bluuebunny/crossref_metadata_2025_split huggingface dataset:
DCE-MRI Evaluation of 10 patients with brain metastases treated with RRx-001, a Myc inhibitor and a CD47 and PD-L1 downregulator, in a phase I/II trial called BRAINSTORM.
Authors: Kim Michelle Miran , Parmar Hemant , Aryal Madhava P , Caroen Scott , Devasia Theresa , Schipper Matthew J , Morikawa Aki , Spratt Daniel Eidelberg , Hayman James , Junck Larry , Lawrence Theodore Steven , Lao Christopher D. , Cao Yue 
Published: May 2020

e14509 Background: In a Phase 1/2 trial called BRAINSTORM (NCT02215512) for brain metastases from any histology, quantitative changes in perfusion MRI after administration of RRx-001, a mic inhibitor and CD47 and PD-L1 downregulator with vascular normalizing properties, were determined and correlated with response. Methods: Ten patients with 64 total lesions evaluable at baseline, 24 hours, and end of radiotherapy (RT) that participated in BRAINSTORM were subjected to a correlative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) examination four days prior to the start of whole brain radiotherapy (WBRT) that evaluated Ktrans (capillary permeability) and Vp (plasma volume). The treatment comprised RRx-001 on Day -4, pre-WBRT then twice weekly during WBRT. Four dose levels were administered (5 mg/m2, 8.4 mg/m2, 16.5 mg/m2, and 27.5 mg/m2. Results: 10 patients underwent DCE-MRI scans and eight patients with 44 total evaluable lesions had available imaging at 1 month, and 6 patients with 29 total evaluable lesions had imaging at 4 months. On univariate analysis, only a decrease in 24-hour Vp from baseline after a single dose of RRx-001 was marginally associated with absolute tumor volume response 1 month after treatment (p-0.07). In a multivariate model, only Vp prior to therapy and 24-hour change in Vp were retained in the model after stepwise selection. A reduction in Vp 24 hours after RRx-001 (prior to WBRT) was associated with reduced tumor volume at 1 month (Estimate 0.88, 95% CI 0.37-1.40, p = 0.001) and 4 months (Estimate 1.51, 95% CI 0.58-2.43, p = 0.003). Likewise, a lower Vp prior to therapy was associated with reduced tumor volume at 1 month (Estimate 0.73, 95% CI 0.29-1.17, p = 0.002) and 4 months (Estimate 1.8, 95% CI 0.95-2.65, p = 0.0002), suggesting anti-angiogenic activity and early potential vascular normalization after a single dose of RRx-001 predictive of longer-term tumor response. Conclusions: RRx-001 induced a reduction in blood plasma volume, which was associated with tumor response and which suggests a vascular normalizing effect that merits further investigation in future planned studies. Clinical trial information: NCT02215512.
Efficacy of anti-programmed cell death-1/ligand 1 monotherapy for non-small cell lung cancer patients with active brain metastases.
Authors: Tozuka Takehiro , Kitazono Satoru , Sakamoto Hiroaki , Yoshida Hiroshi , Amino Yoshiaki , Uematsu Shinya , Yoshizawa Takahiro , Hasegawa Tsukasa , Ariyasu Ryo , Uchibori Ken , Yanagitani Noriko , Horai Takeshi , Nishio Makoto 
Published: May 2020

