tbuckley/cabot-search huggingface dataset:
Evolving concepts in margin strategies and adaptive radiotherapy for glioblastoma: A new future is on the horizon
Authors: Chia-Lin Tseng, K Liang Zeng, Eric A Mellon, Scott G Soltys, Mark Ruschin, Angus Z Lau, Natalia S Lutsik, Rachel W Chan, Jay Detsky, James Stewart, Pejman J Maralani, Arjun Sahgal
Journal: Neuro-Oncology (2024)

Abstract Chemoradiotherapy is the standard treatment after maximal safe resection for glioblastoma (GBM). Despite advances in molecular profiling, surgical techniques, and neuro-imaging, there have been no major breakthroughs in radiotherapy (RT) volumes in decades. Although the majority of recurrences occur within the original gross tumor volume (GTV), treatment of a clinical target volume (CTV) ranging from 1.5 to 3.0 cm beyond the GTV remains the standard of care. Over the past 15 years, the incorporation of standard and functional MRI sequences into the treatment workflow has become a routine practice with increasing adoption of MR simulators, and new integrated MR-Linac technologies allowing for daily pre-, intra- and post-treatment MR imaging. There is now unprecedented ability to understand the tumor dynamics and biology of GBM during RT, and safe CTV margin reduction is being investigated with the goal of improving the therapeutic ratio. The purpose of this review is to discuss margin strategies and the potential for adaptive RT for GBM, with a focus on the challenges and opportunities associated with both online and offline adaptive workflows. Lastly, opportunities to biologically guide adaptive RT using non-invasive imaging biomarkers and the potential to define appropriate volumes for dose modification will be discussed.
The dilemma of radiation necrosis from diagnosis to treatment in the management of brain metastases
Authors: Zachary S Mayo, Cole Billena, John H Suh, Simon S Lo, Samuel T Chao
Journal: Neuro-Oncology (2024)

Abstract Radiation therapy with stereotactic radiosurgery (SRS) or whole brain radiation therapy is a mainstay of treatment for patients with brain metastases. The use of SRS in the management of brain metastases is becoming increasingly common and provides excellent local control. Cerebral radiation necrosis (RN) is a late complication of radiation treatment that can be seen months to years following treatment and is often indistinguishable from tumor progression on conventional imaging. In this review article, we explore risk factors associated with the development of radiation necrosis, advanced imaging modalities used to aid in diagnosis, and potential treatment strategies to manage side effects.
CD19-CD28: An affinity-optimized CD28 agonist for combination with glofitamab (CD20-TCB) as off-the-shelf immunotherapy
Authors: Johannes Sam, Thomas Hofer, Christine Kuettel, Christina Claus, Jenny Thom, Sylvia Herter, Guy Georges, Koorosh Korfi, Martin Lechmann, Miro Julian Eigenmann, Daniel Marbach, Candice Jamois, Katharina Lechner, Sreenath M. Krishnan, Brenda Gaillard, Joana Marinho, Sven Kronenberg, Leo Kunz, Sabine Wilson, Stefanie Briner, Samuel Gebhardt, Ahmet Varol, Birte Appelt, Valeria Nicolini, Dario Speziale, Miriam Bez, Esther Bommer, Jan Eckmann, Carina Hage, Florian Limani, Silvia Jenni, Anne Schoenle, Marine Le Clech, Jean-Baptiste Pierre Vallier, Sara Colombetti, Marina Bacac, Stephan Gasser, Christian Klein, Pablo Umaña
Journal: Blood (2024)

