoid hospitalisations and complicated disease, and the threat of resistant typhoid strains strengthen the need for rapid dispatch and implementation of effective typhoid conjugate vaccines along with measures designed to improve clean water, sanitation, and hygiene practices.

FUNDING: The Bill & Melinda Gates Foundation.

RevDate: 2024-03-16

Quadri NS, Thielen BK, Crichlow R, et al (2021)

12 Tips for Engaging Medical Students in Health Communications.

MedEdPublish (2016), 10:48.

This article was migrated. The article was marked as recommended. The proliferation of misinformation during the COVID-19 pandemic provides a clear example of the harms that can occur when medical professionals do not engage with the public regarding health topics. To address this need for accessible, accurate medical information, we taught medical students a COVID-19-specific curriculum tailored to sharing this information with the lay public via social media. Through active learning, students developed their understanding of disease-specific pathophysiology, prevention techniques, treatments, and public health interventions while practicing new skills in public communication as health professionals. After two cohorts completed the course, students' high-quality medical information about COVID-19 reached >100,000 viewers. To further broaden the impact, we shared the course curriculum through the Association of American Medical College (AAMC) iCollaborative. This curriculum provides a model for future engagement of medical students in health communication with lay audiences.

RevDate: 2024-03-14

Bos S, Murray J, Marchetti M, et al (2024)

ERS/EBMT clinical practice guideline on treatment of pulmonary chronic graft-versus-host disease in adults.

The European respiratory journal pii:13993003.01727-2023 [Epub ahead of print].

Chronic graft-versus-host disease (cGvHD) is a common complication after allogeneic haematopoietic stem cell transplantation, characterised by a broad disease spectrum that can affect virtually any organ. Although pulmonary cGvHD is a less common manifestation, it is of great concern due to its severity and poor prognosis. Optimal management of patients with pulmonary cGvHD is complicated and no standardised approach is available.The purpose of this joint European Respiratory Society and European Society for Blood and Marrow Transplantation Task Force was to develop evidence-based recommendations regarding the treatment of pulmonary cGvHD phenotype bronchiolitis obliterans syndrome in adults. A multidisciplinary group representing specialists in haematology, respiratory medicine, methodology as well as patient advocates formulated eight PICO (Patient, Intervention, Comparison, Outcome) and two narrative questions. Following the ERS standardised methodology, we conducted systematic reviews to address these questions and used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to develop recommendations.The resulting guideline addresses common therapeutic options (inhalation therapy, fluticasone-azithromycin-montelukast, imatinib, ibrutinib, ruxolitinib, belumosudil, extracorporeal photopheresis and lung transplantation), as well as other aspects of general management, such as lung functional and radiological follow-up and pulmonary rehabilitation, for adults with pulmonary cGvHD phenotype bronchiolitis obliterans syndrome. These recommendations include important advancements that could be incorporated in the management of adults with pulmonary cGvHD, primarily aimed at improving and standardising treatment and improving outcomes.

RevDate: 2024-03-14

de Valois B, Young T, Zollman C, et al (2024)

Acupuncture in cancer care: recommendations for safe practice (peer-reviewed expert opinion).

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 32(4):229.

BACKGROUND: Up-to-date recommendations for the safe practice of acupuncture in integrative oncology are overdue with new cancer treatments and an increase in survivors with late effects of disease; 17 years have elapsed since Filshie and Hester's 2006 guidelines. During 2022/2023 an expert panel assembled to produce updated recommendations aiming to facilitate safe and appropriate care by acupuncturists working with people with cancer.

METHODS: A core development team comprising three integrative oncology professionals comprehensively updated pre-existing unpublished recommendations. Twelve invited international experts (senior acupuncturists with and without experience of working in oncology settings, oncologists, physicians and nurses trained in integrative oncology, researchers, academics, and professional body representatives) reviewed the recommendations. In multiple iterations, the core team harmonised comments for final ratification. To aid dissemination and uptake the panel represents national and international integrative oncology associations and major cancer treatment centres in Europe, USA, Australia, and the Middle East.

RESULTS: These recommendations facilitate safe care by articulating contra-indications, cautions, and risks for patients both on and off treatment (surgery, SACT, radiotherapy). Situations where acupuncture may be contra-indicated or practices need adapting are identified. "Red and Amber Flags" highlight where urgent referral is essential.

CONCLUSION: These are the first international, multidisciplinary peer-reviewed recommendations for safe acupuncture practice in integrative oncology. Concerns about safety remain a significant barrier to appropriate referral from oncology teams, to use by acupuncturists and to uptake by patients. Disseminating trustworthy, widely accessible guidance should facilitate informed, confident practice of acupuncture in and outside of oncology healthcare settings.

RevDate: 2024-03-15

Joncas-Schronce L, Ali F, Pepper G, et al (2024)

Evaluation of Three Cytomegalovirus IgG Lateral Flow Assays for Rapid Determination of CMV Serostatus.

Open forum infectious diseases, 11(3):ofae084.

BACKGROUND: Cytomegalovirus (CMV) serostatus is a major determinant of CMV infection, disease risk, and transplant outcomes. Current clinical serology assays are limited by relatively slow turnaround time, design for batched testing, need for trained personnel, and/or specialized equipment. Rapid diagnostic assays in development have a role in emerging settings, such as critically ill patients, but have not been systematically evaluated.

METHODS: We assessed the performance of 3 rapid lateral flow assays (LFAs) for the detection of CMV immunoglobulin (Ig)G antibodies compared with a reference commercially available CMV IgG enzyme-linked immunosorbent assay in residual serum samples from 200 consecutive adults who underwent clinical CMV serology testing. Samples with discrepant results between the LFA and reference assay were tested by a second reference assay. A subset of serum samples was assessed for interoperator variability. Operating characteristics of the QooLabs LFA were separately assessed in plasma samples.

RESULTS: The sensitivity and specificity of the individual LFA assays using serum varied significantly: 86%/83%, 99/93%, and 57/97%, for Healgen, QNow automated reader, and nanoComposix, respectively, compared with the reference assay. Results for the QNow assay were comparable between automated and manual reads. Among a subset of 10 serum samples assessed by 5 individual operators, 44 of 50 (88%) results were concordant. Among 50 plasma samples assessed by the QooLabs LFA, the sensitivity and specificity were 72% and 96%.

CONCLUSIONS: The ease of performance, rapid turnaround time, and good operating characteristics provide the rationale for further evaluation of the Qoolabs QNow LFA in specialized settings where rapid assessment of CMV serostatus would be advantageous.

RevDate: 2024-03-15
CmpDate: 2024-03-15

Emanuels A, Casto AM, Heimonen J, et al (2024)

Remote surveillance and detection of SARS-CoV-2 transmission among household members in King County, Washington.

BMC infectious diseases, 24(1):309.

BACKGROUND: Early during the COVID-19 pandemic, it was important to better understand transmission dynamics of SARS-CoV-2, the virus that causes COVID-19. Household contacts of infected individuals are particularly at risk for infection, but delays in contact tracing, delays in testing contacts, and isolation and quarantine posed challenges to accurately capturing secondary household cases.

METHODS: In this study, 346 households in the Seattle region were provided with respiratory specimen collection kits and remotely monitored using web-based surveys for respiratory illness symptoms weekly between October 1, 2020, and June 20, 2021. Symptomatic participants collected respiratory specimens at symptom onset and mailed specimens to the central laboratory in Seattle. Specimens were tested for SARS-CoV-2 using RT-PCR with whole genome sequencing attempted when positive. SARS-CoV-2-infected individuals were notified, and their household contacts submitted specimens every 2 days for 14 days.

RESULTS: In total, 1371 participants collected 2029 specimens that were tested; 16 individuals (1.2%) within 6 households tested positive for SARS-CoV-2 during the study period. Full genome sequences were generated from 11 individuals within 4 households. Very little genetic variation was found among SARS-CoV-2 viruses sequenced from different individuals in the same household, supporting transmission within the household.

CONCLUSIONS: This study indicates web-based surveillance of respiratory symptoms, combined with rapid and longitudinal specimen collection and remote contact tracing, provides a viable strategy to monitor households and detect household transmission of SARS-CoV-2.

TRIAL REGISTRATION IDENTIFIER: NCT04141930, Date of registration 28/10/2019.

RevDate: 2024-03-13

Reike MJ, de Jong JJ, Bismar TA, et al (2024)

Alignment of molecular subtypes across multiple bladder cancer subtyping classifiers.

Urologic oncology pii:S1078-1439(24)00043-7 [Epub ahead of print].

BACKGROUND: Treatment of patients with muscle-invasive bladder cancer (MIBC) includes cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC). Molecular subtypes have been associated with patient outcomes after NAC and RC, but the reported results have been highly inconsistent.

OBJECTIVE: To evaluate the association of molecular subtypes from different classifiers with overall survival (OS) among patients with MIBC who underwent RC.

