About | BLOGS | Portfolio | Misc | Recommended | What's New | What's Hot

About | BLOGS | Portfolio | Misc | Recommended | What's New | What's Hot


Bibliography Options Menu

04 Mar 2024 at 01:49
Hide Abstracts   |   Hide Additional Links
Long bibliographies are displayed in blocks of 100 citations at a time. At the end of each block there is an option to load the next block.

Bibliography on: Publications by FHCRC Researchers


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

RJR: Recommended Bibliography 04 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®)


RevDate: 2024-03-01

Lindner S, Miltiadous O, Ramos RJF, et al (2024)

Altered microbial bile acid metabolism exacerbates T cell-driven inflammation during graft-versus-host disease.

Nature microbiology [Epub ahead of print].

Microbial transformation of bile acids affects intestinal immune homoeostasis but its impact on inflammatory pathologies remains largely unknown. Using a mouse model of graft-versus-host disease (GVHD), we found that T cell-driven inflammation decreased the abundance of microbiome-encoded bile salt hydrolase (BSH) genes and reduced the levels of unconjugated and microbe-derived bile acids. Several microbe-derived bile acids attenuated farnesoid X receptor (FXR) activation, suggesting that loss of these metabolites during inflammation may increase FXR activity and exacerbate the course of disease. Indeed, mortality increased with pharmacological activation of FXR and decreased with its genetic ablation in donor T cells during mouse GVHD. Furthermore, patients with GVHD after allogeneic hematopoietic cell transplantation showed similar loss of BSH and the associated reduction in unconjugated and microbe-derived bile acids. In addition, the FXR antagonist ursodeoxycholic acid reduced the proliferation of human T cells and was associated with a lower risk of GVHD-related mortality in patients. We propose that dysbiosis and loss of microbe-derived bile acids during inflammation may be an important mechanism to amplify T cell-mediated diseases.

RevDate: 2024-03-01

Barboy O, Bercovich A, Li H, et al (2024)

Modeling T cell temporal response to cancer immunotherapy rationalizes development of combinatorial treatment protocols.

Nature cancer [Epub ahead of print].

Successful immunotherapy relies on triggering complex responses involving T cell dynamics in tumors and the periphery. Characterizing these responses remains challenging using static human single-cell atlases or mouse models. To address this, we developed a framework for in vivo tracking of tumor-specific CD8[+] T cells over time and at single-cell resolution. Our tools facilitate the modeling of gene program dynamics in the tumor microenvironment (TME) and the tumor-draining lymph node (tdLN). Using this approach, we characterize two modes of anti-programmed cell death protein 1 (PD-1) activity, decoupling induced differentiation of tumor-specific activated precursor cells from conventional type 1 dendritic cell (cDC1)-dependent proliferation and recruitment to the TME. We demonstrate that combining anti-PD-1 therapy with anti-4-1BB agonist enhances the recruitment and proliferation of activated precursors, resulting in tumor control. These data suggest that effective response to anti-PD-1 therapy is dependent on sufficient influx of activated precursor CD8[+] cells to the TME and highlight the importance of understanding system-level dynamics in optimizing immunotherapies.

RevDate: 2024-03-01

de Blank PMK, Lange KR, Xing M, et al (2024)

Temporal changes in treatment and late mortality and morbidity in adult survivors of childhood glioma: a report from the Childhood Cancer Survivor Study.

Nature cancer [Epub ahead of print].

Pediatric glioma therapy has evolved to delay or eliminate radiation for low-grade tumors. This study examined these temporal changes in therapy with long-term outcomes in adult survivors of childhood glioma. Among 2,501 5-year survivors of glioma in the Childhood Cancer Survivor Study diagnosed 1970-1999, exposure to radiation decreased over time. Survivors from more recent eras were at lower risk of late mortality (≥5 years from diagnosis), severe/disabling/life-threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs). Adjusting for treatment exposure (surgery only, chemotherapy, or any cranial radiation) attenuated this risk (for example, CHCs (1990s versus 1970s), relative risk (95% confidence interval), 0.63 (0.49-0.80) without adjustment versus 0.93 (0.72-1.20) with adjustment). Compared to surgery alone, radiation was associated with greater than four times the risk of late mortality, CHCs and SNs. Evolving therapy, particularly avoidance of cranial radiation, has improved late outcomes for childhood glioma survivors without increased risk for late recurrence.

RevDate: 2024-03-01

Daniel SK, Sullivan KM, Dickerson LK, et al (2024)

Reversing immunosuppression in the tumor microenvironment of fibrolamellar carcinoma via PD-1 and IL-10 blockade.

Scientific reports, 14(1):5109.

Fibrolamellar carcinoma (FLC) is a rare liver tumor driven by the DNAJ-PKAc fusion protein that affects healthy young patients. Little is known about the immune response to FLC, limiting rational design of immunotherapy. Multiplex immunohistochemistry and gene expression profiling were performed to characterize the FLC tumor immune microenvironment and adjacent non-tumor liver (NTL). Flow cytometry and T cell receptor (TCR) sequencing were performed to determine the phenotype of tumor-infiltrating immune cells and the extent of T cell clonal expansion. Fresh human FLC tumor slice cultures (TSCs) were treated with antibodies blocking programmed cell death protein-1 (PD-1) and interleukin-10 (IL-10), with results measured by cleaved caspase-3 immunohistochemistry. Immune cells were concentrated in fibrous stromal bands, rather than in the carcinoma cell compartment. In FLC, T cells demonstrated decreased activation and regulatory T cells in FLC had more frequent expression of PD-1 and CTLA-4 than in NTL. Furthermore, T cells had relatively low levels of clonal expansion despite high TCR conservation across individuals. Combination PD-1 and IL-10 blockade signficantly increased cell death in human FLC TSCs. Immunosuppresion in the FLC tumor microenvironment is characterized by T cell exclusion and exhaustion, which may be reversible with combination immunotherapy.

RevDate: 2024-03-01

Reyes KR, Liu YC, Huang CY, et al (2024)

Salvage Therapies including Retreatment with BCMA-directed Approaches Following BCMA CAR-T Relapses for Multiple Myeloma.

Blood advances pii:515171 [Epub ahead of print].

For patients with relapsed/refractory multiple myeloma (RRMM) with relapse following B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell therapies (CAR-T), optimal salvage treatment strategies remain unclear. BCMA-directed CAR-T and bispecific antibodies (BsAb) are now commercially available, and the outcomes for retreatment with BCMA-directed approaches are not well-studied. We performed a retrospective analysis of 68 patients with relapsed disease after BCMA-directed CAR-T to evaluate outcomes and responses to salvage therapies. With a median follow-up of 13.5 months, median overall survival from time of relapse until death was 18 months (95% confidence interval (CI): 13.2 months-not reached (NR)). 58 patients received subsequent myeloma-directed therapies, with a total of 265 lines-of-therapy (LOTs). The overall response rate for first-line salvage therapy was 41% (CI: 28-55%). Among all LOTs, high response rates were observed among those receiving another BCMA-directed CAR-T (89%), BCMA-directed BsAb (60%), CD38-directed combinations (80% when combined with BsAb; 50% when combined with immunomodulatory drugs and/or proteasome inhibitors), and alkylator-combinations (50% overall; 69% with high-dose alkylators). Thirty-four patients received at least one line of salvage BCMA-directed therapy; median PFS was 8.3 months (CI: 7.9 months-NR), 3.6 months (CI: 1.4 months-NR), and 1 month (CI: 0.9 months-NR) with median duration of response (DOR) of 8 months, 4.4 months, and 2.8 months for subsequent BCMA-directed CAR-T, BsAb, and belantamab mafadotin, respectively. Retreatment with BCMA-directed CAR-T and BsAb can be effective salvage options post-BCMA-directed CAR-T relapse; however, DORs appear limited and further studies with new combinations and alternative targets are warranted.

RevDate: 2024-03-01

Prentice RL, Aragaki AK, Zheng C, et al (2024)

Biomarker-assessed total energy intake and its cohort study association with all-cause mortality in postmenopausal females.

The American journal of clinical nutrition pii:S0002-9165(24)00166-7 [Epub ahead of print].

BACKGROUND: The association of total energy intake (EI) with all-cause mortality is uncertain, as are the dependencies of this association on age and weight change history.

OBJECTIVES: To identify an EI biomarker suitable for use in epidemiologic association studies, and to study EI associations with total mortality in a Women's Health Initiative (WHI) cohort of postmenopausal U.S. females (1993-present).

DESIGN: EI biomarkers were developed based on doubly-labeled water (DLW) total energy expenditure (TEE) and weight variation during the two-week DLW protocol period using the energy balance method, in an embedded feeding study (n=153). This along with two earlier WHI nutrition biomarker studies having TEE assessments (n=1131 total), with 14.6 years (median) follow-up, constituted a prospective cohort for the study of EI and all-cause mortality.

RESULTS: An empirical biomarker for log (EI) was developed that had a correlation of 0.73 with log (feeding study-consumed EI). The overall association between EI and mortality was non-significant. The association, however, depended on age (P=0.009) with lower EI associated with lower mortality at younger ages, and also on preceding weight change history (P=0.03). Among participants with stable or increasing weight, mortality hazard ratios (HRs) (95% CIs) for a 12% lower EI were 0.66 (0.51, 0.87) at age 60, 0.84 (0.72, 0.98) at age 70, and 1.06 (0.87, 1.29) at age 80. Corresponding values for participants having preceding weight loss were 0.83 (0.61, 1.12) at age 60, 1.05 (0.87 1.26) at age 70, and 1.33 (1.08, 1.63) at age 80. A previously considered EI biomarker, using a theoretical model for variation in body fat- and fat free-mass components over time, gave similar results following rescaling.

CONCLUSIONS: Lower EI is associated with lower all-cause mortality among younger postmenopausal females with stable or increasing weight, and with higher mortality risk among older females with weight loss. This study is registered with clinicaltrials.gov identifier: NCT00000611.

RevDate: 2024-03-01

Paredes MI, Ahmed N, Figgins M, et al (2024)

Underdetected dispersal and extensive local transmission drove the 2022 mpox epidemic.

Cell pii:S0092-8674(24)00124-7 [Epub ahead of print].

The World Health Organization declared mpox a public health emergency of international concern in July 2022. To investigate global mpox transmission and population-level changes associated with controlling spread, we built phylogeographic and phylodynamic models to analyze MPXV genomes from five global regions together with air traffic and epidemiological data. Our models reveal community transmission prior to detection, changes in case reporting throughout the epidemic, and a large degree of transmission heterogeneity. We find that viral introductions played a limited role in prolonging spread after initial dissemination, suggesting that travel bans would have had only a minor impact. We find that mpox transmission in North America began declining before more than 10% of high-risk individuals in the USA had vaccine-induced immunity. Our findings highlight the importance of broader routine specimen screening surveillance for emerging infectious diseases and of joint integration of genomic and epidemiological information for early outbreak control.

RevDate: 2024-03-01

Wagner AJ, Ravi V, Riedel RF, et al (2024)

Phase II Trial of nab-Sirolimus in Patients With Advanced Malignant Perivascular Epithelioid Cell Tumors (AMPECT): Long-Term Efficacy and Safety Update.

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

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.nab-Sirolimus is approved in the United States for the treatment of metastatic or locally advanced malignant perivascular epithelioid cell tumor (PEComa) on the basis of the primary analysis results of the phase II Advanced Malignant Perivascular Epithelioid Cell Tumors (AMPECT) trial (ClinicalTrials.gov identifier: NCT02494570). Results from the primary analysis were previously published; however, the median duration of response (mDOR) had not been reached at that time. Here, 3 years after the primary analysis, we report final efficacy and safety data (data cutoff: April 29, 2022). At study completion, the confirmed overall response rate (by independent radiologist review using RECIST v1.1) was 38.7% (95% CI, 21.8 to 57.8), with an additional converted confirmed complete response (n = 2). Median progression-free survival remained the same at 10.6 months (95% CI, 5.5 to 41.2). The mDOR was reached at 39.7 months (95% CI, 6.5 to not reached [NR]), and the median overall survival at completion was 53.1 months (95% CI, 22.2 to NR). The most common treatment-related adverse events (TRAEs) were stomatitis (82.4%) and fatigue and rash (each 61.8%). No new or unexpected adverse events occurred, and no grade ≥4 TRAEs were reported. These results highlight the long-term clinical benefit of nab-sirolimus in patients with advanced malignant PEComa, with a DOR of >3 years.

RevDate: 2024-03-01

Nimgaonkar I, Yoke LH, Roychoudhury P, et al (2024)

Outcomes in Hematopoietic Cell Transplant and Chimeric Antigen Receptor T Cell Therapy Recipients with Pre-Cellular Therapy SARS-CoV-2 Infection.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:7617431 [Epub ahead of print].

BACKGROUND: Hematopoietic cell transplant (HCT) or chimeric antigen receptor T cell (CAR-T) therapy recipients have high morbidity from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. There are limited data on outcomes from SARS-CoV-2 infection shortly before cellular therapy and uncertainty whether to delay therapy.

METHODS: We conducted a retrospective cohort study of patients with SARS-CoV-2 infection within 90 days prior to HCT or CAR-T therapy between January 2020 and November 2022. We characterized the kinetics of SARS-CoV-2 detection, clinical outcomes following cellular therapy, and impact on delays in cellular therapy.

RESULTS: We identified 37 patients (n=15 allogeneic HCT, n=11 autologous HCT, n=11 CAR-T therapy) with SARS-CoV-2 infections within 90 days of cellular therapy. Most infections (73%) occurred between March and November 2022, when Omicron strains were prevalent. Most patients had asymptomatic (27%) or mild (68%) coronavirus disease 2019 (COVID-19). SARS-CoV-2 positivity lasted a median of 20.0 days [IQR, 12.5-26.25]. The median time from first positive SARS-CoV-2 test to cellular therapy was 45 days [IQR, 37.75-70]; one patient tested positive on the day of infusion. After cellular therapy, no patients had recrudescent SARS-CoV-2 infection or COVID-19-related complications. Cellular therapy delays related to SARS-CoV-2 infection occurred in 70% of patients for a median of 37 days. Delays were more common after allogeneic (73%) and autologous (91%) HCT compared to CAR-T cell therapy (45%).

CONCLUSIONS: Patients with asymptomatic or mild COVID-19 may not require prolonged delays in cellular therapy in the context of contemporary circulating variants and availability of antiviral therapies.

RevDate: 2024-03-01

Chen DG, Xie J, Choi J, et al (2024)

Integrative systems biology reveals NKG2A-biased immune responses correlate with protection in infectious disease, autoimmune disease, and cancer.

Cell reports, 43(3):113872 pii:S2211-1247(24)00200-6 [Epub ahead of print].

Infection, autoimmunity, and cancer are principal human health challenges of the 21[st] century. Often regarded as distinct ends of the immunological spectrum, recent studies hint at potential overlap between these diseases. For example, inflammation can be pathogenic in infection and autoimmunity. T resident memory (TRM) cells can be beneficial in infection and cancer. However, these findings are limited by size and scope; exact immunological factors shared across diseases remain elusive. Here, we integrate large-scale deeply clinically and biologically phenotyped human cohorts of 526 patients with infection, 162 with lupus, and 11,180 with cancer. We identify an NKG2A[+] immune bias as associative with protection against disease severity, mortality, and autoimmune/post-acute chronic disease. We reveal that NKG2A[+] CD8[+] T cells correlate with reduced inflammation and increased humoral immunity and that they resemble TRM cells. Our results suggest NKG2A[+] biases as a cross-disease factor of protection, supporting suggestions of immunological overlap between infection, autoimmunity, and cancer.

RevDate: 2024-03-01

Showman S, Talbert PB, Xu Y, et al (2024)

Expansion of human centromeric arrays in cells undergoing break-induced replication.

Cell reports, 43(3):113851 pii:S2211-1247(24)00179-7 [Epub ahead of print].

Human centromeres are located within α-satellite arrays and evolve rapidly, which can lead to individual variation in array length. Proposed mechanisms for such alterations in length are unequal crossover between sister chromatids, gene conversion, and break-induced replication. However, the underlying molecular mechanisms responsible for the massive, complex, and homogeneous organization of centromeric arrays have not been experimentally validated. Here, we use droplet digital PCR assays to demonstrate that centromeric arrays can expand and contract within ∼20 somatic cell divisions of an alternative lengthening of telomere (ALT)-positive cell line. We find that the frequency of array variation among single-cell-derived subclones ranges from a minimum of ∼7% to a maximum of ∼100%. Further clonal evolution revealed that centromere expansion is favored over contraction. We find that the homologous recombination protein RAD52 and the helicase PIF1 are required for extensive array change, suggesting that centromere sequence evolution can occur via break-induced replication.

RevDate: 2024-03-01

Brown JR, Ghia P, Jurczak W, et al (2024)

Characterization of zanubrutinib safety and tolerability profile and comparison with ibrutinib safety profile in patients with B-cell malignancies: post-hoc analysis of a large clinical trial safety database.

Haematologica [Epub ahead of print].

RevDate: 2024-03-01

Saliba RM, Lee SJ, Carpenter PA, et al (2024)

Mycophenolate mofetil is associated with inferior overall survival in cytomegalovirus seropositive patients with acute myeloid leukemia undergoing hematopoietic cell transplantation.

Haematologica [Epub ahead of print].

Not available.

RevDate: 2024-02-29

Li S, Wong A, Sun H, et al (2024)

A combinatorial genetic strategy for exploring complex genotype-phenotype associations in cancer.

Nature genetics [Epub ahead of print].

Available genetically defined cancer models are limited in genotypic and phenotypic complexity and underrepresent the heterogeneity of human cancer. Here, we describe a combinatorial genetic strategy applied to an organoid transformation assay to rapidly generate diverse, clinically relevant bladder and prostate cancer models. Importantly, the clonal architecture of the resultant tumors can be resolved using single-cell or spatially resolved next-generation sequencing to uncover polygenic drivers of cancer phenotypes.

RevDate: 2024-02-29

Yadav D, Conwell DL, Pandol SJ, et al (2024)

Diagnostic and Prognostic Biomarkers of Chronic Pancreatitis: A Conceptual Framework Based on PRoBE Design.

Gastroenterology pii:S0016-5085(24)00236-1 [Epub ahead of print].

RevDate: 2024-03-01

Rockoff SJ, Flanagan MR, Kim JN, et al (2020)

The Radiologist's Role in a Breast Multidisciplinary Tumor Board.

Journal of breast imaging, 2(4):372-381.

Breast multidisciplinary tumor boards (MTBs) play an important role in determining treatment. This article serves as a guide for the radiologist participating in a breast MTB, as the information presented at MTB can significantly influence treatment plans and dictate future steps for further patient work-up. Multidisciplinary tumor board preparation involves a careful review of the patient's history while gathering all relevant imaging studies, and reinterpreting them when appropriate. Presented images should be carefully selected, annotated, and displayed clearly before providing final recommendations for localization and incompletely assessed findings. Anatomic staging factors from the AJCC Breast Cancer Staging System, such as tumor size and degree of suspected skin involvement, should be described. In addition, there are many other types of information that the treatment specialists want to know. The surgeon is interested in anatomic information that will help them decide whether breast conservation therapy is feasible or if local structures, such as the nipple, can be spared. The radiation oncologist may need to know whether accelerated partial breast irradiation is feasible or if postmastectomy radiation therapy is indicated. The medical oncologist is looking for factors that may provide an indication for neoadjuvant therapy and ensuring there is a reliable follow-up method for evaluating the response to treatment, such as comparative MRI. Additionally, all specialists need to know the extent of suspected nodal involvement. By clearly and comprehensively presenting this information to the rest of the MTB team, the radiologist provides a vital contribution that guides treatment and ensures adherence to clinical guidelines.