e14511 Background: The efficacy of anti-programmed cell death-1/ligand 1 (anti-PD-(L)1) for active brain metastases (BMs) is not established, because most clinical trials excluded patients (pts) with active BMs such as untreated, symptomatic, or unstable BMs. The aim of this study was to evaluate the efficacy of anti-PD-(L)1 monotherapy in non-small cell lung cancer (NSCLC) pts with active BMs. Methods: This retrospective study included NSCLC pts who had received anti-PD-(L)1 monotherapy in 2nd or later line between December 2015 and August 2019. Pts who had not evaluated BMs by CT/MRI before anti-PD-(L)1 were excluded. Pts were classified into those with or without active BMs which were defined as untreated or symptomatic BMs or BMs requiring systemic steroids. Progression free survival (PFS) and overall survival (OS) of pts with or without active BMs were compared. Intra-cranial and extra-cranial tumor responses were evaluated in pts with active BMs. Results: In this study, 242 pts who had received anti-PD-(L)1 monotherapy were identified and 197 pts were analyzed. Twenty-four pts were classified to pts with active BMs. Among pts without active BMs, 145 pts had no BMs and 28 pts had treated asymptomatic BMs. PFS of pts with active BMs was significantly shorter than that of pts without active BMs (1.3 versus 2.7 months; p < 0.001). OS of pts with active BMs was significantly shorter than that of pts without active BMs (4.5 vs 16.3 months; p = 0.001). Intracranial response rate (RR) was 13.3% (2/15) and extracranial RR was 26.7% (4/15) in pts with active BMs. In multivariate Cox regression analysis, active BM, poor PS and EGFR/ALK(+) were selected as significant factors associated with poor PFS. Active BM and poor PS were selected as significant factors associated with poor OS. Conclusions: Anti-PD-(L)1 monotherapy is not recommend for pts with active BMs.
Results of treating children with medulloblastoma in Azerbaijan of 2020.
Authors: Mammadova Naila Agayar , Nizami Malikov Ramin , Alik Aleskerova Gunel , Sadikh Ismailzade Reiman , Akif Nasirli Asif , Pamir Khalafova Leyla 
Published: May 2020

e14519 Background: Medulloblastoma (a primitive neuroectodermal tumor of the posterior cranial fossa) is the most common CNS tumor in children; it takes 20-30% of all brain tumors. In about 40% of cases of primary detected tumors, there are already metastatic lesions of the brain and spinal cord. Treatment of medulloblastoma is a difficult problem. It requires a multidisciplinary approach and modern technical support of the medical institution. Only after the opening of the children's oncology department of the National Oncology Center in 2012, it became possible for children with a medulloblastoma to use modern treatment by HIT-2000 and HIT 2015 protocols. Methods: For the period 2012-2020, a total amount of 45 children were treated with a diagnosis of medulloblastoma (34 boys, girls-11). The average age of children was 12 years. Complete removal of the tumor was reached in 27, subtotal removal of 18 patients. Taking into account the age, the histological variant and the size of the residual tumor after surgery, the patients were divided into high and medium risk groups. Treatment according to the average risk group was carried out in 27 patients and high risk group - in 18. Craniospinal radiation therapy was carried out in 45 patients in the prescribed manner (SOD 25-30 Gy for the entire CNS and additionally for the posterior cranial fossa 25-30 Gy). In parallel with radiation therapy, vincristine is used, in dose of 1.5 mg / m2 weekly, only 8 times, followed by 8 courses of maintenance chemotherapy (cisplatin 70 mg / m2, lomustine 75 mg / m2 and vincristine 1.5 mg / m2). Results: Children in general satisfactorily tolerated both chemo- and radiotherapy. No serious complications of treatment were noted. During the observation period ( 8 years), relapses were observed in 5 children out of 45 treated, in 3 there was a progression during treatment, 8 children died. Thus, out of 45 children, 37 are alive with no signs of illness. 8-year survival rate was 82% ± 7%. Conclusions: The introduction and subsequent modification of modern foreign protocols into the practice of our center made it possible for the first time to achieve quite good results for this difficult category of patients.
Major histocompatibility complex class 1 (MHC1) loss among patients with glioblastoma (GBM).
Authors: Castro Michael , Sipos Bence , Pieper Natalia , Biskup Saskia 
Published: May 2020

