tbuckley/cabot-search huggingface dataset:
Cost Utility of Intensive Home Treatment Compared With Acute Psychiatric Inpatient Admission
Authors: Tamara Waldmann, Andreas Bechdolf, Konstantinos Nikolaidis, Sebastian von Peter, Gerhard Längle, Peter Brieger, Jürgen Timm, Lasse Fischer, Svenja Raschmann, Julian Schwarz, Martin Holzke, Sandeep Rout, Constance Hirschmeier, Johannes Hamann, Uwe Herwig, Johanna Baumgardt, Stefan Weinmann, Reinhold Kilian
Journal: JAMA Network Open (2025)

Importance Intensive home treatment (IHT) is regarded as a safe and effective alternative to psychiatric inpatient care during acute crises. Objective To estimate the cost-effectiveness of implementing IHT in comparison with inpatient treatment for persons with severe mental illness in acute crisis in the German health care system. Design, Setting, and Participants This health economic evaluation was performed as part of a quasiexperimental nonrandomized trial conducted at 10 sites in Germany from January 2021 to December 2022. It included 200 patients with severe mental illness treated by IHT for acute crisis matched by means of propensity scores with 200 patients with severe mental illness receiving inpatient treatment. Participants were observed for 12 months. All analyses were conducted from January 15 to October 30, 2024. Main Outcomes and Measures Incremental cost utility ratios (ICURs) were calculated for 12 months from the societal perspective and from the payer perspective of German statutory health insurance. ICUR uncertainty was estimated by nonparametric bootstrapping and estimated cost-effectiveness acceptability curves for maximum willingness to pay (MWTP) thresholds of €25 000 and €50 000. Results The mean (SD) age of all 400 eligible study participants was 45 (16) years, and 264 (66%) were female. Overall, 374 were considered in the analysis. The ICUR point estimates were €48 786.43 from the perspective of statutory health insurance and €38 433.81 from the societal perspective. Acceptability rates for IHT being a cost-effective alternative compared with inpatient treatment from the societal perspective were 67% at an MWTP threshold of €25 000 and 50% at an MWTP of €50 000 and were 60% at an MWTP of €25 000 and 44% at an MWTP of €50 000 from the perspective of the statutory health insurance. Conclusions and Relevance This economic analysis found that IHT for persons with severe mental illness in acute crisis is expected to be cost-effective compared with inpatient treatment, with a slightly higher acceptability probability for statutory health insurance than for the economy as a whole. Due to the high stochastic uncertainty, the study results suggest that more research is needed to assess the economic efficiency of IHT more clearly.
Oncogenomic profiling in infant–toddler T‐ALL identifies NKX2 family genes as drivers linked to favorable outcomes
Authors: Manon Delafoy, Estelle Balducci, Mathieu Simonin, Antoine Pinton, Guillaume Charbonnier, Lucien Courtois, Ludovic Lhermitte, Camille Gillet, Mélanie Féroul, Aurore Touzart, Agata Cieslak, Charlotte Smith, Marianne Courgeon, Margaux Wiber, Thomas Mercher, Sylvain Latour, Isabelle Arnoux, Paul Saultier, Pierre‐Simon Rohrlich, Damien Bodet, Nathalie Grardel, Marion Lubnau, Isabelle Pellier, Sandrine Thouvenin, Nathalie Garnier, Cédric Pastoret, Benoit Brethon, Arnaud Petit, Elizabeth Macintyre, André Baruchel, Vahid Asnafi
Journal: HemaSphere (2025)

Abstract T‐cell acute lymphoblastic leukemia (T‐ALL) is a rare and aggressive hematological malignancy primarily affecting adolescents and young adults and is scarce in infants and toddlers under age 3. Unlike B‐ALL, T‐ALL in this young population remains poorly characterized due to limited data and lacks evidence‐based guidelines to help clinicians determine the optimal treatment approach. In this study, we conducted a comprehensive genetic analysis of infant/toddler T‐ALL cases from a French national cohort, utilizing high‐throughput targeted sequencing, optical genome mapping, and RNA sequencing. Genetic analysis revealed the absence of TLX1/3 dysregulation. Instead, we identified a significant prevalence of NKX2 rearrangements ( n = 9, 33%), co‐occurring with MYB alterations ( n = 5/9) or chromothripsis‐like events ( n = 3/9). Additional findings included