bluuebunny/crossref_metadata_2025_split huggingface dataset:
Performance status restriction in phase III cancer clinical trials.
Authors: Kouzy Ramez , Abi Jaoude Joseph , Mainwaring Walker , Lin Timothy , Miller Austin B. , Jethanandani Amit , Espinoza Andres F. , Taniguchi Cullen M. , Ludmir Ethan B. 
Published: May 2020

2059 Background: Patients with good performance status (PS) tend to be favored in randomized clinical trials (RCTs), possibly limiting the generalizability of trial findings. We sought to characterize trial-related factors associated with the use of eligibility criteria that restrict patients by PS, and analyze patient accrual breakdown by PS. Methods: We searched ClinicalTrials.gov for phase III RCTs between 2003-2018. Randomized multi-arm trials assessing a therapeutic intervention in cancer patients were included. PS data were extracted from corresponding manuscripts. Trials with PS restriction Eastern Cooperative Oncology Group (ECOG) ≤1 were identified. Factors associated with PS restriction were determined, and trial patient accrual was analyzed. Results: Six-hundred trials were included with PS data for 238,213 patients. In total, 527 studies (87.8%) specified an upper PS restriction cutoff as part of their exclusion criteria, and 237 studies (39.5%) had a strict inclusion criterion of patients with ECOG PS ≤1. Enrollment criteria restrictions based on PS (ECOG PS ≤1) were more common among industry-supported trials (P< 0.001) and lung cancer trials (P < 0.001). Nearly half of trials that led to subsequent FDA approval included strict PS restrictions. Binary logistic regression revealed stable use of restrictive PS eligibility criteria between 2007-2018 (P= 0.789). The vast majority of patients enrolled across all trials had an ECOG PS of 0 to 1 (96.3%). Even among trials that allowed patients with ECOG PS ≥2, only 8.1% of enrolled patients had a poor PS (ECOG 2 or higher).Trials of hematologic cancers had the largest proportion of patients with ECOG PS ≥2 (8.7%), while lung, breast, gastrointestinal and genitourinary trials all included less than 5% of patients with poor PS (P< 0.001). Only 4.8% of patients enrolled in trials that led to subsequent FDA approval had a poor PS. Conclusions: The use of PS restrictions in oncologic RCTs is pervasive, and exceedingly few patients with poor PS are enrolled. The selective accrual of healthier patients has the potential to severely limit and bias trial results. Future trials should consider a wider cancer population with close toxicity monitoring, to ensure generalizability of results, while maintaining patient safety.
Mobile apps: Breaking barriers to early cancer detection in underserved communities.
Authors: Munoz-Zuluaga Carlos A. , Gallo-Perez José David , Perez-Bustos Andres , Orozco-Urdaneta Mavalynne , Druffel Karen , Cordoba-Astudillo Lida Patricia , Parra Lara Luis Gabriel , Velez Carolina , El-Sharkawy Farah , Zambrano-Vera Katherin , Erazo Raul Hernando , King Mary Caitlin , Sardi Armando 
Published: May 2020

2065 Background: Despite being potentially curable with early detection and timely treatment, breast (BC) and cervical cancers (CC) remain leading causes of death for Colombian women. Lack of cancer screening education, tedious administrative processes, and geographical limitations hinder early cancer detection. Today, technological tools permeate all levels of society and could gather data for user risk stratification, deliver clear and customized information, and help with care coordination, tracking, and addressing communication, transportation, and financial barriers. We aimed to assess the effectiveness of a free mobile application (mApp) to reach women, understand misconceptions about cancer screening, identify users at risk for BC and CC, and coordinate screening tests in Cali, Colombia. Methods: The mApp, Ámate, was developed over 4 months and advertised to women (≥14 years) in waiting rooms of 4 healthcare facilities in Cali, Colombia for 23 months. Ámate used educational, evaluative, and risk factor questions followed by brief explanations to assess the population’s knowledge, educate users on BC and CC, and identify users in need of BC and/or CC screenings. Correct answers yielded points redeemable for cellular data. Women who required screening were subsequently navigated to a healthcare provider and enrolled in the national cancer program. Results: From August 2017-August 2019, 1,043 women from Cali downloaded Ámate and answered all questions. Misconceptions about BC included beliefs that BC can be prevented (87%), obesity does not increase the risk of BC (49%), deodorant causes BC (17%), and only women with a relative with BC can get BC (16%). For CC, misconceptions included that pap smears should not be performed while sexually active (64%), vaginal pain is an early sign of CC (44%), and only women contract HPV (33%). Overall, 31.5% (329) were identified as at-risk and needed a mammogram and/or pap smear. So far, 30% (98) were successfully navigated and completed their recommended screening test(s). Barriers to enrollment in these programs included patient unwillingness, using fake contact information, limited available appointments, and denied access due to healthcare coverage. Conclusions: Ámate is an accessible tool that identifies women at-risk for breast and cervical cancer and detects barriers to early cancer detection. Administrative obstacles exist and must be addressed to improve early cancer detection/screening. Ámate is currently being tested in other areas of Colombia and may be useful in other underserved countries.
