@article {pmid39719543,
year = {2024},
author = {Guo, H and Malone, KE and Heckbert, SR and Li, CI},
title = {Statin use after cancer diagnosis and survival among patients with cancer.},
journal = {Cancer causes & control : CCC},
volume = {},
number = {},
pages = {},
pmid = {39719543},
issn = {1573-7225},
support = {T32CA09168/NH/NIH HHS/United States ; },
abstract = {PURPOSE: The association between statin use and cancer survival has been investigated in previous studies with conflicting findings. This study aimed to assess the association between statin use following cancer diagnosis and survival in six common cancers using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database.

METHODS: Individuals aged ≥ 66 years diagnosed with prostate cancer, colorectal cancer, lung cancer, bladder cancer, pancreatic cancer, or non-Hodgkin lymphoma (NHL) from 2008 through 2017 were identified. Statin use was defined as two or more statin prescription fills after cancer diagnosis. Time-dependent Cox proportional hazard regression models were used to estimate the association between statin use and cancer-specific mortality for each cancer.

RESULTS: This study included 34,618 patients with prostate cancer (median follow-up 4.0 years), 20,579 with colorectal cancer (2.9 years), 20,133 with lung cancer (1.7 years), 6,163 with bladder cancer (2.1 years), 4,538 with pancreatic cancer (0.8 years), and 3,270 with NHL (2.9 years). Statin use post-diagnosis was associated with a reduced risk of cancer-specific mortality in lung cancer (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.74-0.88) and pancreatic cancer (HR, 0.72; 95% CI, 0.59-0.87). The association was not statistically significant for prostate cancer, colorectal cancer, bladder cancer, or NHL. A dose-response relationship by duration of statin use was observed in lung cancer and pancreatic cancer.

CONCLUSION: Statin use after cancer diagnosis appears associated with improved survival in lung cancer and pancreatic cancer. Clinical trials of statin therapy in lung and pancreatic cancer patients are warranted to confirm these findings.},
}

@article {pmid39719506,
year = {2024},
author = {Phelps, A and Pazos-Castro, D and Urselli, F and Grydziuszko, E and Mann-Delany, O and Fang, A and Walker, TD and Guruge, RT and Tome-Amat, J and Diaz-Perales, A and Waserman, S and Boonyaratanakornkit, J and Jordana, M and Taylor, JJ and Koenig, JFE},
title = {Author Correction: Production and use of antigen tetramers to study antigen-specific B cells.},
journal = {Nature protocols},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41596-024-01131-7},
pmid = {39719506},
issn = {1750-2799},
}

@article {pmid39713477,
year = {2024},
author = {Baele, G and Carvalho, LM and Brusselmans, M and Dudas, G and Ji, X and McCrone, JT and Lemey, P and Suchard, MA and Rambaut, A},
title = {HIPSTR: highest independent posterior subtree reconstruction in TreeAnnotator X.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {39713477},
issn = {2692-8205},
abstract = {In Bayesian phylogenetic and phylodynamic studies it is common to summarise the posterior distribution of trees with a time-calibrated consensus phylogeny. While the maximum clade credibility (MCC) tree is often used for this purpose, we here show that a novel consensus tree method - the highest independent posterior subtree reconstruction, or HIPSTR - contains consistently higher supported clades over MCC. We also provide faster computational routines for estimating both consensus trees in an updated version of TreeAnnotator X, an open-source software program that summarizes the information from a sample of trees and returns many helpful statistics such as individual clade credibilities contained in the consensus tree. HIPSTR and MCC reconstructions on two Ebola virus and two SARS-CoV-2 data sets show that HIPSTR yields consensus trees that consistently contain clades with higher support compared to MCC trees. The MCC trees regularly fail to include several clades with very high posterior probability (≥ 0.95) as well as a large number of clades with moderate to high posterior probability (≥ 0.50), whereas HIPSTR achieves near-perfect performance in this respect. HIPSTR also exhibits favorable computational performance over MCC in TreeAnnotator X. Comparison to the recently developed CCD0-MAP algorithm yielded mixed results, and requires more in-depth exploration in follow-up studies. TreeAnnotator X - which is part of the BEAST X (v10.5.0) software package - is available at https://github.com/beast-dev/beast-mcmc/releases.},
}

@article {pmid39711698,
year = {2024},
author = {Guo, Y and Akcicek, EY and Hippe, DS and HashemizadehKolowri, S and Wang, X and Akcicek, H and Canton, G and Balu, N and Geleri, DB and Kim, T and Shibata, D and Zhang, K and Ma, X and Ferguson, MS and Mossa-Basha, M and Hatsukami, TS and Yuan, C},
title = {Long-Term Carotid Plaque Progression and the Role of Intraplaque Hemorrhage: Analysis from Deep Learning-based Longitudinal Vessel Wall Imaging.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {39711698},
abstract = {BACKGROUND: Carotid atherosclerosis is a major etiology of stroke. Although intraplaque hemorrhage (IPH) is known to increase stroke risk and plaque burden, its long-term effects on plaque dynamics remain unclear.

OBJECTIVES: This study aimed to evaluate the long-term impact of IPH on carotid plaque burden progression using deep learning-based segmentation on multi-contrast vessel wall imaging (VWI).

METHODS: Twenty-eight asymptomatic subjects with carotid atherosclerosis underwent an average of 4.7 ± 0.6 VWI scans over 5.8 ± 1.1 years. Deep learning pipelines segmented the carotid vessel walls and IPH. Bilateral plaque progression was analyzed using generalized estimating equations, and linear mixed-effects models evaluated long-term associations between IPH occurrence, IPH volume (%HV), and plaque burden (%WV) progression.

RESULTS: Two subjects with ipsilateral IPH developed new ischemic infarcts during follow-up. IPH was detected in 23/50 of arteries. Of arteries without IPH at baseline, 11/39 developed new IPH that persisted, while 5/11 arteries with baseline IPH exhibited it throughout the study. Bilateral plaque growth was significantly correlated (r = 0.54, p < 0.001), but this symmetry was weakened with IPH presence. The progression rate for arteries without IPH was -0.001 %/year (p = 0.895). However, IPH presence or development at any point was associated with a 2.34% absolute increase in %WV (p < 0.001), and %HV was associated with 0.73% per 2-fold increase over the mean of %HV (p = 0.005).

CONCLUSIONS: IPH may persist asymptomatically for extended periods. While arteries without IPH demonstrated minimal progression under contemporary treatment, IPH significantly accelerated long-term plaque growth.},
}

@article {pmid38853984,
year = {2024},
author = {Marsh, NM and MacEwen, MJS and Chea, J and Kenerson, HL and Kwong, AA and Locke, TM and Miralles, FJ and Sapre, T and Gozali, N and Hart, ML and Bammler, TK and MacDonald, JW and Sullivan, LB and Atilla-Gokcumen, GE and Ong, SE and Scott, JD and Yeung, RS and Sancak, Y},
title = {Mitochondrial Calcium Signaling Regulates Branched-Chain Amino Acid Catabolism in Fibrolamellar Carcinoma.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
pmid = {38853984},
issn = {2692-8205},
support = {R35 GM136234/GM/NIGMS NIH HHS/United States ; },
abstract = {Metabolic adaptations in response to changes in energy supply and demand are essential for survival. The mitochondrial calcium uniporter plays a key role in coordinating metabolic homeostasis by regulating TCA cycle activation, mitochondrial fatty acid oxidation, and cellular calcium signaling. However, a comprehensive analysis of uniporter-regulated mitochondrial pathways has remained unexplored. Here, we investigate metabolic consequences of uniporter loss- and gain-of-function using uniporter knockout cells and the liver cancer fibrolamellar carcinoma (FLC), which we demonstrate to have elevated mitochondrial calcium levels. Our results reveal that branched-chain amino acid (BCAA) catabolism and the urea cycle are uniporter-regulated metabolic pathways. Reduced uniporter function boosts expression of BCAA catabolism genes, and the urea cycle enzyme ornithine transcarbamylase (OTC). In contrast, high uniporter activity in FLC suppresses their expression. This suppression is mediated by reduced expression of the transcription factor KLF15, a master regulator of liver metabolism. Thus, uniporter responsive calcium signaling plays a central role in FLC-associated metabolic changes, including hyperammonemia. Our study identifies an important role for mitochondrial calcium signaling in metabolic adaptation through transcriptional regulation of metabolism and elucidates its importance for BCAA and ammonia metabolism in FLC.},
}

