@article {pmid39699103,
year = {2025},
author = {Choe, M and Campbell, M and Albert, CM},
title = {Advances in cellular therapies for children and young adults with solid tumors.},
journal = {Current opinion in pediatrics},
volume = {37},
number = {1},
pages = {67-74},
pmid = {39699103},
issn = {1531-698X},
mesh = {Humans ; *Neoplasms/therapy/immunology ; Child ; *Immunotherapy, Adoptive/methods ; *Tumor Microenvironment/immunology ; Young Adult ; Adolescent ; Receptors, Chimeric Antigen/immunology ; },
abstract = {PURPOSE OF REVIEW: Adoptive immunotherapy brings hope to children and young adults diagnosed with high-risk solid tumors. Cellular (cell) therapies such as chimeric antigen receptor (CAR) T cell, CAR natural killer (NK) cell, and T cell receptor (TCR) T cell therapy are potential avenues of targeted therapy with limited long-term toxicities. However, development of cell therapies for solid tumors is in its nascent stages. Here, we will review the current clinical experience, barriers to efficacy, and strategies to improve clinical response and patient access.

RECENT FINDINGS: Cell therapies are shown to be generally safe and well tolerated. Strategies to optimize antitumor activity have now moved into early-phase trials. The immunosuppressive tumor microenvironment remains a major barrier to efficacy, and efforts are underway to gain better understanding. This will inform future treatment strategies to enhance the antitumor activity of cell therapies.

SUMMARY: Clinical experiences to date provide important insights on how to leverage cell therapies against solid tumors. Key factors in advancing the field include a better understanding of immune cell biology, tumor cell behavior, and the tumor microenvironment. Lastly, improving access to novel cell therapies remains an important consideration in the conduct of clinical trials and for future implementation into standard practice.},
}

Humans
*Neoplasms/therapy/immunology
Child
*Immunotherapy, Adoptive/methods
*Tumor Microenvironment/immunology
Young Adult
Adolescent
Receptors, Chimeric Antigen/immunology

@article {pmid39698781,
year = {2024},
author = {Ghosh, N and Eyre, TA and Brown, JR and Lamanna, N and Manzoor, BS and Coombs, CC and Tuncer, HH and Ujjani, C and Leslie, LA and Roeker, LE and Davids, MS and Rhodes, JM and Skarbnik, AP and Sinai, W and Fleury, I and Hill, BT and Martinez-Calle, N and Barr, PM and Jawaid, D and Emechebe, N and Pearson, L and Lansigan, F and Choi, Y and Jensen, CE and Fakhri, B and Stephens, DM and Marx, SE and Schuster, SJ and Coyle, M and Pivneva, I and Watson, T and Guerin, A and Shadman, M},
title = {Treatment Effectiveness of Venetoclax-Based Therapy After Bruton Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia: An International Real-World Study.},
journal = {American journal of hematology},
volume = {},
number = {},
pages = {},
doi = {10.1002/ajh.27563},
pmid = {39698781},
issn = {1096-8652},
support = {//AbbVie/ ; },
}

@article {pmid39695226,
year = {2024},
author = {Lee, S and Kibler, RD and Ahn, G and Hsia, Y and Borst, AJ and Philomin, A and Kennedy, MA and Huang, B and Stoddard, B and Baker, D},
title = {Four-component protein nanocages designed by programmed symmetry breaking.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {39695226},
issn = {1476-4687},
abstract = {Four, eight or twenty C3 symmetric protein trimers can be arranged with tetrahedral, octahedral or icosahedral point group symmetry to generate closed cage-like structures[1,2]. Viruses access more complex higher triangulation number icosahedral architectures by breaking perfect point group symmetry[3-9], but nature appears not to have explored similar symmetry breaking for tetrahedral or octahedral symmetries. Here we describe a general design strategy for building higher triangulation number architectures starting from regular polyhedra through pseudosymmetrization of trimeric building blocks. Electron microscopy confirms the structures of T = 4 cages with 48 (tetrahedral), 96 (octahedral) and 240 (icosahedral) subunits, each with 4 distinct chains and 6 different protein-protein interfaces, and diameters of 33 nm, 43 nm and 75 nm, respectively. Higher triangulation number viruses possess very sophisticated functionalities; our general route to higher triangulation number nanocages should similarly enable a next generation of multiple antigen-displaying vaccine candidates[10,11] and targeted delivery vehicles[12,13].},
}

@article {pmid39695145,
year = {2024},
author = {Kibler, RD and Lee, S and Kennedy, MA and Wicky, BIM and Lai, SM and Kostelic, MM and Carr, A and Li, X and Chow, CM and Nguyen, TK and Carter, L and Wysocki, VH and Stoddard, BL and Baker, D},
title = {Design of pseudosymmetric protein hetero-oligomers.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {10684},
pmid = {39695145},
issn = {2041-1723},
support = {DGE-1762114//National Science Foundation (NSF)/ ; ALTF 139-2018//European Molecular Biology Organization (EMBO)/ ; P41 GM128577/GM/NIGMS NIH HHS/United States ; P41 GM128577/GM/NIGMS NIH HHS/United States ; P41 GM128577/GM/NIGMS NIH HHS/United States ; R35 GM148166/GM/NIGMS NIH HHS/United States ; shared instrumentation grant S10OD021832//U.S. Department of Health & Human Services | National Institutes of Health (NIH)/ ; #OPP1156262//Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation)/ ; #OPP1156262//Bill and Melinda Gates Foundation (Bill & Melinda Gates Foundation)/ ; R01 GM139752/GM/NIGMS NIH HHS/United States ; },
mesh = {*Protein Multimerization ; Models, Molecular ; Protein Engineering/methods ; Protein Subunits/chemistry/metabolism ; Proteins/chemistry/metabolism ; },
abstract = {Pseudosymmetric hetero-oligomers with three or more unique subunits with overall structural (but not sequence) symmetry play key roles in biology, and systematic approaches for generating such proteins de novo would provide new routes to controlling cell signaling and designing complex protein materials. However, the de novo design of protein hetero-oligomers with three or more distinct chains with nearly identical structures is a challenging unsolved problem because it requires the accurate design of multiple protein-protein interfaces simultaneously. Here, we describe a divide-and-conquer approach that breaks the multiple-interface design challenge into a set of more tractable symmetric single-interface redesign tasks, followed by structural recombination of the validated homo-oligomers into pseudosymmetric hetero-oligomers. Starting from de novo designed circular homo-oligomers composed of 9 or 24 tandemly repeated units, we redesigned the inter-subunit interfaces to generate 19 new homo-oligomers and structurally recombined them to make 24 new hetero-oligomers, including ABC heterotrimers, A2B2 heterotetramers, and A3B3 and A2B2C2 heterohexamers which assemble with high structural specificity. The symmetric homo-oligomers and pseudosymmetric hetero-oligomers generated for each system have identical or nearly identical backbones, and hence are ideal building blocks for generating and functionalizing larger symmetric and pseudosymmetric assemblies.},
}

*Protein Multimerization
Models, Molecular
Protein Engineering/methods
Protein Subunits/chemistry/metabolism
Proteins/chemistry/metabolism

@article {pmid39693737,
year = {2024},
author = {Zhang, Y and Spitzer, BW and Zhang, Y and Wallace, DA and Yu, B and Qi, Q and Argos, M and Avilés-Santa, ML and Boerwinkle, E and Daviglus, ML and Kaplan, R and Cai, J and Redline, S and Sofer, T},
title = {Untargeted metabolome atlas for sleep-related phenotypes in the Hispanic community health study/study of Latinos.},
journal = {EBioMedicine},
volume = {111},
number = {},
pages = {105507},
doi = {10.1016/j.ebiom.2024.105507},
pmid = {39693737},
issn = {2352-3964},
abstract = {BACKGROUND: Sleep is essential to maintaining health and wellbeing of individuals, influencing a variety of outcomes from mental health to cardiometabolic disease. This study aims to assess the relationships between various sleep-related phenotypes and blood metabolites.

METHODS: Utilising data from the Hispanic Community Health Study/Study of Latinos, we performed association analyses between 40 sleep-related phenotypes, grouped in several domains (sleep disordered breathing (SDB), sleep duration, sleep timing, self-reported insomnia symptoms, excessive daytime sleepiness (EDS), and heart rate during sleep), and 768 metabolites measured via untargeted metabolomics profiling. Network analysis was employed to visualise and interpret the associations between sleep phenotypes and metabolites.

FINDINGS: The patterns of statistically significant associations between sleep phenotypes and metabolites differed by superpathways, and highlighted subpathways of interest for future studies. For example, primary bile acid metabolism showed the highest cumulative percentage of statistically significant associations across all sleep phenotype domains except for SDB and EDS phenotypes. Several metabolites were associated with multiple sleep phenotypes, from a few domains. Glycochenodeoxycholate, vanillyl mandelate (VMA) and 1-stearoyl-2-oleoyl-GPE (18:0/18:1) were associated with the highest number of sleep phenotypes, while pregnenolone sulfate was associated with all sleep phenotype domains except for sleep duration. N-lactoyl amino acids such as N-lactoyl phenylalanine (lac-Phe), were associated with sleep duration, SDB, sleep timing and heart rate during sleep.

INTERPRETATION: This atlas of sleep-metabolite associations will facilitate hypothesis generation and further study of the metabolic underpinnings of sleep health.

FUNDING: R01HL161012, R35HL135818, R01AG80598.},
}

@article {pmid39693591,
year = {2024},
author = {Kalinsky, K and Bianchini, G and Hamilton, E and Graff, SL and Park, KH and Jeselsohn, R and Martin, M and Layman, RM and Hurvitz, SA and Sammons, S and Kaufman, PA and Muñoz, M and Lai, JI and Knoderer, H and Sandoval, C and Chawla, AR and Nguyen, B and Zhou, Y and Ravenberg, E and Litchfield, LM and Smyth, L and Wander, SA},
title = {Abemaciclib Plus Fulvestrant in Advanced Breast Cancer Following Progression on CDK4/6 Inhibition: Results from the Phase III postMONARCH Trial.},
journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
volume = {},
number = {},
pages = {JCO2402086},
doi = {10.1200/JCO-24-02086},
pmid = {39693591},
issn = {1527-7755},
abstract = {PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are the standard first-line treatment for hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC); however, disease progression occurs in almost all patients and additional treatment options are needed. Herein we report outcomes of the postMONARCH trial investigating a switch in ET with/without CDK4/6 inhibition with abemaciclib after disease progression on CDK4/6i.

METHODS: This double-blind, randomized Phase III study enrolled patients with disease progression on prior CDK4/6i plus aromatase inhibitor as initial therapy for advanced disease or recurrence on/after adjuvant CDK4/6i+ET. Patients were randomly assigned (1:1) to abemaciclib+fulvestrant or placebo+fulvestrant. The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included PFS by blinded independent central review (BICR), objective response rate (ORR), and safety.

RESULTS: This study randomized 368 patients (abemaciclib+fulvestrant, n=182 placebo+fulvestrant, n=186). At the primary analysis (258 events), the hazard ratio (HR) was 0.73 (95% CI, 0.57-0.95; nominal P=0.017), with median PFS 6.0 (95% CI, 5.6-8.6) vs 5.3 (95% CI, 3.7-5.6) months and 6-month PFS rates of 50% and 37% in the abemaciclib+fulvestrant and placebo+fulvestrant arms, respectively. These results were supported by BICR-assessed PFS (HR, 0.55; 95% CI, 0.39-0.77; nominal P<0.001). A consistent treatment effect was seen across major clinical and genomic subgroups, including with/without ESR1 or PIK3CA mutations. Among patients with measurable disease, investigator-assessed ORR was improved with abemaciclib+fulvestrant versus placebo+fulvestrant (17% vs 7%; nominal P=0.015). No new safety signals were observed, with findings consistent with the known safety profile of abemaciclib.

CONCLUSIONS: Abemaciclib+fulvestrant significantly improved PFS after disease progression on prior CDK4/6i+ET in patients with HR+, HER2- ABC, offering an additional targeted therapy option for these patients.},
}

@article {pmid39693117,
year = {2024},
author = {Kresovich, JK and Richards, AR and Ergas, IJ and Cannioto, R and Thomsen, C and Laurent, CA and Shariff-Marco, S and Rillamas-Sun, E and Kolevska, T and Yao, S and Ambrosone, C and Kushi, L and Greenlee, H and Kwan, ML},
title = {Physical activity and incident cardiovascular disease in breast cancer survivors: the pathways study.},
journal = {JNCI cancer spectrum},
volume = {},
number = {},
pages = {},
doi = {10.1093/jncics/pkae123},
pmid = {39693117},
issn = {2515-5091},
abstract = {PURPOSE: Breast cancer survivors experience higher rates of cardiovascular disease (CVD) than women without breast cancer, due in part to cardiotoxic cancer treatments and shared lifestyle risk factors. Physical activity is associated with lower mortality risk in breast cancer survivors, but associations with CVD have not been examined in detail.

METHODS: The Pathways Study is a prospective cohort study of 4,504 women diagnosed with invasive breast cancer between 2005 and 2013. At enrollment, women self-reported their physical activities during the previous six months, which were dichotomized as meeting the CDC's Physical Activity Guidelines for Americans (≥150 minutes of moderate-intensity or ≥ 75 minutes of vigorous-intensity activity per week) vs not. Incident CVD events (heart failure, cardiomyopathy, cardiac arrest, ischemic heart disease, stroke) occurring between enrollment and December 2021 were identified from electronic health records. Covariate-adjusted, competing risks Cox regression models estimated associations between meeting physical activity guidelines and CVD risk.

RESULTS: Compared with women who did not meet physical activity guidelines at their diagnosis, those who did had a 25% lower risk of CVD (HR: 0.75, 95% CI: 0.60, 0.94). Among the individual CVD outcomes, meeting physical activity guidelines was protective against incident cardiomyopathy (HR: 0.54, 95% CI: 0.31, 0.95), heart failure (HR: 0.66, 95% CI: 0.50, 0.87), and cardiac arrest (HR: 0.68, 95% CI: 0.49, 0.99).

CONCLUSIONS: Meeting physical activity guidelines at breast cancer diagnosis was associated with lower risk of CVD after diagnosis. Studies investigating changes in physical activity after a breast cancer diagnosis and CVD risk are warranted.},
}

@article {pmid39691260,
year = {2024},
author = {Ho, C and Zhu, S and Gooley, T and Gujral, TS and Lynch, RC and Poh, C and Shadman, M and Smith, SD and Tseng, Y and Gopal, AK},
title = {A phase 2 study of frontline pembrolizumab in follicular lymphoma.},
journal = {EJHaem},
volume = {5},
number = {6},
pages = {1173-1181},
pmid = {39691260},
issn = {2688-6146},
abstract = {BACKGROUND: The tumor microenvironment (TME), including infiltrating T-cells, is thought to play a major role in the pathogenesis and prognosis of follicular lymphoma (FL) and may contribute to its widely varied disease course. We hypothesized that programmed death-1 inhibition may be most effective in untreated, immunocompetent FL patients. Thus, we developed a phase 2 study to evaluate the efficacy of pembrolizumab as the initial treatment for indolent B-cell lymphoma.

METHODS: Adults with FL or marginal zone lymphoma and an indication for treatment were eligible. Patients received pembrolizumab 200 mg IV in 21-day cycles for up to 18 cycles, until progression or unacceptable toxicity. Early response assessment was obtained after cycle 3 with computed tomography (CT), and a fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography (PET-CT) was obtained after cycle 6 to determine candidacy for continuation in the study. Immunosecretome profiling was performed at baseline and on cycle 2 day 1.

RESULTS: Nine patients with FL were enrolled between February 2019 and April 2021, including eight (89%) with advanced stage, seven (78%) with intermediate/high Follicular Lymphoma International Prognostic Index, and six (67%) with high-tumor burden by Groupe d'Etude des Lymphomes Folliculaires. The best overall response rate by FDG PET-CT was 33% (three partial metabolic responses). Three patients (33%) had stable disease, and three (33%) had progressive disease (including one patient who only had a follow-up CT). By CT four (44%) experienced a reduction in target lesions, but all were less than partial responses. Grade 3 or higher immune-related adverse events (IRAEs) were seen in two (22%) patients, both with transaminitis and one of whom had concurrent hypophysitis. Another patient had grade 1 pneumonitis, requiring treatment with steroids. No associations between the immunosecretome profile and clinical outcomes could be detected.

CONCLUSION: Frontline pembrolizumab for FL is associated with limited responses and a clinically significant rate of IRAEs. Alternative strategies for targeting the TME in FL should be explored.},
}

@article {pmid39691254,
year = {2024},
author = {Naru, J and Othus, M and Lin, C and Biernacki, MA and Bleakley, M and Chauncey, TR and Erba, HP and Fang, M and Fitzgibbon, MP and Gafken, PR and Ivey, RG and Kennedy, JJ and Lorentzen, TD and Meshinchi, S and Moseley, A and Pogosova-Agadjanyan, EL and Liu, VM and Radich, JP and Voytovich, UJ and Wang, P and Whiteaker, JR and Willman, CL and Wu, F and Paulovich, AG and Stirewalt, DL},
title = {Proteogenomic characterization of highly enriched viable leukemic blasts in acute myeloid leukemia: A SWOG report.},
journal = {EJHaem},
volume = {5},
number = {6},
pages = {1243-1251},
pmid = {39691254},
issn = {2688-6146},
abstract = {INTRODUCTION: Acute myeloid leukemia (AML) remains one of the deadliest hematopoietic malignancies. A better understanding of the molecular biology governing AML may lead to improved risk stratification and facilitate the development of novel therapies. Proteins are responsible for much of the biology of cells. Several studies have examined the global proteome in bulk mononuclear cells (MNCs) from AML specimens, which are comprised a heterogenous population of cells at various stages of differentiation.

METHODS: Given the potential impact of the nonleukemic cells on protein expression profiles, we applied an integrative proteogenomic approach utilizing next-generation sequencing and mass spectrometry-based proteomics to identify novel protein biomarkers in unsorted MNCs and viable leukemic blasts (VLBs) isolated from blood and bone marrow specimens obtained at the time of AML diagnosis.

RESULTS: We identified significant differences in protein expression between VLBs and MNCs. Subsequent studies (N = 27) focused on proteomic profiling of VLBs that identified novel candidate biomarkers associated with mutational genotypes and clinical outcome, some of which were recapitulated in an independent cohort of patients. Using mass spectrometry, we also detected mutated protein products, some of which were predicted via in silico analyses to be potential neoantigens amenable to adoptive immunotherapy. As previously described, analyses comparing transcript and protein expression showed an overall modest correlation between mRNA and protein dataset, but enriching for genes associated with mutations significantly improved the protein-RNA correlation.

CONCLUSION: Together, the results provide insight into the biology of VLBs and demonstrate the gains derived from examining the proteome in addition to genome and transcriptome.},
}

@article {pmid39691239,
year = {2024},
author = {Teymouri, F and Sebastian, G and Gem, H and Minot, SS and Rashidi, A},
title = {Oral acute graft-versus-host disease.},
journal = {EJHaem},
volume = {5},
number = {6},
pages = {1290-1294},
pmid = {39691239},
issn = {2688-6146},
abstract = {Oral acute graft-versus-host disease (aGVHD) is rare and with no diagnostic criteria. We report a case of oral aGVHD with three clinical phases. A self-limited prodrome of largely subjective oral symptoms was followed by concurrent oral and upper gastrointestinal aGVHD. Six months after transplantation, the patient was diagnosed with severe oral and upper gastrointestinal chronic GVHD. We compared the salivary microbiota of our patient at the time of diagnosis of aGVHD with 50 contemporaneous transplant recipients and found no evidence for oral microbiota involvement in pathogenesis. This in-depth N-of-1 analysis reveals novel aspects of oral aGVHD pathogenesis.},
}

@article {pmid39690453,
year = {2024},
author = {Do, OA and Ohlsen, TJD and Shipman, KJ and Ballard, SA and Jenssen, KM and Baker, KS and Rosenberg, AR and Barton, KS and Bhatt, NS},
title = {Return-to-School Experiences of Adolescents After Allogeneic Hematopoietic Cell Transplant: A Qualitative Interview Study of Transplant Recipients.},
journal = {Pediatric blood & cancer},
volume = {},
number = {},
pages = {e31481},
doi = {10.1002/pbc.31481},
pmid = {39690453},
issn = {1545-5017},
support = {//Ben Towne Center for Childhood Cancer and Blood Disorders Research Pilot Award program/ ; //Seattle Children's Research Institute and Rally Foundation for Childhood Cancer Research/ ; //Independent Investigator Award/ ; },
abstract = {BACKGROUND: Returning to school after allogeneic hematopoietic cell transplant (HCT) can improve quality of life and promote positive adjustment. However, this process may be challenging, and there is a limited understanding of school-aged children and adolescents' perspectives on this process.

METHODS: We conducted semi-structured interviews over video with pediatric recipients of HCT (10-18 years of age at HCT; 1-7 years post HCT) who were treated at our institution and had returned to in-person school post HCT. We performed a thematic network analysis focused on exploring salient challenges regarding the return-to-school process post HCT and potential areas for improvement.

RESULTS: We interviewed 16 participants (mean age 13.8 years at HCT). Four themes emerged: (i) challenges of returning to school, (ii) keys for a successful return-to-school experience, (iii) overall perceptions of the process, and (iv) recommendations for improvement. HCT recipients described several social/emotional, physical, and academic challenges while returning to school and cited strong sources of support as critical to a successful transition. Recommendations for a better transition process included the following: (a) fostering peer support, (b) establishing social connections, (c) providing mental health support, (d) identifying a go-to point of contact for issues, and (e) maintaining academic support.

CONCLUSIONS: Our findings highlight perspectives from school-aged recipients of HCT regarding gaps in support and areas for improvement to facilitate successful return to school after HCT. Additional assistance throughout the process may optimize academic and social reintegration and support recovery after HCT.},
}

@article {pmid39689462,
year = {2024},
author = {Biesma, NC and Graus, MUJE and Cirkel, GA and Besselink, MG and de Groot, JWB and Koerkamp, BG and Herbschleb, KH and Los, M and Verdonk, RC and Wilmink, JW and Cervantes, A and Valle, JW and Valkenburg-van Iersel, LBJ and Froeling, FEM and Molenaar, IQ and Daamen, LA and de Vos-Geelen, J and van Santvoort, HC and , },
title = {Perspectives of the medical oncologist regarding adjuvant chemotherapy for pancreatic cancer: An international expert survey and case vignette study.},
journal = {European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology},
volume = {51},
number = {3},
pages = {109544},
doi = {10.1016/j.ejso.2024.109544},
pmid = {39689462},
issn = {1532-2157},
abstract = {INTRODUCTION: Adjuvant chemotherapy improves survival in patients with resected pancreatic ductal adenocarcinoma (PDAC). The decision to initiate chemotherapy involves both patient and physician factors, decision-specific criteria, and contextual considerations. This study aimed to assess medical oncologists' views on adjuvant chemotherapy following pancreatic resection for PDAC.

METHODS: An online survey and case vignette study were distributed to medical oncologists via the Dutch Pancreatic Cancer Group (DPCG), International Hepato-Pancreato-Biliary Association (IHPBA) and related networks.

RESULTS: A total of 91 oncologists from 14 countries participated, 46 % of whom treated more than 40 new PDAC patients annually, with a median experience of 15 years. Significant discrepancies were noted in their recommendations for adjuvant chemotherapy across case vignettes. In patients over 70, 17 % advised against chemotherapy, while 31 % said age was not a factor. Oncologists with less than 10 years of experience and those in non-academic settings were less likely to recommend adjuvant therapy. While 87 % agreed mFOLFIRINOX is the preferred adjuvant treatment, consensus on individual cases was lacking. The recommended interval between surgery and chemotherapy ranged from 3 to 26 weeks, with varying reasons for withholding treatment, primarily due to postoperative recovery and performance status.