MATERIALS AND METHODS: We analyzed gene expression data generated from transurethral resection of MIBC from a previously assembled and published meta-cohort, NACmeta (N = 601, 247 treated with NAC+RC and 354 RC without NAC), where extended follow-up was available. Molecular subtypes were assigned using the Genomic Subtyping Classifier (GSC), the Consensus Classifier, The Cancer Genome Atlas (TCGA) Classifier, and the Lund Classifier. For survival analysis, inverse probability weighting was used to balance the clinical NAC and non-NAC patient groups.

RESULTS: A high consistency in gene expression patterns and nomenclature was observed between luminal-like subtypes, defined as GSC-Luminal, Consensus-Luminal Papillary (LumP), TCGA Luminal-Papillary (LumP) and Lund-UroA, but not for basal-like subtypes such GSC-Basal, Consensus Basal/Squamous, TCGA-Basal/Squamous and Lund-Basal/Squamous. Patients with luminal-like subtypes demonstrated no difference in 3-year OS when treated with or without NAC (P = 0.7 for GSC, P = 0.94 for Consensus, P = 0.87 for TCGA and P = 0.66 for Lund-UroA, respectively).

CONCLUSION: Luminal-like molecular subtypes identify a subgroup of MIBC patients who do not appear to benefit from current NAC regimens, even for locally advanced disease. In addition, we were able to illustrate differences in subtyping nomenclature that are not reflected in the underlying biological definition of the subtypes.

PATIENT SUMMARY: Muscle-invasive bladder cancer exhibits molecular diversity, and various classifications identify different groups who do not benefit from chemotherapy. On the other hand, there is a high inconsistency in the way cancer groupings are named.

RevDate: 2024-03-13

Puschel K, Thompson B, Rioseco A, et al (2024)

Cancer Advocacy in Residency Education: From principles to competencies.

Journal of cancer policy pii:S2213-5383(24)00004-3 [Epub ahead of print].

INTRODUCTION: The global cancer burden is increasing. Current global evidence indicates there will be a 47% rise of cancer cases for the period 2020 to 2040. The cancer rate differential also is evident within countries and regions. Efforts have been used to reduce the health disparities; however, the inequity prevails. One potential way to help reduce the disparity is through advocacy by physicians.

METHODS: Two recent systematic review articles on advocacy among physicians note that physicians are unlikely to be taught advocacy in medical education, and also note there are no advocacy competencies or skill sets that are either taught or valued in medical education. We explore literature and develop a model to understand the components of advocacy in medical education, specifically in resident training. We follow the model's main components by examining principles of advocacy, relevant domains of advocacy, and competencies and values for advocacy education.

RESULTS: Four ethical principles of advocacy education are identified: beneficence, non-maleficence, autonomy, and justice. These principles must be applied in meaningful, culturally sensitive, respectful, and promotion of the well-being ways. Three domains are identified: the practice domain (provider-patient interaction), the community domain (provider-community collaboration), and the health policy domain (the larger social environment). Advocacy occurs differently within each domain. Finally, competencies in the form of knowledge, skills, and values are described. We present a table noting where each competency occurs (by domain) as well as the value of each knowledge and skill.

POLICY SUMMARY: The significance of including advocacy instruction in medical education requires a change in the current medical education field. Besides valuing the concept of including advocacy, principles, domains, and competencies of inclusion are critical. In summary, we encourage the inclusion of advocacy education in resident medical programs so physicians become competent medical providers at diverse levels of society.

RevDate: 2024-03-13

Rashidi A, Ebadi M, Rehman TU, et al (2024)

Long- and short-term effects of fecal microbiota transplantation on antibiotic resistance genes: results from a randomized placebo-controlled trial.

Gut microbes, 16(1):2327442.

In small series, third-party fecal microbiota transplantation (FMT) has been successful in decolonizing the gut from clinically relevant antibiotic resistance genes (ARGs). Less is known about the short- and long-term effects of FMT on larger panels of ARGs. We analyzed 226 pre- and post-treatment stool samples from a randomized placebo-controlled trial of FMT in 100 patients undergoing allogeneic hematopoietic cell transplantation or receiving anti-leukemia induction chemotherapy for 47 ARGs. These patients have heavy antibiotic exposure and a high incidence of colonization with multidrug-resistant organisms. Samples from each patient spanned a period of up to 9 months, allowing us to describe both short- and long-term effects of FMT on ARGs, while the randomized design allowed us to distinguish between spontaneous changes vs. FMT effect. We find an overall bimodal pattern. In the first phase (days to weeks after FMT), low-level transfer of ARGs largely associated with commensal healthy donor microbiota occurs. This phase is followed by long-term resistance to new ARGs as stable communities with colonization resistance are formed after FMT. The clinical implications of these findings are likely context-dependent and require further research. In the setting of cancer and intensive therapy, long-term ARG decolonization could translate into fewer downstream infections.

RevDate: 2024-03-14
CmpDate: 2024-03-14

Chung DC, Gray DM, Singh H, et al (2024)

A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening.

The New England journal of medicine, 390(11):973-983.

BACKGROUND: Colorectal cancer is the third most diagnosed cancer in adults in the United States. Early detection could prevent more than 90% of colorectal cancer-related deaths, yet more than one third of the screening-eligible population is not up to date with screening despite multiple available tests. A blood-based test has the potential to improve screening adherence, detect colorectal cancer earlier, and reduce colorectal cancer-related mortality.

METHODS: We assessed the performance characteristics of a cell-free DNA (cfDNA) blood-based test in a population eligible for colorectal cancer screening. The coprimary outcomes were sensitivity for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions) relative to screening colonoscopy. The secondary outcome was sensitivity to detect advanced precancerous lesions.

RESULTS: The clinical validation cohort included 10,258 persons, 7861 of whom met eligibility criteria and were evaluable. A total of 83.1% of the participants with colorectal cancer detected by colonoscopy had a positive cfDNA test and 16.9% had a negative test, which indicates a sensitivity of the cfDNA test for detection of colorectal cancer of 83.1% (95% confidence interval [CI], 72.2 to 90.3). Sensitivity for stage I, II, or III colorectal cancer was 87.5% (95% CI, 75.3 to 94.1), and sensitivity for advanced precancerous lesions was 13.2% (95% CI, 11.3 to 15.3). A total of 89.6% of the participants without any advanced colorectal neoplasia (colorectal cancer or advanced precancerous lesions) identified on colonoscopy had a negative cfDNA blood-based test, whereas 10.4% had a positive cfDNA blood-based test, which indicates a specificity for any advanced neoplasia of 89.6% (95% CI, 88.8 to 90.3). Specificity for negative colonoscopy (no colorectal cancer, advanced precancerous lesions, or nonadvanced precancerous lesions) was 89.9% (95% CI, 89.0 to 90.7).

CONCLUSIONS: In an average-risk screening population, this cfDNA blood-based test had 83% sensitivity for colorectal cancer, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions. (Funded by Guardant Health; ECLIPSE ClinicalTrials.gov number, NCT04136002.).

RevDate: 2024-03-14
CmpDate: 2024-03-14

Kim D, Olson JM, JA Cooper (2024)

N-cadherin dynamically regulates pediatric glioma cell migration in complex environments.

The Journal of cell biology, 223(6):.

Pediatric high-grade gliomas are highly invasive and essentially incurable. Glioma cells migrate between neurons and glia, along axon tracts, and through extracellular matrix surrounding blood vessels and underlying the pia. Mechanisms that allow adaptation to such complex environments are poorly understood. N-cadherin is highly expressed in pediatric gliomas and associated with shorter survival. We found that intercellular homotypic N-cadherin interactions differentially regulate glioma migration according to the microenvironment, stimulating migration on cultured neurons or astrocytes but inhibiting invasion into reconstituted or astrocyte-deposited extracellular matrix. N-cadherin localizes to filamentous connections between migrating leader cells but to epithelial-like junctions between followers. Leader cells have more surface and recycling N-cadherin, increased YAP1/TAZ signaling, and increased proliferation relative to followers. YAP1/TAZ signaling is dynamically regulated as leaders and followers change position, leading to altered N-cadherin levels and organization. Together, the results suggest that pediatric glioma cells adapt to different microenvironments by regulating N-cadherin dynamics and cell-cell contacts.

RevDate: 2024-03-13

Maxwell E, Moore R, Niendorf K, et al (2024)

Further defining the roles and impact of genetic counselors in the biotechnology and pharmaceutical industry.

Journal of genetic counseling [Epub ahead of print].