@article {pmid39718987,
year = {2024},
author = {Yalagapati, SP and Ahmadli, U and Sinha, A and Kalidass, M and Dabravolski, S and Zuo, S and Yadala, R and Rutten, T and Talbert, P and Berr, A and Lermontova, I},
title = {Centromeric localization of αKNL2 and CENP-C proteins in plants depends on their centromere-targeting domain and DNA-binding regions.},
journal = {Nucleic acids research},
volume = {},
number = {},
pages = {},
doi = {10.1093/nar/gkae1242},
pmid = {39718987},
issn = {1362-4962},
support = {LE2299/3-1//German Research Foundation/ ; 03THWST001//WIPANO Wissens und Technologietransfer durch Patente und Nomen/ ; },
abstract = {In eukaryotes, accurate chromosome segregation during cell division relies on the centromeric histone H3 variant, CENH3. Our previous work identified KINETOCHORE NULL2 (αKNL2) as a plant CENH3 assembly factor, which contains a centromere-targeting motif, CENPC-k, analogous to the CENPC motif found in CENP-C. We also demonstrated that αKNL2 can bind DNA in vitro in a sequence-independent manner, without the involvement of its CENPC-k motif. In this study, we show that the CENPC-k and CENPC motifs alone are insufficient for centromere targeting in Nicotiana benthamiana and Arabidopsis thaliana. In silico analysis identified adjacent DNA-binding regions near the CENPC-k and CENPC motifs, suggesting their role in centromeric DNA interaction. We further demonstrated that protein fragments containing these motifs effectively target centromeres. Deletion of these DNA-binding domains reduced the centromeric localization of αKNL2-C, while fusing CENPC-k to the non-specific DNA-binding domain of histone-like nucleoid structuring protein from Escherichia coli successfully targeted it to centromeres. Our findings suggest that the centromeric targeting of αKNL2 and CENP-C proteins relies on the CENPC-k/CENPC motifs, and that their sequence-independent DNA-binding activity enhances their centromere anchoring. These insights into the mechanisms of αKNL2 and CENP-C targeting may facilitate the engineering of kinetochore structures by directing chromatin-modifying proteins to centromeres.},
}

@article {pmid39718828,
year = {2024},
author = {Li, D and Geng, K and Hao, Y and Gu, J and Kumar, S and Olson, AT and Kuismi, CC and Kim, HM and Pan, Y and Sherman, F and Williams, AM and Li, Y and Li, F and Chen, T and Thakurdin, C and Ranieri, M and Meynardie, M and Levin, DS and Stephens, J and Chafitz, A and Chen, J and Donald-Paladino, MS and Powell, JM and Zhang, ZY and Chen, W and Ploszaj, M and Han, H and Gu, S and Zhang, T and Hu, B and Nacev, BA and Kaiza, ME and Berger, AH and Wang, X and Li, J and Sun, X and Liu, Y and Zhang, X and Bruno, TC and Gray, NS and Nabet, B and Wong, KK and Zhang, H},
title = {Targeted degradation of oncogenic KRASG12V triggers antitumor immunity in lung cancer models.},
journal = {The Journal of clinical investigation},
volume = {},
number = {},
pages = {},
doi = {10.1172/JCI174249},
pmid = {39718828},
issn = {1558-8238},
abstract = {KRAS is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with G12C mutation and advanced our understanding of its function. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V transgenic mouse model. We explore the therapeutic potential of KRASG12V degradation and characterize its impact on the tumor microenvironment (TME). Our study reveals that degrading KRASG12V abolishes lung and pancreatic tumors in mice and causes a robust inhibition of KRAS-regulated cancer intrinsic signaling. Importantly, targeted degradation of KRASG12V reprograms the TME towards a stimulatory milieu and drives antitumor immunity, elicited mainly by effector and cytotoxic CD8+ T cells. Our work provides important insights into the impact of degrading KRASG12V on both tumor progression and immune response, highlighting degraders as a powerful strategy for targeting KRAS mutant cancers.},
}

@article {pmid39718776,
year = {2024},
author = {Nascimento de Lima, P and Rutter, CM and van den Puttelaar, R and Hahn, AI and Ozik, J and Collier, N and Zauber, AG and Lansdorp-Vogelaar, I and Inadomi, JM},
title = {Response to Hu, Yang, and Sun.},
journal = {Journal of the National Cancer Institute},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnci/djae341},
pmid = {39718776},
issn = {1460-2105},
}

@article {pmid39718625,
year = {2024},
author = {Beigrezaei, S and Dianati, M and Salehi-Abargouei, A and Fararouei, M and Akbari-Beni, A and Brinkman, M and White, E and Weiderpass, E and Le Calvez-Kelm, F and Gunter, MJ and Huybrechts, I and Liedberg, F and Skeie, G and Tjonneland, A and Riboli, E and Zeegers, MP and Wesselius, A},
title = {The association between animal protein, plant protein, and their substitution with bladder cancer risk: a pooled analysis of 10 cohort studies.},
journal = {European journal of nutrition},
volume = {64},
number = {1},
pages = {55},
pmid = {39718625},
issn = {1436-6215},
support = {WCRF 2012/590//World Cancer Research Fund International/ ; FP7-PEOPLE-618308//European Commission/ ; },
mesh = {Humans ; *Urinary Bladder Neoplasms/epidemiology ; Female ; Male ; Middle Aged ; Risk Factors ; Prospective Studies ; Animal Proteins, Dietary/administration & dosage ; Proportional Hazards Models ; Aged ; Cohort Studies ; Europe/epidemiology ; Dietary Proteins/administration & dosage ; Follow-Up Studies ; United Kingdom/epidemiology ; Plant Proteins, Dietary/administration & dosage ; United States/epidemiology ; Adult ; Animals ; Plant Proteins/administration & dosage ; Diet/methods/statistics & numerical data ; },
abstract = {PURPOSE: Although total dietary protein intake has been associated with bladder cancer (BC) risk, the effect of the origin (plant or animal) and the substitutions remain to be understood. This study aimed to investigate the effect of total dietary protein, animal-based protein, plant-based protein, and their substitutions with each other on the risk of BC using a pooled analysis of 10 cohort studies.

METHODS: The study was conducted within the "BLadder cancer Epidemiology and Nutritional Determinants" (BLEND) study, including 10 prospective cohort studies from several European countries, the United Kingdom, and the United States. Individual data from 10 prospective cohorts containing 434,412 participants (overall male/female ratio was almost 3:1) with a total of 4,224,643.8 person-years of follow-up was analyzed. Hazard ratios (HRs) and 95% confidence intervals (CIs) for BC risk for animal and plant-based protein substitutions of 30gram (g) per day (g/day) were estimated by multivariable adjusted HRs using Cox proportional hazards models.

RESULTS: During 11.4 years of follow-up, among 434,412 participants (73.28% female), 1,440 new cases of BC were identified. After multivariable adjustment, no association was observed between the intake of total, animal-based protein, and plant-based protein and BC risk. Replacement of every 30 g/day of animal-based protein intake by the same amount of plant-based protein intake or vice versa was not associated with the risk of BC.

