tbuckley/cabot-search huggingface dataset:
Differences in cancer rates among adults born between 1920 and 1990 in the USA: an analysis of population-based cancer registry data
Authors: Hyuna Sung, Chenxi Jiang, Priti Bandi, Adair Minihan, Miranda Fidler-Benaoudia, Farhad Islami, Rebecca L Siegel, Ahmedin Jemal
Journal: The Lancet Public Health (2024)

BackgroundTrends in cancer incidence in recent birth cohorts largely reflect changes in exposures during early life and foreshadow the future disease burden. Herein, we examined cancer incidence and mortality trends, by birth cohort, for 34 types of cancer in the USA.MethodsIn this analysis, we obtained incidence data for 34 types of cancer and mortality data for 25 types of cancer for individuals aged 25–84 years for the period Jan 1, 2000, to Dec 31, 2019 from the North American Association of Central Cancer Registries and the US National Center for Health Statistics, respectively. We calculated birth cohort-specific incidence rate ratios (IRRs) and mortality rate ratios (MRRs), adjusted for age and period effects, by nominal birth cohort, separated by 5 year intervals, from 1920 to 1990.FindingsWe extracted data for 23 654 000 patients diagnosed with 34 types of cancer and 7 348 137 deaths from 25 cancers for the period Jan 1, 2000, to Dec 31, 2019. We found that IRRs increased with each successive birth cohort born since approximately 1920 for eight of 34 cancers (pcohort<0·050). Notably, the incidence rate was approximately two-to-three times higher in the 1990 birth cohort than in the 1955 birth cohort for small intestine (IRR 3·56 [95% CI 2·96–4·27]), kidney and renal pelvis (2·92 [2·50–3·42]), and pancreatic (2·61 [2·22–3·07]) cancers in both male and female individuals; and for liver and intrahepatic bile duct cancer in female individuals (2·05 [1·23–3·44]). Additionally, the IRRs increased in younger cohorts, after a decline in older birth cohorts, for nine of the remaining cancers (pcohort<0·050): oestrogen-receptor-positive breast cancer, uterine corpus cancer, colorectal cancer, non-cardia gastric cancer, gallbladder and other biliary cancer, ovarian cancer, testicular cancer, anal cancer in male individuals, and Kaposi sarcoma in male individuals. Across cancer types, the incidence rate in the 1990 birth cohort ranged from 12% (IRR1990 vs 1975 1·12 [95% CI 1·03–1·21] for ovarian cancer) to 169% (IRR1990 vs 1930 2·69 [2·34–3·08] for uterine corpus cancer) higher than the rate in the birth cohort with the lowest incidence rate. The MRRs increased in successively younger birth cohorts alongside IRRs for liver and intrahepatic bile duct cancer in female individuals, uterine corpus, gallbladder and other biliary, testicular, and colorectal cancers, while MRRs declined or stabilised in younger birth cohorts for most cancers types.Interpretation17 of 34 cancers had an increasing incidence in younger birth cohorts, including nine that previously had declining incidence in older birth cohorts. These findings add to growing evidence of increased cancer risk in younger generations, highlighting the need to identify and tackle underlying risk factors.FundingAmerican Cancer Society.
Mortality due to falls by county, age group, race, and ethnicity in the USA, 2000–19: a systematic analysis of health disparities
Authors: Parkes Kendrick, Yekaterina O Kelly, Mathew M Baumann, Ethan Kahn, Kelly Compton, Chris Schmidt, Dillon O Sylte, Zhuochen Li, Wichada La Motte-Kerr, Farah Daoud, Kanyin Liane Ong, Madeline Moberg, Simon I Hay, Erik J Rodriquez, Paula D Strassle, George A Mensah, Frank C Bandiera, Stephanie M George, Eleanor M Simonsick, Colleen Brown, Eliseo J Pérez-Stable, Christopher J L Murray, Ali H Mokdad, Laura Dwyer-Lindgren
Journal: The Lancet Public Health (2024)