As personalized medicine has gained traction, drug development models in the biotechnology and pharmaceutical industry (BPI) have increasingly sought to address medical conditions with a genetic component, creating an opportunity for genetic counselors (GCs) to fill new roles and utilize their unique training to contribute to drug development. Despite the potential for GCs in BPI, literature around the role of GCs in this industry has been limited. Our mixed methods study aimed to assess how the roles of GCs in BPI have evolved since 2016, investigate the value of and opportunity for GCs in this industry, and further characterize their motivation and job satisfaction. Participants were recruited via social media advertising, snowball sampling, and email listservs from the National Society of Genetic Counseling (NSGC), the Canadian Association of Genetic Counselors (CAGC), and the American Board of Genetic Counseling (ABGC). Survey (n = 20) and interview (n = 6) data indicates many aspects of GC roles in BPI are consistent with the 2016 study. However, there is evidence of roles becoming more varied and with increasing recognition of the value of GCs, opportunities for involvement in BPI are growing. Furthermore, combined study data found that GCs are motivated by the flexibility of BPI roles as well as the opportunity to contribute to rare disease treatment development and that they are overall satisfied with most aspects of their jobs. Interview data also found that genetic counseling training has the potential to improve clinical trial design and outcomes by making drug development more patient-centric. Finally, combined study data found that while GCs continue to utilize Accreditation Council of Genetic Counseling (ACGC) practice-based competencies (PBCs), business-related training may benefit GCs seeking to enter BPI. Together, these findings are critical for informing genetic counseling training programs, employers within BPI, and GCs interested in entering these positions.

RevDate: 2024-03-13

Solomon SR, Powell BL, Koprivnikar J, et al (2024)

CPX-351 Pharmacokinetics and Safety in Adults with Hematologic Malignancies and Renal Function Impairment: Phase 1 Trial.

Cancers, 16(5): pii:cancers16050915.

This open-label phase 1 study (clinicaltrials.gov, NCT03555955) assessed CPX-351 pharmacokinetics (PK) and safety in patients with hematologic malignancies with normal or impaired renal function. Patients were enrolled into three cohorts based on their creatinine clearance (CrCl): ≥90 mL/min (Cohort 1, normal renal function, n = 7), 30 to <59 mL/min (Cohort 2, moderate renal impairment, n = 8), or <30 mL/min (Cohort 3, severe renal impairment, n = 6). Patients received intravenous CPX-351 for initial induction; blood and urine samples were collected for PK analysis. The primary objective was to assess the PK parameters for cytarabine, daunorubicin, and their respective metabolites, arabinosyluracil (Ara-U) and daunorubicinol. Renal impairment did not significantly impact the cytarabine, daunorubicin, or daunorubicinol exposure, but it caused a slight increase in the Ara-U exposure. The CPX-351 side effect profile was similar in patients with impaired renal function compared to those with normal renal function. All the patients reported ≥1 treatment-emergent adverse event (TEAE), most commonly febrile neutropenia and nausea (57% each) and hyperglycemia (43%); no patients discontinued treatment due to TEAEs. These data suggest that CPX-351 dose adjustment is not required for patients with hematologic malignancies with moderate or severe renal impairment.

RevDate: 2024-03-13

Lunn-Halbert MC, Laszlo GS, Erraiss S, et al (2024)

Preclinical Characterization of the Anti-Leukemia Activity of the CD33/CD16a/NKG2D Immune-Modulating TriNKET[®] CC-96191.

Cancers, 16(5): pii:cancers16050877.

Increasing efforts are focusing on natural killer (NK) cell immunotherapies for AML. Here, we characterized CC-96191, a novel CD33/CD16a/NKG2D immune-modulating TriNKET[®]. CC-96191 simultaneously binds CD33, NKG2D, and CD16a, with NKG2D and CD16a co-engagement increasing the avidity for, and activation of, NK cells. CC-96191 was broadly active against human leukemia cells in a strictly CD33-dependent manner, with maximal efficacy requiring the co-engagement of CD16a and NKG2D. A frequent CD33 single nucleotide polymorphism, R69G, reduced CC-96191 potency but not maximal activity, likely because of reduced CD33 binding. Similarly, the potency, but not the maximal activity, of CC-96191 was reduced by high concentrations of soluble CD33; in contrast, the soluble form of the NKG2D ligand MICA did not impact activity. In the presence of CD33+ AML cells, CC-96191 activated NK cells but not T cells; while maximum anti-AML efficacy was similar, soluble cytokine levels were 10- to >100-fold lower than with a CD33/CD3 bispecific antibody. While CC-96191-mediated cytolysis was not affected by ABC transporter proteins, it was reduced by anti-apoptotic BCL-2 family proteins. Finally, in patient marrow specimens, CC-96191 eliminated AML cells but not normal monocytes, suggesting selectivity of TriNKET-induced cytotoxicity toward neoplastic cells. Together, these findings support the clinical exploration of CC-96191 as in NCT04789655.

RevDate: 2024-03-13

Gunn AL, Yashchenko AI, Dubrulle J, et al (2024)

A high-content screen reveals new regulators of nuclear membrane stability.

Scientific reports, 14(1):6013.

Nuclear membrane rupture is a physiological response to multiple in vivo processes, such as cell migration, that can cause extensive genome instability and upregulate invasive and inflammatory pathways. However, the underlying molecular mechanisms of rupture are unclear and few regulators have been identified. In this study, we developed a reporter that is size excluded from re-compartmentalization following nuclear rupture events. This allows for robust detection of factors influencing nuclear integrity in fixed cells. We combined this with an automated image analysis pipeline in a high-content siRNA screen to identify new proteins that both increase and decrease nuclear rupture frequency in cancer cells. Pathway analysis identified an enrichment of nuclear membrane and ER factors in our hits and we demonstrate that one of these, the protein phosphatase CTDNEP1, is required for nuclear stability. Analysis of known rupture determinants, including an automated quantitative analysis of nuclear lamina gaps, are consistent with CTDNEP1 acting independently of actin and nuclear lamina organization. Our findings provide new insights into the molecular mechanism of nuclear rupture and define a highly adaptable program for rupture analysis that removes a substantial barrier to new discoveries in the field.

RevDate: 2024-03-12

Levis MJ, Hamadani M, Logan B, et al (2024)

Gilteritinib as Post-Transplant Maintenance for Acute Myeloid Leukemia With Internal Tandem Duplication Mutation of FLT3.

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

PURPOSE: Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with acute myeloid leukemia (AML) harboring an internal tandem duplication mutation of FLT3 (FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit.

METHODS: Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS.

RESULTS: Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575).

CONCLUSION: Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

RevDate: 2024-03-12

Park ER, Kirchhoff AC, Donelan K, et al (2024)

Health Insurance Navigation Tools Intervention: A Pilot Trial Within the Childhood Cancer Survivor Study.

JCO oncology practice [Epub ahead of print].

PURPOSE: Childhood cancer survivors are at increased risk for underinsurance and health insurance-related financial burden. Interventions targeting health insurance literacy (HIL) to improve the ability to understand and use health insurance are needed.

METHODS: We codeveloped a four-session health insurance navigation tools (HINT) intervention, delivered synchronously by a patient navigator, and a corresponding booklet. We conducted a randomized pilot trial with survivors from the Childhood Cancer Survivor Study comparing HINT with enhanced usual care (EUC; booklet). We assessed feasibility, acceptability, and preliminary efficacy (HIL, primary outcome; knowledge and confidence with health insurance terms and activity) on a 5-month survey and exit interviews.

RESULTS: Among 231 invited, 82 (32.5%) survivors enrolled (53.7% female; median age 39 years, 75.6% had employer-sponsored insurance). Baseline HIL scores were low (mean = 28.5; 16-64; lower scores better); many lacked knowledge of Affordable Care Act (ACA) provisions. 80.5% completed four HINT sessions, and 93.9% completed the follow-up survey. Participants rated HINT's helpfulness a mean of 8.9 (0-10). Exit interviews confirmed HINT's acceptability, specifically its virtual and personalized delivery and helpfulness in building confidence in understanding one's coverage. Compared with EUC, HINT significantly improved HIL (effect size = 0.94. P < .001), ACA provisions knowledge (effect size = 0.73, P = .003), psychological financial hardship (effect size = 0.64, P < .006), and health insurance satisfaction (effect size = 0.55, P = .03).

CONCLUSION: Results support the feasibility and acceptability of a virtual health insurance navigation program targeted for childhood survivors to improve HIL. Randomized trials to assess the efficacy and sustainability of health insurance navigation on HIL and financial burden are needed.

RevDate: 2024-03-13
CmpDate: 2024-03-13

Schoen MW, Montgomery RB, Owens L, et al (2024)

Survival in Patients With De Novo Metastatic Prostate Cancer.

JAMA network open, 7(3):e241970 pii:2815950.

RevDate: 2024-03-12

Xu S, Esmaeili S, Cardozo-Ojeda EF, et al (2024)

Two-way pharmacodynamic modeling of drug combinations and its application to pairs of repurposed Ebola and SARS-CoV-2 agents.

Antimicrobial agents and chemotherapy [Epub ahead of print].