CONCLUSION: In conclusion, our study found no association between protein intake-whether from animal or plant sources-and the risk of BC. Substituting animal-based protein with plant-based protein, or the reverse, did not influence BC risk. Future studies are required to provide information on the link between animal- and plant-based proteins and BC risk.},
}

Humans
*Urinary Bladder Neoplasms/epidemiology
Female
Male
Middle Aged
Risk Factors
Prospective Studies
Animal Proteins, Dietary/administration & dosage
Proportional Hazards Models
Aged
Cohort Studies
Europe/epidemiology
Dietary Proteins/administration & dosage
Follow-Up Studies
United Kingdom/epidemiology
Plant Proteins, Dietary/administration & dosage
United States/epidemiology
Adult
Animals
Plant Proteins/administration & dosage
Diet/methods/statistics & numerical data

@article {pmid39718528,
year = {2024},
author = {Drover, CM and Srinivasan, S and Tapia, KA and Munch, M and Rowlinson, E and Chambers, LC and Fiedler, TL and Lowens, MS and Khosropour, CM and Manhart, LE and Fredricks, DN},
title = {Fannyhessea vaginae and clearance of Lactobacillus iners are associated with incident non-chlamydial non-Mycoplasma genitalium urethritis in men who have sex with women.},
journal = {Sexually transmitted diseases},
volume = {},
number = {},
pages = {},
doi = {10.1097/OLQ.0000000000002129},
pmid = {39718528},
issn = {1537-4521},
abstract = {BACKGROUND: The etiology of nongonococcal urethritis (NGU) is incompletely understood. We sought to determine if genitourinary bacterial diversity or specific taxa were associated with incident NGU.

METHODS: From August 2014-July 2018, men who have sex with women attending a sexual health clinic were clinically evaluated, including Mycoplasma genitalium (MG) and Chlamydia trachomatis (CT) testing, at enrollment and six monthly visits. New cases of NGU (≥5 PMNs/HPF in urethral exudates plus either symptoms or visible discharge) and their visit preceding NGU diagnosis were matched 1:1 to two sequential visits without NGU (controls). We determined associations with incident NGU and applied broad-range 16S rRNA gene polymerase chain reaction and sequencing to urine samples from each visit. We used conditional logistic regression to evaluate the association of Shannon Diversity Index (SDI), species richness, Haemophilus influenzae, Fannyhessea vaginae, Lactobacillus iners, and Streptococcus mitis group with incident non-CT-non-MG-NGU (NCNM-NGU).

RESULTS: Of 62 matched case-control pairs, median age was 32. Higher SDI the previous month was associated with higher odds of incident NCNM-NGU (adjusted odds ratio [aOR] = 2.8 per unit increase; 95% CI = 1.03-7.47), as was F. vaginae at NGU diagnosis (aOR = 5.1; 95% CI = 1.28-20.15), F. vaginae acquisition (aOR = 13.8; 95% CI = 1.96-97.33) and consistent carriage of F. vaginae (aOR = 16.1; 95% CI = 1.66-156.29). Odds of NCNM-NGU were higher when L. iners cleared between visits (aOR = 18.0; 95% CI = 1.08-299.24). Neither H. influenzae nor S. mitis group were associated with incident NCNM-NGU.

CONCLUSIONS: F. vaginae acquisition/detection and L. iners clearance were associated with urethritis. This merits investigation in larger longitudinal studies using species-specific detection methods.},
}

@article {pmid39717769,
year = {2024},
author = {Hou, J and Nakaya, HI},
title = {Editorial: Systems immunology to advance vaccine development.},
journal = {Frontiers in immunology},
volume = {15},
number = {},
pages = {1527238},
doi = {10.3389/fimmu.2024.1527238},
pmid = {39717769},
issn = {1664-3224},
}

@article {pmid39713041,
year = {2024},
author = {Dmello, C and Brenner, A and Piccioni, D and Wen, PY and Drappatz, J and Mrugala, M and Lewis, LD and Schiff, D and Fadul, CE and Chamberlain, M and Kesari, S and Ahluwalia, M and Ghosh, D and Sonabend, AM and Kumthekar, P},
title = {Phase II trial of blood-brain barrier permeable peptide-paclitaxel conjugate ANG1005 in patients with recurrent high-grade glioma.},
journal = {Neuro-oncology advances},
volume = {6},
number = {1},
pages = {vdae186},
pmid = {39713041},
issn = {2632-2498},
abstract = {BACKGROUND: This study is a phase II clinical trial to evaluate the efficacy, safety, and tolerability of the blood-brain barrier (BBB) permeable peptide-paclitaxel conjugate ANG1005 in patients with recurrent high-grade glioma (HGG) (NCT01967810).

METHODS: Seventy-three patients were enrolled in 3 separate arms-recurrent glioblastoma (GBM) (Arm 1), bevacizumab refractory GBM (Arm 2), and grade 3 anaplastic gliomas (AGs) (Arm 3). The study was started in October 2013, and the data were locked on September 29, 2017. Safety was evaluated for all three arms (n = 73), and the primary endpoint for Arms 1 and 3 was objective response rate (ORR), and Arm 2 primary endpoint was progression-free survival rate at 3 months (PFS3).

RESULTS: Overall, the safety of ANG1005 was found to be consistent with a taxane toxicity profile. Otherwise, the primary efficacy endpoints of ORR and PFS were not met. The most common adverse events (AEs) were hematologic (32.9%), alopecia (31.5%), and fatigue (30.1%). The median PFS was 1.4 months (95% CI: 1.4, 2.1) and similar across all the treatment arms. The median overall survival was 13.4 months (95% CI: 3.4, 14.6) in Arm 1, 5.8 months (95% CI: 1.9, 9.7) in Arm 2, and 18.2 months (95% CI: 10.7, 35.3) in Arm 3.

CONCLUSION: A dose of 600 mg/m[2] was determined to be safe in this study. However, the primary efficacy endpoint was not met in the NCT01967810-ANG1005 trial, and no further studies are planned in the glioma setting with this compound.},
}

@article {pmid39712972,
year = {2024},
author = {Abad, PJB and Tumulak, MJR and Yoon, SY and Laurino, MY and Hasan, Q},
title = {Bibliometric analysis of genetic counseling publications in Asia: Insights and implications.},
journal = {Genetics in medicine open},
volume = {2},
number = {Suppl 2},
pages = {101861},
pmid = {39712972},
issn = {2949-7744},
abstract = {PURPOSE: Investigation of genetic counseling-related published papers offers a historical assessment of the cumulative scientific knowledge produced by members of the profession and can be the basis for future practice, training, and research. This paper aims to present a bibliometric analysis of genetic counseling publications in Asia.

METHODS: We conducted a bibliometric analysis of genetic counseling-related manuscripts published in Asia from 1947 to 2023. We excluded articles published in 2024 given an incomplete year of data source. The articles were retrieved through the Scopus database using the search terms "genetic counsel∗" OR "genomic counsel∗" in the article titles. The bibliographic information was downloaded and analyzed descriptively through Microsoft Excel. Network visualization was done through VOSViewer.

RESULTS: A total of 449 genetic counseling-related publications authored by at least one researcher from Asian countries were identified. The most common publication type was original articles (332, 74%) and a total of 299 manuscripts were published from 2012 to 2023, representing 66.5% (299/449) of total publications. Among Asian countries, India had the highest number of publications accounting for 19.4% of the total (n = 87) and publications from Israel had the most citations (n = 1882). Out of the 29 Asian countries represented in the document corpus, 15 have links with other Asian countries. The most common keywords used are genetic counseling, prenatal diagnosis, genetic counselling, genetic testing, and genetics.

CONCLUSION: There is an overall increase in the number of genetic counseling publications authored by at least one researcher affiliated with an Asian institution. This increase has corresponded to various developments in genetic counseling in the continent and is possibly driven by collaboration between and among Asian researchers and other researchers outside of Asia. The analysis of keywords also shows the evolution of topics of genetic counseling publications which also corresponded to the development of genetic counseling as a profession in the region.},
}

@article {pmid39712486,
year = {2024},
author = {Song, H and Wu, MC},
title = {Multivariate differential association analysis.},
journal = {Stat (International Statistical Institute)},
volume = {13},
number = {2},
pages = {},
pmid = {39712486},
issn = {2049-1573},
abstract = {Identifying how dependence relationships vary across different conditions plays a significant role in many scientific investigations. For example, it is important for the comparison of biological systems to see if relationships between genomic features differ between cases and controls. In this paper, we seek to evaluate whether relationships between two sets of variables are different or not across two conditions. Specifically, we assess: do two sets of high-dimensional variables have similar dependence relationships across two conditions? We propose a new kernel-based test to capture the differential dependence. Specifically, the new test determines whether two measures that detect dependence relationships are similar or not under two conditions. We introduce the asymptotic permutation null distribution of the test statistic and it is shown to work well under finite samples such that the test is computationally efficient, significantly enhancing its usability in analyzing large datasets. We demonstrate through numerical studies that our proposed test has high power for detecting differential linear and non-linear relationships. The proposed method is implemented in an R package kerDAA.},
}