RevDate: 2024-02-29

Bardia A, Rugo HS, Tolaney SM, et al (2024)

Final Results From the Randomized Phase III ASCENT Clinical Trial in Metastatic Triple-Negative Breast Cancer and Association of Outcomes by Human Epidermal Growth Factor Receptor 2 and Trophoblast Cell Surface Antigen 2 Expression.

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

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Sacituzumab govitecan (SG), a first-in-class anti-trophoblast cell surface antigen 2 (Trop-2) antibody-drug conjugate, demonstrated superior efficacy over single-agent chemotherapy (treatment of physician's choice [TPC]) in patients with metastatic triple-negative breast cancer (mTNBC) in the international, multicenter, phase III ASCENT study.Patients were randomly assigned 1:1 to receive SG or TPC until unacceptable toxicity/progression. Final efficacy secondary end point analyses and post hoc analyses of outcomes stratified by Trop-2 expression and human epidermal growth factor receptor 2 status are reported. Updated safety analyses are provided.In this final analysis, SG (n = 267) improved median progression-free survival (PFS; 4.8 v 1.7 months; hazard ratio (HR), 0.41 [95% CI, 0.33 to 0.52]) and median overall survival (OS; 11.8 v 6.9 months; HR, 0.51 [95% CI, 0.42 to 0.63]) over TPC (n = 262). SG improved PFS over TPC in each Trop-2 expression quartile (n = 168); a trend was observed for improved OS across quartiles. Overall, SG had a manageable safety profile, with ≤5% of treatment-related discontinuations because of adverse events and no treatment-related deaths. The safety profile was consistent across all subgroups.These data confirm the clinical benefit of SG over chemotherapy, reinforcing SG as an effective treatment option in patients with mTNBC in the second line or later.

RevDate: 2024-02-29

Ray S, Gurung P, Manning RS, et al (2024)

Neuron cilia restrain glial KCC-3 to a microdomain to regulate multisensory processing.

Cell reports, 43(3):113844 pii:S2211-1247(24)00172-4 [Epub ahead of print].

Glia interact with multiple neurons, but it is unclear whether their interactions with each neuron are different. Our interrogation at single-cell resolution reveals that a single glial cell exhibits specificity in its interactions with different contacting neurons. Briefly, C. elegans amphid sheath (AMsh) glia apical-like domains contact 12 neuron-endings. At these ad-neuronal membranes, AMsh glia localize the K/Cl transporter KCC-3 to a microdomain exclusively around the thermosensory AFD neuron to regulate its properties. Glial KCC-3 is transported to ad-neuronal regions, where distal cilia of non-AFD glia-associated chemosensory neurons constrain it to a microdomain at AFD-contacting glial membranes. Aberrant KCC-3 localization impacts both thermosensory (AFD) and chemosensory (non-AFD) neuron properties. Thus, neurons can interact non-synaptically through a shared glial cell by regulating microdomain localization of its cues. As AMsh and glia across species compartmentalize multiple cues like KCC-3, we posit that this may be a broadly conserved glial mechanism that modulates information processing across multimodal circuits.

RevDate: 2024-02-29

Lynch RC (2024)

Toward a cure for cHL without chemotherapy.

Blood, 143(9):741-742.

RevDate: 2024-02-29

Gorfine M, Qu C, Peters U, et al (2024)

Unveiling challenges in Mendelian randomization for gene-environment interaction.

Genetic epidemiology [Epub ahead of print].

Gene-environment (GxE) interactions play a crucial role in understanding the complex etiology of various traits, but assessing them using observational data can be challenging due to unmeasured confounders for lifestyle and environmental risk factors. Mendelian randomization (MR) has emerged as a valuable method for assessing causal relationships based on observational data. This approach utilizes genetic variants as instrumental variables (IVs) with the aim of providing a valid statistical test and estimation of causal effects in the presence of unmeasured confounders. MR has gained substantial popularity in recent years largely due to the success of genome-wide association studies. Many methods have been developed for MR; however, limited work has been done on evaluating GxE interaction. In this paper, we focus on two primary IV approaches: the two-stage predictor substitution and the two-stage residual inclusion, and extend them to accommodate GxE interaction under both the linear and logistic regression models for continuous and binary outcomes, respectively. Comprehensive simulation study and analytical derivations reveal that resolving the linear regression model is relatively straightforward. In contrast, the logistic regression model presents a considerably more intricate challenge, which demands additional effort.

RevDate: 2024-02-29

Walsh CA, Currin-McCulloch J, Faris NR, et al (2024)

"Living with Loss": A qualitative exploration of existential fears among people with advanced lung cancer in online lung cancer support groups.

Palliative & supportive care pii:S147895152400004X [Epub ahead of print].

OBJECTIVES: With targeted therapies, people are surviving longer with advanced lung cancer and engaging in online lung cancer support communities. While these groups provide a sense of community, witnessing the death of peers can lead to emotional distress. This qualitative study aims to (1) explore the experience of witnessing death in online cancer support groups; (2) identify factors that contribute to the emotional struggles of witnessing the death of peers; and (3) identify strategies/options for dealing with losses in the cancer community.

METHODS: We conducted a cross-sectional analysis of qualitative interviews exploring existential concerns with participants (n = 25) from oncogene-specific online lung cancer support groups. The principal investigator conducted study interviews between August 2018 and March 2019 where participants were asked about their cancer experiences and existential concerns. We used thematic analysis and NVIVO 11 software to examine and store the de-identified interview data.

RESULTS: Participants indicated that they had often witnessed their peers die and felt the pain of the loss. Factors that played a part in their struggle with witnessing others' death included the closeness of the relationship with the person, the age of the person who died, seeing oneself in the experience of the other dying, disparities in care, and losing touch in the final stages. Participants used varied coping strategies such as celebrating the life of the individual who died, engaging in advocacy efforts, not focusing on the loss, participating in therapy, and bringing self-preserving thoughts.

SIGNIFICANCE OF RESULTS: Our study highlights the importance of addressing existential fears in online lung cancer support groups and incorporating conversations about death in spaces that deal with cancer.

RevDate: 2024-02-29

Otth M, Kasteler R, Mulder RL, et al (2024)

Recommendations for surveillance of pulmonary dysfunction among childhood, adolescent, and young adult cancer survivors: a report from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

EClinicalMedicine, 69:102487.

Childhood, adolescent, and young adult (CAYA) cancer survivors are at risk of pulmonary dysfunction. Current follow-up care guidelines are discordant. Therefore, the International Late Effects of Childhood Cancer Guideline Harmonization Group established and convened a panel of 33 experts to develop evidence-based surveillance guidelines. We critically reviewed available evidence regarding risk factors for pulmonary dysfunction, types of pulmonary function testing, and timings of surveillance, then we formulated our recommendations. We recommend that CAYA cancer survivors and healthcare providers are aware of reduced pulmonary function risks and pay vigilant attention to potential symptoms of pulmonary dysfunction, especially among survivors treated with allogeneic haematopoietic stem cell transplantation, thoracic radiotherapy, and thoracic surgery. Based on existing limited evidence and current lack of interventions, our panel recommends pulmonary function testing only for symptomatic survivors. Since scarce existing evidence informs our recommendation, we highlight the need for prospective collaborative studies to address pulmonary function knowledge gaps among CAYA cancer survivors.

RevDate: 2024-02-29

Baker SG, R Etzioni (2024)

Prediagnostic evaluation of multicancer detection tests: Design and analysis considerations.

Journal of the National Cancer Institute pii:7616135 [Epub ahead of print].

There is growing interest in multicancer detection (MCD) tests, which identify molecular signals in the blood indicating a potential preclinical cancer. A key stage in evaluating MCD tests is a prediagnostic performance study, in which investigators store specimens from asymptomatic persons and later test stored specimens from cancer cases and a random sample of controls to determine predictive performance. Performance metrics include cancer-specific true and false positive rates and a cancer-specific positive predictive value, with the latter compared to a decision-analytic threshold. The sample size tradeoff method, which trades imprecise targeting of the true positive rate for precise targeting of a zero false positive rate can substantially reduce sample size while increasing the lower bound of positive predictive value. For a 1-year follow-up, with ovarian cancer as the rarest cancer considered, the sample size tradeoff method yields a sample size of 163,000 compared with a sample size of 720,000 based on standard calculations. These design and analysis recommendations should be considered in planning a specimen repository and in the prediagnostic evaluation of MCD tests.

RevDate: 2024-02-28

Aßmann ES, Ose J, Hathaway CA, et al (2024)

Risk factors and health behaviors associated with loneliness among cancer survivors during the COVID-19 pandemic.

Journal of behavioral medicine [Epub ahead of print].

Loneliness may exacerbate poor health outcomes particularly among cancer survivors during the COVID-19 pandemic. Little is known about the risk factors of loneliness among cancer survivors. We evaluated the risk factors of loneliness in the context of COVID-19 pandemic-related prevention behaviors and lifestyle/psychosocial factors among cancer survivors. Cancer survivors (n = 1471) seen at Huntsman Cancer Institute completed a survey between August-September 2020 evaluating health behaviors, medical care, and psychosocial factors including loneliness during COVID-19 pandemic. Participants were classified into two groups: 'lonely' (sometimes, usually, or always felt lonely in past month) and 'non-lonely' (never or rarely felt lonely in past month). 33% of cancer survivors reported feeling lonely in the past month. Multivariable logistic regression showed female sex, not living with a spouse/partner, poor health status, COVID-19 pandemic-associated lifestyle factors including increased alcohol consumption and marijuana/CBD oil use, and psychosocial stressors such as disruptions in daily life, less social interaction, and higher perceived stress and financial stress were associated with feeling lonely as compared to being non-lonely (all p < 0.05). A significant proportion of participants reported loneliness, which is a serious health risk among vulnerable populations, particularly cancer survivors. Modifiable risk factors such as unhealthy lifestyle behaviors and psychosocial stress were associated with loneliness. These results highlight the need to screen for unhealthy lifestyle factors and psychosocial stressors to identify cancer survivors at increased risk of loneliness and to develop effective management strategies.

RevDate: 2024-02-28

Zhang Y, Yu B, Qi Q, et al (2024)

Metabolomic profiles of sleep-disordered breathing are associated with hypertension and diabetes mellitus development.

Nature communications, 15(1):1845.

Sleep-disordered breathing (SDB) is a prevalent disorder characterized by recurrent episodic upper airway obstruction. Using data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we apply principal component analysis (PCA) to seven SDB-related measures. We estimate the associations of the top two SDB PCs with serum levels of 617 metabolites, in both single-metabolite analysis, and a joint penalized regression analysis. The discovery analysis includes 3299 individuals, with validation in a separate dataset of 1522 individuals. Five metabolite associations with SDB PCs are discovered and replicated. SDB PC1, characterized by frequent respiratory events common in older and male adults, is associated with pregnanolone and progesterone-related sulfated metabolites. SDB PC2, characterized by short respiratory event length and self-reported restless sleep, enriched in young adults, is associated with sphingomyelins. Metabolite risk scores (MRSs), representing metabolite signatures associated with the two SDB PCs, are associated with 6-year incident hypertension and diabetes. These MRSs have the potential to serve as biomarkers for SDB, guiding risk stratification and treatment decisions.

RevDate: 2024-02-28

Bahakel H, Waghmare A, RP Madan (2024)

Impact of Respiratory Viral Infections in Transplant Recipients.

Journal of the Pediatric Infectious Diseases Society, 13(Supplement_1):S39-S48.

Respiratory viral infections (RVIs) are among the leading cause of morbidity and mortality in pediatric hematopoietic stem cell transplant (HCT) and solid organ transplant (SOT) recipients. Transplant recipients remain at high risk for super imposed bacterial and fungal pneumonia, chronic graft dysfunction, and graft failure as a result of RVIs. Recent multicenter retrospective studies and prospective studies utilizing contemporary molecular diagnostic techniques have better delineated the epidemiology and outcomes of RVIs in pediatric transplant recipients and have advanced the development of preventative vaccines and treatment interventions in this population. In this review, we will define the epidemiology and outcomes of RVIs in SOT and HSCT recipients, describe the available assays for diagnosing a suspected RVI, highlight evolving management and vaccination strategies, review the risk of donor derived RVI in SOT recipients, and discuss considerations for delaying transplantation in the presence of an RVI.

RevDate: 2024-02-28

Baumrin E, Shin DB, Mitra N, et al (2024)

Patient-Reported Outcomes and Mortality in Cutaneous Chronic Graft-vs-Host Disease.

JAMA dermatology pii:2815574 [Epub ahead of print].

IMPORTANCE: Chronic graft-vs-host disease (GVHD) is associated with impaired quality of life and symptom burden. The independent association of skin involvement with patient-reported outcomes (PROs) and their utility as a clinical prognostic marker remain unknown. Identification of patients with cutaneous chronic GVHD and impaired PROs could assist in initial risk stratification and treatment selection.

OBJECTIVE: To compare the association of sclerotic and epidermal-type chronic GVHD with longitudinal PROs and to evaluate whether PROs can identify patients with cutaneous chronic GVHD at high risk for death.

This multicenter prospective cohort study involved patients from the Chronic GVHD Consortium of 9 US medical centers, enrolled between August 2007 and April 2012, and followed up until December 2020. Participants included adults 18 years and older with a diagnosis of chronic GVHD requiring systemic immunosuppression and with skin involvement during the study period.

MAIN OUTCOMES AND MEASURES: Patient-reported symptom burden was assessed using the Lee Symptom Scale (LSS) skin subscale with higher scores indicating worse outcomes. Quality of life was measured using the Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT) instrument with lower scores indicating worse outcomes. Nonrelapse mortality, overall survival, and their association with PROs at diagnosis were also assessed.

RESULTS: Among 436 patients with cutaneous chronic GVHD (median [IQR] age at transplant, 51 [41.5-56.6] years; 261 [59.9%] male), 229 patients had epidermal-type chronic GVHD (52.5%), followed by 131 with sclerotic chronic GVHD (30.0%), and 76 with combination disease (17.4%). After adjusting for confounders, patients with sclerotic chronic GVHD had mean FACT-BMT scores 6.1 points worse than those with epidermal disease (95% CI, 11.7-0.4; P = .04). Patients with combination disease had mean LSS skin subscale scores 9.0 points worse than those with epidermal disease (95% CI, 4.2-13.8; P < .001). Clinically meaningful differences were defined as at least 7 points lower for FACT-BMT and 11 points higher for LSS skin subscale. At diagnosis, clinically meaningful worsening in FACT-BMT score was associated with an adjusted odds of nonrelapse mortality increased by 9.1% (95% CI, 2.0%-16.7%; P = .01). Similarly, for clinically meaningful worsening in LSS skin subscale score, adjusted odds of nonrelapse mortality increased by 16.4% (95% CI, 5.4%-28.5%; P = .003). These associations held true after adjusting for clinical severity by the National Institutes of Health Skin Score.

CONCLUSIONS AND RELEVANCE: The results of this cohort study demonstrated that skin chronic GVHD was independently associated with long-term PRO impairment, with sclerotic and combination disease carrying the highest morbidity. The degree of impairment at skin chronic GVHD diagnosis was a prognostic marker for mortality. Therefore, PROs could be useful for risk stratification and treatment selection in clinical practice and clinical trials.

RevDate: 2024-02-28

Bui JK, Starke CE, Poole NH, et al (2024)

CD20 CAR T-cells safely and reversibly ablate B-cell follicles in a nonhuman primate model of HIV persistence.

Molecular therapy : the journal of the American Society of Gene Therapy pii:S1525-0016(24)00099-6 [Epub ahead of print].

CAR T-cell therapies have demonstrated immense clinical successes for B-cell and plasma-cell malignancies. We tested their impact on the viral reservoir in a macaque model of HIV persistence, comparing the function of CD20 CAR T cells between animals infected with simian/human immunodeficiency virus (SHIV) and uninfected controls. We focused on the potential of this approach to disrupt B-cell follicles (BCFs), exposing infected cells for immune clearance. In SHIV-infected animals, CAR T cells were highly functional with rapid expansion and trafficking to tissue-associated viral sanctuaries including BCFs and gut-associated lymphoid tissues (GALT). CD20 CAR T-cells potently ablated BCFs and depleted lymph node-associated T follicular helper (TFH) cells, with complete restoration of BCF architecture and TFH cells following CAR T-cell contraction. BCF ablation decreased the splenic SHIV reservoir but was insufficient for effective reductions in systemic viral reservoirs. Although associated with moderate hematologic toxicity, CD20 CAR T-cells were well tolerated in SHIV-infected and control animals, supporting the feasibility of this therapy in people living with HIV with underlying B-cell malignancies. Our findings highlight the unique ability of CD20 CAR T cells to safely and reversibly unmask TFH cells within BCF sanctuaries, informing future combinatorial HIV cure strategies designed to augment antiviral efficacy.

RevDate: 2024-02-28

Carrillo MA, Zhen A, Mu W, et al (2024)

Stem cell-derived CAR T cells show greater persistence, trafficking, and plasma viral control compared to ex vivo transduced CAR T cells in vivo.

Molecular therapy : the journal of the American Society of Gene Therapy pii:S1525-0016(24)00095-9 [Epub ahead of print].

Adoptive cell therapy (ACT) using T cells expressing chimeric antigen receptors (CARs) is an area of intense investigation in the treatment of malignancies and chronic viral infections. One of the limitations of ACT-based CAR therapy is the lack of in vivo persistence and maintenance of optimal cell function. Therefore, alternative strategies that increase the function and maintenance of CAR-expressing T cells are needed. In our studies using the humanized bone marrow/liver/thymus (BLT) mouse model and nonhuman primate model (NHP) of HIV infection, we evaluated two CAR-based gene therapy approaches. In ACT approach, we utilized cytokine enhancement and preconditioning to generate greater persistence of anti-HIV CAR+ T cells. We observed limited persistence and expansion of anti-HIV CAR T cells which led to minimal control of the virus. In our stem-cell based approach, we modified hematopoietic stem/progenitor cells (HSPCs) with anti-HIV CAR to generate anti-HIV CAR T cells in vivo. We observed CAR-expressing T cell expansion which led to better plasma viral load suppression. HSPC-derived CAR cells in infected NHPs showed superior trafficking and persistence in multiple tissues. Our results suggest a stem cell-based CAR T cell approach may be superior to generate long-term persistence and functional antiviral responses against HIV infection.

RevDate: 2024-02-27

Rotz SJ, Bhatt NS, Hamilton BK, et al (2024)

International recommendations for screening and preventative practices for long-term survivors of transplantation and cellular therapy: a 2023 update.

Bone marrow transplantation [Epub ahead of print].