e14523 Background: Immune evasion represents a hallmark behavior of cancer and may occur through many mechanisms. Among these, intact tumor antigen presentation at the cell surface is a fundamental prerequisite to achieving successful adaptive immunotherapy. The loss of MHC1 expression due to molecular events, including mutation, deletion, or epigenetic silencing of B2M is commonly acquired during immunotherapy. On the other hand, molecular events affecting antigen presentation machinery may be present prior to immunotherapy administration. Among these, TP53 mutations causing loss of ERAP1 and TAP1 expression compromise transport of MHC1 molecules from the endoplasmic reticulum to the cell surface and mutant peptide integration into the HLA context resulting in absent antigen presentation. Thus far, clinical trials of PD-1/L1 agents have failed to demonstrate a benefit for GBM patients and responses are seen only among a minority. Hence, we set out to assess the integrity of MHC1 expression by using immunohistochemistry. Methods: Immunohistochemical (IHC) stains for HLA, B and C were developed and validated with internal controls. Staining intensity and location (membrane-bound or cytoplasmic) was evaluated semi-quantitatively. The first 10 consecutive patients with GBM who were referred for neoepitope vaccine were evaluated. Results: Absent staining was seen among 6/10, negligible, or faint staining was present in 2, and only 2 tumors demonstrated intact membrane-bound expression. Conclusions: In addition to low tumor mutation burden and an immunosuppressive tumor microenvironment, MHC1 loss is a frequent event among patients with GBM, and may be a dominant cause of immunotherapy failure for as many as 80% of patients. Thus, development of strategies to reverse this loss may be an essential component of successful adaptive immunotherapy for this disease. These data suggest that routine assessment of MHC1 should become a component of eligibility checking for GBM patients being considered for an MHC-restricted approaches. [Table: see text]
Predictive evaluation of quantitative spatial profiling of the tumor microenvironment by multiplex immunofluorescence in recurrent glioblastoma treated with PD-1 inhibitors.
Authors: Cieremans David , Kim Ju Young , Valencia Ariana , Santos Justin , Bordeaux Jennifer , Tran Thai , Vaupel Christine , Dakappagari Naveen , Tangri Shabnam , Iwamoto Fabio Massaiti 
Published: May 2020

e14524 Background: PD-1 inhibitors have shown limited efficacy in glioblastoma (GBM) due to microenvironment immunosuppression and low tumor mutational burden. In GBM, PD-L1 expression is not a predictive marker for response to PD-1 or PD-L1 inhibitors. Multiplex immunostaining panel technology allows for detailed analyses of tumor microenvironment cells and their interaction. Methods: Pre-treatment tumor tissue was collected retrospectively from 27 patients in our neurooncology database at Columbia University Irving Medical Center with primary glioblastoma who were diagnosed within the past three years, had surgery here, and were either treated with SOC therapy (n = 8) or PD-1 inhibitors at recurrence (n = 19). Multiplex immunofluorescence was done for 1) CD11b/IDO1/HLADR/GFAP, 2) PD1/PD-L1/GFAP, and 3) CD4/CD8/CD25/FoxP3/Ki67/GFAP. Results: Multiplex immunofluorescence panels did not show any correlation with outcomes in patients treated with SOC therapy (non-immunotherapy). Among the 19 patients treated with PD-1 inhibitors, those with more HLA-DR positive cells had worse outcomes (p = 0.02). PD-L1 expression on tumor cells was not predictive of outcomes. There was a correlation trend between PD-1/PD-L1 interaction score (p = 0.08), which measures density of PD-1-positive cells in proximity to PD-L1-positive cells, and outcomes. This assay allowed us to evaluate tumor-associated macrophages, myeloid-derived suppressor cells, CD8+ lymphocytes, and CD4+ T regulatory cells; however, none of these were predictive of survival. Conclusions: Quantitative spatial profiling by multiplex immunofluorescence is feasible in FFPE glioblastoma tissue. More refined and extensive quantitative and spatial microenvironment analyses may allow for the development of biomarkers for immunotherapy in GBM.
Effect of temozolomide chronotherapy in patients with high-grade glioma.
Authors: Atluri Himachandana , Campian Jian Li , Talcott Grayson , Meyer Melissa , Slat Emily , Rubin Joshua , Huang Jiayi , Chheda Milan G , Johanns Tanner Michael , Tao Yu , Govindan Ashwin 
Published: May 2020