@article {pmid39711614,
year = {2024},
author = {Visani, GM and Pun, MN and Angaji, A and Nourmohammad, A},
title = {Holographic-(V)AE: An end-to-end SO(3)-equivariant (variational) autoencoder in Fourier space.},
journal = {Physical review research},
volume = {6},
number = {2},
pages = {},
pmid = {39711614},
issn = {2643-1564},
abstract = {Group-equivariant neural networks have emerged as an efficient approach to model complex data, using generalized convolutions that respect the relevant symmetries of a system. These techniques have made advances in both the supervised learning tasks for classification and regression, and the unsupervised tasks to generate new data. However, little work has been done in leveraging the symmetry-aware expressive representations that could be extracted from these approaches. Here, we present holographic-(variational) autoencoder [H-(V)AE], a fully end-to-end SO(3)-equivariant (variational) autoencoder in Fourier space, suitable for unsupervised learning and generation of data distributed around a specified origin in 3D. H-(V)AE is trained to reconstruct the spherical Fourier encoding of data, learning in the process a low-dimensional representation of the data (i.e., a latent space) with a maximally informative rotationally invariant embedding alongside an equivariant frame describing the orientation of the data. We extensively test the performance of H-(V)AE on diverse datasets. We show that the learned latent space efficiently encodes the categorical features of spherical images. Moreover, the low-dimensional representations learned by H-VAE can be used for downstream data-scarce tasks. Specifically, we show that H-(V)AE's latent space can be used to extract compact embeddings for protein structure microenvironments, and when paired with a random forest regressor, it enables state-of-the-art predictions of protein-ligand binding affinity.},
}

@article {pmid39711146,
year = {2024},
author = {Nguyen, T and Koric, A and Chang, CE and Barul, C and Radoi, L and Serraino, D and Purdue, MP and Kelsey, KT and McClean, MD and Negri, E and Edefonti, V and Moysich, K and Zhang, ZF and Morgenstern, H and Levi, F and Vaughan, TL and La Vecchia, C and Garavello, W and Hayes, RB and Benhamou, S and Schantz, SP and Yu, GP and Brenner, H and Chuang, SC and Boffetta, P and Hashibe, M and Lee, YA},
title = {Coffee and tea consumption and the risk of head and neck cancer: An updated pooled analysis in the International Head and Neck Cancer Epidemiology Consortium.},
journal = {Cancer},
volume = {},
number = {},
pages = {},
doi = {10.1002/cncr.35620},
pmid = {39711146},
issn = {1097-0142},
support = {T32CA009142/CA/NCI NIH HHS/United States ; T32CA190194/CA/NCI NIH HHS/United States ; },
abstract = {INTRODUCTION: The relations between coffee and tea consumption and head and neck cancer (HNC) incidence are unclear. With increasing global HNC burden, this study aims to examine the association between coffee, tea, and HNC.

METHODS: A pooled analysis of 9548 HNC cases and 15,783 controls from 14 individual-level case-control studies was conducted from the International Head and Neck Cancer Epidemiology consortium. Random-effects logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for HNC and its subsites, adjusting for sociodemographic and lifestyle factors.

RESULTS: Compared to non-coffee drinkers, drinking >4 cups of caffeinated coffee daily was inversely associated with HNC (OR, 0.83; 95% CI, 0.69-1.00), oral cavity (OR, 0.70; 95% CI, 0.55-0.89), and oropharyngeal cancers (OR, 0.78; 95% CI, 0.61-0.99). Drinking 3-4 cups of caffeinated coffee was inversely associated with hypopharyngeal cancer (OR, 0.59; 95% CI, 0.39-0.91). Drinking decaffeinated coffee and drinking between >0 to <1 cup daily were inversely associated with oral cavity cancer (OR, 0.75; 95% CI, 0.64-0.87 and OR, 0.66; 95% CI, 0.54-0.81). Drinking tea was inversely associated with hypopharyngeal cancer (OR, 0.71; 95% CI, 0.59-0.87). Daily tea consumption of >0 to ≤1 cup was inversely associated with HNC (OR, 0.91; 95% CI, 0.84-0.98) and hypopharyngeal cancer (OR, 0.73; 95% CI, 0.59-0.91), but drinking >1 cup was associated with laryngeal cancer (OR, 1.38; 95% CI, 1.09-1.74).

CONCLUSION: These findings support reduced HNC risk among coffee and tea drinkers. Future studies are needed to address geographical differences in types of coffee and tea to improve our understanding of the association of coffee and tea and global HNC risk.},
}

@article {pmid39710572,
year = {2024},
author = {Donzella, SM and VoPham, T and Patel, AV and McCullough, ML and Phipps, AI and Zhong, C},
title = {Associations of sleep duration and weekend catch up sleep with cancer risk among US adults in the Cancer Prevention Study-3 cohort.},
journal = {Sleep health},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.sleh.2024.10.011},
pmid = {39710572},
issn = {2352-7226},
abstract = {OBJECTIVE: Our objective was to investigate the associations of sleep duration and weekend catch-up sleep with cancer risk among US adults in the Cancer Prevention Study-3.

METHODS: Cancer Prevention Study-3 is a prospective cohort of approximately 250,000 US adults aged 30-65years. At baseline (2006-2013), participants were asked to report their average daily sleep duration over the past year for weekdays and weekends separately. Using the midpoint of each sleep duration category, a 5:2 weekday:weekend weighted average was created. Weekend catch-up sleep was calculated using the difference of weekend and weekday sleep duration category midpoints and categorized as -4 or -2, 0, 2, and 4 hours. Cancer incidence (overall and female breast) was determined via linkage to state registries; follow-up time ended at the time of cancer diagnosis, time of death, or end of follow-up (12/31/2018). We used multivariable Cox proportional hazards models to estimate adjusted hazard ratios and 95% confidence intervals for the associations of sleep duration and weekend catch-up sleep with cancer risk adjusted for sociodemographics, socioeconomic status, comorbidities, and lifestyle behaviors.

RESULTS: A total of 10,256 incident cancer cases were reported among the 248,086 participants included in the study. We found no statistically significant associations between the examined sleep characteristics with overall or breast cancer-specific risk.

CONCLUSION: Our research strengthens the existing null findings of the association between sleep duration and cancer risk. This was the first study to investigate the relationship of weekend catch-up sleep with cancer risk and more research is necessary to further elucidate this relationship.},
}

@article {pmid39709975,
year = {2024},
author = {Pelzer, PT and Stuck, L and Martinez, L and Richards, AS and Acuña-Villaorduña, C and Aronson, NE and Bonnet, M and Carvalho, AC and Chan, PC and Huang, LM and Fang, CT and Churchyard, G and Corral-Londoño, HD and Datta, M and Espinal, MA and Fielding, K and Fiore-Gartland, AJ and Garcia-Basteiro, A and Hanekom, W and Hatherill, M and Hill, PC and Huerga, H and Jones-López, EC and Kritski, A and Mandalakas, AM and Mangtani, P and Martins Netto, E and Mayanja, H and Mazahir, R and Murray, M and Rangaka, M and Scriba, T and Singh, J and Singh, S and Stein, CM and Vekemans, J and Verhagen, LM and Villalba, JA and Wajja, A and Watson, B and White, RG and Cobelens, FGJ},
title = {Effectiveness of the primary Bacillus Calmette-Guérin vaccine against the risk of Mycobacterium tuberculosis infection and tuberculosis disease: a meta-analysis of individual participant data.},
journal = {The Lancet. Microbe},
volume = {},
number = {},
pages = {100961},
doi = {10.1016/j.lanmic.2024.100961},
pmid = {39709975},
issn = {2666-5247},
abstract = {BACKGROUND: Tuberculosis vaccine trials using disease as the primary endpoint are large, time consuming, and expensive. An earlier immunological measure of the protection against disease would accelerate tuberculosis vaccine development. We aimed to assess whether the effectiveness of the Bacillus Calmette-Guérin (BCG) vaccine for prevention of Mycobacterium tuberculosis infection was consistent with that for prevention of tuberculosis disease.

