bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alliance A071401: Phase II trial of abemaciclib in patients with grade 2/3 meningiomas harboring somatic NF2 or CDK pathway alterations.
Authors: Brastianos Priscilla Kaliopi , Dooley Katharine , Geyer Susan Michelle , Gerstner Elizabeth R , Kaufmann Timothy J. , Iafrate A. John , Milhem Mohammed M. , Welch Mary Roberta , Kaley Thomas Joseph , Drappatz Jan , Chan Amy , Kumthekar Priya , Kamiya-Matsuoka Carlos , Strowd Roy E. , Cohen Adam Louis , Jaeckle Kurt A. , Robell Lindsay , Santagata Sandro , Barker Frederick G. , Galanis Evanthia 
Published: June 2024

2001 Background: Systemic treatments are limited for patients with meningiomas that have progressed after surgery and/or radiation. Loss of NF2and CDKN2A/Bare common in higher grade meningiomas and promote meningioma progression in preclinical models. We evaluated the efficacy of abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, as part of Alliance umbrella trial A071401, a genomically driven phase II study in recurrent or progressive meningiomas. Methods: Eligible patients (pts) with grade 2/3 tumors and NF2 mutations or CDK pathway alterations were treated with abemaciclib 200 mg orally twice daily until progressive disease. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; the trial would be declared positive if either endpoint was met. Twenty-four evaluable pts provided >85% power to detect a PFS6 >41.5% (vs. null 15%; alpha =0.02). The threshold for promising results for PFS6 was 8+/24 pts. For RR, 24 evaluable pts provided >89% power to detect RR >20% (vs. null 2.5%; alpha = 0.021). The threshold for promising results for RR was 3+/24 pts. Results: Of 83 pts screened while the abemaciclib arm was open between September 15, 2021 and October 3, 2022, 36 eligible pts received treatment. The mean number of treatment cycles administered was 7 and median follow-up since start of treatment was 11 months. The first 24 pts that met eligibility criteria and began treatment were considered evaluable for the primary endpoint analysis. Of the 24 pts evaluated, 58% were female and the median age was 62 years. The observed PFS6 rate was 54% (13/24 pts, 95% confidence interval 33-75%), thus the study met PFS6 endpoint. No objective responses were observed. Of the 36 pts who started treatment, eight had a grade 3 and two had a grade 4 adverse event at least possibly related to treatment. Grade 3 toxicities included anemia (2), neutropenia (2), leukopenia (1), blurry vision (1), diarrhea (2), fatigue (2), ALT elevation (1), dehydration (1), hyperkalemia (1), hyponatremia (1), dizziness (1), acute kidney injury (1), and thromboembolic event (1). Grade 4 toxicities included ALT elevation (1), AST elevation (1) and vomiting (1). Conclusions: Abemaciclib was well tolerated and resulted in an improved PFS6. The overall trial endpoint was met. Abemaciclib warrants further investigation for the treatment of patients with progressive grade 2/3 meningiomas. Support: U10CA180821, U10CA180882; UG1CA189867 (NRG Oncology); Eli Lilly; https://acknowledgments.alliancefound.org . Clinical trial information: NCT02523014 .
Effect of breast cancer receptor subtypes and CSF cytology status on survival for patients with leptomeningeal disease.
