bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting myeloid derived suppressor cells: Phase 0/1 trial of low dose capecitabine + bevacizumab in patients with recurrent glioblastoma.
Authors: Peereboom David M. , Lathia Justin D. , Alban Tyler , Sinyuk Maksim , Ahluwalia Manmeet Singh , Mohammadi Alireza Mohammad , Brewer Cathy J. , Vogelbaum Michael A. 
Published: September 2018

e13507 Background: Glioblastoma (GBM) creates an immunosuppressive environment that allows tumor growth. Myeloid derived suppressor cells (MDSCs), a heterogeneous class of immunosuppressive cells, mediate immune suppression in GBMs. MDSCs are up-regulated in the blood of patients with GBM and multiple other tumor types. We have developed a novel strategy to target GBM immunosuppression using low dose 5-fluorouracil (5-FU) that, targets immune cells and does not depend on blood brain or blood tumor barrier penetration. Marked MDSC depletion occurs at 5-FU doses in mice equivalent to < 10% of the normal human dosing. Goal: proof of concept that MDSC suppression in feasible in GBM pts with low-dose capecitabine [cap], an oral 5-FU analogue). Methods: Eligibility: Recurrent GBM in need of surgical resection; no prior cap or bevacizumab (bev). Cohorts of 3-6 patients receive low-dose cap 150 mg/m2/d (dose level [DL] 1) for 7 days before surgery. After surgery, patients resume cap for one cycle after which bev is added. Blood MDSC, immune cell levels, and relevant secreted factors are measured at baseline; pre- and post-op; and after the addition of bev. Tumors are assayed for MDSCs and glioma stem-like cells (GSCs). Primary endpoint: MDSC and T-Regulatory cell reduction after cap. Secondary endpoints: Tumor concentrations of MDSCs, GSCs, and T-reg cells; safety; and PFS6. Results: Three of the 4 patients enrolled have data available. All patients received 5 days of pre-op cap at DL 1 with MDSC reductions of 20, 26, and 79% from baseline. The first patient reached a reduction of 93% (measured 2 days after pre-op course) whereas the other 2 experienced return to baseline. The regulatory T cells (T-reg) also fell approximately 15, 20, and 50%, respectively. CD8 concentrations appeared to rise at the time of MDSC and T-reg reduction. No patient experienced grade 3 or higher toxicity. Conclusions: Low dose capecitabine appears to reduce MDSC concentrations with minimal toxicity. During this course T-regs also fell and CD8 concentrations rose. Dose escalation continues. (NCT02669173) (Supported by Musella Foundation, Blast GBM, Sontag Foundation, Velosano, Mylan Pharmaceuticals) Clinical trial information: NCT02669173.
Effect of BPM31510 on radiosensitivity of temozolomide-resistant glioblastoma cell model and survival in in vivo C6 glioma rat model supporting phase I clinical investigation in GBM.
Authors: Nagpal Seema , Dadali Tulin , Jang Taichang , Merchant Milton , Diers Anne R. , Gesta Stephane , Stevens Janice , Wilson Megan , Vishnudas Vivek , Kiebish Michael , Akmaev Viacheslav R , Narain Niven R. , Sarangarajan Rangaprasad , Recht Lawrence David 
Published: September 2018

e13509 Background: Glioblastoma (GB) is characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone containing lipid nanodispersion effectuates a switch in cancer energy sourcing from glycolysis towards mitochondrial OXPHOS, i.e. reverses Warburg effect, providing rationale for its potential utility in treatment of GB. The current study investigated utility of BPM31510 alone and in combination with temozolomide. Methods: In vitro (U251-MG human GB cell line) and in vivo (C6 glioma rat model) preclinical models of GB were used to assess the anti-cancer activity of BPM 31510 alone (100 mg/kg/d) and combination with TMZ/bevacizumab (BEV). In addition, an in vitro model of acquired TMZ chemo-resistance was established by progressive adaptation of parental U251-MG cells to increasing doses of TMZ. Parental and resistant subclones (TMZ-R) were used to define activity of BPM31510 in the TMZ-refractory setting. Results: In vitro results demonstrated that BPM 31510 has anti-cancer activity in both parental and TMZ-R U251-MG cells with EC50 values of ~400 µM and 800 µM, respectively. Importantly, BPM 31510 treatment also resensitized TMZ-R cell lines to TMZ. In vivo, BPM 31510 treatment was associated with increasing duration of survival; one fifth of the rats treated achieved survival greater than 15 days post implantation, a response not observed in the control or irradiation arms of the study. Assessment of the combination of BPM 31510 with TMZ or BEV in the in vivoC6 glioma rat model is ongoing. A phase I open-label, non-randomized clinical trial to evaluate the safety and tolerability of BPM31510 in patients with recurrent BEV-refractory GB, as well as the changes in GB metabolism by SUV-PET imaging in response to treatment is under investigation. Conclusions: Preclinical data demonstrate that BPM 31510 has potential anti-cancer activity alone and in combination with standard therapy regimens and alleviates TMZ chemo-resistance in preclinical models of GB. These results provide support of a Phase 1 clinical study of BPM31510 in GB; this study is actively enrolling.
Prospective study of the impact of neuro-oncology multi-disciplinary meetings on clinical decision making.
Authors: Ameratunga Malaka , Miller Dorothea , Ng Wayne , Cher Lawrence , Gonzalvo Augusto , Wada Morikatsu , Gan Hui Kong 
Published: September 2018