Fall-related mortality has increased rapidly over the past two decades in the USA, but the extent to which mortality varies across racial and ethnic populations, counties, and age groups is not well understood. The aim of this study was to estimate age-standardised mortality rates due to falls by racial and ethnic population, county, and age group over a 20-year period.
The long-term effects of domestic and international tuberculosis service improvements on tuberculosis trends within the USA: a mathematical modelling study
Authors: Nicolas A Menzies, Nicole A Swartwood, Ted Cohen, Suzanne M Marks, Susan A Maloney, Courtney Chappelle, Jeffrey W Miller, Garrett R Beeler Asay, Anand A Date, C Robert Horsburgh, Joshua A Salomon
Journal: The Lancet Public Health (2024)
Molecularly guided therapy versus chemotherapy after disease control in unfavourable cancer of unknown primary (CUPISCO): an open-label, randomised, phase 2 study
Authors: Alwin Krämer, Tilmann Bochtler, Chantal Pauli, Kai-Keen Shiu, Natalie Cook, Juliana Janoski de Menezes, Roberto A Pazo-Cid, Ferran Losa, Debbie Gj Robbrecht, Jiří Tomášek, Cagatay Arslan, Mustafa Özgüroğlu, Michael Stahl, Frédéric Bigot, Sun Young Kim, Yoichi Naito, Antoine Italiano, Nasséra Chalabi, Gonzalo Durán-Pacheco, Chantal Michaud, Jeremy Scarato, Marlene Thomas, Jeffrey S Ross, Holger Moch, Linda Mileshkin
Journal: The Lancet (2024)
Risk factors underlying racial and ethnic disparities in tuberculosis diagnosis and treatment outcomes, 2011–19: a multiple mediation analysis of national surveillance data
Authors: Mathilda Regan, Terrika Barham, Yunfei Li, Nicole A Swartwood, Garrett R Beeler Asay, Ted Cohen, C Robert Horsburgh, Awal Khan, Suzanne M Marks, Ranell L Myles, Joshua A Salomon, Julie L Self, Carla A Winston, Nicolas A Menzies
Journal: The Lancet Public Health (2024)

Despite an overall decline in tuberculosis incidence and mortality in the USA in the past two decades, racial and ethnic disparities in tuberculosis outcomes persist. We aimed to examine the extent to which inequalities in health and neighbourhood-level social vulnerability mediate these disparities.
Otitis media sequelae and hearing in adolescence after administration of an 11-valent conjugate pneumococcal vaccine in infancy: a prospective cohort study with long-term follow-up of the ARIVAC trial
Authors: Eric A F Simões, Phyllis Carosone-Link, Diozele M Sanvictores, Kristin M Uhler, Marilla Lucero, Veronica Tallo, Kenny H Chan
Journal: The Lancet Child & Adolescent Health (2024)
A Belantamab Mafodotin Revival in Multiple Myeloma Therapy
Authors: Suzanne Trudel, A Keith Stewart
Journal: New England Journal of Medicine (2024)

Combination drug regimens that incorporate anti-CD38 monoclonal antibodies, immunomodulatory drugs, proteasome inhibitors, and glucocorticoids are routinely used for the treatment of newly diagnosed multiple myeloma.1 Consequently, at the first relapse, patients have already been exposed to the most effective available drug classes and potentially have refractory disease, so agents with different mechanisms of action are needed. B-cell maturation antigen (BCMA)–targeting therapy has had impressive activity when administered as a single agent in heavily pretreated patients — a finding that has positioned this drug class to fill the need for treatment options for multiple myeloma at early relapse.2 In 2020, the . . .
Going Down the Rabbit Hole
Authors: Kendall J Burdick, William Ealick, Hector Vargas Acevedo, Theodore C Sectish, Thomas J Sandora
Journal: New England Journal of Medicine (2024)