4-miRNA signature combined with MGMT methylation status in glioblastoma: A multicentric retrospective biomarker analysis with accompanying prospective cohort study.
Authors: Niyazi Maximilian , Fleischmann Daniel F , Reifenberger Guido , Herms Jochen , Tonn Joerg , Belka Claus , Unger Kristian 
Published: May 2020

2517 Background: Previously, we identified a prognostic 4-miRNA signature (built from let-7a-5p, let-7b-5p, miR-125a-5p and miR-615-5p) in glioblastoma patients treated according to the EORTC26981/22981-NCIC CE3 protocol. We present results of a novel external validation and will report on a completed prospective study on blood plasma samples of glioblastoma patients prior to chemoradiotherapy (CRT). Methods: The external validation cohort (n = 103) contained IDH1/2 wildtype tumors with known MGMT promoter methylation from the LMU-Munich (n = 37), the University Hospital Düsseldorf (n = 33) and TCGA (n = 33). Risk groups from the combination of miRNA signature with MGMT promoter methylation were analyzed for overall survival (OS) and prognostic performance using C-index. Within the prospective study (n = 52), blood samples were taken prior to RT, on d42 and d84 (22 cases analyzed up to now). Risk scores were obtained from signature miRNA expression levels in resection or biopsy specimen (retrospective, endpoint OS) and blood plasma (prospective, PFS). Results: The 4-miRNA signature was independent of sex and MGMT promoter methylation (p > 0.1) and defined high-risk (n = 47, med. OS: 16.4months) and low-risk (n = 56, med. OS: 26.9months) patients (HR: 2.08, 95%CI: 1.25-3.46, p = 0.004). Patients with methylated (med. OS: 23.7months, n = 54) compared to non-methylated MGMT promoter (med. OS: 16.8months, n = 49) had superior OS (p = 0.007, HR: 0.48, 95%-CI: 0.28-0.82). Combining the 4-miRNA signature and MGMT promoter methylation resulted in the signature-low-risk/ MGMT-promoter-methylated (med. OS: 37.4months), signature-low-risk/ MGMT-promoter-unmethylated (med. OS: 24.7months), signature-high-risk/ MGMT-promoter-methylated (med. OS: 16.4 months) and signature-high-risk/ MGMT-unmethylated groups (med. OS: 14.3months, Log-rank p = 0.002) with superior prediction performance. Conclusions: We confirmed the 4-miRNA signature as an independent prognosticator in IDH-wildtype glioblastoma while combination with MGMT promoter methylation outperformed other established prognostic factors. Our hypothesis is, that blood plasma samples will allow the risk stratification of glioblastoma patients before CRT. Phenotypic alterations driving its prognostic value remain to be determined and will allow for 1) risk stratified trials, 2) pathway analysis and targeting and 3) testing in healthy subjects to elucidate its screening potential.
The imaging substudy of the randomized ARTE trial: MRI and 18FET PET associations with overall survival benefit from bevacizumab in elderly patients with newly diagnosed IDH wildtype glioblastoma.