As hematopoietic cell transplantation (HCT) and cellular therapy expand to new indications and international access improves, the volume of HCT performed annually continues to rise. Parallel improvements in HCT techniques and supportive care entails more patients surviving long-term, creating further emphasis on survivorship needs. Survivors are at risk for developing late complications secondary to pre-, peri- and post-transplant exposures and other underlying risk-factors. Guidelines for screening and preventive practices for HCT survivors were originally published in 2006 and updated in 2012. To review contemporary literature and update the recommendations while considering the changing practice of HCT and cellular therapy, an international group of experts was again convened. This review provides updated pediatric and adult survivorship guidelines for HCT and cellular therapy. The contributory role of chronic graft-versus-host disease (cGVHD) to the development of late effects is discussed but cGVHD management is not covered in detail. These guidelines emphasize special needs of patients with distinct underlying HCT indications or comorbidities (e.g., hemoglobinopathies, older adults) but do not replace more detailed group, disease, or condition specific guidelines. Although these recommendations should be applicable to the vast majority of HCT recipients, resource constraints may limit their implementation in some settings.

RevDate: 2024-02-27

Rotz SJ, Bhatt NS, Hamilton BK, et al (2024)

International Recommendations for Screening and Preventative Practices for Long-Term Survivors of Transplantation and Cellular Therapy: A 2023 Update.

As hematopoietic cell transplantation (HCT) and cellular therapy expand to new indications and international access improves, the number of HCTs performed annually continues to rise. Parallel improvements in HCT techniques and supportive care entails more patients surviving long term, creating further emphasis on survivorship needs. Survivors are at risk for developing late complications secondary to pretransplantation, peritransplantation, and post-transplantation exposures and other underlying risk factors. Guidelines for screening and preventive practices for HCT survivors were originally published in 2006 and then updated in 2012. An international group of experts was convened to review the contemporary literature and update the recommendations while considering the changing practices of HCT and cellular therapy. This review provides updated pediatric and adult survivorship guidelines for HCT and cellular therapy. The contributory role of chronic graft-versus-host disease (cGVHD) to the development of late effects is discussed, but cGVHD management is not covered in detail. These guidelines emphasize the special needs of patients with distinct underlying HCT indications or comorbidities (eg, hemoglobinopathies, older adults) but do not replace more detailed group-, disease-, or condition-specific guidelines. Although these recommendations should be applicable to the vast majority of HCT recipients, resource constraints may limit their implementation in some settings.

RevDate: 2024-02-27

Chun C, Lee JH, Bothwell M, et al (2024)

Human Motor Neurons Elicit Pathological Hallmarks of ALS and Reveal Potential Biomarkers of the Disease in Response to Prolonged IFNγ Exposure.

The Journal of neuroscience : the official journal of the Society for Neuroscience pii:JNEUROSCI.1787-23.2024 [Epub ahead of print].

Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder marked by progressive motor neuron degeneration and muscle denervation. A recent transcriptomic study integrating a wide range of human ALS samples revealed that upregulation of p53, a downstream target of inflammatory stress, is commonly detected in familial and sporadic ALS cases by a mechanism linked to TDP-43 dysfunction. In this study, we show that prolonged IFNγ treatment of human iPSC-derived spinal motor neurons results in severe cytoplasmic aggregation of TDP-43. Either TDP-43 dysfunction resulting from IFNγ exposure or from an ALS-associated TDP-43 mutation was associated with activation of the p53 pathway. This was accompanied by hyperactivation of neuronal firing, followed by the complete loss of their electrophysiological function. Through comparative single-cell transcriptome analysis, we have identified significant alterations in ALS-associated genes in motor neurons exposed to IFNγ, implicating their direct involvement in ALS pathology. Interestingly, IFNγ was found to induce significant levels of PD-L1 expression in motor neurons without affecting the levels of any other immune checkpoint proteins. This finding suggests a potential role for excessive PD-L1 expression in ALS development, given that PD-L1 was recently reported to impair neuronal firing ability in mice. Our findings suggest that exposing motor neurons to IFNγ could directly derive ALS pathogenesis, even without the presence of inherent genetic mutation or functional glia component. Furthermore, this study provides a comprehensive list of potential candidate genes for future immunotherapeutic targets with which to treat sporadic forms of ALS, which account for 90% of all reported cases.Significance statement ALS is currently an incurable neurodegenerative disease that primarily damages motor function. 90% of the reported cases have unknown reasons, but their progression is extremely fast once triggered. A pathologic hallmark of ALS is an aggregation of RNA/DNA binding protein, TDP-43, but its pathologic link to the disease is yet to be elucidated. In this study, we found the Interferon-gamma (IFNγ), an immune-derived cytokine activates p53 pathway which appears in common in post-mortem ALS tissue. Importantly, IFNγ triggered a significant cytoplasmic TDP-43 aggregation and impaired electrophysiological function of human motor neurons. Furthermore, we found that ALS risk genes related to the mitochondrial dysfunction are aberrantly expressed under the IFNγ exposure, which constitutes potential therapeutic targets of immune-dysregulated neurodegeneration in ALS.

RevDate: 2024-02-28

Arimura Y, Konishi HA, H Funabiki (2024)

MagIC-Cryo-EM: Structural determination on magnetic beads for scarce macromolecules in heterogeneous samples.

bioRxiv : the preprint server for biology.

High-resolution structural reconstitution of biomolecules by cryo-EM single-particle analyses typically demand concentrated samples (0.05~5.0 mg/ml). Here, we introduce Magnetic Isolation and Concentration (MagIC)-cryo-EM, a technique enabling direct structural analysis of targets captured on magnetic beads, thereby reducing the targets' concentration requirement to < 0.0005 mg/ml. Adapting MagIC-cryo-EM to a Chromatin Immunoprecipitation protocol, we characterized structural variations of oocyte-specific linker histone H1.8 associated nucleosomes isolated from interphase and metaphase chromosomes in Xenopus egg extract. Combining Duplicated Selection To Exclude Rubbish particles (DuSTER), a particle curation method that removes low signal-to-noise ratio particles, we also resolved the 3D cryo-EM structures of H1.8-bound nucleoplasmin NPM2 isolated from interphase chromosomes, revealing distinct open and closed structural variants. Our study demonstrates the utility of MagIC-cryo-EM for structural analysis of macromolecules difficult to purify and offers structural insights into the chaperone NPM2 interacts with its targets and the cell cycle-regulation of H1.8 association to nucleosomes.

RevDate: 2024-02-28

Carnahan MB, Sharpe RE, Oluyemi E, et al (2022)

Women's Experience With Screening Mammography During the COVID-19 Pandemic: A Multi-Institutional Prospective Survey Study.

Journal of breast imaging, 4(3):253-262.

OBJECTIVE: Evaluate women's anxiety and experience undergoing screening mammography during the COVID-19 pandemic.

METHODS: An IRB-approved anonymous survey was administered to women receiving screening mammography across six sites in the U.S. and Singapore from October 7, 2020, to March 11, 2021. Using a 1-5 Likert scale, women rated their pre- and post-visit anxiety regarding having their mammogram during the COVID-19 pandemic, importance of observed COVID-19 precautions, and personal risk factors for breast cancer and severe COVID-19 illness. Post-visit change in anxiety was evaluated. Multivariable logistic regression was used to test associations of pre-visit anxiety with breast cancer and COVID-19 risk factors.

RESULTS: In total, 1086 women completed the survey. Of these, 59% (630/1061) had >1 breast cancer risk factor; 27% (282/1060) had >1 COVID-19 risk factors. Forty-two percent (445/1065) experienced pre-visit anxiety. Pre-visit anxiety was independently associated with risk factors for severe COVID-19 (OR for >2 vs 0 risk factors: 2.04, 95% confidence interval [CI]: 1.11-3.76) and breast cancer (OR for >2 vs 0 risk factors: 1.71, 95% CI: 1.17-2.50), after adjusting for age and site. Twenty-six percent (272/1065) of women reported post-visit anxiety, an absolute 16% decrease from pre-visit anxiety (95% CI: 14%-19%, P < 0.001). Provider masking (941/1075, 88%) and physical distancing (861/1085, 79%) were rated as the most important precautions.

CONCLUSION: Pre-visit anxiety was associated with COVID-19 or breast cancer risk factors and declined significantly after screening mammography. Provider masking and physical distancing were rated the most important precautions implemented by imaging clinics.

RevDate: 2024-02-27

Torres-Blasco N, Peña-Vargas C, Costas-Muñiz R, et al (2024)

Psychosocial symptoms associated with spiritual well-being in Latino patients and caregivers coping with advanced cancer.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 32(3):195.

PURPOSE: The objective of this study was to investigate the relationship among hopelessness, anxiety, and depression, with spiritual well-being in patients and family caregivers.

METHODS: A cross-sectional survey was administered to patients (n = 57) and caregivers (n = 57) that incorporated assessments that measured spiritual well-being, depression, anxiety, hopelessness, quality of life, family relationship, burden, fatalism, religiosity, and distress. Logistic regression and cross-tabulation analyses were conducted to examine the relationship between hopelessness, anxiety, and depression, with spiritual well-being. Logistic regression was used to quantify the impact of spiritual well-being on anxiety, depression, and hopelessness. Additionally, cross-tabulations with chi-square tests were conducted to explore associations between severity of hopelessness and severity of anxiety and depression.

RESULTS: Logistic regression analyses showed negative associations between spiritual well-being and mental health outcomes, although not all findings were statistically significant. Among caregivers, a significant negative relationship was observed for depression (B =  - 0.161, p = 0.022). Hopelessness also exhibited a negative association with spiritual well-being among caregivers (B =  - 0.099, p = 0.054) and patients (B =  - .152, p = 0.038). Cross-tabulations highlighted significant associations in the severity of hopelessness symptoms with anxiety and depression levels among caregivers (p < .001).

CONCLUSION: Results reveal a relationship among psychosocial symptoms among Latino patient-caregivers coping with cancer. By emphasizing spiritual well-being, hopelessness, and anxiety and involving family patients and caregivers in the treatment process as a unit of care. Also, it indicates the need to develop culturally tailored interventions that aim to provide valuable assistance to Latino patients and caregivers coping with cancer.

RevDate: 2024-02-27

Nguyen S, Bellettiere J, Anuskiewicz B, et al (2024)

Prospective Associations of Accelerometer-Measured Machine-Learned Sedentary Behavior With Death Among Older Women: The OPACH Study.

Journal of the American Heart Association [Epub ahead of print].

BACKGROUND: Sedentary behavior is a recognized mortality risk factor. The novel and validated convolutional neural network hip accelerometer posture algorithm highly accurately classifies sitting and postural changes compared with accelerometer count cut points. We examined the prospective associations of convolutional neural network hip accelerometer posture-classified total sitting time and mean sitting bout duration with all-cause and cardiovascular disease (CVD) death.

METHODS AND RESULTS: Women (n=5856; mean±SD age, 79±7 years; 33% Black women, 17% Hispanic or Latina women, 50% White women) in the Women's Health Initiative Objective Physical Activity and Cardiovascular Health (OPACH) Study wore the ActiGraph GT3X+ for ~7 days from May 2012 to April 2014 and were followed through February 19, 2022 for all-cause and CVD death. The convolutional neural network hip accelerometer posture algorithm classified total sitting time and mean sitting bout duration from GT3X+ output. Over follow-up (median, 8.4 years; range, 0.1-9.9), there were 1733 deaths (632 from CVD). Adjusted Cox regression hazard ratios (HRs) comparing women in the highest total sitting time quartile (>696 min/d) to those in the lowest (<556.0 min/d) were 1.57 (95% CI; 1.35-1.83; P-trend<0.001) for all-cause death and 1.78 (95% CI; 1.36-2.31; P-trend<0.001) for CVD death. HRs comparing women in the longest mean sitting bout duration quartile (>15 minutes) to the shortest (<9.3 minutes) were 1.43 (95% CI; 1.23-1.66; P-trend<0.001) for all-cause death and 1.52 (95% CI; 1.18-1.96; P-trend<0.001) for CVD death. Apparent nonlinear associations for total sitting time suggested higher all-cause death (P nonlinear=0.009) and CVD death (P nonlinear=0.008) risk after ~660 to 700 min/d.

CONCLUSIONS: Higher total sitting time and longer mean sitting bout duration are associated with higher all-cause and CVD mortality risk among older women. These data support interventions aimed at reducing both total sitting time and interrupting prolonged sitting.

RevDate: 2024-02-26

Laskar RS, Qu C, Huyghe JR, et al (2024)

Genome-wide association study and Mendelian randomization analyses provide insights into the causes of early-onset colorectal cancer.

Annals of oncology : official journal of the European Society for Medical Oncology pii:S0923-7534(24)00058-9 [Epub ahead of print].

BACKGROUND: The incidence of early-onset colorectal cancer (EOCRC; diagnosed <50 years of age) is rising globally; however, the causes underlying this trend are largely unknown. Colorectal cancer (CRC) has strong genetic and environmental determinants, yet common genetic variants and causal modifiable risk factors underlying EOCRC are unknown. We conducted the first EOCRC-specific genome-wide association study (GWAS) and Mendelian randomization analyses to explore germline genetic and causal modifiable risk factors associated with EOCRC.

PATIENTS AND METHODS: We conducted a genome-wide association study meta-analysis of 6,176 EOCRC cases and 65,829 controls from Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), Colorectal Transdisciplinary study (CORECT), Colon Cancer Family Registry (CCFR), and UK Biobank. We then used the EOCRC GWAS to investigate 28 modifiable risk factors using two-sample Mendelian randomization (MR).

RESULTS: We found two novel risk loci for EOCRC at 1p34.1 and 4p15.33, not previously associated with CRC risk. We identified a deleterious coding variant (rs36053993, G396D) at polyposis-associated DNA repair gene MUTYH (OR=1.80 [95%CI=1.47-2.22]) but show that most of the common genetic susceptibility was from non-coding signals enriched in epigenetic markers present in gastrointestinal tract cells. We identified new EOCRC susceptibility genes, and in addition to pathways such as TGFβ, SMAD, BMP, and PI3K signaling, our study highlights a role for insulin signaling and immune/infection-related pathways in EOCRC. In our MR analyses, we found novel evidence of probable causal associations for higher levels of body size and metabolic factors - such as body fat percentage, waist circumference, waist to hip ratio, basal metabolic rate, and fasting insulin - higher alcohol drinking and lower education attainment, with increased EOCRC risk.

CONCLUSION: Our novel findings indicate inherited susceptibility to EOCRC and suggest modifiable lifestyle and metabolic targets that could also be used to risk stratify individuals for personalized screening strategies or other interventions.

RevDate: 2024-02-26

Collins AM, Ohlin M, Corcoran M, et al (2023)

AIRR-C IG Reference Sets: curated sets of immunoglobulin heavy and light chain germline genes.

Frontiers in immunology, 14:1330153.

INTRODUCTION: Analysis of an individual's immunoglobulin (IG) gene repertoire requires the use of high-quality germline gene reference sets. When sets only contain alleles supported by strong evidence, AIRR sequencing (AIRR-seq) data analysis is more accurate and studies of the evolution of IG genes, their allelic variants and the expressed immune repertoire is therefore facilitated.

METHODS: The Adaptive Immune Receptor Repertoire Community (AIRR-C) IG Reference Sets have been developed by including only human IG heavy and light chain alleles that have been confirmed by evidence from multiple high-quality sources. To further improve AIRR-seq analysis, some alleles have been extended to deal with short 3' or 5' truncations that can lead them to be overlooked by alignment utilities. To avoid other challenges for analysis programs, exact paralogs (e.g. IGHV1-69*01 and IGHV1-69D*01) are only represented once in each set, though alternative sequence names are noted in accompanying metadata.

RESULTS AND DISCUSSION: The Reference Sets include less than half the previously recognised IG alleles (e.g. just 198 IGHV sequences), and also include a number of novel alleles: 8 IGHV alleles, 2 IGKV alleles and 5 IGLV alleles. Despite their smaller sizes, erroneous calls were eliminated, and excellent coverage was achieved when a set of repertoires comprising over 4 million V(D)J rearrangements from 99 individuals were analyzed using the Sets. The version-tracked AIRR-C IG Reference Sets are freely available at the OGRDB website (https://ogrdb.airr-community.org/germline_sets/Human) and will be regularly updated to include newly observed and previously reported sequences that can be confirmed by new high-quality data.

RevDate: 2024-02-26

Huang TJ, Luedtke A, IW McKeague (2023)


Annals of statistics, 51(5):1965-1988.

This paper develops a new approach to post-selection inference for screening high-dimensional predictors of survival outcomes. Post-selection inference for right-censored outcome data has been investigated in the literature, but much remains to be done to make the methods both reliable and computationally-scalable in high-dimensions. Machine learning tools are commonly used to provide predictions of survival outcomes, but the estimated effect of a selected predictor suffers from confirmation bias unless the selection is taken into account. The new approach involves the construction of semi-parametrically efficient estimators of the linear association between the predictors and the survival outcome, which are used to build a test statistic for detecting the presence of an association between any of the predictors and the outcome. Further, a stabilization technique reminiscent of bagging allows a normal calibration for the resulting test statistic, which enables the construction of confidence intervals for the maximal association between predictors and the outcome and also greatly reduces computational cost. Theoretical results show that this testing procedure is valid even when the number of predictors grows superpolynomially with sample size, and our simulations support this asymptotic guarantee at moderate sample sizes. The new approach is applied to the problem of identifying patterns in viral gene expression associated with the potency of an antiviral drug.

RevDate: 2024-02-26

Mayr NA, Mohiuddin M, Snider JW, et al (2024)

Practice Patterns of Spatially Fractionated Radiation Therapy: A Clinical Practice Survey.

Advances in radiation oncology, 9(2):101308.

PURPOSE: Spatially fractionated radiation therapy (SFRT) is increasingly used for bulky advanced tumors, but specifics of clinical SFRT practice remain elusive. This study aimed to determine practice patterns of GRID and Lattice radiation therapy (LRT)-based SFRT.

METHODS AND MATERIALS: A survey was designed to identify radiation oncologists' practice patterns of patient selection for SFRT, dosing/planning, dosimetric parameter use, SFRT platforms/techniques, combinations of SFRT with conventional external beam radiation therapy (cERT) and multimodality therapies, and physicists' technical implementation, delivery, and quality procedures. Data were summarized using descriptive statistics. Group comparisons were analyzed with permutation tests.

RESULTS: The majority of practicing radiation oncologists (United States, 100%; global, 72.7%) considered SFRT an accepted standard-of-care radiation therapy option for bulky/advanced tumors. Treatment of metastases/recurrences and nonmetastatic primary tumors, predominantly head and neck, lung cancer and sarcoma, was commonly practiced. In palliative SFRT, regimens of 15 to 18 Gy/1 fraction predominated (51.3%), and in curative-intent treatment of nonmetastatic tumors, 15 Gy/1 fraction (28.0%) and fractionated SFRT (24.0%) were most common. SFRT was combined with cERT commonly but not always in palliative (78.6%) and curative-intent (85.7%) treatment. SFRT-cERT time sequencing and cERT dose adjustments were variable. In curative-intent treatment, concurrent chemotherapy and immunotherapy were found acceptable by 54.5% and 28.6%, respectively. Use of SFRT dosimetric parameters was highly variable and differed between GRID and LRT. SFRT heterogeneity dosimetric parameters were more commonly used (P = .008) and more commonly thought to influence local control (peak dose, P = .008) in LRT than in GRID therapy.