Authors: Niraula Sujan , Gouli Sugam , Baran Andrea M. , Tyburski Haley , Zhang Huina , O'Regan Ruth , Mohile Nimish , Anders Carey K. , Hardy Sara , Dhakal Ajay 
Published: June 2024

2025 Background: Leptomeningeal disease (LMD) in metastatic breast cancer (MBC) carries a poor prognosis. Data on the effect of BC sub types and CSF cytology results on overall survival (OS) are lacking. This single institution retrospective study compares OS among MBC with LMD across BC sub types and CSF cytology results. Methods: This study included patients (pts) diagnosed with MBC LMD from Jan 2010 to Jan 2023. BC sub types were defined as (1) ER positive (+)/HER2 negative (-), HER2+, triple-negative BC (TNBC), (2) HER2 0 [immunohistochemistry (IHC) score 0], HER 2 low [ IHC 2+ with fluorescence in-situ hybridization negative OR IHC 1+], HER2+. ER and HER2 positivity were defined per ASCO/CAP criteria. CSF cytology sub types were CSF+ (for malignant cells), CSF-, and CSF not tested. Baseline characteristics were compared using Fisher’s Exact and Wilcoxon rank-sum tests. OS among sub types was evaluated using Kaplan-Meier analysis and compared using log rank test. For multivariate analysis, a step wise model selection was performed after inclusion of sub type of interest; and variables meeting entry (p<0.10) and staying criteria (p<0.05) were included in final Cox model. Results: Out of 219 patients screened, 69 pts were registered. Median OS and associated 95% confidence interval (CI) within BC sub types in analyses 1 and 2 and CSF sub type analysis are shown in the table. OS in analysis 1 was not significantly different by BC sub types. In multivariate analysis, TNBC sub type had significantly shorter OS than ER+/HER2- group [Hazard Ratio (HR) 2.64, 95% CI (1.23, 5.80) (p=0.04)] after adjusting for interval from MBC to LMD diagnosis and CSF cytology status. OS by BC sub types in analysis 2 was not significantly different in unadjusted and multivariate analyses. CSF- group had significantly better OS compared to CSF+ or CSF not tested group in unadjusted analysis (Table) and multivariate analysis [CSF+ vs CSF- HR 4.5 95% CI (1.75-12.11); CSF not tested vs CSF- HR 2.91 95% CI (1.45-6.26), overall p=0.002]. Conclusions: This single institution study on MBC pts with LMD showed that BC receptor sub types were significantly associated with OS when adjusted for the interval from MBC to LMD diagnosis and CSF cytology group. This study showed significantly improved OS among patients with negative CSF cytology compared to those with positive cytology or those not tested, indicating a novel prognostic value of CSF cytology (currently on diagnostic value) for MBC LMD. These findings will be further validated. [Table: see text]
A randomized, controlled, phase 2 trial of nivolumab plus standard-dose or low-dose bevacizumab for recurrent glioblastoma (NAVAL).
Authors: Ahluwalia Manmeet Singh , Peereboom David M. , Ozair Ahmad , Khosla Atulya Aman , Rauf Yasmeen , Nayak Lakshmi , Ciolfi Marci , Alban Tyler , Grabowski Matthew , Rayman Pat , Diaz Marcella , Lathia Justin , Lee Eudocia Quant , Wen Patrick Y. , Reardon David A. 
Published: June 2024

2072 Background: PD-1/PD-L1 inhibition has demonstrated limited efficacy for recurrent glioblastoma (rGBM) across prior RCTs. VEGF, a proangiogenic factor upregulated in rGBM, contributes to tumor-associated immunosuppression. Preclinical and observational clinical data indicate a potential dose-dependent effect of anti-VEGF therapy on immune response. This RCT evaluated anti-PD-1 plus anti-VEGF therapy for rGBM. Methods: NAVAL was a multicenter, open label, phase 2 RCT that enrolled 90 patients (≥18 years) with GBM at first recurrence. Participants received nivolumab (240 mg IV Q2 weeks), and were 1:1 randomized to concurrent 10 mg/kg bevacizumab ( standard-dose arm) or 3 mg/kg bevacizumab ( low-dose arm) administered IV biweekly. Stratification factors included age, performance status, extent of resection, and MGMT methylation status. Primary endpoint was overall survival (OS) at 12 months (OS-12). Other outcomes were overall objective response rate (ORR), median progression-free survival (PFS), PFS at 6 months (PFS-6), and safety. Exploratory genomic and immune profiling using CITEseq was performed in 16 patients. Results: 90 patients were enrolled with median age of 60.6 years (range 27-86). 