Effective T-cell responses not only require the engagement of T-cell receptors (TCRs; "signal 1"), but also the availability of costimulatory signals ("signal 2"). T-cell bispecific antibodies (TCBs) deliver a robust signal 1 by engaging the TCR signaling component CD3ε, while simultaneously binding to tumor antigens. The CD20-TCB glofitamab redirects T cells to CD20-expressing malignant B cells. Although glofitamab exhibits strong single-agent efficacy, adding costimulatory signaling may enhance the depth and durability of T-cell-mediated tumor cell killing. We developed a bispecific CD19-targeted CD28 agonist (CD19-CD28), RG6333, to enhance the efficacy of glofitamab and similar TCBs by delivering signal 2 to tumor-infiltrating T cells. CD19-CD28 distinguishes itself from the superagonistic antibody TGN1412, because its activity requires the simultaneous presence of a TCR signal and CD19 target binding. This is achieved through its engineered format incorporating a mutated Fc region with abolished FcγR and C1q binding, CD28 monovalency, and a moderate CD28 binding affinity. In combination with glofitamab, CD19-CD28 strongly increased T-cell effector functions in ex vivo assays using peripheral blood mononuclear cells and spleen samples derived from patients with lymphoma and enhanced glofitamab-mediated regression of aggressive lymphomas in humanized mice. Notably, the triple combination of glofitamab with CD19-CD28 with the costimulatory 4-1BB agonist, CD19-4-1BBL, offered substantially improved long-term tumor control over glofitamab monotherapy and respective duplet combinations. Our findings highlight CD19-CD28 as a safe and highly efficacious off-the-shelf combination partner for glofitamab, similar TCBs, and other costimulatory agonists. CD19-CD28 is currently in a phase 1 clinical trial in combination with glofitamab. This trial was registered at www.clinicaltrials.gov as #NCT05219513.
How proton therapy fits into the management of adult intracranial tumors
Authors: Rupesh Kotecha, Alonso La Rosa, Minesh P Mehta
Journal: Neuro-Oncology (2024)

Abstract Intracranial tumors include a challenging array of primary and secondary parenchymal and extra-axial tumors which cause neurologic morbidity consequential to location, disease extent, and proximity to critical neurologic structures. Radiotherapy can be used in the definitive, adjuvant, or salvage setting either with curative or palliative intent. Proton therapy (PT) is a promising advance due to dosimetric advantages compared to conventional photon radiotherapy with regards to normal tissue sparing, as well as distinct physical properties, which yield radiobiologic benefits. In this review, the principles of efficacy and safety of PT for a variety of intracranial tumors are discussed, drawing upon case series, retrospective and prospective cohort studies, and randomized clinical trials. This manuscript explores the potential advantages of PT, including reduced acute and late treatment-related side effects and improved quality of life. The objective is to provide a comprehensive review of the current evidence and clinical outcomes of PT. Given the lack of consensus and directives for its utilization in patients with intracranial tumors, we aim to provide a guide for its judicious use in clinical practice.
Abstract P23: RHOA inactivation subverts IFN-γ response and promotes antigen escape in CAR-T resistant diffuse large B-cell lymphoma
Authors: Austin D Newsam, Caroline A Coughlin, Yitzhar E Goretsky, Abdessumad Y Alaoui, Daniel E Tsai, David G Coffey, Anya K Sondhi, Evan R Roberts, Natalia Campos Gallego, Paola Manara, Daniel Bilbao, Bachisio Ziccheddu, Jay Y Spiegel, Michael D Jain, Frederick L Locke, Juan P Alderuccio, Francesco Maura, Jonathan H Schatz
Journal: Blood Cancer Discovery (2024)

