bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase 0/2 trigger trial of niraparib in patients with newly diagnosed glioblastoma.
Authors: Mehta Shwetal , Sanai Nader , Margaryan Tigran , Molloy Jennifer , Zhang Hualin , Knight William , Harmon Jocelyn , Hong Amy , Wanebo John , Braun Kelly , Kennedy William R. , Garcia Michael A. , Barani Igor J. , Yoo Wonsuk , Tien An-Chi , Tovmasyan Artak 
Published: June 2023

2069 Background: Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients with O6-methylguanine methyltransferase (MGMT) unmethylated tumors into a therapeutic regimen of niraparib plus fractionated radiotherapy when high unbound drug concentrations are present in gadolinium-nonenhancing tumor. Methods: Patients with presumed newly-diagnosed GBM were enrolled in a phase 0 study receiving 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after 10 Gy ex vivo irradiation in surgical tissue compared to non-irradiated control tissue. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound [niraparib] > 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors exceeding this PK threshold were eligible for expansion phase dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib. Results: All patients (n=35) enrolled in the phase 0 portion of the study met the PK threshold. In non-enhancing tumor regions, the mean unbound concentration of niraparib was 253.2 nM in 32 evaluable GBM patients. The suppression of PAR levels after ex vivo radiation was observed in 75% of the patients (18/24). Eleven out of 18 patients with unmethylated tumors enrolled in phase 2. Five of the 6 initial patients enrolled in phase 2 experienced thrombocytopenia related to niraparib, and 3/5 cases were deemed serious and life-threatening. Consequently, starting dose in both phases was lowered to 200 mg, and no serious AEs were observed thereafter. At a median follow-up of 8.1 months [range: 6.0-12.9 months], PFS6 was 64% (n=11) with 4 patients remaining on treatment and 5 patients ongoing survival follow-up. Conclusions: Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor. Clinical trial information: NCT05076513 .
Detection of methylation-based prognostic signatures in liquid biopsy specimens from patients with meningiomas.
Authors: Herrgott Grayson , Snyder James , Castro Ana Valeria , Noushmehr Houtan A. 
Published: June 2023

2073 Background: Detection of distinct epigenetic biomarkers in circulating cell-free DNA (cfDNA) of liquid biopsy (LB) specimens (e.g. blood) fosters opportunity for prognostication of central nervous system (CNS) tumors and has not been thoroughly explored in patients with meningiomas. Methods: We profiled the cfDNA methylome (EPIC array) in serum from patients with meningiomas (MNG; n = 93) and harnessed internal and external meningioma tissue methylome data with reported follow up (n = 77). To predict recurrence risk (RR), we consolidated a tissue cohort with at least 5 years of follow up and divided them into confirmed recurrence (CR; either reported progressive disease in post-surgical imaging, or additional resections following initial surgery) and confirmed no-recurrence (CNR: no confirmed disease progression w/in at least 5-years of follow-up). Then through application of an iterative process consisting of multiple tissue- and serum-based supervised analyses, we identified risk-specific methylation markers with potential for serum application. which, when inputted into a random forest algorithm allowed for segregation of both tumor tissue and liquid biopsy specimens according to recurrence risk. We estimated immune cell composition using MethylCIBERSORT, where a reference methylome atlas of chosen immune cell types was utilized to deconvolute the MNG samples. Results: The resulting recurrence risk classifier demonstrated an appreciable predictive power in classifying samples as high or low recurrence risk across the tumor tissue cohort (ACC: 87.7%, CUI+: 86.4%). When compared to another classifier of rivaling purpose, our model demonstrated statistically significant agreement across primary meningioma samples (κ = 0.269, p = 0.01), and more accurately predicted samples to recur across expanded time windows (time to recurrence > 5 yrs). Across resulting liquid biopsy classifications, recurrence risk subgroups were analogous with reported risk factors, including WHO grade, extent of resection, and tumor location. Recurrence risk subgroups also demonstrated differential estimated immune cell contributions, with low-risk samples exhibiting a “hot” profile, or enrichment of B-Cells, CD56- and CD4 T-Cells, and natural killer cells. Notably, the estimated neutrophil to lymphocyte ratio, previously purported to be relevant to tumor prognosis, was appreciably higher for those meningioma samples with the highest recurrence risk. Conclusions: DNA methylation markers identified in the serum are suitable for the development of machine learning-based models which present high predictive power to prognosticate patients with meningioma and estimate a differential immune profile across recurrence risk groups. After validation in an external cohort, this noninvasive approach may improve the presurgical therapeutic management of patients with meningiomas.