CONCLUSIONS: Our study revealed substantial variation among oncologists in counseling on adjuvant chemotherapy after PDAC resection. This emphasizes the need for more patient involvement in decision-making and improving shared decision-making.},
}

@article {pmid39689429,
year = {2024},
author = {Hodan, R and Gupta, S and Weiss, JM and Axell, L and Burke, CA and Chen, LM and Chung, DC and Clayback, KM and Felder, S and Foda, Z and Giardiello, FM and Grady, W and Gustafson, S and Hagemann, A and Hall, MJ and Hampel, H and Idos, G and Joseph, N and Kassem, N and Katona, B and Kelly, K and Kieber-Emmons, A and Kupfer, S and Lang, K and Llor, X and Markowitz, AJ and Prats, MM and Niell-Swiller, M and Outlaw, D and Pirzadeh-Miller, S and Samadder, NJ and Shibata, D and Stanich, PP and Swanson, BJ and Szymaniak, BM and Welborn, J and Wiesner, GL and Yurgelun, MB and Dwyer, M and Darlow, S and Diwan, Z},
title = {Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024, NCCN Clinical Practice Guidelines In Oncology.},
journal = {Journal of the National Comprehensive Cancer Network : JNCCN},
volume = {22},
number = {10},
pages = {695-711},
doi = {10.6004/jnccn.2024.0061},
pmid = {39689429},
issn = {1540-1413},
mesh = {Humans ; Female ; *Endometrial Neoplasms/genetics/diagnosis ; *Genetic Testing/standards/methods ; Risk Assessment/methods ; *Genetic Predisposition to Disease ; Colorectal Neoplasms/genetics/diagnosis ; Stomach Neoplasms/genetics/diagnosis/therapy ; Neoplastic Syndromes, Hereditary/diagnosis/genetics/therapy ; Medical Oncology/standards/methods ; Male ; },
abstract = {Multigene panel testing has allowed for the detection of a growing number of inherited pathogenic/likely pathogenic variants in people at high risk of cancer, including endometrial cancer (EC). Hereditary syndromes associated with EC include Lynch syndrome, PTEN hamartoma tumor syndrome, and Peutz-Jeghers syndrome. This manuscript provides the latest recommendations from the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric on the screening and management of EC in patients at high risk for these syndromes, as well as the advantages and limitations of multigene panel testing. This manuscript also describes recent updates to these guidelines regarding de-implementation of colon cancer screening in individuals with CHEK2 pathogenic/likely pathogenic variants, based on the most up-to-date evidence regarding the association between CHEK2 pathogenic/likely pathogenic variants and colon cancer risk.},
}

Humans
Female
*Endometrial Neoplasms/genetics/diagnosis
*Genetic Testing/standards/methods
Risk Assessment/methods
*Genetic Predisposition to Disease
Colorectal Neoplasms/genetics/diagnosis
Stomach Neoplasms/genetics/diagnosis/therapy
Neoplastic Syndromes, Hereditary/diagnosis/genetics/therapy
Medical Oncology/standards/methods
Male

@article {pmid39689426,
year = {2024},
author = {Sanft, T and Day, AT and Goldman, M and Ansbaugh, S and Armenian, S and Baker, KS and Ballinger, TJ and Demark-Wahnefried, W and Fairman, NP and Feliciano, J and Flores, TF and Friedman, DL and Gabel, N and Hill-Kayser, C and Koura, D and Lee, K and Lee, N and McDonough, AL and Melisko, M and Mooney, K and Moore, HCF and Moryl, N and Neuman, H and Overholser, L and Patel, C and Peterson, L and Pirl, W and Porpiglia, A and Schapira, L and Schwartz, A and Smith, S and Tevaarwerk, A and Von Ah, D and Wake, R and Yang, E and Zee, P and McMillian, N and Freedman-Cass, D},
title = {NCCN Guidelines® Insights: Survivorship, Version 2.2024.},
journal = {Journal of the National Comprehensive Cancer Network : JNCCN},
volume = {22},
number = {10},
pages = {648-658},
doi = {10.6004/jnccn.2024.0062},
pmid = {39689426},
issn = {1540-1413},
mesh = {Humans ; *Survivorship ; *Neoplasms/therapy/psychology ; *Cancer Survivors/psychology ; },
abstract = {The NCCN Guidelines for Survivorship include recommendations for screening, evaluation, and treatment of psychosocial and physical problems resulting from adult-onset cancer and its treatment. They also include recommendations to promote healthy behaviors and immunizations in survivors and provide a framework for care coordination. These NCCN Guidelines Insights summarize the panel's current recommendations regarding sexual health and fertility.},
}

Humans
*Survivorship
*Neoplasms/therapy/psychology
*Cancer Survivors/psychology

@article {pmid39689352,
year = {2024},
author = {Vutien, P and Barnard Giustini, A and Kim, NJ and Moon, AM and Hsu, CN and Mezzacappa, C and Borgerding, JA and Johnson, KM and VoPham, T and Berry, K and Beste, LA and Kaplan, DE and Taddei, TH and Ioannou, GN},
title = {Validation and expansion of Baveno VII criteria for cACLD and CSPH based on liver stiffness and platelet count: Correlation with risk of hepatic decompensation and death.},
journal = {Hepatology (Baltimore, Md.)},
volume = {},
number = {},
pages = {},
doi = {10.1097/HEP.0000000000001183},
pmid = {39689352},
issn = {1527-3350},
abstract = {BACKGROUND AND AIMS: Recently proposed "Rule-of-Five" criteria define compensated advanced chronic liver disease (cACLD) and clinically significant portal hypertension (CSPH) using liver stiffness (LS) and platelet count. We aimed to validate these criteria by determining whether they are associated with risk of adverse outcomes.

METHODS AND RESULTS: Patients without prior hepatic decompensation or hepatocellular carcinoma (HCC) who underwent LS and platelet measurements (n=17,076), were categorized as follows: no cACLD (LS 2.5-9.9 kPa); probable cACLD (LS 10-14.9 kPa); certain cACLD-no CSPH (LS 15-19.9 kPa and platelets ≥110,000/µL or LS 20-24.9 kPa and platelets ≥150,000/µL); probable CSPH (LS 15-19.9 kPa and platelets <110,000/µL or LS 20-24.9 and platelets <150,000/µL); and certain CSPH (LS ≥25 Kpa), which we further sub-divided into 25-49.9 kPa and 50-75 kPa.During a median follow-up of 2.82 years, each increase in "Rule-of-Five" category was associated linearly with higher risks of death (hazard ratio [HR] 1.22, 95% CI 1.18-1.25) and decompensation (HR 1.52, 95% CI 1.46-1.58). Compared to patients with LS 25-49.9 kPa, those with LS 50-75 kPa ("critical" CSPH) had approximately double the risk of decompensation (11.24 vs. 4.20 per 100 patient-years) and death (9.85 vs. 6.98 per 100 patient-years).

CONCLUSIONS: The Baveno VII "Rule-of-Five" criteria provide a valid system for stratifying risks of death and hepatic decompensation and should be used routinely in patients with chronic liver disease. Among patients with CSPH (LS ≥25 kPa), the subgroup with LS 50-75 kPa ("critical" CSPH) has approximately double the risk of death and hepatic decompensation than LS 25-49.9 kPa.},
}

@article {pmid39688693,
year = {2024},
author = {Ohlsen, TJD and Hale, MR and Larson, AJ and Jones, SMW and Wilkinson, F and Chow, EJ and Ko, LK and Desai, AD},
title = {Financial toxicity among pediatric oncology families during therapy and early survivorship: a qualitative analysis.},
journal = {Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer},
volume = {33},
number = {1},
pages = {36},
pmid = {39688693},
issn = {1433-7339},
mesh = {Humans ; Female ; Male ; *Qualitative Research ; *Neoplasms/psychology/therapy/economics ; Child ; Adult ; *Caregivers/psychology/economics ; Adolescent ; Middle Aged ; Child, Preschool ; Interviews as Topic ; Cost of Illness ; Survivorship ; Family/psychology ; Young Adult ; Cancer Survivors/psychology ; },
abstract = {PURPOSE: Cancer treatment often results in adverse financial consequences-also termed financial toxicity. To build upon limited research in pediatric oncology, we conducted a qualitative study exploring families' lived experiences with financial toxicity and their perspectives on potential mitigation strategies.

METHODS: We conducted in-depth semi-structured interviews with a purposive sample of English- and Spanish-speaking family caregivers, 3-24 months following diagnosis. We performed a thematic analysis focused on elucidating relationships between components/domains of financial toxicity, identifying mitigating and exacerbating factors, eliciting latent constructs for measurement, and querying caregivers' perspectives on interventions. We organized relationships between themes into a framework to compare with prior theoretically derived models.

RESULTS: We interviewed 21 caregivers, diverse with respect to income, age, race and ethnicity, family structure/composition, and patient characteristics. We identified four themes relating to financial toxicity: increased spending on providing care to patients/siblings, reduced income due to challenges in maintaining employment, new or worsened material hardship, and heightened psychological distress regarding finances. We also identified an additional theme pertaining to response behaviors directed at managing financial toxicity, with helpful or harmful downstream effects. Factors that exacerbated or lessened financial toxicity included awareness of resources, geography, and community. Caregivers suggested potential mitigation strategies, including proactive education and resource provision.

CONCLUSION: Pediatric patients and families can experience substantial financial impacts, which may differ from experiences of adults with cancer. These findings suggest a need for careful screening and measurement, as well as family-centered interventions and policies to reduce long-term consequences.},
}

Humans
Female
Male
*Qualitative Research
*Neoplasms/psychology/therapy/economics
Child
Adult
*Caregivers/psychology/economics
Adolescent
Middle Aged
Child, Preschool
Interviews as Topic
Cost of Illness
Survivorship
Family/psychology
Young Adult
Cancer Survivors/psychology

@article {pmid39677796,
year = {2024},
author = {Nicoletti, C and Massenet, J and Pintado-Urbanc, AP and Connor, LJ and Nicolau, M and Sundar, S and Xu, M and Schmitt, A and Zhang, W and Fang, Z and Chan, TCI and Tapscott, SJ and Cheung, TH and Simon, MD and Caputo, L and Puri, PL},
title = {E-box independent chromatin recruitment turns MYOD into a transcriptional repressor.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {39677796},
issn = {2692-8205},
abstract = {MYOD is an E-box sequence-specific basic Helix-Loop-Helix (bHLH) transcriptional activator that, when expressed in non-muscle cells, induces nuclear reprogramming toward skeletal myogenesis by promoting chromatin accessibility at previously silent loci. Here, we report on the identification of a previously unrecognized property of MYOD as repressor of gene expression, via E-box-independent chromatin binding within accessible genomic elements, which invariably leads to reduced chromatin accessibility. MYOD-mediated repression requires the integrity of functional domains previously implicated in MYOD-mediated activation of gene expression. Repression of mitogen- and growth factor-responsive genes occurs through promoter binding and requires a highly conserved domain within the first helix. Repression of cell-of-origin/alternative lineage genes occurs via binding and decommissioning of distal regulatory elements, such as super-enhancers (SE), which requires the N-terminal activation domain as well as two chromatin-remodeling domains and leads to reduced strength of CTCF-mediated chromatin interactions. Surprisingly, MYOD-mediated chromatin compaction and repression of transcription do not associate with reduction of H3K27ac, the conventional histone mark of enhancer or promoter activation, but with reduced levels of the recently discovered histone H4 acetyl-methyl lysine modification (Kacme). These results extend MYOD biological properties beyond the current dogma that restricts MYOD function to a monotone transcriptional activator and reveal a previously unrecognized functional versatility arising from an alternative chromatin recruitment through E-box or non-E-box sequences. The E-box independent repression of gene expression by MYOD might provide a promiscuous mechanism to reduce chromatin accessibility and repress cell-of-origin/alternative lineage and growth factor/mitogen-responsive genes to safeguard the integrity of cell identity during muscle progenitor commitment toward the myogenic lineage.},
}

@article {pmid39687983,
year = {2024},
author = {Williams, JT and Goodpaster, TA and Haraguchi, M},
title = {Optimizing tissue adherence on glass slides using polyurethane glue: a new slide preparation method.},
journal = {Journal of histotechnology},
volume = {},
number = {},
pages = {1-3},
doi = {10.1080/01478885.2024.2440679},
pmid = {39687983},
issn = {2046-0236},
abstract = {The application of Clear Gorilla Glue® household adhesive to microscope slides has been found to enhance the mounting and retention of traditionally difficult tissue types, notably bone and tooth specimens. Improvement in end results were observed across H&E staining, immunohistochemistry, and in situ hybridization.},
}

@article {pmid39682018,
year = {2024},
author = {Boiko, JR and Hill, GR},
title = {Chronic Graft-versus-host Disease: Immune Insights, Therapeutic Advances, and Parallels for Solid Organ Transplantation.},
journal = {Transplantation},
volume = {},
number = {},
pages = {},
doi = {10.1097/TP.0000000000005298},
pmid = {39682018},
issn = {1534-6080},
abstract = {Chronic graft-versus-host disease remains a frequent and morbid outcome of allogeneic hematopoietic cell transplantation, in which the donor-derived immune system attacks healthy recipient tissue. Preceding tissue damage mediated by chemoradiotherapy and alloreactive T cells compromise central and peripheral tolerance mechanisms, leading to aberrant donor T cell and germinal center B cell differentiation, culminating in pathogenic macrophage infiltration and differentiation in a target tissue, with ensuant fibrosis. This process results in a heterogeneous clinical syndrome with significant morbidity and mortality, frequently requiring prolonged therapy. In this review, we discuss the processes that interrupt immune tolerance, the subsequent clinical manifestations, and new Food and Drug Administration-approved therapeutic approaches that have been born from a greater understanding of disease pathogenesis in preclinical systems, linking to parallel processes following solid organ transplantation.},
}

@article {pmid39681126,
year = {2024},
author = {Velloza, J and Poovan, N and Meisner, A and Ndlovu, N and Ndimande-Khoza, N and Grabow, C and Zwane, P and Mbele, S and Molefe, M and Donnell, D and Baeten, JM and Hosek, S and Celum, C and Delany-Moretlwe, S},
title = {Adaptive HIV pre-exposure prophylaxis adherence interventions for young women in Johannesburg, South Africa: a sequential multiple-assignment randomised trial.},
journal = {The lancet. HIV},
volume = {},
number = {},
pages = {},
doi = {10.1016/S2352-3018(24)00268-6},
pmid = {39681126},
issn = {2352-3018},
abstract = {BACKGROUND: Adherence to daily oral pre-exposure prophylaxis (PrEP) is low among African young women, and layered support strategies are needed to improve PrEP adherence in this population. We aimed to evaluate potentially scalable adherence-support strategies for young women aged 18-25 years who initiated PrEP in Johannesburg, South Africa.

METHODS: We conducted a sequential multiple-assignment randomised trial at Ward 21 of the Wits Reproductive Health and HIV Institute clinical research site, affiliated with University of the Witwatersrand, Johannesburg, South Africa. Participants were eligible if they were assigned female sex at birth, aged 18-25 years, not living with HIV, sexually active, newly initiating PrEP, had regular access to a mobile telephone, and could read. Using sequentially numbered, sealed, opaque envelopes containing group allocation, a staff member assigned enrolled participants (1:1) to receive one of two adherence-support interventions: once per week two-way SMS communication or participation in a WhatsApp peer-support group. Participants assigned to WhatsApp were put into groups with approximately 25 participants, during which they were prompted by staff facilitators to discuss any challenges with PrEP use or other events happening in their lives. The allocation sequence was generated by the data manager using random numbers with variable block sizes between 10 and 14. Only trial investigators were masked to participant intervention assignments; participants, people giving interventions, people assessing outcomes, and people analysing data were not masked to group assignment. All enrolled participants were offered PrEP (ie, co-formulated, once per day oral emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg). The primary outcome was high PrEP adherence at month 9, defined as concentration of tenofovir diphosphate on dried blood sample of 700 fmol per punch or more. At month 3, participants with low PrEP adherence were randomly assigned to a secondary, intensified intervention of issue-focused counselling once per month or drug-level feedback counselling based on PrEP drug concentrations at months 3 and 6. The protocol was registered at ClinicalTrials.gov (NCT04038060) and the trial is complete.

FINDINGS: Participants were enrolled and followed up between May 16, 2019, and Jan 25, 2022. From May 16, 2019, to Jan 29, 2021, 401 participants were screened and 360 were enrolled and initiated PrEP. 180 (50%) were randomly assigned to two-way SMS and 180 (50%) were randomly assigned to WhatsApp support groups. At month 9, 34 (20%) of 174 participants in the two-way SMS arm had tenofovir diphosphate 700 fmol per punch or more, compared with 32 (18%) of 174 in the WhatsApp arm (relative risk 1·06, 95% CI 0·69-1·64; p=0·78). At month 9, four (5%) of 76 participants in the drug-level feedback arm had tenofovir diphosphate 700 fmol per punch or more, compared with three (4%) of 76 participants in the monthly counselling arm (1·33, 0·31-5·76; p=0·70). 22 serious adverse events were reported during the trial, but were all deemed unrelated to the trial.

INTERPRETATION: PrEP adherence did not differ across interventions among young women in Johannesburg, South Africa. Future research is needed on whether and how to scale-up PrEP support for young women in resource-constrained settings.

FUNDING: US National Institutes of Health.},
}

@article {pmid39680601,
year = {2024},
author = {Grinde, KE and Browning, BL and Reiner, AP and Thornton, TA and Browning, SR},
title = {Adjusting for principal components can induce collider bias in genome-wide association studies.},
journal = {PLoS genetics},
volume = {20},
number = {12},
pages = {e1011242},
doi = {10.1371/journal.pgen.1011242},
pmid = {39680601},
issn = {1553-7404},
abstract = {Principal component analysis (PCA) is widely used to control for population structure in genome-wide association studies (GWAS). Top principal components (PCs) typically reflect population structure, but challenges arise in deciding how many PCs are needed and ensuring that PCs do not capture other artifacts such as regions with atypical linkage disequilibrium (LD). In response to the latter, many groups suggest performing LD pruning or excluding known high LD regions prior to PCA. However, these suggestions are not universally implemented and the implications for GWAS are not fully understood, especially in the context of admixed populations. In this paper, we investigate the impact of pre-processing and the number of PCs included in GWAS models in African American samples from the Women's Health Initiative SNP Health Association Resource and two Trans-Omics for Precision Medicine Whole Genome Sequencing Project contributing studies (Jackson Heart Study and Genetic Epidemiology of Chronic Obstructive Pulmonary Disease Study). In all three samples, we find the first PC is highly correlated with genome-wide ancestry whereas later PCs often capture local genomic features. The pattern of which, and how many, genetic variants are highly correlated with individual PCs differs from what has been observed in prior studies focused on European populations and leads to distinct downstream consequences: adjusting for such PCs yields biased effect size estimates and elevated rates of spurious associations due to the phenomenon of collider bias. Excluding high LD regions identified in previous studies does not resolve these issues. LD pruning proves more effective, but the optimal choice of thresholds varies across datasets. Altogether, our work highlights unique issues that arise when using PCA to control for ancestral heterogeneity in admixed populations and demonstrates the importance of careful pre-processing and diagnostics to ensure that PCs capturing multiple local genomic features are not included in GWAS models.},
}

@article {pmid39680021,
year = {2024},
author = {Yamamoto, N and Dobersch, S and Loveless, I and Samraj, AN and Jang, GH and Haraguchi, M and Kang, LI and Ruzinova, MB and Vij, KR and Mudd, JL and Walsh, T and Safyan, RA and Chiorean, EG and Hingorani, SR and Bolton, NM and Li, L and Fields, RC and DeNardo, DG and Notta, F and Crawford, HC and Steele, NG and Kugel, S},
title = {HMGA2 Expression Predicts Subtype, Survival, and Treatment Outcome in Pancreatic Ductal Adenocarcinoma.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {},
number = {},
pages = {},
doi = {10.1158/1078-0432.CCR-24-2200},
pmid = {39680021},
issn = {1557-3265},
abstract = {PURPOSE: To establish HMGA2 as a marker of basal-like disease in pancreatic ductal adenocarcinoma (PDAC) and explore its use as a biomarker for prognosis and treatment resistance.

EXPERIMENTAL DESIGN: We identified high expression of HMGA2 in basal PDAC cells in a scRNAseq Atlas of 172 patient samples. We then analyzed HMGA2 expression, along with expression of the classical marker GATA6, in a cohort of 580 PDAC samples with multiplex immunohistochemistry. We further supplemented these data with an additional 30 diverse patient samples and multiple independent single-cell RNAseq databases.

RESULTS: We found that expression of HMGA2, but not previously described basal markers CK5 or CK17, predicted overall survival in our cohort. Combining HMGA2 and GATA6 status allowed for identification of two key study groups: an HMGA2+/GATA6- cohort with worse survival, low tumor-infiltrating CD8+ T cells, increased FAP+ fibroblasts, and poorer response to gemcitabine-based chemotherapies (n=94, median survival=11.2 months post-surgery); and an HMGA2-/GATA6+ cohort with improved survival, increased CD8+ T-cell infiltrate, decreased FAP+ fibroblasts, and improved survival with gemcitabine-based chemotherapy (n=198, median survival=21.7 months post-surgery). HMGA2 was also prognostic for overall survival in RNA sequencing from an independent cohort.

CONCLUSIONS: IHC stratification of primary tumors by HMGA2 and GATA6 status in pancreatic cancer is associated with differential outcomes, survival following chemotherapy, and tumor microenvironments. As a nuclear marker for basal disease, HMGA2 complements GATA6 to identify disease subtypes in PDAC.},
}

@article {pmid39679349,
year = {2024},
author = {Follmann, D and Wang, X and Baden, LR and El Sahly, HM and Essink, B and Gilbert, P and Janes, HE and Kelley, CF and Berman, MA and Frank, I and Chu, E and Deng, W and Priddy, F and Dixit, A and Tomassini, JE and Das, R and Miller, J and Zhou, H},
title = {Who to Boost When: The Effect of Age and Dosing Interval on Delta and Omicron COVID-19 Incidence in the Open-label Phase of the COVE Trial.},
journal = {Open forum infectious diseases},
volume = {11},
number = {12},
pages = {ofae689},
pmid = {39679349},
issn = {2328-8957},
abstract = {BACKGROUND: To help inform COVID-19 vaccination recommendations, we evaluated the impact of age and dosing interval on clinical benefit of a third dose of mRNA-1273.

METHODS: Approximately 17 000 participants from the phase 3 Coronavirus Efficacy trial who previously received 2 doses of 100 µg mRNA-1273 were evaluated for COVID-19 between September 2021 and April 2022 during uptake of a third booster dose of 50 µg of mRNA-1273. Cox models assessed booster relative efficacy of a third dose.

RESULTS: Initial booster relative efficacy against Delta COVID-19 was 83% (95% confidence interval, 60-93) 14 days postdose and 83% (67-91) 60 days later. Initial booster efficacy against Omicron COVID-19 was 56% (44-65) at 14 days postdose and 4% (-27 to 28) 120 days later. For those aged ≥65 years, initial booster efficacy against Omicron COVID-19 was 86% (69-93) compared with 50% (36-61) for those <65 years. Placebo crossover to 2 doses of mRNA-1273 induced a median 5-month difference from the second to third dose between the original randomized arms. Postboost, the mRNA-1273 arm had a 24% (16%, 32%) lower risk of Omicron COVID-19 compared to the placebo-mRNA-1273 arm. Modeling predicted a 41% postboost reduction in Omicron COVID-19 for a 15- versus 7-month interval between the second and third doses.

CONCLUSIONS: Boosting reduced Delta COVID-19 risk by 83% through 2 months and reduced Omicron COVID-19 risk by 56% but declined by 4 months. A 15- versus 7-month dosing interval predicted a 41% postboost reduction in Omicron COVID-19 but increased preboost risk.

PRIMARY FUNDING SOURCE: The National Institutes of Health/National Institute of Allergy and Infectious Diseases. Registration for the COVE Trial.  ClinicalTrials.gov ID# NCT04470427.},
}

@article {pmid39678499,
year = {2024},
author = {Moloney, B and Li, X and Hirano, M and Saad Eddin, A and Lim, JY and Biswas, D and Kazerouni, AS and Tudorica, A and Li, I and Bryant, ML and Wille, C and Pyle, C and Rahbar, H and Hsieh, SK and Rice-Stitt, TL and Dintzis, SM and Bashir, A and Hobbs, E and Zimmer, A and Specht, JM and Phadke, S and Fleege, N and Holmes, JH and Partridge, SC and Huang, W},
title = {Initial experience in implementing quantitative DCE-MRI to predict breast cancer therapy response in a multi-center and multi-vendor platform setting.},
journal = {Frontiers in oncology},
volume = {14},
number = {},
pages = {1395502},
pmid = {39678499},
issn = {2234-943X},
abstract = {Quantitative dynamic contrast-enhanced (DCE) MRI as a promising method for the prediction of breast cancer response to neoadjuvant chemotherapy (NAC) has been demonstrated mostly in single-center and single-vendor platform studies. This preliminary study reports the initial experience in implementing quantitative breast DCE-MRI in multi-center (MC) and multi-vendor platform (MP) settings to predict NAC response. MRI data, including B1 mapping, variable flip angle (VFA) measurements of native tissue R1 (R1,0), and DCE-MRI, were acquired during NAC at three sites using 3T systems with Siemens, Philips, and GE platforms, respectively. High spatiotemporal resolution DCE-MRI was performed using similar vendor product sequences with k-space undersampling during acquisition and view sharing during reconstruction. A breast phantom was used for quality assurance/quality control (QA/QC) across sites. The Tofts model (TM) and shutter-speed model (SSM) were used for pharmacokinetic (PK) analysis of the DCE data. Additionally, tumor region of interest (ROI)- vs. voxel-based analyses in combination with the use of VFA-measured R1,0 vs. fixed, literature-reported R1,0 were investigated to determine the optimal analysis approach. Results from 15 patients who completed the study are reported. Voxel-based PK analysis using fixed R1,0 was deemed the optimal approach, which allowed the inclusion of data from one vendor platform where VFA measurements produced ≥100% overestimation of R1,0. The semi-quantitative signal enhancement ratio (SER) and quantitative PK parameters outperformed the tumor longest diameter (LD) in the prediction of pathologic complete response (pCR) vs. non-pCR after the first NAC cycle, whereas K[trans] consistently provided more accurate predictions than both SER and LD after the first NAC cycle and at the NAC midpoint. Both TM and SSM K[trans] and kep were excellent predictors of response at the NAC midpoint with ROC AUC >0.90, while the SSM parameters (AUC ≥0.80) performed better than their TM counterparts (AUC <0.80) after the first NAC cycle. The initial experience of this ongoing study indicates the importance of QA/QC using a phantom and suggests that deploying voxel-based PK analysis using a fixed R1,0 may mitigate random errors from R1,0 measurements across platforms and potentially eliminate the need for B1 and VFA acquisitions in MC and MP trials.},
}

@article {pmid39678495,
year = {2024},
author = {Saini, J and Erickson, DPJ and Vander Stappen, F and Ruth, M and Cui, S and Gorman, V and Rossomme, S and Cao, N and Ford, EC and Meyer, J and Bloch, C and Wong, T and Grassberger, C and Rengan, R and Zeng, J and Schwarz, M},
title = {Commissioning a clinical proton pencil beam scanning beamline for pre-clinical ultra-high dose rate irradiations on a cyclotron-based system.},
journal = {Frontiers in oncology},
volume = {14},
number = {},
pages = {1460288},
pmid = {39678495},
issn = {2234-943X},
abstract = {BACKGROUND: This manuscript describes modifications to a pencil beam scanning (PBS) proton gantry that enables ultra-high dose rates (UHDR) irradiation, including treatment planning and validation.

METHODS: Beamline modifications consisted of opening the energy slits and setting the degrader to pass-through mode to maximize the dose rate. A range shifter was inserted upstream from the isocenter to enlarge the spot size and make it rotationally symmetric. We measured the beamline transport efficiency and investigated the variation in output due to the recombination of charge in the dose monitoring chamber. The output calibration was performed through a parallel plate chamber (PPC05), and an intercomparison was performed for various detectors. The pre-clinical field for mice irradiation consisted of different dose levels to deliver uniform doses in transmission mode. The field dose rates were determined through log files while scripting in TPS was used to estimate PBS dose rates. The survival experiments consisted of irradiating the full pelvis of the mice at UHDR and conventional dose rates.