METHODS: We conducted an individual participant data (IPD) meta-analysis on experimental and observational longitudinal studies before April 6, 2018, identified through systematic reviews, known to us through expert knowledge in the field, reporting on BCG vaccination status, M tuberculosis infection test (QuantiFERON IFN-γ release assay [IGRA] and tuberculin skin test [TST]), and tuberculosis incidence. Cohort studies were included only for countries with a mandatory neonatal BCG vaccination policy. Exclusion criteria were previous or current tuberculosis disease, HIV infection, tuberculosis preventive treatment usage, and for household contacts, a positive baseline IGRA or TST test and young children aged 0-2 years; for randomised controlled trials, TST results within 2 years after random assignation were excluded. We contacted the investigators of the identified studies to provide IPD. We compared the protective efficacy of the BCG vaccine against M tuberculosis infection with that against tuberculosis disease using mixed-effects, multivariable proportional hazards modelling, by study type, M tuberculosis infection test (IGRA and TST), cutoff for defining test positivity, age, sex, and latitude.

FINDINGS: We identified 79 studies eligible for full screening and of these, IPD datasets from 14 studies were included in our analysis: 11 household contact studies (29 147 participants), two adolescent cohort studies (11 368 participants), and one randomised controlled trial (2963 participants). Among 28 188 participants we found no protection by the BCG vaccine against TST conversion regardless of cutoff in any type of study. Among 1491 household contacts, but not among 5644 adolescents, the BCG vaccine protected against QuantiFERON conversion at the primary cutoff of 0·7 IU/mL or more with the adjusted hazard ratio (0·65, 95% CI 0·51-0·82) being consistent with that for protection against disease (0·68, 0·18-2·59). Protection against QuantiFERON conversion at cutoff of 0·35 IU/mL or more (0·64, 0·51-0·81) was similar.

INTERPRETATION: Protection from the BCG vaccination against M tuberculosis infection, measured as QuantiFERON conversion, is inconsistent across different groups. Among groups with recent household exposure, QuantiFERON conversion is consistent with protection against disease and could be evaluated as a proxy for disease in tuberculosis vaccine trials. We found that TST lacks value for prevention in phase 2b proof-of-concept trials.

FUNDING: Bill & Melinda Gates Foundation.},
}

@article {pmid39709604,
year = {2024},
author = {Poluben, L and Nouri, M and Liang, J and Chen, S and Varkaris, A and Ersoy-Fazlioglu, B and Voznesensky, O and Lee, II and Qiu, X and Cato, L and Seo, JH and Freedman, ML and Sowalsky, AG and Lack, NA and Corey, E and Nelson, PS and Brown, M and Long, HW and Russo, JW and Balk, SP},
title = {Increased nuclear factor I-mediated chromatin access drives transition to androgen receptor splice variant dependence in prostate cancer.},
journal = {Cell reports},
volume = {44},
number = {1},
pages = {115089},
doi = {10.1016/j.celrep.2024.115089},
pmid = {39709604},
issn = {2211-1247},
abstract = {Androgen receptor (AR) splice variants, of which ARv7 is the most common, are increased in castration-resistant prostate cancer, but the extent to which they drive AR activity is unclear. We generated a subline of VCaP cells (VCaP16) that is resistant to the AR inhibitor enzalutamide (ENZ). AR activity in VCaP16 is driven by ARv7, independently of full-length AR (ARfl), and its cistrome and transcriptome mirror those of ARfl in VCaP cells. ARv7 expression increases rapidly in response to ENZ, but there is a delay in gaining chromatin binding and transcriptional activity, which is associated with increased chromatin accessibility. AR and nuclear factor I (NFI) motifs are most enriched at more accessible sites, and NFIB/X knockdown greatly diminishes ARv7 function. These findings indicate that ARv7 can drive the AR program but that its activity is dependent on adaptations that increase chromatin accessibility to enhance its intrinsically weak chromatin binding.},
}

@article {pmid39709257,
year = {2024},
author = {Jindal, T and Jiang, C and Alhalabi, O and Nizam, A and Nguyen, C and Talukder, R and Bakaloudi, D and Davidsohn, M and Freeman, D and Glover, M and Khaki, AR and Evans, S and Lemke, E and Bose, R and Sim, W and Pywell, C and Basu, A and Kilari, D and Barata, PC and Bilen, MA and Zakharia, Y and Milowsky, MI and Shah, SA and Bellmunt, J and Grivas, P and Emamekhoo, H and Davis, NB and Gupta, S and Hoimes, C and Campbell, MT and Alva, A and Koshkin, VS},
title = {Genomic Biomarkers Associated with Enfortumab Vedotin Outcomes for Patients with Advanced Urothelial Carcinoma: Analysis of UNITE Study Data.},
journal = {European urology oncology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.euo.2024.12.006},
pmid = {39709257},
issn = {2588-9311},
abstract = {Enfortumab vedotin (EV) is used as monotherapy or combined with pembrolizumab in advanced urothelial carcinoma (aUC), but biomarker data associated with EV outcomes are limited. We identified 170 patients in the UNITE study who received EV monotherapy and had molecular biomarker data available. Outcomes for groups with and without a particular biomarker were compared using logistic regression (unadjusted) for the objective response rate (ORR), and a log-rank test and Cox proportional-hazard models (CPHMs) for progression-free survival (PFS) and overall survival (OS) from EV initiation. Molecular biomarkers were also evaluated in separate multivariable analyses using CPHMs that accounted for clinical characteristics. Median patient age was 70 yr; 78% of the cohort were male and 65% had pure UC histology. Median PFS was shorter for patients with CDKN2A alterations (4.6 vs 6 mo; p = 0.024) and for patients with CDKN2B alterations (4.4 vs 6 mo; p = 0.008). Median OS was longer for patients with high tumor mutational burden (13.6 vs 8.3 mo; p = 0.014). ORR was higher for patients with TSC1 alterations (87% vs 51%; p = 0.018). In multivariable analyses, CDKN2A and CDKN2B alterations were associated with inferior median PFS. This multi-institutional retrospective study of patients with aUC identified potential biomarkers associated with EV monotherapy outcomes that should be further investigated. PATIENT SUMMARY: We investigated genetic changes in urinary tract tumors that might be associated with response to enfortumab vedotin (EV) treatment in patients with advanced disease. Survival after EV treatment was longer for tumors with a higher number of mutations than for tumors with fewer mutations. However, mutations in two genes (CDKN2A and CDKN2B) were associated with worse outcomes after EV treatment. These findings will not affect current clinical practice, but should be investigated further in future studies.},
}

@article {pmid39708145,
year = {2024},
author = {Klein-Murrey, L and Tirschwell, DL and Hippe, DS and Kharaji, M and Sanchez-Vizcaino, C and Haines, B and Balu, N and Hatsukami, TS and Yuan, C and Akoum, NW and Lila, E and Mossa-Basha, M},
title = {Using clinical data to reclassify ESUS patients to large artery atherosclerotic or cardioembolic stroke mechanisms.},
journal = {Journal of neurology},
volume = {272},
number = {1},
pages = {87},
pmid = {39708145},
issn = {1432-1459},
support = {R01NS125635/NS/NINDS NIH HHS/United States ; },
mesh = {Humans ; Male ; Female ; *Embolic Stroke/etiology/diagnostic imaging/blood ; Aged ; Middle Aged ; Retrospective Studies ; *Atherosclerosis/complications ; *Machine Learning ; Ischemic Stroke/classification/blood ; Aged, 80 and over ; },
abstract = {PURPOSE: Embolic stroke of unidentified source (ESUS) represents 10-25% of all ischemic strokes. Our goal was to determine whether ESUS could be reclassified to cardioembolic (CE) or large-artery atherosclerosis (LAA) with machine learning (ML) using conventional clinical data.

METHODS: We retrospectively collected conventional clinical features, including patient, imaging (MRI, CT/CTA), cardiac, and serum data from established cases of CE and LAA stroke, and factors with p < 0.2 in univariable analysis were used for creating a ML predictive tool. We then applied this tool to ESUS cases, with ≥ 75% likelihood serving as the threshold for reclassification to CE or LAA. In patients with longitudinal data, we evaluated future cardiovascular events.