Abstract CD19-directed chimeric antigen receptor T-cell (CAR-T) therapies have shown breakthrough responses for relapsed or refractory diffuse large B-cell lymphoma (DLBCL), however, over half of patients still progress. Whole genome sequencing of CAR-T treated patients revealed RHOA (3p21.31) deletions highly enriched in patients with poor responses (p = 0.0013). RHOA is altered in approximately 25% of newly diagnosed DLBCL, yet no work has comprehensively defined its role in lymphoma biology or immune resistance. We created RHOA loss-of-function (LoF) cell lines and performed RNA-sequencing followed by drug viability assays to interrogate pathways of dependence in RHOA deficient DLBCL. We also created immunocompetent models of RHOA deficient lymphoma in vivo and conducted single-cell RNA sequencing to assess the resulting lymphoma microenvironments. CAR-T cells were engineered and used to challenge RHOA LoF tumors in vitro. Upon discovering highly upregulated gene sets involving PI3K/AKT/mTOR signaling, we employed drug viability assays and established a critical reliance on AKT signaling in RHOA LoF cell lines. Upregulated AKT was found to suppress JAK2-STAT1 mediated (IFN-γ) signaling and this effect was reversed with PI3K inhibition. Single-cell transcriptomics of RHOA deficient mouse lymphomas revealed decreased Cd8a expression and increased Cd4 expression of T-cells (p = 0.09 and p = 0.028, respectively), suggesting an immunosuppressive microenvironment as a result of abolished IFN-γ mediated immunorecognition. RHOA deficient cell lines were also found to downregulate surface CD19 expression (p &amp;lt; 0.0001) and demonstrated significantly decreased CAR-T cell killing in vitro (p = 0.0005). Future experiments will challenge RHOA deficient immunocompetent tumors in vivo with and without PI3K inhibitors to assess efficacy of combinatorial therapy. Citation Format: Austin D Newsam, Caroline A Coughlin, Yitzhar E Goretsky, Abdessumad Y Alaoui, Daniel E Tsai, David G Coffey, Anya K Sondhi, Evan R Roberts, Natalia Campos Gallego, Paola Manara, Daniel Bilbao, Bachisio Ziccheddu, Jay Y Spiegel, Michael D Jain, Frederick L Locke, Juan P Alderuccio, Francesco Maura, Jonathan H Schatz. RHOA inactivation subverts IFN-γ response and promotes antigen escape in CAR-T resistant diffuse large B-cell lymphoma [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P23.
Cumulative All-Cause Mortality in Diverse Hispanic/Latino Adults
Authors: Jianwen Cai, Amber Pirzada, Pedro L. Baldoni, Gerardo Heiss, John Kunz, Wayne D. Rosamond, Marston E. Youngblood, M. Larissa Aviles-Santa, Linda C. Gallo, Carmen R. Isasi, Robert Kaplan, James P. Lash, David J. Lee, Maria M. Llabre, Neil Schneiderman, Sylvia Wassertheil-Smoller, Gregory A. Talavera, Martha L. Daviglus
Journal: Annals of Internal Medicine (2024)

All-cause mortality among diverse Hispanic/Latino groups in the United States and factors underlying mortality differences have not been examined prospectively.
Stereotactic body radiation therapy for spinal metastases: A new standard of care
Authors: Amanda N Sacino, Hanbo Chen, Arjun Sahgal, Chetan Bettegowda, Laurence D Rhines, Pejman Maralani, Kristin J Redmond
Journal: Neuro-Oncology (2024)

Advancements in systemic therapies for patients with metastatic cancer have improved overall survival and, hence, the number of patients living with spinal metastases. As a result, the need for more versatile and personalized treatments for spinal metastases to optimize long-term pain and local control has become increasingly important. Stereotactic body radiation therapy (SBRT) has been developed to meet this need by providing precise and conformal delivery of ablative high-dose-per-fraction radiation in few fractions while minimizing risk of toxicity. Additionally, advances in minimally invasive surgical techniques have also greatly improved care for patients with epidural disease and/or unstable spines, which may then be combined with SBRT for durable local control. In this review, we highlight the indications and controversies of SBRT along with new surgical techniques for the treatment of spinal metastases.
In adults with ATTR cardiac amyloidosis, patisiran reduced decline in functional capacity at 12 mo
Authors: Ahmad Masri, Harriette G.C. Van Spall
Journal: Annals of Internal Medicine (2024)

