Dana-Farber Research News 09.01.2026
Welcome to Dana-Farber's Research News
September 1, 2026
This twice-monthly newsletter highlights recently published research where Dana-Farber faculty are listed as first or senior authors. The information is pulled from PubMed and this issue notes papers published from August 1 - 15.
If you are a Dana-Farber faculty member and you think your paper is missing from Research News, please let us know by emailing dfciresearchnews@dfci.harvard.edu.
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Blood Pound Wise, Penny Foolish: Improving Value in SCD Care Kelkar AH, Antin JH In this issue of Blood, Chetlapalli et al conducted a cost-effectiveness analysis comparing haploidentical allogeneic hematopoietic stem cell transplantation (allo-HSCT), gene therapy (GT), and nontransplant standard of care (SOC) for sickle cell disease (SCD). Their findings are striking: allo-HSCT was cost-effective compared to both SOC and GT, and SOC was cost-effective compared to GT. The authors modeled GT generously, projecting 22.1 lifetime quality-adjusted life-years (QALYs; $2.75 million lifetime costs) vs 20.1 QALYs ($1.15 million lifetime costs) for allo-HSCT and 14.3 QALYs ($1.22 million lifetime costs) for SOC. This assumed GT improved quality of life (QOL) over allo-HSCT by avoiding graft-versus-host disease and preventing end-organ damage, despite lacking long-term evidence with GT. It also relied on cross-trial comparisons and historical assumptions about SOC (ie, transfusions, frequent hospitalizations, hydroxyurea) that would ideally be measured through continuously enrolled registries of patients receiving optimized contemporary SCD care. |
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Cancer Discovery Haradhvala NJ, Yiu SPT, Beckmann L, Sadigh S, Leibowitz Z, Landolsi E, Rivero S, Hu S, Zhang M, Pospistle A, Yeo YY, Maurer K, Gustafsson J, Stewart K, Shanmugam V, Van Orden M, Li S, Livak KJ, Qiu H, Danysh BP, McDonough M, Gohil SH, Ren Y, Zhou Y, Neuberg DS, Tyekucheva S, Rodig S, Jacobsen ED, Murakami MA, Kurt H, Wu CJ, Getz G, Jiang S, Parry EM Across cancer, one of the most frequent examples of histologic transformation is the evolution of follicular lymphoma (FL) to an aggressive large cell lymphoma. Despite recent progress, understanding of the molecular and cellular underpinnings of transformation remains incomplete. Here, we dissect the interplay of tumor and microenvironment cell populations across transformation through a multimodal investigation of 95 FL and transformed FL (tFL) samples, including single-cell and bulk RNA-sequencing alongside spatial transcriptomics and proteomics, and validate findings across independent FL-tFL pairs. Upon transformation, fibroblasts and GPNMB+ macrophages increase while lymph-node organizing follicular dendritic and CCL21+ fibroblastic reticular cells were lost, resulting in an altered spatial distribution of cytokines that impacts T cell infiltration and macrophage differentiation and function. Secreted stromal and macrophage signals were further evident by non-invasive plasma proteomics. Taken together, our data reveal expansion of macrophages and fibroblasts as key features of transformation with potential diagnostic and therapeutic implications. |
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Cancer Discovery Goyette MA, Graser C, Seehawer M, Patmanidis A, Rojas Jimenez E, Kamat A, Yan P, Fassl A, Foidart P, Li Z, James A, Sicinski P, Michor F, Polyak K Intratumor heterogeneity for human epidermal growth factor receptor 2 (HER2) in HER2-positive breast cancer is a driver of resistance to HER2-targeted therapies. The advancement of treatments for HER2 heterogeneous (HET) tumors has been hindered by the lack of preclinical models that accurately mimic the human disease. In this study, we describe human HER2 HET breast cancer models composed of ERBB2-amplified (HER2hi) and nonamplified (HER2lo) cell populations derived from the same tumor. Utilizing these models, together with cellular barcoding, we demonstrate subclonal cooperation between HER2hi and HER2lo subpopulations. Furthermore, HER2lo cells drive resistance to HER2-targeting antibody-drug conjugates (ADC) like trastuzumab deruxtecan (T-DXd) but are sensitive to HER2 kinase inhibitors. CRISPR screens in HET cocultures identified sensitizers of HER2lo cells to T-DXd, including ATP-binding cassette subfamily C member 1 and ubiquitin-specific peptidase 9 X (USP9X). USP9X inhibition enhances the lysosomal targeting of HER2, thereby potentiating ADC payload release and reducing tumor recurrence after T-DXd treatment. Our results elucidate the functional relevance of HER2 heterogeneity and propose improved therapies for these tumors. SIGNIFICANCE: Studies of HER2 HET breast cancer models demonstrated that HER2lo cells drive HER2-targeting ADC resistance and accelerate recurrence by cooperating with HER2hi cells. We identified novel therapeutic strategies to sensitize HER2lo cells to T-DXd, providing mechanistic insight and offering promising avenues to overcome resistance and improve patient outcomes. |