MTHFR polymorphisms and neurotoxicity and overall survival after methotrexate-based therapy in primary CNS lymphoma.
Authors: Karschnia Philipp , Kurz Sylvia C. , Brastianos Priscilla Kaliopi , Winter Sebastian F. , Gordon Amanda , Jones SooAe , Pisapia Michelle , Nayyar Naema , Tonn Joerg , Batchelor Tracy , Plotkin Scott Randall , Dietrich Jorg 
Published: June 2023

2079 Background: The folate-antagonist methotrexate (HD-MTX) is an integral to induction chemotherapy for primary CNS lymphoma (PCNSL); however, it can be associated with toxicities, including injury to cerebral white matter known as leukoencephalopathy. Methylenetetrahydrofolate Reductase (MTHFR) is involved in intracellular folate metabolism, and MTHFR polymorphisms may affect CNS-specific side effects of HD-MTX. Here, we evaluated the possible association of MTHFR polymorphisms an HD-MTX related CNS toxicity. Methods: We retrospectively searched our institutional database at the Massachusetts General Hospital for newly diagnosed PCNSL patients treated with HD-MTX (without use of radiotherapy or intrathecal chemotherapy). MTHFR polymorphisms were correlated with evolution of leukoencephalopathy over a time period of five years and patient outcomes. ROC curves were generated to estimate the diagnostic ability of specific MTHFR genotypes. Survival was calculated using Kaplan-Meier survival analysis and log-rank test. The significance level was set at p ≤ 0.05. Results: Among 68 PCNSL patients, MTHFR polymorphisms were found in 60 individuals (88.2%; 677C>T: 29 patients, 1298A>C: 18 patients, combined 677C>T & 1298A>C: 13 patients). Neither MTX clearance nor disease response to HD-MTX was affected by specific genotypes, and complete response was achieved in 72.1% of patients by induction with HD-MTX-based therapy. However, the 1298A>C genotype was associated with increased frequency and severity of leukoencephalopathy over time (χ2 = 7.43). Such genotype predicted treatment-induced leukoencephalopathy with a sensitivity of 71.0%% and a specificity of 62.2% (ROC: p = 0.019). While progression-free survival did not differ in genotype-based subgroups, overall survival was significantly lower when the 1298A>C genotype was present. Conclusions: The MTHFR 1298A>C genotype may serve to identify PCNSL patients at elevated risk for HD-MTX-induced leukoencephalopathy. This was associated with reduced overall survival, potentially due to decreased functional status in patients less suitable for aggressive subsequent therapies.
Evaluation of change in RECIST tumor size and survival in patients with rare cancers treated with checkpoint inhibitor therapy (SWOG S1609).