RESULTS: 191 ischemic stroke patients (80 CE, 61 LAA, 50 ESUS) were included. Seven and 6 predictors positively associated with CE and LAA etiology, respectively. The c-statistic for discrimination between CE and LAA was 0.88. The strongest predictors for CE were left atrial volume index (OR = 2.17 per 1 SD increase) and BNP (OR = 1.83 per 1 SD increase), while the number of non-calcified stenoses ≥ 30% upstream (OR = 0.34 per 1 SD increase) and not upstream (OR = 0.74 per 1 SD increase) from the infarct were for LAA. When applied to ESUS cases, the model reclassified 40% (20/50), with 11/50 reclassified to CE and 9/50 reclassified to LAA. In 21/50 ESUS with 30-day cardiac monitoring, 1/4 in CE and 3/16 equivocal reclassifications registered cardiac events, while 0/1 LAA reclassifications showed events.

CONCLUSION: ML tools built using standard ischemic stroke workup clinical biomarkers can potentially reclassify ESUS stroke patients into cardioembolic or atherosclerotic etiology categories.},
}

Humans
Male
Female
*Embolic Stroke/etiology/diagnostic imaging/blood
Aged
Middle Aged
Retrospective Studies
*Atherosclerosis/complications
*Machine Learning
Ischemic Stroke/classification/blood
Aged, 80 and over

@article {pmid39707483,
year = {2024},
author = {Byrne, A and Diener, C and Brown, BP and Maust, BS and Feng, C and Alinde, BL and Gibbons, SM and Koch, M and Gray, CM and Jaspan, HB and Nyangahu, DD},
title = {Neonates exposed to HIV but uninfected exhibit an altered gut microbiota and inflammation associated with impaired breast milk antibody function.},
journal = {Microbiome},
volume = {12},
number = {1},
pages = {261},
pmid = {39707483},
issn = {2049-2618},
mesh = {Humans ; *Milk, Human/immunology ; *Gastrointestinal Microbiome ; *HIV Infections/immunology/microbiology ; Female ; Infant, Newborn ; *Inflammation ; *Immunoglobulin A/blood ; Feces/microbiology/virology ; Pregnancy ; Bacteria/classification/isolation & purification ; Adult ; Male ; Virome ; C-Reactive Protein/analysis ; },
abstract = {BACKGROUND: Infants exposed to HIV but uninfected have altered immune profiles which include heightened systemic inflammation. The mechanism(s) underlying this phenomenon is unknown. Here, we investigated differences in neonatal gut bacterial and viral microbiome and associations with inflammatory biomarkers in plasma. Further, we tested whether HIV exposure impacts antibody-microbiota binding in neonatal gut and whether antibodies in breast milk impact the growth of commensal bacteria.

RESULTS: Neonates exposed to HIV but uninfected (nHEU) exhibited altered gut bacteriome and virome compared to unexposed neonates (nHU). In addition, HIV exposure differentially impacted IgA-microbiota binding in neonates. The relative abundance of Blautia spp. in the whole stool or IgA-bound microbiota was positively associated with plasma concentrations of C-reactive protein. Finally, IgA from the breast milk of mothers living with HIV displayed a significantly lower ability to inhibit the growth of Blautia coccoides which was associated with inflammation in nHEU.

CONCLUSION: nHEU exhibits profound alterations in gut bacterial microbiota with a mild impact on the enteric DNA virome. Elevated inflammation in nHEU could be due to a lower capacity of breast milk IgA from mothers living with HIV to limit growth the of gut bacteria associated with inflammation. Video Abstract.},
}

Humans
*Milk, Human/immunology
*Gastrointestinal Microbiome
*HIV Infections/immunology/microbiology
Female
Infant, Newborn
*Inflammation
*Immunoglobulin A/blood
Feces/microbiology/virology
Pregnancy
Bacteria/classification/isolation & purification
Adult
Male
Virome
C-Reactive Protein/analysis

@article {pmid39706832,
year = {2024},
author = {Jaberi-Douraki, M and Xu, X and Dima, D and Ailawadhi, S and Anwer, F and Mazzoni, S and Valent, J and Habib, MH and Riviere, JE and Raza, S},
title = {Global disparities in drug-related adverse events of patients with multiple myeloma: a pharmacovigilance study.},
journal = {Blood cancer journal},
volume = {14},
number = {1},
pages = {223},
pmid = {39706832},
issn = {2044-5385},
mesh = {Humans ; *Multiple Myeloma/drug therapy/epidemiology ; Male ; Female ; *Pharmacovigilance ; *Drug-Related Side Effects and Adverse Reactions/epidemiology/etiology ; Middle Aged ; Aged ; Adult ; Antineoplastic Agents/adverse effects/therapeutic use ; },
abstract = {Multiple myeloma (MM) is a complex hematological malignancy of clonal plasma cells driven by alterations to the chromosomal material leading to uncontrolled proliferation in the bone marrow. Ethnic and racial disparities persist in the prevalence, diagnosis, management, and outcomes of MM. These disparities are multifaceted and intersect with various factors, including demographics, geography, socioeconomic status, genetics, and access to healthcare. This study utilized the openFDA human drug adverse events (AEs) to analyze global data pertaining to MM patients and patterns of treatment-related AEs. We identified ten most frequently used drugs and drug regimens in six distinct regions, including North America (NA), Europe (EU), Asia (AS), Africa (AF), Oceania (OC), and Latin America & the Caribbean (LA). AE patterns were evaluated using the reporting odds ratio combined with a 95% confidence interval. AE reports were more prevalent in men than in women across all regions. Cardiotoxicities were more likely observed in AS and EU, while secondary neoplasms were more frequently reported in the EU. Nephropathies were prominent in OC, AF (in males), and AS (in females), while vascular toxicity, including embolism and thrombosis, was more common in NA (in males). A notable improvement in survival, particularly in AS, EU, and NA, with a significant decline in death rates was observed. Hospitalization rates displayed less variation in AS and EU but exhibited more pronounced fluctuations in AF, LA, and OC. In conclusion, this comprehensive analysis offers valuable insights into the demographic, geographic, and AE patterns of MM patients across the globe.},
}

Humans
*Multiple Myeloma/drug therapy/epidemiology
Male
Female
*Pharmacovigilance
*Drug-Related Side Effects and Adverse Reactions/epidemiology/etiology
Middle Aged
Aged
Adult
Antineoplastic Agents/adverse effects/therapeutic use

@article {pmid39706786,
year = {2024},
author = {St-Laurent, MP and Bochner, B and Catto, J and Davies, BJ and Fankhauser, CD and Garg, T and Hamilton-Reeves, J and Master, V and Jensen, BT and Lauridsen, SV and Wulff-Burchfield, E and Psutka, SP},
title = {Increasing Life Expectancy in Patients with Genitourinary Malignancies: Impact of Treatment Burden on Disease Management and Quality of Life.},
journal = {European urology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.eururo.2024.11.026},
pmid = {39706786},
issn = {1873-7560},
abstract = {BACKGROUND AND OBJECTIVE: Treatment burden refers to the overall impact of medical treatments on a patient's well-being and daily life. Our objective is to evaluate the impact of treatment burden on quality of life (QoL) in patients with genitourinary (GU) malignancies, highlighting the importance of patient-reported outcomes (PROs) in clinical trials to inform treatment decisions and improve patient care.

METHODS: We conducted a narrative review of clinical trials focused on GU malignancy (prostate, bladder, and kidney) between January 2000 and June 2024, analyzing related PROs and findings regarding treatment burden.

KEY FINDINGS AND LIMITATIONS: Recent landmark clinical trials demonstrate significant improvements in overall survival across GU malignancies with novel therapies. However, the reporting of QoL outcomes in these trials is often inadequate, with many lacking comprehensive data or long-term impact. Current publications are increasingly evaluating treatment burden and its impact on patient well-being as a critical outcome, but most clinical trials to date have failed to assess treatment burden across key domains including financial, time and travel, and medication management.