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Cancer Discovery Yiu SPT, Chang Y, Yeo YY, Qiu H, Wu W, Michel HA, Kure S, Parmelee L, Luo S, Cramer P, Lee JL, Wang Y, Zhao Z, Yeung J, El Ahmar N, Simsek B, Mohanna R, Van Orden M, Lu WS, Livak KJ, Li S, Gao C, Nkosi D, Sadigh S, Zhu B, Basak A, Dhanikonda N, Chan CN, Cho YW, Chen CY, Wang H, Zhao B, Kim DM, Boussiotis VA, Zhang B, Wei K, Shalek AK, Signoretti S, Hodi FS, Rodig SJ, Jiang S Spatial transcriptomics and proteomics have enabled profound insights into tissue organization, yet these technologies remain largely disparate, and emerging same-slide multiomics approaches are limited in plex, spatial resolution, signal retention, and integrative analytics. We introduce IN-situ DEtailed Phenotyping To High-resolution transcriptomics (IN-DEPTH), a streamlined, resource-efficient, commercially compatible workflow using single-cell spatial proteomics-derived imaging to guide transcriptomic capture on the same slide without RNA signal loss. To integrate modalities beyond niche-level mapping, we developed Spectral Graph Cross-Correlation (SGCC), a proteomic-transcriptomic framework resolving spatially coordinated functional state changes across interacting cell populations. Applied to diffuse large B-cell lymphoma (DLBCL), IN-DEPTH and SGCC enabled stepwise discovery from Epstein-Barr virus (EBV)-positive and EBV-negative tumor comparisons with single-cell resolution, revealing coordinated tumor-macrophage-CD4 T-cell remodeling, immunosuppressive C1Q macrophage enrichment, CD4 T-cell dysfunction, and a candidate IL27-STAT3 signaling axis. Collectively, IN-DEPTH enables scalable spatial multiomics to uncover clinically relevant microenvironmental mechanisms and toward robust spatial multimodal AI models. SIGNIFICANCE: IN-DEPTH enables same-slide spatial multiomics across commercial platforms via a protein-first strategy preserving protein epitopes, RNA quality, and tissue integrity. Coupled with SGCC, it resolves coordinated spatial immune remodeling, revealing EBV/LMP1-driven C1Q macrophage polarization and CD4 T-cell dysfunction in DLBCL, with broad applicability to other diseases. |
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Cancer Discovery Transposable Element Activation: A Hallmark of Cancer Burns KH Transposable elements (TE), mobile DNA sequences that can move independently about the genome, make up about half of the human genome and are mostly silenced by epigenetic modifications in healthy differentiated cells. Global epigenetic dysregulation during oncogenic transformation causes TE expression, contributing to transcriptional rewiring and TE activity as insertional mutagens. TE nucleic acids are sensed in the cytoplasm, initiating inflammation that can be therapeutically manipulated to activate antitumor immune responses. In this study, we detail how TEs contribute to six of the classic hallmarks of cancer and propose widespread TE expression and activation as a new hallmark of cancer. SIGNIFICANCE: TEs are expressed at significantly higher levels in cancer cells compared with normal cells as a consequence of epigenetic dysregulation. These elements contribute to transcriptional rewiring, genomic instability, and innate and adaptive immune responses to cancer. Altered TE expression in cancers is a therapeutic vulnerability that scientists are beginning to harness for novel diagnostics and anticancer therapies. See related commentary by Sun and Greenbaum, p. 1489. |
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Journal of Clinical Oncology Rethinking Cardiovascular Events, End Points, and Surveillance in Oncology Trials Nohria A, LaCasce AS Advances in cancer therapeutics have transformed cancer into a curable or chronic disease for many patients. Consequently, long-term morbidity and competing risks have become increasingly relevant. Cardiovascular disease is the leading cause of non-cancer-related mortality among cancer survivors, prompting increased interest in the assessment of cardiovascular safety in oncology trials. The accompanying scientific statement, cosponsored by the American Heart Association and ASCO, calls for standardized definitions of cardiovascular adverse events, cardiovascular specialist involvement, and incorporation of cardiovascular end points in oncology clinical trials to promote better understanding of cancer therapy-related cardia toxicities with the goal of improving outcomes for cancer survivors. However, translating these recommendations into practice requires careful consideration of both historical precedents and the unintended consequences of increased surveillance. |
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Journal of Clinical Oncology Taplin ME, Serzan MT Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix I and Appendix II). Updates are published regularly and can be found on the ASCO Publications website. |