CONCLUSIONS: SFRT has already evolved as a clinical practice pattern for advanced/bulky tumors. Major treatment approaches are consistent and follow the literature, but SFRT-cERT combination/sequencing and clinical utilization of dosimetric parameters are variable. These areas may benefit from targeted education and standardization, and knowledge gaps may be filled by incorporating identified inconsistencies into future clinical research.

RevDate: 2024-02-26

Barbour AB, Kotecha R, Lazarev S, et al (2024)

Radiation Therapy in the Management of Leptomeningeal Disease From Solid Tumors.

Advances in radiation oncology, 9(2):101377.

PURPOSE: Leptomeningeal disease (LMD) is clinically detected in 5% to 10% of patients with solid tumors and is a source of substantial morbidity and mortality. Prognosis for this entity remains poor and treatments are palliative. Radiation therapy (RT) is an essential tool in the management of LMD, and a recent randomized trial demonstrated a survival benefit for proton craniospinal irradiation (CSI) in select patients. In the setting of this recent advance, we conducted a review of the role of RT in LMD from solid tumors to evaluate the evidence basis for RT recommendations.

METHODS AND MATERIALS: In November 2022, we conducted a comprehensive literature search in PubMed, as well as a review of ongoing clinical trials listed on ClinicalTrials.gov, to inform a discussion on the role of RT in solid tumor LMD. Because of the paucity of high-quality published evidence, discussion was informed more by expert consensus and opinion, including a review of societal guidelines, than evidence from clinical trials.

RESULTS: Only 1 prospective randomized trial has evaluated RT for LMD, demonstrating improved central nervous system progression-free survival for patients with breast and lung cancer treated with proton CSI compared with involved-field RT. Modern photon CSI techniques have improved upon historical rates of acute hematologic toxicity, but the overall benefit of this modality has not been prospectively evaluated. Multiple retrospective studies have explored the use of involved-field RT or the combination of RT with chemotherapy, but clear evidence of survival benefit is lacking.

CONCLUSIONS: Optimal management of LMD with RT remains reliant upon expert opinion, with proton CSI indicated in patients with good performance status and extra-central nervous system disease that is either well-controlled or for which effective treatment options are available. Photon-based CSI traditionally has been associated with increased marrow and gastrointestinal toxicities, though intensity modulated RT/volumetric-modulated arc therapy based photon CSI may have reduced the toxicity profile. Further work is needed to understand the role of radioisotopes as well as combined modality treatment with intrathecal or central nervous system penetrating systemic therapies.

RevDate: 2024-02-25

Chambers LC, Tapia KA, Srinivasan S, et al (2024)

The Relationship Between Insertive Oral and Anal Sex and Select Measures of the Composition of the Urethral Microbiota Among Men Who Have Sex With Men.

Sexually transmitted diseases pii:00007435-990000000-00334 [Epub ahead of print].

BACKGROUND: Sexual behavior may influence the composition of the male urethral microbiota, but this hypothesis has not been tested in longitudinal studies of men who have sex with men (MSM).

METHODS: From 12/2014-7/2018, we enrolled MSM with non-gonococcal urethritis (NGU) attending a sexual health clinic. Men attended five in-clinic visits at 3-week intervals, collected weekly urine specimens at home, and reported daily antibiotics and sexual activity on weekly diaries. We applied broad-range 16S rRNA gene sequencing to urine. We used generalized estimating equations to estimate the association between urethral sexual exposures in the prior 7 days (insertive oral sex [IOS] only, condomless insertive anal intercourse [CIAI] only, IOS with CIAI [IOS + CIAI], or none) and Shannon index, number of species (observed, oral indicator, and rectal indicator), and specific taxa, adjusting for recent antibiotics, age, race/ethnicity, HIV, and pre-exposure prophylaxis.

RESULTS: Ninety-six of 108 MSM with NGU attended ≥1 follow-up visit. They contributed 1,140 person-weeks of behavioral data and 1,006 urine specimens. Compared to those with no urethral sexual exposures, those with IOS only had higher Shannon index (P = 0.03) but similar number of species and presence of specific taxa considered, adjusting for confounders; the exception was an association with Haemophilus parainfluenzae. CIAI only was not associated with measured aspects of the urethral microbiota. IOS + CIAI was only associated with presence of H. parainfluenzae and Haemophilus.

CONCLUSIONS: Among MSM after NGU, IOS and CIAI did not appear to have a substantial influence on measured aspects of the composition of the urethral microbiota.

RevDate: 2024-02-26
CmpDate: 2024-02-26

Motzer RJ, Jonasch E, Agarwal N, et al (2024)

NCCN Guidelines® Insights: Kidney Cancer, Version 2.2024.

Journal of the National Comprehensive Cancer Network : JNCCN, 22(1):4-16.

The NCCN Guidelines for Kidney Cancer provide multidisciplinary recommendations for diagnostic workup, staging, and treatment of patients with renal cell carcinoma (RCC). These NCCN Guidelines Insights focus on the systemic therapy options for patients with advanced RCC and summarize the new clinical data evaluated by the NCCN panel for the recommended therapies in Version 2.2024 of the NCCN Guidelines for Kidney Cancer.

RevDate: 2024-02-26
CmpDate: 2024-02-26

Shah NP, Bhatia R, Altman JK, et al (2024)

Chronic Myeloid Leukemia, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Journal of the National Comprehensive Cancer Network : JNCCN, 22(1):43-69.

Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22 [t9;22] that gives rise to a BCR::ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase in developed countries. Tyrosine kinase inhibitor (TKI) therapy is a highly effective treatment option for patients with chronic phase-CML. The primary goal of TKI therapy in patients with chronic phase-CML is to prevent disease progression to accelerated phase-CML or blast phase-CML. Discontinuation of TKI therapy with careful monitoring is feasible in selected patients. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with chronic phase-CML.

RevDate: 2024-02-26

Carr CR, Crawford KHD, Murphy M, et al (2024)

Deep mutational scanning reveals functional constraints and antigenic variability of Lassa virus glycoprotein complex.

bioRxiv : the preprint server for biology.

Lassa virus is estimated to cause thousands of human deaths per year, primarily due to spillovers from its natural host, Mastomys rodents. Efforts to create vaccines and antibody therapeutics must account for the evolutionary variability of Lassa virus's glycoprotein complex (GPC), which mediates viral entry into cells and is the target of neutralizing antibodies. To map the evolutionary space accessible to GPC, we use pseudovirus deep mutational scanning to measure how nearly all GPC amino-acid mutations affect cell entry and antibody neutralization. Our experiments define functional constraints throughout GPC. We quantify how GPC mutations affect neutralization by a panel of monoclonal antibodies and show that all antibodies are escaped by mutations that exist among natural Lassa virus lineages. Overall, our work describes a biosafety-level-2 method to elucidate the mutational space accessible to GPC and shows how prospective characterization of antigenic variation could aid design of therapeutics and vaccines.

RevDate: 2024-02-26

Ravishankar S, Towlerton AMH, Mooka P, et al (2024)

The signature of a T-cell response to KSHV persists across space and time in individuals with epidemic and endemic KS from Uganda.

bioRxiv : the preprint server for biology.

Inadequate T-cell control of Kaposi sarcoma-associated herpesvirus (KSHV) infection predisposes to development of Kaposi sarcoma (KS), but little is known about the T-cell response to KSHV. Postulating that KS tumors contain abundant KSHV-specific T-cells, we performed transcriptional profiling and T-cell receptor (TCR) repertoire analysis of tumor biopsies from 144 Ugandan adults with KS. We show that CD8[+] T-cells and M2-polarized macrophages dominate the tumor micro-environment (TME). The TCR repertoire of KS tumor infiltrating lymphocytes (TIL) is shared across non-contiguous tumors and persists across time. Clusters of T-cells with predicted shared specificity for uncharacterized antigens, potentially encoded by KSHV, comprise ~25% of KS TIL, and are shared across tumors from different time points and individuals. Single-cell RNA-sequencing of blood identifies a non-proliferating effector memory phenotype and captured the TCRs in 14,698 putative KSHV-specific T-cells. These results suggest that a polyspecific KSHV-specific T-cell response inhibited by M2 macrophages exists within the KS TME, and provide a foundation for studies to define its specificity at a large scale.

RevDate: 2024-02-26

Ford ES, Li A, Laing KJ, et al (2024)

Expansion of the HSV-2-specific T cell repertoire in skin after immunotherapeutic HSV-2 vaccine.

medRxiv : the preprint server for health sciences.

The skin at the site of HSV-2 reactivation is enriched for HSV-2-specific T cells. To evaluate whether an immunotherapeutic vaccine could elicit skin-based memory T cells, we studied skin biopsies and HSV-2-reactive CD4[+] T cells from peripheral blood mononuclear cells (PBMCs) by T cell receptor β (TRB) sequencing before and after vaccination with a replication-incompetent whole virus HSV-2 vaccine candidate (HSV529). The representation of HSV-2-reactive CD4[+] TRB sequences from PBMCs in the skin TRB repertoire increased after the first vaccine dose. We found sustained expansion after vaccination of unique, skin-based T-cell clonotypes that were not detected in HSV-2-reactive CD4[+] T cells isolated from PBMCs. In one participant a switch in immunodominance occurred with the emergence of a T cell receptor (TCR) αβ pair after vaccination that was not detected in blood. This TCRαβ was shown to be HSV-2-reactive by expression of a synthetic TCR in a Jurkat-based NR4A1 reporter system. The skin in areas of HSV-2 reactivation possesses an oligoclonal TRB repertoire that is distinct from the circulation. Defining the influence of therapeutic vaccination on the HSV-2-specific TRB repertoire requires tissue-based evaluation.

RevDate: 2024-02-25

Gomez SE, Larson J, Hlatky MA, et al (2024)

Prevalence of frequent premature ventricular contractions and nonsustained ventricular tachycardia in older women screened for atrial fibrillation in the Women's Health Initiative.

Heart rhythm pii:S1547-5271(24)00212-1 [Epub ahead of print].

BACKGROUND: Frequent premature ventricular contractions (PVCs) and nonsustained ventricular tachycardia (NSVT) have been associated with cardiovascular disease and mortality. Their prevalence, especially in ambulatory populations, is under-studied and limited by few female participants and the use of short-duration (24-48 hour) monitoring.

OBJECTIVE: Report the prevalence of frequent PVCs and NSVT in a community-based population of women likely to undergo ECG screening using sequential patch monitoring.

METHODS: Participants from the Women's Health Initiative Strong and Healthy (WHISH) trial with no history of atrial fibrillation (AF) but 5-year predicted risk of incident AF ≥ 5% by CHARGE-AF score were randomly selected to undergo screening with 7-day ECG patch monitors at baseline, 6 months, and 12 months. Recordings were reviewed for PVCs and NSVT (> 5 beats); data was analyzed using multivariate regression models.

RESULTS: There were 1,067 participants who underwent ECG screening at baseline, 866 at 6-months and 777 at 12-months. Frequent PVCs were found on at least one patch from 4.3% of participants and one or more episodes of NSVT was found in 12 (1.1%) women. PVC frequency directly correlated with CHARGE-AF score and NSVT on any patch. Detection of frequent PVCs increased with sequential monitoring.

CONCLUSION: Among postmenopausal women at high risk for AF, frequent PVCs were relatively common (4.3%), and correlated with higher CHARGE-AF score. As strategies for AF screening continue to evolve, particularly in those individuals at high risk of AF, the prevalence of incidental ventricular arrhythmias is an important benchmark to guide clinical decision-making.

RevDate: 2024-02-25

Wang CY, Hsu L, T Harrison (2024)

Robust best linear weighted estimator with missing covariates in survival analysis.

Statistics in medicine [Epub ahead of print].

Missing data in covariates can result in biased estimates and loss of power to detect associations. We consider Cox regression in which some covariates are subject to missing. The inverse probability weighted approach is often applied to regression analysis with missing covariates. Inverse probability weighted estimators typically are less efficient than likelihood-based estimators, but in general are more robust against model misspecification. In this article, we propose a robust best linear weighted estimator for Cox regression with missing covariates. Our proposed estimator is the projection of the simple inverse probability weighted estimator onto the orthogonal complement of the score space based on a working regression model of the observed data. The efficiency gain is from the use of the association between the survival outcome variable and the available covariates, which is the working regression model. The asymptotic distribution is derived, and the finite sample performance of the proposed estimator is examined via extensive simulation studies. The methods are applied to a colorectal cancer study to assess the association of the microsatellite instability status with colorectal cancer-specific mortality.

RevDate: 2024-02-24

Kuczmarski TM, Roemer L, OO Odejide (2024)

Depression in patients with hematologic malignancies: The current landscape and future directions.

Blood reviews pii:S0268-960X(24)00015-8 [Epub ahead of print].

Patients with hematologic malignancies experience high rates of depression. These patients are vulnerable to depression throughout the disease trajectory, from diagnosis to survivorship, and at the end of life. In addition to the distressing nature of depression, it has substantial downstream effects including poor quality of life, increased risk of treatment complications, and worse survival. Therefore, systematic screening for depression and integration of robust psychological interventions for affected patients is crucial. Although depression has been historically studied mostly in patients with solid malignancies, research focusing on patients with hematologic malignancies is growing. In this article, we describe what is known about depression in patients with hematologic malignancies, including its assessment, prevalence, risk factors, and implications. We also describe interventions to ameliorate depression in this population. Future research is needed to test effective and scalable interventions to reduce the burden of depression among patients with blood cancers.

RevDate: 2024-02-24

Bell-Brown A, Hopkins T, Watabayashi K, et al (2024)

A proactive financial navigation intervention in patients with newly diagnosed gastric and gastroesophageal junction adenocarcinoma.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 32(3):189.

PURPOSE: Many cancer patients and caregivers experience financial hardship, leading to poor outcomes. Gastric and gastroesophageal junction (GEJ) cancer patients are particularly at risk for financial hardship given the intensity of treatment. This pilot randomized study among gastric/GEJ cancer patients and caregivers tested a proactive financial navigation (FN) intervention to obtain a signal of efficacy to inform a larger, more rigorous randomized study.

METHODS: We tested a 3-month proactive FN intervention among gastric/GEJ cancer patients and caregivers compared to usual care. Caregiver participation was optional. The primary endpoint was incidence of financial hardship, defined as follows: accrual of debt, income decline of ≥ 20%, or taking loans to pay for treatment. Data from participant surveys and documentation by partner organizations delivering the FN intervention was analyzed and outcomes were compared between study arms.

RESULTS: Nineteen patients and 12 caregivers consented. Primary FN resources provided included insurance navigation, budget planning, and help with out-of-pocket medical expenses. Usual care patients were more likely to experience financial hardship (50% vs 40%) and declines in quality of life (37.5% vs 0%) compared to intervention patients. Caregivers in both arms reported increased financial stress and poorer quality of life over the study period.

CONCLUSIONS: Proactive financial navigation has potentially positive impacts on financial hardship and quality of life for cancer patients and more large-scale randomized interventions should be conducted to rigorously explore the impact of similar interventions. Interventions that have the potential to lessen caregiver financial stress and burden need further exploration.

TRIAL REGISTRATION: TRN: NCT03986502, June 14, 2019.

RevDate: 2024-02-24

Zhang M, Chen C, Li G, et al (2024)

Cocaine use and head and neck cancer risk: A pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.

Cancer medicine, 13(3):e7019.

BACKGROUND: Cocaine is an illegal recreational drug used worldwide, yet little is known about whether cocaine inhalation (smoking/snorting) increases the risk of head and neck cancer (HNC).

METHODS: The analyses were conducted by pooling data from three case-control studies with 1639 cases and 2506 controls from the International Head and Neck Cancer Epidemiology Consortium. Epidemiologic data, including cocaine use histories, were obtained in face-to-face interviews. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using hierarchical logistic regression models.

RESULTS: Controlling for cumulative tobacco and alcohol use, we observed a weak positive association between cocaine use and HNC (ORever vs. never  = 1.35, 95% CI: 0.96, 1.90). In stratified analysis, while we did not detect associations among never tobacco or alcohol users due to the limited sample size, the association with cocaine use was observed among tobacco users and alcohol drinkers. ORs for ever and high cumulative use (>18 times) versus never use were 1.40 (95% CI: 0.98, 2.00) and 1.66 (95% CI: 1.03, 2.69) among tobacco users, and 1.34 (95% CI: 0.93, 1.92) and 1.59 (95% CI: 1.00, 2.51) among alcohol drinkers, respectively.

CONCLUSION: In this pooled analysis, we observed a weak positive association between cocaine inhalation and HNC risk. Our findings provide preliminary evidence of the potential carcinogenic effect of cocaine on HNC. Because of study limitations, including limited number of cocaine users, confounding, and heterogeneity across studies, future investigations will require larger studies with more detailed information on cocaine use history.

RevDate: 2024-02-24

McGale JP, Howell HJ, Beddok A, et al (2024)

Integrating Artificial Intelligence and PET Imaging for Drug Discovery: A Paradigm Shift in Immunotherapy.

Pharmaceuticals (Basel, Switzerland), 17(2): pii:ph17020210.

The integration of artificial intelligence (AI) and positron emission tomography (PET) imaging has the potential to become a powerful tool in drug discovery. This review aims to provide an overview of the current state of research and highlight the potential for this alliance to advance pharmaceutical innovation by accelerating the development and deployment of novel therapeutics. We previously performed a scoping review of three databases (Embase, MEDLINE, and CENTRAL), identifying 87 studies published between 2018 and 2022 relevant to medical imaging (e.g., CT, PET, MRI), immunotherapy, artificial intelligence, and radiomics. Herein, we reexamine the previously identified studies, performing a subgroup analysis on articles specifically utilizing AI and PET imaging for drug discovery purposes in immunotherapy-treated oncology patients. Of the 87 original studies identified, 15 met our updated search criteria. In these studies, radiomics features were primarily extracted from PET/CT images in combination (n = 9, 60.0%) rather than PET imaging alone (n = 6, 40.0%), and patient cohorts were mostly recruited retrospectively and from single institutions (n = 10, 66.7%). AI models were used primarily for prognostication (n = 6, 40.0%) or for assisting in tumor phenotyping (n = 4, 26.7%). About half of the studies stress-tested their models using validation sets (n = 4, 26.7%) or both validation sets and test sets (n = 4, 26.7%), while the remaining six studies (40.0%) either performed no validation at all or used less stringent methods such as cross-validation on the training set. Overall, the integration of AI and PET imaging represents a paradigm shift in drug discovery, offering new avenues for more efficient development of therapeutics. By leveraging AI algorithms and PET imaging analysis, researchers could gain deeper insights into disease mechanisms, identify new drug targets, or optimize treatment regimens. However, further research is needed to validate these findings and address challenges such as data standardization and algorithm robustness.

RevDate: 2024-02-24

Hippalgaonkar N, Nguyen RH, Cohn EB, et al (2024)

Are We the Problem? A Call to Action for Addressing Institutional Challenges to Engaging Community Partners in Research.

International journal of environmental research and public health, 21(2): pii:ijerph21020236.