Existing pharmacodynamic (PD) mathematical models for drug combinations discriminate antagonistic, additive, multiplicative, and synergistic effects, but fail to consider how concentration-dependent drug interaction effects may vary across an entire dose-response matrix. We developed a two-way pharmacodynamic (TWPD) model to capture the PD of two-drug combinations. TWPD captures interactions between upstream and downstream drugs that act on different stages of viral replication, by quantifying upstream drug efficacy and concentration-dependent effects on downstream drug pharmacodynamic parameters. We applied TWPD to previously published in vitro drug matrixes for repurposed potential anti-Ebola and anti-SARS-CoV-2 drug pairs. Depending on the drug pairing, the model recapitulated combined efficacies as or more accurately than existing models and can be used to infer efficacy at untested drug concentrations. TWPD fits the data slightly better in one direction for all drug pairs, meaning that we can tentatively infer the upstream drug. Based on its high accuracy, TWPD could be used in concert with PK models to estimate the therapeutic effects of drug pairs in vivo.

RevDate: 2024-03-12

deCamp AC, Corcoran MM, Fulp WJ, et al (2024)

Human immunoglobulin gene allelic variation impacts germline-targeting vaccine priming.

NPJ vaccines, 9(1):58.

Vaccine priming immunogens that activate germline precursors for broadly neutralizing antibodies (bnAbs) have promise for development of precision vaccines against major human pathogens. In a clinical trial of the eOD-GT8 60mer germline-targeting immunogen, higher frequencies of vaccine-induced VRC01-class bnAb-precursor B cells were observed in the high dose compared to the low dose group. Through immunoglobulin heavy chain variable (IGHV) genotyping, statistical modeling, quantification of IGHV1-2 allele usage and B cell frequencies in the naive repertoire for each trial participant, and antibody affinity analyses, we found that the difference between dose groups in VRC01-class response frequency was best explained by IGHV1-2 genotype rather than dose and was most likely due to differences in IGHV1-2 B cell frequencies for different genotypes. The results demonstrate the need to define population-level immunoglobulin allelic variations when designing germline-targeting immunogens and evaluating them in clinical trials.

RevDate: 2024-03-12

Magaret CA, Li L, deCamp AC, et al (2024)

Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features.

Nature communications, 15(1):2175.

In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p < 0.05]. VE differed by residue match vs. mismatch to the vaccine-insert at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20); significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 antibody-epitope escape scores and 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccinee sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against the most distant viruses.

RevDate: 2024-03-11

Luce C, Palazzo L, Anderson ML, et al (2024)

A pragmatic randomized clinical trial of multilevel interventions to improve adherence to lung cancer screening (The Larch Study): Study protocol.

Contemporary clinical trials pii:S1551-7144(24)00069-7 [Epub ahead of print].

BACKGROUND: In real-world settings, low adherence to lung cancer screening (LCS) diminishes population-level benefits of reducing lung cancer mortality. We describe the Larch Study protocol, which tests the effectiveness of two patient-centered interventions (Patient Voices Video and Stepped Reminders) designed to address barriers and improve annual LCS adherence.

METHODS: The Larch Study is a pragmatic randomized clinical trial conducted within Kaiser Permanente Washington. Eligible patients (target n = 1606) are aged 50-78 years with an index low-dose CT (LDCT) of the chest with negative or benign findings. With a 2 × 2 factorial-design, patients are individually randomized to 1 of 4 arms: video only, reminders only, both video and reminders, or usual care. The Patient Voices video addresses patient education needs by normalizing LCS, reminding patients when LCS is due, and encouraging social support. Stepped Reminders prompts primary care physicians to order patient's repeat screening LDCT and patients to schedule their scan. Intervention delivery is embedded within routine healthcare, facilitated by shared electronic health record components. Primary outcome is adherence to national LCS clinical guidelines, defined as repeat LDCT within 9-15 months. Patient-reported outcomes are measured via survey (knowledge of LCS, perception of stigma) approximately 8 weeks after index LDCT. Our mixed-methods formative evaluation includes process data, collected during the trial, and interviews with trial participants and stakeholders.

DISCUSSION: Results will fill an important scientific gap on multilevel interventions to increase annual LCS adherence and provide opportunities for spread and scale to other healthcare settings.

REGISTRATION: Trial is registered at clinicaltrials.gov (#NCT05747443).

RevDate: 2024-03-11

Mehta RS, Petersdorf EW, Spellman SR, et al (2024)

Combined Effect of Unrelated Donor Age and HLA Peptide-Binding Motifs (PBM) Match Status on HCT Outcomes.

Blood advances pii:515271 [Epub ahead of print].

An HLA-mismatched unrelated donor (MMUD) who is class I protein binding motifs (PBM)-matched is preferred over a PBM-mismatched donor. We hypothesized that using a younger donor (<35 years vs >35 years) could compensate for the inferior overall survival (OS) associated with PBM-mismatches. We compared six groups: HLA-matched/younger donor (n=10,531), HLA-matched/older donor (n=3572), PBM-matched/younger donor (n=357), PBM-matched/older donor (n=257), PBM-mismatched/younger donor (n=616), and PBM-mismatched/older donor (n=339) in patients undergoing transplantation with conventional graft-versus-host disease (GVHD) prophylaxis. In multivariate analysis, HLA-matched/younger donors were associated with superior OS relative to any other group. Pairwise comparisons showed that donor age significantly impacted OS in both HLA-matched and HLA-mismatched groups. Moreover, younger donors appeared to negate the detrimental effect of PBM-mismatching: the PBM-matched/younger donor group had similar OS as the HLA-matched/older donor group and the PBM-mismatched/younger donor group had similar OS as the PBM-matched/older donor group. Our study suggests that older unrelated donor age and PBM-mismatching confer similarly adverse effects on OS and the impacts are additive - a finding which may widen the "acceptable" donor pool. The best OS is observed with HLA-matched/younger donors and the worst with PBM-mismatched/older donors. These findings should be validated with other datasets and with post-transplantation cyclophosphamide-based prophylaxis.

RevDate: 2024-03-12

Chai W, Maskarinec G, Lim U, et al (2023)

Association of Habitual Intake of Probiotic Supplements and Yogurt with Characteristics of the Gut Microbiome in the Multiethnic Cohort Adiposity Phenotype Study.

Gut microbiome (Cambridge, England), 4:.

Consumption of probiotics and/or yogurt could be a solution for restoring the balance of the gut microbiota. This study examined associations of regular intake of probiotic supplements or yogurt with the gut microbiota among a diverse population of older adults (N=1,861; 60-72 years). Fecal microbial composition was obtained from 16S rRNA gene sequencing (V1-V3 region). General Linear Models were used to estimate the associations of probiotic supplement or yogurt intake with microbiome measures adjusting for covariates. Compared to non-yogurt consumers (N=1,023), regular yogurt consumers (≥once/week, N=818) had greater Streptococcus (β=0.29, P=0.0003) and lower Odoribacter (β=-0.33, P<0.0001) abundance. The directions of the above associations were consistent across the five ethnic groups but stronger among Japanese Americans (Streptococcus: β=0.56, P=0.0009; Odoribacter: β=-0.62, P=0.0005). Regular intake of probiotic supplements (N=175) was not associated with microbial characteristics (i.e., alpha diversity and the abundance of 152 bacteria genera). Streptococcus is one of the predominant bacteria genera in yogurt products, which may explain the positive association between yogurt consumption and Streptococcus abundance. Our analyses suggest that changes in Odoribacter were independent of changes in Streptococcus abundance. Future studies may investigate whether these microbial genera and their sub-level species mediate potential pathways between yogurt consumption and health.

RevDate: 2024-03-11

Thomson CA, Aragaki AK, Prentice RL, et al (2024)

Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women : Postintervention Follow-up of a Randomized Clinical Trial.

Annals of internal medicine [Epub ahead of print].

BACKGROUND: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited.

OBJECTIVE: To evaluate long-term health outcomes among postmenopausal women in the Women's Health Initiative CaD trial.

DESIGN: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611).

SETTING: A multicenter (n = 40) trial across the United States.

PARTICIPANTS: 36 282 postmenopausal women with no history of breast or colorectal cancer.

INTERVENTION: Random 1:1 assignment to 1000 mg of calcium carbonate (400 mg of elemental calcium) with 400 IU of vitamin D3 daily or placebo.

MEASUREMENTS: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use.

RESULTS: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality.

LIMITATION: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled.

CONCLUSION: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality.

PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute of the National Institutes of Health.

RevDate: 2024-03-11

Hubbard RA, Su YR, Bowles EJ, et al (2024)

Predicting five-year interval second breast cancer risk in women with prior breast cancer.

Journal of the National Cancer Institute pii:7625569 [Epub ahead of print].

BACKGROUND: Annual surveillance mammography is recommended for women with a personal history of breast cancer. Risk prediction models that estimate mammography failures such as interval second breast cancers could help to tailor surveillance imaging regimens to women's individual risk profiles.