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JAMA Ng K, Jackson NA, Kohn CG, Thalappillil JS, Meyerhardt JA IMPORTANCE: In a phase 2 randomized clinical trial, high-dose vitamin D3 added to standard treatment improved progression-free survival (PFS) compared with standard-dose vitamin D3 in patients with metastatic colorectal cancer (mCRC). OBJECTIVE: To determine if high-dose vitamin D3 added to standard chemotherapy improves outcomes in patients with previously untreated mCRC. DESIGN, SETTING, AND PARTICIPANTS: Double-blind phase 3 randomized clinical trial enrolling 455 patients with previously untreated mCRC, conducted in the US through the National Clinical Trials Network from October 2019 to December 2022 (database freeze: July 15, 2024). INTERVENTIONS: mFOLFOX6 (modified FOLFOX6 [5-fluorouracil, leucovorin, oxaliplatin]) or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus bevacizumab every 2 weeks with either high-dose vitamin D3 (8000 IU daily?×?14 days as loading dose followed by 4000 IU daily) or standard-dose vitamin D3 (400 IU daily) until disease progression, intolerable toxicity, or withdrawal of consent. MAIN OUTCOMES AND MEASURES: The primary end point was PFS assessed by the unstratified log-rank test. Secondary end points included objective response rate, overall survival, and toxicity. Prespecified subgroup analyses of PFS were performed according to known prognostic factors. RESULTS: Among 455 randomized patients (median age, 59 years; 181 [40%] female) with median follow-up 20 months, the median PFS for high-dose vitamin D3 (n?=?228) was 11.8 months (95% CI, 10.3-13.3) vs 10.3 months (95% CI, 9.4-12.2) for standard-dose vitamin D3 (n?=?227) (1-sided log-rank P?=?.25). There were no significant differences in objective response rate between high-dose and standard-dose vitamin D3 (51% [95% CI, 44%-58%] vs 44% [95% CI, 37%-50%], respectively; P?=?.12), or in overall survival (median, 25.6 vs 27.0 months; 1-sided log-rank P?=?.66). There were no clinically meaningful differences in the most common grade 3 or greater adverse events between the high- and standard-dose groups, including neutropenia (n?=?67 [32%] vs n?=?62 [30%]) and hypertension (n?=?42 [20%] vs n?=?49 [23%]) or in incidence of vitamin D-associated toxicities. CONCLUSIONS AND RELEVANCE: Among patients with previously untreated mCRC, addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy plus bevacizumab did not improve PFS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04094688. |
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Lancet Davids MS BACKGROUND: Venetoclax-rituximab (VR) following covalent Bruton tyrosine kinase (BTK) inhibitor therapy is the fixed-duration standard of care for patients with chronic lymphocytic leukaemia (including small lymphocytic lymphoma). Pirtobrutinib, a non-covalent BTK inhibitor, is approved for use after treatment with a covalent BTK inhibitor as a continuous therapy option. We aimed to evaluate the addition of pirtobrutinib to VR as a fixed-duration regimen in patients with relapsed or refractory chronic lymphocytic leukaemia. METHODS: This open-label, multicentre, randomised, controlled, phase 3 trial was conducted at 152 sites (comprising community hospitals and academic centres) across 22 countries. Eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic lymphocytic leukaemia (including small lymphocytic lymphoma), and had previously been treated with at least one line of therapy that could include a covalent BTK inhibitor. Patients who had previously received a non-covalent BTK inhibitor, venetoclax, or another BCL2 inhibitor were not eligible. Enrolled patients were randomly assigned (1:1) using an interactive web-based randomisation system, stratified by del(17p) status and previous exposure to covalent BTK inhibitors, and assigned to receive either pirtobrutinib plus VR (PVR) or VR. Both groups received oral venetoclax (25 cycles) and intravenous rituximab (six cycles); the PVR group also received oral pirtobrutinib for 28 cycles, with a three-cycle pirtobrutinib-rituximab lead-in before venetoclax initiation. For this prespecified interim analysis, the primary endpoint was progression-free survival in the intention-to-treat population, assessed by a masked independent review committee (IRC) as per 2018 International Workshop on Chronic Lymphocytic Leukemia guidelines. Safety analyses were conducted in the safety population, defined as all randomly assigned patients who took at least one dose of any study treatment. All analyses were based on a data cutoff date of Feb 2, 2026. The trial is registered at ClinicalTrials.gov, NCT04965493, and is ongoing but no longer recruiting. FINDINGS: Between Oct 13, 2021, and Oct 28, 2024, 784 patients were screened, of whom 639 were randomly assigned: 321 to the PVR group and 318 to the VR group. The median age of patients was 68·0 years (IQR 60·0-74·0), of whom 439 (69%) were male and 200 (31%) were female. The median number of previous therapies was 2 (IQR 