e14525 Background: High grade gliomas (HGG) (the most common being glioblastoma) are the most common primary CNS malignancy in adults. Mainstay of therapy is surgical resection followed by concurrent radiation and temozolomide (TMZ) followed by adjuvant TMZ. Unfortunately, prognosis remains poor and optimization of current therapy is critical. Chronotherapy is defined as improvement in treatment outcomes by maximizing treatment efficacy and minimizing toxicity by administering medications in accordance with biological rhythms of the patient. In a mouse model, there was greater anti-tumor efficacy during morning administration of TMZ. This trial was designed to determine the feasibility and potential clinical impact of chrono-therapeutically administering TMZ in patients with HGG. Methods: Adult patients ( > 18 years) with HGG (WHO Grade III/IV) were eligible. Patients were screened and consented prior to initiation of monthly TMZ therapy. Eligible patients were randomized to TMZ in the morning (AM) before 10AM or in the evening (PM) after 8PM. Pill diaries were recorded for drug administration time and compliance. Fact-Br Quality of Life (QoL) surveys were administered to patients at the time of enrollment in the trial and at the end of treatment to measure differences in QoL in both groups. Circadian rhythm was recorded by Actiwatch. Adverse events (AE), overall survival (OS) and progression free survival (PFS) were measured for each group. Results: At the time of submission, a total of 28 patients were evaluated. 15 patients were in AM group and 13 in PM group. It is feasible for participants to take TMZ per study assignment. There was no significant difference in the QoL based on the Fact-Br dataset in the four main categories of physical well-being, social/family well-being, functional well-being and emotional well-being. The Friedman’s two-way nonparametric ANOVA tests were used to analyze the differences across time points. Cytopenias are a known adverse effect of TMZ. There was a trend towards worsening lymphocyte counts in the AM group compared to PM group, although not statistically significant. There was no statistical significance in PFS or OS in patients with newly diagnosed glioblastoma. Conclusions: Chronotherapy with TMZ is feasible. A trend of worsening lymphocyte counts is noted in AM treatment group compared to PM group but was not statistically significant. No difference in OS or PFS was noted, although sample size was too small to effectively assess this. A larger study will need to be conducted to effectively assess the effect of chronotherapy on survival. Clinical trial information: NCT02781792.
Combined structural and perfusion MRI enhanced by machine learning may outperform standalone modalities and radiological expertise in high-grade glioma surveillance: A proof-of-concept study.
Authors: Roettger Diana , Siakallis Loizos , Sudre Carole , Panovska-Griffiths Jasmina , Mulholland Paul , Thorne Lewis , Shaikh Faiq , Bisdas Sotirios 
Published: May 2020

e14528 Background: Treatment monitoring in patients with High-Grade Glioma (HGG) and identification of disease progression, remains a major challenge in clinical neurooncology. We aimed to develop a support vector machine (SVM) classifier utilising combined longitudinal conventional and Dynamic Susceptibility Contrast (DSC) perfusion MRI to classify between Stable Disease (SD), Pseudoprogression (PsP) and Progressive Disease (PD) in glioma patients under surveillance. Methods: Conventional (269) and perfusion (62) MRI studies of HGG patients acquired between 2012 and 2018 were prospectively analysed. Study participants were separated into two groups: Group I with a single DSC time point (64 participants) and Group II with multiple DSC time points (19 participants). The SVM classifier was trained using all available MRI for each group. Classification accuracy was assessed for the use of features extracted from different feature dataset and time point combinations and compared to the experienced radiologists’ predictions. Results: The study included 64 participants (mean age: 48.5 ± 12.8 yrs [standard deviation], 24 female). SVM classification based on combined perfusion and structural features outperformed standalone datasets across all groups. For the clinically relevant classification step (SD/PSP vs PD), both feature combination as well as the addition of multiple DSC time points, improved classification performance (lowest median error rate: 0.016). The SVM algorithm outperformed radiologists in predicting lesion destiny in both groups. Optimal performance was observed in Group II, in which SVM sensitivity/specificity/accuracy was 100/91.67/94.7% for analysis based on the first time point and 85.71/100/ 94.7% based on multiple time points compared to 60/78/68% and 70/90/84.2% for the respective radiologist classifications. In Group I, the SVM also exceeded radiologist predictions, albeit by a smaller margin and resulted in sensitivity/specificity of 86.49/75.00/81.53% (SVM) compared to 75.7/68.9/73.84% (radiologists). Conclusions: Our results indicate that the addition of multiple longitudinal perfusion time points as well as the combination of structural and perfusion features significantly enhance classification outcome in treatment monitoring of HGGs and machine-learning-assisted diagnosis has potentially superior accuracy than the radiologist's visual evaluation and expertise.
Survival in adult and pediatric patients with medulloblastoma: A 2018 SEER-based analysis.
Authors: Moisander-Joyce Hanna , Sinha Anoushka , Fernandez-Ledon Shannon , Lee Davon , Hatano Satoki , Kahn Justine , Garvin James , Zacharoulis Stergios , Gartrell-Corrado Robyn D 
Published: May 2020