Authors: Othus Megan , Patel Sandip Pravin , Chae Young Kwang , Dietrich Eliana , Streicher Howard , Sharon Elad , Kurzrock Razelle 
Published: June 2023

2504 Background: RECIST has been used for over twenty years to evaluate changes in tumor burden. At each scan, the sum of maximum diameters of “target” lesions are measured. Changes in the sum are categorized into an “objective status” at each scan, including complete and partial response and stable and progressive disease. Prior research among patients treated with chemotherapy did not find a threshold effect corresponding to the RECIST categories; instead a linear association was observed. Herein we use a unique clinical trial resource, a basket trial of patients with rare cancer treated with combination anti-CTLA-4 and anti-PD-1 therapy, to evaluate the association between quantitative change in RECIST tumor burden and survival among patients treated with checkpoint inhibitor therapy. Methods: The study population was 796 patients enrolled on the S1609 DART (Dual Anti-CTLA-4 & Anti-PD-1 blockade in Rare Tumors) trial, a basket immunotherapy trial evaluating ipilimumab plus nivolumab across solid rare tumor subtypes. The analysis population was 720 patients; patients not eligible (n=50; mostly due to non-rare diagnosis), THOSE who did not receive protocol therapy (n=22), OR WHOSE DISEASE WAS NOT evaluated by RECIST (n=4; gestational trophoblastic disease evaluated by -hCG) were excluded. All patients had RECIST-measurable disease at study entry. Associations between overall and progression-free survival (OS and PFS) and change in tumor burden between baseline and the first scan were evaluated using log-rank tests and Cox regression models stratified by basket. Landmark analyses (at day 65) controlled for lead-time bias. Linear regression models and R2 were estimated for median and 2-year estimates across tumor change intervals. Results: The median age of the cohort was 61, 52% werethe distribution of percent change in tumor burden at the first scan. The linear correlation between median and 6-month PFS and change in tumor burden had R2 = 0.92 and 0.74.; median and 1-year OS had R2 = 0.79 and 0.79. Martingale residuals for both PFS and OS showed linear trends up to tumor increase of +50% with no thresholds at definitions of partial response or stable disease. Conclusions: This is the first evaluation of the association between numeric changes in RECIST tumor burden among patients receiving checkpoint therapy. Our results suggest that similar to results among patients who received chemotherapy there is a linear correlation with PFS and OS. As a consequence, the thresholds for RECIST categories do not correspond to thresholds in patient outcomes. [Table: see text]
Interim update of the ATRC-101 phase 1b trial in advanced solid tumors.
Authors: Chmielowski Bartosz , Weroha Saravut John , Ulahannan Susanna Varkey , Doroshow Deborah Blythe , Valdes Frances , Bekaii-Saab Tanios S. , Powderly John D. , Recio-Boiles Alejandro , Berlin Jordan , Xing Yan , Khurana Sudha , Bishop Philippe , Isakoff Steven J. , Weinberg Benjamin Adam 
Published: June 2023

2505 Background: ATRC-101 monoclonal antibody targets tumor-specific ribonucleoprotein complex (RNP) and elicits anti-tumor immunity, innate and adaptive, in preclinical models. Methods: Phase 1b is evaluating ATRC-101 as monotherapy, every 3 (3M) or 2 (2M) weeks (wk), and ATRC-101 in combination with pembrolizumab (3P) in participants (pts) with advanced solid tumors. ATRC-101 target expression is determined by CAP-CLIA IHC assay. For pts described herein, pre-treatment (tx) tumor biopsies were assessed for target expression by IHC retrospectively or prospectively. Enrollment in 3M and 3P is currently open to pts who are target positive (RNP+ve) by IHC with an H-score ≥ 50. Objectives are safety (primary), PK, immunogenicity, recommended dose for expansion, activity by RECIST1.1 and biomarker analyses in pre-tx and on-tx tumors. Results: As of Nov 18th, 2022, 67 pts received ≥1 dose of ATRC-101 (median prior tx 5, range 1-12). Tumor types were colorectal (CRC, 28), ovarian (10), breast (9), melanoma (8), non-small cell lung (NSCLC, 6), head and neck squamous cell (3), urothelial (1), esophageal (1) and small bowel (1). Tx emergent adverse events (TEAEs) Grade ≥3 occurred in 22 (33%) pts and were related to ATRC-101 in 2 (3%). No tx discontinuations or dose reductions related to ATRC-101. RECIST1.1 best overall responses in efficacy evaluable 61 pts included 1 complete response (CR) in RNP+ve melanoma (3P, 10mg/kg), and 1 partial response (PR) in RNP+ve NSCLC (3M, 30mg/kg). Further, disease stabilized (SD) in 24 pts (39%) and 35 pts had disease progression (PD, 57%) with evidence of association between anti-tumor activity and target expression. Of 24 SD, 22 were in monotherapy cohorts and included 9 CRC pts with highly refractory disease. Conclusions: ATRC-101 alone and in combination with pembrolizumab continues to be well tolerated with evidence of anti-tumor activity. Interim data support ongoing enrollment of pts with RNP+ve pre-tx tumors. Updated and new data including durability of disease control will be presented. Clinical trial information: NCT04244552 . [Table: see text]
Clinical and immune phenotypes associated with immune checkpoint inhibitor-induced autoimmune diabetes.