ACP Journal Club5 March 2024In adults with ATTR cardiac amyloidosis, patisiran reduced decline in functional capacity at 12 moAhmad Masri, MD, MS, Harriette G.C. Van Spall, MD, MPHAhmad Masri, MD, MSOregon Health & Science University, Portland, Oregon, USA (A.M.), Harriette G.C. Van Spall, MD, MPHMcMaster University, Hamilton, Ontario, Canada (H.G.V.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/J24-0004 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Source CitationMaurer MS, Kale P, Fontana M, et al; APOLLO-B Trial Investigators. Patisiran treatment in patients with transthyretin cardiac amyloidosis. N Engl J Med. 2023;389:1553-1565. https://pubmed.ncbi.nlm.nih.gov/37888916Clinical Impact RatingsGIM/FP/GP: Cardiology: References1. Food and Drug Administration. FDA briefing document: sNDA/015. Drug name: patisiran. Applicant: Alnylam Pharmaceuticals, Inc. Cardiovascular and Renal Products Advisory Committee meeting: 09/13/2023. Accessed at www.fda.gov/media/171977/download on 1 Dec 2023. [PMID: 210922] Google Scholar2. Maurer MS, Schwartz JH, Gundapaneni B, et al; ATTR-ACT Study Investigators. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379:1007-1016. [PMID: 30145929] Google Scholar3. Solomon SD, Adams D, Kristen A, et al. Effects of patisiran, an RNA interference therapeutic, on cardiac parameters in patients with hereditary transthyretin-mediated amyloidosis. Circulation. 2019;139:431-443. [PMID: 30586695] Google Scholar4. HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy [clinical trial]. Accessed at www.clinicaltrials.gov/study/NCT04153149 on 7 Dec 2023. Google Scholar Author, Article, and Disclosure InformationAuthors: Ahmad Masri, MD, MS; Harriette G.C. Van Spall, MD, MPHAffiliations: Oregon Health & Science University, Portland, Oregon, USA (A.M.)McMaster University, Hamilton, Ontario, Canada (H.G.V.)Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=J24-0004.This article was published at Annals.org on 5 March 2024.ACP Journal Club is editorially independent from Annals of Internal Medicine. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics LatestKeywordsAmyloidosisCardiomyopathiesHazard ratioHeart failureHospitalizationsMortalityPatientsSubgroup analysisWalking ePublished: 5 March 2024 Copyright & PermissionsCopyright © 2024 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Adipose Stromal Cell–Derived Cancer-Associated Fibroblasts Suppress FGFR Inhibitor Efficacy
Authors: Mikhail G. Kolonin, Dimitris Anastassiou
Journal: Cancer Research (2024)

Abstract Cancer aggressiveness has been linked with obesity, and studies have shown that adipose tissue can enhance cancer progression. In this issue of Cancer Research, Hosni and colleagues discover a paracrine mechanism mediated by adipocyte precursor cells through which urothelial carcinomas become resistant to erdafitinib, a recently approved therapy inhibiting fibroblast growth factor receptors (FGFR). They identified neuregulin 1 (NRG1) secreted by adipocyte precursor cells as an activator of HER3 signaling that enables resistance. The NRG1-mediated FGFR inhibitor resistance was amenable to intervention with pertuzumab, an antibody blocking the NRG1/HER3 axis. To investigate the nature of the resistance-associated NRG1-expressing cells in human patients, the authors analyzed published single-cell RNA sequencing data and observed that such cells appear in a cluster assigned as inflammatory cancer-associated fibroblasts (iCAF). Notably, the gene signature corresponding to these CAFs is highly similar to that shared by adipose stromal cells (ASC) in fat tissue and fibro-adipogenic progenitors (FAP) in skeletal muscle of cancer-free individuals. Because fibroblasts with the ASC/FAP signature are enriched in various carcinomas, it is possible that the paracrine signaling conferred by NRG1 is a pan-cancer mechanism of FGFR inhibitor resistance and tumor aggressiveness. See related article by Hosni et al., p. 725
Integrating multi-modal imaging in radiation treatments for glioblastoma
Authors: William G Breen, Madhava P Aryal, Yue Cao, Michelle M Kim
Journal: Neuro-Oncology (2024)

Abstract Advances in diagnostic and treatment technology along with rapid developments in translational research may now allow the realization of precision radiotherapy. Integration of biologically informed multimodality imaging to address the spatial and temporal heterogeneity underlying treatment resistance in glioblastoma is now possible for patient care, with evidence of safety and potential benefit. Beyond their diagnostic utility, several candidate imaging biomarkers have emerged in recent early-phase clinical trials of biologically based radiotherapy, and their definitive assessment in multicenter prospective trials is already in development. In this review, the rationale for clinical implementation of candidate advanced magnetic resonance imaging and positron emission tomography imaging biomarkers to guide personalized radiotherapy, the current landscape, and future directions for integrating imaging biomarkers into radiotherapy for glioblastoma are summarized. Moving forward, response-adaptive radiotherapy using biologically informed imaging biomarkers to address emerging treatment resistance in rational combination with novel systemic therapies may ultimately permit improvements in glioblastoma outcomes and true individualization of patient care.
Abstract P17: Epigenomic fingerprinting of limited primary immune cells using automated CUT&amp;RUN
Authors: Ellen N. Weinzapfel, Keith E. Maier, Matthew R. Marunde, Vishnu U. Sunitha Kumary, Carolina P. Lin Windham, Danielle N Maryanski, Liz Albertorio-Saez, Dughan J. Ahimovic, Michael J. Bale, Juliana J. Lee, Bryan J. Venters, Michael-Christopher Keogh
Journal: Blood Cancer Discovery (2024)