RESULTS: The spot size was constant with beam current and had a sigma of 8.5 mm at the isocenter. The beam output increased by 35% at 720 nA compared to 5.6 nA, primarily due to recombination in the dose-monitoring ion chambers. The Faraday Cup and PPC05 agreed within 2%, while other detectors were within 3% of FC for dose rates <60 Gy/s. The pre-clinical fields' PBS dose rate is above 45 Gy/sec for all voxels within the target volume. The average and PBS dose rates decrease as field size increases and approaches 40 Gy/s for a field size of 7x7 cm[2]. All UHDR arms showed better survival than the corresponding conventional dose rate arms.

CONCLUSIONS: We successfully modified a clinical system to perform UHDR pre-clinical experiments. As part of our pre-clinical experiments, we observed the FLASH effect concerning mice survival.},
}

@article {pmid39651227,
year = {2024},
author = {Liu, B and Greenwood, NF and Bonzanini, JE and Motmaen, A and Sharp, J and Wang, C and Visani, GM and Vafeados, DK and Roullier, N and Nourmohammad, A and Garcia, KC and Baker, D},
title = {Design of high specificity binders for peptide-MHC-I complexes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {39651227},
issn = {2692-8205},
support = {R01 AI103867/AI/NIAID NIH HHS/United States ; R35 GM142795/GM/NIGMS NIH HHS/United States ; },
abstract = {Class I MHC molecules present peptides derived from intracellular antigens on the cell surface for immune surveillance, and specific targeting of these peptide-MHC (pMHC) complexes could have considerable utility for treating diseases. Such targeting is challenging as it requires readout of the few outward facing peptide antigen residues and the avoidance of extensive contacts with the MHC carrier which is present on almost all cells. Here we describe the use of deep learning-based protein design tools to denovo design small proteins that arc above the peptide binding groove of pMHC complexes and make extensive contacts with the peptide. We identify specific binders for ten target pMHCs which when displayed on yeast bind the on-target pMHC tetramer but not closely related peptides. For five targets, incorporation of designs into chimeric antigen receptors leads to T-cell activation by the cognate pMHC complexes well above the background from complexes with peptides derived from proteome. Our approach can generate high specificity binders starting from either experimental or predicted structures of the target pMHC complexes, and should be widely useful for both protein and cell based pMHC targeting.},
}

@article {pmid39649604,
year = {2024},
author = {Unsworth, M and Fabens, I and Setswe, G and Moyo, K and Pienaar, J and Makhele, C and Phohole, M and Igaba, N and Hlongwane, S and Sardini, M and Dong, T and Sharma, M and Tweya, H and Ndebele, F and Holec, M and Feldacker, C},
title = {What does it cost to expand two-way texting for post-operative follow-up? A cost analysis in routine voluntary medical male circumcision settings in South Africa.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {39649604},
support = {P30 AI027757/AI/NIAID NIH HHS/United States ; R01 NR019229/NR/NINR NIH HHS/United States ; },
abstract = {Up to 98% of adult voluntary medical male circumcision (VMMC) clients heal without adverse events (AEs) in South Africa and in the sub-Saharan Africa (SSA) region, yet all clients in South Africa (SA) are still required to attend in-person reviews, creating added work for providers and barriers for clients. A randomized controlled trial (RCT) using our fee-free, open-source, two-way texting (2wT) approach showed that males could independently monitor their healing with support from VMMC nurse-led telehealth and that 2wT was more cost-effective than routine visits for quality post-operative monitoring. The objectives of this costing activity were to assess the additive cost of 2wT vs. SoC during a stepped wedge design (SWD) expansion trial; costing an augmentation of 2wT with dedicated personnel during peak VMMC periods; and estimate the cost savings of 2wT from the payer perspective if scaled in routine VMMC settings. Data was collected from routine financial reports and complemented by previous RCT time-motion estimates. We conducted activity-based costing of SWD and peak season periods; sensitivity analysis estimated 2wT costs at scale. We included data from 6,842 males, with 2,586 (38%) opting for 2wT. 2wT participants attended an average of zero visits; SoC males had an average of 2 visits. Under 2wT, quality care markers improved and AE ascertainment increased while loss to follow-up (LTFU) decreased. Given a VMMC population of 10,000 adults, scenario analysis suggests that: 1) 2wT becomes cost neutral with 45% 2wT enrollment; 2) 2wT saves $0.29/client with 60% 2wT enrollment; and 3) 2wT saves $0.46/client with 80% 2wT enrollment. When implemented at scale, 2wT appears to significantly reduce costs to the healthcare system while improving the quality of post-operative care and requiring no additional client costs. 2wT should be expanded for eligible males across VMMC and other post-operative contexts in South Africa.},
}

@article {pmid39656951,
year = {2024},
author = {Abdou, Y and Barlow, WE and Gralow, JR and Meric-Bernstam, F and Albain, KS and Hayes, DF and Lin, NU and Perez, EA and Goldstein, LJ and Chia, SKL and Dhesy-Thind, S and Rastogi, P and Alba, E and Delaloge, S and Schott, AF and Shak, S and Sharma, P and Lew, DL and Miao, J and Unger, JM and Tripathy, D and Hortobagyi, GN and Pusztai, L and Kalinsky, K},
title = {Race and Clinical Outcomes in Hormone Receptor-Positive, HER2-Negative, Node-Positive Breast Cancer in the Randomized RxPONDER Trial.},
journal = {Journal of the National Cancer Institute},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnci/djae314},
pmid = {39656951},
issn = {1460-2105},
abstract = {BACKGROUND: The phase III RxPONDER trial has impacted treatment for node-positive(1-3), hormone receptor-positive, HER2-negative breast cancer with 21-gene recurrence score (RS) ≤ 25. We investigated how these findings apply to different racial and ethnic groups within the trial.

METHODS: The trial randomized women to endocrine therapy (ET) or to chemotherapy plus ET. The primary clinical outcome was invasive disease-free survival (IDFS) with distant relapse-free survival (DRFS) as a secondary outcome. Multivariable Cox models were used to evaluate the association between race/ethnicity and survival outcomes, adjusting for clinicopathologic characteristics, RS, and treatment.

RESULTS: A total of 4,048 women with self-reported race/ethnicity were included: Hispanic (15.1%), non-Hispanic Black (NHB)(6.1%), Native American/Pacific Islander (0.8%), Asian (8.0%), and non-Hispanic White (NHW)(70%). No differences in RS distribution, tumor size, or number of positive nodes were observed by race/ethnicity. Relative to NHWs, IDFS was worse for NHBs (5-year IDFS 91.6% vs 87.1%, HR = 1.37; 95% CI 1.03-1.81) and better for Asians (91.6% vs 93.9%, HR = 0.64; 95% CI 0.46-0.91). Relative to NHW, DRFS was worse for NHBs (5-year DRFS 95.8% vs 91.0%, HR = 1.65; 95% CI 1.17-2.32) and better for Asians (95.8% vs 96.7%, HR = 0.59; 95% CI 0.37-0.95). Adjusting for clinical characteristics, particularly body mass index, diminished the effect of race on outcomes. Chemotherapy treatment efficacy did not differ by race/ethnicity.

CONCLUSIONS: NHB women had worse clinical outcomes compared to NHWs in the RxPONDER trial despite similar RS and comparable treatment. Our study emphasizes the persistent racial disparities in breast cancer outcomes while highlighting complex interactions among contributing factors.

TRIAL REGISTRATION: ClinicalTrials.gov: NCT01272037.},
}

@article {pmid39674548,
year = {2024},
author = {Duarte, FB and Garcia, YDO and Hamerschlak, N and Funke, VAM and Moreira, MCR and Paz, AA and Filho, JS and Astigarraga, CC and da Silva, RL and de Molla, VC and Silvério, A and Rocha, VG and Feliciano, JVP and Barros, GMN and Colturato, VAR and Nabhan, SK and Farias, JSH and Maia, ACA and Atalla, Â and Chiattone, R and Macedo, MCMA and Aranha, MAF and Zogbi, YAN and Lener, D and Soares, RDA and Scheinberg, P and Calixto, RF and Teixeira, GM and Colella, MP and Rodrigues, CA and Simione, AJ and da Silva, CC and Martin, PJ and Flowers, ME},
title = {Allogeneic Hematopoietic Cell Transplantation in Elderly Patients in a Latin American Country: Analysis of 11 Years of Data from the Brazilian Registry SBTMO/CIBMTR.},
journal = {Transplantation and cellular therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jtct.2024.12.003},
pmid = {39674548},
issn = {2666-6367},
abstract = {This study analyzed recent changes in the utilization of allogeneic HCT for treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and myeloproliferative diseases (MPD) and the survival of HCT recipients ≥60 years of age in Brazil. This retrospective registry study included patients who received a first allogeneic HCT from any donor between 2012 and 2023. Of the 6657 patients, 444 (7%) were 60 years of age or older who received grafts from HLA-matched related (42%) or unrelated (20%) donors or HLA-haploidentical donors (32%). The proportion of HCT recipients 60 years of age or older increased gradually from 3.2% in 2012 to 16% in 2023 mostly due to the increased use of HLA-haploidentical donors since 2018. Overall survival (OS) at day 100 was 77%, and estimated OS at 12 months was 53% (95% CI, 48-58). OS at 12-months was higher for transplants during 2015-2017 (58%) and 2018-2020 (68%) compared to 2012-2014 (45%), but it did not differ for those during 2021-2023 (49%). Mortality with HLA-haploidentical donors (HR 2.35; 95%CI; 1.65-3.34 [p <0.001]) and cord blood donors (HR 4.68; 95%CI,1.29-16.9 [p= 0.01]) was higher than with HLA-matched related donors. Mortality was lower for transplants during the 2015-2020 period (HR 0.57; 95%CI, 0.34-0.96 [0.037]) than for those during 2012-2014.This study revealed a gradual increase in the use of allogeneic HCT in individuals aged 60 years and older in Brazil. While use of haploidentical donor has increased worldwide, its association with increased mortality in elderly population deserves caution.},
}

@article {pmid39673790,
year = {2024},
author = {Chiu, AP and Gowda, GAN and Zhu, W and Arendt-Nielsen, L and Raftery, D and Curatolo, M},
title = {Cerebrospinal Fluid Metabolomics of Pain in Patients with Spinal Muscle Atrophy.},
journal = {Pain medicine (Malden, Mass.)},
volume = {},
number = {},
pages = {},
doi = {10.1093/pm/pnae129},
pmid = {39673790},
issn = {1526-4637},
}

@article {pmid39673461,
year = {2024},
author = {Macinnis, RJ and Jenkins, MA and Milne, RL and John, EM and Daly, MB and Andrulis, IL and Colonna, SV and Phillips, KA and , and Le Marchand, L and Newcomb, PA and Phipps, A and Schmit, S and Macrae, F and Buchanan, D and Gallinger, S and Pai, RK and Samadder, NJ and Giles, GG and Southey, MC and Hopper, JL and Terry, MB},
title = {Menopausal hormone therapy: assessing associations with breast and colorectal cancers by familial risk.},
journal = {JNCI cancer spectrum},
volume = {},
number = {},
pages = {},
doi = {10.1093/jncics/pkae121},
pmid = {39673461},
issn = {2515-5091},
abstract = {Menopausal hormone therapy (MHT) users are at increased breast cancer (BC) risk and decreased colorectal cancer (CRC) risk compared with never users, but these opposing associations might differ by familial risk of BC and CRC. We harmonized data from three cohorts and generated separate BC and CRC familial risk scores (FRS) based on cancer family history. We defined moderate/strong family history as FRS ≥ 0.4, where 0.4 was equivalent to a 50-year-old woman with one parent diagnosed with either cancer at age 55 years. Of 24,486 women, 1,243 and 405 were diagnosed with incident BC and CRC, respectively. For BC, MHT hazard ratios (HRs) were 1.27 (95%CI = 1.11-1.45) for FRSBC<0.4, 1.01 (95%CI = 0.82-1.25) for FRSBC≥0.4 (P-difference = 0.08). For CRC, MHT HRs were 0.63 (95%CI = 0.50-0.78) for FRSCRC<0.4, 1.21 (95%CI = 0.73-2.00) for FRSCRC≥0.4 (P-difference = 0.03). Associations with MHT that apply to the general population might not hold for women at moderate/strong familial risk of these cancers.},
}

@article {pmid39672162,
year = {2024},
author = {Pasquesi, GIM and Allen, H and Ivancevic, A and Barbachano-Guerrero, A and Joyner, O and Guo, K and Simpson, DM and Gapin, K and Horton, I and Nguyen, LL and Yang, Q and Warren, CJ and Florea, LD and Bitler, BG and Santiago, ML and Sawyer, SL and Chuong, EB},
title = {Regulation of human interferon signaling by transposon exonization.},
journal = {Cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.cell.2024.11.016},
pmid = {39672162},
issn = {1097-4172},
abstract = {Innate immune signaling is essential for clearing pathogens and damaged cells and must be tightly regulated to avoid excessive inflammation or autoimmunity. Here, we found that the alternative splicing of exons derived from transposable elements is a key mechanism controlling immune signaling in human cells. By analyzing long-read transcriptome datasets, we identified numerous transposon exonization events predicted to generate functional protein variants of immune genes, including the type I interferon receptor IFNAR2. We demonstrated that the transposon-derived isoform of IFNAR2 is more highly expressed than the canonical isoform in almost all tissues and functions as a decoy receptor that potently inhibits interferon signaling, including in cells infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our findings uncover a primate-specific axis controlling interferon signaling and show how a transposon exonization event can be co-opted for immune regulation.},
}

@article {pmid39672634,
year = {2025},
author = {Tseng, YD and Mikhaeel, NG},
title = {The seemingly contradictory roles of radiation as focal to systemic therapy in hematologic malignancies.},
journal = {Seminars in radiation oncology},
volume = {35},
number = {1},
pages = {1-3},
doi = {10.1016/j.semradonc.2024.12.001},
pmid = {39672634},
issn = {1532-9461},
}

@article {pmid39671534,
year = {2024},
author = {Shroff, RT and King, G and Colby, S and Scott, AJ and Borad, MJ and Goff, L and Matin, K and Mahipal, A and Kalyan, A and Javle, MM and El Dika, I and Tan, B and Cheema, P and Patel, A and Iyer, R and Kelley, RK and Thumar, J and El-Khoueiry, A and Guthrie, KA and Chiorean, EG and Hochster, H and Philip, PA},
title = {SWOG S1815: A Phase III Randomized Trial of Gemcitabine, Cisplatin, and Nab-Paclitaxel Versus Gemcitabine and Cisplatin in Newly Diagnosed, Advanced Biliary Tract Cancers.},
journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
volume = {},
number = {},
pages = {JCO2401383},
doi = {10.1200/JCO-24-01383},
pmid = {39671534},
issn = {1527-7755},
abstract = {PURPOSE: SWOG S1815 was a randomized, open label phase III trial, evaluating gemcitabine, nab-paclitaxel, and cisplatin (GAP) versus gemcitabine and cisplatin (GC) in patients with newly diagnosed advanced biliary tract cancers (BTCs).

METHODS: Patients with newly diagnosed locally advanced unresectable or metastatic BTC, including intrahepatic cholangiocarcinoma (ICC) and extrahepatic cholangiocarcinoma (ECC) and gallbladder carcinoma (GBC), were randomly assigned 2:1 to either GAP (gemcitabine 800 mg/m[2], cisplatin 25 mg/m[2], and nab-paclitaxel 100 mg/m[2] intravenously once per day on days 1 and 8 of a 21-day cycle) or GC (gemcitabine 1,000 mg/m[2] and cisplatin 25 mg/m[2] intravenously once per day on days 1 and 8 of a 21-day cycle).

RESULTS: Among 452 randomly assigned participants, 441 were eligible and analyzable, 67% with ICC, 16% with GBC, and 17% with ECC. There was no significant difference in overall survival (OS) between GAP versus GC. Median OS with GAP was 14.0 months (95% CI, 12.4 to 16.1) and 13.6 months with GC (95% CI, 9.7 to 16.6); hazard ratio (HR), 0.91 (95% CI, 0.72 to 1.14); P = .41. Median progression-free survival (PFS) was similar between groups with median PFS for GAP being 7.5 months (95% CI, 6.4 to 8.5) versus 6.3 months for GC (95% CI, 4.4 to 8.2); HR, 0.89 (95% CI, 0.71 to 1.12); P = .32. In exploratory subset analyses, the OS and PFS benefits of GAP versus GC treatment were greater in locally advanced disease compared with metastatic disease, although not statistically significant (interaction P = .14 for OS and P = .17 for PFS). Moreover, GAP versus GC showed greater improvement in PFS among participants with GBC than those with ICC or ECC (interaction P = .01), but not OS (interaction P = .28).

CONCLUSION: The addition of a taxane in the GAP regimen to the standard gemcitabine-cisplatin regimen did not improve OS in newly diagnosed BTC. More toxicity was encountered with GAP versus GC.},
}

@article {pmid39671174,
year = {2024},
author = {Wilson, GJ and Church, LWP and Kelley, CF and Robinson, ST and Lu, Y and Furch, BD and Fong, Y and Paez, CA and Yacovone, M and Jacobsen, T and Maughan, M and Martik, D and Heptinstall, JR and Zhang, L and Montefiori, DC and Tomaras, GD and Kublin, JG and Corey, L},
title = {HVTN 123: A Phase 1, Randomized Trial Comparing Safety and Immunogenicity of CH505TF gp120 Produced by Stably and Transiently Transfected Cell Lines.},
journal = {The Journal of infectious diseases},
volume = {},
number = {},
pages = {},
doi = {10.1093/infdis/jiae558},
pmid = {39671174},
issn = {1537-6613},
support = {//National Institute of Allergy and Infectious Diseases/ ; UM1 AI068614/NH/NIH HHS/United States ; },
abstract = {Utilizing transiently transfected cell lines could significantly reduce manufacturing timelines for protein subunit vaccines. This trial compared safety and immunogenicity of human immunodeficiency virus (HIV) envelope CH505TF gp120 vaccines produced by upstream stable and transient transfection (each admixed with GLA-SE adjuvant, a TL4 agonist). Both vaccines were safe and well tolerated. Serum IgG binding antibody response rates 2 weeks after final injection were 92% in the stable group and 93% in the transient group (P = 1.000). Neutralization response rates against CH505.w4.3 were also equivalent (92% vs 100%, P = .291). These data support transient transfection as an available tool for accelerating HIV vaccine testing and iteration. Clinical Trials Registration. NCT03856996.},
}

@article {pmid39669607,
year = {2024},
author = {Tumulak, MJR and Padilla, CD and Ongchangco, JCE and Laurino, MY and Lagarde, JBB and Regalado, ES and Legaspi, AV and Ventura, ER},
title = {Living with a child with MSUD: Psychosocial issues of Filipino parents with a child with maple syrup urine disease.},
journal = {Genetics in medicine open},
volume = {2},
number = {},
pages = {101847},
pmid = {39669607},
issn = {2949-7744},
abstract = {PURPOSE: Maple syrup urine disease (MSUD) is a common inborn error of metabolism diagnosed in the Philippines. A family may experience stress, anxiety, sorrow, or feelings of helplessness when a child is diagnosed to have a genetic disorder, which can lead to chronic care and disability. This study aims to explore the psychosocial issues experienced by Filipino parents with children having MSUD.

METHODS: This is a descriptive and qualitative study. One-to-one interviews using a semi-structured set of questions were done between the months of November 2015 to March 2016. A total of 12 parents were interviewed. Thematic analysis was used.

RESULTS: The diagnosis of MSUD in a child is, indeed, a stressful event for the family. Parents experienced fear, confusion, and hurt, among other emotions. Having a child with MSUD had a negative impact on their families, especially in terms of financial burden, dietary restriction, and marital conflicts leading to separation. However, some parents reported positive effects, such as increased confidence in one's abilities to care for the affected child and closer relationships among family members.

CONCLUSION: A diagnosis of MSUD on the child places considerable caregiver burden on the parents. Findings have important implications for genetic counselors.},
}

@article {pmid39669077,
year = {2024},
author = {Schnuck, JO and Chauhan, SSB and Sham, JG},
title = {Surrogate endpoints in clinical trials: when is good...good enough?.},
journal = {Hepatobiliary surgery and nutrition},
volume = {13},
number = {6},
pages = {1062-1064},
pmid = {39669077},
issn = {2304-3881},
}

@article {pmid39668236,
year = {2024},
author = {Orvain, C and Milano, F and Rodríguez-Arbolí, E and Othus, M and Petersdorf, EW and Sandmaier, BM and Appelbaum, FR and Walter, RB},
title = {Relationship between donor source, pre-transplant measurable residual disease, and outcome after allografting for adults with acute myeloid leukemia.},
journal = {Leukemia},
volume = {},
number = {},
pages = {},
pmid = {39668236},
issn = {1476-5551},
abstract = {Lack of HLA-matched related/unrelated donor remains a barrier to allogeneic hematopoietic cell transplantation (HCT) for adult acute myeloid leukemia (AML), with ongoing uncertainty about optimal donor type if more than one alternative donor is available. To assess the relationship between donor type, pre-HCT measurable residual disease (MRD), and post-HCT outcomes, we retrospectively analyzed 1265 myelodysplastic neoplasm (MDS)/AML and AML patients allografted in first or second remission with an HLA-matched sibling (MSD) or unrelated donor (MUD), HLA-mismatched unrelated donor (MMD), an HLA-haploidentical donor, or umbilical cord blood (UCB) at a single institution. Relapse risk was non-significantly higher after HLA-haploidentical and lower after UCB HCT. Non-relapse mortality (NRM) was significantly higher in patients undergoing MMD HCT, HLA-haploidentical HCT, and UCB, translating into significantly lower relapse-free survival (RFS) and overall survival for MMD and HLA-haploidentical HCT. There was a significant interaction between conditioning intensity and post-HCT outcomes for UCB HCT with better RFS for UCB HCT after MAC but higher NRM after non-MAC. In patients with pre-HCT MRD receiving MAC, relapse risk was significantly lower and RFS higher in those who underwent UCB HCT in comparison to MSD/MUD. Together, UCB HCT is a valuable alternative for MAC HCT, particularly in patients with pre-HCT MRD.},
}

@article {pmid39667756,
year = {2024},
author = {Biernacki, MA and Bleakley, M},
title = {Clinical trials, challenges, and changes in tcr-based therapeutics for hematologic malignancies.},
journal = {Expert review of hematology},
volume = {},
number = {},
pages = {},
doi = {10.1080/17474086.2024.2441962},
pmid = {39667756},
issn = {1747-4094},
abstract = {INTRODUCTION: T cells engineered to express antigen-specific T cell receptors (TCR; TCR-T) are a promising class of immunotherapeutic for patients with hematologic malignancies. Like chimeric antigen receptor-engineered T cells (CAR-T), TCR-T are cell products with defined specificity and composition. Unlike CAR-T, TCR-T can recognize targets arising both from intracellular and cell surface proteins and leverage the sensitivity of natural TCR signaling machinery. A growing number of TCR-T targeting various antigens in different hematologic malignancies are in early-phase clinical trials, and more are in preclinical development.

AREAS COVERED: This review covers results from early-phase TCR-T clinical trials for hematologic malignancies. Challenges in the field are reviewed, including identifying optimal targets, engaging CD4[+] help for CD8[+] T cells, and overcoming tumor-induced suppression; recent innovations to overcome these challenges are also highlighted.

EXPERT OPINION: In the future, TCR-T's promise for hematologic malignancies will be borne out in later-phase clinical trials and approvals for clinical use. Improved antigen discovery methods will help build the toolbox of targets needed for broadly applicable TCR-T. Rationally designed TCR-T modifications including incorporation of accessory receptors and gene editing will enhance TCR-T function. New hybrid receptors combining features of TCR and CAR will enter the clinic.},
}

@article {pmid39667379,
year = {2024},
author = {Edupuganti, S and Hurt, CB and Stephenson, KE and Huang, Y and Paez, CA and Yu, C and Yen, C and Hanscom, B and He, Z and Miner, MD and Gamble, T and Heptinstall, J and Seaton, KE and Domin, E and Lin, BC and McKee, K and Doria-Rose, N and Regenold, S and Spiegel, H and Anderson, M and McClosky, N and Zhang, L and Piwowar-Manning, E and Ackerman, ME and Pensiero, M and Dye, BJ and Landovitz, RJ and Mayer, K and Siegel, M and Sobieszczyk, M and Walsh, SR and Gama, L and Barouch, DH and Montefiori, DC and Tomaras, GD and , },
title = {Safety, tolerability, pharmacokinetics, and neutralisation activities of the anti-HIV-1 monoclonal antibody PGT121.414.LS administered alone and in combination with VRC07-523LS in adults without HIV in the USA (HVTN 136/HPTN 092): a first-in-human, open-label, randomised controlled phase 1 trial.},
journal = {The lancet. HIV},
volume = {},
number = {},
pages = {},
doi = {10.1016/S2352-3018(24)00247-9},
pmid = {39667379},
issn = {2352-3018},
abstract = {BACKGROUND: Multiple broadly neutralising monoclonal antibodies (mAbs) are in development for HIV-1 prevention. The aim of this trial was to test the PGT121.414.LS and VRC07-523LS mAbs for safety and pharmacokinetics in adults.