1-3); 510 (80%) of 639 patients had previous exposure to covalent BTK inhibitors, of whom 362 (71%) discontinued their most recent drug of this class owing to progressive disease. At a median follow-up of 27·3 months (IQR 19·5-38·7), PVR showed a significant improvement in IRC-assessed progression-free survival compared with VR (hazard ratio 0·547 [95% CI 0·400-0·748]; p=0·0001). The median 24-month progression-free survival rate was 87% (95% CI 82·3-90·4) in the PVR group versus 72% (65·7-77·0) in the VR group, and the median progression-free survival was not reached (IQR 31·7-not estimable) in the PVR group versus 39·7 months (21·5-50·0) in the VR group. This benefit was consistent across prespecified subgroups, including patients with previous exposure to covalent BTK inhibitors. The most frequent treatment-emergent adverse event of any grade in both groups was diarrhoea, reported in 106 (34%) of 316 patients in the PVR group and 110 (35%) of 311 patients in the VR group. The frequency of treatment-emergent adverse events of grade 3 or higher was similar in both groups (249 [79%] of 316 patients in the PVR group vs 227 [73%] of 311 patients in the VR group); the rate of tumour lysis syndrome of grade 3 or higher was lower in the PVR group (1%; three of 316) than in the VR group (4%; 12 of 311). Rates of atrial fibrillation or flutter of any grade were low (11 [3%] of 316 patients in the PVR group vs eight [3%] of 311 patients in the VR group). Rates of treatment discontinuation owing to treatment-emergent adverse events deemed as related to any of the study drugs were similar: 5% (17 of 316 patients) in the PVR group versus 5% (16 of 311 patients) in the VR group. There were five treatment-related deaths: one in the PVR group and four in the VR group. INTERPRETATION: In patients with previously treated chronic lymphocytic leukaemia, PVR showed significant improvement in progression-free survival compared with VR, with consistent results in patients who had previously received covalent BTK inhibitors and no new safety signals. To our knowledge, these results represent the first randomised phase 3 evidence comparing a novel fixed-duration regimen to the current standard of VR in relapsed or refractory chronic lymphocytic leukaemia, supporting PVR as a potential new standard of care. FUNDING: Eli Lilly and Company. |
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Lancet Systemic Light Chain and Transthyretin Amyloidosis-Treatment Advancements and Future Directions Bianchi G, Cuddy SAM Once rapidly fatal, neglected, and orphan diseases without approved therapeutic options, systemic amyloidoses are now highly treatable. Basic scientific discoveries regarding the molecular mechanisms of transthyretin misfolding and aggregation have driven the development of drugs for the treatment of transthyretin (ATTR) amyloidosis, with six novel therapies approved since 2018. The combination of daratumumab, cyclophosphamide, bortezomib, and dexamethasone was approved for the treatment of light chain (AL) amyloidosis in 2021. Since then, highly effective immunotherapies, such as bispecific T-cell engagers, have been tested in clinical trials in patients with relapsed AL amyloidosis, with unprecedented efficacy. Thus, suspicion of systemic amyloidosis should be raised early in individuals with a suggestive clinical presentation, followed by rapid tissue diagnosis, with appropriate protein typing and prompt commencement of active therapy. These rapid and exciting therapeutic advancements set the stage for this Review on the epidemiology, pathophysiology, and diagnosis of systemic amyloidosis. Through the lens of the molecular mechanisms underlying amyloidosis pathogenesis, we will focus on approved and investigational therapies. We also discuss future directions and challenges concerning a cure for patients with AL or ATTR amyloidosis. |
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Lancet Oncology Now or Later? Switching Therapies in Metastatic Breast Cancer Valenza C, Regan MM, Burstein HJ In contemporary management of patients with hormone receptor-positive, HER2-negative metastatic breast cancer, it is standard to switch therapies at tumour progression, defined by RECIST criteria in clinical trials, and by other measures (many, ironically, considered non-measurable by RECIST) in clinical practice, including subtler radiological changes, findings on examination, rising tumour markers, or increased symptoms related to cancer. Accordingly, in the clinic, a treatment change can be considered for symptomatic progression despite radiologically stable disease, or the same treatment might be continued beyond asymptomatic oligoprogression. These approaches reflect the core goals of controlling tumour-related symptoms, preserving quality of life, and navigating a chronic disease where patients will pursue multiple therapeutic options. |