A previously healthy 8-year-old girl was transferred to a Boston hospital from Nantucket (an island off the coast of Massachusetts) with a 12-day history of fevers, sore throat, and cervical lymphadenopathy.
Phase 1 Trials of PNPLA3 siRNA in I148M Homozygous Patients with MAFLD
Authors: Elisa Fabbrini, Brian Rady, Anastasiya Koshkina, Jae Yoon Jeon, Vivaswath S Ayyar, Cynthia Gargano, Nicholas DiProspero, Susan Wendel, Julia Hegge, Holly Hamilton, Zhi-Ming Ding, Maria Afrazi, Anthony Nicholas, Tao Pei, Masayoshi Nakano, Shohei Ouchi, Yuki Saito, Aimi Yamashita, Ryo Tamamura, Hernan Salazar, Craig Shapiro, Tatsuya Yoshihara, Takuma Yonemura, Satoshi Inoue, Osamu Matsuoka, Mark Erion, Alessandro Pocai, Hideo Makimura
Journal: New England Journal of Medicine (2024)

Homozygosity for the PNPLA3 risk allele is linked to liver fat accumulation. In phase 1 trials, JNJ-75220795, a hepatocyte-targeted GalNAc-conjugated PNPLA3 siRNA, reduced liver fat in PNPLA3 I148M homozygous patients with metabolic dysfunction–associated fatty liver disease.
Neutralizing Autoantibodies against Interleukin-10 in Inflammatory Bowel Disease
Authors: Helen Griffin, Lourdes Ceron-Gutierrez, Nima Gharahdaghi, Soraya Ebrahimi, Sophie Davies, Peh Sun Loo, Andras Szabo, Eleri Williams, Anirban Mukhopadhyay, Louise McLoughlin, Steven Irwin, Simon Travis, Paul Klenerman, Su Bunn, Andrew J Cant, Sophie Hambleton, Holm H Uhlig, Rainer Doffinger
Journal: New England Journal of Medicine (2024)

We discovered high-titer neutralizing autoantibodies against interleukin-10 in a child with infantile-onset inflammatory bowel disease (IBD), a phenocopy of inborn errors of interleukin-10 signaling. After B-cell-depletion therapy and an associated decrease in the anti-interleukin-10 titer, conventional IBD therapy could be withdrawn. A second child with neutralizing anti-interleukin-10 autoantibodies had a milder course of IBD and has been treated without B-cell depletion. We conclude that neutralizing anti-interleukin-10 autoantibodies may be a causative or modifying factor in IBD, with potential implications for therapy. (Funded by the National Institute for Health and Care Research and others.).
Race-Based Screening under the Public Health Ethics Microscope — The Case of Prostate Cancer
Authors: Camilo Arenas-Gallo, Marsha Michie, Nora Jones, Peter J Pronovost, Randy A Vince
Journal: New England Journal of Medicine (2024)

Principles of public health ethics suggest that committees developing prostate cancer–screening guidelines should thoroughly examine the scientific rationale and social impact of using race-based criteria.
Identification and characterization of chemotherapy resistant high-risk neuroblastoma persister cells
Authors: Liron D. Grossmann, Chia-Hui Chen, Yasin Uzun, Anusha Thadi, Adam J. Wolpaw, Kevin Louault, Yael Goldstein, Lea F. Surrey, Daniel Martinez, Matteo Calafatti, Mark Gerelus, Peng Gao, Lobin Lee, Khushbu Patel, Rebecca S. Kaufman, Guy Shani, Alvin Farrel, Sharon Moshitch-Moshkovitz, Paris Grimaldi, Matthew Shapiro, Nathan M. Kendsersky, Jarrett M. Lindsay, Colleen E. Casey, Kateryna Krytska, Laura Scolaro, Matthew Tsang, David Groff, Smita Matkar, Josh R. Kalna, Emily Mycek, Jayne McDevitt, Erin Runbeck, Tasleema Patel, Kathrin M. Bernt, Shahab Asgharzadeh, Yves A. DeClerck, Yael P. Mosse, Kai Tan, John M. Maris
Journal: Cancer Discovery (2024)