METHODS: In this first-in-human phase 1 trial (HVTN 136/HPTN 092), adults without HIV were enrolled at six university-affiliated clinical research sites in the USA. Part A evaluated escalating single intravenous doses or subcutaneous infusion of PGT121.414.LS, in four groups: 3 mg/kg intravenous (treatment group 1; n=3), 10 mg/kg intravenous (treatment group 2; n=4), 30 mg/kg intravenous (treatment group 3; n=3), and 5 mg/kg subcutaneous (treatment group 4; n=3). Part B evaluated repeated sequential intravenous administrations of 20 mg/kg PGT121.414.LS plus 20 mg/kg VRC07-523LS (treatment group 5; n=10) and sequential subcutaneous administrations of 5 mg/kg PGT121.414.LS plus 5 mg/kg VRC07-523LS (treatment group 6; n=10) on days 0, 112, and 224. Participants in treatment groups 1 and 2 were enrolled sequentially, with participants enrolled and randomly assigned to treatment groups 3 and 4 after a review of safety data. Participants in treatment groups 5 and 6 were randomly assigned in blocks after a review of safety data from treatment groups 1-4. The primary endpoints were safety and tolerability of mAbs, serum concentrations and pharmacokinetics of mAbs, and serum neutralising activity, assessed in participants who received all scheduled product administrations. Serum concentrations of each mAb were measured via a multiplex assay, and neutralisation activity against multiple HIV viruses was measured via the TZM-bl assay. Serum concentrations were estimated via an open, two-compartment model with first-order elimination from the central compartment. This study was registered with ClinicalTrials.gov (NCT04212091) and has been completed.

FINDINGS: Between Nov 10, 2020, and Oct 5, 2021, we enrolled 33 participants without HIV: median age was 31 years (range 22-48); 19 were assigned female sex at birth and 11 were assigned male sex at birth. Three participants and four participants were sequentially assigned to treatment groups 1 and 2, respectively, and, after safety review, six participants were randomly assigned to treatment groups 3 (n=3) and 4 (n=3); after safety review, 20 participants were randomly assigned to treatment groups 5 (n=10) and 6 (n=10). Intravenous and subcutaneous infusions were safe and well tolerated, without serious adverse events or dose-limiting toxicities. Dose escalation of PGT121.414.LS from 3 mg/kg to 30 mg/kg (intravenous) resulted in a dose-proportional increase in serum concentration of PGT121.414.LS, whether administered alone or in combination with VRC07-523LS. The estimated elimination half-life of PGT121.414.LS was 71 days (95% CI 66-75), three times that of its parental form, PGT121. The estimated subcutaneous (vs intravenous) bioavailability of PGT121.414.LS was 86·1% (95% CI 64·0-95·5). Neutralisation activities were greater in the higher-dose and dual combination intravenous groups than in the subcutaneous administration groups.

INTERPRETATION: These findings support further evaluation of PGT121.414.LS in combination with other mAbs for HIV-1 prevention.

FUNDING: US National Institute of Allergy and Infectious Diseases and US National Institutes of Health.},
}

@article {pmid39668099,
year = {2024},
author = {Robichaux, K and Billings, T and Termini, CM},
title = {Inventories invite independence.},
journal = {Trends in biochemical sciences},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.tibs.2024.11.003},
pmid = {39668099},
issn = {0968-0004},
abstract = {In this piece, we use an antibody inventory system to exemplify the potential benefits of laboratory organization in research environments. We highlight how inventories can support resource accessibility and strengthen a sense of independence for scientists, especially those new to research environments.},
}

@article {pmid39666929,
year = {2024},
author = {Gien, LT and Song, Z and Poklepovic, A and Collisson, EA and Zwiebel, JA and Gray, RJ and Wang, V and McShane, LM and Rubinstein, LV and Patton, DR and Williams, PM and Hamilton, SR and Tricoli, JV and Conley, BA and Arteaga, CL and Harris, LN and O'Dwyer, PJ and Chen, AP and Flaherty, KT},
title = {Phase II Study of Sunitinib in Tumors With c-KIT Mutations: Results From the NCI MATCH ECOG-ACRIN Trial (EAY131) Subprotocol V.},
journal = {JCO precision oncology},
volume = {8},
number = {},
pages = {e2400514},
doi = {10.1200/PO-24-00514},
pmid = {39666929},
issn = {2473-4284},
mesh = {Humans ; *Sunitinib/therapeutic use ; Middle Aged ; *Proto-Oncogene Proteins c-kit/genetics ; Male ; Female ; Adult ; Aged ; *Mutation ; *Antineoplastic Agents/therapeutic use/adverse effects ; Neoplasms/drug therapy/genetics ; },
abstract = {PURPOSE: The NCI-MATCH study is a tumor-agnostic platform trial enrolling patients to targeted therapies on the basis of genomic alterations. Subprotocol V investigated sunitinib in patients with tumors harboring c-KIT mutations.

METHODS: EAY131-V, is an open-label, single-arm, phase II study. Eligible patients had malignancies containing somatic c-KIT mutation on exons 9, 11, 13, or 14. Exclusions were mutations on exons 17 and 18, gastrointestinal stromal tumors, renal cell carcinoma, and pancreatic neuroendocrine tumors. Patients received sunitinib 50 mg orally once daily for 4 weeks with 2-week rest per cycle, until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR); secondary end points were progression-free survival (PFS) at 6 months, PFS, overall survival, and toxicities.

RESULTS: Between November 1, 2016, and May 21, 2020, 10 patients were enrolled and nine were eligible and started treatment. The median age was 62 years (range, 30-76), 77.8% received two previous lines of systemic therapy, and 22.2% received >3 lines. The most common histology was melanoma (44%) and then squamous cell carcinoma of the lung or thymus (33%). There were two partial responses with an ORR of 22.2% (90% CI, 4.1 to 55) and stable disease in 44%. All patients demonstrated tumor shrinkage of target lesions. The estimated 6-month PFS was 33.3% (90% CI, 15.4 to 72.4). Grade 3-4 toxicities occurred in five patients (55.6%). This arm was closed in 2022 on the basis of low accrual. Prevalence of eligible c-KIT mutations after screening 5,540 patients was 0.45%.

CONCLUSION: Sunitinib for c-KIT mutations did not meet the primary end point, but in this small sample size, a potential signal cannot be ruled out. Rate of eligible c-KIT mutations was low, affecting accrual to this arm.},
}

Humans
*Sunitinib/therapeutic use
Middle Aged
*Proto-Oncogene Proteins c-kit/genetics
Male
Female
Adult
Aged
*Mutation
*Antineoplastic Agents/therapeutic use/adverse effects
Neoplasms/drug therapy/genetics

@article {pmid39666464,
year = {2024},
author = {Landy, R and Katki, HA and Huang, WY and Wang, D and Thomas, M and Qu, F and Freedman, ND and Loftfield, E and Shi, J and Peters, U and Hsu, L and Schoen, RE and Berndt, SI},
title = {Evaluating the Use of Environmental and Polygenic Risk Scores to Inform Colorectal Cancer Risk-Based Surveillance Intervals.},
journal = {Clinical and translational gastroenterology},
volume = {},
number = {},
pages = {},
doi = {10.14309/ctg.0000000000000782},
pmid = {39666464},
issn = {2155-384X},
support = {//Division of Cancer Epidemiology and Genetics, National Cancer Institute/ ; },
abstract = {INTRODUCTION: United States Multi-Society Task Force colonoscopy surveillance intervals are based solely on adenoma characteristics, without accounting for other risk factors. We investigated whether a risk model including demographic, environmental, and genetic risk factors could individualize surveillance intervals under an "equal management of equal risks" framework.

METHODS: Using 14,069 individuals from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial who had a diagnostic colonoscopy following an abnormal flexible sigmoidoscopy, we modeled the risk of colorectal cancer, considering the diagnostic colonoscopy finding, baseline risk factors (e.g., age and sex), 19 lifestyle and environmental risk factors, and a polygenic risk score for colorectal cancer. Ten-year absolute cancer risks for each diagnostic colonoscopy finding (advanced adenomas [N = 2,446], ≥3 non-advanced adenomas [N = 483], 1-2 non-advanced adenomas [N = 4,400], and no adenoma [N = 7,183]) were used as implicit risk thresholds for recommended surveillance intervals.

RESULTS: The area under the curve for the model including colonoscopy findings, baseline characteristics, and polygenic risk score was 0.658. Applying the equal management of equal risks framework, 28.2% of individuals with no adenoma and 42.7% of those with 1-2 non-advanced adenomas would be considered high risk and assigned a significantly shorter surveillance interval than currently recommended. Among individuals who developed cancer within 10 years, 52.4% with no adenoma and 48.3% with 1-2 non-advanced adenomas would have been considered high risk and assigned a shorter surveillance interval.

DISCUSSION: Using a personalized risk-based model has the potential to identify individuals with no adenoma or 1-2 non-advanced adenomas, who are higher risk and may benefit from shorter surveillance intervals.},
}

@article {pmid39666350,
year = {2024},
author = {Goss, LB and Liu, M and Zheng, Y and Guo, B and Conti, DV and Haiman, CA and Kachuri, L and Catalona, WJ and Witte, JS and Lin, DW and Newcomb, LF and Darst, BF},
title = {Polygenic Risk Score and Upgrading in Patients With Prostate Cancer Receiving Active Surveillance.},
journal = {JAMA oncology},
volume = {},
number = {},
pages = {},
doi = {10.1001/jamaoncol.2024.5398},
pmid = {39666350},
issn = {2374-2445},
abstract = {IMPORTANCE: Active surveillance is the preferred management strategy for patients with low- or favorable intermediate-risk prostate cancer (PCa); however, frequent health care visits can be costly and burdensome to patients. Identifying patients who may benefit from intensive vs passive surveillance could reduce these burdens.

OBJECTIVE: To investigate associations between a polygenic risk score (PRS) and risk of upgrading and other prostate tumor features in patients receiving active surveillance.

This prospective multicenter cohort study across 10 US sites included 1220 patients from the Canary Prostate Active Surveillance Study (PASS) enrolled from July 2008 to November 2017, with follow-up (median, 5.3 years) through August 2022. Participants were those with clinically localized PCa (cT1-T2) receiving active surveillance. Analyses took place from January 2023 to April 2024.

EXPOSURE: Multi-ancestry PRS of 451 PCa risk variants (PRS-451) and 400 PCa risk variants (PRS-400) after excluding prostate-specific antigen (PSA)-associated variants.

MAIN OUTCOMES AND MEASURES: The primary outcome was PCa upgrading (any Gleason grade increase) vs no upgrading. Secondary outcomes included prostate volume, PSA, PSA density, percentage of biopsy cores with cancer, and Gleason grade group at diagnosis.

RESULTS: The median (IQR) age at diagnosis of the 1220 patients receiving active surveillance was 63 (58-67) years. During follow-up, 470 patients upgraded; the 2- and 5-year risks of upgrading were 17.7% (95% CI, 15.5%-19.9%) and 33.3% (95% CI, 30.5%-36.3%), respectively. Each 1-SD unit increase in PRS-451 was associated with 23% increased hazard of upgrading (95% CI, 1.11-1.35; P < .001), whereas PRS-400 was associated with 27% increased hazard (95% CI, 1.15-1.39; P < .001) at any point in time during follow-up. Except for PSA, associations with remaining outcomes were similar or stronger using PRS-400. Higher PRS-400 was associated with smaller prostate volume, a higher percentage of biopsy cores with cancer, and higher PSA density. A model with clinical risk factors had a C-index of 0.64 (95% CI, 0.62-0.67); adding PRS-400 led to a C-index of 0.65 (95% CI, 0.63-0.68).

CONCLUSIONS AND RELEVANCE: In this cohort study, among patients receiving active surveillance, high PRS was associated with risk of upgrading and possibly tumor multifocality. Excluding PSA variants from the PRS revealed an association with smaller prostate size, which has been previously associated with more aggressive tumors. Although PRS may inform active surveillance, it is yet to be seen whether they improve clinical decisions.},
}

@article {pmid39660025,
year = {2024},
author = {Lubwama, M and Holte, SE and Zhang, Y and Mubiru, KR and Katende, G and Orem, J and Kateete, DP and Bwanga, F and Phipps, W},
title = {Etiology, Risk Factors, and Outcomes of Bacteremia in Patients With Hematologic Malignancies and Febrile Neutropenia in Uganda.},
journal = {Open forum infectious diseases},
volume = {11},
number = {12},
pages = {ofae682},
doi = {10.1093/ofid/ofae682},
pmid = {39660025},
issn = {2328-8957},
abstract = {BACKGROUND: We determined the etiology, risk factors, and outcomes associated with bacteremia in patients with hematologic malignancies and febrile neutropenia (FN) at the Uganda Cancer Institute (UCI).

METHODS: UCI adult and pediatric inpatients with hematologic malignancies and FN were prospectively enrolled and followed up to determine 30-day mortality. Blood drawn from participants with FN was cultured in the BACTEC 9120 blood culture system. Antimicrobial susceptibility testing was performed with the disk diffusion method on identified bacteria. Logistic regression and Cox proportional hazards regression were applied to estimate associations between participant characteristics and FN, bacteremia, and mortality.

RESULTS: Of 495 participants, the majority (n = 306 [62%]) were male. Median age was 23 years (interquartile range, 11-42 years). Of the 132 participants who experienced FN, 43 (33%) had bacteremia. Participants with younger age (odds ratio [OR], 0.98; P = .05), severe neutropenia (OR, 2.9; P = .01), hypotension (OR, 2.46; P = .04), mucositis (OR, 2.77; P = .01), and receipt of chemotherapy (OR, 2.25; P = .03) were more likely to have bacteremia. Fifty (78%) bacteria isolated were gram negative. Escherichia coli (n = 25 [50%]) was predominant. Thirty-seven of 43 (86%) episodes were caused by multidrug-resistant (MDR) bacteria. Thirty-day overall survival for participants with bacteremia was significantly lower than that for participants with no bacteremia (P = .05). MDR bacteremia (hazard ratio, 1.84; P = .05) was associated with increased risk of death.

CONCLUSIONS: Bacteremia was frequent in patients with hematologic cancer and FN and was associated with poor survival. MDR bacteria were the main cause of bacteremia and mortality. There is a need for robust infection control and antimicrobial stewardship programs in cancer centers in sub-Saharan Africa.},
}

@article {pmid39653676,
year = {2024},
author = {Gati Mirembe, B and Donnell, D and Krows, M and Zwane, Z and Bukusi, E and Panchia, R and Louw, C and Mwelase, N and Selepe, P and Senne, M and Naidoo, L and Chihana, R and Kasaro, M and Nuwagaba-Biribonwoha, H and Kotze, P and Gill, K and MacDonald, P and vanHeerden, A and Bosman, S and Jaggernath, M and du Preez, P and Ward, A and Peters, RPH and Delany-Moretlwe, S and Peacock, S and Johnson, R and Caucutt, J and Morrison, S and Wang, G and Gandhi, M and Velloza, J and Heffron, R and Celum, C and , },
title = {High recent PrEP adherence with point-of-care urine tenofovir testing and adherence counselling among young African women: results from the INSIGHT cohort.},
journal = {Journal of the International AIDS Society},
volume = {27},
number = {12},
pages = {e26389},
doi = {10.1002/jia2.26389},
pmid = {39653676},
issn = {1758-2652},
support = {INV-004743/GATES/Bill & Melinda Gates Foundation/United States ; },
mesh = {Humans ; Female ; *HIV Infections/prevention & control/drug therapy ; *Pre-Exposure Prophylaxis/methods/statistics & numerical data ; *Tenofovir/therapeutic use/urine ; Adolescent ; Young Adult ; *Medication Adherence/statistics & numerical data ; Adult ; *Anti-HIV Agents/therapeutic use ; *Counseling ; Point-of-Care Testing ; Point-of-Care Systems ; Cohort Studies ; },
abstract = {INTRODUCTION: Adolescent girls and young women (AGYW) account for two-thirds of new HIV infections in Africa. African AGYW have had high uptake of oral HIV pre-exposure prophylaxis (PrEP) but low adherence, which might be improved by point-of-care adherence monitoring with tailored counselling.

METHODS: From August 2022 to July 2023, we conducted a PrEP demonstration project with sexually active AGYW ages 16-30 years from 20 sites in South Africa, Eswatini, Kenya, Malawi, Uganda and Zambia. Participants were offered oral tenofovir-based PrEP at enrolment and followed up at 1, 3 and 6 months. PrEP adherence was assessed by a point-of-care qualitative lateral flow urine tenofovir (TFV) assay indicating PrEP use in the prior 4 days, which accompanied real-time adherence counselling that incorporated urine TFV results when testing was available (70.8% of month 1, 35.3% of month 3 and 83.9% of month 6 visits). We estimated overall adherence, correcting for missing test results, and analysed the association of having received urine TFV results at month 1 or 3 with subsequent urine TFV test positivity, using modified Poisson regression.

RESULTS: Of the 3087 AGYW enrolled, the median age was 24 years (interquartile range 21-27), 75.7% were from South Africa, 2878 (93.2%) initiated PrEP at enrolment and 107 (3.5%) after enrolment. Visit retention was 92.0-96.2% for months 1, 3 and 6, and 2518 (90.1%) exited the study with a PrEP refill. Adherence, based on the point-of-care urine tenofovir test positivity rate, was estimated as 72%, 71% and 65% at months 1, 3 and 6, respectively. Women who received one prior urine TFV test had a 42% higher likelihood of a subsequent positive urine TFV test (adjusted odds ratio, OR = 1.42, 95% confidence interval, CI 1.27-1.60), and those having received two prior tests had a 67% higher likelihood (adjusted OR = 1.67; 95% CI 1.41-1.98). Observed HIV incidence was 1.38/100 person-years (95% CI 0.97-2.08).

CONCLUSIONS: Oral PrEP uptake, recent adherence and persistence were high in a multisite cohort of young African women over 6 months of follow-up. The use of a novel point-of-care tenofovir assay with tailored real-time adherence counselling was associated with increased adherence to PrEP at subsequent visits, warranting further study.

CLINICAL TRIALS REGISTRATION: clinicaltrials.gov NCT05746065.},
}

Humans
Female
*HIV Infections/prevention & control/drug therapy
*Pre-Exposure Prophylaxis/methods/statistics & numerical data
*Tenofovir/therapeutic use/urine
Adolescent
Young Adult
*Medication Adherence/statistics & numerical data
Adult
*Anti-HIV Agents/therapeutic use
*Counseling
Point-of-Care Testing
Point-of-Care Systems
Cohort Studies

@article {pmid39653279,
year = {2024},
author = {Santos, PMG and Silverwood, S and Suneja, G and Ford, E and Thaker, NG and Ostroff, JS and Weiner, BJ and Gillespie, EF},
title = {Dissemination and Implementation - A Primer for Accelerating "Time to Translation" in Radiation Oncology.},
journal = {International journal of radiation oncology, biology, physics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ijrobp.2024.11.101},
pmid = {39653279},
issn = {1879-355X},
abstract = {The field of radiation oncology has achieved significant technological and scientific advancements in the 21[st] century. Yet uptake of new evidence-based practices has been heterogeneous, even in the presence of national and international guidelines. Addressing barriers to practice change requires a deliberate focus on developing and testing strategies tailored to improving care delivery and quality, especially for vulnerable patient populations. Implementation science provides a systematic approach to developing and testing strategies, though applications in radiation oncology remain limited. In this critical review, we aim to 1) assess the time from first evidence to widespread adoption, or "time to translation," across multiple evidence-based practices involving radiation therapy, and 2) provide a primer on the application of implementation science to radiation oncology. Specifically, we discuss potential targets for implementation research in radiation oncology, including both evidence-based practices and quality metrics, and highlight examples of studies evaluating implementation strategies. We also define key concepts and frameworks in the field of implementation science, review common study designs including hybrid trials and cluster randomization, and discuss the interaction with related disciplines such as quality improvement and behavioral economics. Ultimately, this review aims to illustrate how a comprehensive understanding of implementation science could be used to promote equity and quality in cancer care through the development of effective, scalable, and sustainable care delivery solutions.},
}

@article {pmid39652675,
year = {2024},
author = {Dimopoulos, MA and Voorhees, PM and Schjesvold, F and Cohen, YC and Hungria, V and Sandhu, I and Lindsay, J and Baker, RI and Suzuki, K and Kosugi, H and Levin, MD and Beksac, M and Stockerl-Goldstein, K and Oriol, A and Mikala, G and Garate, G and Theunissen, K and Spicka, I and Mylin, AK and Bringhen, S and Uttervall, K and Pula, B and Medvedova, E and Cowan, AJ and Moreau, P and Mateos, MV and Goldschmidt, H and Ahmadi, T and Sha, L and Cortoos, A and Katz, EG and Rousseau, E and Li, L and Dennis, RM and Carson, R and Rajkumar, SV and , },
title = {Daratumumab or Active Monitoring for High-Risk Smoldering Multiple Myeloma.},
journal = {The New England journal of medicine},
volume = {},
number = {},
pages = {},
doi = {10.1056/NEJMoa2409029},
pmid = {39652675},
issn = {1533-4406},
abstract = {BACKGROUND: Daratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved.

METHODS: In this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria.

RESULTS: Among the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified.

CONCLUSIONS: Among patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.).},
}

@article {pmid39652470,
year = {2024},
author = {Chesner, LN and Polesso, F and Graff, JN and Hawley, JE and Smith, AK and Lundberg, A and Das, R and Shenoy, T and Sjöström, M and Zhao, F and Hu, YM and Linder, S and Chen, WS and Hawkins, RM and Shrestha, R and Zhu, X and Foye, A and Li, H and Kim, LM and Bhalla, M and O'loughlin, T and Kuzuoglu-Ozturk, D and Hua, JT and Badura, ML and Wilkinson, S and Trostel, SY and Bergman, AM and Ruggero, D and Drake, CG and Sowalsky, AG and Fong, L and Cooperberg, MR and Zwart, W and Guan, X and Ashworth, A and Xia, Z and Quigley, DA and Gilbert, LA and Feng, FY and Moran, AE},
title = {Androgen receptor inhibition increases MHC Class I expression and improves immune response in prostate cancer.},
journal = {Cancer discovery},
volume = {},
number = {},
pages = {},
doi = {10.1158/2159-8290.CD-24-0559},
pmid = {39652470},
issn = {2159-8290},
abstract = {Tumors escape immune detection and elimination through a variety of mechanisms. Here, we used prostate cancer as a model to examine how androgen-dependent tumors undergo immune evasion through downregulation of the major histocompatibility complex class I (MHCI). We report that response to immunotherapy in late-stage prostate cancer is associated with elevated MHC expression. To uncover the mechanism, we performed a whole genome CRISPRi screen and identified AR as a repressor of the MHCI pathway. Syngeneic mouse models of aggressive prostate cancer deficient in AR also demonstrated increased tumor immunogenicity and promoted T cell mediated tumor-control. Notably, the increase in MHCI expression upon androgen receptor blockade is transient and correlates with resistance to AR inhibition. Mechanistic studies identified androgen response elements upstream of MHCI transcription start sites which increased MHCI expression when deleted. Together, this body of work highlights another mechanism by which hormones can promote immune escape.},
}

@article {pmid39652116,
year = {2024},
author = {Azhideh, A and Pouramini, A and Haseli, S and Abbaspour, E and Karande, G and Kafi, F and Chalian, M},
title = {Radiological assessment of extremity bone involvement in Erdheim-Chester disease: a systematic review of case reports.},
journal = {Skeletal radiology},
volume = {},
number = {},
pages = {},
pmid = {39652116},
issn = {1432-2161},
abstract = {OBJECTIVE: To describe the clinical presentations and radiological manifestations of Erdheim-Chester disease (ECD) in the extremities, with particular emphasis on radiologic findings, as radiographs are typically the initial imaging modality used in clinical practice.

METHODS: Following the PRISMA guidelines, a comprehensive systematic search was performed across Scopus, PubMed, Web of Science, and Embase databases, covering case reports from inception until August 1, 2024. Included were studies with pathologically confirmed ECD (CD68 positive and CD1a negative) that were evaluated with at least one imaging modality and provided detailed descriptions of radiological findings.

RESULTS: Out of 401 identified articles, 20 articles comprising 20 histologically confirmed cases of ECD met the inclusion criteria following screening and full-text review. Pathological reports were assessed for the presence of lipid-laden cells and Touton giant cells, which were identified in 84.2% and 75% of cases, respectively. Upper extremities were affected in 65% of cases and lower extremities in all cases. Symmetric involvement was observed in 84.6% of upper extremity cases and 84.2% of lower extremity cases. Radiological findings were categorized as pure sclerosis (53.3%) and cortical thickening (42.8%) identified as the most common findings. Clinical manifestations were assessed, with pain and swelling in the extremities being the most common symptoms, occurring in 70% of cases.

CONCLUSION: The hallmark of ECD is bilateral, symmetric diaphyseal and/or metaphyseal osteosclerosis in the long tubular bones of the lower extremities. Epiphyseal sparing is observed in more than half of the patients.},
}

@article {pmid39651955,
year = {2024},
author = {von Itzstein, MS and Burns, TF and Dowell, JE and Horn, L and Camidge, DR and York, SJ and Eaton, KD and Kyle, K and Fattah, FJ and Liu, J and Mu-Mosley, H and Gupta, A and Nadeem, U and Gao, A and Zhang, S and Gerber, DE},
title = {Phase 1/2 trial of XPO1 inhibitor selinexor plus docetaxel in previously treated, advanced KRAS mutant non-small cell lung cancer.},
journal = {Clinical cancer research : an official journal of the American Association for Cancer Research},
volume = {},
number = {},
pages = {},
doi = {10.1158/1078-0432.CCR-24-1722},
pmid = {39651955},
issn = {1557-3265},
abstract = {PURPOSE: Patients with KRAS mutant non-small cell lung cancer (NSCLC) have limited therapeutic options. Based on activity of nuclear export inhibition in preclinical models, we evaluated this strategy in previously treated advanced KRAS mutant NSCLC.

PATIENTS AND METHODS: The primary outcome of this multi-center phase 1/2 dose escalation trial of selinexor plus docetaxel was safety and tolerability. Selinexor was started one week before docetaxel to permit monotherapy pharmacodynamic assessment.

RESULTS: Among 40 enrolled patients, median age was 66 years, 55% were female, and 85% were white. Maximum tolerated dose was selinexor 60 mg orally weekly plus docetaxel 75 mg/m2 every three weeks. The most common adverse events were nausea (73%, 8% Gr ≥3), fatigue (70%, 5% Gr ≥3), neutropenia (65%, 60% Gr ≥3), and diarrhea (58%, 10% Gr ≥3). Of 32 efficacy evaluable patients, 7 (22%) had partial responses and 18 (56%) had stable disease. Outcomes were not associated with KRAS mutation type but were significantly better in cases with wild type TP53 (42%), including disease control and response rates (27% and 80%, vs. 9% and 27%, respectively; P=0.03) and progression-free survival (median 7.4 vs. 1.8 months; HR, 0.2; 95% CI, 0.07-0.67; P=0.003). Post-selinexor / pre-docetaxel, serum LDH levels increased an average 51 U/L in TP53 altered and decreased an average 48 U/L in TP53 wild type cases (P=0.06).

