tbuckley/cabot-search huggingface dataset:
INB-200: Fully enrolled phase 1 study of gene-modified autologous gamma-delta (γδ) T cells in patients with newly diagnosed glioblastoma multiforme (GBM) receiving maintenance temozolomide (TMZ).
Authors: Mina Lobbous, Trishna Goswami, Lawrence S. Lamb, Kate Rochlin, Thriumaine Pillay, Mariska ter Haak, Louis B. Nabors
Journal: Journal of Clinical Oncology (2024)

2042 Background: γδ T cells can target NKG2D ligands that are upregulated on tumor cells after alkylating chemotherapy exposure. IN8bio’s DeltEx drug resistant immunotherapy (DRI) are genetically engineered γδ T cells expressing methylguanine-DNA methyltransferase (MGMT), which conveys TMZ resistance to enable concomitant therapy and continued surveillance against tumor cells. Updated results from the Phase 1 trial which fully enrolled adult newly diagnosed GBM patients with adequate organ function, KPS ≥ 70% follow. Methods: Cohorts (C) 1, 2 and 3 received 1, 3 or 6 doses (1 x 10 7 DRI cells/dose) into the resection cavity with 150 mg/m 2 of IV TMZ on Day (D) 1 of each Stupp maintenance cycle. The primary endpoint is safety and secondary endpoints include survival; immunologic correlative analyses are included. Dose limiting toxicities (DLTs) are defined as treatment related ≥ grade (G) 3 cardiopulmonary or hepatic toxicity, G4 toxicity exceeding 72 hours or neurologic deterioration that exceeds 2 weeks. Results: 23 patients were enrolled, with 11 dosed and 2 awaiting dosing (61% male; median age 68 (range: 21-74); 92% IDH-WT, 54% MGMT unmethylated). No DLTs, cytokine release syndrome (CRS) or neurotoxicity (ICANS) are reported. Most common adverse events were decreased WBC/platelet count, asthenia, fatigue, hydrocephalus, headache, decreased appetite, urinary tract infection, thrombosis and balance disorder. Conclusions: γδ T cells successfully infused with peripheral TMZ-based lymphodepletion evidenced with near or below normal range T, B, and NK subsets for up to 1 year. The majority of dosed patients who received DRI exceeded the expected median PFS of 7 months (5.8-8.2 months) with Stupp alone and had manageable toxicity with a continued encouraging trend in PFS. Long-term follow-up for durability of PFS and OS continue. Clinical trial information: NCT04165941 . [Table: see text]
Targeting glioma stem cells with thyroid hormone suppression: Phase 1/2 trial of methimazole in patients with progressive grade 4 gliomas.
Authors: David M. Peereboom, Andras Ponti, Kailin Yang, Daniel Silver, Rachel Hufsey, Lea El Hage, Hong Li, Christine Cordova, Andrew Dhawan, Mina Lobbous, Mark Gordon Malkin, Glen Stevens, Alejandro Torres-Trejo, Lilyana Angelov, Gene Barnett, Matthew Grabowski, Alireza Mohammadi, Pranay Soni, Justin Lathia, Christopher Hine
Journal: Journal of Clinical Oncology (2024)

2044 Background: Gaseous hydrogen sulfide (H 2 S), a by-product of cysteine metabolism, inhibits the growth of glioblastoma (GBM) cells and impairs GBM progression in mice. Likewise, H 2 S generation and sulfhydration are decreased in human GBM specimens as compared to non-tumor controls. Thus, boosting H 2 S production is a novel strategy for GBM treatment. Suppression of thyroid hormone (TH) signaling increases endogenous production of H 2 S. We hypothesize that methimazole-induced hypothyroidism will enhance the efficacy of chemotherapy in WHO grade 4 gliomas by boosting H 2 S production capacity (HPC) within the tumor. The goal of this trial is to provide proof of concept that suppression of TH signaling, via methimazole and subsequent augmentation of H 2 S synthesis and signaling, is feasible in patients with WHO grade 4 gliomas (G4G). Methods: This modified phase 1/2 study evaluates the safety and efficacy of methimazole + chemotherapy with pharmacodynamic correlates in patients with progressive G4G. The main objective is a 10% increase in HPC and a 1.5-fold increase in peripheral blood sulfhydration signaling (SS). Patients who are planned for a clinically-indicated resection receive pre-op (5-7 days) and post-op methimazole with the addition of investigator’s choice of chemotherapy 1 month after starting post op methimazole. Patients receive methimazole + chemotherapy until progression. Resected tumor will be assayed for HPC and for proteins relevant to H 2 S production. Peripheral blood lead-acetate assays for HPC and SS are obtained at baseline, pre-op, intra-op, post-op, before the addition of chemotherapy, and before each cycle of methimazole + chemo. Key eligibility criteria: progressive G4G for whom a clinically-indicated resection is planned, and normal thyroid function with no history of thyroid disease. Patients may have had unlimited prior regimens including bevacizumab. Results: To date six patients (4 male) ages 49-59 years have enrolled. At all time points tested post-methimazole treatment relative to baseline age/sex matched no-methimazole control patients, there were significant increases in plasma H 2 S production capacity (table). Conclusions: In this early cohort, it appears methimazole treatment in recurrent GBM patients enhances HPC on a systemic level. Next steps will be to measure sulfide signaling and sulfhydration alterations in patient tumor samples. The protocol is being modified to allow earlier addition (2 weeks) of post-op chemotherapy. Clinical trial information: NCT05607407 . [Table: see text]
Can targeting TSP-1 with gabapentin enhance survival in glioblastoma? A 20-year retrospective cohort study.