35 patients were MGMT methylated, 53 were unmethylated and 2 were indeterminate. Final analysis had 87 evaluable patients, with median follow-up of 146 days (range 7-1239). There were 3 complete responses (3.4%), 29 partial responses (33.3%), 37 stable disease (42.5%), and 18 progressive disease (20.7%). OS-12 was 41.1% and 37.7% in standard-dose and low-dose arms respectively, with PFS and ORR data in table. Post-hoc analysis demonstrated survival benefit for patients aged ≥60 years in standard-dose arm. Most frequent toxicities (>20%) included fatigue (45.6%), proteinuria (34.4 %), diarrhea (28.9%), hypertension (23.3%) and lipase increase (21.1%). Grade 3-4 toxicities included hypertension (7.8%), fatigue (5.6) and non-neurological toxicities. Differential changes across trial arms were seen in myeloid-derived suppressor cells (MDSCs) post-therapy. Network medicine identified VEGF as target to reduce MDSCs. VEGF was found expressed by MDSCs of mainly responder patients. Differential gene expression analysis identified increased pro-inflammatory gene signatures in standard-dose arm. Conclusions: Overall PFS and OS were similar for nivolumab plus standard- or low-dose bevacizumab for rGBM, with post-hoc survival benefit seen in standard-dose arm in elderly. Standard-dose bevacizumab was associated with increased systemic inflammatory response and reduced immunosuppressive MDSCs. Clinical trial information: NCT03452579 . [Table: see text]
Gender disparity in chimeric antigen receptor T-cell therapy utilization and outcomes in the United States.
Authors: Solipuram Divya , Mehta Kathan , Siddappa Malleshappa Sudeep Kumar 
Published: June 2024

2556 Background: Chimeric antigen receptor T-cell [CART] therapy has marked a new era in the treatment of relapsed/refractory hematological malignancies since its approval in 2017. Racial disparity was studies previously but not gender. Current study aimed to evaluate gender disparity in CART therapy utilization and outcomes. Methods: This cross sectional study was done using National Inpatient Sample [NIS], the largest database available in the US. Inpatient admissions of adults who received CART therapy for various indications during year 2020 were included. Results: A total of 6915 patients were admitted to hospital for CART therapy in 2020 with an overall inpatient mortality rate of 1%. Mean age of the patients was 57yr. Majority were White [64%], with a higher median household income, admitted to urban and large sized hospitals and predominantly covered by Medicare or private insurance [~80%]. Study population was divided into males and females and outcomes were compared. Females were significantly younger with lower Charlson comorbidity index and higher utilization of CART therapy [81% vs 19%] compared to males. Females had 86% lesser odds of mortality compared to males (Odds Ratio [OR] 0.14; 95% confidence interval [CI] 0.04-0.47; p value 0.001). Females had significantly lesser hospitalization charges [mean decrease $471,193; p value 0.000] and length of stay [mean decrease 8 days; p value 0.000] compared to males after adjusting for confounders. Racial differences in outcome were compared after multiple imputation was used to correct for 4% missing data in the race category in NIS 2020. There was no statistically significant difference in mortality, length of stay or hospitalization charges between Whites, Blacks and Hispanic races similar to previous studies. Conclusions: Eligibility criteria for CART therapy includes patients with good performance status and organ function with less comorbidities. Our study found that females were younger, healthier and therefore qualified better for CART therapy compared to males. Hence they had significantly higher utilization of CART therapy. In addition, among the population receiving CART therapy, females had better outcomes compared to males in terms of mortality, length of stay and hospitalization charges. In general, males have higher incidence and mortality with poorer outcomes in most hematological malignancies where CART therapy is a treatment option. Measures at modifying and improvising CART therapy to cater to more male subjects will not only reduce gender disparity but also improve overall survival and reduce disease burden. [Table: see text]
A plasma-based proteomic platform for predicting clinical benefit from immune checkpoint inhibitors in multiple cancers.