Abstract Chromatin structure drives gene expression programs during immune cell development and in cancer, making it central to the advancement of precision medicine. Indeed, the study of chromatin regulation has provided valuable insight on effector cell differentiation and function, anti-tumor immune responses, and therapeutic resistance. Epigenomic features – such as histone post-translational modifications (PTMs) and chromatin-associated proteins – mark distinct genomic compartments (e.g., promoters, enhancers) and regulate chromatin function/gene expression. Mapping the genomic distribution of these may uncover new biomarkers or drug targets and provides a rich context for exploring immunology. Despite widespread interest, integration of epigenomics in large-scale immunotherapy and/or drug research has been hampered by the poor sensitivity, high background, and low throughput of traditional chromatin mapping technologies, most notably ChIP-seq. Instead, efforts to characterize chromatin dynamics have focused on DNA methylation (bisulfite-seq) or chromatin accessibility (ATAC-seq). However, these assays provide an incomplete view of the chromatin landscape, limiting their ability to define cell differentiation pathways or derive mechanistic insight into disease etiology. Here, we present autoCUT&amp;RUN, a high-throughput assay for rapid, ultra-sensitive profiling of epigenomic features from FACS-isolated primary cells or tissues. This workflow generates reliable profiles from ~10,000 cells per reaction, and is supported by a rigorous optimization strategy, high-quality antibodies, and quantitative spike-in controls. As part of a multi-site collaboration with the Immunological Genome Consortium, we used our autoCUT&amp;RUN platform to build a comprehensive epigenomic database of primary mouse immune cells - composed of &amp;gt;1,500 epigenomic profiles from &amp;gt;100 different FACS-isolated immune cell types. These studies set the stage to leverage high-throughput epigenomics in immunotherapy and precision medicine applications. Citation Format: Ellen N. Weinzapfel, Keith E. Maier, Matthew R. Marunde, Vishnu U. Sunitha Kumary, Carolina P. Lin Windham, Danielle N Maryanski, Liz Albertorio-Saez, Dughan J. Ahimovic, Michael J. Bale, Juliana J. Lee, Bryan J. Venters, Michael-Christopher Keogh, Immunological Genome Consortium. Epigenomic fingerprinting of limited primary immune cells using automated CUT&amp;RUN [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P17.
Prevalence of multimorbidity and polypharmacy among adults and older adults: a systematic review
Authors: Kathryn Nicholson, Winnie Liu, Daire Fitzpatrick, Kate Anne Hardacre, Sarah Roberts, Jennifer Salerno, Saverio Stranges, Martin Fortin, Dee Mangin
Journal: The Lancet Healthy Longevity (2024)

Multimorbidity (multiple conditions) and polypharmacy (multiple medications) are increasingly common, yet there is a need to better understand the prevalence of co-occurrence. In this systematic review, we examined the prevalence of multimorbidity and polypharmacy among adults (≥18 years) and older adults (≥65 years) in clinical and community settings. Six electronic databases were searched, and 87 studies were retained after two levels of screening. Most studies focused on adults 65 years and older and were done in population-based community settings. Although the operational definitions of multimorbidity and polypharmacy varied across studies, consistent cut-points (two or more conditions and five or more medications) were used across most studies. In older adult samples, the prevalence of multimorbidity ranged from 4·8% to 93·1%, while the prevalence of polypharmacy ranged from 2·6% to 86·6%. High heterogeneity between studies indicates the need for more consistent reporting of specific lists of conditions and medications used in operational definitions.
Efficacy and safety of one anastomosis gastric bypass versus Roux-en-Y gastric bypass at 5 years (YOMEGA): a prospective, open-label, non-inferiority, randomised extension study
Authors: Maud Robert, Tigran Poghosyan, Delphine Maucort-Boulch, Alexandre Filippello, Robert Caiazzo, Adrien Sterkers, Lita Khamphommala, Fabian Reche, Vincent Malherbe, Adriana Torcivia, Toufic Saber, Dominique Delaunay, Carole Langlois-Jacques, Augustin Suffisseau, Sylvie Bin, Emmanuel Disse, François Pattou
Journal: The Lancet Diabetes & Endocrinology (2024)