Authors: Wirsching Hans-Georg , Roelcke Ulrich , Weller Jonathan , Hundsberger Thomas , Hottinger Andreas Felix , Von Moos Roger Anton Fredy , Caparrotti Francesca , Conen Katrin Lisa , Remonda Luca , Roth Patrick , Ochsenbein Adrian , Tabatabai Ghazaleh , Weller Michael 
Published: May 2020

2520 Background: Bevacizumab failed to demonstrate overall survival benefit despite markedly prolonged progression-free survival in glioblastoma patients. Reasons for this divergence may include suboptimal patient selection and delayed diagnosis of progression on MRI scans under bevacizumab. Imaging analyses of retrospective and uncontrolled clinical trial cohorts suggest MRI diffusion mapping as a predictor of benefit from bevacizumab. Moreover, amino acid PET has been proposed by the RANO working group for the differentiation of tumor versus edema or gliosis based on proof-of-principle studies demonstrating earlier detection of progression with PET compared to MRI. Methods: ARTE (NCT01443676) was a 2:1 randomized, multi-center, open-label trial of hypofractionated radiotherapy in combination with intravenous bevacizumab every 2 weeks (BEV/RT) versus RT alone in patients with newly diagnosed glioblastoma aged 65 years or older. Patients with histologically and molecularly confirmed IDH wildtype glioblastoma aged 65 years or older were analyzed. MRI was available from 67 and serial 18FET PET from 30 patients in this post hoc analysis. 18FET PET intensity ratios and herein reported MRI parameters including tumor volumetric analyses and ADC were analyzed blinded for outcome and study arm. Results: Demographic, clinical and molecular parameters were balanced between treatment arms. Overall survival benefit from bevacizumab was observed for larger contrast-enhancing tumor volumes (hazard ratio [HR] per cm3 0.94, 95% CI 0.89-0.99, p = 0.032) and higher ADC (HR 0.18, 95% CI 0.05-0.66, p = 0.025) on pre-treatment MRI. Response in the BEV/RT arm by the standard MRI-based RANO criteria was associated with overall survival by trend (HR 0.56, 95% CI 0.30-1.10, time-dependent p = 0.094). In a multivariate model controlling for established risk factors, 18FET tumor-to-brain uptake ratios (TBR) of non-contrast-enhancing tumor portions predicted inferior overall survival specifically in the BEV/RT arm (HR [per 0.1 18FET TBR] 1.50, 95% CI 1.05-2.13, time-dependent p = 0.025). Controlling for 18FET TBR at first follow-up identified benefit from BEV/RT by trend (HR 0.41, 95% CI 0.16-1.07, p = 0.069). Conclusions: Large contrast-enhancing tumor mass and high ADC identify patients with overall survival benefit from bevacizumab. Under bevacizumab, non-contrast enhancing tumor portions can be adequately monitored by amino acid PET.
Eradication of medulloblastoma by NKG2D-specific CAR T-cells.
Authors: Dai Hong-jiu , Sun Bin , Yang Dong , Xu Hui , Zhu Jingjing , Wei Jia , Zhao Xudong 
Published: May 2020

2522 Background: Medulloblastoma (MB) is a cancerous malignant brain tumor, that most often occurs in young children. Standard-of-care therapies for treating pediatric MB have long-term side effects, even in children who are cured. Recently people are exploring the potential of chimeric antigen receptor T (CAR-T) cell therapy in brain tumor, yet the clinical outcome is limited. It's reported that NKG2D ligands are wildly expressed in MB cells, which supports NKG2D system might play an important role in MB therapy. Here, we take advantage of NKG2D-specific CAR-T cells (KD-025) for MB treatment. Methods: HTB186, HTB185 and HTB187 MB cell lines as well as MB cancer patient samples were evaluated for NKG2D ligands expression. The KD-025 showed antigen-specific stimulation by cytokine secretion and target cell lysis. HTB186 cells, which stably express luciferase protein, were used to establish in vivo subcutaneous and xenograft models in NSG mice. Mice received a single treatment of 10 million KD-025 intravenously. Results: NKG2D ligands were detected on HTB186 and HTB187 cells and most of screened BM patient samples. The KD-025 was generated with CD8 hinge region and transmembrane region, 4-1BB costimulatory region and CD3 zeta region. The KD-025 expression was > 50% on the surface of T cells confirmed by flow cytometry. Co-incubation of KD-025 with HTB186 cells specifically upregulates TNF-α, IFN-γ, IL-10 and IL-2 cytokines and strongly lysis tumor cells even at low E:T ratio (70-80% at 8:1). Strikingly, KD-025 markedly eliminated xenograft tumors in vivo and did not exhibit significant treatment-related toxicity in the treated mice. Regarding to T cell persistence, the CAR-T cells are barely detectable 24 days after injection, which is comparable with CD19 CAR in our experiments as well as published data. No obvious pathological changes were found in the tested organs. Conclusions: Our work with the KD-025 contributes to the growing body of research committed to discovering a novel therapy for MB. NKG2D ligands are highly expressed on human MB samples. KD-025 potently respond to MB and eliminate tumor in a xenograft mouse model with no obvious safety issues. The results support future clinical trial of KD-025 in patients with MB, where the need for effective treatment is great.