Community-engaged research (CEnR) is a potent tool for addressing health inequities and fostering equitable relationships among communities, researchers, and institutions. CEnR involves collaboration throughout the research process, demonstrating improvements in study recruitment and retention, intervention efficacy, program sustainability, capacity building among partners, and enhanced cultural relevance. Despite the increasing demand for CEnR, institutional policies, particularly human participation protection training (HPP), lag behind, creating institutional barriers to community partnerships. Here, we highlight challenges encountered in our ongoing study, Fostering Opportunities in Research through Messaging and Education (FOR ME), focused on promoting shared decision-making around clinical trial participation among Black women diagnosed with breast cancer. Grounded in CEnR methods, FOR ME has a partnership with a community-based organization (CBO) that addresses the needs of Black women with breast cancer. Our CBO partner attempted to obtain HPP training, which was administratively burdensome and time-consuming. As CEnR becomes more prevalent, academic and research institutions, along with researchers, are faced with a call to action to become more responsive to community partner needs. Accordingly, we present a guide to HPP training for community partners, addressing institutional barriers to community partner participation in research. This guide outlines multiple HPP training pathways for community partners, aiming to minimize institutional barriers and enhance their engagement in research with academic partners.

RevDate: 2024-02-23

Wright JL, Gray R, Rahbar H, et al (2024)

Lumpectomy without radiation for ductal carcinoma in situ of the breast: 20-year results from the ECOG-ACRIN E5194 study.

NPJ breast cancer, 10(1):16.

We report the 20-year rate of ipsilateral breast event (IBE) for patients with ductal carcinoma in situ (DCIS) treated with lumpectomy without radiation on a non-randomized prospective clinical trial. Patients were enrolled in cohort 1: low- or intermediate-grade DCIS, size ≤ 2.5 cm (n = 561); or cohort 2: high-grade DCIS, size ≤ 1 cm (n = 104). The Kaplan-Meier method was used to estimate time-to-event distributions. Cox proportional hazard methods were used to estimate hazard ratios (HRs) and tests for significance for event times. 561 patients were enrolled in cohort 1 and 104 in cohort 2. After central pathology review, 26% in cohort 1 were recategorized as high-grade and 26% in cohort 2 as low- or intermediate-grade. Mean DCIS size was similar at 7.5 mm in cohort 1 and 7.8 mm in cohort 2. Surgical margin was ≥3 mm in 96% of patients, and about 30% received tamoxifen. Median follow-up was 19.2 years. There were 104 IBEs, of which 54 (52%) were invasive. The IBE and invasive IBE rates increased in both cohorts up to 15 years, then plateaued. The 20-year IBE rates were 17.8% for cohort 1 and 28.7% for cohort 2 (p = 0.005), respectively. Invasive IBE occurred in 9.8% and 15.1% (p = 0.09), respectively. On multivariable analysis, IBE risk increased with size and was higher in cohort 2, but grade and margin width were not significantly associated with IBE. For patients with DCIS treated with excision without radiation, the rate of IBE increased with size and assigned cohort mostly in the first 15 years.

RevDate: 2024-02-23

Chlebowski RT, Aragaki AK, Pan K, et al (2024)

Dietary intervention favorably influences physical functioning: the Women's Health Initiative randomized Dietary Modification trial.

Journal of the Academy of Nutrition and Dietetics pii:S2212-2672(24)00091-1 [Epub ahead of print].

BACKGROUND: In the Women's Health Initiative Dietary Modification (WHI DM) randomized trial, the dietary intervention reduced breast cancer mortality by 21% (P = 0.02) and increased physical activity as well.

OBJECTIVE: Therefore, the aim was to examine whether these lifestyle changes attenuated age-related physical functioning decline.

DESIGN: In a randomized trial, the influence of 8-years of a low-fat dietary pattern intervention was examined through 20 years cumulative follow-up.

PARTICIPANTS: /setting; From 1993-1998, 48,835 postmenopausal women, ages 50-79 years with no prior breast cancer and negative baseline mammogram were randomized at 40 US clinical centers to dietary intervention or usual diet comparison groups (40/60). The intervention significantly reduced fat intake and increased vegetable, fruit, and grain intake.

MAIN OUTCOME MEASURES: In post hoc analyses, physical functioning, assessed using the RAND 36-Item Short Form Health Survey (SF-36), evaluated quality or limitations of 10 hierarchical physical activities. Longitudinal physical functioning, reported against a disability threshold (when assistance in daily activities is required) was the primary study outcome.

Semiparametric linear mixed effect models (LME) were used to contrast physical functioning trajectories by randomization groups.

RESULTS: Physical functioning score, assessed 495,317 times with 11.0 (median) assessments per participant, was significantly higher in the intervention versus comparison groups through 12-years cumulative follow-up (P = 0.001), representing a reduction in age-related functional decline. The intervention effect subsequently attenuated and did not delay time to the disability threshold. Among women in the dietary intervention versus comparison groups, aged 50-59 years, who were physically inactive at entry, a persistent, statistically significant, favorable influence on physical functioning with associated delay in crossing the disability threshold by approximately a year was seen (P-interaction = 0.007).

CONCLUSIONS: In the WHI DM randomized trial, a dietary intervention which significantly reduced breast cancer mortality also significantly reduced age-related functional decline through 12 years, which was attenuated with longer follow-up.

RevDate: 2024-02-23

Khan HM (2024)

Editorial Commentary on Improving Racial Disparities in Prostate Cancer.

RevDate: 2024-02-23

Davidsen K, Marvin JS, Aggarwal A, et al (2024)

An engineered biosensor enables dynamic aspartate measurements in living cells.

eLife, 12: pii:90024.

Intracellular levels of the amino acid aspartate are responsive to changes in metabolism in mammalian cells and can correspondingly alter cell function, highlighting the need for robust tools to measure aspartate abundance. However, comprehensive understanding of aspartate metabolism has been limited by the throughput, cost, and static nature of the mass spectrometry (MS)-based measurements that are typically employed to measure aspartate levels. To address these issues, we have developed a green fluorescent protein (GFP)-based sensor of aspartate (jAspSnFR3), where the fluorescence intensity corresponds to aspartate concentration. As a purified protein, the sensor has a 20-fold increase in fluorescence upon aspartate saturation, with dose-dependent fluorescence changes covering a physiologically relevant aspartate concentration range and no significant off target binding. Expressed in mammalian cell lines, sensor intensity correlated with aspartate levels measured by MS and could resolve temporal changes in intracellular aspartate from genetic, pharmacological, and nutritional manipulations. These data demonstrate the utility of jAspSnFR3 and highlight the opportunities it provides for temporally resolved and high-throughput applications of variables that affect aspartate levels.

RevDate: 2024-02-23

Nelson CJ, Schuler TA, Reiner AS, et al (2024)

A psychoeducational intervention to improve sexual functioning in male rectal and anal cancer patients: A pilot randomized controlled trial study.

Palliative & supportive care pii:S1478951523001906 [Epub ahead of print].

OBJECTIVES: Male rectal and anal cancer patients demonstrate high rates of sexual dysfunction. This pilot randomized controlled trial tested a psychoeducational intervention designed to improve psychosexual adjustment.

METHODS: Rectal or anal cancer patients were randomized to a Sexual Health Intervention for Men (intervention) or to a referral and information control (control). The intervention included control activities plus 4 sexual health intervention sessions every 4-6 weeks and 3 brief telephone calls timed between these sessions. Assessments were completed pre-intervention (baseline) and 3 months (follow-up 1) and 8 months (follow-up 2) post-intervention. Differences were assessed with statistical significance and Cohen's d effect sizes (d = 0.2, small effect; d = 0.5, moderate effect; d = 0.8, large effect).

RESULTS: Ninety subjects enrolled. Forty-three participants completed at least 1 follow-up assessment (intervention, n = 14; control n = 29). At follow-up 1, men in intervention, compared to control, improved on all domains of the International Index of Erectile Function (IIEF) (p < 0.001 to p < 0.05) and demonstrated large effects (d = 0.8 to d = 1.5). Similarly, at follow-up 2, changes in all domains of the IIEF except the orgasm domain were either statistically significant or marginally statistically significant (p = 0.01 to p = 0.08) and demonstrated moderate to large treatment effects for intervention versus control (d = 0.5 to d = 0.8). Men in the intervention, compared to control, demonstrated decreased sexual bother at follow-up 1 (p = 0.009, d = 1.1), while Self-Esteem and Relationship (SEAR) total scores and the SEAR sexual relationship subscale demonstrated moderate increases for intervention versus control (d = 0.4 to d = 0.6).

SIGNIFICANCE OF RESULTS: This study provides initial evidence for combining a psychoeducational intervention with medical interventions to address sexual dysfunction following rectal and anal cancer. Trials register number: NCT00712751 (date of registration: 7/10/2008).

RevDate: 2024-02-22

Olivieri DJ, Othus M, Orvain C, et al (2024)

Impact of socioeconomic disparities on outcomes in adults undergoing allogeneic hematopoietic cell transplantation for acute myeloid leukemia.

Leukemia [Epub ahead of print].

Racial and socioeconomic disparities impact outcomes after chemotherapy and limit access to allogeneic hematopoietic cell transplantation (HCT) in acute myeloid leukemia (AML), yet studies have yielded mixed results on the influence of disparities on post-HCT outcomes. Therefore, we studied 1024 adults with AML who underwent allogeneic HCT between 5/2006 and 10/2021 at a single large university-affiliated cancer center. Collected data included non-biologic and demographic characteristics (including race/ethnicity, marital status, distance traveled, and household size), transplant- and disease-related characteristics, and area-level and individual-level socioeconomic factors (i.e., area deprivation index and occupational status). After multivariable adjustment, no socioeconomic- or non-biologic factors were associated with non-relapse mortality (NRM), overall survival (OS), relapse-free survival (RFS), or relapse except being married (associated with improved NRM: hazard ratio [HR] = 0.7 [0.50-0.97]) and having no insurance (associated with worse OS: HR = 1.49 [1.05-2.12] and RFS: HR = 1.41 [1.00-1.98]). Despite a relatively racially homogenous cohort, Asian race was associated with improved NRM (HR = 0.47 [0.23-0.93]) and American Indian/Alaskan Native race was associated with higher relapse risk (HR = 2.45 [1.08-5.53]). In conclusion, in our retrospective analysis, socioeconomic-, demographic-, and non-biologic factors had limited impact on post-HCT outcomes in AML patients allografted in morphologic remission. Further research is needed to investigate disparities among HCT-eligible patients.

RevDate: 2024-02-22

Sun V, Guthrie KA, Crane TE, et al (2024)

SWOG S1820: A pilot randomized trial of the Altering Intake, Managing Bowel Symptoms Intervention in Survivors of Rectal Cancer.

Cancer [Epub ahead of print].

BACKGROUND: Survivors of rectal cancer experience persistent bowel dysfunction after treatments. Dietary interventions may be an effective approach for symptom management and posttreatment diet quality. SWOG S1820 was a pilot randomized trial of the Altering Intake, Managing Symptoms in Rectal Cancer (AIMS-RC) intervention for bowel dysfunction in survivors of rectal cancer.

METHODS: Ninety-three posttreatment survivors were randomized to the AIMS-RC group (N = 47) or the Healthy Living Education attention control group (N = 46) after informed consent and completion of a prerandomization run-in. Outcome measures were completed at baseline and at 18 and 26 weeks postrandomization. The primary end point was total bowel function score, and exploratory end points included low anterior resection syndrome (LARS) score, quality of life, dietary quality, motivation, self-efficacy, and positive/negative affect.

RESULTS: Most participants were White and college educated, with a mean age of 55.2 years and median time since surgery of 13.1 months. There were no statistically significant differences in total bowel function score by group, with the AIMS-RC group demonstrating statistically significant improvements in the exploratory end points of LARS (p = .01) and the frequency subscale of the bowel function index (p = .03). The AIMS-RC group reported significantly higher acceptability of the study.

CONCLUSIONS: SWOG S1820 did not provide evidence of benefit from the AIMS-RC intervention relative to the attention control. Select secondary end points did demonstrate improvements. The study was highly feasible and acceptable for participants in the National Cancer Institute Community Oncology Research Program. Findings provide strong support for further refinement and effectiveness testing of the AIMS-RC intervention.

RevDate: 2024-02-22

Peters MQ, Domenjo-Vila E, Carlson M, et al (2024)

A Noninvasive Method to Sample Immune Cells in the Lower Female Genital Tract Using Menstrual Discs.

ImmunoHorizons, 8(2):182-192.

T cells in the human female genital tract (FGT) are key mediators of susceptibility to and protection from infection, including HIV and other sexually transmitted infections. There is a critical need for increased understanding of the distribution and activation of T cell populations in the FGT, but current sampling methods require a healthcare provider and are expensive, limiting the ability to study these populations longitudinally. To address these challenges, we have developed a method to sample immune cells from the FGT utilizing disposable menstrual discs which are noninvasive, self-applied, and low in cost. To demonstrate reproducibility, we sampled the cervicovaginal fluid of healthy, reproductive-aged individuals using menstrual discs across 3 sequential days. Cervicovaginal fluid was processed for cervicovaginal cells, and high-parameter flow cytometry was used to characterize immune populations. We identified large numbers of live, CD45+ leukocytes, as well as distinct populations of T cells and B cells. Within the T cell compartment, activation and suppression status of T cell subsets were consistent with previous studies of the FGT utilizing current approaches, including identification of both tissue-resident and migratory populations. In addition, the T cell population structure was highly conserved across days within individuals but divergent across individuals. Our approach to sample immune cells in the FGT with menstrual discs will decrease barriers to participation and empower longitudinal sampling in future research studies.

RevDate: 2024-02-22

Moran S, Cheng HH, Weg E, et al (2024)

Prostate-specific membrane antigen-positron emission tomography (PSMA-PET) of prostate cancer: current and emerging applications.

Abdominal radiology (New York) [Epub ahead of print].

Prostate-specific membrane antigen-positron emission tomography (PSMA-PET) is transforming the management of patients with prostate cancer. In appropriately selected patients, PSMA-PET offers superior sensitivity and specificity compared to conventional imaging (e.g., computed tomography and bone scintigraphy) as well as choline and fluciclovine PET, with the added benefit of consolidating bone and soft tissue evaluation into a single study. Despite being a newly available imaging tool, PSMA-PET has established indications, interpretation guidelines, and reporting criteria, which will be reviewed. The prostate cancer care team, from imaging specialists to those delivering treatment, should have knowledge of physiologic PSMA radiotracer uptake, patterns of disease spread, and the strengths and limitations of PSMA-PET. In this review, current and emerging applications of PSMA-PET, including appropriateness use criteria as well as image interpretation and pitfalls, will be provided with an emphasis on clinical implications.

RevDate: 2024-02-22

Hattangady NG, Carter K, Maroni-Rana B, et al (2024)

Mapping the core senescence phenotype of primary human colon fibroblasts.

Aging, 16: pii:205577 [Epub ahead of print].

Advanced age is the largest risk factor for many diseases and several types of cancer, including colorectal cancer (CRC). Senescent cells are known to accumulate with age in various tissues, where they can modulate the surrounding tissue microenvironment through their senescence associated secretory phenotype (SASP). Recently, we showed that there is an increased number of senescent cells in the colons of CRC patients and demonstrated that senescent fibroblasts and their SASP create microniches in the colon that are conducive to CRC onset and progression. However, the composition of the SASP is heterogenous and cell-specific, and the precise senescence profile of colon fibroblasts has not been well-defined. To generate a SASP atlas of human colon fibroblasts, we induced senescence in primary human colon fibroblasts using various in vitro methods and assessed the resulting transcriptome. Using RNASequencing and further validation by quantitative RT-PCR and Luminex assays, we define and validate a 'core senescent profile' that might play a significant role in shaping the colon microenvironment. We also performed KEGG analysis and GO analyses to identify key pathways and biological processes that are differentially regulated in colon fibroblast senescence. These studies provide insights into potential driver proteins involved in senescence-associated diseases, like CRC, which may lead to therapies to improve overall health in the elderly and to prevent CRC.

RevDate: 2024-02-22

Roche SD, Ekwunife OI, Mendonca R, et al (2024)

Measuring the performance of computer vision artificial intelligence to interpret images of HIV self-testing results.

Frontiers in public health, 12:1334881.

INTRODUCTION: HIV self-testing (HIVST) is highly sensitive and specific, addresses known barriers to HIV testing (such as stigma), and is recommended by the World Health Organization as a testing option for the delivery of HIV pre-exposure prophylaxis (PrEP). Nevertheless, HIVST remains underutilized as a diagnostic tool in community-based, differentiated HIV service delivery models, possibly due to concerns about result misinterpretation, which could lead to inadvertent onward transmission of HIV, delays in antiretroviral therapy (ART) initiation, and incorrect initiation on PrEP. Ensuring that HIVST results are accurately interpreted for correct clinical decisions will be critical to maximizing HIVST's potential. Early evidence from a few small pilot studies suggests that artificial intelligence (AI) computer vision and machine learning could potentially assist with this task. As part of a broader study that task-shifted HIV testing to a new setting and cadre of healthcare provider (pharmaceutical technologists at private pharmacies) in Kenya, we sought to understand how well AI technology performed at interpreting HIVST results.

METHODS: At 20 private pharmacies in Kisumu, Kenya, we offered free blood-based HIVST to clients ≥18 years purchasing products indicative of sexual activity (e.g., condoms). Trained pharmacy providers assisted clients with HIVST (as needed), photographed the completed HIVST, and uploaded the photo to a web-based platform. In real time, each self-test was interpreted independently by the (1) client and (2) pharmacy provider, with the HIVST images subsequently interpreted by (3) an AI algorithm (trained on lab-captured images of HIVST results) and (4) an expert panel of three HIVST readers. Using the expert panel's determination as the ground truth, we calculated the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for HIVST result interpretation for the AI algorithm as well as for pharmacy clients and providers, for comparison.

RESULTS: From March to June 2022, we screened 1,691 pharmacy clients and enrolled 1,500 in the study. All clients completed HIVST. Among 854 clients whose HIVST images were of sufficient quality to be interpretable by the AI algorithm, 63% (540/854) were female, median age was 26 years (interquartile range: 22-31), and 39% (335/855) reported casual sexual partners. The expert panel identified 94.9% (808/854) of HIVST images as HIV-negative, 5.1% (44/854) as HIV-positive, and 0.2% (2/854) as indeterminant. The AI algorithm demonstrated perfect sensitivity (100%), perfect NPV (100%), and 98.8% specificity, and 81.5% PPV (81.5%) due to seven false-positive results. By comparison, pharmacy clients and providers demonstrated lower sensitivity (93.2% and 97.7% respectively) and NPV (99.6% and 99.9% respectively) but perfect specificity (100%) and perfect PPV (100%).

CONCLUSIONS: AI computer vision technology shows promise as a tool for providing additional quality assurance of HIV testing, particularly for catching Type II error (false-negative test interpretations) committed by human end-users. We discuss possible use cases for this technology to support differentiated HIV service delivery and identify areas for future research that is needed to assess the potential impacts-both positive and negative-of deploying this technology in real-world HIV service delivery settings.

RevDate: 2024-02-22

Lubwama M, Kateete DP, Katende G, et al (2024)

CTX-M, TEM, and SHV Genes in Escherichia coli, Klebsiella pneumoniae, and Enterobacter spp Isolated from Hematologic Cancer Patients with Bacteremia in Uganda.

Infection and drug resistance, 17:641-653.