Authors: Mulki Mehari, Vardhaan Ambati, Saritha Krishna, Mikias Negussie, Cesar Nava Gonzales, Abraham Dada, Aymen Kabir, Jasleen Kaur, Sena Oten, Youssef Sibih, Andy Daniel, John Frederick de Groot, Yazmin Odia, Shawn L. Hervey-Jumper
Journal: Journal of Clinical Oncology (2024)

2048 Background: Molecularly-defined cellular subpopulations of glioblastoma secrete high levels of the synaptogenic protein thrombospondin-1 (TSP-1) which promotes functional integration of tumor into neural circuity. A greater extent of glioma-neuronal crosstalk portends worse survival for patients. In preclinical studies, gabapentin was shown to inhibit TSP-1, in turn disrupting neuronal synaptogenesis and neuronal activity-dependent glioblastoma proliferation; however, clinical survival data is lacking. We aim to determine whether treatment with gabapentin is associated with improved survival and reduced serum TSP-1 in a retrospective cohort of patients with IDH-wildtype glioblastoma. Methods: Newly-diagnosed, IDH-wildtype glioblastoma patients who received care at the UCSF Brain Tumor Center between 1997-2017 were included in this study. Kaplan-Meier curves and multivariate Cox proportional-hazards models, controlled for age, MGMT promoter methylation status, preoperative tumor volume, and extent of resection, were used for survival analyses. Differences in serum TSP-1 measured by ELISA for gabapentin treated patients and matched non-gabapentin treated controls were assessed using unpaired two-tailed student’s t-test. Control samples were matched 2:1 by age, tumor volume, and extent of resection. After 2005, patients were treated with chemoradiation with concurrent and adjuvant temodar. Results: Among 379 adult patients with glioblastoma, 36 (9.5%) were treated with gabapentin. The median daily dose of gabapentin was 600 mg (IQR: 300-900 mg). There were no significant differences between gabapentin treated and non-gabapentin treated patients by age (0.06), sex (p=0.14), or race (p=0.52). Median overall survival for gabapentin treated and non-gabapentin treated patients was 20.8 months (IQR: 11.7 - 32.1) and 14.7 months (IQR: 8.9-23.5), respectively (p= 0.02). On Kaplan-Meier survival analysis, overall survival was longer for gabapentin treated patients compared with non-gabapentin treated patients (p=0.005). In the multivariate Cox proportional-hazards model, gabapentin use was associated with decreased hazard of death (HR 0.67, p=0.030). Mean serum TSP-1 in gabapentin-treated patients was significantly lower than in the matched control group (10181 ng/ml vs 17015 ng/ml, p=0.017). Conclusions: Gabapentin use is associated with a survival benefit for patients with glioblastoma, possibly mediated through a reduction in TSP-1. This promising result lays the foundation for future prospective studies to further evaluate TSP-1 as a circulating prognostic biomarker as well as to explore the therapeutic benefits of gabapentin as a life-prolonging treatment for patients with newly diagnosed glioblastoma.
Retrospective study of ivosidenib for patients with recurrent IDH mutant gliomas.