Advanced imaging to assess longitudinal vascular changes in brain metastases treated with immune checkpoint inhibition.
Authors: Kim Albert Eusik , Chang Ken , Beers Andrew , Emblem Kyrre E. , Kalpathy-Cramer Jayashree , Lee Eudocia Quant , Lin Nancy U. , Nayak Lakshmi , Chukwueke Ugonma Nnenna , Oh Kevin S. , Shih Helen Alice , White Michael , Lawrence Donald P. , Moy Beverly , Cohen Justine Vanessa , Giobbie-Hurder Anita , Cahill Daniel P. , Sullivan Ryan J. , Brastianos Priscilla Kaliopi , Gerstner Elizabeth Robins 
Published: May 2020

2529 Background: Immune checkpoint inhibitors (ICI) have recently been shown to be effective for brain metastases (BM) for melanoma and lung cancer. This breakthrough has prompted interest in evaluating ICI in BM of other histologies. However, accurately assessing intracranial response in patients undergoing ICI is a challenge, as current measures cannot distinguish pseudoprogression from true tumor progression. To shed light on potential biomarkers of response, we prospectively use perfusion MRI to identify characteristic vascular signatures in a BM-specific trial of ICI. Methods: As part of an ongoing phase II study of pembrolizumab for patients with untreated or progressive, previously treated BM from any histology, patients underwent advanced MRI that includes tumor volume measurements and perfusion imaging with dynamic susceptibility contrast MRI. To calculate volumetric radiographic response, all enhancing voxels were summated. A volumetric increase of >40% was categorized as progressive disease (PD), a decrease of >60% as partial response (PR), and stable disease (SD) as between -60% and +40%. Results: 53 patients have been enrolled, of whom 44 have received at least baseline advanced MR imaging. Histologies include 21 with breast cancer, 5 with non-small cell lung cancer, 4 with melanoma, and 13 with other cancers. At baseline, the total number of BM was 1-50+ per patient. Based on summing the entire enhancing intracranial disease burden, best volumetric responses for the 33 evaluable patients include 4 PR, 10 SD, and 19 PD. On preliminary analysis, there was a correlation between increased tumor cerebral blood volume/flow with tumor progression. Correlation of additional vascular physiologic parameters (e.g. vessel caliber, tissue oxygenation) and volumetric response to patient outcome and standardized response criteria (iRANO) are ongoing. Conclusions: Pembrolizumab likely has anti-tumor efficacy in BM. Our data provides potential evidence that effective ICI is associated with a decrease in perfusion. Ongoing analyses to uncover additional vascular changes – specifically longitudinal metrics reflecting vascular structure and function - within BM to ICI are pending. These findings have potential to illustrate mechanisms of efficacy for ICI and biomarkers of response in this patient population.
Intra-operative radiation therapy as salvage treatment option for recurrent glioblastoma multiforme.
Authors: Salim Nidal , Krivoshapkin Alexey , Zvereva Daria , Gaytan Alexey , Abdullaev Orkhan , Sergeev Gleb , Marmazeev Ilya , Krotenkova Irina , Kiselev Roman , Semin Pavel 
Published: May 2020

2535 Background: Glioblastoma multiforme (GBM) is an extremely aggressive cerebral tumor with poor prognosis. The majority of patients relapse after the initial surgery plus adjuvant radiation and chemotherapy. In case of recurrence there is no established standard therapy. The optimal techniques for salvage re-irradiation are unclear, so that procedure poses a challenge. In contrast to traditional external beam radiotherapy (EBRT) intra-operative radiotherapy (IORT) may improve patient’s outcome at the cost of minimal side effects and short treatment duration. Methods: A total of 30 patients were treated with recurrent GBM between August 2016 and June 2019. All patients underwent maximal safe resection; patients were divided into IORT and EBRT groups. 15 patients were included in each group with similar clinical characteristics. All patients in IORT group underwent maximal safe microsurgical resection with subsequent intraoperative balloon electronic brachytherapy (IBEB) and no further adjuvant treatment. IBEB was performed using Axxent electronic brachytherapy device (Xoft Electronic Brachytherapy (eBx) System, USA. Patients in EBRT group underwent same surgery followed by external beam radiotherapy. Contrast-enhanced brain MRI with perfusion was performed within 24 hours of surgery +/- brain PET-CT with 18-FDOPA and then every 3 months. Both groups were also assigned to subgroups (≤ 2.5cm3 and > 2.5cm3) based on post-operative contrast-enhancing volume (POCEV). Median overall survival (OS) since diagnosis and local progression-free survival (locPFS) following the second surgery were analyzed. Possible toxicities and prognostic factors were also evaluated. Results: Median OS was 27 months in IORT group and 21 months in EBRT group. The locPFS range between 3.5 to 39 months in IORT group and only 2 to 10 months in group with EBRT. Kaplan-Meier OS curves in patients with POCEV ≤ 2.5cm3 showed more favorable outcomes for patients in the IORT group (p < 0.05). In patients with POCEV > 2.5cm3 the median OS was 17 months in IORT group and 13.5 months in EBRT group. Conclusions: IORT of recurrent GBM is feasible and provides encouraging local progression-free and overall survival; no high-grade radiation induced toxicities occur and further studies to establish this method are mandatory. The toxicity profile of additional IBEB was manageable. Maximal safe microsurgical resection is the most important prognostic factor and could determine the effectiveness of post-surgical IBEB.