METHODS: In a cohort of women with a history of breast cancer receiving surveillance mammography in the Breast Cancer Surveillance Consortium in 1996-2019, we used LASSO-penalized regression to estimate the probability of an interval second cancer (invasive cancer or ductal carcinoma in situ) in the one-year following a negative surveillance mammogram. Based on predicted risks from this one-year risk model, we generated cumulative risks of an interval second cancer for the five-year period following each mammogram. Model performance was evaluated using cross-validation in the overall cohort and within race and ethnicity strata.

RESULTS: In 173,290 surveillance mammograms, we observed 496 interval cancers. One-year risk models were well-calibrated (expected/observed ratio = 1.00) with good accuracy (area under the receiver operating characteristic curve = 0.64). Model performance was similar across race and ethnicity groups. The median five-year cumulative risk was 1.20% (interquartile range 0.93-1.63%). Median five-year risks were highest in women who were under age 40 or pre- or peri-menopausal at diagnosis and those with estrogen receptor-negative primary breast cancers.

CONCLUSIONS: Our risk model identified women at high risk of interval second breast cancers who may benefit from additional surveillance imaging modalities. Risk models should be evaluated to determine if risk-guided supplemental surveillance imaging improves early detection and decreases surveillance failures.

RevDate: 2024-03-11

Song Y, Loomans-Kropp H, Baugher RN, et al (2024)

Frameshift mutations in peripheral blood as a biomarker for surveillance of lynch syndrome.

Journal of the National Cancer Institute pii:7625568 [Epub ahead of print].

BACKGROUND: Lynch syndrome (LS) is a hereditary cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes, which lead to high microsatellite instability (MSI-H) and frameshift mutations (FSMs) at coding mononucleotide repeats (cMNRs) in the genome. Recurrent FSMs in these regions are thought to play a central role in the increased risk of various cancers. However, there are no biomarkers currently available for the surveillance of MSI-H-associated cancers.

METHODS: An FSM-based biomarker panel was developed and validated by targeted next generation sequencing of supernatant DNA from cultured MSI-H colorectal cancer cells. This supported selection of 122-FSM targets as potential biomarkers. This biomarker panel was then tested using matched tumor, adjacent normal tissue, and buffy coat (53 samples), and blood-derived cell-free DNA (cfDNA; 38 samples) obtained from 45 cases of MSI-H/MMR deficient (MMRd) patients/carriers. cfDNA from 84 healthy individuals was also sequenced to assess background noise.

RESULTS: Recurrent FSMs at cMNRs were detectable not only in tumors, but also in cfDNA from MSI-H/MMRd cases including a LS carrier with a varying range of target detection (up to 85.2%), whereas they were virtually undetectable in healthy individuals. ROC analysis showed high sensitivity and specificity (AUC = 0.94) of the investigated panel.

CONCLUSIONS: We demonstrated that FSMs can be detected in cfDNA from MSI-H/MMRd cases and asymptomatic carriers. The 122-target FSM panel described here has promise as a tool for improved surveillance of MSI-H/MMRd carriers with the potential to reduce the frequency of invasive screening methods for this high-cancer-risk cohort.

RevDate: 2024-03-11

Lee M, Larose H, Gräbeldinger M, et al (2024)

The evolving value assessment of cancer therapies: Results from a modified Delphi study.

Health policy OPEN, 6:100116.

The move toward early detection and treatment of cancer presents challenges for value assessment using traditional endpoints. Current cancer management rarely considers the full economic and societal benefits of therapies. Our study used a modified Delphi process to develop principles for defining and assessing value of cancer therapies that aligns with the current trajectory of oncology research and reflects broader notions of value. 24 experts participated in consensus-building activities across 5 months (16 took part in structured interactions, including a survey, plenary sessions, interviews, and off-line discussions, while 8 participated in interviews). Discussion focused on: 1) which oncology-relevant endpoints should be used for assessing treatments for early-stage cancer and access decisions for early-stage treatments, and 2) the importance of additional value components and how these can be integrated in value assessments. The expert group reached consensus on 4 principles in relation to the first area (consider oncology-relevant endpoints other than overall survival; build evidence for endpoints that provide earlier indication of efficacy; develop evidence for the next generation of predictive measures; use managed entry agreements supported by ongoing evidence collection to address decision-maker evidence needs) and 3 principles in relation to the second (routinely use patient reported outcomes in value assessments; assess broad economic impact of new medicines; consider other value aspects of relevance to patients and society).

RevDate: 2024-03-11

Greenlaw A, Dell R, T Tsukiyama (2024)

Initial acidic media promotes quiescence entry in Saccharomyces cerevisiae.

microPublication biology, 2024:.

Quiescence is a conserved cellular state wherein cells cease proliferation and remain poised to re-enter the cell cycle when conditions are appropriate. Budding yeast is a powerful model for studying cellular quiescence. In this work, we demonstrate that the pH of the YPD media strongly affects quiescence entry efficiency in Saccharomyces cerevisiae. Adjusting the initial media pH to 5.5 significantly improves quiescence entry efficiency compared to unadjusted YPD media. Thermotolerance of the produced quiescence yeast are similar, suggesting the media pH influences the quantity of quiescent cells more than quality of quiescence reached.

RevDate: 2024-03-10

Muyinda Z, Davis KM, Kalungi S, et al (2024)

Using patient navigation to reduce time to diagnosis of breast cancer in Uganda.

Journal of the American College of Radiology : JACR pii:S1546-1440(24)00273-4 [Epub ahead of print].

OBJECTIVE: The Ugandan Ministry of Health adopted the Breast Imaging-Reporting and Data System (BI-RADS) as standard of care in 2016. We performed a medical audit of breast ultrasound practices at four tertiary-level hospitals to assess interpretive performance. We also determined the effect of a low-cost navigation program linking breast imaging and pathology, on percent of patients completing diagnostic care.

METHODS: We retrieved 966 consecutive diagnostic breast ultrasound reports, with complete data, performed on women aged >18 years, presenting with symptoms of breast cancer between 2018-2020 from participating hospitals. Ultrasound results were linked to tumor registries and patient follow-up. A medical audit was performed according to the American College of Radiology BI-RADS Atlas, 5[th] edition, and compared to results from a prior audit performed in 2013. At Mulago hospital, we piloted an intervention based on patient navigation, cost sharing, and same day imaging/tissue sampling/pathology.

RESULTS: 888 (91.9%) of breast ultrasound examinations were eligible for inclusion. Compared to 2013, the post-intervention cancer detection rate increased from 38 to 148.7 cancers/1,000 examinations; Positive Predictive Value (PPV)2 from 29.6% to 48.9%; and PPV3 from 62.7% to 79.9%. Specificity decreased from 90.5% to 87.7%, and sensitivity from 92.3% to 81.1%. Mean time from tissue sampling to receipt of a diagnosis decreased from 60 days to 7 days. The intervention increased the percentage of patients completing diagnostic care from zero to 100%.

DISCUSSION: Efforts to establish a culture of continuous quality improvement in breast ultrasound require robust data collection that links imaging results to pathology and patient follow-up. Interpretive performance met BI-RADS benchmarks for palpable masses, except sensitivity. Our resource appropriate strategy linking imaging, tissue sampling, and pathology interpretation decreased time to diagnosis and lost to follow-up rates and improved the precision of the audit.

RevDate: 2024-03-10

Kumar S, B Nabet (2024)

A chemical magnet: Approaches to guide precise protein localization.

Bioorganic & medicinal chemistry, 102:117672 pii:S0968-0896(24)00086-5 [Epub ahead of print].

Small molecules that chemically induce proximity between two proteins have been widely used to precisely modulate protein levels, stability, and activity. Recently, several studies developed novel strategies that employ heterobifunctional molecules that co-opt shuttling proteins to control the spatial localization of a target protein, unlocking new potential within this domain. Together, these studies lay the groundwork for novel targeted protein relocalization modalities that can rewire the protein circuitry and interactome to influence biological outcomes.

RevDate: 2024-03-09

Choi JK, Xiao W, Chen X, et al (2024)

5[TH] EDITION OF THE WORLD HEALTH ORGANIZATION CLASSIFICATION OF TUMORS OF THE HEMATOPOIETIC AND LYMPHOID TISSUES.

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc pii:S0893-3952(24)00046-2 [Epub ahead of print].

This manuscript represents a review of lymphoblastic leukemia/lymphoma (acute lymphoblastic leukemia/lymphoblastic lymphoma), acute leukemias of ambiguous lineage, mixed-phenotype acute leukemias, myeloid/lymphoid neoplasms with eosinophilia and defining gene rearrangements, histiocytic and dendritic neoplasms and genetic tumor syndromes of the 5[th] edition of the World Health Organization Classification of Tumors of the Haematopoietic and Lymphoid Tissues (WHO-HEM5). The diagnostic clinicopathologic, cytogenetic and molecular genetic features are discussed. The differences in comparison to the 4th revised edition of the WHO classification of hematolymphoid neoplasms are highlighted.