Abstract Relapse rates in high-risk neuroblastoma remain exceedingly high. The malignant cells that are responsible for relapse have not been identified, and mechanisms of therapy resistance remain poorly understood. In this study, we used single-nucleus RNA sequencing and bulk whole-genome sequencing to identify and characterize the residual malignant persister cells that survive chemotherapy from a cohort of 20 matched diagnosis and definitive surgery tumor samples from patients treated with high-risk neuroblastoma induction chemotherapy. We show that persister cells share common mechanisms of chemotherapy escape, including suppression of MYC(N) activity and activation of NFκB signaling, and the latter is further enhanced by cell–cell communication between the malignant cells and the tumor microenvironment. Overall, our work dissects the transcriptional landscape of cellular persistence in high-risk neuroblastoma and paves the way to the development of new therapeutic strategies to prevent disease relapse. Significance: Approximately 50% of patients with high-risk neuroblastoma die of relapsed refractory disease. We identified the malignant cells that likely contribute to relapse and discovered key signaling pathways that mediate cellular persistence. Inhibition of these pathways and their downstream effectors is postulated to eliminate persister cells and prevent relapse.
Botensilimab, an Fc-Enhanced Anti–CTLA-4 Antibody, Is Effective against Tumors Poorly Responsive to Conventional Immunotherapy
Authors: Dhan Chand, David A. Savitsky, Shanmugarajan Krishnan, Gabriel Mednick, Chloe Delepine, Pilar Garcia-Broncano, Kah Teong Soh, Wei Wu, Margaret K. Wilkens, Olga Udartseva, Sylvia Vincent, Bishnu Joshi, Justin G. Keith, Mariana Manrique, Marilyn Marques, Antoine Tanne, Daniel L. Levey, Haiyong Han, Serina Ng, Jackson Ridpath, Olivia Huber, Benjamin Morin, Claire Galand, Sean Bourdelais, Randi B. Gombos, Rebecca Ward, Yu Qin, Jeremy D. Waight, Matthew R. Costa, Alvaro Sebastian-Yague, Nils-Petter Rudqvist, Malgorzata Pupecka-Swider, Vignesh Venkatraman, Andrew Slee, Jaymin M. Patel, Joseph E. Grossman, Nicholas S. Wilson, Daniel D. Von Hoff, Justin Stebbing, Tyler J. Curiel, Jennifer S. Buell, Steven J. O’Day, Robert B. Stein
Journal: Cancer Discovery (2024)

Abstract Conventional immune checkpoint inhibitors (ICI) targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) elicit durable survival but primarily in patients with immune-inflamed tumors. Although the mechanisms underlying response to anti–CTLA-4 remain poorly understood, Fc-gamma receptor (FcγR) IIIA coengagement seems critical for activity, potentially explaining the modest clinical benefits of approved anti–CTLA-4 antibodies. We demonstrate that anti–CTLA-4 engineered for enhanced FcγR affinity leverages FcγR-dependent mechanisms to potentiate T-cell responsiveness, reduce intratumoral regulatory T cells, and enhance antigen-presenting cell activation. Fc-enhanced anti–CTLA-4 promoted superior efficacy in mouse models and remodeled innate and adaptive immunity versus conventional anti–CTLA-4. These findings extend to patients treated with botensilimab, an Fc-enhanced anti–CTLA-4 antibody, with clinical activity across multiple poorly immunogenic and ICI treatment–refractory cancers. Efficacy was independent of tumor neoantigen burden or FCGR3A genotype. However, FCGR2A and FCGR3A expression emerged as potential response biomarkers. These data highlight the therapeutic potential of Fc-enhanced anti–CTLA-4 antibodies in cancers unresponsive to conventional ICI therapy. Significance: This study reveals that Fc-enhanced anti–CTLA-4 harnesses novel mechanisms to overcome the limitations of conventional anti–CTLA-4, effectively treating poorly immunogenic and treatment-refractory cancers. Our findings support the development of a new class of immuno-oncology agents, capable of extending clinical benefit to patients with cancers resistant to current immunotherapies.
Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission
Authors: Gill Livingston, Jonathan Huntley, Kathy Y Liu, Sergi G Costafreda, Geir Selbæk, Suvarna Alladi, David Ames, Sube Banerjee, Alistair Burns, Carol Brayne, Nick C Fox, Cleusa P Ferri, Laura N Gitlin, Robert Howard, Helen C Kales, Mika Kivimäki, Eric B Larson, Noeline Nakasujja, Kenneth Rockwood, Quincy Samus, Kokoro Shirai, Archana Singh-Manoux, Lon S Schneider, Sebastian Walsh, Yao Yao, Andrew Sommerlad, Naaheed Mukadam
Journal: The Lancet (2024)
Efficacy and Safety of Sacituzumab Govitecan in Patients With Advanced Solid Tumors (TROPiCS-03): Analysis in Patients With Advanced Endometrial Cancer
Authors: Alessandro D. Santin, Bradley R. Corr, Alexander Spira, Lyndsay Willmott, James Butrynski, Ka Yu Tse, Jilpa Patel, Sabeen Mekan, Tia Wu, Kai-Wen Lin, Peiwen Kuo, Ecaterina E. Dumbrava
Journal: Journal of Clinical Oncology (2024)