CONCLUSIONS: Selinexor plus docetaxel was relatively well tolerated in patients with advanced KRAS mutant NSCLC. The regimen has promising efficacy in TP53 wild type cases, where selinexor monotherapy may also have activity.},
}

@article {pmid39651886,
year = {2024},
author = {Painter, H and Larsen, SE and Williams, BD and Abdelaal, HFM and Baldwin, SL and Fletcher, HA and Fiore-Gartland, A and Coler, RN},
title = {Backtranslation of human RNA biosignatures of tuberculosis disease risk into the preclinical pipeline is condition dependent.},
journal = {mSphere},
volume = {},
number = {},
pages = {e0086424},
doi = {10.1128/msphere.00864-24},
pmid = {39651886},
issn = {2379-5042},
abstract = {UNLABELLED: It is unclear whether human progression to active tuberculosis disease (TB) risk signatures are viable endpoint criteria for evaluations of treatments in development. TB is the deadliest infectious disease globally and more efficacious vaccines are needed to reduce this mortality. However, the immune correlates of protection for either preventing infection with Mycobacterium tuberculosis or preventing TB disease have yet to be completely defined, making the advancement of candidate vaccines through the pipeline slow, costly, and fraught with risk. Human-derived correlate of risk (COR) gene signatures, which identify an individual's risk of progressing to active TB disease, provide an opportunity for evaluating new therapies for TB with clear and defined endpoints. Though prospective clinical trials with longitudinal sampling are prohibitively expensive, the characterization of COR gene signatures is practical with preclinical models. Using a 3Rs (replacement, reduction, and refinement) approach we reanalyzed heterogeneous publicly available transcriptional data sets to determine whether a specific set of COR signatures are viable endpoints in the preclinical pipeline. We selected RISK6, Sweeney3, and BATF2 human-derived blood-based RNA biosignatures because they require relatively few genes and have been carefully evaluated across several clinical cohorts. These data suggest that in certain experimental designs and in several tissue types, human COR signatures correlate with disease progression as measured by the bacterial burden in the preclinical TB model pipeline. We observed the best performance when the model most closely reflected human infection or disease conditions. Human-derived COR signatures offer an opportunity for high-throughput preclinical endpoint criteria of vaccine and drug therapy evaluations.

IMPORTANCE: Understanding the strengths or limitations of back-translating human-derived correlate of risk (COR) RNA signatures into the preclinical pipeline may help streamline down-selection of therapeutic vaccine and drug candidates and better align preclinical models with proposed clinical trial efficacy endpoints.},
}

@article {pmid39651791,
year = {2024},
author = {Gupta, S and Rau, RE and Kairalla, JA and Rabin, KR and Wang, C and Angiolillo, AL and Alexander, S and Carroll, AJ and Conway, S and Gore, L and Kirsch, I and Kubaney, HR and Li, AM and McNeer, JL and Militano, O and Miller, TP and Moyer, Y and O'Brien, MM and Okada, M and Reshmi, SC and Shago, M and Wagner, E and Winick, N and Wood, BL and Haworth-Wright, T and Zaman, F and Zugmaier, G and Zupanec, S and Devidas, M and Hunger, SP and Teachey, DT and Raetz, EA and Loh, ML},
title = {Blinatumomab in Standard-Risk B-Cell Acute Lymphoblastic Leukemia in Children.},
journal = {The New England journal of medicine},
volume = {},
number = {},
pages = {},
doi = {10.1056/NEJMoa2411680},
pmid = {39651791},
issn = {1533-4406},
support = {U10CA180899/CA/NCI NIH HHS/United States ; U20CA180886/CA/NCI NIH HHS/United States ; },
abstract = {BACKGROUND: B-cell acute lymphoblastic leukemia (B-cell ALL) is the most common childhood cancer. Despite a high overall cure rate, relapsed B-cell ALL remains a leading cause of cancer-related death among children. The addition of the bispecific T-cell engager molecule blinatumomab (an anti-CD19 and anti-CD3 single-chain molecule) to therapy for newly diagnosed standard-risk (as defined by the National Cancer Institute) B-cell ALL in children may improve outcomes.

METHODS: We conducted a phase 3 trial involving children with newly diagnosed standard-risk B-cell ALL who had an average or high risk of relapse. Patients were randomly assigned to receive chemotherapy alone or chemotherapy plus two nonsequential 28-day cycles of blinatumomab. The primary end point was disease-free survival.

RESULTS: The data and safety monitoring committee reviewed the results from the first interim efficacy analysis, which included 1440 patients who had undergone randomization (722 to chemotherapy alone and 718 to blinatumomab and chemotherapy) and recommended early termination of randomization. At a median follow-up of 2.5 years, the estimated 3-year disease-free survival (±SE) was 96.0±1.2% with blinatumomab and chemotherapy and 87.9±2.1% with chemotherapy alone (difference in restricted mean survival time, 72 days; 95% confidence interval, 36 to 108; P<0.001 by stratified log-rank test). The estimated 3-year disease-free survival among patients with an average relapse risk was 97.5±1.3% with blinatumomab and chemotherapy and 90.2±2.3% with chemotherapy alone; among those with a high relapse risk, the corresponding values were 94.1±2.5% and 84.8±3.8%. Cytokine release syndrome, seizures, and sepsis of grade 3 or higher were rare during blinatumomab cycles, but the overall incidence of nonfatal sepsis and catheter-related infections was significantly higher among patients with an average relapse risk who had been assigned to receive blinatumomab and chemotherapy than among those assigned to receive chemotherapy alone.

CONCLUSIONS: Adding blinatumomab to combination chemotherapy in patients with newly diagnosed childhood standard-risk B-cell ALL of average or high risk of relapse significantly improved disease-free survival. (Funded by the National Institutes of Health and others; AALL1731 ClinicalTrials.gov number, NCT03914625.).},
}

@article {pmid39647999,
year = {2024},
author = {Shadman, M and Munir, T and Robak, T and Brown, JR and Kahl, BS and Ghia, P and Giannopoulos, K and Šimkovič, M and Österborg, A and Laurenti, L and Walker, PA and Opat, SS and Ciepluch, H and Greil, R and Hanna, M and Tani, M and Trněný, M and Brander, D and Flinn, IW and Grosicki, S and Verner, E and Tedeschi, A and de Guibert, S and Tumyan, G and Laribi, K and García-Marco, JA and Li, JY and Tian, T and Liu, Y and Korolkiewicz, R and Szeto, A and Tam, CS and Jurczak, W},
title = {Zanubrutinib Versus Bendamustine and Rituximab in Patients With Treatment-Naïve Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Median 5-Year Follow-Up of SEQUOIA.},
journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
volume = {},
number = {},
pages = {JCO2402265},
doi = {10.1200/JCO-24-02265},
pmid = {39647999},
issn = {1527-7755},
abstract = {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.SEQUOIA (ClinicalTrials.gov identifier: NCT03336333) is a phase III, randomized, open-label trial that compared the oral Bruton tyrosine kinase inhibitor zanubrutinib to bendamustine plus rituximab (BR) in treatment-naïve patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The initial prespecified analysis (median follow-up, 26.2 months) and subsequent analysis (43.7 months) found superior progression-free survival (PFS; the primary end point) in patients who received zanubrutinib compared with BR. At a median follow-up of 61.2 months, median PFS was not reached in zanubrutinib-treated patients; median PFS was 44.1 months in BR-treated patients (hazard ratio [HR], 0.29; one-sided P = .0001). Prolonged PFS was seen with zanubrutinib versus BR in patients with mutated immunoglobulin heavy-chain variable region (IGHV) genes (HR, 0.40; one-sided P = .0003) and unmutated IGHV genes (HR, 0.21 [95% CI, 0.14 to 0.33]; one-sided P < .0001). Median overall survival (OS) was not reached in either treatment arm; estimated 60-month OS rates were 85.8% and 85.0% in zanubrutinib- and BR-treated patients, respectively. No new safety signals were detected. Adverse events were as expected with zanubrutinib; rate of atrial fibrillation was 7.1%. At a median follow-up of 61.2 months, the results supported the initial SEQUOIA findings and suggested that zanubrutinib was a favorable treatment option for untreated patients with CLL/SLL.},
}

@article {pmid39645377,
year = {2024},
author = {, },
title = {Burden of disease scenarios by state in the USA, 2022-50: a forecasting analysis for the Global Burden of Disease Study 2021.},
journal = {Lancet (London, England)},
volume = {404},
number = {10469},
pages = {2341-2370},
doi = {10.1016/S0140-6736(24)02246-3},
pmid = {39645377},
issn = {1474-547X},
mesh = {Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Cause of Death/trends ; Disability-Adjusted Life Years/trends ; *Forecasting ; *Life Expectancy/trends ; Risk Factors ; United States/epidemiology ; *Cost of Illness ; *Population Health ; },
abstract = {BACKGROUND: The capacity to anticipate future health issues is important for both policy makers and practitioners in the USA, as such insights can facilitate effective planning, investment, and implementation strategies. Forecasting trends in disease and injury burden is not only crucial for policy makers but also garners substantial interest from the general populace and leads to a better-informed public. Through the integration of new data sources, the refinement of methodologies, and the inclusion of additional causes, we have improved our previous forecasting efforts within the scope of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) to produce forecasts at the state and national levels for the USA under various possible scenarios.

METHODS: We developed a comprehensive framework for forecasting life expectancy, healthy life expectancy (HALE), cause-specific mortality, and disability-adjusted life-years (DALYs) due to 359 causes of disease and injury burden from 2022 to 2050 for the USA and all 50 states and Washington, DC. Using the GBD 2021 Future Health Scenarios modelling framework, we forecasted drivers of disease, demographic drivers, risk factors, temperature and particulate matter, mortality and years of life lost (YLL), population, and non-fatal burden. In addition to a reference scenario (representing the most probable future trajectory), we explored various future scenarios and their potential impacts over the next several decades on human health. These alternative scenarios comprised four risk elimination scenarios (including safer environment, improved behavioural and metabolic risks, improved childhood nutrition and vaccination, and a combined scenario) and three USA-specific scenarios based on risk exposure or attributable burden in the best-performing US states (improved high adult BMI and high fasting plasma glucose [FPG], improved smoking, and improved drug use [encompassing opioids, cocaine, amphetamine, and others]).

FINDINGS: Life expectancy in the USA is projected to increase from 78·3 years (95% uncertainty interval 78·1-78·5) in 2022 to 79·9 years (79·5-80·2) in 2035, and to 80·4 years (79·8-81·0) in 2050 for all sexes combined. This increase is forecasted to be modest compared with that in other countries around the world, resulting in the USA declining in global rank over the 2022-50 forecasted period among the 204 countries and territories in GBD, from 49th to 66th. There is projected to be a decline in female life expectancy in West Virginia between 1990 and 2050, and little change in Arkansas and Oklahoma. Additionally, after 2023, we projected almost no change in female life expectancy in many states, notably in Oklahoma, South Dakota, Utah, Iowa, Maine, and Wisconsin. Female HALE is projected to decline between 1990 and 2050 in 20 states and to remain unchanged in three others. Drug use disorders and low back pain are projected to be the leading Level 3 causes of age-standardised DALYs in 2050. The age-standardised DALY rate due to drug use disorders is projected to increase considerably between 2022 and 2050 (19·5% [6·9-34·1]). Our combined risk elimination scenario shows that the USA could gain 3·8 additional years (3·6-4·0) of life expectancy and 4·1 additional years (3·9-4·3) of HALE in 2050 versus the reference scenario. Using our USA-specific scenarios, we forecasted that the USA could gain 0·4 additional years (0·3-0·6) of life expectancy and 0·6 additional years (0·5-0·8) of HALE in 2050 under the improved drug use scenario relative to the reference scenario. Life expectancy and HALE are likewise projected to be 0·4-0·5 years higher in 2050 under the improved adult BMI and FPG and improved smoking scenarios compared with the reference scenario. However, the increases in these scenarios would not substantially improve the USA's global ranking in 2050 (from 66th of 204 in life expectancy in the reference scenario to 63rd-64th in each of the three USA-specific scenarios), indicating that the USA's best-performing states are still lagging behind other countries in their rank throughout the forecasted period. Regardless, an estimated 12·4 million (11·3-13·5) deaths could be averted between 2022 and 2050 if the USA were to follow the combined scenario trajectory rather than the reference scenario. There would also be 1·4 million (0·7-2·2) fewer deaths over the 28-year forecasted period with improved adult BMI and FPG, 2·1 million (1·3-2·9) fewer deaths with improved exposure to smoking, and 1·2 million (0·9-1·5) fewer deaths with lower rates of drug use deaths.

INTERPRETATION: Our findings highlight the alarming trajectory of health challenges in the USA, which, if left unaddressed, could lead to a reversal of the health progress made over the past three decades for some US states and a decline in global health standing for all states. The evidence from our alternative scenarios along with other published studies suggests that through collaborative, evidence-based strategies, there are opportunities to change the trajectory of health outcomes in the USA, such as by investing in scientific innovation, health-care access, preventive health care, risk exposure reduction, and education. Our forecasts clearly show that the time to act is now, as the future of the country's health and wellbeing-as well as its prosperity and leadership position in science and innovation-are at stake.

FUNDING: Bill & Melinda Gates Foundation.},
}

Adult
Aged
Female
Humans
Male
Middle Aged
Cause of Death/trends
Disability-Adjusted Life Years/trends
*Forecasting
*Life Expectancy/trends
Risk Factors
United States/epidemiology
*Cost of Illness
*Population Health

@article {pmid39644910,
year = {2024},
author = {Goya, S and Greninger, AL},
title = {Pneumovirus genome misassemblies associated with duplications in glycoprotein genes.},
journal = {The Lancet. Infectious diseases},
volume = {},
number = {},
pages = {},
doi = {10.1016/S1473-3099(24)00801-6},
pmid = {39644910},
issn = {1474-4457},
}

@article {pmid39644492,
year = {2024},
author = {Chao, CW and Sprouse, KR and Miranda, MC and Catanzaro, NJ and Hubbard, ML and Addetia, A and Stewart, C and Brown, JT and Dosey, A and Valdez, A and Ravichandran, R and Hendricks, GG and Ahlrichs, M and Dobbins, C and Hand, A and McGowan, J and Simmons, B and Treichel, C and Willoughby, I and Walls, AC and McGuire, AT and Leaf, EM and Baric, RS and Schäfer, A and Veesler, D and King, NP},
title = {Protein nanoparticle vaccines induce potent neutralizing antibody responses against MERS-CoV.},
journal = {Cell reports},
volume = {43},
number = {12},
pages = {115036},
doi = {10.1016/j.celrep.2024.115036},
pmid = {39644492},
issn = {2211-1247},
abstract = {Middle East respiratory syndrome coronavirus (MERS-CoV) is a betacoronavirus that causes severe respiratory illness in humans. There are no licensed vaccines against MERS-CoV and only a few candidates in phase I clinical trials. Here, we develop MERS-CoV vaccines utilizing a computationally designed protein nanoparticle platform that has generated safe and immunogenic vaccines against various enveloped viruses, including a licensed vaccine for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Two-component nanoparticles displaying spike (S)-derived antigens induce neutralizing responses and protect mice against challenge with mouse-adapted MERS-CoV. Epitope mapping reveals the dominant responses elicited by immunogens displaying the prefusion-stabilized S-2P trimer, receptor binding domain (RBD), or N-terminal domain (NTD). An RBD nanoparticle elicits antibodies targeting multiple non-overlapping epitopes in the RBD. Our findings demonstrate the potential of two-component nanoparticle vaccine candidates for MERS-CoV and suggest that this platform technology could be broadly applicable to betacoronavirus vaccine development.},
}

@article {pmid39644022,
year = {2024},
author = {Radich, J},
title = {Mutations and MRD: clinical implications of clonal ontogeny.},
journal = {Hematology. American Society of Hematology. Education Program},
volume = {2024},
number = {1},
pages = {150-157},
doi = {10.1182/hematology.2024000541},
pmid = {39644022},
issn = {1520-4383},
mesh = {Humans ; *Neoplasm, Residual ; *Leukemia, Myeloid, Acute/genetics/pathology ; *Mutation ; Recurrence ; },
abstract = {Measurable residual disease (MRD) is a strong but imprecise predictor of relapse in acute myeloid leukemia. Many patients fall into the outlier categories of MRD positivity without relapse or MRD negativity with relapse. Why? We will discuss these states in the context of "clonal ontogeny" examining how mutations, clonal structure, and Darwinian rules impact response, resistance, and relapse.},
}

Humans
*Neoplasm, Residual
*Leukemia, Myeloid, Acute/genetics/pathology
*Mutation
Recurrence

@article {pmid39643988,
year = {2024},
author = {Kuczmarski, TM and Lynch, RC},
title = {Has PD-1 blockade changed the standard of care for cHL?.},
journal = {Hematology. American Society of Hematology. Education Program},
volume = {2024},
number = {1},
pages = {505-510},
doi = {10.1182/hematology.2024000574},
pmid = {39643988},
issn = {1520-4383},
mesh = {Humans ; *Hodgkin Disease/drug therapy/therapy ; *Programmed Cell Death 1 Receptor/antagonists & inhibitors ; *Standard of Care ; Immune Checkpoint Inhibitors/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Nivolumab/therapeutic use ; },
abstract = {The treatment paradigm for classic Hodgkin lymphoma (CHL) continues to evolve, particularly in light of the incorporation of programmed cell death protein 1 (PD-1) inhibitors into a variety of therapeutic settings. PD-1 inhibitors have demonstrated high efficacy and a favorable toxicity profile when added to a doxorubicin, vinblastine, dacarbazine chemotherapy backbone in patients with untreated CHL. PD-1 inhibitors are also effective treatment options in the relapsed/refractory setting. For patients who are pursuing autologous stem cell transplant (ASCT), pembrolizumab plus gemcitabine, vinorelbine, and liposomal doxorubicin has shown marked efficacy and is an effective treatment regimen to administer prior to transplant. For patients who either are not eligible for ASCT or have relapsed after ASCT, pembrolizumab or nivolumab monotherapy have been well studied and demonstrate high efficacy even when patients have been exposed to numerous lines of prior therapy. As data from previous trials continue to mature and new clinical trials are conducted, PD-1 inhibitors will continue to become an integral component for successful management of CHL.},
}

Humans
*Hodgkin Disease/drug therapy/therapy
*Programmed Cell Death 1 Receptor/antagonists & inhibitors
*Standard of Care
Immune Checkpoint Inhibitors/therapeutic use
Antibodies, Monoclonal, Humanized/therapeutic use
Antineoplastic Combined Chemotherapy Protocols/therapeutic use
Nivolumab/therapeutic use

@article {pmid39643004,
year = {2024},
author = {El Kalach, N and Julceus, EF and Rudisill, AC and Malik, FS and Flory, K and Frongillo, EA and Sauder, KA and Mendoza, JA and Liese, AD},
title = {Association between Food Insecurity and Inability to Obtain Provider-Recommended Medications, Multidisciplinary Services, and Technology in Youth and Young Adults with Diabetes: A Cross-Sectional Study.},
journal = {Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.eprac.2024.11.014},
pmid = {39643004},
issn = {1530-891X},
abstract = {OBJECTIVE: We assessed if food insecurity (FI) is associated with not obtaining recommended diabetes medications, technology, and multidisciplinary services, and explored the most common reasons for not obtaining recommended treatments in youth and young adults (YYA) with diabetes.

METHODS: In this cross-sectional study, among 911 YYA with type 1 diabetes (T1D) and 144 with type 2 diabetes (T2D) from the SEARCH Food Security Cohort Study Follow-up 1 (2018-2021), FI (≥3 items affirmed from the 18-item Household Food Security Survey module) and inability to obtain recommended treatments were self-reported.

RESULTS: Almost 30% of YYA with T1D and FI and 20% of YYA with T2D and FI did not obtain one or more recommended treatments. Participants with T1D who reported FI had higher odds of not obtaining insulin (OR 3.2, 95% CI 1.2-8.4), mental health counseling (OR 3.3, 95% CI 1.3-8.2), diabetes education (OR 3.6, 95% CI 1.4-9.3), an insulin pump (OR 2.2, 95% CI 1.2- 4.4), and a continuous glucose monitor (CGM) (OR 2.5, 95% CI 1.5-4.4) compared to those who reported food security (FS). Among participants with T2D, FI was related to not obtaining dietician services (OR 8.1, 95% CI 1.2-53.8). Participants with T1D and FI reported more financial reasons for not obtaining a CGM compared to FS participants.

CONCLUSION: YYA with diabetes and FI face constraints in obtaining medications, diabetes technology, and multidisciplinary services, largely due to financial and structural reasons. New strategies are needed to bridge the gap between medical care required versus obtained by YYA with diabetes.},
}

@article {pmid39642888,
year = {2024},
author = {Qiu, Y and Su, Y and Xie, E and Cheng, H and Du, J and Xu, Y and Pan, X and Wang, Z and Chen, DG and Zhu, H and Greenberg, PD and Li, G},
title = {Mannose metabolism reshapes T cell differentiation to enhance anti-tumor immunity.},
journal = {Cancer cell},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ccell.2024.11.003},
pmid = {39642888},
issn = {1878-3686},
abstract = {Cellular metabolic status profoundly influences T cell differentiation, persistence, and anti-tumor efficacy. Our single-cell metabolic analyses of T cells reveal that diminished mannose metabolism is a prominent feature of T cell dysfunction. Conversely, experimental augmentation/restoration of mannose metabolism in adoptively transferred T cells via D-mannose supplementation enhances anti-tumor activity and restricts exhaustion differentiation both in vitro and in vivo. Mechanistically, D-mannose treatment induces intracellular metabolic programming and increases the O-GlcNAc transferase (OGT)-mediated O-GlcNAcylation of β-catenin, which preserves Tcf7 expression and epigenetic stemness, thereby promoting stem-like programs in T cells. Furthermore, in vitro expansion with D-mannose supplementation yields T cell products for adoptive therapy with stemness characteristics, even after extensive long-term expansion, that exhibits enhanced anti-tumor efficacy. These findings reveal cell-intrinsic mannose metabolism as a physiological regulator of CD8[+] T cell fate, decoupling proliferation/expansion from differentiation, and underscoring the therapeutic potential of mannose modulation in cancer immunotherapy.},
}

@article {pmid39642637,
year = {2024},
author = {Rosenberg, JE and Galsky, MD and Powles, T and Petrylak, DP and Bellmunt, J and Loriot, Y and Necchi, A and Hoffman-Censits, J and Perez-Gracia, JL and van der Heijden, MS and Dreicer, R and Durán, I and Castellano, D and Drakaki, A and Retz, M and Sridhar, SS and Grivas, P and Yu, EY and O'Donnell, PH and Burris, HA and Mariathasan, S and Shi, Y and Goluboff, E and Bajorin, D},
title = {Atezolizumab monotherapy for metastatic urothelial carcinoma: final analysis from the phase II IMvigor210 trial.},
journal = {ESMO open},
volume = {9},
number = {12},
pages = {103972},
doi = {10.1016/j.esmoop.2024.103972},
pmid = {39642637},
issn = {2059-7029},
abstract = {BACKGROUND: The IMvigor210 trial demonstrated clinical benefit and manageable toxicity with atezolizumab monotherapy [anti-programmed death-ligand 1 (PD-L1)] in patients with metastatic urothelial carcinoma (UC) in primary analyses. Final efficacy and safety results after long-term follow-up are reported.

PATIENTS AND METHODS: This phase II single-arm trial of atezolizumab monotherapy in patients with advanced UC included two cohorts: untreated patients ineligible for cisplatin-based chemotherapy (cohort 1; n = 119) and those previously treated with platinum-based chemotherapy (cohort 2; n = 310). Atezolizumab was administered i.v. (1200 mg every 21 days) until progression or unacceptable toxicity. Primary endpoints were independent review facility-assessed confirmed objective response rate (ORR) per RECIST 1.1 in cohort 1 and independent review facility-assessed ORR per RECIST 1.1 and investigator-assessed modified (m)RECIST in cohort 2. Overall survival (OS), efficacy by PD-L1 status, and safety were also assessed.

RESULTS: At data cut-off (1 June 2023), the median survival follow-up was 96.4 months (range, 0.2-103.4 months) in cohort 1 and 46.2 months [0.2 (censored)-54.9 months] in cohort 2. In cohort 1, the ORR [95% confidence interval (CI)] was 23.5% (16.2% to 32.2%) in all patients and 28.1% (13.8% to 46.8%) in the PD-L1 tumor-infiltrating immune cell (IC)2/3 subgroup. Median OS (95% CI) was 16.3 months (10.4-24.5 months) overall and 12.3 months (6.0-49.8 months) in the PD-L1 IC2/3 subgroup. In cohort 2, the ORR (95% CI) was 16.5% (12.5% to 21.1%) per RECIST 1.1 and 19.7% (95% CI 15.4% to 24.6%) per mRECIST in all patients and 27.0% (18.6% to 36.8%) and 28.0% (19.5% to 37.9%), respectively, in the PD-L1 IC2/3 subgroup. Median OS (95% CI) was 7.9 months (6.7-9.3 months) in all patients and 11.9 months (9.0-22.8 months) in the IC2/3 subgroup. Treatment-related grade 3/4 adverse events occurred in 21.8% (cohort 1) and 18.7% (cohort 2); one treatment-related death occurred in cohort 1.