Authors: Joseph El-Ghoubaira, Jan Drappatz, Megan Mantica
Journal: Journal of Clinical Oncology (2024)

2040 Background: IDH mutant gliomas are the most common primary malignant brain tumors in adults under the age of 50 and accounts for approximately 12% of all glioma diagnoses each year. While lower grade gliomas (LGG) encompassing WHO grades II and III are less aggressive than their higher-grade counterparts, treatment is not curative, and most patients develop tumor recurrence in which there are a paucity of effective treatment options. Mutations in IDH1/ 2 occur upwards of 80% of patients with LGG and drive specific epigenetic programs to dysregulate and impair differentiation leading to tumorigenesis. As such, pharmacologic blockage of IDH mutant enzymes is being actively investigated as potential treatment option. Ivosidenib (AG-120), a second-generation IDH inhibitor, is an FDA approved medication for treatment of IDH-mutated acute myeloid leukemia and has demonstrated safety and clinical activity in patients with progressive IDH mutant gliomas. We explored the efficacy of Ivosidenib in IDH mutant gliomas. Methods: We retrospectively analyzed patients with IDHm gliomas treated with ivosidenib in our institution. We included patients with an IDH1 mutation who received at least one cycle of ivosidenib. Data collected included patient demographics, tumor histology, tumor location, grade, 1p/19q co-deletion, MGMT, CDKN2A, TERT, EGFR, P53, PTEN mutational status, prior treatment history, duration of treatment, toxicities, radiographic response, PFS, and OS. Descriptive statistics were used to summarize patients' characteristics. The distribution of mPFS was estimated by the Kaplan-Meier method. Results: Between April 2010 and December 2023, we identified 33 patients that received ivosidenib. 7 patients received ivosidenib in combination with bevacizumab, 3 patients received ivosidenib in combination with radiation, and 1 patient received ivosidenib and nivolumab. The median age was 52 (range 31-81). 21 (63%) were male. The median lines of medical therapy and radiation/surgery prior to starting ivosidenib were 3.03(range 0-6) and 1.5(range 0-4), respectively. 27(81%) were grade 2, 5(15%) were grade 3, and 1(3%) were grade 4. 19(57%) had 1p/19q co-deletion. As of 12/31/2023, 48%(16) patients were alive. The median PFS was 7.52 months (1-26) and median OS 12.7 months (3-25). 11(33%) patients experienced partial response (PR), 20(60%) experienced stable disease (SD) and 2(6%) demonstrated progressive disease (PD) at 12-week assessment. Nine patients experienced adverse events: grade 1 fatigue (3), grade 1 diarrhea (1), grade 2 fever (1), grade 2 weakness (1), and grade 3 confusion (1). One patient experienced grade 4 lobar hemorrhage thought to be related to concurrent bevacizumab use. Conclusions: Treatment with Ivosidenib therapy was associated with a manageable safety profile. In a subset of patients, there was disease stabilization in heavily pre-treated recurrent IDH mutant gliomas.
On the Influence of Fabrication Methods and Materials for mRNA‐LNP Production: From Size and Morphology to Internal Structure and mRNA Delivery Performance In Vitro and In Vivo
Authors: Dongdong Bi, Christoph Wilhelmy, Dennis Unthan, Isabell Sofia Keil, Bonan Zhao, Bastian Kolb, Roman I. Koning, Melissa A. Graewert, Bert Wouters, Raphaël Zwier, Jeroen Bussmann, Thomas Hankemeier, Mustafa Diken, Heinrich Haas, Peter Langguth, Matthias Barz, Heyang Zhang
Journal: Advanced Healthcare Materials (2024)

Lipid nanoparticle (LNP) remains the most advanced platform for messenger RNA (mRNA) delivery. To date, mRNA LNPs synthesis is mostly performed by mixing lipids and mRNA with microfluidics. In this study, a cost-effective microfluidic setup for synthesizing mRNA LNPs is developed. It allows to fine-tune the LNPs characteristics without compromising LNP properties. It is compared with a commercial device (NanoAssemblr) and ethanol injection and the influence of manufacturing conditions on the performance of mRNA LNPs is investigated. LNPs prepared by ethanol injection exhibit broader size distributions and more inhomogeneous internal structure (e.g., bleb-like substructures), while other LNPs show uniform structure with dense cores. Small angel X-ray scattering (SAXS) data indicate a tighter interaction between mRNA and lipids within LNPs synthesized by custom device, compared to LNPs produced by NanoAssemblr. Interestingly, the better transfection efficiency of polysarcosine (pSar)-modified LNPs correlates with a higher surface roughness than that of PEGylated ones. The manufacturing approach, however, shows modest influence on mRNA expression in vivo. In summary, the home-developed cost-effective microfluidic device can synthesize LNPs and represents a potent alternative to NanoAssemblr. The preparation methods show notable effect on LNPs' structure but a minor influence on mRNA delivery in vitro and in vivo.