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Nature A Compendium of Next-Generation Patient-Derived Models for Diverse Cancers ElHarouni D, Al-Jazrawe M, Misek SA, Tseng YY, Loinaz X, Keskula P, Walsh S, Sinai C, Bhatia S, Beroukhim R, Cherniack AD, Ligon KL, Boehm JS The development of new therapeutics and the validation of pathogenetic cancer mechanisms require representative laboratory models1,2. However, existing collections represent only a fraction of the diversity observed in human cancer2-4. Recent technologies have enabled efficient in vitro model derivation (for example, tumour organoids)5. However, whether these maintain essential properties of patient tumours during long-term expansion has not been systematically investigated. Here we present results of a large-scale international programme-the Human Cancer Models Initiative-which involved the generation of a resource of 665 next-generation models from 2,780 donors with 25 cancer types and integrated tumour-model whole genome, exome, methylome and transcriptome analyses. The resource provides 522 models with comprehensive clinical data, 153 models of rare cancers and 71 models from participants with non-European ancestry. Analyses of 421 matched tumour-model pairs reveal high genetic (97.8%) and epigenetic (95%) concordance and define correlates of model discordance. Single-nucleus RNA sequencing of tumour-model pairs reveals subsets of models in which culture conditions significantly influence cell states. Finally, we characterize model preservation of extrachromosomal DNA and post-treatment mutational signatures to provide opportunities to study therapeutic resistance. This model repository is being made available to the community-including multimodal molecular profiling, clinical information and integrative software tools-thus providing a valuable resource for preclinical investigation of cancer pathogenesis and treatment response. |
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Nature DCAF11-Dependent Molecular Glue Degrader Activated by Glutathionylation Yoon H, Wachter F, Barrett KA, Jin C, Rodríguez-Pöhnlein A, Rutter JC, Lumpkin RJ, Metivier RJ, Donovan KA, Baek K, Kalis RW, Che J, Xiong Y, Fischer ES, Ebert BL Targeted protein degradation is a powerful pharmacological strategy that harnesses the ubiquitin proteasome system to eliminate disease-relevant proteins, including otherwise undruggable proteins1. Here we report an unbiased and broadly applicable platform for the systematic discovery of molecular glues across diverse E3 ligases. Using multiplexed mass spectrometry-based chemical screening, we identified M12, a molecular glue that reprogrammes the E3 ligase DCAF11 to degrade DDX18. Mechanistically, M12 functions as a prodrug that is activated through glutathione S-transferase-mediated glutathionylation. The glutathione moiety binds to an evolutionary conserved glutathione-binding site on DCAF11, and the exposed M12 moiety facilitates neo-substrate recruitment. We demonstrate that this glutathione-dependent mechanism readily enables targeted degradation of a range of proteins. Collectively, these findings establish that metabolically activated compounds can redirect E3 ligase function, thereby expanding the scope of targeted protein degradation and chemically induced proximity. |
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Nature Shared Principles of Human and Bacterial Antiviral Immunity Kranzusch PJ Defence against viral infection is a conserved feature of all cellular life. From single-cell bacteria to humans and complex multicellular animals, constitutive and inducible forms of immunity are required to inhibit viruses and safeguard cellular fitness. Recent studies reveal that the components of human antiviral immunity are surprisingly ancient, originating billions of years ago in bacteria as pathways that defend against phage replication. The unification of previously disparate fields of human and bacterial immunity creates a foundation to explain key features of host-virus interactions. This Review defines principles of pathogen recognition, signal amplification and immune effector function that shape mechanisms of antiviral immunity that are shared across kingdoms of life. Shared forms of immunity, including cGAS-STING, inflammasomes, argonautes and viperin, reveal ancient features of antiviral defence. Similarly, direct comparisons of pattern recognition receptors and interferon-stimulated genes in human cells with CRISPR immunity and anti-phage defence systems in bacteria explain prevalent strategies to effectively sense and inhibit viral replication. Cross-kingdom analysis reveals universal rules that control host-virus interactions and highlights open questions in understanding of antiviral immunity. |