Authors: Ruiz-Esteves Karina Nicole , Shank Kaitlyn , Ouyang Tianqi , Colling Caitlin , Zubiri Leyre , Villani Alexandra-Chloé , Reynolds Kerry Lynn , Rengarajan Michelle 
Published: June 2023

2509 Background: ICI-induced autoimmune diabetes (ICI-DM) is an immune-related adverse event (IrAE) that affects approximately 1% of patients who receive ICI. Most reports of ICI-DM suggest that it resembles fulminant type 1 diabetes, with low or absent endogenous insulin production at presentation. However, milder cases have recently been reported, suggesting a more heterogeneous disease. In this study, we identified distinct clinical phenotypes of ICI-DM that may improve individualized approaches to management. Methods: We performed a retrospective chart review of 16,582 patients treated with either anti-PD1, anti- PDL1, anti-CTLA4, or combination between 2010 and 2022 in a multi-centered academic hospital system. We identified patients with ICI-DM as those with a new diagnosis of type 1 diabetes or drug-induced diabetes and a prescription for medium- or long-acting insulin following ICI therapy; cases were confirmed by chart review by two board-certified endocrinologists. To phenotype ICI-DM based on endogenous insulin production, we reviewed all patients with ICI-DM who had a C-peptide level in our system, which allowed us to identify and subdivide 57 cases of ICI-DM. These patients were further characterized at both initial presentation and up to 30 months of follow-up. Results: We identified six distinct groups of ICI-DM based on the presence (A+) or absence (A-) of diabetes-specific autoantibodies, further divided by level of endogenous insulin production, preserved (B+), low (B+/-) or undetectable (B-). In our cohort, A+B- patients showed to have the lowest time to diagnosis (median 45 days) and high rates of both DKA and hospitalization (67%) at presentation. At the other end of the spectrum, A-B+ patients had a longer time to diagnosis (median 176 days) and no evidence of DKA or hospitalization at presentation. Surprisingly, all groups had similar insulin requirements without significant dosage variations at 30-month follow up. Elevated lipase levels varied widely across groups with the highest rate (66.7%) reported in the A+B- cohort. The prevalence of thyroiditis in our cohort was highest in the A-B- group but did not seem to follow any specific distribution. Conclusions: Our study examined the largest data set to date of deep clinical phenotyping of patients with ICI-DM. We define at least three distinct subsets of ICI-DM, with A+B- patients being most similar to the initially described cases of fulminant type 1 diabetes. Patients with negative antibodies seem to have a milder form of the disease. Our findings also suggest significant heterogeneity and distinct underlying mechanisms amongst cases of ICI-DM. Further studies will be needed to elucidate whether these findings could extrapolate to other individual IrAEs, which may also encompass distinct phenotypes with distinct mechanisms.
First-line treatment of fecal microbiota transplantation for immune-mediated colitis.
Authors: Wang Yinghong , Varatharajalu Krishnavathana , Shatila Malek , Campbell Matthew T , Msaouel Pavlos , Kovitz Craig A. 