CONCLUSIONS: With long-term follow-up, atezolizumab monotherapy demonstrated clinically meaningful efficacy with durable responses in a subset of patients with metastatic UC; there were no new safety signals.},
}

@article {pmid39642635,
year = {2024},
author = {Choueiri, TK and Kuzel, TM and Tykodi, SS and Verzoni, E and Kluger, H and Nair, S and Perets, R and George, S and Gurney, H and Pachynski, RK and Folefac, E and Castonguay, V and Lee, CH and Vaishampayan, U and Miller, WH and Bhagavatheeswaran, P and Wang, Y and Gupta, S and DeSilva, H and Lee, CW and Escudier, B and Motzer, RJ},
title = {Nivolumab plus relatlimab and nivolumab plus ipilimumab for patients with advanced renal cell carcinoma: results from the open-label, randomised, phase II FRACTION-RCC trial.},
journal = {ESMO open},
volume = {9},
number = {12},
pages = {104073},
doi = {10.1016/j.esmoop.2024.104073},
pmid = {39642635},
issn = {2059-7029},
abstract = {BACKGROUND: The Fast Real-time Assessment of Combination Therapies in Immuno-ONcology study in patients with aRCC (FRACTION-RCC) was designed to assess new immuno-oncology (IO) combinations in patients with advanced renal cell carcinoma (aRCC). We present results in IO-naive patients treated with nivolumab (NIVO) + relatlimab (RELA) or NIVO + ipilimumab (IPI) in track 1.

METHODS: The open-label, randomised, phase II FRACTION-RCC trial enrolled patients with aRCC from 32 hospitals and cancer centres across six countries. Patients were enrolled in track 1 (IO-naive) or track 2 (IO-experienced). IO-naive patients were stratified by previous tyrosine kinase inhibitor therapy and randomised to NIVO (240 mg) + RELA (80 mg) intravenously once every 2 weeks or NIVO (3 mg/kg) + IPI (1 mg/kg) intravenously once every 3 weeks for four doses, followed by NIVO (480 mg) once every 4 weeks, each up to ∼2 years. The primary endpoints were objective response by investigator (RECIST version 1.1), duration of response (DOR), and progression-free survival (PFS) rate at 24 weeks. Safety was a secondary endpoint; biomarker analyses were exploratory.

RESULTS: FRACTION-RCC enrolled patients between 2 February 2017 and 23 January 2020. In track 1, 30 patients each were treated with NIVO + RELA or NIVO + IPI (clinical database lock, 1 November 2021). With NIVO + RELA [median follow-up, 48.6 months; interquartile range (IQR) 46.9-51.7 months], objective response was 30% [95% confidence interval (CI) 15% to 49%], with 33 weeks (95% CI 16-53 weeks) median DOR. The PFS rate at 24 weeks was 43% (95% CI 25% to 60%). With NIVO + IPI (median follow-up, 48.7 months; IQR 47.1-52.0 months), the objective response was 20% (95% CI 8% to 39%), with the median DOR not reached (95% CI 33 weeks-not estimable). The PFS rate at 24 weeks was 49% (95% CI 29% to 66%). Higher baseline lymphocyte activation gene 3 (LAG-3) and programmed death-ligand 1 (PD-L1) expression levels were detected among track 1 NIVO + RELA responders. Grade 3-4 treatment-related adverse events were reported in 4/30 (13%) patients treated with NIVO + RELA and 10/30 (33%) patients treated with NIVO + IPI. No deaths were attributed to study treatments.

CONCLUSIONS: Results showed antitumour activity and manageable safety with NIVO + RELA. Findings also support NIVO + IPI as an effective combination regimen in IO-naive patients with aRCC.},
}

@article {pmid39640936,
year = {2024},
author = {Hawwash, NK and Sperrin, M and Martin, GP and Sinha, R and Matthews, CE and Ricceri, F and Tjønneland, A and Heath, AK and Neuhouser, ML and Joshu, CE and Platz, EA and Freisling, H and Gunter, MJ and Renehan, AG},
title = {Excess weight by degree and duration and cancer risk (ABACus2 consortium): a cohort study and individual participant data meta-analysis.},
journal = {EClinicalMedicine},
volume = {78},
number = {},
pages = {102921},
pmid = {39640936},
issn = {2589-5370},
abstract = {BACKGROUND: Elevated body mass index (BMI) ≥25 kg/m[2] is a major preventable cause of cancer. A single BMI measure does not capture the degree and duration of exposure to excess BMI. We investigate associations between adulthood overweight-years, incorporating exposure time to BMI ≥25 kg/m[2,] and cancer incidence, and compare this with single BMI.

METHODS: In this cohort study and individual participant data meta-analysis, we obtained data from the ABACus 2 Consortium, consisting of four US cohorts: Atherosclerosis Risk in Communities (ARIC) study (1987-2015), Women's Health Initiative (WHI; 1991 to 2005 [main study], to 2010 [Extension 1], and to 2020 [Extension 2]), Prostate, Lung, Colorectal, Ovarian Cancer Screening (PLCO) Trial (1993-2009), NIH-AARP Diet and Health Study (1996-2011), and one European cohort, the European Prospective Investigation into Cancer and Nutrition (EPIC; participants enrolled in 1990 and administrative censoring was centre-specific). Participants with at least 3 BMI measurements and complete cancer follow-up data were included. We calculated overweight-years: degree of overweight (BMI ≥25 kg/m[2]) multiplied by the duration of overweight (years). Using random effects two-stage individual participant data meta-analyses, associations between cancer and overweight-years, single BMI, cumulative overweight degree and duration, measured at the same time and captured over a median of 41 years in men and 39 years in women, were evaluated with Cox proportional hazards models. Models were age-adjusted or multivariable (MV) adjusted for baseline age, ethnicity, alcohol, smoking and hormone replacement therapy (HRT). Harrell's C-statistic of metrics were compared. This study is registered at PROSPERO, CRD42021238270.

FINDINGS: 720,210 participants, including 312,132 men and 408,078 women, were followed up for cancer incidence over a median 9.85 years (interquartile range (IQR) 8.03, 11.67) in men and 10.80 years (IQR 6.05, 15.55) in women. 12,959 men (4.15%) and 36,509 women (8.95%) were diagnosed with obesity-related cancer. Hazard ratios for obesity-related cancers in men, per 1 standard deviation (SD) overweight-years were 1.15 (95% CI: 1.14, 1.16, I[2]: 0) age-adjusted and 1.15 (95% CI: 1.13, 1.17, I[2]: 0%) MV-adjusted and per 1SD increment in single BMI were 1.17 (95% CI: 1.16, 1.18, I[2]: 0) age-adjusted and 1.16 (95% CI: 1.15, 1.18, I[2]: 0%) MV-adjusted. The HR for overweight-years in women per 1 SD increment was 1.08 (95% CI: 1.04, 1.13, I[2]: 82%) age-adjusted and 1.08 (95% CI: 1.04, 1.13, I[2]: 83%) MV-adjusted and per 1SD increment in single BMI was 1.10 (95% CI: 1.07, 1.14, I[2]: 72%) age-adjusted and 1.11 (95% CI: 1.07, 1.15, I[2]: 79%) MV-adjusted. C-statistics for overweight-years and single BMI for obesity-related cancers were 0.612 (95% CI: 0.578, 0.646) and 0.611 (95% CI: 0.578, 0.644) respectively for men and 0.566 (95% CI: 0.534, 0.598) and 0.573 (95% CI: 0.546, 0.600) for women.

INTERPRETATION: Adulthood degree and duration of excess BMI were associated with cancer risk. Both factors should be considered in cancer prevention strategies and policies. This study only focused on adulthood exposure to excess BMI, so the minimal differences in the predictive performance between adiposity metrics may be due to underestimation of cumulative excess BMI exposure.

FUNDING: Cancer Research UK, the Manchester NIHR Biomedical Research Centre, the National Cancer Institute, the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, U.S. Department of Health and Human Services, the Intramural Research Program of the National Cancer Institute, the International Agency for Research on Cancer, Imperial College London, European Commission (DG-SANCO), the Danish Cancer Society, Ligue Contre le Cancer, Institut Gustave-Roussy, Mutuelle Générale de l'Education Nationale, Institut National de la Santé et de la Recherche Médicale, Deutsche Krebshilfe, Deutsches Krebsforschungszentrum, German Federal Ministry of Education and Research, the Hellenic Health Foundation, Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council, Dutch Ministry of Public Health, Welfare, and Sports, Netherlands Cancer Registry, LK Research Funds, Dutch Prevention Funds, Dutch Zorg Onderzoek Nederland, World Cancer Research Fund, Statistics Netherlands, Health Research Fund, Instituto de Salud Carlos III, regional Spanish governments of Andalucía, Asturias, Basque Country, Murcia, and Navarra, the Catalan Institute of Oncology, Swedish Cancer Society, Swedish Scientific Council, and Region Skåne and Region Västerbotten, and the Medical Research Council.},
}

@article {pmid39638730,
year = {2024},
author = {Barata, PC and Zarrabi, KK and Bex, A and Grivas, P and Hermann, K and Hofman, MS and Li, R and Lopez-Beltran, A and Padani, AR and Powles, T and Taplin, ME and Loriot, Y},
title = {Novel Methods to Assess Tumor Burden and Minimal Residual Disease in Genitourinary Cancers.},
journal = {European urology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.eururo.2024.11.011},
pmid = {39638730},
issn = {1873-7560},
abstract = {BACKGROUND AND OBJECTIVE: Advances in molecular diagnostics have ushered in a new era for patients with prostate, renal, and urothelial cancers, with novel radiographic and molecular modalities for the assessment of disease burden and minimal residual disease (MRD). Conventional imaging has a limited threshold for disease detection and is often unable to discern clinically occult disease with varying risks of false-negative or false-positive findings depending on the disease state and type of imaging.

METHODS: We provide an overview of emerging radiographic and molecular tools in development within the genitourinary (GU) disease space. A literature review of contemporary basic, translational, and clinical research studies was performed, covering the timeframe of 1980-2024 through the MEDLINE (via PubMed) and Scopus databases. We highlight select examples of emerging technologies and biomarker-informed clinical trials, which aim to quantify disease at lower thresholds and have the potential for integrating MRD in clinical practice for GU patients.

KEY FINDINGS AND LIMITATIONS: The development of novel radiotracers, such as prostate-specific membrane antigen or carbonic anhydrase IX, is being evaluated in both clinical practice and trial setting, aiming to change the management of these tumors. Molecular tools including circulating tumor cells and byproducts such as plasma and urine cell-free circulating tumor DNA provide the opportunity for MRD detection. MRD capture on single-cell or cellular byproducts can serve as a conduit for genomic and transcriptomic analyses, providing insight into the molecular underpinnings and clonal evolution of disease.

While the full potential for MRD applications has yet to be realized, we are witnessing the emergence of novel techniques aimed at MRD detection and the rapid development of elegantly designed studies implementing iterative detection of MRD as means to provide biological rationale and tailor therapeutic options in GU tumors.},
}

@article {pmid39638687,
year = {2024},
author = {Zacchi, F and Abida, W and Antonarakis, ES and Bryce, AH and Castro, E and Cheng, HH and Shandhu, S and Mateo, J},
title = {Recent and Future Developments in the Use of Poly (ADP-ribose) Polymerase Inhibitors for Prostate Cancer.},
journal = {European urology oncology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.euo.2024.11.011},
pmid = {39638687},
issn = {2588-9311},
abstract = {BACKGROUND AND OBJECTIVE: Advanced prostate cancer (PCa) is enriched for alterations in DNA damage repair genes; poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are a class of drugs that have demonstrated effectiveness in PCa, particularly in tumors with alterations in BRCA1/2 and other homologous recombination repair (HRR) genes, acting through a synthetic lethal mechanism. To prevent or delay drug resistance, and to expand the patient population that can benefit from this class of drug, combination treatment strategies have been developed in preclinical and clinical studies.

METHODS: This review examines the latest developments in clinical trials testing PARPi for advanced PCa and their emerging role in earlier disease settings. Furthermore, it discusses the critical role of careful patient selection and identification of additional biomarkers to enhance treatment efficacy.

KEY FINDINGS AND LIMITATIONS: Two PARPi (olaparib and rucaparib) have been approved as monotherapy in metastatic castration-resistant PCa, thereby establishing the first biomarker-guided drug indications in PCa. Several combinations of PARPi with androgen receptor pathway inhibitors have now also been approved. Anemia and fatigue are the main adverse events associated with this drug class in clinical trials; gastrointestinal toxicities are common but usually manageble.

PARPi are active against PCa with HRR mutations, especially in those with germline or somatic BRCA1/2 mutations.  There is still a need to further optimize patient stratification strategies, particularly for combination approaches. Future research should focus on refining predictive biomarkers, improving treatment delivery strategies, and exploring the potential benefits of PARPi in earlier stages of the disease.

PATIENT SUMMARY: Here, we summarize the results from clinical trials testing different poly (ADP-ribose) polymerase inhibitors (PARPi), a novel targeted drug class, in prostate cancer. Overall, the data from these trials confirm the efficacy of this drug class in those metastatic prostate cancers that show specific gene alterations, such as mutations in the BRCA1/2 genes. Several studies combining PARPi with other standard drugs for prostate cancer suggest that there may be efficacy in larger patient populations, but some of these data still need validation in longer follow-up analyses.},
}

@article {pmid39636638,
year = {2024},
author = {Back, AL and Freeman-Young, TK and Morgan, L and Sethi, T and Baker, KK and Myers, S and McGregor, BA and Harvey, K and Tai, M and Kollefrath, A and Thomas, BJ and Sorta, D and Kaelen, M and Kelmendi, B and Gooley, TA},
title = {Psilocybin Therapy for Clinicians With Symptoms of Depression From Frontline Care During the COVID-19 Pandemic: A Randomized Clinical Trial.},
journal = {JAMA network open},
volume = {7},
number = {12},
pages = {e2449026},
pmid = {39636638},
issn = {2574-3805},
mesh = {Humans ; *Psilocybin/therapeutic use ; *COVID-19/psychology ; Female ; Male ; Adult ; Double-Blind Method ; *Depression/drug therapy ; *Stress Disorders, Post-Traumatic/drug therapy ; *Burnout, Professional/drug therapy ; *SARS-CoV-2 ; Middle Aged ; Pandemics ; Hallucinogens/therapeutic use ; Treatment Outcome ; },
abstract = {IMPORTANCE: The psychological morbidity experienced by physicians, advanced practice practitioners (APPs), and nurses from working during the COVID-19 pandemic includes burnout, depression, and posttraumatic stress disorder (PTSD).

OBJECTIVE: To investigate whether psilocybin therapy could improve symptoms of depression, burnout, and PTSD in US clinicians who developed these symptoms from frontline clinical work during the pandemic.

This double-blind randomized clinical trial enrolled participants from February to December 2022. Participants included physicians, APPs, and nurses who provided frontline care for more than 1 month during the pandemic and had no prepandemic mental health diagnoses but had moderate or severe symptoms of depression at enrollment. Participants were randomly assigned to either the psilocybin or niacin arm. Data analysis was conducted between December 2023 and May 2024 and was based on the intention-to-treat principle.

INTERVENTION: One intervention episode consisted of 2 preparation visits, 1 medication session, and 3 integration visits. At the medication session, participants received psilocybin, 25 mg, or niacin, 100 mg, orally.

MAIN OUTCOME AND MEASURES: The primary outcome was a change from baseline (preparation 1 session) to day 28 (after medication administration) in symptoms of depression as measured by the clinician-administered Montgomery-Asberg Depression Rating Scale (MADRS) used by blinded raters. The secondary outcomes were a change in symptoms of burnout (measured with the Stanford Professional Fulfillment Index [SPFI]) and symptoms of PTSD (measured with the Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition [PCL-5]).

RESULTS: A total of 30 clinicians (15 females [50%]; mean [range] age, 38 [29-60] years) participated, of whom 15 were randomly assigned to receive psilocybin and 15 to receive niacin. The mean change in symptoms of depression (MADRS scores) from preparation 1 session to day 28 was -21.33 (7.84) in the psilocybin arm compared with -9.33 (7.32) in the niacin arm, with a mean difference between arms of -12.00 (95% CI, -17.67 to -6.33; P < .001), a decrease in MADRS scores indicating improvement. The mean change in SPFI scores from preparation 1 session to day 28 showed a numerically larger improvement in symptoms of burnout in the psilocybin compared with the niacin arm (-6.40 [5.00] vs -2.33 [5.97]; P = .05) but was not statistically significant. Since the SPFI score change did not reach statistical significance, the PCL-5 score change was evaluated descriptively. The mean change in PCL-5 scores showed a numerically larger decrease in symptoms of PTSD from preparation 1 session to day 28 in the psilocybin vs the niacin arm (-16.67 [15.04] vs -6.73 [10.69]), but this difference was not statistically tested.

CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that psilocybin therapy resulted in a significant, sustained reduction in symptoms of depression experienced by clinicians after frontline work during the COVID-19 pandemic. The findings establish psilocybin therapy as a new paradigm of treatment for this postpandemic condition.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05163496.},
}

Humans
*Psilocybin/therapeutic use
*COVID-19/psychology
Female
Male
Adult
Double-Blind Method
*Depression/drug therapy
*Stress Disorders, Post-Traumatic/drug therapy
*Burnout, Professional/drug therapy
*SARS-CoV-2
Middle Aged
Pandemics
Hallucinogens/therapeutic use
Treatment Outcome

@article {pmid39636625,
year = {2024},
author = {Goddard, KAB and Feuer, EJ and Mandelblatt, JS and Meza, R and Holford, TR and Jeon, J and Lansdorp-Vogelaar, I and Gulati, R and Stout, NK and Howlader, N and Knudsen, AB and Miller, D and Caswell-Jin, JL and Schechter, CB and Etzioni, R and Trentham-Dietz, A and Kurian, AW and Plevritis, SK and Hampton, JM and Stein, S and Sun, LP and Umar, A and Castle, PE},
title = {Estimation of Cancer Deaths Averted From Prevention, Screening, and Treatment Efforts, 1975-2020.},
journal = {JAMA oncology},
volume = {},
number = {},
pages = {},
pmid = {39636625},
issn = {2374-2445},
abstract = {IMPORTANCE: Cancer mortality has decreased over time, but the contributions of different interventions across the cancer control continuum to averting cancer deaths have not been systematically evaluated across major cancer sites.

OBJECTIVE: To quantify the contributions of prevention, screening (to remove precursors [interception] or early detection), and treatment to cumulative number of cancer deaths averted from 1975 to 2020 for breast, cervical, colorectal, lung, and prostate cancers.

In this model-based study using population-level cancer mortality data, outputs from published models developed by the Cancer Intervention and Surveillance Modeling Network were extended to quantify cancer deaths averted through 2020. Model inputs were based on national data on risk factors, cancer incidence, cancer survival, and mortality due to other causes, and dissemination and effects of prevention, screening (for interception and early detection), and treatment. Simulated or modeled data using parameters derived from multiple birth cohorts of the US population were used.

INTERVENTIONS: Primary prevention via smoking reduction (lung), screening for interception (cervix and colorectal) or early detection (breast, cervix, colorectal, and prostate), and therapy (breast, colorectal, lung, and prostate).

MAIN OUTCOMES AND MEASURES: The estimated cumulative number of cancer deaths averted with interventions vs no advances.

RESULTS: An estimated 5.94 million cancer deaths were averted for breast, cervical, colorectal, lung, and prostate cancers combined. Cancer prevention and screening efforts averted 8 of 10 of these deaths (4.75 million averted deaths). The contribution of each intervention varied by cancer site. Screening accounted for 25% of breast cancer deaths averted. Averted cervical cancer deaths were nearly completely averted through screening and removal of cancer precursors as treatment advances were modest during the study period. Averted colorectal cancer deaths were averted because of screening and removal of precancerous polyps or early detection in 79% and treatment advances in 21%. Most lung cancer deaths were avoided by smoking reduction (98%) because screening uptake was low and treatment largely palliative before 2014. Screening contributed to 56% of averted prostate cancer deaths.

CONCLUSIONS AND RELEVANCE: Over the past 45 years, cancer prevention and screening accounted for most cancer deaths averted for these causes; however, their contribution varied by cancer site according to these models using population-level cancer mortality data. Despite progress, efforts to reduce the US cancer burden will require increased dissemination of effective interventions and new technologies and discoveries.},
}

@article {pmid39634680,
year = {2024},
author = {Alamin, T and Lin-Martore, M and Kornblith, AE and O'Donnell, A and Gragalia, S},
title = {Piloting a Diagnostic Foot and Ankle Fracture Sonographic Algorithm with Rural and Adolescent Patients.},
journal = {POCUS journal},
volume = {9},
number = {2},
pages = {102-108},
pmid = {39634680},
issn = {2369-8543},
abstract = {Background: Foot and ankle injuries are a common presenting complaint to the Emergency Department (ED) and are often assessed with plain radiography. Rural environments may not have access to radiography mandating the referral or transfer patients to regional centers for definitive diagnosis. The Ottawa Foot and Ankle Rules (OFAR) is a clinical decision rule that can assist in ruling out fractures. Point of care ultrasound (POCUS) can augment this decision rule. The objective of this study was to assess both the feasibility and test characteristics of a previously described POCUS augmented clinical assessment, OFAR-POCUS, for adolescent and adult patients with foot and ankle pain in a rural environment. Methods: This was a prospective cohort study from June to August 2022 including patients with chief complaint of foot or ankle injury presenting to a rural clinic. Patients were included if they had positive finding(s) on the OFAR Test and required radiographic imaging. Patients were excluded if they did not consent, speak English, were unable to be scanned, had obvious joint deformities, had altered mental status, were not physiologically stable, had other injuries preventing sonography, were pregnant, or had previous injury with internal fixation, osteomyelitis, or rheumatoid arthritis. POCUS was performed before transport for radiography. POCUS examiners were POCUS novices who underwent a one and a half to two-hour, standardized foot and ankle POCUS training session. All POCUS studies were reviewed by two emergency medicine ultrasound fellowship trained faculty for quality assurance. Standard test characteristics were calculated for bedside clinician and expert POCUS interpretations compared to the radiographic control. Results: Thirteen POCUS examiners performed exams on 20 patients included in analysis; four patients had fractures on radiograph (20%). The bedside clinician POCUS interpretation had sensitivity (SN) = 100% (95% Cl, 40%-100%), specificity (SP) =94% (95% Cl, 70%-100%), and negative likelihood ratio (-LR) = 16.00 (95% Cl, 2.40-106.73). Expert POCUS interpretation had SN=75% (95% Cl, 19%-99%), SP=75% (95% Cl, 48%-93%), and -LR=0.33 (95% Cl, 0.06-1.86). Conclusion: A POCUS enhanced clinical strategy for clinically significant foot and ankle fractures in adolescent and adult patients in a rural setting is feasible. Larger studies are required to further characterize test characteristics and use of foot and ankle POCUS where plain radiography is unavailable.},
}

@article {pmid39633050,
year = {2024},
author = {Lyu, A and Fan, Z and Clark, M and Lea, A and Luong, D and Setayesh, A and Starzinski, A and Wolters, R and Arias-Badia, M and Allaire, K and Wu, K and Gurunathan, V and Valderrábano, L and Wei, XX and Miller, RA and Van Allen, EM and Fong, L},
title = {Evolution of myeloid-mediated immunotherapy resistance in prostate cancer.},
journal = {Nature},
volume = {},
number = {},
pages = {},
pmid = {39633050},
issn = {1476-4687},
abstract = {Patients with advanced metastatic castration-resistant prostate cancer (mCRPC) are refractory to immune checkpoint inhibitors (ICIs)[1,2], partly because there are immunosuppressive myeloid cells in tumours[3,4]. However, the heterogeneity of myeloid cells has made them difficult to target, making blockade of the colony stimulating factor-1 receptor (CSF1R) clinically ineffective. Here we use single-cell profiling on patient biopsies across the disease continuum and find that a distinct population of tumour-associated macrophages with elevated levels of SPP1 transcripts (SPP1[hi]-TAMs) becomes enriched with the progression of prostate cancer to mCRPC. In syngeneic mouse modelling, an analogous macrophage population suppresses CD8[+] T cell activity in vitro and promotes ICI resistance in vivo. Furthermore, Spp1[hi]-TAMs are not responsive to anti-CSF1R antibody treatment. Pathway analysis identifies adenosine signalling as a potential mechanism for SPP1[hi]-TAM-mediated immunotherapeutic resistance. Indeed, pharmacological inhibition of adenosine A2A receptors (A2ARs) significantly reverses Spp1[hi]-TAM-mediated immunosuppression in CD8[+] T cells in vitro and enhances CRPC responsiveness to programmed cell death protein 1 (PD-1) blockade in vivo. Consistent with preclinical results, inhibition of A2ARs using ciforadenant in combination with programmed death 1 ligand 1 (PD-L1) blockade using atezolizumab induces clinical responses in patients with mCRPC. Moreover, inhibiting A2ARs results in a significant decrease in SPP1[hi]-TAM abundance in CRPC, indicating that this pathway is involved in both induction and downstream immunosuppression. Collectively, these findings establish SPP1[hi]-TAMs as key mediators of ICI resistance in mCRPC through adenosine signalling, emphasizing their importance as both a therapeutic target and a potential biomarker for predicting treatment efficacy.},
}

@article {pmid39632080,
year = {2024},
author = {Alamdarloo, SM and Hashemi, A and Hessami, K and Askary, E and Barzegar, H and Haseli, S and Abbaspour, E},
title = {Gross hematuria and placenta percreta: Report of two cases and literature review.},
journal = {The journal of obstetrics and gynaecology research},
volume = {},
number = {},
pages = {},
doi = {10.1111/jog.16177},
pmid = {39632080},
issn = {1447-0756},
abstract = {Placenta percreta, a rare variant of placenta accreta spectrum (PAS) disorders, poses a significant risk of life-threatening hemorrhage associated with the adherent placenta. Bladder involvement signifies an even rarer incidence and may sometimes present solely with gross hematuria. Therefore, it is imperative to consider both microscopic and gross hematuria during pregnancy as alarming signs. Among 342 cases of PAS admitted to our hospital between 2016 and 2023, 48 patients were diagnosed with placenta percreta. Two patients, one at 18 weeks and the other at 25 weeks of pregnancy, were referred to our tertiary care center due to severe gross hematuria. Following thorough preoperative evaluation, both pregnancies were terminated due to their unstable conditions. The first case underwent an elective supracervical cesarean hysterectomy at the 19th week of gestation, while the second case underwent an emergency total cesarean hysterectomy due to lack of response to blood transfusions. Both procedures included bilateral internal iliac artery ligation. Postoperatively, patients recovered without any complications; however, the fetuses did not survive. Placenta percreta, protruding into the bladder, can lead to severe hematuria at any stage of pregnancy, increasing the risk of life-threatening hemorrhage. Therefore, both microscopic and macroscopic hematuria during pregnancy should be considered alarming signs that require immediate attention. Early involvement of a urologist and a multidisciplinary medical team is also essential in suspected or confirmed cases of placenta percreta, as immediate surgical intervention may be necessary to ensure patient safety.},
}