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Nature Communications Mendez-Dorantes C, Kalinowski JC, Burn A, Schofield P, Law C, Isik E, Burns KH LINE-1 (L1) retrotransposition is common in human cancers and rearrangements at insertion sites can contribute to cancer-driving oncogene amplifications and promote genome instability. However, the mechanisms underlying rearrangements of L1 retrotransposition intermediates are poorly understood. To address this gap, we developed GFP-based recombination reporter assays to study the formation of L1 retrotransposition-mediated rearrangements. Using these reporters combined with long-read sequencing, we find that L1 retrotransposition cDNA intermediates can recombine with distal DNA breaks to generate chromosomal rearrangements. We also find that two independent L1 insertion cDNA intermediates on distinct genomic loci can recombine with each other to generate chromosomal rearrangements. Both types of rearrangements depend on L1-encoded ORF2p endonuclease and reverse transcriptase activities. Using these reporters, we discover that L1 retrotransposition-mediated rearrangements are robustly induced when the recombining sequences share extensive homology and that their formation requires the homologous recombination factor BRCA1. In contrast, we find L1 retrotransposition-mediated rearrangements are suppressed by the mismatch repair factor MSH2 when the recombining sequences contain mismatches. Given the repetitive nature of our genome, these findings highlight the risk of L1 insertion intermediates becoming substrates for aberrant recombination and promoting genome instability. |
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Nature Communications Diller L, Cherkerzian S, Cinelli AE, Gillani R, Hamilton KV, Yeh JM, Bhattacharjee A, Parad RB Population-based genomic newborn screening identifying newborns at risk for early-onset cancers has not been evaluated. Here, within a Michigan birth cohort (1987-2020), we identify all children developing a solid or central nervous system malignancy by age 8 years (n?=?1948). We perform targeted sequencing of 11 cancer predisposition genes using archived newborn dried blood spot DNA. We find pathogenic or likely-pathogenic germline variants (P/LP) in 6.8% of cases (n?=?132): RB1 (n?=?69), TP53 (n?=?24), SMARCB1 (n?=?8), WT1 (n?=?7), RET (n?=?6), SUFU (n?=?6), PTCH1 (n?=?4), DICER1 (n?=?4), APC (n?=?3) and PHOX2B (n?=?1). We show approximately 1/27,000 newborns develop an early-onset malignancy with an associated pathogenic or likely-pathogenic variant. Germline variant prevalence is 100% in medullary thyroid carcinoma, 40% in retinoblastoma, and 11-30% across five additional diagnoses, with strong gene-tumor specificity (p?<?0.001). P/LP variants are rare in comparison datasets from healthy newborns and gnomAD. Our data support newborn screening for selected cancer-risk genes. |
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New England Journal of Medicine Perioperative Apalutamide in High-Risk Localized Prostate Cancer Taplin ME, Nguyen PL, Kibel AS BACKGROUND: Radical prostatectomy is potentially curative in patients with high-risk localized or locally advanced prostate cancer; however, relapse occurs within 5 years in up to 50% of patients. METHODS: We conducted a phase 3, double-blind, placebo-controlled trial in which patients with newly diagnosed high-risk localized or locally advanced prostate cancer were randomly assigned in a 1:1 ratio to receive androgen-deprivation therapy (ADT) plus apalutamide (240 mg per day) or ADT plus placebo for 6 cycles (28 days each) before and after radical prostatectomy with pelvic lymph-node dissection. The dual primary end points were a composite of pathological complete response or minimal residual disease (defined as a pathological stage of ypT2 or lower, with a tumor size of ?5 mm in the greatest dimension) and metastasis-free survival, as assessed with conventional imaging or prostate-specific membrane antigen positron-emission tomography. Secondary end points included event-free survival, first subsequent treatment, and distant metastasis (assessed in time-to-event analyses), as well as safety. RESULTS: A total of 2109 patients underwent randomization: 1057 were assigned to receive ADT plus apalutamide, and 1052 to receive ADT plus placebo. The median follow-up was 61.7 months. The percentage of patients with a pathological complete response or minimal residual disease was significantly higher in the apalutamide group than in the placebo group (8.9% vs. 1.0%; odds ratio, 10.17; 95% confidence interval [CI], 5.27 to 19.64; P<0.001), as was the percentage of patients with metastasis-free survival (probability of metastasis-free survival at 5 years, 78.2% vs. 73.5%; hazard ratio for distant metastasis or death, 0.80; 95% CI, 0.67 to 0.96; P?=?0.02). Event-free survival, time to the first subsequent treatment, and time to distant metastasis significantly favored ADT plus apalutamide over ADT plus placebo (P<0.001 for all between-group comparisons). Grade 3 or 4 adverse events occurred in 39.6% of the patients in the apalutamide group and in 31.0% of those in the placebo group, with the difference between the groups driven primarily by a higher incidence of rash in the apalutamide group. CONCLUSIONS: Perioperative treatment with ADT plus apalutamide was associated with better oncologic outcomes of radical prostatectomy in patients with high-risk localized or locally advanced prostate cancer than treatment with ADT plus placebo. Adverse events were more common in the apalutamide group than in the placebo group. (Funded by Johnson & Johnson; PROTEUS ClinicalTrials.gov number, NCT03767244.). |