Magnitude and Temporal Variations of Socioeconomic Inequalities in the Quality of Life After Early Breast Cancer: Results From the Multicentric French CANTO Cohort
Authors: José Luis Sandoval, Maria Alice Franzoi, Antonio di Meglio, Arlindo R. Ferreira, Alessandro Viansone, Fabrice André, Anne-Laure Martin, Sibille Everhard, Christelle Jouannaud, Marion Fournier, Philippe Rouanet, Laurence Vanlemmens, Asma Dhaini-Merimeche, Baptiste Sauterey, Paul Cottu, Christelle Levy, Silvia Stringhini, Idris Guessous, Ines Vaz-Luis, Gwenn Menvielle
Journal: Journal of Clinical Oncology (2024)

PURPOSE Socioeconomic status (SES) influences the survival outcomes of patients with early breast cancer (EBC). However, limited research investigates social inequalities in their quality of life (QoL). This study examines the socioeconomic inequalities in QoL after an EBC diagnosis and their time trends. PATIENTS AND METHODS We used data from the French prospective multicentric CANTO cohort (ClinicalTrials.gov identifier: NCT01993498 ), including women with EBC enrolled between 2012 and 2018. QoL was assessed using the European Organisation for Research and Treatment of Cancer QoL Core 30 questionnaire (QLQ-C30). summary score at diagnosis and 1 and 2 years postdiagnosis. We considered three indicators of SES separately: self-reported financial difficulties, household income, and educational level. We first analyzed the trajectories of the QLQ-C30 summary score by SES group. Then, social inequalities in QLQ-C30 summary score and their time trends were quantified using the regression-based slope index of inequality (SII), representing the absolute change in the outcome along socioeconomic gradient extremes. The analyses were adjusted for age at diagnosis, Charlson Comorbidity Index, disease stage, and type of local and systemic treatment. RESULTS Among the 5,915 included patients with data on QoL at diagnosis and at the 2-year follow-up, social inequalities in QLQ-C30 summary score at baseline were statistically significant for all SES indicators (SII financial difficulties = –7.6 [–8.9; –6.2], SII income = –4.0 [–5.2; –2.8]), SII education = –1.9 [–3.1; –0.7]). These inequalities significantly increased (interaction P &lt; .05) in year 1 and year 2 postdiagnosis, irrespective of prediagnosis health, tumor characteristics, and treatment. Similar results were observed in subgroups defined by menopausal status and type of adjuvant systemic treatment. CONCLUSION The magnitude of preexisting inequalities in QoL increased over time after EBC diagnosis, emphasizing the importance of considering social determinants of health during comprehensive cancer care planning.
Live‐Cell Imaging of MicroRNA Expression via Photoinduced Electron Transfer Controlled by Catalytic Hairpin Assembly
Authors: Hyebin Na, Bon Il Koo, Jae Chul Park, Jiwoo Lim, Yoosik Kim, Hyun Jung Chung, Yoon Sung Nam
Journal: Advanced Healthcare Materials (2024)

MicroRNAs (miRNAs) serve as emerging biomarkers for a range of diseases, and their quantitative analysis draws increasing attention. Yet, current invasive methods limit continuous tracking within living cells. To overcome this, a nonenzymatic DNA-based nanoprobe is developed for dynamic, noninvasive miRNA tracking via live-cell imaging. This probe features a unique hairpin DNA structure with five guanines that act as internal quenchers, suppressing fluorescence from an attached fluorophore via photoinduced electron transfer. Target miRNA initiates toehold-mediated strand displacement, restoring, and amplifying the fluorescence signal. Additionally, by introducing a single mismatch to the hairpin DNA, the nanoprobe's sensitivity is significantly enhanced, lowering the detection limit to about 60 pM without compromising specificity. To optimize intracellular delivery for prolonged monitoring, the nanoprobe is encapsulated within multilamellar lipid nanovesicles, fluorescently labeled for dual-wavelength ratiometric analysis. The proposed nanoprobe demonstrates a significant advance in live-cell miRNA detection, promising enhanced in situ analysis for a better understanding of miRNAs' pathophysiological function.