@article {pmid39626349,
year = {2024},
author = {Liang, EC and Huang, JJ and Portuguese, AJ and Ortiz-Maldonado, V and Albittar, A and Wuliji, N and Basom, R and Jeon, Y and Wu, QV and Torkelson, A and Kirchmeier, DR and Chutnik, A and Pender, BS and Sorror, ML and Hill, JA and Kopmar, NE and Banerjee, R and Cowan, AJ and Green, DJ and Gopal, AK and Poh, C and Shadman, M and Hirayama, AV and Till, BG and Kimble, EL and Iovino, L and Chapuis, AG and Otegbeye, F and Cassaday, RD and Milano, F and Turtle, CJ and Maloney, DG and Gauthier, J},
title = {Development and validation of predictive models of early immune effector cell-associated hematotoxicity (eIPMs).},
journal = {Blood advances},
volume = {},
number = {},
pages = {},
doi = {10.1182/bloodadvances.2024014455},
pmid = {39626349},
issn = {2473-9537},
abstract = {Immune effector cell-associated hematotoxicity (ICAHT) is associated with morbidity and mortality after chimeric antigen receptor (CAR) T-cell therapy. To date, the factors associated with ICAHT are poorly characterized, and there is no validated predictive model of ICAHT specifically. Therefore, we performed comprehensive univariate analyses to identify factors associated with severe (grade 3-4) early ICAHT (eICAHT) in 691 patients who received commercial or investigational CAR T-cell therapy for hematologic malignancies. In univariate logistic regression, pre-infusion factors associated with severe eICAHT included disease type (acute lymphoblastic leukemia), pre-lymphodepletion (LD) blood counts including absolute neutrophil count (ANC), lactate dehydrogenase (LDH), and inflammatory (C-reactive protein [CRP]; ferritin, interleukin-6 [IL-6]), and coagulopathy biomarkers (D-dimer). Post-infusion laboratory markers associated with severe eICAHT included early and peak levels of inflammatory biomarkers (CRP, ferritin, IL-6), coagulopathy biomarkers (D-dimer), peak cytokine release syndrome (CRS) grade, and peak neurotoxicity grade. We trained (n = 483) and validated (n = 208) two Early ICAHT Prediction Models (eIPM): eIPMPre including pre-infusion factors only (disease type and pre-LD ANC, platelet count, LDH, and ferritin) and eIPMPost containing both pre- (disease type and pre-LD ANC, platelet count, and LDH) and post-infusion (day +3 ferritin) factors. Both models generated calibrated predictions and high discrimination (area under the receiver operating characteristic curve [AUROC] in test set: 0.87 for eIPMPre and 0.88 for eIPMPost), with higher net benefit in decision curve analysis for eIPMPost. Individualized predictions of severe eICAHT can be generated from both eIPMs utilizing our online tool (available at https://eipm.fredhutch.org).},
}

@article {pmid39626158,
year = {2024},
author = {Crupi, E and Costa de Padua, T and Marandino, L and Fallara, G and Pederzoli, F and Cimadamore, A and Goetz, EC and Cigliola, A and Patané, DA and Mercinelli, C and Tateo, V and Salonia, A and Briganti, A and Montorsi, F and Meeks, JJ and Spiess, PE and Alhalabi, O and Gao, J and Kamat, AM and Grivas, P and Necchi, A and Raggi, D},
title = {Nectin-4 Positivity in Genitourinary Malignancies: A Systematic Review.},
journal = {JCO precision oncology},
volume = {8},
number = {},
pages = {e2400470},
doi = {10.1200/PO-24-00470},
pmid = {39626158},
issn = {2473-4284},
mesh = {Humans ; *Urogenital Neoplasms/pathology/metabolism ; *Cell Adhesion Molecules/analysis ; Urinary Bladder Neoplasms/pathology/metabolism ; Male ; Nectins ; },
abstract = {PURPOSE: Aberrant expression of nectin-4 (N4) has been observed in several malignancies emerging as new target for antibody-drug conjugates, especially in urothelial carcinoma of the bladder (UBC). Limited data on N4 positivity in nonurothelial genitourinary (GU) cancers are available. This systematic-review aimed to investigate N4 positivity among GU malignancies.

METHODS: A systematic literature review was performed on March 2023 using PubMed, MEDLINE, and Embase databases according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Protocol was amended to incorporate a new updated search on March 2024.

RESULTS: Twenty-five studies evaluating N4 positivity in GU tumors were included, 14 on UBC, three on upper tract urothelial carcinoma (UTUC), six on histologic subtypes (HS) and divergent histology of the bladder, one on papillary renal cell carcinoma (pRCC), one in chromophobe RCC (chRCC), two on penile cancer, one in prostate cancer (PCa). Among UBC, stratifying per stage N4 positivity was higher in metastatic (weighted mean [WM], 90.8; range, 59.6-100) and in non-muscle-invasive (WM, 87.4; range, 86.7-88.3) than in muscle-invasive UC (WM, 83.1; range, 68.2-100). The N4 positivity of UBC was higher than UTUC (WM, 62.9; range, 44.4-65.7). Immunohistochemistry N4 positivity was reported to be lower in non-UC malignancies, including pRCC (WM, 44.1; range, 44.1-44.1), HS (WM, 63.5; range, 0-100), PCa (WM0; range, 0-0), chRCC (WM, 18.5; range, 18.5-18.5), and penile cancer (WM, 86.5; range, 61.4-98.3), compared with UBC overall (WM, 87.1; range, 59.6-100).

CONCLUSION: Non-UC malignancies seem to have a lower N4 positivity rate than UC. N4 positivity in bladder cancer appears to vary according to stage and presence of HS. The predictive and prognostic role of N4 must be further characterized in larger and prospective studies.},
}

Humans
*Urogenital Neoplasms/pathology/metabolism
*Cell Adhesion Molecules/analysis
Urinary Bladder Neoplasms/pathology/metabolism
Male
Nectins

@article {pmid39625477,
year = {2024},
author = {Sinnott-Armstrong, N and Fields, S and Roth, F and Starita, LM and Trapnell, C and Villen, J and Fowler, DM and Queitsch, C},
title = {Understanding genetic variants in context.},
journal = {eLife},
volume = {13},
number = {},
pages = {},
pmid = {39625477},
issn = {2050-084X},
support = {5RM1HG010461/NH/NIH HHS/United States ; RM1 HG010461/HG/NHGRI NIH HHS/United States ; NIGMS R35GM139532/NH/NIH HHS/United States ; Creativity Award//Bruce G. Cochener Foundation/ ; R35 GM139532/GM/NIGMS NIH HHS/United States ; },
mesh = {Humans ; *Genetic Variation ; Genomics/methods ; Genetic Predisposition to Disease ; Animals ; Phenotype ; },
abstract = {Over the last three decades, human genetics has gone from dissecting high-penetrance Mendelian diseases to discovering the vast and complex genetic etiology of common human diseases. In tackling this complexity, scientists have discovered the importance of numerous genetic processes - most notably functional regulatory elements - in the development and progression of these diseases. Simultaneously, scientists have increasingly used multiplex assays of variant effect to systematically phenotype the cellular consequences of millions of genetic variants. In this article, we argue that the context of genetic variants - at all scales, from other genetic variants and gene regulation to cell biology to organismal environment - are critical components of how we can employ genomics to interpret these variants, and ultimately treat these diseases. We describe approaches to extend existing experimental assays and computational approaches to examine and quantify the importance of this context, including through causal analytic approaches. Having a unified understanding of the molecular, physiological, and environmental processes governing the interpretation of genetic variants is sorely needed for the field, and this perspective argues for feasible approaches by which the combined interpretation of cellular, animal, and epidemiological data can yield that knowledge.},
}

Humans
*Genetic Variation
Genomics/methods
Genetic Predisposition to Disease
Animals
Phenotype

@article {pmid39624798,
year = {2024},
author = {Liu, WL and Kampouri, E and Bui, JK and Sekhon, MK and Tercero, A and Finlay, D and Asghedom, LH and Romasanta, GR and Rice, NT and Ranjbaran, F and Stoltzman, C and Cook, J and Blake, J and Delaney, CS and Hill, JA},
title = {Off-the-shelf allogeneic natural killer cells for the treatment of COVID-19.},
journal = {Molecular therapy. Methods & clinical development},
volume = {32},
number = {4},
pages = {101361},
pmid = {39624798},
issn = {2329-0501},
abstract = {Low levels and function of natural killer (NK) cells are associated with increased coronavirus disease 2019 (COVID-19) severity. NK cell immunotherapy may improve immune function to reduce infection severity. We conducted a first-in-human, open-label, phase 1, dose-escalating (100 × 10[6], 300 × 10[6], or 900 × 10[6] cells) study of a single dose of DVX201, a cord-blood-derived allogeneic NK cell therapy, in hospitalized patients with COVID-19. Participants were followed for 28 days. The maximum allowed steroid dose for eligibility was up to 0.5 mg/kg prednisone (or equivalent) daily. We enrolled nine participants, 3 per dose level. Eight participants had ≥1 comorbidity associated with increased COVID-19 severity, three of whom had a hematologic malignancy. Infusions were well tolerated, with no treatment-related adverse events. There was no evidence of inflammatory complications related to infusions. Peripheral blood NK cells generally increased after infusion, peaking by day 7. The median time from infusion to discharge was 2 days (range: 1-13). Two patients (both with acute lymphoblastic leukemia) were readmitted with recurrent COVID-19. This trial demonstrates the safety of allogeneic NK cell immunotherapy as a potential antiviral. Larger controlled trials are needed to establish efficacy.},
}

@article {pmid39624744,
year = {2024},
author = {Mittal, V and So, JY and Li, S and Swetter, SM and Linos, E and Van Horn, L and Neuhouser, ML and Stefanick, ML and Tang, JY},
title = {Associations between dietary and supplemental vitamin A intake and melanoma and non-melanoma skin cancer.},
journal = {Skin health and disease},
volume = {4},
number = {6},
pages = {e462},
pmid = {39624744},
issn = {2690-442X},
abstract = {BACKGROUND: Cutaneous melanoma (CM) and non-melanoma skin cancer (NMSC) are rising in postmenopausal women. Although high doses of oral vitamin A reduce NMSC risk in high-risk patients, the role of vitamin A in preventing skin cancer in this group remains unexplored.

OBJECTIVES: To determine the association between total (dietary and supplemental) vitamin A and risk of CM and NMSC in postmenopausal women.

METHODS: This retrospective cohort study included 52 877 White women from the Women's Health Initiative cohort, spanning from 1993 to 2019. Exposures were intake of total vitamin A, retinol and provitamin A carotenoids. Cox proportional hazard models estimated hazard ratios for overall CM incidence, whereas logistic regression determined odds ratios (ORs) for melanoma subtypes and NMSC.

RESULTS: 1154 cases of CM and 9085 cases of NMSC were identified over an average follow-up period of 17.8 years (SD 6.7). No associations were identified between total vitamin A intake and melanoma risk. Higher dietary vitamin A intake was associated with higher risk of NMSC (OR of 3rd vs. 1st tertile of dietary intake = 1.12, 95% confidence interval [CI] [1.06, 1.18]), as was dietary beta-cryptoxanthin, a provitamin A carotenoid (OR of 3rd vs. 1st tertile of dietary intake = 1.22, 95% CI [1.15, 1.29]); these results were consistent across both age- and fully adjusted regression models.

CONCLUSIONS: Total vitamin A intake was not associated with lower risk of CM or NMSC. Dietary vitamin A and beta-cryptoxanthin intake were associated with a slightly higher risk of NMSC in postmenopausal women.},
}

@article {pmid39624634,
year = {2024},
author = {Huang, Y and Dasgupta, S},
title = {Biomarker Panel Development Using Logic Regression in the Presence of Missing Data.},
journal = {The New England Journal of Statistics in Data Science},
volume = {2},
number = {1},
pages = {3-14},
pmid = {39624634},
issn = {2693-7166},
support = {R01 CA277133/CA/NCI NIH HHS/United States ; R37 AI054165/AI/NIAID NIH HHS/United States ; U24 CA086368/CA/NCI NIH HHS/United States ; },
abstract = {We consider the problem of developing flexible and parsimonious biomarker combinations for cancer early detection in the presence of variable missingness at random. Motivated by the need to develop biomarker panels in a cross-institute pancreatic cyst biomarker validation study, we propose logic-regression based methods for feature selection and construction of logic rules under a multiple imputation framework. We generate ensemble trees for classification decision, and further select a single decision tree for simplicity and interpretability. We demonstrate superior performance of the proposed methods compared to alternative methods based on complete-case data or single imputation. The methods are applied to the pancreatic cyst data to estimate biomarker panels for pancreatic cysts subtype classification and malignant potential prediction.},
}

@article {pmid39624016,
year = {2024},
author = {Georges, GE and Khanna, D and Wener, MH and Mei, MG and Mayes, MD and Simms, RW and Sanchorawala, V and Hosing, C and Kafaja, S and Pawarode, A and Holmberg, LA and Kolfenbach, J and Furst, DE and Sullivan, KM and Huang, S and Gooley, T and Nash, RA},
title = {Autologous non-myeloablative hematopoietic stem cell transplantation for diffuse cutaneous systemic sclerosis: identifying disease risk factors for toxicity and long-term outcomes in a prospective, single-arm trial.},
journal = {Arthritis & rheumatology (Hoboken, N.J.)},
volume = {},
number = {},
pages = {},
doi = {10.1002/art.43072},
pmid = {39624016},
issn = {2326-5205},
abstract = {OBJECTIVE: Two randomized trials for patients with diffuse systemic sclerosis (SSc) demonstrated an overall survival (OS) and event-free survival (EFS) advantage of autologous hematopoietic stem cell transplantation (AHSCT) using CD34+ selected peripheral blood stem cells (PBSC) compared to monthly cyclophosphamide. We asked if an unmodified PBSC graft followed by maintenance mycophenolate mofetil (MMF) after AHSCT, instead of CD34+ selected graft, could provide comparable AHSCT outcomes.

METHODS: 20 patients with high-risk SSc were enrolled in a prospective, single-arm trial with cyclophosphamide 200 mg/kg and horse anti-thymocyte globulin (CY200/ATG), followed by unmanipulated autologous PBSC, then MMF maintenance starting at 2 months after AHSCT.

RESULTS: Point estimates of OS and EFS at 5 years after AHSCT were 85% (95% CI, 60.4%-94.9%) and 75% (95% CI, 50%-88.7%), respectively. Median follow-up was 7.5 years (range, 5.6-11.6) after transplant for living patients. Eight patients (40%) required intensive care unit treatment early after transplant. Early transplant-related mortality occurred in 2 patients (10%). Five patients developed relapse/progression of SSc after AHSCT. Four of 9 patients with anti-RNA polymerase-III antibody had both prior scleroderma renal crisis and the lowest quartile of estimated glomerular filtration rate (eGFR) upon study entry; all 4 patients developed prolonged organ failure/death early post-transplant.

CONCLUSION: We observed favorable OS and EFS after AHSCT for SSc patients, using CY200/ATG, unmanipulated PBSC and MMF post-transplant maintenance, that was comparable to trials with CD34+ graft selection. We identified a possible risk factor, pretransplant low eGFR, for adverse outcome after AHSCT.},
}

@article {pmid39621969,
year = {2024},
author = {Tregnago, C and Benetton, M and Ries, RE and Peplinski, JH and Alonzo, TA and Stirewalt, D and Othus, M and Duployez, N and Sonneveld, E and Abrahamsson, J and Fogelstrand, L and von Neuhoff, N and Hasle, H and Reinhardt, D and Meshinchi, S and Locatelli, F and Pigazzi, M},
title = {Influence of Nucleophosmin (NPM1) Genotypes on Outcome of Patients With AML: An AIEOP-BFM and COG-SWOG Intergroup Collaboration.},
journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
volume = {},
number = {},
pages = {JCO2401715},
doi = {10.1200/JCO-24-01715},
pmid = {39621969},
issn = {1527-7755},
abstract = {PURPOSE: Several genomic subsets of NPM1 mutations with varying sequences (type A, B, D, etc) have been identified. Despite molecular heterogeneity, NPM1 mutations cumulatively portend a more favorable outcome, but biology and prognostic implications of different genomic subsets have not been extensively studied. In this multicentric study, we investigated the impact of NPM1 genotypes on patient's outcomes and interrogated the underlying biology of the different subtypes.

MATERIALS AND METHODS: Of more than 4,000 patients enrolled in multiple pediatric cooperative (AIEOP, BFM, ELAM02, NOPHO, DCOG, and COG trials), or adult (SWOG) trials, 348 pediatric and 75 adult AML patients with known NPM1 genotype and available outcome were selected for this study. Diverse NPM1 variants were correlated with the probabilities of overall survival (OS) and event-free survival. Nuclear localization and translational efficiency of the NPM1 variants was studied.

RESULTS: Evaluation of clinical outcome on the basis of NPM1 genotypes showed that patients with type A, B, and other rare variants had similarly favorable outcomes, whereas those with type D had a significantly worse outcome (OS of 63% for type D v 86% for type non-D, P = .005). Multivariate analysis confirmed type D as an independent prognostic factor associated with inferior OS (hazard ratio, 3; P = .005). In vitro, we demonstrated that in type D versus type A synonymous variants, codon optimality plays major roles in determining gene expression levels, and translation efficiency, which resulted in a more expressed NPM1-D mRNA and protein, mediating peculiar mitochondrial gene expression.

CONCLUSION: The evaluation of specific NPM1 genotypes identified AML patients with type D mutations being significantly associated with inferior outcomes, suggesting a reclassification of D cases to higher-risk groups.},
}

@article {pmid39621968,
year = {2024},
author = {Pusztai, L and Hoag, JR and Albain, KS and Barlow, WE and Stemmer, SM and Meisner, A and Hortobagyi, GN and Shak, S and Rae, JM and Baehner, R and Sharma, P and Kalinsky, KM},
title = {Development and Validation of the RSClinN+ Tool to Predict Prognosis and Chemotherapy Benefit for Hormone Receptor-Positive, Node-Positive Breast Cancer.},
journal = {Journal of clinical oncology : official journal of the American Society of Clinical Oncology},
volume = {},
number = {},
pages = {JCO2401507},
doi = {10.1200/JCO-24-01507},
pmid = {39621968},
issn = {1527-7755},
abstract = {PURPOSE: Clinicopathological factors and the 21-gene Oncotype DX Breast Recurrence Score (RS) test both influence prognosis. Our goal was to develop a new tool, RSClinN+, to individualize recurrence risk and chemotherapy benefit predictions by menopausal status for patients with HR+/human epidermal growth factor receptor 2-negative, lymph node-positive breast cancer by integrating the RS result with clinicopathological factors (grade, tumor size, age).

METHODS: We used patient-level data from 5,283 patients treated with chemoendocrine therapy (CET) versus endocrine therapy alone (ET) in the S1007 (N = 4,916) and S8814 (N = 367) trials to develop the tool. Cox proportional hazards regression models stratified by trial were used to estimate 5-year invasive disease-free survival for pre- and postmenopausal woman, respectively. The integrated RSClinN+ model was compared with RS alone and clinicopathological models using likelihood ratio tests. Absolute CET benefit was estimated as the difference between ET and CET risk estimates. Validation of RSClinN+ was performed in 592 patients with node-positive disease in the Clalit Health Services registry.

RESULTS: RSClinN+ provides better prognostic information than RS model alone (premenopausal P = .034; postmenopausal P < .001) or clinicopathological model alone (premenopausal P = .002; postmenopausal, P < .001). In postmenopausal women, RS showed interaction with CET benefit (P = .016), with RSClinN+ absolute CET benefit ranging from <0.1% to 21.5% over RS ranges 0-50. In premenopausal patients with RS ≤25, there was no significant interaction between RS and CET benefit. In external validation, RSClinN+ risk estimates were prognostic (hazard ratio, 1.75 [95% CI, 1.38 to 2.20]) and concordant with observed risk (Lin's concordance, 0.92).

CONCLUSION: RSClinN+ provides improved estimates of prognosis and absolute CET benefit for individual patients compared with RS or with clinical data alone and could be used in patient counseling.},
}

@article {pmid39621930,
year = {2024},
author = {Zanders, SE and Smith, GR},
title = {Killer meiotic drive executed by two alternative conformations of a single protein.},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
volume = {121},
number = {50},
pages = {e2420620121},
doi = {10.1073/pnas.2420620121},
pmid = {39621930},
issn = {1091-6490},
support = {R35 GM151982/GM/NIGMS NIH HHS/United States ; GM118120//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; },
}

@article {pmid39621322,
year = {2024},
author = {Terry, KL and Harris, HR and Missmer, SA},
title = {Endometriosis and Ovarian Cancer.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2024.21905},
pmid = {39621322},
issn = {1538-3598},
}

@article {pmid39619675,
year = {2024},
author = {Little, A and Deek, RA and Zhang, A and Zhao, N and Ling, W and Wu, MC},
title = {Enhanced visualization of microbiome data in repeated measures designs.},
journal = {Frontiers in genetics},
volume = {15},
number = {},
pages = {1480972},
pmid = {39619675},
issn = {1664-8021},
abstract = {INTRODUCTION: Repeated measures microbiome studies, including longitudinal and clustered designs, offer valuable insights into the dynamics of microbial communities and their associations with various health outcomes. However, visualizing such multivariate data poses significant challenges, particularly in distinguishing meaningful biological patterns from noise introduced by covariates and the complexities of repeated measures.

METHODS: In this study, we propose a framework to enhance the visualization of repeated measures microbiome data using Principal Coordinates Analysis (PCoA) adjusted for covariates through linear mixed models (LMM). Our method adjusts for confounding variables and accounts for the repeated measures structure of the data, enabling clearer identification of microbial community variations across time points or clusters.

RESULTS: We demonstrate the utility of our approach through simulated scenarios and real datasets, showing that it effectively mitigates the influence of nuisance covariates and highlights key axes of microbiome variation.

DISCUSSION: This refined visualization technique provides a robust tool for researchers to explore and understand microbial community dynamics in repeated measures microbiome studies.},
}

@article {pmid39619274,
year = {2024},
author = {Tsao, AS and Hsieh, MH and Koczywas, M and Tu, J and Riess, J and Tanvetyanon, T and Ma, BT and Zhao, YQ and Redman, MW and Edelman, MJ and Gandara, DR and Gray, JE and Kelly, KL},
title = {S1701, A Randomized Phase 2 Trial of Carboplatin-Paclitaxel With and Without Ramucirumab in Patients With Locally Advanced, Recurrent, or Metastatic Thymic Carcinoma.},
journal = {JTO clinical and research reports},
volume = {5},
number = {12},
pages = {100738},
pmid = {39619274},
issn = {2666-3643},
abstract = {INTRODUCTION: Thymic carcinoma is a rare and aggressive malignancy with few treatment options. Preclinical studies suggested that targeting the angiogenic pathway may be beneficial in this disease.

METHODS: This randomized phase 2 trial enrolled patients with unresectable, locally advanced, recurrent, or metastatic thymic carcinoma. Patients were randomized to receive carboplatin-paclitaxel with or without ramucirumab. The primary end point was progression-free survival (PFS) and secondary end points included response by Response Evaluation Criteria in Solid Tumors, disease control, toxicity, and overall survival. The primary analysis was done using a one-sided 10%-level log-rank test. Target sample size was 66 patients.

RESULTS: Between 2018 and 2022, 21 patients enrolled to ramucirumab plus carboplatin-paclitaxel (RCP, n = 8) and to the control arm (carboplatin-paclitaxel [CP], n = 13) with one patient on CP not meeting eligibility criteria. Owing to slow accrual, the study was terminated early by the Data and Safety Monitoring Board. Of the 20 eligible patients, eight on RCP and nine on CP received protocol treatment. PFS was not statistically different (hazard ratio = 0.51, 80% confidence interval [CI]: 0.24-1.09, p = 0.13). There were no grade 4 or higher treatment-related adverse events with RCP, although 50% experienced grade 3 adverse events, in which one patient had a grade 3 thromboembolic event. Among nine assessable patients for toxicity on CP, one patient (11%) encountered grade 4 neutropenia and one patient (11%) reported grade 3 thromboembolic events. Response rates favored the RCP arm, with an 88% (seven of eight, 80% CI: 59%-99%) response rate compared with 40% (four of 10, 80% CI: 19%-65%) on CP arm (p = 0.04). Disease control rate was higher in the RCP arm (100% versus 70%, p = 0.09). At the time of analysis, as only one death has been reported, overall survival remains immature.