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Science A CDK1 Phospho-Switch Reprograms TRAIP to Unload Replisomes in Mitosis Can G, Shyian M, Krishnamoorthy A, Lim Y, Wu A, Zaher MS, Walter JC, Pellman D Cells entering mitosis with incompletely replicated DNA face catastrophic chromosome segregation failure. During interphase, the replisome-associated E3 ubiquitin ligase TRAIP ubiquitylates barriers in front of the fork to allow replisome progression. In mitosis, TRAIP is reprogrammed from a trans-acting to a cis-acting ligase that can ubiquitylate the replisome itself. This enables the processing of unreplicated DNA by promoting replisome disassembly, fork breakage, and joining of the broken chromosome arms. Here, we describe a mechanism for this reprogramming: The adenosine triphosphatase transcription termination factor 2 (TTF2) is recruited to the replisome, where its noncatalytic N-terminal domain tethers cyclin B-cyclin-dependent kinase 1-phosphorylated TRAIP to the leading strand DNA polymerase ? in a geometry that allows replisome ubiquitylation. Thus, a phosphoregulated architectural switch alters replisome organization in mitosis to safeguard genome integrity before chromosome segregation. |
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American Journal of Hematology Plasmablastic Lymphoma: 2026 Update on Diagnosis, Risk Stratification, and Management Castillo JJ |
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Annals of Surgical Oncology ASO Visual Abstract: Receipt of Combined Axillary Dissection and Nodal Irradiation Varies by Age Mittendorf EA, King TA, Kantor O |
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Annals of Surgical Oncology Receipt of Combined Axillary Dissection and Nodal Irradiation Varies by Age Mittendorf EA, King TA, Kantor O |
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Blood Neoplasia Zhu F, Wang J, Ryan CE, Hackett L, Zhang J, Chamberlain S, Ung J, Chong SJF, Davids MS |
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Breast Cancer Research and Treatment Lynce F |
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Cell Genomics Torlai Triglia E, Miller TE, Durand NC, Kim KL, Casaní-Galdón S, D'Antonio J, Javed N, Paz Hernandez A, Raman A, Cruz AJ, Issner R, Choudhary A, Aguet F, Verga J, Ramanathan V, Li CM, Hecht V, Hansen AS, Aryee MJ, Epstein CB, Najm FJ, Shoresh N, Ardlie K, Bernstein BE, Gaskell E |
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Cell Reports Meli K, Ricker CA, Camp SY, Smith CC, Labaki C, Saad E, Karlow JA, Reardon B, Park J, Burns KH, Choueiri TK, Van Allen EM |
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Cell Reports Medicine Biomarker-Guided Responses in Patient-Derived Organoids Predict Effective Therapies in Breast Cancer Moore K, Dillon D, Overmoyer B, Lynce F, Rosenbluth JM |
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Clinical Cancer Research Shulman DS, Place AE, Chi SN, Kamihara J, O'Neill AF, Church AJ, Crompton BD, Klega K, Tanhaemami M, Armant M, Pikman Y, Stegmaier K, Ezrre S, Czaplinski J, Walensky LD, Bhushan K, Kao PC, London WB, DuBois SG |
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Clinical Cancer Research Gariazzo E, Santo V, Pecci F, Aldea M, Garbo E, Alessi JV, LoPiccolo J, Paoloni F, Nishino M, Sholl LM, Florez N, Rotow J, Frumm SM, Wang X, Rakaee M, Ricciuti B |
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Clinical Cancer Research El Ahmar N, Paul MA, Simsek B, Matar S, Jegede OA, Laimon YN, Savla V, Mohanna R, de Oliveira GR, Baghei Sheshdeh A, Denize T, West DJ, Seager MD, Sun M, Choueiri TK, Xie W, Freeman GJ, Sharpe AH, Braun DA, Wu CJ, McDermott DF, Signoretti S |
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Clinical Cancer Research Chen EC, Liu Y, Bell HL, Ryan J, Wu J, Minihane EJ, Luskin MR, Winer ES, Vedula R, Volpe V, Stahl M, Roberts D, Galinsky I, Gerard M, Hersch M, Lee J, Neuberg D, Stone RM, DeAngelo DJ, Letai A, Lane AA, Garcia JS |
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Clinical Cancer Research Immune Spatial Organization Predicts Distant Metastasis Risk in Aggressive Localized Prostate Cancer Yang DD, Abdelnaser A, Haas AJ, Wala J, Barney AA, Saad E, Crowdis JP, Ricker CA, Awad S, Park J, King MT, Nguyen PL, Choueiri TK, Einstein DJ, Balk SP, Tewari AK, Salari K, Taplin ME, Wu CL, Van Allen EM |
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Clinical Cancer Research Michaud D, Tolaney SM, McAllister SS, Guerriero JL, Sammons S |
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Clinical Cancer Research The Biology of Hypomorphic TP53 Variants and Implications for Clinical Management Moses R, Levine AS, Garber JE, Rana HQ |