Improved Survival With Adjuvant Cyclooxygenase 2 Inhibition in <i>PIK3CA</i>-Activated Stage III Colon Cancer: CALGB/SWOG 80702 (Alliance)
Authors: Jonathan A. Nowak, Tyler Twombly, Chao Ma, Qian Shi, Koichiro Haruki, Kenji Fujiyoshi, Juha Väyrynen, Melissa Zhao, James Knight, Shrikant Mane, Ardaman Shergill, Pankaj Kumar, Felix Couture, Philip Kuebler, Smitha Krishnamurthi, Benjamin Tan, Philip Philip, Eileen M. O'Reilly, Anthony F. Shields, Shuji Ogino, Charles S. Fuchs, Jeffrey A. Meyerhardt
Journal: Journal of Clinical Oncology (2024)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Observational studies have associated aspirin or cyclooxygenase 2 (COX-2) inhibitor usage either before or after colorectal cancer diagnosis with lower risk of recurrence and suggest that PIK3CA mutational status is predictive of better response to COX-2 inhibition. To prospectively test whether adding the COX-2 inhibitor celecoxib to standard adjuvant chemotherapy reduces the risk of recurrence and improves survival, the National Cancer Institute sponsored the CALGB/SWOG 80702 trial (ClinicalTrials.gov identifier: NCT01150045 ) for patients with stage III resected colon cancer. Although the primary hypothesis for all patients did not show a statistically significant improvement in disease-free survival (DFS) with celecoxib, subgroup analysis by PIK3CA mutational status was a preplanned study. PIK3CA gain-of-function mutations were detected in 259 of 1,197 tumors with available whole-exome sequencing data. When stratified by PIK3CA status, patients with PIK3CA gain-of-function mutations treated with celecoxib exhibited improved DFS (adjusted hazard ratio [HR], 0.56 [95% CI, 0.33 to 0.96]) compared with PIK3CA wildtype patients (adjusted HR, 0.89 [95% CI, 0.70 to 1.14]), although the interaction test was nonsignificant ( P interaction = .13). Overall survival was similarly improved for patients with PIK3CA gain-of-function mutations (adjusted HR, 0.44 [95% CI, 0.22 to 0.85]) compared with PIK3CA wildtype patients (adjusted HR, 0.94 [95% CI, 0.68 to 1.30]; P interaction = .04). Although the test for heterogeneity in DFS did not reach statistical significance, the results suggest potential utility of PIK3CA to consider selective usage of COX-2 inhibitors in addition to standard treatment for stage III colon cancer.
Detection of Bronchiolitis Obliterans Syndrome Following Pediatric Hematopoietic Stem Cell Transplantation. An Official American Thoracic Society Clinical Practice Guideline
Authors: Shivanthan Shanthikumar, Society Document, William A. Gower, Saumini Srinivasan, Jonathan H Rayment, Paul D Robinson, Jennifer Bracken, Anne Stone, Shailendra Das, Amisha Barochia, Edward Charbek, Maximiliano Tamae-Kakazu, Erin E Reardon, Matthew Abts, Thane Blinman, Charlotte Calvo, Pi Chun Cheng, Theresa S. Cole, Kenneth R Cooke, Stella M Davies, Aliva De, Jessica Gross, Francoise Mechinaud, Ajay Sheshadri, Roopa Siddaiah, Ashley Teusink-Cross, Christopher T Towe, Laura L Walkup, Gregory A Yanik, Anne Bergeron, Alicia Casey, Robin R Deterding, Deborah R. Liptzin, Kirk R Schultz, Narayan P Iyer, Samuel Goldfarb
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Many children undergo allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of malignant and nonmalignant conditions. Unfortunately, pulmonary complications occur frequently post-HSCT, with bronchiolitis obliterans syndrome (BOS) being the most common noninfectious pulmonary complication. Current international guidelines contain conflicting recommendations regarding post-HSCT surveillance for BOS, and a recent NIH workshop highlighted the need for a standardized approach to post-HSCT monitoring. As such, this guideline provides an evidence-based approach to detection of post-HSCT BOS in children.
Corrigendum to “Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostat Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial” [Eur. Eurol. 84(2) (2023) 156–163]
Authors: Oliver Sartor, Theodore G. Karrison, Howard M. Sandler, Leonard G. Gomella, Mahul Amin, James Purdy, Jeff M. Michalski, Mark G. Garzotto, Nadeem Pervez, Alexander G. Balogh, George B. Rodrigues, Luis Souhami, M. Neil Reaume, Scott G. Williams, Raquibul Hannan, Christopher U. Jones, Eric M. Horwitz, Joseph P. Rodgers, Felix Y. Feng, Seth A. Rosenthal
Journal: European Urology (2024)