PURPOSE Patients with advanced endometrial cancer (EC) who progress on or after platinum-based therapy and immunotherapy have poor prognosis. We report efficacy and safety of sacituzumab govitecan (SG), a trophoblast cell-surface antigen 2 (Trop-2)–directed antibody-drug conjugate, in patients with advanced EC. METHODS TROPiCS-03 (ClinicalTrials.gov identifier: NCT03964727 ) is a multicohort, open-label, phase II basket study in patients with metastatic solid tumors. Eligible patients in the EC cohort received SG 10 mg/kg once on days 1 and 8 every 3 weeks. Primary end point was objective response rate (ORR) by investigator's assessment per RECIST v1.1. Secondary end points included clinical benefit rate (CBR; complete and partial response, and stable disease ≥6 months), duration of response (DOR), and progression-free survival (PFS) per investigator assessment, overall survival, and safety. Trop-2 expression of archival or baseline tumor specimens was analyzed by immunohistochemistry. RESULTS At data extraction date, 41 patients were enrolled. Median follow-up was 5.8 months (range, 0.7-19.3); median previous therapies was three (range, 1-6); and 85% of patients received previous chemotherapy and immunotherapy. ORR was 22% (95% CI, 11 to 38); CBR was 32% (95% CI, 18 to 48). Median DOR was 8.8 months (95% CI, 2.8 to not estimable); median PFS was 4.8 months (95% CI, 2.8 to 9.8). Trop-2 exploratory analysis was conducted retrospectively for 39 patients. Tumor Trop-2 protein was highly expressed in EC, showing limited correlation with efficacy. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 73% of patients. Study drug discontinuation due to TRAEs was 5%. Two deaths occurred, deemed unrelated to SG. CONCLUSION Findings from TROPiCS-03 showed encouraging efficacy of SG with a manageable toxicity profile in a heavily pretreated population with advanced EC. Safety findings were consistent with the known SG safety profile.
Deep Learning Artificial Intelligence Predicts Homologous Recombination Deficiency and Platinum Response From Histologic Slides
Authors: Erik N. Bergstrom, Ammal Abbasi, Marcos Díaz-Gay, Loïck Galland, Sylvain Ladoire, Scott M. Lippman, Ludmil B. Alexandrov
Journal: Journal of Clinical Oncology (2024)