RevDate: 2024-03-09

Friedman DN, Goodman PJ, Leisenring WM, et al (2024)

Impact of Risk-Based therapy on late morbidity and mortality in neuroblastoma survivors: a report from the childhood cancer survivor study.

Journal of the National Cancer Institute pii:7625106 [Epub ahead of print].

BACKGROUND: Early efforts at risk-adapted therapy for neuroblastoma are predicted to result in differential late effects; the magnitude of these differences have not been well-described.

METHODS: Late mortality, subsequent malignant neoplasms (SMN), and severe/life-threatening chronic health conditions (CHCs), graded according to CTCAE v4.03, were assessed among 5-year CCSS survivors of neuroblastoma diagnosed 1987-1999. Using age, stage at diagnosis, and treatment, survivors were classified into risk groups (low [n = 425]; intermediate [n = 252]; high [n = 245]). Standardized mortality ratios (SMR) and standardized incidence ratios (SIR) of SMNs were compared to matched population controls. Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for CHC compared to 1,029 CCSS siblings.

RESULTS: Among survivors (49.8% male; median age 21 years, range 7-42; median follow-up 19.3 years, range 5-29.9), 80% with low-risk disease were treated with surgery alone, while 79.1% with high-risk disease received surgery, radiation, chemotherapy ± autologous stem cell transplant (ASCT). All-cause mortality was elevated across risk groups (SMRhigh=27.7 [21.4-35.8]; SMRintermediate=3.3 [1.7-6.5]; SMRlow=2.8 [1.7-4.8]). SMN risk was increased among high- and intermediate-risk survivors (SIRhigh=28.0 [18.5-42.3]; SIRintermediate=3.7 [1.2-11.3]), but did not differ from the US population for survivors of low-risk disease. Compared to siblings, survivors had an increased risk of grade 3-5 CHCs, particularly among those with high-risk disease (HRhigh=16.1 [11.2-23.2]; HRintermediate=6.3 [3.8-10.5]; HRlow=1.8 [1.1-3.1]).

CONCLUSION: Survivors of high-risk disease treated in the early days of risk stratification carry a markedly elevated burden of late recurrence, SMN, and organ-related multi-morbidity, while survivors of low/intermediate-risk disease have a modest risk of late adverse outcomes.

RevDate: 2024-03-09

Nakasone ES, Bustillos HC, Gui X, et al (2024)

Multidisciplinary Approach for the Management of Metastatic Poorly Differentiated Neuroendocrine Carcinoma of the Pancreas: A Case Report of an Exceptional Responder.

Pancreas pii:00006676-990000000-00129 [Epub ahead of print].

Poorly differentiated pancreatic neuroendocrine carcinomas (pNECs) are rare, highly aggressive neoplasms. Frequently metastatic at diagnosis, prognosis is poor with median overall survival estimated to be less than 1 year. Although multidisciplinary management, including systemic medications and locoregional therapies aimed at reducing and preventing symptoms caused by mass effect, is the mainstay of treatment for patients with metastatic well-differentiated pancreatic neuroendocrine tumors, rapid progression, organ dysfunction, and poor performance status often preclude initiation of even single-modality palliative chemotherapy for patients with metastatic pNEC, limiting the use of and recommendation for multidisciplinary management.We describe the case of a 51-year-old male patient diagnosed with pNEC metastatic to liver and lymph nodes presenting with impending cholestatic liver failure for whom we were able to successfully initiate and dose-escalate cytotoxic chemotherapy with excellent radiographic response. After multidisciplinary review of his case, the patient underwent pancreaticoduodenectomy and hepatic wedge biopsies, with pathology demonstrating a pathologic complete response to chemotherapy in both the pancreas and liver. Surveillance scans at 2 years from initial diagnosis and 1 year from surgery remain without evidence of locoregional or distant recurrence, highlighting the importance and utility of multidisciplinary management in select cases.

RevDate: 2024-03-09

Crandall CJ, Larson J, Shadyab AH, et al (2024)

Physical function trajectory after wrist or lower arm fracture in postmenopausal women: results from the Women's Health Initiative Study.

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA [Epub ahead of print].

UNLABELLED: Long-term physical functioning trajectories following distal forearm fracture are unknown. We found that women with versus those without distal forearm fracture were more likely to experience a 5-year decline in physical functioning, independent of initial physical functioning level. This association was most evident among women 80 years and older.

INTRODUCTION: Physical functioning trajectory following lower arm or wrist fracture is not well understood.

PURPOSE: This study is to evaluate physical functioning trajectory before vs. after lower arm or wrist fracture, stratified by age.

METHODS: We performed a nested case-control study of prospective data from the Women's Health Initiative Study (n = 2097 cases with lower arm or wrist fracture, 20,970 controls). Self-reported fractures and the physical functioning subscale of the RAND 36-item Short-Form Health Survey were assessed annually. We examined three physical functioning trajectory groups: stable, improving, and declining.

RESULTS: Mean (SD) number of physical functioning measurements was 5.2 (1.5) for cases and 5.0 (1.4) for controls. Declining physical functioning was observed among 20.4% of cases and 16.0% of controls. Compared to women without lower arm or wrist fracture, women with lower arm or wrist fracture were 33% more likely to experience declining physical functioning (adjusted odds ratio [aOR] 1.33 95% confidence interval [CI] 1.19-1.49, reference group stable or improving physical functioning trajectory). Associations varied by age: age ≥ 80 years aOR 1.56 (95% CI 1.29-1.88); age 70-79 years aOR 1.29 (95% CI 1.09-1.52); age < 70 years aOR 1.15 (95% CI 0.86-1.53) (pinteraction = 0.06). Associations between lower arm or wrist fracture and odds of declining physical functioning did not vary by baseline physical functioning or physical activity level.

CONCLUSIONS: Women with lower arm or wrist fracture, particularly those aged 80 and older, were more likely to experience declines in physical functioning than women without such fractures, independent of baseline physical functioning level.

RevDate: 2024-03-09

Reynolds G, J Lindsay (2024)

Antibacterial prophylaxis for neutropenic and high-risk hematology patients-Do the benefits outweigh the risk?.

RevDate: 2024-03-09

Liu W, Lewis FM, Oxford M, et al (2024)

Common dyadic coping and its congruence in couples facing breast cancer: The impact on couples' psychological distress.

Psycho-oncology, 33(3):e6314.

OBJECTIVE: Psychological distress is prevalent in couples facing breast cancer. Couples often deal with breast cancer as a unit instead of as individuals. Couple's dyadic coping is important for their adjustment to breast cancer; however, little is known about how couple's coping congruence influences their distress. This study examined how common dyadic coping (CDC) and coping congruence impact psychological distress in couples facing breast cancer.

METHODS: Baseline data were analyzed from 343 women with recently diagnosed early-stage breast cancer and their partners who participated in a randomized clinical trial. Psychological distress was indicated by depressed mood and state anxiety. Common dyadic coping was measured by a self-report scale. Coping congruence was assessed by the absolute difference between a woman's and her partner's CDC scores.

RESULTS: Higher CDC scores were associated with lower psychological distress in both women and partners. In the CDC subscales, women who suffered less scored higher on open communication, sharing a positive outlook, and lower on avoidance coping. Partners who suffered less scored higher on open communication, sharing a positive outlook, spending time talking, and lower on avoidance coping. Greater congruence in CDC was associated with lower psychological distress in women and their partners. Congruence in sharing a positive outlook benefited both members of the dyad; congruence in avoidance coping significantly benefited patients; congruence in open communication significantly benefited partners.

CONCLUSIONS: CDC and its congruence in specific areas have potential benefit to couple's psychological distress when facing breast cancer. Health care providers could consider enhancing couple's CDC and coping congruence to improve their adjustment.

RevDate: 2024-03-08

Farland LV, Lind KE, Thomson CA, et al (2024)

Infertility and risk of postmenopausal breast cancer in the women's health initiative.

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

PURPOSE: Although infertility (i.e., failure to conceive after ≥ 12 months of trying) is strongly correlated with established breast cancer risk factors (e.g., nulliparity, number of pregnancies, and age at first pregnancy), its association with breast cancer incidence is not fully understood. Previous studies were primarily small clinic-based or registry studies with short follow-up and predominantly focused on premenopausal breast cancer. The objective of this study was to assess the relationship between infertility and postmenopausal breast cancer risk among participants in the Women's Health Initiative (analytic sample = 131,784; > 25 years of follow-up).

METHODS: At study entry, participants were asked about their pregnancy history, infertility history, and diagnosed reasons for infertility. Incident breast cancers were self-reported with adjudication by trained physicians reviewing medical records. Cox proportional hazards models were used to estimate risk of incident postmenopausal breast cancer for women with infertility (overall and specific infertility diagnoses) compared to parous women with no history of infertility. We examined mediation of these associations by parity, age at first term pregnancy, postmenopausal hormone therapy use at baseline, age at menopause, breastfeeding, and oophorectomy.