TAL1/‐like anomalies (30%), STAG2::LMO2 (15%), ETS rearrangements (15%), and rarely, KMT2A rearrangements (7%). Comparative analyses with 245 patients aged 3–18 years, enrolled in the pediatric FRALLE2000T French protocol, underscored the distinct clinical and genetic profiles of infants/toddlers. Despite presenting with higher rates of hyperleukocytosis and slower responses to treatment, they demonstrated comparable survival outcomes to older pediatric patients, with a 5‐year overall survival (OS) rate of 75.4% (95% confidence interval [CI]: 60.0%–94.8%) versus 75.2% (95% CI: 69.8%–81.1%), p = 0.86. Notably, alterations in NKX2 , KMT2A , and STAG2::LMO2 delineated oncogenic subgroups exhibiting a remarkable 100% OS rate, while patients with TAL1 or ETS dysregulation experienced less favorable outcomes. This was further supported by analyses of data from the COG AALL0434 trial, enhancing our understanding of T‐ALL in infants/toddlers. Large‐scale collaborative studies remain essential to confirm these findings and refine treatment strategies.
Quantifying Transcriptome Turnover on Phylogenies by Modeling Gene Expression as a Binary Trait
Authors: Ammon Thompson, Michael R May, Ben R Hopkins, Nerisa Riedl, Olga Barmina, Benjamin J Liebeskind, Li Zhao, David Begun, Artyom Kopp
Journal: Molecular Biology and Evolution (2025)

Abstract Changes in gene expression are a key driver of phenotypic evolution, leading to a persistent interest in the evolution of transcriptomes. Traditionally, gene expression is modeled as a continuous trait, leaving qualitative transitions largely unexplored. In this paper, we detail the development of new Bayesian inference techniques to study the evolutionary turnover of organ-specific transcriptomes, which we define as instances where orthologous genes gain or lose expression in a particular organ. To test these techniques, we analyze the transcriptomes of 2 male reproductive organs, testes and accessory glands, across 11 species of the Drosophila melanogaster species group. We first discretize gene expression states by estimating the probability that each gene is expressed in each organ and species. We then define a phylogenetic model of correlated transcriptome evolution in 2 or more organs and fit it to the expression state data. Inferences under this model imply that many genes have gained and lost expression in each organ, and that the 2 organs experienced accelerated transcriptome turnover on different branches of the Drosophila phylogeny.
Characterization of cancer‐associated fibroblasts and their spatial architecture reveals heterogeneity and survival associations in classic Hodgkin lymphoma
Authors: Suvi‐Katri Leivonen, Kristiina Karihtala, Teijo Pellinen, Marja‐Liisa Karjalainen‐Lindsberg, Tomohiro Aoki, Christian Steidl, Sirpa Leppä
Journal: HemaSphere (2025)

Abstract Cancer‐associated fibroblasts (CAFs) are a heterogeneous population of stromal cells, which modulate the immune system and can have both pro‐ and anti‐tumorigenic effects. In classic Hodgkin lymphoma (cHL), the role of CAFs has remained largely undefined. We applied multiplexed immunofluorescence imaging and spatial analysis on tumor samples from two independent cHL patient cohorts ( n = 131 and n = 148) to study CAFs and their interactions with Hodgkin Reed–Sternberg (HRS) and tumor microenvironment (TME) cells at the single‐cell resolution. We show that higher proportions of CAFs are associated with favorable outcomes, independent of the clinical covariables. In contrast, a subset of CD45 + immune cells with strong fibroblast‐activation protein positivity, classified as macrophages, was less abundant in nodular sclerosis subtype and associated with worse outcomes. Neighborhood analysis allowed for the identification of colocalization or regional exclusion of phenotypically defined cell types and recurrent cellular neighborhoods. Despite the positive impact of CAF proportions on survival, patients with enrichment of platelet‐derived growth factor receptor beta (PDGFRB)‐positive CAFs in the vicinity of HRS cells had worse survival in both cohorts, independent of the clinical determinants. Our findings distinguish various subsets of CAFs and macrophages impacting survival in cHL and underscore the importance of the spatial arrangements in the TME.