e14529 Background: Medulloblastoma (MB) is a malignant neuroectodermal tumor accounting for 30% of pediatric and only 1% of adult brain tumors. In previous studies comparing survival in pediatric and adult MB from the National Cancer Institute Surveillance Epidemiology and End Results (SEER) database no difference has been found. However, diagnostic subgroup analyses have been limited. Methods: We examined survival in children (age 0-19) and adults (20-79) coded as MB in the 2018 SEER database (2000-2016). We used Kaplan Meier analysis, log-rank test and Cox proportional hazard ratios (HR) with 95% confidence intervals (CI). MB in SEER-18 is defined as ICD-O-3 histology codes 9470–9474 (n = 1,728). ICD 9473, supratentorial PNET (sPNET, n = 97) is biologically distinct and therefore it was analyzed separately. Results: We found that 5-year survival for MB, excluding sPNET, was similar in children (n = 1,091, 75.3%) and adults (n = 488, 79.1%) (HR = 0.97, CI: 0.79 – 1.17, p = 0.50). Furthermore, subtype analyses showed no survival difference comparing adults and children with desmoplastic nodular MB (n = 222, p = 0.09), large cell MB (n = 73, p = 0.46), or MB NOS (n = 1330, p = 0.10). Yet, children with sPNET had improved 5-year survival (n = 65, 72.3%) compared to adults (n = 29, 51.7%) (HR = 2.0, CI: 1.10 – 3.92; p = 0.02,). These findings indicate that while survival in patients with MB is similar across age groups, children with sPNET have improved outcomes. Conclusions: In summary, 2018 SEER data for MB continue to show no survival difference between adults and children, suggesting adult patients could appropriately be entered on pediatric MB treatment protocols. Further analyses of the 2018 data are ongoing adjusting for sex, race, and treatment (chemotherapy or radiation). For sPNET, the apparent improved outcomes for children merit further detailed investigation and will be re-evaluated using the new 2016 World Health Organization classification.
Craniospinal irradiation in patients diagnosed with glioblastoma with primitive neuronal component prevents distant intracranial and leptomeningeal recurrences.
Authors: Eastman Boryana M , Cimino Patrick J , McGranahan Tresa , Halasz Lia Moriguchi 
Published: May 2020

e14540 Background: Glioblastoma (GBM) is the most common primary central nervous system (CNS) malignancy. In recent years, molecular and histological analyses have identified GBM with primitive neuronal component (GBM-PNC) as a distinct entity with poor regional control and worse overall prognosis. GBM-PNCs are more prone to CNS dissemination and leptomeningeal (LM) metastasis, occurring in up to 40% of patients. Given the concern for distal CNS spread, we hypothesized that craniospinal irradiation (CSI) may be an effective treatment option for GBM-PNC. Methods: We performed a retrospective chart review of patients diagnosed with GBM-PNC treated at a large academic center with institutional review board approval. Clinical, histologic and treatment characteristics, as well as disease outcomes were obtained from the electronic medical record. Results: Ten patients diagnosed with GBM-PNC were identified in the period of 2005-2019. Median follow-up was 17 months. Overall, 80% of patients were men, median age was 49 years (range 20-64) and ECOG 0-1. Fifty percent of patients received CSI as opposed to involved field radiation therapy (IFRT). Four of five patients receiving CSI were treated with proton therapy. All patients, but one received concurrent Temozolomide. Both IFRT and CSI were tolerated well with minimal grade 3-4 toxicities. Patients treated with CSI were more likely to experience transient grade 3-4 lymphopenia (60% vs 0%). Eighty percent of patients experienced a recurrence after treatment with median progression free survival (PFS) of 13 months (range 8-26). PFS did not differ between patients receiving IFRT and CSI (14 vs 12.5 months, p = 0.9). Median overall survival (OS) was 30 months for patients who received IFRT, and median OS was not reached in the CSI group. Of the patients who received CSI as part of their treatment, all recurrences were within the high dose radiation area. On the contrary, 75% of patients who received IFRT experienced multiple recurrences at new intracranial sites and later in the leptomeninges or the spine, requiring multiple treatment courses. Conclusions: This hypothesis generating study demonstrates that CSI may prevent distant intracranial metastasis and LM disease progression. CSI delivered with proton therapy was well tolerated with minimal additional toxicity. A larger study is needed to guide the optimal treatment of patients diagnosed with glioblastoma with primitive neuronal component.