RESULTS: We observed a modest association between infertility (n = 23,406) and risk of postmenopausal breast cancer (HR = 1.07; 95% CI 1.02-1.13). The association was largely mediated by age at first term pregnancy (natural indirect effect: 46.4% mediated, CI 12.2-84.3%).

CONCLUSION: These findings suggest that infertility may be modestly associated with future risk of postmenopausal breast cancer due to age at first pregnancy and highlight the importance of incorporating reproductive history across the life course into breast cancer analyses.

RevDate: 2024-03-08

Saunders EJ, Dadaev T, Brook MN, et al (2024)

Identification of Genes with Rare Loss of Function Variants Associated with Aggressive Prostate Cancer and Survival.

European urology oncology pii:S2588-9311(24)00047-6 [Epub ahead of print].

BACKGROUND: Prostate cancer (PrCa) is a substantial cause of mortality among men globally. Rare germline mutations in BRCA2 have been validated robustly as increasing risk of aggressive forms with a poorer prognosis; however, evidence remains less definitive for other genes.

OBJECTIVE: To detect genes associated with PrCa aggressiveness, through a pooled analysis of rare variant sequencing data from six previously reported studies in the UK Genetic Prostate Cancer Study (UKGPCS).

We accumulated a cohort of 6805 PrCa cases, in which a set of ten candidate genes had been sequenced in all samples.

We examined the association between rare putative loss of function (pLOF) variants in each gene and aggressive classification (defined as any of death from PrCa, metastatic disease, stage T4, or both stage T3 and Gleason score ≥8). Secondary analyses examined staging phenotypes individually. Cox proportional hazards modelling and Kaplan-Meier survival analyses were used to further examine the relationship between mutation status and survival.

RESULTS AND LIMITATIONS: We observed associations between PrCa aggressiveness and pLOF mutations in ATM, BRCA2, MSH2, and NBN (odds ratio = 2.67-18.9). These four genes and MLH1 were additionally associated with one or more secondary analysis phenotype. Carriers of germline mutations in these genes experienced shorter PrCa-specific survival (hazard ratio = 2.15, 95% confidence interval 1.79-2.59, p = 4 × 10[-16]) than noncarriers.

CONCLUSIONS: This study provides further support that rare pLOF variants in specific genes are likely to increase aggressive PrCa risk and may help define the panel of informative genes for screening and treatment considerations.

PATIENT SUMMARY: By combining data from several previous studies, we have been able to enhance knowledge regarding genes in which inherited mutations would be expected to increase the risk of more aggressive PrCa. This may, in the future, aid in the identification of men at an elevated risk of dying from PrCa.

RevDate: 2024-03-08

Gilbert PB, Fong Y, Hejazi NS, et al (2024)

Four statistical frameworks for assessing an immune correlate of protection (surrogate endpoint) from a randomized, controlled, vaccine efficacy trial.

Vaccine pii:S0264-410X(24)00247-0 [Epub ahead of print].

A central goal of vaccine research is to characterize and validate immune correlates of protection (CoPs). In addition to helping elucidate immunological mechanisms, a CoP can serve as a valid surrogate endpoint for an infectious disease clinical outcome and thus qualifies as a primary endpoint for vaccine authorization or approval without requiring resource-intensive randomized, controlled phase 3 trials. Yet, it is challenging to persuasively validate a CoP, because a prognostic immune marker can fail as a reliable basis for predicting/inferring the level of vaccine efficacy against a clinical outcome, and because the statistical analysis of phase 3 trials only has limited capacity to disentangle association from cause. Moreover, the multitude of statistical methods garnered for CoP evaluation in phase 3 trials renders the comparison, interpretation, and synthesis of CoP results challenging. Toward promoting broader harmonization and standardization of CoP evaluation, this article summarizes four complementary statistical frameworks for evaluating CoPs in a phase 3 trial, focusing on the frameworks' distinct scientific objectives as measured and communicated by distinct causal vaccine efficacy parameters. Advantages and disadvantages of the frameworks are considered, dependent on phase 3 trial context, and perspectives are offered on how the frameworks can be applied and their results synthesized.

RevDate: 2024-03-08

Shahid Z, Etra AM, Levine JE, et al (2024)

Defining and Grading Infections in Clinical Trials Involving Hematopoietic Cell Transplantation: A Report from the BMT CTN Infectious Disease Technical Committee.

Transplantation and cellular therapy pii:S2666-6367(24)00251-3 [Epub ahead of print].

The Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) was established in 2001 to conduct large multi-institutional clinical trials addressing important issues towards improving the outcomes of HCT and other cellular therapies. Trials conducted by the network investigating new advances in HCT and cellular therapy not only assess efficacy but require careful capturing and severity assessment of adverse events and toxicities. Adverse infectious events in cancer clinical trials are typically graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). However, there are limitations to this framework as it relates to HCT given the associated immunodeficiency and delayed immune reconstitution. The BMT-CTN Infection Grading System is a monitoring tool developed by the BMT CTN to capture and monitor infectious complications and differs from the CTCAE by its classification of infections based on their potential impact on morbidity and mortality for HCT recipients. Here we offer a report from the BMT CTN Infectious Disease Technical Committee regarding the rationale, development, and revising of BMT-CTN Infection Grading System and future directions as it applies to future clinical trials involving HCT and cellular therapy recipients.

RevDate: 2024-03-09

Karmarkar EN, Golden MR, Kerani RP, et al (2024)

Association of Tecovirimat Therapy With Mpox Symptom Improvement: A Cross-sectional Study-King County, Washington, May-October 2022.

Open forum infectious diseases, 11(3):ofae029.

BACKGROUND: Data on tecovirimat effectiveness for human mpox are limited. We conducted a retrospective cross-sectional interview-based study to identify associations between tecovirimat treatment and the mpox clinical course.

METHODS: Using public health surveillance data from King County, Washington, we recruited and interviewed persons diagnosed with mpox during May-October 2022. We calculated descriptive statistics on demographics, vaccination status, comorbidities, and symptoms including 3 self-reported dates (symptom onset, first date of symptom improvement, and illness resolution). We used multivariable linear regression, stratified by illness severity, to evaluate the association of tecovirimat treatment with time to symptom improvement and time to illness resolution. We compared individuals who did not receive tecovirimat to participants who started tecovirimat early (≤5 days from symptom onset) and late (>5 days and ≤28 days from symptom onset) in their illness.

RESULTS: Of 465 individuals diagnosed with mpox, 115 (25%) participated in this study. Eighty participants (70%) received tecovirimat and 43 (37%) initiated tecovirimat early. Sixty-eight (59%) reported severe symptoms during their illness, including proctitis (n = 38 [33%]), rectal bleeding (n = 27 [24%]), or severe pain (n = 24 [21%]). In the multivariable analysis, early tecovirimat was associated with shorter time to symptom improvement (-5.5 days, P = .04) among participants with severe illness but not among those with nonsevere illness (0.9 day, P = .66). Early tecovirimat was not associated with faster illness resolution, regardless of severity.

CONCLUSIONS: Our small study suggests that early tecovirimat initiation may hasten subjective symptomatic improvement in people with severe mpox. Larger randomized trials are needed to evaluate this finding.

RevDate: 2024-03-07

Gibson TM, Karyadi DM, Hartley SW, et al (2024)

Polygenic risk scores, radiation treatment exposures and subsequent cancer risk in childhood cancer survivors.

Nature medicine [Epub ahead of print].

Survivors of childhood cancer are at increased risk for subsequent cancers attributable to the late effects of radiotherapy and other treatment exposures; thus, further understanding of the impact of genetic predisposition on risk is needed. Combining genotype data for 11,220 5-year survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort, we found that cancer-specific polygenic risk scores (PRSs) derived from general population, genome-wide association study, cancer loci identified survivors of European ancestry at increased risk of subsequent basal cell carcinoma (odds ratio per s.d. of the PRS: OR = 1.37, 95% confidence interval (CI) = 1.29-1.46), female breast cancer (OR = 1.42, 95% CI = 1.27-1.58), thyroid cancer (OR = 1.48, 95% CI = 1.31-1.67), squamous cell carcinoma (OR = 1.20, 95% CI = 1.00-1.44) and melanoma (OR = 1.60, 95% CI = 1.31-1.96); however, the association for colorectal cancer was not significant (OR = 1.19, 95% CI = 0.94-1.52). An investigation of joint associations between PRSs and radiotherapy found more than additive increased risks of basal cell carcinoma, and breast and thyroid cancers. For survivors with radiotherapy exposure, the cumulative incidence of subsequent cancer by age 50 years was increased for those with high versus low PRS. These findings suggest a degree of shared genetic etiology for these malignancy types in the general population and survivors, which remains evident in the context of strong radiotherapy-related risk.