While advancements in treatment have extended longevity in patients with GU malignancies, the treatment burden associated with the receipt of novel agents and its implications for QoL remain inadequately uncharacterized.},
}

@article {pmid39706336,
year = {2024},
author = {Goyal, L and DiToro, D and Facchinetti, F and Martin, EE and Peng, P and Baiev, I and Iyer, R and Maurer, J and Reyes, S and Zhang, K and Majeed, U and Berchuck, JE and Chen, CT and Walmsley, C and Pinto, C and Vasseur, D and Gordan, JD and Mody, K and Borad, M and Karasic, T and Damjanov, N and Danysh, BP and Wehrenberg-Klee, E and Kambadakone, AR and Saha, SK and Hoffman, ID and Nelson, KJ and Iyer, S and Qiang, X and Sun, C and Wang, H and Li, L and Javle, M and Lin, B and Harris, W and Zhu, AX and Cleary, JM and Flaherty, KT and Harris, T and Shroff, RT and Leshchiner, I and Parida, L and Kelley, RK and Fan, J and Stone, JR and Uboha, NV and Hirai, H and Sootome, H and Wu, F and Bensen, DC and Hollebecque, A and Friboulet, L and Lennerz, JK and Getz, G and Juric, D},
title = {A Model for Decoding Resistance in Precision Oncology: Acquired Resistance to FGFR inhibitors in Cholangiocarcinoma.},
journal = {Annals of oncology : official journal of the European Society for Medical Oncology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.annonc.2024.12.011},
pmid = {39706336},
issn = {1569-8041},
abstract = {BACKGROUND: Fibroblast growth factor receptor (FGFR) inhibitors have significantly improved outcomes for patients with FGFR-altered cholangiocarcinoma, leading to their regulatory approval in multiple countries. However, as with many targeted therapies, acquired resistance limits their efficacy. A comprehensive, multimodal approach is crucial to characterizing resistance patterns to FGFR inhibitors.

PATIENTS AND METHODS: This study integrated data from six investigative strategies: cell-free DNA, tissue biopsy, rapid autopsy, statistical genomics, in vitro and in vivo studies, and pharmacology. We characterized the diversity, clonality, frequency, and mechanisms of acquired resistance to FGFR inhibitors in patients with FGFR-altered cholangiocarcinoma. Clinical samples were analyzed longitudinally as part of routine care across 10 institutions.

RESULTS: Among 138 patients evaluated, 77 met eligibility, yielding a total of 486 clinical samples. Patients with clinical benefit exhibited a significantly higher rate of FGFR2 kinase domain mutations compared to those without clinical benefit (65% vs 10%, p<0.0001). We identified 26 distinct FGFR2 kinase domain mutations, with 63% of patients harboring multiple. While IC50 assessments indicated strong potency of pan-FGFR inhibitors against common resistance mutations, pharmacokinetic studies revealed that low clinically achievable drug concentrations may underly polyclonal resistance. Molecular brake and gatekeeper mutations predominated, with 94% of patients with FGFR2 mutations exhibiting one or both, whereas mutations at the cysteine residue targeted by covalent inhibitors were rare. Statistical genomics and functional studies demonstrated that mutation frequencies were driven by their combined effects on drug binding and kinase activity rather than intrinsic mutational processes.

CONCLUSION: Our multimodal analysis led to a model characterizing the biology of acquired resistance, informing the rational design of next-generation FGFR inhibitors. FGFR inhibitors should be small, high-affinity, and selective for specific FGFR family members. Tinengotinib, a novel small molecule inhibitor with these characteristics, exhibited preclinical and clinical activity against key resistance mutations. This integrated approach offers a blueprint for advancing drug resistance research across cancer types.},
}

@article {pmid39705656,
year = {2024},
author = {Olivieri, DJ and Banerjee, R},
title = {Impatient for Outpatient: Operationalizing Bispecific Antibodies for Multiple Myeloma in the Ambulatory Setting.},
journal = {JCO oncology practice},
volume = {},
number = {},
pages = {OP2400921},
doi = {10.1200/OP-24-00921},
pmid = {39705656},
issn = {2688-1535},
}

@article {pmid39705106,
year = {2024},
author = {Lee, J and Wein, PY and Heffner, JL and Weinberger, AH and Hinds, JT and , },
title = {Practicing inclusive language related to people who are lesbian, gay, bisexual, transgender, queer, intersex, asexual and other sexual and gender identities (LGBTQIA+) in nicotine and tobacco research.},
journal = {Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco},
volume = {},
number = {},
pages = {},
doi = {10.1093/ntr/ntae305},
pmid = {39705106},
issn = {1469-994X},
}

@article {pmid39704522,
year = {2024},
author = {Kader, T and Lin, JR and Hug, CB and Coy, S and Chen, YA and de Bruijn, I and Shih, N and Jung, E and Pelletier, RJ and Lopez Leon, M and Mingo, G and Omran, DK and Lee, JS and Yapp, C and Satravada, BA and Kundra, R and Xu, Y and Chan, S and Tefft, JB and Muhlich, JL and Kim, SH and Gysler, SM and Agudo, J and Heath, JR and Schultz, N and Drescher, CW and Sorger, PK and Drapkin, R and Santagata, S},
title = {Multimodal Spatial Profiling Reveals Immune Suppression and Microenvironment Remodeling in Fallopian Tube Precursors to High-Grade Serous Ovarian Carcinoma.},
journal = {Cancer discovery},
volume = {},
number = {},
pages = {},
doi = {10.1158/2159-8290.CD-24-1366},
pmid = {39704522},
issn = {2159-8290},
abstract = {High-Grade Serous Ovarian Cancer (HGSOC) originates from fallopian tube (FT) precursors. However, the molecular changes that occur as precancerous lesions progress to HGSOC are not well understood. To address this, we integrated high-plex imaging and spatial transcriptomics to analyze human tissue samples at different stages of HGSOC development, including p53 signatures, serous tubal intraepithelial carcinomas (STIC), and invasive HGSOC. Our findings reveal immune modulating mechanisms within precursor epithelium, characterized by chromosomal instability, persistent interferon (IFN) signaling, and dysregulated innate and adaptive immunity. FT precursors display elevated expression of MHC-class I, including HLA-E, and IFN-stimulated genes, typically linked to later-stage tumorigenesis. These molecular alterations coincide with progressive shifts in the tumor microenvironment, transitioning from immune surveillance in early STICs to immune suppression in advanced STICs and cancer. These insights identify potential biomarkers and therapeutic targets for HGSOC interception and clarify the molecular transitions from precancer to cancer.},
}

@article {pmid39703032,
year = {2024},
author = {Zhang, Y and Lindström, S and Kraft, P and Liu, Y},
title = {Response to zhang and Lv.},
journal = {Journal of the National Cancer Institute},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnci/djae323},
pmid = {39703032},
issn = {1460-2105},
}

@article {pmid39701546,
year = {2024},
author = {Perlow, HK and Raleigh, DR and Wang, TJC and Pollom, EL and Milano, MT and Breen, WG and Detsky, J and Chang, EL and Tom, MC and Shiue, KR and Lehrer, EJ and Saeed, H and Pike, LRG and Lo, SS and Mishra, MV and Knisely, JPS and Chao, ST and Sahgal, A and Palmer, JD},
title = {Consensus Radiation Treatment Planning Guidelines Utilizing (68)Ga-DOTATATE PET/CT for Resected Meningiomas.},
journal = {International journal of radiation oncology, biology, physics},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.ijrobp.2024.12.003},
pmid = {39701546},
issn = {1879-355X},
abstract = {BACKGROUND: Meningiomas are the most common primary intracranial tumor. Somatostatin receptor 2 (SSTR 2) is almost universally expressed in meningioma tissue. For patients who require adjuvant radiation, SSTR based (68)Ga-DOTATATE positron emission tomography (PET) imaging can detect additional or residual disease not discernible on magnetic resonance imaging (MRI). PET-guided radiation treatments may improve local control, minimize toxicity by allowing for more precise radiotherapy plans, and allow for more precise dose escalation to maximize local control. The aim of this study was to develop consensus PET-guided treatment planning guidelines for common meningioma presentations.