CINSARC AND SARCULATOR IN PATIENTS WITH PRIMARY RETROPERITONEAL SARCOMA: A COMBINED ANALYSIS OF SINGLE INSTITUTION DATA AND EORTC-STBSG-62092 TRIAL (STRASS)
Authors: Dario Callegaro, Gabriele Tinè, Felix Boakye. Oppong, Axelle Nzokirantevye, Saskia Litière, Stefano Percio, Andrea Carenzo, Loris De Cecco, Frederic Chibon, Silvia Brich, Alessia Bertolotti, Paola Collini, Anna Maria. Frezza, Paul Huang, Rick Haas, Sylvie Bonvalot, Winan J. van Houdt, Rosalba Miceli, Sandro Pasquali, Alessandro Gronchi
Journal: Clinical Cancer Research (2025)

Abstract Purpose: The Complexity Index in SARComas (CINSARC) predicts the metastatic risk in patients with soft tissue sarcoma. The aims of this study were to provide the first independent validation of CINSARC in patients with retroperitoneal sarcoma (RPS) and to evaluate whether CINSARC could enhance the performance of Sarculator. Experimental design: A retrospective cohort included patients with primary localized RPS resected with curative intent (2011-2015) at a single institution. The STRASS cohort comprised patients from the surgery-only arm of the EORTC-STBSG-62092 (STRASS) trial who had undergone CINSARC categorization. Patients were classified as CINSARC low-risk (C1) vs high-risk (C2). Primary study endpoints were overall survival (OS) and disease-free survival (DFS). Sarculator performance was assessed in terms of discrimination (Harrell’s C-index) and calibration (calibration plots, Brier score) before and after adding CINSARC. Results: The study cohorts included 104 and 69 patients, respectively, with similar OS. In a pooled cohort, at multivariable analysis for OS considering Sarculator and CINSARC, only Sarculator was significantly associated with OS (HR 1.93, 95%CI 1.35, 2.74, p&amp;lt;0.001). In multivariable analysis for DFS, both Sarculator (HR 1.51, 95%CI 1.09, 2.09, p=0.013) and CINSARC (HR 2.01, 95%CI 1.26, 3.23, p=0.004) were significantly associated with DFS. However, the addition of CINSARC did not improve Sarculator's discrimination or calibration for either OS or DFS. Conclusion: This study validates CINSARC as a prognostic predictor for OS and DFS in patients with primary RPS. CINSARC did not improve the performance of Sarculator, suggesting that its addition to the Sarculator may not provide added clinical benefit.
Identification and Targeting of POLQ-Associated Hereditary Colorectal Cancer
Authors: Ning Xu, Deng-Feng Zhang, Xiao-Xiao Shi, Ke-Xin Yang, Bei-Bei Gan, Yu Fan, Feng-Chang Huang, Jun-Yu Ren, Rui Bi, Yu Li, Mao-Sen Ye, Min Xu, Yong-Chun Zhou, Wen-Hui Li, Yong-Gang Yao, Wen-Liang Li
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Hereditary colorectal cancer (CRC) syndromes remain incompletely understood, with many cases lacking defined genetic causes. This study aimed to identify pathogenic mutations associated with hereditary CRC and explore their potential for targeted therapies. Experimental Design: This observational study was conducted in Yunnan Province, China. We analyzed 43 individuals from 12 hereditary CRC families using whole-exome sequencing, screened 84 polyposis families and 310 sporadic CRC cases, and an expanded cohort of 285 individuals with potential hereditary CRC. A series of in vivo and in vitro assays were conducted to evaluate the mutation's effects on tumorigenesis. Results: A germline heterozygous stop-gain mutation, p.Arg1953X in the POLQ (polymerase theta) gene, was identified in two CRC families, showing co-segregation with disease status. A third POLQ mutation-positive family was identified in the expanded validation cohort. Cells carrying the mutation showed potential of tumorigenesis. The mutation hyperactivates error-prone theta-mediated end-joining (TMEJ), leading to high tumor mutational burden (TMB) and resistance to DNA-damaging treatments. Indeed, the probands exhibited mismatch repair deficient/microsatellite instability–high status (dMMR/MSI-H) that indicates high TMB. Treatment with the POLQ inhibitor Novobiocin suppressed TMEJ activity and restored tumor sensitivity to DNA damage, providing a combined medication scheme for drug-resistant POLQ-type CRC. Conclusions:This study identifies POLQ as a pathogenic gene in hereditary CRC, unveiling a novel POLQ-type CRC driven by TMEJ hyperactivation. Screening for POLQ mutations in patients with hereditary adenomas or early-onset CRC would benefit early diagnosis and personalized therapy for POLQ-associated CRC, while further clinical validation is warranted.