CONCLUSIONS: Accrual to this population is challenging, and the study was closed early because of feasibility. Although PFS was not statistically better with RCP, the hazard ratio was 0.51 and the lack of significance was likely due to small sample sizes. Notably, addition of ramucirumab to CP led to higher response rates than CP alone. Future research should consider exploring larger multicenter trials and other combinations to improve outcomes. Challenges in enrollment emphasize the need for innovative strategies and larger collaborations in rare malignancies such as thymic carcinoma.},
}

@article {pmid39617269,
year = {2024},
author = {Franić, D and Pravica, M and Zubčić, K and Miles, S and Bedalov, A and Boban, M},
title = {Quiescent cells maintain active degradation-mediated protein quality control requiring proteasome, autophagy and nucleus-vacuole junctions.},
journal = {The Journal of biological chemistry},
volume = {},
number = {},
pages = {108045},
doi = {10.1016/j.jbc.2024.108045},
pmid = {39617269},
issn = {1083-351X},
abstract = {Many cells spend a major part of their life in quiescence, a reversible state characterized by a distinct cellular organization and metabolism. In glucose-depleted quiescent yeast cells, there is a metabolic shift from glycolysis to mitochondrial respiration, and a large fraction of proteasomes are reorganized into cytoplasmic granules containing disassembled particles. Given these changes, the operation of protein quality control (PQC) in quiescent cells, in particular the reliance on degradation-mediated PQC and the specific pathways involved, remains unclear. By examining model misfolded proteins expressed in glucose-depleted quiescent yeast cells, we found that misfolded proteins are targeted for selective degradation requiring functional 26S proteasomes. This indicates that a significant pool of proteasomes remains active in degrading quality control substrates. Misfolded proteins were degraded in a manner dependent on the E3 ubiquitin ligases Ubr1 and San1, with Ubr1 playing a dominant role. In contrast to exponentially growing cells, the efficient clearance of certain misfolded proteins additionally required intact nucleus-vacuole junctions (NVJ) and Cue5-independent selective autophagy. Our findings suggest that proteasome activity, autophagy, and NVJ-dependent degradation operate in parallel. Together the data demonstrate that quiescent cells maintain active PQC that relies primarily on selective protein degradation. The necessity of multiple degradation pathways for the removal of misfolded proteins during quiescence underscores the importance of misfolded protein clearance in this cellular state.},
}

@article {pmid39617028,
year = {2024},
author = {Bender Ignacio, RA and Shapiro, AE and Montaño, MA and Titanji, BK},
title = {An urgent call to address the intersection of mpox and HIV in Africa.},
journal = {Lancet (London, England)},
volume = {},
number = {},
pages = {},
doi = {10.1016/S0140-6736(24)02542-X},
pmid = {39617028},
issn = {1474-547X},
support = {K23 AI140918/AI/NIAID NIH HHS/United States ; R24 AI067039/AI/NIAID NIH HHS/United States ; },
}

@article {pmid39616600,
year = {2024},
author = {Hatlen, TJ and Bender Ignacio, R and Daar, ES},
title = {Advances in Treatment and Prevention of HIV.},
journal = {JAMA},
volume = {},
number = {},
pages = {},
doi = {10.1001/jama.2024.24027},
pmid = {39616600},
issn = {1538-3598},
}

@article {pmid39616467,
year = {2024},
author = {Bryce, AH and Agarwal, N and Beltran, H and Hussain, MH and Sartor, O and Shore, N and Antonarakis, ES and Armstrong, AJ and Calais, J and Carducci, MA and Dorff, TB and Efstathiou, JA and Gleave, M and Gomella, LG and Higano, C and Hope, TA and Iagaru, A and Morgans, AK and Morris, DS and Morris, MJ and Petrylak, DP and Reiter, RE and Rettig, MB and Ryan, CJ and Sellinger, SB and Spratt, DE and Srinivas, S and Tagawa, ST and Taplin, ME and Yu, EY and Zhang, T and McKay, RR and Koo, PJ and Crawford, ED},
title = {Implementing evidence-based strategies for men with biochemically recurrent and advanced prostate cancer: Consensus recommendations from the US Prostate Cancer Conference 2024.},
journal = {Cancer},
volume = {},
number = {},
pages = {},
doi = {10.1002/cncr.35612},
pmid = {39616467},
issn = {1097-0142},
abstract = {Current US clinical practice guidelines for advanced prostate cancer management contain recommendations based on high-level evidence from randomized controlled trials; however, these guidelines do not address the nuanced clinical questions that are unanswered by prospective trials but nonetheless encountered in day-to-day practice. To address these practical questions, the 2024 US Prostate Cancer Conference (USPCC 2024) was created to generate US-focused expert clinical decision-making guidance for circumstances in which level 1 evidence is lacking. At the second annual USPCC meeting (USPCC 2024), a multidisciplinary panel of experts convened to discuss ongoing clinical challenges related to 5 topic areas: biochemical recurrence; metastatic, castration-resistant prostate cancer; poly [ADP-ribose] polymerase inhibitors; prostate-specific membrane antigen radioligand therapy; and metastatic, castration-resistant prostate cancer. Through a modified Delphi process, 34 consensus recommendations were developed and are intended to provide clinicians who manage prostate cancer with guidance related to the implementation of novel treatments and technologies. In this report, the authors review the areas of consensus identified by the USPCC 2024 experts and evaluate ongoing unmet needs regarding translational application of the current clinical evidence.},
}

@article {pmid39616411,
year = {2024},
author = {Newton, H and Colla, CH and Busch, SH and Tomaino, M and Hardy, B and Brunette, MF and Agravat, D and Meara, E},
title = {Medicare Accountable Care Organization Treatment of Serious Mental Illness: Associations Between Behavioral Health Integration Activities and Outcomes.},
journal = {Medical care},
volume = {},
number = {},
pages = {},
pmid = {39616411},
issn = {1537-1948},
abstract = {OBJECTIVE: Characterize the association between Medicare Accountable Care Organizations' (ACOs) behavioral health integration capability and quality and utilization among adults with serious mental illness (SMI).

BACKGROUND: Controlled research supports the efficacy of integrating physical and mental health care for adults with SMI, yet little is known about the organizations integrating care and associations between integration capability and quality.

METHODS: We surveyed Medicare ACOs (2017-2018 National Survey of ACOs, response rate 69%) and linked responses to 2016-2017 fee-for-service Medicare claims for beneficiaries with SMI. We examined the cross-sectional association between ACO-reported integration capability (tertiles of a 14-item index) and 7 patient-level quality and utilization outcomes. We fit generalized linear models for each outcome as a function of ACO integration capability, adjusting for ACO and beneficiary characteristics.

RESULTS: Study sample included 274,928 beneficiary years (199,910 unique beneficiaries) attributed to 265 Medicare ACOs. ACOs with high behavioral health integration capability (top-tertile) served more dual-eligible beneficiaries (67.8%) than bottom-tertile (63.7%) and middle-tertile ACOs (63.3%). Most beneficiaries received follow-up 30 days after mental health hospitalization and chronic disease monitoring-exceeding national quality benchmarks-but beneficiaries receiving care from top-tertile (vs bottom-tertile) ACOs were modestly less likely to receive follow-up [-2.17 percentage points (pp), P < 0.05], diabetes monitoring (-2.19 pp, P < 0.05), and cardiovascular disease monitoring (-6.07 pp, P < 0.05). Integration capability was not correlated with utilization.

CONCLUSIONS: ACOs serving adults with substantial physical and mental health needs were more likely to report comprehensive integration capability but were not yet meeting the primary care needs of many adults with SMI.},
}

@article {pmid39616199,
year = {2024},
author = {Vadathya, AK and Garza, T and Alam, U and Ho, A and Musaad, SMA and Beltran, A and Moreno, JP and Baranowski, T and Haidar, N and Hughes, SO and Mendoza, JA and Veeraraghavan, A and Young, J and Sano, A and O'Connor, TM},
title = {Validation studies of the FLASH-TV system to passively measure children's TV viewing.},
journal = {Scientific reports},
volume = {14},
number = {1},
pages = {29805},
pmid = {39616199},
issn = {2045-2322},
support = {R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; R01DK113269//National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH)/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; P01HD109876//Eunice Kennedy Shriver National Institute of Child Health and Human Development/ ; },
mesh = {Humans ; *Television ; Female ; Male ; Child ; Screen Time ; Machine Learning ; Child, Preschool ; },
abstract = {TV viewing is associated with health risks, but existing measures of TV viewing are imprecise due to relying on self-report. We developed the Family Level Assessment of Screen use in the Home (FLASH)-TV, a machine learning pipeline with state-of-the-art computer vision methods to measure children's TV viewing. In three studies, lab pilot (n = 10), lab validation (n = 30), and home validation (n = 20), we tested the validity of FLASH-TV 3.0 in task-based protocols which included video observations of children for 60 min. To establish a gold-standard to compare FLASH-TV output, the videos were labeled by trained staff at 5-second epochs for whenever the child watched TV. For the combined sample with valid data (n = 59), FLASH-TV 3.0 provided a mean 85% (SD 8%) accuracy, 80% (SD 17%) sensitivity, 86% (SD 8%) specificity, and 0.71 (SD 0.15) kappa, compared to gold-standard. The mean intra-class correlation (ICC) of child's TV viewing durations of FLASH-TV 3.0 to gold-standard was 0.86. Overall, FLASH-TV 3.0 correlated well with the gold standard across a diverse sample of children, but with higher variability among Black children than others. FLASH-TV provides a tool to estimate children's TV viewing and increase the precision of research on TV viewing's impact on children's health.},
}

Humans
*Television
Female
Male
Child
Screen Time
Machine Learning
Child, Preschool

@article {pmid39612623,
year = {2024},
author = {Lee, MJ and Litchford, ML and Vendrame, E and Vergara, R and Ranganath, T and Fish, CS and Chebet, D and Langat, A and Mburu, C and Neary, J and Benki, S and Wamalwa, D and John-Stewart, G and Lehman, DA and Blish, CA},
title = {Distinct immune profiles in children living with HIV based on timing and duration of suppressive antiretroviral treatment.},
journal = {Virology},
volume = {602},
number = {},
pages = {110318},
doi = {10.1016/j.virol.2024.110318},
pmid = {39612623},
issn = {1096-0341},
abstract = {Timely initiation of antiretroviral therapy (ART) remains a major challenge in the effort to treat children living with HIV ("CLH") and little is known regarding the dynamics of immune normalization following ART in CLH with varying times to and durations of ART. Here, we leveraged two cohorts of virally-suppressed CLH from Nairobi, Kenya to examine differences in the peripheral immune systems between two cohorts of age-matched children (to control for immune changes with age): one group which initiated ART during early HIV infection and had been on ART for 5-6 years at evaluation (early, long-term treated; "ELT" cohort), and one group which initiated ART later and had been on ART for approximately 9 months at evaluation (delayed, short-term treated; "DST" cohort). We profiled PBMC and purified NK cells from these two cohorts by mass cytometry time-of-flight (CyTOF). Although both groups of CLH had undetectable viral RNA load at evaluation, there were marked differences in both immune composition and immune phenotype between the ELT cohort and the DST cohort. DST donors had reduced CD4 T cell percentages, decreased naive to effector memory T cell ratios, and markedly higher expression of stress-induced markers. Conversely, ELT donors had higher naive to effector memory T cell ratios, low expression of stress-induced markers, and increased expression of markers associated with an effective antiviral response and resolution of inflammation. Collectively, our results demonstrate key differences in the immune systems of virally-suppressed CLH with different ages at ART initiation and durations of treatment and provide further rationale for emphasizing early onset of ART.},
}

@article {pmid39612163,
year = {2024},
author = {Swensen, SN and Figuracion, KCF and Venur, VA and Emerson, S and Tseng, YD and Lo, SS and Ermoian, RP and Halasz, LM},
title = {Treatment Options for IDH-Mutant Malignant Gliomas.},
journal = {Current treatment options in oncology},
volume = {},
number = {},
pages = {},
pmid = {39612163},
issn = {1534-6277},
abstract = {As the peak incidence of isocitrate dehydrogenase (IDH)-mutant gliomas is amongst young adults, there is a need to balance tumor control with long term side effects of therapy. Following initial clinical presentation and acquisition of contrasted diagnostic imaging, tissue diagnosis is essential in suspected diffuse glioma. Depending on the location and extent of disease, maximal surgical resection is preferred both for histologic diagnosis and initial therapy. Partial resection or biopsy alone is considered when the tumor cannot be completely resected or if there are clinical reservations regarding a more significant operation. The classification of diffuse glioma has evolved over time, with histopathology and molecular marker status guiding discussions of prognosis and postoperative management. In patients with IDH-mutant grade 2 glioma and low-risk features, observation with active surveillance is generally recommended following a gross total resection. For those with high-risk features, which historically included age > 40 years or subtotal resection, adjuvant chemotherapy and radiation therapy are generally recommended, however decisions for adjuvant therapy pose challenges as many of the landmark historical trials guiding adjuvant therapy were performed prior to the molecularly defined era. This is an area where multiple clinical trials are ongoing and hold promise to inform treatment paradigms, including recent data on the use of IDH-mutant inhibitors in grade 2 tumors with recurrent or residual disease. For IDH-mutant grade 3 and 4 glioma, adjuvant chemotherapy and radiation are recommended for all patients after initial resection.},
}

@article {pmid39610699,
year = {2024},
author = {Wu, P and Barros-Becker, F and Ogelman, R and Camci, ED and Linbo, TH and Simon, JA and Rubel, EW and Raible, DW},
title = {Multiple mechanisms of aminoglycoside ototoxicity are distinguished by subcellular localization of action.},
journal = {Frontiers in neurology},
volume = {15},
number = {},
pages = {1480435},
pmid = {39610699},
issn = {1664-2295},
support = {R01 DC005987/DC/NIDCD NIH HHS/United States ; },
abstract = {Mechanosensory hair cells of the inner ears and lateral line of vertebrates display heightened vulnerability to environmental insult, with damage resulting in hearing and balance disorders. An important example is hair cell loss due to exposure to toxic agents including therapeutic drugs such as the aminoglycoside antibiotics neomycin and gentamicin and antineoplastic agents. We describe two distinct cellular pathways for aminoglycoside-induced hair cell death in zebrafish lateral line hair cells. Neomycin exposure results in death from acute exposure with most cells dying within 1 h of exposure. By contrast, exposure to gentamicin results primarily in delayed hair cell death, taking up to 24 h for maximal effect. Washout experiments demonstrate that delayed death does not require continuous exposure, demonstrating two mechanisms where downstream responses differ in their timing. Acute damage is associated with mitochondrial calcium fluxes and can be alleviated by the mitochondrially-targeted antioxidant mitoTEMPO, while delayed death is independent of these factors. Conversely delayed death is associated with lysosomal accumulation and is reduced by altering endolysosomal function, while acute death is not sensitive to lysosomal manipulations. These experiments reveal the complexity of responses of hair cells to closely related compounds, suggesting that intervention focusing on early events rather than specific death pathways may be a successful therapeutic strategy.},
}

@article {pmid39610652,
year = {2024},
author = {Nanduri, S and Black, A and Bedford, T and Huddleston, J},
title = {Dimensionality reduction distills complex evolutionary relationships in seasonal influenza and SARS-CoV-2.},
journal = {Virus evolution},
volume = {10},
number = {1},
pages = {veae087},
pmid = {39610652},
issn = {2057-1577},
abstract = {Public health researchers and practitioners commonly infer phylogenies from viral genome sequences to understand transmission dynamics and identify clusters of genetically-related samples. However, viruses that reassort or recombine violate phylogenetic assumptions and require more sophisticated methods. Even when phylogenies are appropriate, they can be unnecessary or difficult to interpret without specialty knowledge. For example, pairwise distances between sequences can be enough to identify clusters of related samples or assign new samples to existing phylogenetic clusters. In this work, we tested whether dimensionality reduction methods could capture known genetic groups within two human pathogenic viruses that cause substantial human morbidity and mortality and frequently reassort or recombine, respectively: seasonal influenza A/H3N2 and SARS-CoV-2. We applied principal component analysis, multidimensional scaling (MDS), t-distributed stochastic neighbor embedding (t-SNE), and uniform manifold approximation and projection to sequences with well-defined phylogenetic clades and either reassortment (H3N2) or recombination (SARS-CoV-2). For each low-dimensional embedding of sequences, we calculated the correlation between pairwise genetic and Euclidean distances in the embedding and applied a hierarchical clustering method to identify clusters in the embedding. We measured the accuracy of clusters compared to previously defined phylogenetic clades, reassortment clusters, or recombinant lineages. We found that MDS embeddings accurately represented pairwise genetic distances including the intermediate placement of recombinant SARS-CoV-2 lineages between parental lineages. Clusters from t-SNE embeddings accurately recapitulated known phylogenetic clades, H3N2 reassortment groups, and SARS-CoV-2 recombinant lineages. We show that simple statistical methods without a biological model can accurately represent known genetic relationships for relevant human pathogenic viruses. Our open source implementation of these methods for analysis of viral genome sequences can be easily applied when phylogenetic methods are either unnecessary or inappropriate.},
}

@article {pmid39609636,
year = {2024},
author = {Thomas, CE and Peters, U},
title = {Genomic landscape of cancer in racially and ethnically diverse populations.},
journal = {Nature reviews. Genetics},
volume = {},
number = {},
pages = {},
pmid = {39609636},
issn = {1471-0064},
abstract = {Cancer incidence and mortality rates can vary widely among different racial and ethnic groups, attributed to a complex interplay of genetic, environmental and social factors. Recently, substantial progress has been made in investigating hereditary genetic risk factors and in characterizing tumour genomes. However, most research has been conducted in individuals of European ancestries and, increasingly, in individuals of Asian ancestries. The study of germline and somatic genetics in cancer across racial and ethnic groups using omics technologies offers opportunities to identify similarities and differences in both heritable traits and the molecular features of cancer genomes. An improved understanding of population-specific cancer genomics, as well as translation of those findings across populations, will help reduce cancer disparities and ensure that personalized medicine and public health approaches are equitable across racial and ethnic groups.},
}

@article {pmid39609400,
year = {2024},
author = {Lemos, MP and Astronomo, RD and Huang, Y and Narpala, S and Prabhakaran, M and Mann, P and Paez, CA and Lu, Y and Mize, GJ and Glantz, H and Westerberg, K and Colegrove, H and Smythe, KS and Lin, M and Pierce, RH and Hutter, J and Frank, I and Mascola, JR and McDermott, AB and Bekker, LG and McElrath, MJ},
title = {Enhanced and sustained biodistribution of HIV-1 neutralizing antibody VRC01LS in human genital and rectal mucosa.},
journal = {Nature communications},
volume = {15},
number = {1},
pages = {10332},
pmid = {39609400},
issn = {2041-1723},
support = {UM1 AI068618/AI/NIAID NIH HHS/United States ; UM1 AI069481/AI/NIAID NIH HHS/United States ; UM1 AI069501/AI/NIAID NIH HHS/United States ; UM1 AI069534/AI/NIAID NIH HHS/United States ; UM1 AI068635/AI/NIAID NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; },
mesh = {Humans ; Female ; *HIV-1/immunology ; *Rectum/virology ; *HIV Antibodies/immunology ; Adult ; Male ; *HIV Infections/immunology/prevention & control/virology ; *Broadly Neutralizing Antibodies/immunology ; *Antibodies, Monoclonal/pharmacokinetics/immunology/administration & dosage ; Tissue Distribution ; Mucous Membrane/immunology/virology/metabolism ; Antibodies, Neutralizing/immunology ; Middle Aged ; Vagina/virology/immunology ; Young Adult ; Half-Life ; Intestinal Mucosa/metabolism/immunology ; },
abstract = {To prevent sexually-acquired HIV-1 infection by immunoprophylaxis, effective concentrations of broadly neutralizing antibodies are likely needed at mucosal sites of exposure. Here, we examine the biodistribution of monoclonal antibody VRC01 and its extended half-life variant, VRC01LS, in colorectal and genitourinary tracts of healthy adults 1-52 weeks after intravenous infusion. At 1-2 weeks, VRC01LS levels are ~3-4 times higher than VRC01 in serum (p = 0.048), rectal (p = 0.067), vaginal (p = 0.003) and cervical tissues (p = 0.003); these differences increase over time. Both antibodies primarily localize within rectal lamina propria and cervicovaginal stroma, with limited and variable epithelial distribution. Although 8-28% of serum mAb levels reach mucosal tissues, <3% are in seminal and rectal secretions. Elimination half-lives in mucosal tissues are 20-28 days for VRC01 and 51-68 days for VRC01LS. Thus, VRC01LS infusion achieves higher, sustained concentrations in human mucosal tissues than VRC01, supporting the future investigation of potent, long-acting LS-modified antibodies to prevent HIV-1.},
}

Humans
Female
*HIV-1/immunology
*Rectum/virology
*HIV Antibodies/immunology
Adult
Male
*HIV Infections/immunology/prevention & control/virology
*Broadly Neutralizing Antibodies/immunology
*Antibodies, Monoclonal/pharmacokinetics/immunology/administration & dosage
Tissue Distribution
Mucous Membrane/immunology/virology/metabolism
Antibodies, Neutralizing/immunology
Middle Aged
Vagina/virology/immunology
Young Adult
Half-Life
Intestinal Mucosa/metabolism/immunology

@article {pmid39607987,
year = {2024},
author = {Weiss, NS},
title = {Gauging the efficacy of multicancer screening: the road ahead may be long and bumpy.},
journal = {Journal of the National Cancer Institute},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnci/djae267},
pmid = {39607987},
issn = {1460-2105},
support = {/CA/NCI NIH HHS/United States ; },
}

@article {pmid39607599,
year = {2024},
author = {Ondeng'e, K and Guo, X and Mbeda, C and Schnabel, D and Panchia, R and Dominguez, K and Dadabhai, S and Hamilton, EL and Sandfort, TGM},
title = {Bisexuality among Men who have Sex with Men in Sub-Saharan Africa: Findings from the HPTN 075 Study.},
journal = {AIDS and behavior},
volume = {},
number = {},
pages = {},
pmid = {39607599},
issn = {1573-3254},
support = {R21-MH130217//National Institute of Mental Health and Neurosciences/ ; UM1-AI068613//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1-AI068617//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; P30-MH43520/MH/NIMH NIH HHS/United States ; UM1 AI068619/AI/NIAID NIH HHS/United States ; UM1-AI068619//Division of Intramural Research, National Institute of Allergy and Infectious Diseases/ ; UM1 AI068617/AI/NIAID NIH HHS/United States ; },
abstract = {Studies among men who have sex with men (MSM) in sub-Saharan Africa (SSA) focus mainly on HIV epidemiology, revealing little about the diversity within this population. We utilized data from the HIV Prevention Trials Network (HPTN) 075 study, to explore demographic and psychosexual characteristics of MSM in SSA who also have sex with women. Persons included in the analyses were aged 18-44 years and assigned male sex at birth and identified as male, reported anal sex with a man in the past 3 months, and had enrolled at one of four study sites (Kisumu, Kenya; Blantyre, Malawi; Cape Town and Soweto, South Africa). Nearly a quarter of the participants had recently engaged in sex with both men and women (MSMW). These men differed in terms of demographic and psychosexual characteristics, and sexual behavior from men who only had had sex with men (MSME). Compared to the latter, MSMW were more likely to prefer the insertive sexual role, reported more sexual partners in the past three months, and had more instances of condomless insertive anal intercourse with a man. These findings suggest that men who have sex with both men and women have specific characteristics and need tailored interventions that take their specific needs into account.},
}

@article {pmid39606729,
year = {2024},
author = {Jennings-Shaffer, C and Rich, DH and Macaulay, M and Karcher, MD and Ganapathy, T and Kiami, S and Kooperberg, A and Zhang, C and Suchard, MA and Matsen, FA},
title = {Finding high posterior density phylogenies by systematically extending a directed acyclic graph.},
journal = {ArXiv},
volume = {},
number = {},
pages = {},
pmid = {39606729},
issn = {2331-8422},
support = {R01 AI162611/AI/NIAID NIH HHS/United States ; S10 OD028685/OD/NIH HHS/United States ; },
abstract = {Bayesian phylogenetics typically estimates a posterior distribution, or aspects thereof, using Markov chain Monte Carlo methods. These methods integrate over tree space by applying local rearrangements to move a tree through its space as a random walk. Previous work explored the possibility of replacing this random walk with a systematic search, but was quickly overwhelmed by the large number of probable trees in the posterior distribution. In this paper we develop methods to sidestep this problem using a recently introduced structure called the subsplit directed acyclic graph (sDAG). This structure can represent many trees at once, and local rearrangements of trees translate to methods of enlarging the sDAG. Here we propose two methods of introducing, ranking, and selecting local rearrangements on sDAGs to produce a collection of trees with high posterior density. One of these methods successfully recovers the set of high posterior density trees across a range of data sets. However, we find that a simpler strategy of aggregating trees into an sDAG in fact is computationally faster and returns a higher fraction of probable trees.},
}

@article {pmid39606437,
year = {2024},
author = {Vo, P and Sandmaier, B and Othus, M and Ali, N and Rodríguez-Arbolí, E and Orvain, C and Davis, C and Basom, R and Storb, R and Walter, R},
title = {Relationship Between Age, Conditioning Intensity, and Outcome After Allografting in Adults Age ≥60 Years with AML.},
journal = {Research square},
volume = {},
number = {},
pages = {},
pmid = {39606437},
issn = {2693-5015},
support = {P01 CA018029/CA/NCI NIH HHS/United States ; P01 CA078902/CA/NCI NIH HHS/United States ; P30 CA015704/CA/NCI NIH HHS/United States ; },
abstract = {Methodological advancements now allow older adults with AML to receive allografts although conflicting data exist regarding relative outcomes across age groups and benefits of different conditioning intensities. We retrospectively analyzed 495 adults aged 60-64 (n = 184), 65-69 (n = 189), or ≥ 70 (n = 122) who underwent allogeneic HCT for AML in remission at our institution from 2006 to 2023. There were no significant differences in relapse or relapse-free survival (RFS) among the 3 age cohorts after multivariable adjustment. Patients aged ≥ 70 years had a higher risk of non-relapse mortality (NRM) than those aged ≥ 60-64 (P = 0.022) but their overall survival (OS) was only statistically non-significantly shorter (P = 0.11). There was an important interplay between age, conditioning intensity, and outcomes. Age ≥ 70 years was associated with a higher risk of relapse (hazard ratio [HR] = 3.47; P = 0.012) and NRM (HR = 3.88; P = 0.001) with reduced intensity conditioning (RIC), leading to shorter RFS (HR = 3.79; P < 0.001) and OS (HR = 3.46; P < 0.001), while no association was found with nonmyeloablative conditioning. Conversely, patients aged 60-64 and 65-69, not those aged ≥ 70, had a significantly lower risk of relapse with RIC, but NRM risk increased with age. Our findings support allogeneic HCT for adults with AML in remission even if aged beyond 70, especially with nonmyeloablative conditioning.},
}