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Clinical Cancer Research Jänne PA |
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Clinical Lymphoma, Myeloma, Leukemia Crombie JL, Kim AI, Redd R, Patterson V, Carey C, Balasubramanian S, Odejide O, Merryman RW, LaCasce A, Jacobson CA, Jacobsen E, Parry E, Fisher D, Davids MS, Shipp M, Armand P |
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ESMO Open HER2DX in Early-Stage HER2-Positive Breast Cancer: A Review of Clinical Utility Tolaney SM, Tung N, Waks AG |
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Gynecologic Oncology Roller L, Zhou N, Atre I, Xiong N, Li J, Cheng SC, Liu N, Lacad D, Adjei M, Matulonis UA, Konstantinopoulos PA, Liu JF, Tayob N, Stover EH, Shinagare AB |
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JAMIA Open Development of a Benchmarking Dataset for Symptom Detection Using Large Language Models Davis J, Durieux BN, Van Dongen C, Sciacca K, Gutierrez JM, Lindvall C |
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Journal of Clinical Investigation Diabetic and ER-Stressed Pancreatic Islet ? Cells are in need of some JNK Removal Palozzi JM, Puigserver P |
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Journal of Clinical Investigation Parashar Y, Wang X, Bala P, Kiran Cavale S, Ukaegbu C, Syngal S, Maoz A, Biller LH, Lim R, Yurgelun MB, Sethi NS |
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Journal of General Internal Medicine The Medicare Hospice Benefit's Origins: Lessons on End-of-Life Caregiving Knight HP, Leiter RE |
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Journal of Pain and Symptom Management Safety and Efficacy of Psilocybin During Anticancer Treatment: A Phase II Trial Secondary Analysis Schaefer DA, Mazzola E, Kematick BS, Beaussant Y |
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Journal of Pain and Symptom Management The Journey of Hope from Diagnosis to the Future among Children with Leukemia Mack JW |
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Journal of Palliative Medicine Cronin A, Stal J, Uno H, Fisher L, Lakin JR, Mack JW |
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Journal of Palliative Medicine Kwok A, Sciacca K, Ljungberg BF, Samineni S, Tulsky JA, Lindvall C, Gray TF |
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Journal of the American Geriatrics Society Hoffman DI, Moore S, Sheu C, Ruan M, Iqbal S, Sciacca K, Tabata-Kelly M, Cooper Z, Lindvall C |
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Journal of Thoracic Oncology Brunetti L, Santo V, Pecci F, Rotow JK, Adib E, Ricciuti B, Aerts HJWL |
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Journal of Thoracic Oncology Pecci F, Wang X, Santo V, Gariazzo E, Garbo E, Paoloni F, Almeida GR, Aldea M, Di Federico A, Alessi JV, Canty S, Bruschi G, Lotter W, Awad MM, Gusev A, Florez N, Christiani DC, Rodig SJ, Nishino M, Jänne PA, Sharon E, Ricciuti B |
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Journal of Thrombosis and Thrombolysis Sylvester KW, Kanaan DM, Lupi KE, Schuler BR, Connors JM |
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Leukemia Research Castillo JJ |
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Nature Reviews Clinical Oncology Current Evidence and Future Directions for KIM-1 as a Blood-Based Biomarker in RCC Xu W, Bonventre JV, Choueiri TK |
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Neurology Characteristics, Diagnosis, and Treatment of Aphasia in Patients with Brain Tumors: A Scoping Review Finnemore A, Miller PJ, Maguire AJ, Vinh J, Caplan D, Wade CG, Tulsky JA, Wright AA, Lindvall C, Rhee JY |
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Neuro-Oncology Practice Rhee JY, Miller P, Finnemore A, Tentor Z, Durieux B, Ardeljan LD, Lindvall C, Fitzgerald Jones K, Sager Z |
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Pediatric Blood and Cancer Access to Anticancer Drug Trials for Adolescents with Cancer in the United States Grobman B, Shulman DS, Venkataraman V, DuBois SG |
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Pediatric Blood and Cancer Burns MA, Flamand Y, Keating J, Koch V, Cronholm SM, Hunt SK, Neuberg DS, Place AE, Sallan SE, Vrooman LM |
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Physics in Medicine and Biology From Optimization of Radiation Dose Distributions to Optimal Cancer Treatments Bortfeld TR |
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Science Advances Defective Microhomology-Mediated End Joining in SMARCB1-Deficient Tumors Zhu G, Asada S, Nguyen H, Hirohashi Y, Sun L, Mukkavalli S, Shapiro GI, D'Andrea AD |
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Transplantation and Cellular Therapy Conway S, Gudenkauf LM, Keane EP, Larizza IS, Monahan JA, Wolfe ED, Schaefer D, Wu JH, Agboola F, Song MT, Peteet J, Amonoo HL |
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Transplantation and Cellular Therapy Pozo-Kaderman C, Miran DM, Keane EP, Amonoo HL |