Antigen selection reflected in the subclonal architecture of the B‐cell receptor immunoglobulin gene repertoire in splenic marginal zone lymphoma
Authors: Laura Zaragoza‐Infante, Andreas Agathangelidis, Anastasia Iatrou, Valentin Junet, Nikos Pechlivanis, Maria Karypidou, Triantafyllia Koletsa, Giorgos Karakatsoulis, Alessio Bruscaggin, Zadie Davis, Valeria Spina, Aurelie Verney, Eleftheria Polychronidou, Fotis Psomopoulos, David Oscier, Alexandra Traverse‐Glehen, Maria Papaioannou, Paolo Ghia, Davide Rossi, Anastasia Chatzidimitriou, Kostas Stamatopoulos
Journal: HemaSphere (2025)

Abstract Almost one‐third of all splenic marginal zone lymphoma (SMZL) cases express B‐cell receptor immunoglobulin (BcR IG) encoded by the IGHV1‐2*04 gene, implicating antigen selection in disease ontogeny. Evidence supporting this notion mostly derives from low‐throughput sequencing approaches, which have limitations in capturing the full complexity of the BcR IG gene repertoire. This hinders the comprehensive assessment of the subclonal architecture of SMZL as shaped by antigen selection. To address this, we conducted a high‐throughput immunogenetic investigation of SMZL aimed at the comprehensive characterization of the somatic hypermutation (SHM) and intraclonal diversification within the IG genes. We identified significant differences in the SHM and ID profiles between cases expressing the IGHV1‐2*04 gene and those expressing other IGHV genes. Specifically, IGHV1‐2*04 cases displayed (i) targeted SHM resulting in recurrent replacement SHMs, and (ii) significantly more pronounced intraclonal diversification, reflecting ongoing antigen selection. Overall, our findings suggest that SMZL cases expressing the IGHV1‐2*04 gene have a distinct immunogenetic signature shaped by microenvironmental pressure on the clonotypic BcR IG, corroborating the idea that this group may represent a distinct molecular variant of SMZL.