Authors: Sela Itamar , Lahav Coren , Lowenthal Gil , Harel Michal , Elon Yehonatan , Yellin Ben , Dicker Adam P. , Halaban Ruth , Marte Jenn , Sznol Mario , Gulley James L. 
Published: June 2024

2568 Background: Immune checkpoint inhibitor (ICI)-based therapies are preferred treatment options for multiple cancer types. However, there is an unmet need for predictive tests that can identify patients likely to benefit. PROphet-NSCLC is a commercially available pretreatment plasma proteomic test that predicts clinical benefit from first-line PD-(L)1 inhibitor-based therapy in patients with metastatic non-small cell lung cancer (NSCLC), guiding the choice between ICI monotherapy versus ICI-chemotherapy. Here, we evaluate the broader clinical utility of PROphet-NSCLC by testing its predictive capabilities across diverse cancer types. Methods: Pre-treatment plasma samples and clinical data were collected for an observational study from patients with metastatic melanoma (n=68) and HPV-related cancers (n=43; NCT03427411) treated with PD-(L)1 inhibitor-based therapies. HPV-related cancers included anogenital squamous cell carcinoma (n=16), cervical carcinoma (n=18), and head and neck squamous cell carcinoma (n=9). Patients were assigned a PROphet-positive or -negative result based on computational analysis of SomaScan-derived proteomic profiles in pre-treatment plasma samples. Overall survival (OS) and progression-free survival (PFS) in PROphet-positive- and -negative groups was analyzed with the Kaplan-Meier method. Hazard ratios (HR) were calculated from univariate and multivariate Cox proportional hazard models. Results: In the melanoma cohort, PROphet-positive patients (n=51) displayed a significant OS benefit in comparison to PROphet-negative patients (n=17; median OS 92.8 months vs. 9.5 months, HR=0.14, 95% CI: 0.06-0.34, p<0.0001), consistent with the clinically validated predictive performance of the test in patients with NSCLC. OS results remained significant after correcting for sex, age, histology, ECOG performance status, and treatment type (HR=0.05, 95% CI: 0.01-0.25, p<0.001). In PROphet-positive patients, PD-1+CTLA-4 inhibitor combination therapy (n=27) was superior to PD-1 inhibitor monotherapy (n=24; OS: median 118.4 vs. 48.3 months, HR=0.58, p=0.24; PFS: median not reached vs. 10.8 months, HR=0.48, p=0.04). PROphet-negative patients displayed similarly poor outcomes with either treatment, providing a rationale to consider alternative therapies for such patients. In the HPV-related cohort, the median OS in PROphet-positive (n=10) vs PROphet-negative (n=33) groups was 43.6 vs 4.4 months (HR=0.22, 95% CI: 0.08-0.59, p=0.001), with similar trends per sub-cohort. Conclusions: Our findings show that the PROphet-NSCLC test can be applied to PD-(L)1 inhibitor-treated melanoma and HPV-related cancers, suggesting applicability to cancers beyond NSCLC. Analysis of additional patient samples is needed to explore the potential utility of PROphet-NSCLC for informing treatment decisions for a broad range of cancer types.
Updated results from ERAS-007 plus encorafenib and cetuximab (EC) in patients (pts) with EC-naïve metastatic BRAF V600E colorectal cancer (CRC) in the phase 1b/2 HERKULES-3 study.