PURPOSE: We determined the phenotypic resistance to third-generation cephalosporins, phenotypic extended spectrum beta-lactamase (ESBL) prevalence, and genotypic prevalence of ESBL-encoding genes blaCTX-M, blaTEM, and blaSHV in Enterobacteriaceae isolated from hematologic cancer patients with febrile neutropenia and bacteremia at the Uganda Cancer Institute (UCI).

PATIENTS AND METHODS: Blood cultures from hematologic cancer patients with febrile neutropenia were processed in BACTEC 9120. E. coli, K. pneumoniae, and Enterobacter spp. isolates were identified using conventional biochemical methods. Antimicrobial susceptibility tests, phenotypic ESBL characterization, and genotypic characterization of the ESBL-encoding genes blaCTX-M, blaTEM, and blaSHV were determined for pure isolates of E. coli, K. pneumoniae, and Enterobacter spp.

RESULTS: Two hundred and two patients were included in the study. Median age of patients was 19 years (IQR: 10-30 years). Majority (N=119, 59%) were male patients. Sixty (30%) of the participants had at least one febrile episode due to Enterobacteriaceae. Eighty-three organisms were isolated with E. coli being predominant (45, 54%). Seventy-nine (95%) Enterobacteriaceae were multidrug resistant. The ESBL phenotype was detected in 54/73 (74%) of Enterobacteriaceae that were resistant to third-generation cephalosporins. A higher proportion of Enterobacteriaceae with ESBL-positive phenotype were resistant to piperacillin-tazobactam (p=0.024), gentamicin (p=0.000), ciprofloxacin (p=0.000), and cotrimoxazole (p=0.000) compared to Enterobacteriaceae, which were sensitive to third-generation cephalosporins. The organisms were more susceptible to carbapenems and chloramphenicol than resistant. ESBL-encoding genes (blaCTX-M, blaTEM, and blaSHV) were detected in 55 (75%) of the 73 Enterobacteriaceae that were resistant to third-generation cephalosporins. BlaCTX-M, was the most common ESBL-encoding gene identified with 50 (91%).

CONCLUSION: ESBL-producing Enterobacteriaceae are a predominant cause of bacteremia in hematologic cancer patients at UCI. The most common ESBL-encoding gene identified in the ESBL-PE was blaCTX-M. Resistance to imipenem and meropenem was low.

RevDate: 2024-02-22

Zengin ZB, Henderson NC, Park JJ, et al (2024)

Clinical implications of AR alterations in advanced prostate cancer: a multi-institutional collaboration.

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

BACKGROUND: AR gene alterations can develop in response to pressure of testosterone suppression and androgen receptor targeting agents (ARTA). Despite this, the relevance of these gene alterations in the context of ARTA treatment and clinical outcomes remains unclear.

METHODS: Patients with castration-resistant prostate cancer (CRPC) who had undergone genomic testing and received ARTA treatment were identified in the Prostate Cancer Precision Medicine Multi-Institutional Collaborative Effort (PROMISE) database. Patients were stratified according to the timing of genomic testing relative to the first ARTA treatment (pre-/post-ARTA). Clinical outcomes such as time to progression, PSA response, and overall survival were compared based on alteration types.

RESULTS: In total, 540 CRPC patients who received ARTA and had tissue-based (n = 321) and/or blood-based (n = 244) genomic sequencing were identified. Median age was 62 years (range 39-90) at the time of the diagnosis. Majority were White (72.2%) and had metastatic disease (92.6%) at the time of the first ARTA treatment. Pre-ARTA genomic testing was available in 24.8% of the patients, and AR mutations and amplifications were observed in 8.2% and 13.1% of the patients, respectively. Further, time to progression was longer in patients with AR amplifications (25.7 months) compared to those without an AR alteration (9.6 months; p = 0.03). In the post-ARTA group (n = 406), AR mutations and AR amplifications were observed in 18.5% and 35.7% of the patients, respectively. The most common mutation in post-ARTA group was L702H (9.9%).

CONCLUSION: In this real-world clinicogenomics database-driven study we explored the development of AR alterations and their association with ARTA treatment outcomes. Our study showed that AR amplifications are associated with longer time to progression on first ARTA treatment. Further prospective studies are needed to optimize therapeutic strategies for patients with AR alterations.

RevDate: 2024-02-21

Gorfinkel L, Raghunandan S, Watkins B, et al (2024)

Overlap chronic GVHD is associated with adverse survival outcomes compared to classic chronic GVHD.

Bone marrow transplantation [Epub ahead of print].

Chronic graft-versus-host-disease (cGVHD) is divided into two subtypes: classic (absence of acute GVHD features) and overlap cGVHD ('ocGVHD'), in which both chronic and acute GVHD clinical features are present simultaneously. While worse outcomes with ocGVHD have been reported, there are few recent analyses. We performed a secondary analysis of data from the ABA2 trial (N = 185), in which detailed GVHD data were collected prospectively and systematically adjudicated. Analyses included cumulative incidence of classic versus ocGVHD, their specific organ manifestations, global disease severity scores, non-relapse mortality (NRM), disease-free survival (DFS) and overall survival (OS) in these two cGVHD subtypes. Of 92 patients who developed cGVHD, 35 were classified as ocGVHD. The 1-year cumulative incidence, organ involvement, and global severity of classic and ocGVHD were similar between ABA2 patients receiving CNI/MTX+placebo and CNI/MTX+abatacept; thus, cohorts were combined for ocGVHD evaluation. This analysis identified ocGVHD as having significantly higher severity at presentation and at maximum global severity compared to classic cGVHD. OS and DFS were significantly lower for ocGVHD versus classic cGVHD. OcGVHD is associated with increased cGVHD severity scores, and is associated with decreased OS and DFS compared to classic cGVHD, underscoring the high risks with this cGVHD subtype.

RevDate: 2024-02-21

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

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

NPJ vaccines, 9(1):39.

RevDate: 2024-02-21

Bottinor W, Im C, Doody DR, et al (2024)

Mortality After Major Cardiovascular Events in Survivors of Childhood Cancer.

Journal of the American College of Cardiology, 83(8):827-838.

BACKGROUND: Adult survivors of childhood cancer are at risk for cardiovascular events.

OBJECTIVES: In this study, we sought to determine the risk for mortality after a major cardiovascular event among childhood cancer survivors compared with noncancer populations.

METHODS: All-cause and cardiovascular cause-specific mortality risks after heart failure (HF), coronary artery disease (CAD), or stroke were compared among survivors and siblings in the Childhood Cancer Survivor Study (CCSS) and participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Cox proportional hazard regression models were used to estimate HRs and 95% CIs between groups, adjusted for demographic and clinical factors.

RESULTS: Among 25,658 childhood cancer survivors (median age at diagnosis 7 years, median age at follow-up or death 38 years) and 5,051 siblings, 1,780 survivors and 91 siblings had a cardiovascular event. After HF, CAD, and stroke, 10-year all-cause mortalities were 30% (95% CI: 26%-33%), 36% (95% CI: 31%-40%), and 29% (95% CI: 24%-33%), respectively, among survivors vs 14% (95% CI: 0%-25%), 14% (95% CI: 2%-25%), and 4% (95% CI: 0%-11%) among siblings. All-cause mortality risks among childhood cancer survivors were increased after HF (HR: 7.32; 95% CI: 2.56-20.89), CAD (HR: 5.54; 95% CI: 2.37-12.93), and stroke (HR: 3.57; 95% CI: 1.12-11.37). CAD-specific mortality risk was increased (HR: 3.70; 95% CI: 1.05-13.02). Among 5,114 CARDIA participants, 345 had a major event. Although CARDIA participants were on average decades older at events (median age 57 years vs 31 years), mortality risks were similar, except that all-cause mortality after CAD was significantly increased among childhood cancer survivors (HR: 1.85; 95% CI: 1.16-2.95).

CONCLUSIONS: Survivors of childhood cancer represent a population at high risk for mortality after major cardiovascular events.

RevDate: 2024-02-21

Alavattam KG, Esparza JM, Hu M, et al (2024)

ATF7IP2/MCAF2 directs H3K9 methylation and meiotic gene regulation in the male germline.

Genes & development pii:gad.351569.124 [Epub ahead of print].

H3K9 trimethylation (H3K9me3) plays emerging roles in gene regulation, beyond its accumulation on pericentric constitutive heterochromatin. It remains a mystery why and how H3K9me3 undergoes dynamic regulation in male meiosis. Here, we identify a novel, critical regulator of H3K9 methylation and spermatogenic heterochromatin organization: the germline-specific protein ATF7IP2 (MCAF2). We show that in male meiosis, ATF7IP2 amasses on autosomal and X-pericentric heterochromatin, spreads through the entirety of the sex chromosomes, and accumulates on thousands of autosomal promoters and retrotransposon loci. On the sex chromosomes, which undergo meiotic sex chromosome inactivation (MSCI), the DNA damage response pathway recruits ATF7IP2 to X-pericentric heterochromatin, where it facilitates the recruitment of SETDB1, a histone methyltransferase that catalyzes H3K9me3. In the absence of ATF7IP2, male germ cells are arrested in meiotic prophase I. Analyses of ATF7IP2-deficient meiosis reveal the protein's essential roles in the maintenance of MSCI, suppression of retrotransposons, and global up-regulation of autosomal genes. We propose that ATF7IP2 is a downstream effector of the DDR pathway in meiosis that coordinates the organization of heterochromatin and gene regulation through the spatial regulation of SETDB1-mediated H3K9me3 deposition.

RevDate: 2024-02-21

Ramirez M, Shah PD, Chu HY, et al (2024)

Reopening schools safely and educating youth (ROSSEY) study: Protocol for a community-based, cluster randomized controlled trial.

Contemporary clinical trials pii:S1551-7144(24)00054-5 [Epub ahead of print].

INTRODUCTION: ROSSEY is a community-academic partnership aiming to develop and test a COVID-19 risk communication intervention for elementary school students and families in Yakima County, Washington. We describe the ROSSEY study protocol that will be implemented in the Yakima School District.

METHODS: Aim 1 is to identify the community's social, ethical, and behavioral needs and resources for students to return to school and maintain onsite learning. We will conduct semi-structured interviews with students and school employees and focus groups with parents. Aim 2 is to evaluate the effectiveness of risk communication on students' school attendance. We will conduct a cluster randomized control trial. We will enroll 14 Yakima School District elementary schools with 900 student participants and randomize the schools into the COVID-19 risk communication intervention or control group. Aim 3 will assess implementation of the risk communication intervention and schools' COVID-19 mitigation strategies. We will use the RE-AIM framework to guide this work, which will entail conducting semi-structured interviews with students and school employees and focus groups with parents.

DISCUSSION: Implementation of science-based risk communication can educate the community on the benefits and safety of COVID-19 testing and vaccination. Risk communication may also inform families about the role of COVID-19 testing and vaccines as part of mitigation strategies to allow for safe in-person learning. Schools have extraordinary influence to promote children's health through policy and practice change. Study findings will provide evidence to facilitate policy decisions and best practices at schools that facilitate adoption of COVID-19 risk communication.

TRIAL REGISTRATION: ClinicalTrials.govNCT04859699. Registered on April 26, 2021.

RevDate: 2024-02-21

Roos CR, Kiluk B, Carroll KM, et al (2024)

Development and initial testing of mindful journey: a digital mindfulness-based intervention for promoting recovery from Substance use disorder.

Annals of medicine, 56(1):2315228.

BACKGROUND/OBJECTIVES: There is a great unmet need for accessible adjunctive interventions to promote long-term recovery from substance use disorder (SUD). This study aimed to iteratively develop and test the initial feasibility and acceptability of Mindful Journey, a novel digital mindfulness-based intervention for promoting recovery among individuals with SUD.

PATIENTS/MATERIALS: Ten adults receiving outpatient treatment for SUD.

METHODS: Phase 1 (n = 5) involved developing and testing a single introductory digital lesson. Phase 2 included a separate sample (n = 5) and involved testing all 15 digital lessons (each 30- to 45-minutes) over a 6-week period, while also receiving weekly brief phone coaching for motivational/technical support.

RESULTS: Across both phases, quantitative ratings (rated on a 5-point scale) were all at or above a 4 (corresponding with 'agree') for key acceptability dimensions, such as usability, understandability, appeal of visual content, how engaging the content was, and helpfulness for recovery. Additionally, in both phases, qualitative feedback indicated that participants particularly appreciated the BOAT (Breath, Observe, Accept, Take a Moment) tool for breaking down mindfulness into steps. Qualitative feedback was used to iteratively refine the intervention. For example, based on feedback, we added a second core mindfulness tool, the SOAK (Stop, Observe, Appreciate, Keep Curious), and we added more example clients and group therapy videos. In Phase 2, 4 out of 5 participants completed all 15 lessons, providing initial evidence of feasibility. Participants reported that the phone coaching motivated them to use the app. The final version of Mindful Journey was a smartphone app with additional features, including brief on-the-go audio exercises and a library of mindfulness practices. Although, participants used these additional features infrequently.

CONCLUSIONS: Based on promising initial findings, future acceptability and feasibility testing in a larger sample is warranted. Future versions might include push notifications to facilitate engagement in the additional app features.

RevDate: 2024-02-21

Park SC, Steffan BN, Yun Lim F, et al (2024)

Terpenoid balance in Aspergillus nidulans unveiled by heterologous squalene synthase expression.

Science advances, 10(8):eadk7416.

Filamentous fungi produce numerous uncharacterized natural products (NPs) that are often challenging to characterize because of cryptic expression in laboratory conditions. Previously, we have successfully isolated novel NPs by expressing fungal artificial chromosomes (FACs) from a variety of fungal species into Aspergillus nidulans. Here, we demonstrate a twist to FAC utility wherein heterologous expression of a Pseudogymnoascus destructans FAC in A. nidulans altered endogenous terpene biosynthetic pathways. In contrast to wild type, the FAC transformant produced increased levels of squalene and aspernidine type compounds, including three new nidulenes (1- 2, and 5), and lost nearly all ability to synthesize the major A. nidulans characteristic terpene, austinol. Deletion of a squalene synthase gene in the FAC restored wild-type chemical profiles. The altered squalene to farnesyl pyrophosphate ratio leading to synthesis of nidulenes and aspernidines at the expense of farnesyl pyrophosphate-derived austinols provides unexpected insight into routes of terpene synthesis in fungi.

RevDate: 2024-02-21

Sasani TA, Quinlan AR, K Harris (2024)

Epistasis between mutator alleles contributes to germline mutation spectrum variability in laboratory mice.

eLife, 12: pii:89096.

Maintaining germline genome integrity is essential and enormously complex. Although many proteins are involved in DNA replication, proofreading, and repair, mutator alleles have largely eluded detection in mammals. DNA replication and repair proteins often recognize sequence motifs or excise lesions at specific nucleotides. Thus, we might expect that the spectrum of de novo mutations - the frequencies of C>T, A>G, etc. - will differ between genomes that harbor either a mutator or wild-type allele. Previously, we used quantitative trait locus mapping to discover candidate mutator alleles in the DNA repair gene Mutyh that increased the C>A germline mutation rate in a family of inbred mice known as the BXDs (Sasani et al., 2022, Ashbrook et al., 2021). In this study we developed a new method to detect alleles associated with mutation spectrum variation and applied it to mutation data from the BXDs. We discovered an additional C>A mutator locus on chromosome 6 that overlaps Ogg1, a DNA glycosylase involved in the same base-excision repair network as Mutyh (David et al., 2007). Its effect depends on the presence of a mutator allele near Mutyh, and BXDs with mutator alleles at both loci have greater numbers of C>A mutations than those with mutator alleles at either locus alone. Our new methods for analyzing mutation spectra reveal evidence of epistasis between germline mutator alleles and may be applicable to mutation data from humans and other model organisms.

RevDate: 2024-02-21

LaMonte MJ, LaCroix AZ, Nguyen S, et al (2024)

Accelerometer-Measured Physical Activity, Sedentary Time, and Heart Failure Risk in Women Aged 63 to 99 Years.

JAMA cardiology pii:2815080 [Epub ahead of print].

IMPORTANCE: Heart failure (HF) prevention is paramount to public health in the 21st century.

OBJECTIVE: To examine incident HF and its subtypes with preserved ejection fraction (HFpEF) and reduced EF (HFrEF) according to accelerometer-measured physical activity (PA) and sedentary time.

This was a prospective cohort study, the Objective Physical Activity and Cardiovascular Health (OPACH) in Older Women study, conducted from March 2012 to April 2014. Included in the analysis were women aged 63 to 99 years without known HF, who completed hip-worn triaxial accelerometry for 7 consecutive days. Follow-up for incident HF occurred through February 2022. Data were analyzed from March to December 2023.

EXPOSURE: Daily PA (total, light, moderate to vigorous PA [MVPA], steps) and sedentary (total, mean bout duration) behavior.

MAIN OUTCOMES AND MEASURES: Adjudicated incident HF, HFpEF, and HFrEF.

RESULTS: A total of 5951 women (mean [SD] age, 78.6 [6.8] years) without known HF were included in this analysis. Women self-identified with the following race and ethnicity categories: 2004 non-Hispanic Black (33.7%), 1022 Hispanic (17.2%), and 2925 non-Hispanic White (49.2%). There were 407 HF cases (257 HFpEF; 110 HFrEF) identified through a mean (SD) of 7.5 (2.6) years (range, 0.01-9.9 years) of follow-up. Fully adjusted hazard ratios (HRs) for overall HF, HFpEF, and HFrEF associated with a 1-SD increment were 0.85 (95% CI, 0.75-0.95), 0.78 (95% CI, 0.67-0.91), and 1.02 (95% CI, 0.81-1.28) for minutes per day total PA; 0.74 (95% CI, 0.63-0.88), 0.71 (95% CI, 0.57-0.88), and 0.83 (95% CI, 0.62-1.12) for steps per day; and 1.17 (95% CI, 1.04-1.33), 1.29 (95% CI, 1.10-1.51), and 0.94 (95% CI, 0.75-1.18) for minutes per day total sedentary. Cubic spline curves for overall HF and HFpEF were significant inverse for total PA and steps per day and positive for total sedentary. Light PA and MVPA were inversely associated with overall HF (HR per 1 SD: 0.88; 95% CI, 0.78-0.98 and 0.84; 95% CI, 0.73-0.97) and HFpEF (0.80; 95% CI, 0.70-0.93 and 0.85; 95% CI, 0.72-1.01) but not HFrEF. Associations did not meaningfully differ when stratified by age, race and ethnicity, body mass index, physical function, or comorbidity score. Results for sedentary bout duration were inconsistent.

CONCLUSIONS AND RELEVANCE: Higher accelerometer-measured PA (MVPA, light PA, steps per day) was associated with lower risk (and greater total sedentary time with higher risk) of overall HF and HFpEF in a racially and ethnically diverse cohort of older women. Increasing PA and reducing sedentary time for primary HFpEF prevention may have relevant implications for cardiovascular resilience and healthy aging in later life.

RevDate: 2024-02-21

Orvain C, Ali N, Othus M, et al (2024)

Relative prognostic value of flow cytometric measurable residual disease before allogeneic hematopoietic cell transplantation for adults with MDS/AML or AML.

American journal of hematology [Epub ahead of print].