Phase II trial of bevacizumab and temozolomide for treatment of elderly patients with newly diagnosed glioblastoma.
Authors: Molaie Donna , Lai Albert , Ellingson Benjamin M. , Nguyen Thien , Bahng Hye Hyun , Filka Emese , Green Stacey , Pope Whitney B. , Leng Mei , Yong William H. , Green Richard M. , Polikoff Jonathan , Spier Liz , Iwamoto Fabio Massaiti , Lassman Andrew B. , Cloughesy Timothy Francis , Nghiemphu Phioanh Leia 
Published: May 2020

2540 Background: Glioblastoma (GBM) in elderly patients differ molecularly as compared to younger patients, and may have increased angiogenic activity. Bevacizumab (BV) is an anti-angiogenic monoclonal antibody against vascular endothelial growth factor. We conducted a clinical trial to evaluate the efficacy and safety of BV and temozolomide (TMZ) for elderly patients with a new diagnosis of GBM, while deferring radiotherapy. Methods: This is a phase II, single-arm, multicenter, open label trial. Eligible patients have a tissue diagnosis of GBM with no treatment other than surgery, age ≥ 70, KPS ≥ 60, and adequate organ function. TMZ was initiated within 2 weeks of surgery and BV was initiated within 4 weeks thereafter. TMZ was administered at 150-200 mg/m2/day for 5 days every 4 weeks and BV at 10mg/kg every 2 weeks. A historical control group of 42 patients with similar criteria who received concurrent TMZ and RT followed by adjuvant TMZ, was derived for comparison from an institutional patient database. The primary endpoint is overall survival (OS) and secondary endpoints are progression-free-survival and safety. Results: 50 patients were enrolled from June 2010 to January 2016. Median age is 75 (range 70-87), and median KPS is 80 (range 60-100). 17 patients had a biopsy only, 26 patients have MGMT promoter methylation, and all patients are IDH wildtype. The study and control group are well matched in terms of age and molecular markers, however, the study patients had worse initial KPS and higher baseline tumor volume. At time of analysis, all but 2 patients were deceased. The median OS was 12.6 months for study patients (95% CI, 10.9-15.9 months) and 16.3 months for control patients (95% CI, 12.9-22.4 months). In a multivariate Cox analysis, baseline tumor volume (HR = 2.6, p = 0.0001) and MGMT promoter methylation (HR = 0.49, p = 0.004) were significant prognostic markers. Treatment type did not have a significant impact on OS (HR = 1.5, p = 0.14). Treatment-related serious adverse events included: pulmonary embolism (5), cerebral hemorrhage (3), pneumonia (1), intestinal perforation (1), deep venous thrombosis (6), hypertension (2), atrial fibrillation (1), congestive heart failure (1), cardio-respiratory arrest (1), lymphopenia (2), thrombocytopenia (8), and neutropenia (5). Conclusions: The results of this study suggest for patients with newly diagnosed GBM age ≥70 and KPS ≥60, treatment with BV and TMZ is equivalent to standard chemoradiotherapy, and has tolerable side effects. Complete endpoint analysis will be presented with the poster. Clinical trial information: NCT01149850 .