Authors: Parikh Aparna Raj , Chiorean E. Gabriela , Atreya Chloe Evelyn , Zheng Lei , Kopetz Scott , Spira Alexander I. , Spigel David R. , Cui Yue , Osgood Ryan , Tran Rebecca , Morris Shannon R. , Ulahannan Susanna Varkey 
Published: June 2024

3517 Background: The RAS/MAPK pathway (including BRAF) is dysregulated in a broad range of cancers including CRC, resulting in downstream activation of ERK1/2. Patients (pts) with metastatic CRC with BRAF V600E mutation (BRAF V600E mCRC) have dramatically poorer survival rates than those with non-BRAF V600E mutated CRC, highlighting the need for novel therapies. The combination of a BRAF plus EGFR inhibitor is approved for the treatment of pts with BRAF V600E mCRC; however, objective response occurs in only 20% of pts. ERAS-007 is a novel, potent, and orally bioavailable inhibitor of ERK. ERAS-007 alone or in combination with encorafenib and cetuximab (EC) showed promising in vitro and in vivo activity in BRAF V600E CRC models, supporting investigation of the potential clinical benefit of ERAS-007 + EC in pts with BRAF V600E mCRC. Methods: HERKULES-3 is a Phase 1b/2 study to assess the safety, tolerability, pharmacokinetics (PK), and preliminary clinical activity of ERAS-007 combinations targeting the MAPK pathway in pts with advanced GI cancers. Within this study, we are currently evaluating the safety, tolerability, PK, and preliminary clinical activity of the combination of ERAS-007 + EC in pts with EC-naïve BRAF V600E CRC. Results: As of 30 November 2023, 19 (EC-naïve and EC-pretreated) pts have been dosed with ERAS-007 100 mg twice daily-once a week (BID-QW) in combination with EC (300 mg oral daily + 500 mg/m2 intravenous infusion every 2 weeks). The treatment-emergent AEs (TEAEs) occurring in ≥25% of pts were dermatitis acneiform (52.6%); nausea and fatigue (47.4% each); diarrhea (42.1%); constipation, headache, and hematuria (31.6% each); and vomiting, anemia, and infusion-related reaction (26.3% each). There were no Grade 4 TEAEs. One pt suffered a Grade 5 unrelated event of respiratory failure. There were no Grade 3 treatment-related AEs that occurred in more than 1 pt. There were no ERAS-007-related AEs that led to discontinuation of ERAS-007. Of the 19 pts, 11 were EC naïve and 10 of 11 were efficacy evaluable. In the EC naïve efficacy evaluable pts, the ORR was 40% with 3 of the 4 responses confirmed. The maximum duration of response is > 15 months; updated data will be presented. Conclusions: ERAS-007 100 mg BID-QW in combination with EC was safe and well tolerated with preliminary evidence of promising clinical activity. These results support continued evaluation of this combination in EC naïve pts with BRAF V600E CRC. Clinical trial information: NCT05039177 .
PREVECOL, a predictive model for early detection of colorectal cancer and precancerous lesions in liquid biopsy.
Authors: Planelles Lourdes , Guler Ipek , Jiménez-Martínez Marta , Babiker Rashid , Castillo Lourdes , Monsalve Carmen , Sanchez-Viñes Elena , Arroyo Rocío 
Published: June 2024

3629 Background: Colorectal cancer (CRC) is the second cause of cancer-related deaths worldwide. Most of these deaths could have been prevented by increasing the effectiveness of CRC screening programs, which exhibit a low participation rate, partly due to the limited available screening options, alongside discomfort associated with the screening procedure (faecal test). Liquid biopsy-based technology offers new alternatives to improve CRC early detection. CRC and advanced adenoma (AA) patients show molecular alterations at different biological levels that can be detected in peripheral blood and used for diagnostic purposes. AMADIX has developed PreveCol, an innovative blood test based on molecular biomarkers and clinical features for early detection of CRC and AA, before the onset of the first symptoms. We present the validation of PreveCol predictive model through a European prospective clinical study involving average-risk population actively engaged in a real CRC screening program. PreveCol has been granted with the Breakthrough Device Designation by the FDA in December 2023. Methods: Samples from two prospective clinical studies were used for training and validation. A case-control study (n= 538 individuals: 173 CRC, 181 AA, 184 Controls; 13 Spanish sites) and a clinical study based on a real CRC screening program (n= 3163 individuals: 78 CRC, 156 AA, 146 HRPL, and 2783 Controls; 9 European sites). PreveCol