Published: June 2023

2510 Background: The management of moderate to severe immune-mediated colitis (IMC) includes immunosuppression with steroids and/or biologic agents. Long-term immunosuppression increases the risk for infections and steroid side-effects. Fecal microbiota transplantation (FMT) is increasingly used for the treatment of refractory IMC but has not been studied in the front-line setting. Here we aim to test the hypothesis that front-line FMT can alleviate IMC symptoms while reducing unnecessary exposure to steroids and their complications. Methods: We will report interim data from a prospective clinical trial exploring the efficacy and safety of FMT as a first-line treatment for IMC. To be included, patients had to 1) have symptoms of immune-mediated diarrhea or colitis grade ≥ 2 within 45 days of FMT and 2) not have received any immunosuppressive treatment for IMC or any other indication around the time of FMT. Results: Seven patients have been enrolled in the trial thus far. Patients received front-line FMT within a median of 35 days (IQR: 18-57 days) from IMC onset. Five (71.4%) patients had symptom improvement within a median of 1 day (IQR: 1-5 days) after FMT. The only FMT-related adverse events reported were transient fever and self-resolving abdominal cramping in three patients (42.8%) within the first week of FMT. All patients stopped immunotherapy due to IMC. Six (85.7%) were able to resume cancer treatment after FMT with 4 patients (57.1%) resuming immunotherapy. Four patients (57.1%) had colitis remission by the end of the study period, with one additional patient showing signs of symptom improvement but passing away before IMC outcome could be assessed. Conclusions: This study is the first to evaluate the safety and efficacy of front-line FMT for the treatment of IMC. While more patients are needed before final conclusions can be drawn, our initial results suggest that FMT can be an effective first-line treatment for IMC that can be delivered in a timely manner and quickly provide symptom relief in a majority of patients while avoiding the use of steroids and allowing the safe resumption of immunotherapy. Therefore, first-line FMT may be a safe and effective steroid sparing alternative to the current standard of care treatment for IMC. Clinical trial information: NCT04038619 . [Table: see text]
Identifying molecular targets for rational immunosuppressive strategies in patients with immune checkpoint therapy-induced myocarditis and myositis.
Authors: Siddiqui Bilal Ahmed , Palaskas Nicolas , Basu Sreyashi , He Zhong , Sheth Rahul , Buja Maximillian , Bhattacharjee Meenakshi , Mancuso James , Fu Tihui , Iliescu Cezar , Deswal Anita , Rawther-Karedath Anishia , Yadav Shalini S. , Allison James Patrick , Sharma Padmanee , Subudhi Sumit Kumar 
Published: June 2023

2511 Background: Immune checkpoint therapies (ICTs) can induce durable anti-tumor responses but also life-threatening immune-related adverse events (irAEs). Myocarditis, myositis, and myasthenia gravis (MG) are rare, often concurrent irAEs with mortality up to 40%. Steroids are the standard first-line treatment and have significant adverse events with prolonged use. We and others have identified serum autoantibodies in these irAEs, suggestive of B cell contribution to pathogenesis. Furthermore, although prior studies have shown T cells and myeloid cells in inflamed muscle tissue, their specific subtype and role in disease pathogenesis have yet to be defined. This understanding may contribute to the development of more effective immunosuppressive strategies. Hypothesis: In addition to T cells, plasma B and myeloid cells contribute to the pathogenesis of ICT-induced myocarditis, myositis, and MG. Methods: We enrolled patients with suspected ICT-induced myocarditis, myositis, and MG on an IRB-approved laboratory protocol. Diagnosis required: 1) symptoms requiring hospitalization; 2) elevated serum markers (creatine kinase ≥5x normal, troponin >99th percentile or detection of autoantibodies for MG); and 3) positive biopsy, electromyography, or cardiac MRI. Patients underwent standard diagnostic testing (including endomyocardial and/or skeletal muscle biopsy) and treatment as clinically indicated. Results: 23 patients were enrolled (n=13, confirmed irAE; n=10, negative control). Most patients received combination ICT (10/13, 77%). Anti-striated muscle and/or acetylcholine receptor binding antibodies were detected in 7/13 patients (54%), including 3 without MG (known to have both T and B cell etiologies). Single cell RNA sequencing of patient tissue (confirmed irAEs: cardiac n=10, skeletal n=9; control: cardiac n=4, skeletal n=5) identified specific populations of myeloid and CD8+ T cells conserved between inflamed cardiac and skeletal muscle. Conclusions: Specific populations of T cells, myeloid cells, and plasma B cells are potential targets for rational immunosuppressive strategies in ICT-induced myocarditis and myositis and will be tested in murine models to inform future clinical trial design. [Table: see text]