Multiparameter flow cytometry (MFC) measurable residual disease (MRD) before allogeneic hematopoietic cell transplantation (HCT) independently predicts poor outcomes in acute myeloid leukemia (AML). Conversely, its prognostic value in the newly defined disease entity, myelodysplastic neoplasm (MDS)/AML is unknown. To assess the relationship between disease type, pre-HCT MRD, and post-HCT outcomes, we retrospectively analyzed 1265 adults with MDS/AML (n = 151) or AML (n = 1114) who received a first allograft in first or second morphologic remission at a single institution between April 2006 and March 2023. At 3 years, relapse rates (29% for MDS/AML vs. 29% for AML, p = .98), relapse-free survival (RFS; 50% vs. 55%, p = .22), overall survival (OS; 52% vs. 60%, p = .073), and non-relapse mortality (22% vs. 16%, p = .14) were not statistically significantly different. However, a significant interaction was found between pre-HCT MFC MRD and disease type (MDS/AML vs. AML) for relapse (p = .009), RFS (p = .011), and OS (p = .039). The interaction models indicated that the hazard ratios (HRs) for the association between pre-HCT MRD and post-HCT outcomes were lower in patients with MDS/AML (for relapse: HR = 1.75 [0.97-3.15] in MDS/AML vs. 4.13 [3.31-5.16] in AML; for RFS: HR = 1.58 [1.02-2.45] vs. 2.98 [2.48-3.58]; for OS: HR = 1.50 [0.96-2.35] vs. 2.52 [2.09-3.06]). On the other hand, residual cytogenetic abnormalities at the time of HCT were equally informative in MDS/AML as in AML patients. Our data indicate that MFC-based pre-HCT MRD testing, but not testing for residual cytogenetic abnormalities, is less informative for MDS/AML than AML patients when used for prognostication of post-HCT outcomes.

RevDate: 2024-02-21

Babu TM, Shen X, McClelland RS, et al (2024)

Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Subvariant Neutralization Following a Primary Vaccine Series of NVX-CoV2373 and BNT162b2 Monovalent Booster Vaccine.

Open forum infectious diseases, 11(2):ofad673.

We evaluated the immunologic response to a novel vaccine regimen that included 2 doses of NVX-CoV2373 (Novavax) followed by 1 dose of BNT162b2 (Pfizer-BioNTech) monovalent booster vaccine. A durable neutralizing antibody response to Omicron BA.4/BA.5 and BA.1 variants was observed at month 6 after the booster, while immune escape was noted for the XBB.1.5 variant.

RevDate: 2024-02-21

Bhatt NS, Meyer CL, Mau LW, et al (2024)

Return to school practices after hematopoietic cell transplantation: a survey of transplant centers in the United States.

Bone marrow transplantation [Epub ahead of print].

To understand transplant center recommendations on return-to-school timing and related support for hematopoietic cell transplant (HCT) survivors, we conducted a two-phase, cross-sectional, web-based survey: In Phase I, medical directors of pediatric HCT centers from the National Marrow Donor Program/ Be The Match Registry were asked regarding the availability of a return to school standardized operating procedure (SOP). In Phase II, HCT physician members of the Pediatric Transplantation and Cellular Therapy Consortium were approached to study inter-physician practice variability regarding return to school post-HCT, factors affecting their decision-making, and support provided by HCT centers for return to school. Out of 46 respondents in Phase I (55% response rate), 28 (61%) reported having a SOP. Wide variations in recommendations were noted in 12 received SOPs. In Phase II, 122 physicians (60 centers) responded (30.6% response rate). The majority (60%) recommended autologous HCT recipients return to school within 6 months post-HCT but 65% recommended allogeneic HCT recipients return to school after 6 months or once off immunosuppression. Our findings indicate a lack of consensus within and across HCT centers regarding recommended return to school timing and underscore need for a guideline to standardize this process to ensure patient safety and re-integration into school.

RevDate: 2024-02-20

Wallace-Povirk A, O'Connor C, Dekhne AS, et al (2024)

Mitochondrial and cytosolic one-carbon metabolism is a targetable metabolic vulnerability in cisplatin-resistant ovarian cancer.

Molecular cancer therapeutics pii:734701 [Epub ahead of print].

One-carbon (C1) metabolism is compartmentalized between the cytosol and mitochondria with the mitochondrial C1 pathway as the major source of glycine and C1 units for cellular biosynthesis. Expression of mitochondrial C1 genes including SLC25A32, serine hydroxymethyl transferase (SHMT) 2, 5,10-methylene tetrahydrofolate dehydrogenase 2, and 5,10-methylene tetrahydrofolate dehydrogenase 1-like was significantly elevated in primary epithelial ovarian cancer (EOC) specimens compared to normal ovaries. 5-Substituted pyrrolo[3,2-d]pyrimidine antifolates (AGF347, AGF359, AGF362) inhibited proliferation of cisplatin sensitive (A2780, CaOV3, IGROV1) and resistant (A2780-E80, SKOV3) EOC cells. In SKOV3 and A2780-E80 cells, colony formation was inhibited. AGF347 induced apoptosis in SKOV3 cells. In IGROV1 cells, AGF347 was transported by folate receptor (FR) α. AGF347 was also transported into IGROV1 and SKOV3 cells by the proton-coupled folate transporter (SLC46A1) and the reduced folate carrier (SLC19A1). AGF347 accumulated to high levels in the cytosol and mitochondria of SKOV3 cells. By targeted metabolomics with [2,3,3-2H]L-serine, AGF347, AGF359 and AGF362 inhibited SHMT2 in the mitochondria. In the cytosol, SHMT1 and de novo purine biosynthesis (i.e., glycinamide ribonucleotide formyltransferase, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase) were targeted; AGF359 also inhibited thymidylate synthase. Antifolate treatments of SKOV3 cells depleted cellular glycine, mitochondrial NADH and glutathione, and showed synergistic in vitro inhibition toward SKOV3 and A2780-E80 cells when combined with cisplatin. In vivo studies with subcutaneous SKOV3 EOC xenografts in SCID mice confirmed significant antitumor efficacy of AGF347. Collectively, our studies demonstrate a unique metabolic vulnerability in EOC involving mitochondrial and cytosolic C1 metabolism that offers a promising new platform for therapy.

RevDate: 2024-02-20

Castellano CA, Sun T, Ravindranathan D, et al (2024)

The impact of cancer metastases on COVID-19 outcomes: A COVID-19 and Cancer Consortium registry-based retrospective cohort study.

Cancer [Epub ahead of print].

BACKGROUND: COVID-19 can have a particularly detrimental effect on patients with cancer, but no studies to date have examined if the presence, or site, of metastatic cancer is related to COVID-19 outcomes.

METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, the authors identified 10,065 patients with COVID-19 and cancer (2325 with and 7740 without metastasis at the time of COVID-19 diagnosis). The primary ordinal outcome was COVID-19 severity: not hospitalized, hospitalized but did not receive supplemental O2 , hospitalized and received supplemental O2 , admitted to an intensive care unit, received mechanical ventilation, or died from any cause. The authors used ordinal logistic regression models to compare COVID-19 severity by presence and specific site of metastatic cancer. They used logistic regression models to assess 30-day all-cause mortality.

RESULTS: Compared to patients without metastasis, patients with metastases have increased hospitalization rates (59% vs. 49%) and higher 30 day mortality (18% vs. 9%). Patients with metastasis to bone, lung, liver, lymph nodes, and brain have significantly higher COVID-19 severity (adjusted odds ratios [ORs], 1.38, 1.59, 1.38, 1.00, and 2.21) compared to patients without metastases at those sites. Patients with metastasis to the lung have significantly higher odds of 30-day mortality (adjusted OR, 1.53; 95% confidence interval, 1.17-2.00) when adjusting for COVID-19 severity.

CONCLUSIONS: Patients with metastatic cancer, especially with metastasis to the brain, are more likely to have severe outcomes after COVID-19 whereas patients with metastasis to the lung, compared to patients with cancer metastasis to other sites, have the highest 30-day mortality after COVID-19.

RevDate: 2024-02-20

Lennon NJ, Kottyan LC, Kachulis C, et al (2024)

Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations.

Nature medicine, 30(2):480-487.

Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer. Standardized metrics were considered in the selection process, with additional consideration given to strength of evidence in African and Hispanic populations. We then developed a pipeline for clinical PRS implementation (score transfer to a clinical laboratory, validation and verification of score performance), and used genetic ancestry to calibrate PRS mean and variance, utilizing genetically diverse data from 13,475 participants of the All of Us Research Program cohort to train and test model parameters. Finally, we created a framework for regulatory compliance and developed a PRS clinical report for return to providers and for inclusion in an additional genome-informed risk assessment. The initial experience from eMERGE can inform the approach needed to implement PRS-based testing in diverse clinical settings.

RevDate: 2024-02-19

Suzuki K, Hatzikotoulas K, Southam L, et al (2024)

Genetic drivers of heterogeneity in type 2 diabetes pathophysiology.

Nature [Epub ahead of print].

Type 2 diabetes (T2D) is a heterogeneous disease that develops through diverse pathophysiological processes[1,2] and molecular mechanisms that are often specific to cell type[3,4]. Here, to characterize the genetic contribution to these processes across ancestry groups, we aggregate genome-wide association study data from 2,535,601 individuals (39.7% not of European ancestry), including 428,452 cases of T2D. We identify 1,289 independent association signals at genome-wide significance (P < 5 × 10[-8]) that map to 611 loci, of which 145 loci are, to our knowledge, previously unreported. We define eight non-overlapping clusters of T2D signals that are characterized by distinct profiles of cardiometabolic trait associations. These clusters are differentially enriched for cell-type-specific regions of open chromatin, including pancreatic islets, adipocytes, endothelial cells and enteroendocrine cells. We build cluster-specific partitioned polygenic scores[5] in a further 279,552 individuals of diverse ancestry, including 30,288 cases of T2D, and test their association with T2D-related vascular outcomes. Cluster-specific partitioned polygenic scores are associated with coronary artery disease, peripheral artery disease and end-stage diabetic nephropathy across ancestry groups, highlighting the importance of obesity-related processes in the development of vascular outcomes. Our findings show the value of integrating multi-ancestry genome-wide association study data with single-cell epigenomics to disentangle the aetiological heterogeneity that drives the development and progression of T2D. This might offer a route to optimize global access to genetically informed diabetes care.

RevDate: 2024-02-19

van der Plas E, Darji H, Srivastava DK, et al (2024)

Risk factors for neurocognitive impairment, emotional distress, and poor quality of life in survivors of pediatric rhabdomyosarcoma: A report from the Childhood Cancer Survivor Study.

Cancer [Epub ahead of print].

BACKGROUND: Prevalence and risk of poor psychological outcomes following rhabdomyosarcoma (RMS) are not well-established.

METHODS: Participants in this cross-sectional, case-control study (n = 713 survivors, 42.5% female; mean [SD] age, 30.5 [6.6] years; n = 706 siblings, 57.2% female; mean age, 32.8,[7.9] years) completed measures of neurocognition, emotional distress, and health-related quality of life (HRQOL). Multivariable logistic regression models identified treatments, health behaviors, and chronic conditions associated with impairment.

RESULTS: Relative to siblings, more survivors reported neurocognitive impairment (task efficiency: 21.1% vs. 13.7%, emotional regulation: 16.7% vs. 11.0%, memory: 19.3% vs. 15.1%), elevated emotional distress (somatic distress: 12.9% vs. 4.7%, anxiety: 11.7% vs. 5.9%, depression: 22.8% vs. 16.9%) and poorer HRQOL (physical functioning: 11.1% vs. 2.8%, role functioning due to physical problems: 16.8% vs. 8.2%, pain: 17.5% vs. 10.0%, vitality: 22.3% vs. 13.8%, social functioning: 14.4% vs. 6.8%, emotional functioning: 17.1% vs. 10.6%). Cranial radiation increased risk for impaired task efficiency (odds ratio [OR], 2.30; 95% confidence interval [CI], 1.14-4.63), whereas chest and pelvic radiation predicted increased risk of physical functioning (OR, 2.68; 95% CI, 1.16-6.21 and OR, 3.44; 95% CI, 1.70-6.95, respectively). Smoking was associated with impaired task efficiency (OR, 2.06; 95% CI, 1.14-3.70), memory (OR, 2.23; 95% CI, 1.26-3.95), anxiety (OR, 2.71; 95% CI, 1.36-5.41) and depression (OR, 1.77; 95% CI, 1.01-3.11). Neurologic conditions increased risk of anxiety (OR, 2.30; 95% CI, 1.04-5.10), and hearing conditions increased risk of depression (OR, 1.79; 95% CI, 1.05-3.03). Neurologic and hearing conditions, respectively, were associated with impaired memory (OR, 2.44; 95% CI, 1.20-4.95 and OR, 1.87; 95% CI, 1.05-3.35) and poor health perception (OR, 2.62; 95% CI, 1.62-1.28 and OR, 2.33; 95% CI, 1.34-4.06).

CONCLUSIONS: RMS survivors are at significant risk for poor psychological outcomes. Advancing therapies for local control, smoking cessation, and managing chronic medical conditions may mitigate poor outcomes following RMS.

RevDate: 2024-02-19

Follmann D, Mateja A, Fay MP, et al (2024)

Durability of Protection Against COVID-19 Through the Delta Surge for the NVX-CoV2373 Vaccine.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:7610213 [Epub ahead of print].

BACKGROUND: Protein-based vaccines for COVID-19 provide a traditional vaccine platform with long-lasting protection for non-SARS-CoV-2 pathogens and may complement messenger RNA vaccines as a booster dose. While NVX-CoV2373 showed substantial early efficacy, the durability of protection has not been delineated.

METHODS: The PREVENT-19 vaccine trial employed a blinded crossover design; the original placebo arm received NVX-CoV2373 after efficacy was established. Using novel statistical methods that integrate surveillance data of circulating strains with post-crossover cases, we estimated placebo-controlled vaccine efficacy and durability of NVX-CoV2373 against both pre-Delta and Delta strains of SARS-CoV-2.

RESULTS: Vaccine efficacy against pre-Delta strains of COVID-19 was 89% (95% CI: 75%, 95%) and 87% (72%, 94%) at 0 and 90 days after 2 doses of NVX-CoV2373, respectively, with no evidence of waning (p=0.93). Vaccine efficacy against the Delta strain was 88% (71%, 95%), 82% (56%, 92%), and 77% (44%, 90%) at 40, 120, and 180 days, respectively, with evidence of waning (p<0.01). In sensitivity analyses, the estimated Delta vaccine efficacy at 120 days ranged from 66% (15%, 86%) to 89% (74%, 95%) per various assumptions of the surveillance data.

CONCLUSION: NVX-CoV2373 has high initial efficacy against pre-Delta and Delta strains of COVID-19 with little evidence of waning for pre-Delta strains through 90 days and moderate waning against Delta strains over 180 days.

RevDate: 2024-02-16

Psutka SP (2024)

Prehabilitation: A multidimensional adjunct to comprehensive personalized oncologic care. But, can we make it pragmatic?.

RevDate: 2024-02-16

Baisley K, Kemp TJ, Mugo NR, et al (2024)

Comparing one dose of HPV vaccine in girls aged 9-14 years in Tanzania (DoRIS) with one dose in young women aged 15-20 years in Kenya (KEN SHE): an immunobridging analysis of randomised controlled trials.

The Lancet. Global health, 12(3):e491-e499.

BACKGROUND: The first randomised controlled trial of single-dose human papillomavirus (HPV) vaccine efficacy, the Kenya single-dose HPV-vaccine efficacy (KEN SHE) trial, showed greater than 97% efficacy against persistent HPV16 and HPV18 infection at 36 months among women in Kenya. We compared antibody responses after one dose of HPV vaccine in the Dose Reduction Immunobridging and Safety Study (DoRIS), the first randomised trial of the single- dose regimen in girls aged 9-14 years, the target age range for vaccination, with those after one dose of the same vaccine in KEN SHE.

METHODS: In the DoRIS trial, 930 girls aged 9-14 years in Tanzania were randomly assigned to one, two, or three doses of the 2-valent vaccine (Cervarix) or the 9-valent vaccine (Gardasil-9). The proportion seroconverting and geometric mean concentrations (GMCs) at month 24 after one dose were compared with those in women aged 15-20 years who were randomly assigned to one dose of the same vaccines at the same timepoint in KEN SHE. Batched samples were tested together by virus-like particle ELISA for HPV16 and HPV18 IgG antibodies. Non-inferiority of GMC ratios (DoRIS trial:KEN SHE) was predefined as a lower bound of the 95% CI less than 0·50.

FINDINGS: Month 24 HPV16 and HPV18 antibody GMCs in DoRIS were similar or higher than those in KEN SHE. 2-valent GMC ratios were 0·90 (95% CI 0·72-1·14) for HPV16 and 1·02 (0·78-1·33) for HPV18. 9-valent GMC ratios were 1·44 (95% CI 1·14-1·82) and 1·47 (1·13-1·90), respectively. Non-inferiority of antibody GMCs and seropositivity was met for HPV16 and HPV18 for both vaccines.

INTERPRETATION: HPV16 and HPV18 immune responses in young girls 24 months after a single dose of 2-valent or 9-valent HPV vaccine were comparable to those in young women who were randomly assigned to a single dose of the same vaccines and in whom efficacy had been shown. A single dose of HPV vaccine, when given to girls in the target age range for vaccination, induces immune responses that could be effective against persistent HPV16 and HPV18 infection at least two years after vaccination.

FUNDING: The UK Department of Health and Social Care, the Foreign, Commonwealth, & Development Office, the Global Challenges Research Fund, the UK Medical Research Council and Wellcome Trust Joint Global Health Trials scheme, the Bill and Melinda Gates Foundation, the US National Cancer Institute; the US National Institutes of Health, and the Francis and Dorothea Reed Endowed Chair in Infectious Diseases.

TRANSLATION: For the KiSwahili translation of the abstract see Supplementary Materials section.

RevDate: 2024-02-16

Bloom JD (2024)

Importance of quantifying the number of viral reads in metagenomic sequencing of environmental samples from the Huanan Seafood Market.

Virus evolution, 10(1):vead089 pii:vead089.

In March 2023, the Chinese CDC publicly released raw metagenomic sequencing data for environmental samples collected in early 2020 from the Huanan Seafood Market. Prior to that data release, some scientists had suggested that these samples could be informative for establishing if animals such as raccoon dogs had been infected with severe acute respiratory syndrome virus 2 (SARS-CoV-2). However, no one had analyzed how much SARS-CoV-2 was actually present in the metagenomic sequencing data. After the raw data became available, I fully analyzed the abundance of both viral and animal genetic material in the samples. That analysis, which was published in Virus Evolution, found that the SARS-CoV-2 content of most samples was very low and that the abundance of SARS-CoV-2 was most strongly associated with animals such as largemouth bass that are not plausible candidates for having been infected. Based on these results, I concluded that the metagenomic content of the samples was not informative for determining if any non-human animals in the market had been infected with SARS-CoV-2. One of the authors of an earlier study of these samples, Florence Débarre, recently submitted a response to my paper. Here, I reply in turn to explain why it is important to quantify the abundance of viral material before drawing conclusions from metagenomic sequencing. I also report new analyses of other animal coronaviruses in the samples and show that material from some other animal coronaviruses is much more abundant than SARS-CoV-2 in samples collected on the date when most wildlife stall sampling was performed. I further show that material from some of these animal coronaviruses is associated with the animals they probably infect but that no such association exists for SARS-CoV-2. Overall, these new analyses further emphasize the importance of quantifying the actual amount of viral material in metagenomic samples and underscore why the environmental samples from the Huanan Seafood Market are not informative for determining if any non-human animals were infected with SARS-CoV-2.