<scp>ALK</scp>+ Large B‐Cell Lymphoma With Novel <scp><i>ZNF296::ALK</i></scp>: A Morphologic Mimic of <scp>ALK</scp>+ Anaplastic Large Cell Lymphoma
Authors: Wei J. Wang, Pei Lin, John M. Stewart, Guilin Tang, Shaoying Li, Sanam Loghavi, L. Jeffrey Medeiros, Jie Xu
Journal: American Journal of Hematology (2025)
Early dynamics of circulating tumor HPV-DNA with neoadjuvant chemotherapy and response-adapted de-escalation in human papillomavirus-associated oropharyngeal cancer
Authors: Ari J. Rosenberg, Evgeny Izumchenko, Aditya Juloori, Rohan Katipally, John Cursio, Noura Choudhury, Zhen Gooi, Elizabeth Blair, Jeffrey Chin, Rifat Hasina, Augustin Vannier, Anna Starus, Frederick S. Jones, Emily L. Gramiccioni, Yuxuan Miao, Daniel J. Haraf, Everett E. Vokes, Alexander T. Pearson, Nishant Agrawal
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Human papillomavirus-associated (HPV+) oropharyngeal carcinoma (OPC) is associated with excellent survival, yet treatment drives substantial toxicity. Improved biomarkers are needed to select patients for de-escalated treatment. Circulating tumor HPV-DNA (ctHPV-DNA) represents a promising non-invasive biomarker to gauge treatment response and surveil for disease recurrence. Patients and Methods: A prospective biomarker clinical trial of response-stratified de-escalation was conducted. Eligible patients with non-metastatic HPV+ OPC received neoadjuvant chemotherapy followed by risk/response-stratified de-escalation with transoral robotic surgery, de-escalated (chemo)radiation to 50Gy, or standard chemoradiation to 70Gy. Deep response (&amp;gt;=50% tumor shrinkage per RECIST v1.1) qualified patients for de-escalation. ctHPV-DNA was measured using HPV-SEQ in plasma at baseline, during neoadjuvant chemotherapy, radiation, and following treatment. Primary endpoint was correlation of ctHPV-DNA kinetics and radiographic response. Results: Forty-six eligible patients were enrolled, and 488 ctHPV-DNA samples were analyzed (median 11 per patient). Median follow-up was 30 months, and five recurrences were observed (10.9%). Baseline ctHPV-DNA was detected in 96% of evaluable patients. Rapid early ctHPV-DNA clearance after one cycle of neoadjuvant therapy (&amp;gt;=95% reduction) predicted radiographic deep response (p=0.04). Detection of ctHPV-DNA 3 months or later after treatment was associated with worse progression free and overall survival; p&amp;lt;0.001. Sensitivity, specificity, positive and negative predictive value of longitudinal ctHPV-DNA was 100%. The longest lead-time from positive ctHPV-DNA to detection of recurrent disease was 25 months. Conclusions: Rapid early clearance of ctHPV-DNA during neoadjuvant therapy demonstrates utility in predicting response to treatment. Detectable ctHPV-DNA following treatment is predictive of both disease recurrence and worse survival.
<sup>129</sup>Xe-MRI ventilation and acinar abnormalities highlight the significance of spirometric dysanapsis: findings from the NOVELTY ADPro UK substudy
Authors: Laurie J Smith, Helen Marshall, Demi Jakymelen, Alberto Biancardi, Guilhem J Collier, Ho-Fung Chan, Paul J C Hughes, Martin L Brook, Josh R Astley, Ryan Munro, Smitha Rajaram, Andrew J Swift, David Capener, Jody Bray, Jimmy E Ball, Oliver Rodgers, Bilal A Tahir, Madhwesha Rao, Graham Norquay, Nicholas D Weatherley, Leanne Armstrong, Latife Hardaker, Alberto Papi, Rod Hughes, Jim M Wild
Journal: Thorax (2025)

Rationale Airways dysanapsis is defined by CT or spirometry as a mismatch between the size of the airways and lung volume and is associated with increased risk of developing chronic obstructive pulmonary disease (COPD). Lung disease in participants with dysanapsis and a label of asthma and/or COPD remains poorly understood. Methods In participants with asthma and/or COPD, we used 129 Xe-MRI to assess ventilation, acinar dimensions and gas exchange, and pulmonary function tests, and compared people with spirometric dysanapsis (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC)&lt;−1.64 z and FEV1&gt;−1.64 z) to those with normal spirometry (FEV1, FVC and FEV1/FVC&gt;−1.64 z). Results From 165 participants assessed in the NOVELTY (NOVEL observational longiTudinal studY) ADPro (advanced diagnostic profiling) study with a physician-assigned diagnosis of asthma and/or COPD, 43 had spirometric dysanapsis and were age-matched to 43 participants with normal spirometry. Participants with dysanapsis had significantly increased ventilation defects (median difference (md) (95% CI) = 4.0% (1.42% to 5.38%), p&lt;0.001), ventilation heterogeneity (md (95% CI) = 2.56% (1.31% to 3.56%), p&lt;0.001) and measures of acinar dimensions (md (95% CI) = 0.004 cm 2 .s −1 (0.0009 to 0.007), p=0.009) from 129 Xe-MRI, than those with normal spirometry. At the 1-year follow-up, only participants with dysanapsis had a significant increase in ventilation defects (md (95% CI)=0.45% (0.09% to 2.1%),p=0.016). Lower FEV1/FVC in the dysanapsis cohort was associated with increased ventilation defects (r=−0.64, R 2 =0.41, p&lt;0.001) and increased acinar dimensions (r=−0.52, R 2 =0.38, p&lt;0.001), with the highest values seen in those with an FVC above the upper limit of normal. Conclusions Participants with asthma and/or COPD, presenting to primary care with spirometric dysanapsis, exhibited increased lung abnormalities on 129 Xe-MRI, when compared with those with normal spirometry. Spirometric dysanapsis in asthma and/or COPD is therefore associated with significant lung disease, and the FEV1/FVC is related to the degree of airways abnormality on 129Xe-MRI.