PURPOSE Cancers with homologous recombination deficiency (HRD) can benefit from platinum salts and poly(ADP-ribose) polymerase inhibitors. Standard diagnostic tests for detecting HRD require molecular profiling, which is not universally available. METHODS We trained DeepHRD, a deep learning platform for predicting HRD from hematoxylin and eosin (H&amp;E)–stained histopathological slides, using primary breast (n = 1,008) and ovarian (n = 459) cancers from The Cancer Genome Atlas (TCGA). DeepHRD was compared with four standard HRD molecular tests using breast (n = 349) and ovarian (n = 141) cancers from multiple independent data sets, including platinum-treated clinical cohorts with RECIST progression-free survival (PFS), complete response (CR), and overall survival (OS) endpoints. RESULTS DeepHRD predicted HRD from held-out H&amp;E-stained breast cancer slides in TCGA with an AUC of 0.81 (95% CI, 0.77 to 0.85). This performance was confirmed in two independent primary breast cancer cohorts (AUC, 0.76 [95% CI, 0.71 to 0.82]). In an external platinum-treated metastatic breast cancer cohort, samples predicted as HRD had higher complete CR (AUC, 0.76 [95% CI, 0.54 to 0.93]) with 3.7-fold increase in median PFS (14.4 v 3.9 months; P = .0019) and hazard ratio (HR) of 0.45 ( P = .0047). There were no significant differences in nonplatinum treatment outcome by predicted HRD status in three breast cancer cohorts, including CR (AUC, 0.39) and PFS (HR, 0.98, P = .95) in taxane-treated metastatic breast cancer. Through transfer learning to high-grade serous ovarian cancer, DeepHRD-predicted HRD samples had better OS after first-line (HR, 0.46; P = .030) and neoadjuvant (HR, 0.49; P = .015) platinum therapy in two cohorts. CONCLUSION DeepHRD can predict HRD in breast and ovarian cancers directly from routine H&amp;E slides across multiple external cohorts, slide scanners, and tissue fixation variables. When compared with molecular testing, DeepHRD classified 1.8- to 3.1-fold more patients with HRD, which exhibited better OS in high-grade serous ovarian cancer and platinum-specific PFS in metastatic breast cancer.
Evaluation of CD3 and CD8 T-Cell Immunohistochemistry for Prognostication and Prediction of Benefit From Adjuvant Chemotherapy in Early-Stage Colorectal Cancer Within the QUASAR Trial
Authors: Christopher J.M. Williams, Richard Gray, Robert K. Hills, Michael Shires, Liping Zhang, Zuo Zhao, Tracie Gardner, Nancy Sapanara, Xiao-Meng Xu, Isaac Bai, Dongyao Yan, Andrea Muranyi, Sarah Dance, Faranak Aghaei, Gemma Hemmings, Michael Hale, Uday Kurkure, Christoph Guetter, Susan D. Richman, Gordon Hutchins, Jenny F. Seligmann, Nicholas P. West, Shalini Singh, Kandavel Shanmugam, Philip Quirke
Journal: Journal of Clinical Oncology (2024)

PURPOSE High densities of tumor infiltrating CD3 and CD8 T-cells are associated with superior prognosis in colorectal cancer (CRC). Their value as predictors of benefit from adjuvant chemotherapy is uncertain. PATIENTS AND METHODS Tumor tissue from 868 patients in the QUASAR trial (adjuvant fluorouracil/folinic acid v observation in stage II/III CRC) was analyzed by CD3 and CD8 immunohistochemistry. Pathologists, assisted by artificial intelligence, calculated CD3 and CD8 cell densities (cells/mm 2 ) in the core tumor (CT) and invasive margin (IM). Participants were randomly partitioned into training and validation sets. The primary outcome was recurrence-free interval (RFI), 2-year RFI for assessment of biomarker-treatment interactions. Maximum-likelihood methods identified optimal high-risk/low-risk group cutpoints in the training set. Prognostic analyses were repeated in the validation set. RESULTS In the training set, the recurrence rate in the high-risk group was twice that in the low-risk group for all measures (CD3-CT: rate ratio [RR], 2.00, P = .0008; CD3-IM: 2.38, P &lt; .00001; CD8-CT: 2.17, P = .0001; CD8-IM: 2.13, P = .0001). This was closely replicated in the validation set (RR, 1.96, 1.79, 1.72, 1.72, respectively). In multivariate analyses, prognostic effects were similar in colon and rectal cancers, and in stage II and III disease. Proportional reductions in recurrence with adjuvant chemotherapy were of similar magnitude in the high- and low-recurrence risk groups. Combining information from CD3-IM and CD3-CT (CD3 Score) generated high-, intermediate-, and low-risk groups with numbers needed to treat (NNTs) to prevent one disease recurrence being 11, 21, and 36, respectively. CONCLUSION Recurrence rates in the high-risk CD3/CD8 groups are twice those in the low-risk groups. Proportional reductions with chemotherapy are similar, allowing NNTs derived in QUASAR to be updated using contemporary, nonrandomized data sets.