RevDate: 2024-03-07

Loeb S, Keith SW, Cheng HH, et al (2024)

TARGET: A Randomized, Noninferiority Trial of a Pretest, Patient-Driven Genetic Education Webtool Versus Genetic Counseling for Prostate Cancer Germline Testing.

JCO precision oncology, 8:e2300552.

PURPOSE: Germline genetic testing (GT) is important for prostate cancer (PCA) management, clinical trial eligibility, and hereditary cancer risk. However, GT is underutilized and there is a shortage of genetic counselors. To address these gaps, a patient-driven, pretest genetic education webtool was designed and studied compared with traditional genetic counseling (GC) to inform strategies for expanding access to genetic services.

METHODS: Technology-enhanced acceleration of germline evaluation for therapy (TARGET) was a multicenter, noninferiority, randomized trial (ClinicalTrials.gov identifier: NCT04447703) comparing a nine-module patient-driven genetic education webtool versus pretest GC. Participants completed surveys measuring decisional conflict, satisfaction, and attitudes toward GT at baseline, after pretest education/counseling, and after GT result disclosure. The primary end point was noninferiority in reducing decisional conflict between webtool and GC using the validated Decisional Conflict Scale. Mixed-effects regression modeling was used to compare decisional conflict between groups. Participants opting for GT received a 51-gene panel, with results delivered to participants and their providers.

RESULTS: The analytic data set includes primary outcome data from 315 participants (GC [n = 162] and webtool [n = 153]). Mean difference in decisional conflict score changes between groups was -0.04 (one-sided 95% CI, -∞ to 2.54; P = .01), suggesting the patient-driven webtool was noninferior to GC. Overall, 145 (89.5%) GC and 120 (78.4%) in the webtool arm underwent GT, with pathogenic variants in 15.8% (8.7% in PCA genes). Satisfaction did not differ significantly between arms; knowledge of cancer genetics was higher but attitudes toward GT were less favorable in the webtool arm.

CONCLUSION: The results of the TARGET study support the use of patient-driven digital webtools for expanding access to pretest genetic education for PCA GT. Further studies to optimize patient experience and evaluate them in diverse patient populations are warranted.

RevDate: 2024-03-07

Colón W, Oriol Mathieu V, Hural J, et al (2024)

HIV Diagnostics and Vaccines: It Takes Two to Tango.

The Journal of infectious diseases pii:7623683 [Epub ahead of print].

Current serological tests for HIV screening and confirmation of infection present challenges to the adoption of HIV vaccines. The detection of vaccine-induced HIV-1 antibodies in the absence of HIV-1 infection, referred to as vaccine-induced seropositivity/seroreactivity, confounds the interpretation of test results, causing misclassification of HIV-1 status with potential affiliated stigmatization. For HIV vaccines to be widely adopted with high community confidence and uptake, tests that are agnostic to vaccination status (i.e., only positive for true HIV-1 infection) of tested individuals are needed. Successful development and deployment of such tests will require HIV vaccine developers to work in concert with diagnostic developers. Such tests will need to match today's high-performance standards (accuracy, cost-effectiveness, simplicity) for use in both vaccinated and unvaccinated populations, especially in low- and middle-income countries with high HIV burden. Herein, we discuss the challenges and strategies for developing modified serological HIV tests for concurrent deployment with HIV vaccines.

RevDate: 2024-03-07

Arends T, Tsuchida H, Adeyemi RO, et al (2024)

DUX4-induced HSATII transcription causes KDM2A/B-PRC1 nuclear foci and impairs DNA damage response.

The Journal of cell biology, 223(5):.

Polycomb repressive complexes regulate developmental gene programs, promote DNA damage repair, and mediate pericentromeric satellite repeat repression. Expression of pericentromeric satellite repeats has been implicated in several cancers and diseases, including facioscapulohumeral dystrophy (FSHD). Here, we show that DUX4-mediated transcription of HSATII regions causes nuclear foci formation of KDM2A/B-PRC1 complexes, resulting in a global loss of PRC1-mediated monoubiquitination of histone H2A. Loss of PRC1-ubiquitin signaling severely impacts DNA damage response. Our data implicate DUX4-activation of HSATII and sequestration of KDM2A/B-PRC1 complexes as a mechanism of regulating epigenetic and DNA repair pathways.

RevDate: 2024-03-07

Cieniewicz B, Oliveira E, Saxton M, et al (2024)

Therapeutic Targeting of TIM-4-L With Engineered T Cells for Acute Myeloid Leukemia.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:735079 [Epub ahead of print].

PURPOSE: Disruption of lipid bilayer asymmetry is a common feature observed in cancer cells and offers novel routes for therapeutic targeting. We utilized the natural immune receptor TIM-4 to interrogate for loss of plasma membrane phospholipid polarity in primary acute myelogenous leukemia (AML) samples and evaluated the anti-leukemic activity of TIM-4-L-directed T cell therapy in preclinical AML models.

METHODS: We performed FACs analysis on 33 primary AML bone marrow specimens and correlated TIM-4-L expression frequency and intensity with molecular disease characteristics. Using Kasumi-1 and MV-4-11 AML cell lines, we further tested the anti-leukemic effects of TIM-4-L-directed engineered T cells in vitro and in vivo.

RESULTS: 86% of untreated AML blasts displayed upregulation of cell surface TIM-4-L. These observations were agnostic to AML genetic classification, as samples with mutations in TP53, ASXL1, and RUNX1 displayed TIM-4-L upregulation similar to that seen in favorable and intermediate subtypes. TIM-4-L dysregulation was also stably present in AML cell lines. To evaluate the potential of targeting upregulated TIM-4-L with adoptive T cell therapy (ACT), we constructed TIM-4-L-directed engineered T cells, which demonstrated potent anti-leukemic effects, effectively eliminating AML cell lines with a range of endogenous TIM-4-L expression levels both in vitro and in vivo.

CONCLUSIONS: These results highlight TIM-4-L as a highly prevalent target on AML across a range of genetic classifications and novel target for T cell-based therapy in AML. Further investigations into the role of TIM-4-L in AML pathogenesis and its potential as an anti-leukemic target for clinical development are warranted.

RevDate: 2024-03-07

Hybiske K, Paktinat S, Newman K, et al (2024)

Antibodies from chlamydia-infected individuals facilitate phagocytosis via Fc receptors.

Infection and immunity [Epub ahead of print].

Non-neutralizing functions of antibodies, including phagocytosis, may play a role in Chlamydia trachomatis (CT) infection, but these functions have not been studied and assays are lacking. We utilized a flow-cytometry-based assay to determine whether serum samples from a well-characterized cohort of CT-infected and naïve control individuals enhanced phagocytosis via Fc-receptor-expressing THP-1 cells, and whether this activity correlated with antibody titers. Fc-receptor-mediated phagocytosis was detected only in CT+ donors. Phagocytosis generally did not correlate well with antibody titer. In addition, we found that complement from both CT+ and negative individuals enhanced phagocytosis of CT into primary neutrophils. These results suggest that anti-CT antibodies can have functions that are not reflected by titer. This method could be used to quantitively measure Fc-receptor-mediated function of anti-CT antibodies or complement activity and could reveal new immune correlates of protection.

RevDate: 2024-03-07

Yu B, Liu C, Proll SC, et al (2024)

Identification of fallopian tube microbiota and its association with ovarian cancer.

eLife, 12: pii:89830.

Investigating the human fallopian tube (FT) microbiota has significant implications for understanding the pathogenesis of ovarian cancer (OC). In this large prospective study, we collected swabs intraoperatively from the FT and other surgical sites as controls to profile the microbiota in the FT and to assess its relationship with OC. Eighty-one OC and 106 non-cancer patients were enrolled and 1001 swabs were processed for 16S rRNA gene PCR and sequencing. We identified 84 bacterial species that may represent the FT microbiota and found a clear shift in the microbiota of the OC patients when compared to the non-cancer patients. Of the top 20 species that were most prevalent in the FT of OC patients, 60% were bacteria that predominantly reside in the gastrointestinal tract, while 30% normally reside in the mouth. Serous carcinoma had higher prevalence of almost all 84 FT bacterial species compared to the other OC subtypes. The clear shift in the FT microbiota in OC patients establishes the scientific foundation for future investigation into the role of these bacteria in the pathogenesis of OC.

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ESP Quick Facts

ESP Origins

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

ESP Support

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

ESP Rationale

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

ESP Goal

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

ESP Usage

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

ESP Content

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

ESP Help

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

ESP Plans

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

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

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Papers in Classical Genetics

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

Digital Books

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

Timelines

ESP now offers a large collection of user-selected side-by-side timelines (e.g., all science vs. all other categories, or arts and culture vs. world history), designed to provide a comparative context for appreciating world events.

Biographies

Biographical information about many key scientists (e.g., Walter Sutton).

Selected Bibliographies

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

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