RevDate: 2024-02-16

Graham JB, Swarts JL, Leist SR, et al (2024)

Unique immune profiles in collaborative cross mice linked to survival and viral clearance upon infection.

iScience, 27(3):109103 pii:S2589-0042(24)00324-9.

The response to infection is generally heterogeneous and diverse, with some individuals remaining asymptomatic while others present with severe disease or a diverse range of symptoms. Here, we address the role of host genetics on immune phenotypes and clinical outcomes following viral infection by studying genetically diverse mice from the Collaborative Cross (CC), allowing for use of a small animal model with controlled genetic diversity while maintaining genetic replicates. We demonstrate variation by deeply profiling a broad range of innate and adaptive immune cell phenotypes at steady-state in 63 genetically distinct CC mouse strains and link baseline immune signatures with virologic and clinical disease outcomes following infection of mice with herpes simplex virus 2 (HSV-2) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This work serves as a resource for CC strain selection based on steady-state immune phenotypes or disease presentation upon viral infection, and further, points to possible pre-infection immune correlates of survival and early viral clearance upon infection.

RevDate: 2024-02-16

Hill JA, Martens MJ, Young JH, et al (2024)

SARS-CoV-2 vaccination in the first year after hematopoietic cell transplant or chimeric antigen receptor T cell therapy: A prospective, multicenter, observational study (BMT CTN 2101).

medRxiv : the preprint server for health sciences.

BACKGROUND: The optimal timing of vaccination with SARS-CoV-2 vaccines after cellular therapy is incompletely understood.

OBJECTIVE: To describe humoral and cellular responses after SARS-CoV-2 vaccination initiated <4 months versus 4-12 months after cellular therapy.

DESIGN: Multicenter prospective observational study.

SETTING: 34 centers in the United States.

PARTICIPANTS: 466 allogeneic hematopoietic cell transplant (HCT; n=231), autologous HCT (n=170), or chimeric antigen receptor T cell (CAR-T cell) therapy (n=65) recipients enrolled between April 2021 and June 2022.

INTERVENTIONS: SARS-CoV-2 vaccination as part of routine care.

MEASUREMENTS: We obtained blood prior to and after vaccinations at up to five time points and tested for SARS-CoV-2 spike (anti-S) IgG in all participants and neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains, as well as SARS-CoV-2-specific T cell receptors (TCRs), in a subgroup.

RESULTS: Anti-S IgG and neutralizing antibody responses increased with vaccination in HCT recipients irrespective of vaccine initiation timing but were unchanged in CAR-T cell recipients initiating vaccines within 4 months. Anti-S IgG [≥]2,500 U/mL was correlated with high neutralizing antibody titers and attained by the last time point in 70%, 69%, and 34% of allogeneic HCT, autologous HCT, and CAR-T cell recipients, respectively. SARS-CoV-2-specific T cell responses were attained in 57%, 83%, and 58%, respectively. Humoral and cellular responses did not significantly differ among participants initiating vaccinations <4 months vs 4-12 months after cellular therapy. Pre-cellular therapy SARS-CoV-2 infection or vaccination were key predictors of post-cellular therapy anti-S IgG levels.

LIMITATIONS: The majority of participants were adults and received mRNA vaccines.

CONCLUSIONS: These data support starting mRNA SARS-CoV-2 vaccination three to four months after allogeneic HCT, autologous HCT, and CAR-T cell therapy.

FUNDING: National Marrow Donor Program, Leukemia and Lymphoma Society, Multiple Myeloma Research Foundation, Novartis, LabCorp, American Society for Transplantation and Cellular Therapy, Adaptive Biotechnologies, and the National Institutes of Health.

RevDate: 2024-02-16

Reyes RA, Raghavan SSR, Hurlburt NK, et al (2024)

Broadly inhibitory antibodies against severe malaria virulence proteins.

bioRxiv : the preprint server for biology.

Plasmodium falciparum pathology is driven by the accumulation of parasite-infected erythrocytes in microvessels. This process is mediated by the parasite's polymorphic erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. A subset of PfEMP1 variants that bind human endothelial protein C receptor (EPCR) through their CIDRα1 domains is responsible for severe malaria pathogenesis. A longstanding question is whether individual antibodies can recognize the large repertoire of circulating PfEMP1 variants. Here, we describe two broadly reactive and binding-inhibitory human monoclonal antibodies against CIDRα1. The antibodies isolated from two different individuals exhibited a similar and consistent EPCR-binding inhibition of 34 CIDRα1 domains, representing five of the six subclasses of CIDRα1. Both antibodies inhibited EPCR binding of both recombinant full-length and native PfEMP1 proteins as well as parasite sequestration in bioengineered 3D brain microvessels under physiologically relevant flow conditions. Structural analyses of the two antibodies in complex with two different CIDRα1 antigen variants reveal similar binding mechanisms that depend on interactions with three highly conserved amino acid residues of the EPCR-binding site in CIDRα1. These broadly reactive antibodies likely represent a common mechanism of acquired immunity to severe malaria and offer novel insights for the design of a vaccine or treatment targeting severe malaria.

RevDate: 2024-02-15

Goodman-Meza D, Shoptaw S, Hanscom B, et al (2024)

Delivering integrated strategies from a mobile unit to address the intertwining epidemics of HIV and addiction in people who inject drugs: the HPTN 094 randomized controlled trial protocol (the INTEGRA Study).

Trials, 25(1):124.

BACKGROUND: Persons with opioid use disorders who inject drugs (PWID) in the United States (US) face multiple and intertwining health risks. These include interference with consistent access, linkage, and retention to health care including medication for opioid use disorder (MOUD), HIV prevention using pre-exposure prophylaxis (PrEP), and testing and treatment for sexually transmitted infections (STIs). Most services, when available, including those that address substance misuse, HIV prevention, and STIs, are often provided in multiple locations that may be difficult to access, which further challenges sustained health for PWID. HPTN 094 (INTEGRA) is a study designed to test the efficacy of an integrated, "whole-person" strategy that provides integrated HIV prevention including antiretroviral therapy (ART), PrEP, MOUD, and STI testing and treatment from a mobile health delivery unit ("mobile unit") with peer navigation compared to peer navigation alone to access these services at brick and mortar locations.

METHODS: HPTN 094 (INTEGRA) is a two-arm, randomized controlled trial in 5 US cities where approximately 400 PWID without HIV are assigned either to an experimental condition that delivers 26 weeks of "one-stop" integrated health services combined with peer navigation and delivered in a mobile unit or to an active control condition using peer navigation only for 26 weeks to the same set of services delivered in community settings. The primary outcomes include being alive and retained in MOUD and PrEP at 26 weeks post-randomization. Secondary outcomes measure the durability of intervention effects at 52 weeks following randomization.

DISCUSSION: This trial responds to a need for evidence on using a "whole-person" strategy for delivering integrated HIV prevention and substance use treatment, while testing the use of a mobile unit that meets out-of-treatment PWID wherever they might be and links them to care systems and/or harm reduction services. Findings will be important in guiding policy for engaging PWID in HIV prevention or care, substance use treatment, and STI testing and treatment by addressing the intertwined epidemics of addiction and HIV among those who have many physical and geographic barriers to access care.

TRIAL REGISTRATION: ClinicalTrials.gov NCT04804072 . Registered on 18 March 2021.

RevDate: 2024-02-15

Petralia F, Ma W, Yaron TM, et al (2024)

Pan-cancer proteogenomics characterization of tumor immunity.

Cell pii:S0092-8674(24)00064-3 [Epub ahead of print].

Despite the successes of immunotherapy in cancer treatment over recent decades, less than <10%-20% cancer cases have demonstrated durable responses from immune checkpoint blockade. To enhance the efficacy of immunotherapies, combination therapies suppressing multiple immune evasion mechanisms are increasingly contemplated. To better understand immune cell surveillance and diverse immune evasion responses in tumor tissues, we comprehensively characterized the immune landscape of more than 1,000 tumors across ten different cancers using CPTAC pan-cancer proteogenomic data. We identified seven distinct immune subtypes based on integrative learning of cell type compositions and pathway activities. We then thoroughly categorized unique genomic, epigenetic, transcriptomic, and proteomic changes associated with each subtype. Further leveraging the deep phosphoproteomic data, we studied kinase activities in different immune subtypes, which revealed potential subtype-specific therapeutic targets. Insights from this work will facilitate the development of future immunotherapy strategies and enhance precision targeting with existing agents.

RevDate: 2024-02-15

Ng SS, De Labastida Rivera F, Yan J, et al (2024)

Author Correction: The NK cell granule protein NKG7 regulates cytotoxic granule exocytosis and inflammation.

RevDate: 2024-02-15

Jaycox JR, Dai Y, AM Ring (2024)

Decoding the autoantibody reactome.

Science (New York, N.Y.), 383(6684):705-707.

Autoantibodies influence a wide range of conditions beyond autoimmune diseases.

RevDate: 2024-02-15

Patel SP, Guadarrama E, Chae YK, et al (2024)

SWOG 1609 cohort 48: anti-CTLA-4 and anti-PD-1 for advanced gallbladder cancer.

Cancer [Epub ahead of print].

INTRODUCTION: Most patients with advanced gallbladder cancer are treated with multiagent chemotherapy. Immune checkpoint inhibitors offer the possibility of a durable response with less toxicity. This prospective, multicenter, open-label study was designed to evaluate the anticancer activity of nivolumab plus ipilimumab in patients with advanced gallbladder cancer.

METHODS: Nineteen patients with advanced gallbladder cancer refractory to ≥1 previous therapy received nivolumab 240 mg intravenously every 2 weeks and ipilimumab 1 mg/kg intravenously every 6 weeks until disease progression or unacceptable toxicity. The primary end point was confirmed radiographic overall response rate (ORR) (complete response [CR] + partial response [PR] confirmed on subsequent scan); secondary end points included unconfirmed overall response, clinical benefit rate (confirmed and unconfirmed responses + stable disease >6 months), progression-free survival, overall survival, and toxicity.

RESULTS: The confirmed ORR was 16% (CR, n = 1 [5%]; PR, n = 2 [11%]); all were microsatellite stable, and the confirmed CR had undetectable programmed death-ligand 1 by immunohistochemistry. The unconfirmed ORR and clinical benefit rates were both 32%. The median duration of response was 14.8 months (range, 4-35.1+ months). The 6-month progression-free survival was 26% (95% CI, 12-55). The median overall survival was 7.0 months (95% CI, 3.9-19.1). The most common toxicities were fatigue (32%), anemia (26%), and anorexia (26%). Aspartate aminotransferase elevation was the most common grade 3/4 toxicity (11%). There was 1 possibly related death (sepsis with attendant hepatic failure).

CONCLUSIONS: Ipilimumab plus nivolumab was well tolerated and showed modest efficacy with durable responses in previously treated patients with advanced gallbladder cancer.

CLINICAL TRIAL REGISTRATION: NCT02834013 (ClincialTrials.gov).

PLAIN LANGUAGE SUMMARY: This prospective study assessed the efficacy and safety of nivolumab plus ipilimumab in 19 patients with advanced gallbladder cancer refractory to previous therapy. The combination demonstrated modest efficacy with a 16% confirmed overall response rate, durable responses, and manageable toxicities, suggesting potential benefits for this challenging patient population.

RevDate: 2024-02-15

Amonoo HL, Daskalakis E, Deary EC, et al (2024)

Gratitude, optimism, and satisfaction with life and patient-reported outcomes in patients undergoing hematopoietic stem cell transplantation.

Psycho-oncology, 33(2):e6307.

OBJECTIVE: Associations between positive psychological well-being (PPWB) and patient-reported outcomes (PROs, e.g., quality of life [QOL]) have yet to be studied extensively in patients with hematologic malignancies who are allogeneic hematopoietic stem cell transplant (HSCT) survivors, despite substantial evidence that PPWB impacts PROs of other medical populations.

METHODS: We conducted a secondary analysis of cross-sectional data examining the association of PPWB and PROs at day 100 post-transplant among 158 allogeneic HSCT recipients. Optimism, gratitude, life satisfaction, and PROs (i.e., QOL, anxiety, depression, and PTSD symptoms) were assessed using the Life Orientation Test-Revised, Gratitude Questionnaire, Satisfaction with Life Scale, Functional Assessment of Cancer Therapy-Bone Marrow Transplant, Hospital Anxiety and Depression Scale, and Post-Traumatic Stress Disorder (PTSD) Checklist-Civilian Version, respectively. We used linear and multivariate regressions for all analyses and controlled for patient factors.

RESULTS: Optimism was associated with better QOL (β = 1.46; p < 0.001) and lower levels of anxiety (β = -0.28; p < 0.001), depression (β = -0.31; p < 0.001), and PTSD (β = -0.58; p < 0.001). Gratitude was associated with better QOL (β = 1.11; p < 0.001) and lower levels of anxiety (β = -0.21; p = 0.001), depression (β = -0.14; p = 0.021), and PTSD (β = -0.32; p = 0.032). Finally, satisfaction with life was associated with better QOL (β = 1.26; p < 0.001) and lower levels of anxiety (β = -0.18; p < 0.001), depression (β = -0.21; p < 0.001), and PTSD (β = -0.49; p < 0.001).

CONCLUSION: Optimism, gratitude, and satisfaction with life were all associated with better QOL and lower levels of psychological distress in allogeneic HSCT survivors. These data support studies to harness PPWB as a therapeutic intervention for this population throughout HSCT recovery.

RevDate: 2024-02-15

Gagelmann N, Hobbs GS, Campodonico E, et al (2024)

Splenic irradiation for myelofibrosis prior to hematopoietic cell transplantation: A global collaborative analysis.

American journal of hematology [Epub ahead of print].

Splenomegaly is the clinical hallmark of myelofibrosis. Splenomegaly at the time of allogeneic hematopoietic cell transplantation (HCT) is associated with graft failure and poor graft function. Strategies to reduce spleen size before HCT especially after failure to Janus kinase (JAK) inhibition represent unmet clinical needs in the field. Here, we leveraged a global collaboration to investigate the safety and efficacy of splenic irradiation as part of the HCT platform for patients with myelofibrosis. We included 59 patients, receiving irradiation within a median of 2 weeks (range, 0.9-12 weeks) before HCT. Overall, the median spleen size prior to irradiation was 23 cm (range, 14-35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1-6.3 cm). The most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3-year overall survival was 62% (95% CI, 48%-76%) and 1-year non-relapse mortality was 26% (95% CI, 14%-38%). Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant-specific risk score, higher-intensity conditioning, and present portal vein thrombosis. When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse (p = .01), showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy. In conclusion, splenic irradiation immediately before HCT is a reasonable approach in patients experiencing JAK inhibition failure and is associated with a low incidence of relapse.

RevDate: 2024-02-15

Kimura A, Bell-Brown A, Akinsoto N, et al (2024)

Implementing an Organized Colorectal Cancer Screening Program: Lessons Learned From an Academic-Community Practice.

AJPM focus, 3(2):100188.

INTRODUCTION: The effectiveness of mailed fecal immunochemical test outreach might be enhanced through an organized colorectal cancer screening program, yet published real-world experiences are limited. We synthesized the process of implementing a colorectal cancer screening program that used mailed fecal immunochemical test outreach in a large integrated academic-community practice.

METHODS: Data from a pilot mailed fecal immunochemical test program were shared with healthcare system leadership, which inspired the creation of a cross-institutional organized colorectal cancer screening program. In partnership with a centralized population health team and primary care, we defined (1) the institutional approach to colorectal cancer screening, (2) the target population and method for screening, (3) the team responsible for implementation, (4) the healthcare team responsible for decisions and care, (5) a quality assurance structure, and (6) a method for identifying cancer occurrence.

RESULTS: The Fred Hutch/UW Medicine Population Health Colorectal Cancer Screening Program began in September 2021. The workflow for mailed fecal immunochemical test outreach included a mailed postcard, a MyChart message from the patient's primary care provider, a fecal immunochemical test kit with a letter signed by the primary care provider and program director, and up to 3 biweekly reminders. Patients without a colonoscopy 3 months after an abnormal fecal immunochemical test result received navigation through the program. In the first program year, we identified 9,719 patients eligible for outreach, and in an intention-to-treat analysis, 32% of patients completed colorectal cancer screening by fecal immunochemical test or colonoscopy.

CONCLUSIONS: Real-world experiences detailing how to implement organized colorectal cancer screening programs might increase adoption. In our experience, broadly disseminating pilot data, early institutional support, robust data management, and strong cross-departmental relationships were critical to successfully implementing a colorectal cancer screening program that benefits all patients.

RevDate: 2024-02-15

Kato Y, Ambale-Venkatesh B, Naveed M, et al (2024)

HIV, HIV-specific Factors and Myocardial Disease in Women.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:7607232 [Epub ahead of print].

BACKGROUND: People with HIV (PWH) have an increased risk of cardiovascular disease (CVD). Cardiac magnetic resonance (CMR) has documented higher myocardial fibrosis, inflammation and steatosis in PWH, but studies have mostly relied on healthy volunteers as comparators and focused on men.

METHODS: We investigated the associations of HIV and HIV-specific factors with CMR phenotypes in female participants enrolled in the Women's Interagency HIV Study's New York and San Francisco sites. Primary phenotypes included myocardial native (n) T1 (fibro-inflammation), extracellular volume fraction (ECV, fibrosis) and triglyceride content (steatosis). Associations were evaluated with multivariable linear regression, and results pooled or meta-analyzed across centers.

RESULTS: Among 261 women with HIV (WWH, total n = 362), 76.2% had undetectable viremia at CMR. For the 82.8% receiving continuous antiretroviral therapy (ART) in the preceding 5 years, adherence was 51.7%, and 71.3% failed to achieve persistent viral suppression (42.2% with peak viral load < 200 cp/mL). Overall, WWH showed higher nT1 than women without HIV (WWOH) after full adjustment. This higher nT1 was more pronounced in those with antecedent or current viremia or nadir CD4+ count < 200 cells/μL, the latter also associated with higher ECV. WWH and current CD4+ count < 200 cells/μL had less cardiomyocyte steatosis. Cumulative exposure to specific ART showed no associations.

CONCLUSIONS: Compared with sociodemographically similar WWOH, WWH on ART exhibit higher myocardial fibro-inflammation, which is more prominent with unsuppressed viremia or CD4+ lymphopenia. These findings support the importance of improved ART adherence strategies, along with better understanding of latent infection, to mitigate cardiac end-organ damage in this population.


RJR Experience and Expertise


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


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


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


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


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


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


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


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

Support this website:
Order from Amazon
We will earn a commission.

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

963 Red Tail Lane
Bellingham, WA 98226


E-mail: RJR8222@gmail.com

Collection of publications by R J Robbins

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

Research Gate page for R J Robbins

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

Curriculum Vitae for R J Robbins

short personal version

Curriculum Vitae for R J Robbins

long standard version

RJR Picks from Around the Web (updated 11 MAY 2018 )