molecular signature (11 proteins and 10 miRNAs), was determined in plasma samples using RT-qPCR and ELISA/CLIA. Machine learning techniques were used to develop an ensemble algorithm. K-fold cross validation techniques were used in the training to set the hyperparameters for each model. Hyperparameter optimalization was performed to find the best parameters of the grid. Once the algorithm was locked and the clinical cut-off was established in the training set, the signature was validated in the European prospective study sub-cohort. Results: For CRC detection, PreveCol demonstrates an Area Under the ROC curve (AUC) of 92%, with a sensitivity (SS) of 81.8% and specificity (SP) of 86%. Moreover, the model exhibits high sensitivity (above 90%) in identifying CRC in early stages (stages 1 and 2), as well as lesions located in the proximal colon. In addition, the AUC of PreveCol for Advanced Adenomas detection is 86.88%, (SS of 70.8% and SP of 86%), showing that PreveCol presents higher sensitivity compared to other identified tests for detecting precancerous lesions. Conclusions: These findings highlight PreveCol's potential to significantly impact on patient prognosis and survival by facilitating the early detection of CRC and premalignant lesions as well as lesions in critical areas of the colon, thereby contributing to improved screening efficacy and patient outcomes.
Association of plasma kynurenine (KYN) with plasma osteopontin (OPN) in patients with locally invasive breast cancer.
Authors: Ephraim Adam , Leatheng Chanbormey , Lu Ziyao Eric , Xia Xiaoqing , Pirruccello Jonathan P. , Marotti Jonathan D , MacKenzie Todd , Chamberlin Mary D. 
Published: June 2024

e12551 Background: OPN is a matricellular protein implicated in several aggressive malignancies as both a prognostic marker and mechanistic driver of tumor development and metastasis, but little is known about what drives its increased expression in these settings. KYN, the biochemically active metabolite of tryptophan metabolism, is known to be involved in cancer immune evasion, cancer cell proliferation, chromosomal instability, angiogenesis, metastatic dissemination, and chemoresistance. In this study, we demonstrate that OPN levels are significantly elevated in plasma of patients requiring breast surgery for suspicious masses and is directly correlated with KYN plasma levels, which were also elevated in this population. Methods: We prospectively collected peripheral blood samples of 60 patients who required routine breast surgery for either benign or malignant masses. Plasma was obtained by centrifugation from the collected blood samples that were stored at -80℃. Samples were collected prior to any treatments or surgeries. This study is IRB approved, and participants provided written informed consent. High-performance liquid chromatography (HPLC) tandem mass spectrometry was carried out by the Dartmouth Clinical Pharmacology Shared Resource. Logistic regression was used to assess relationships among variables in the study population using the R language. Results: There is strong evidence to suggest that plasma KYN is directly related to OPN plasma levels in this group of 60 patients’ plasma samples with a correlation coefficient of 0.296 (p=0.024), 95% CI [0.0414-0.515]. Based on the p-value and confidence interval, there is statistical evidence to suggest a positive significant linear relationship between plasma KYN and OPN levels. Increased age and BMI, menopausal status, KYN’s substrate Tryptophan (TRP), and TNFα correlated neither with OPN levels nor event free survival (as defined by disease progression, complications including fractures, development of metabolic disease, or occurrence of secondary malignancy). Conclusions: Our data demonstrates a statistically significant linear relationship between KYN and OPN in plasma samples of patients undergoing breast surgery for suspicious lesions—offering new mechanistic insights into OPN—a biomarker implicated in cancer metastasis across several different cancer types. This data suggests that KYN, which is a known agonist of several harmful cancer-driving pathways, is directly related to OPN concentration in plasma of patients with early breast cancer. Further research investigating systemic concentrations of OPN in plasma is essential for gaining a comprehensive understanding of its mechanisms in tumor metastasis, as well as for exploring targeted therapeutic strategies to mitigate its detrimental effects.