Addressing heterogeneous treatment effects in acute care syndromes: principles and practical considerations
Authors: Fernando G Zampieri, Sean M Bagshaw, Alexandre B Cavalcanti
Journal: Thorax (2025)

Background Critical care medicine has historically relied on syndromic diagnoses such as sepsis, acute respiratory distress syndrome (ARDS) and acute kidney injury to guide research and treatment. While this approach has advanced clinical practice, the growing recognition of patient heterogeneity presents significant challenges for treatment optimisation and trial interpretation. Understanding heterogeneous treatment effects (HTE) has emerged as a crucial methodological frontier, particularly for complex critical care syndromes where patient responses to interventions vary substantially. Findings There are three major methodological frameworks for analysing HTE: (1) Risk-based analyses, guided by the Predictive Approaches to Treatment effect Heterogeneity statement, provide an accessible framework for examining treatment effect variation across baseline risk strata but may overlook important effect modifiers. (2) Clustering techniques have successfully identified distinct phenotypes in both ARDS and sepsis, though external validation remains challenging. (3) Effect-based methods employing new methods offer sophisticated capabilities for identifying treatment effect modifiers but require careful consideration to model specification. Conclusion This review examines these methodological approaches through both theoretical framework and practical application. Considerations on the applicability of HTE are also provided. We conclude that while HTE methods offer promising tools for personalising critical care interventions, their successful implementation requires careful consideration of both methodological rigour and practical feasibility.
Epithelial damage and ageing: the perfect storm
Authors: Richard J Hewitt, Laurence Pearmain, Elisavet Lyka, Jennifer Dickens
Journal: Thorax (2025)

Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease of lung parenchymal scarring that is triggered by repeated microinjury to a vulnerable alveolar epithelium. It is increasingly recognised that cellular ageing, whether physiological or accelerated due to telomere dysfunction, renders the epithelium less able to cope with injury and triggers changes in epithelial behaviour that ultimately lead to the development of disease. Aims This review aims to highlight how, with increasing age, the alveolar epithelium becomes vulnerable to exogenous insults. We discuss the downstream consequences of alveolar epithelial dysfunction on epithelial phenotype, alveolar repair and pro-pathogenic interactions with other alveolar niche-resident cell types which drive IPF pathogenesis. Narrative We highlight how a wide array of cellular mechanisms that maintain cellular homeostasis become dysfunctional with ageing. Waning replicative capacity, genomic stability, mitochondrial function, proteostasis and metabolic function all contribute to a phenotype of vulnerability to ‘second hits’. We discuss how in IPF the alveolar epithelium becomes dysfunctional, highlighting changes in repair capacity and fundamental cellular phenotype and how interactions between abnormal epithelium and other alveolar niche-resident cell types perpetuate disease. Conclusions The ageing epithelium is a vulnerable epithelium which, with the cumulative effects of environmental exposures, fundamentally changes its behaviour towards stalled differentiation, failed repair and profibrotic signalling. Further dissection of aberrant epithelial behaviour, and its impact on other alveolar cell types, will allow identification of novel therapeutic targets aimed at earlier pathogenic events.