METHODS: Five post-operative clinically relevant meningioma cases were selected from a prospective single-institutional registry of patients. Each patient had a preoperative and post-operative contrast enhanced T1-weighted volumetric MRI, and a post-operative (68)Ga-DOTATATE PET/CT, to assist with target delineation. The full treatment scenario including clinical history, histology, surgical history, and imaging were provided for each patient. Nineteen international experts who have published on the treatment and management of meningiomas, and who utilize (68)Ga-DOTATATE PET/CT in their practice, evaluated each case. Individual prescription recommendations were created, pooled, and discussed to create consensus recommendations.

RESULTS: Consensus recommendations were created for each case. In most cases, PET-based contouring allowed for more precise-dose escalation to 66-70Gy targeting residual disease. When compared to RTOG 0539 and modern clinical trial contouring guidelines, a smaller CTV expansion from the surgical cavity was recommended using PET-guided radiation plans in the absence of radiographic or pathologic evidence of brain or bone invasion.

CONCLUSION: This report provides consensus target volume delineation guidelines for meningiomas receiving postoperative radiation in common clinical situations. Integration of these guidelines into clinical practice may allow for more precise biomarker-guided radiation treatments and standardize radiotherapy on future meningioma clinical trials.},
}

@article {pmid39701289,
year = {2024},
author = {Bhatt, NS and Harris, AC and Gorfinkel, L and Ibanez, K and Tkaczyk, ER and Mitchell, SA and Albuquerque, S and Schechter, T and Pavletic, S and Duncan, CN and Rotz, SJ and Williams, K and Carpenter, PA and Cuvelier, GDE},
title = {Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-Versus-Host Disease Survivorship After Hematopoietic Cell Transplantation: Part I. Phases of Chronic GVHD, Supportive Care, and Systemic Therapy Discontinuation.},
journal = {Transplantation and cellular therapy},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.jtct.2024.12.011},
pmid = {39701289},
issn = {2666-6367},
abstract = {Current literature lacks details on the impact of pediatric chronic graft-versus-host disease (cGVHD) on long-term survivorship after allogeneic hematopoietic cell transplantation (HCT). Nonetheless, cGVHD remains a leading cause of post-transplant morbidity and mortality in children and adolescents, which is particularly relevant given the longer life-expectancy after HCT (measured in decades) compared to older adults. To address this knowledge gap, leaders of the Pediatric Transplant and Cellular Therapy Consortium convened a multidisciplinary taskforce of experts in pediatric cGVHD and HCT late effects known as RESILIENT after Chronic GVHD (Research and Education towards Solutions for Late effects to Innovate, Excel, and Nurture after cGVHD). Our goals were to define: (1) the current state of understanding about how cGVHD impacts long-term survivorship in children transplanted <18 years of age; (2) practical aspects of care to help clinicians managing long-term pediatric cGVHD survivors; and (3) develop a research framework for the next decade to further our knowledge. Four working groups were formed, each tasked with addressing a unique theme: (1) cGVHD natural history (phases of cGVHD) and its impact on clinicians' ability to taper and durably discontinue systemic therapy; (2) organ dysfunction and immune reconstitution in relation to survivorship; (3) how cGVHD and its treatment impact growth, metabolism, and development in children; and (4) psychosocial health and patient reported outcomes. The four groups met before the 2024 BMT Tandem Meeting in San Antonio, Texas, and then convened a larger in-person RESILIENT conference held on February 20, 2024, at the Tandem meeting to put forth recommendations from their respective working groups and garner feedback. These recommendations are now presented in a series of 4 manuscripts. This current manuscript focuses on the first theme and discusses the phases of cGVHD, challenges in differentiating clinically active from quiescent cGVHD in clinical practice, and the resultant difficulties in determining when and if to taper systemic therapy. To overcome these challenges, we propose revised categorization of long-term cGVHD outcomes and practical recommendations for clinicians and researchers around the long-term follow-up for these patients, including determining when and if to taper systemic therapy, along with the integration of non-immunosuppressive supportive care interventions.},
}

@article {pmid39701282,
year = {2024},
author = {Daoudlarian, D and Segot, A and Latifyan, S and Bartolini, R and Joo, V and Mederos, N and Bouchaab, H and Demicheli, R and Abdelhamid, K and Ferahta, N and Doms, J and Stalder, G and Noto, A and Mencarelli, L and Mosimann, V and Berthold, D and Stravodimou, A and Sartori, C and Shabafrouz, K and Thompson, JA and Wang, Y and Peters, S and Pantaleo, G and Obeid, M},
title = {Tocilizumab and immune signatures for targeted management of cytokine release syndrome in immune checkpoint therapy.},
journal = {Annals of oncology : official journal of the European Society for Medical Oncology},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.annonc.2024.12.004},
pmid = {39701282},
issn = {1569-8041},
abstract = {BACKGROUND: This study aimed to identify specific biomarkers in oncology patients experiencing immune-related cytokine release syndrome (irCRS)-like symptoms during immune checkpoint inhibitor (ICI) therapy, including severe cases like hemophagocytic lymphohistiocytosis (irHLH), and to distinguish these from sepsis. A secondary objective was to retrospectively analyze the efficacy of tocilizumab (TCZ) in treating corticosteroid (CS)-refractory high-grade irCRS.

PATIENTS AND METHODS: A cohort of 35 patients presenting with irCRS-like symptoms was studied, including 9 with irHLH-like manifestations and 8 with sepsis. Immune profiling was performed using 48 mass cytometry markers, along with an analysis of 45 serum biomarkers, including 27 cytokines and 18 additional markers from the HScore. Twelve patients with high-grade irCRS refractory to CS were treated with TCZ.

RESULTS: 24 biomarkers significantly distinguished between irHLH and Grade 3 irCRS (P=0.0027-0.0455). Hepatocyte growth factor (HGF) and ferritin had superior predictive values compared to the traditional HScore, both with a positive predictive value (PPV) and negative predictive value (NPV) of 100%. CXCL9 differentiated irHLH from Grade 3 irCRS and predicted the need for TCZ treatment intensification (PPV=90%, NPV=100%). Additional biomarkers, including leukocyte count, neutrophils, ferritin, IL-6, IL-7, EGF, fibrinogen, and GM-CSF, discriminated sepsis from high-grade irCRS (PPV=75-80%, NPV=100%). Elevated frequencies of CXCR5+ or CCR4+ CD8 memory cells, CD38+ intermediate monocytes, and CD62L+ neutrophils were observed in high-grade irCRS compared to sepsis. All 12 patients with high-grade irCRS refractory to CS treated with TCZ experienced complete resolution.

CONCLUSIONS: This study highlights the importance of specific immunologic biomarkers in determining irCRS severity, predicting outcomes, and distinguishing between irHLH, irCRS, and sepsis. It also demonstrates the efficacy of TCZ in managing high-grade irCRS, underscoring the need for personalized therapeutic strategies based on these biomarkers.},
}

@article {pmid39699239,
year = {2024},
author = {Weiss, NS},
title = {Reducing-a little-the high price of randomized trials of the efficacy of multicancer early detection.},
journal = {Journal of the National Cancer Institute},
volume = {},
number = {},
pages = {},
doi = {10.1093/jnci/djae292},
pmid = {39699239},
issn = {1460-2105},
support = {/CA/NCI NIH HHS/United States ; },
}

@article {pmid39677467,
year = {2024},
author = {Figgins, MD and Bedford, T},
title = {Frequency dynamics predict viral fitness, antigenic relationships and epidemic growth.},
journal = {medRxiv : the preprint server for health sciences},
volume = {},
number = {},
pages = {},
pmid = {39677467},
abstract = {During the COVID-19 pandemic, SARS-CoV-2 variants drove large waves of infections, fueled by increased transmissibility and immune escape. Current models focus on changes in variant frequencies without linking them to underlying transmission mechanisms of intrinsic transmissibility and immune escape. We introduce a framework connecting variant dynamics to these mechanisms, showing how host population immunity interacts with viral transmissibility and immune escape to determine relative variant fitness. We advance a selective pressure metric that provides an early signal of epidemic growth using genetic data alone, crucial with current underreporting of cases. Additionally, we show that a latent immunity space model approximates immunological distances, offering insights into population susceptibility and immune evasion. These insights refine real-time forecasting and lay the groundwork for research into the interplay between viral genetics, immunity, and epidemic growth.},
}

@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.},
}