e13512 Background: Multi-disciplinary team (MDT) meetings are considered essential to quality cancer care. For some malignancies, MDTs have been associated with improved outcomes, but data is limited for their utility in neuro-oncology. The aim of this study was to prospectively describe the MDT at our institution and evaluate its impact on clinical management. Methods: All cases discussed over three months at the Austin Health neuro-oncology MDT were prospectively evaluated. Cases were discussed amongst the treating team and a provisional plan (PP) and reason for discussion (RFD) was documented preceding the MDT. The PP was recorded as: surgery, radiation, chemoradiation, further diagnostic tests, surveillance and other. Patient specific clinical data was captured prospectively, with further pathological and radiological information captured during the MDT. Subsequently, the MDT reached a consensus decision, which was recorded. High impact decisions (HID) were those in which a substantial modification to the PP was made. Subsequent data regarding patient adherence to the MDT plan was recorded. Results: Over the period 79 cases were discussed at the MDT. Twenty-seven (34%) cases were female, 52 (66%) were male. The median age was 53. Six patients were discussed more than once. Forty-three cases were new diagnoses. Forty-two cases were primary brain tumours, twenty-five were metastatic solid organ malignancies. Thirty-four per cent of cases had HID. On chi-square analysis, the RFD was not statistically associated with HID (p = 0.28), nor was the primary versus recurrent setting (p = 0.80) however, the nature of the PP was (p = 0.023). Adherence data was collected for 95% (75) of cases. Adherence to the MDT plan occurred 90% (67) of cases. For cases of non-adherence, six out of eight (75%) were due to patient choice. Conclusions: A significant proportion of treatment modifications are made following discussion at the neuro-oncology MDT. The nature of the provisional treatment plan may influence which cases are likely to have a change in management determined in the MDT. MDT recommendations are broadly adhered to, and in cases of non-adherence, are largely due to patient factors.
Comparative outcomes in glioblastoma based on age and MGMT analysis: The Cleveland Clinic experience.
Authors: Mohapatra Suryanarayan , Choi April , Braun Kelly , Murphy Erin Sennett , Chao Samuel T. , Suh John H. , Stevens Glen , Peereboom David M. , Jia Xuefei , Ahluwalia Manmeet Singh 
Published: September 2018

e13514 Background: Half of glioblastoma (GBM) patients are > 65 years old (yo). We report our experience with GBM patients treated at a tertiary care center and compared outcomes in the two age groups. Methods: Half of glioblastoma (GBM) patients are > 65 years old (yo). We report our experience with GBM patients treated at a tertiary care center and compared outcomes in the two age groups. Results: 1165 patients were included in the final analysis. 598 patients were < 65 yo, and 567 were > 65 yo. Patients who received chemotherapy + radiation (chemoRT) had a lower risk of death compared to patients who received RT only (p < 0.001). Although the benefit of chemoRT seems more pronounced in patients ≥ 65 years of age [HR 0.45 (95% CI 0.36, 0.57) vs 0.61 in patients < 65 yo (0.48, 0.80), (p = 0.04)], the difference in effects is not significant (p = 0.07). For both MGMT-unmethylated and MGMT-methylated patients, although chemoRT had a better OS/PFS than RT only, the impact was similar in both age groups. Patients who underwent GTR or STR had a better OS/PFS than biopsy only (all p < 0.0001). The impact of extent of resection was not different in two age groups (all p ≥ 0.09). Patients diagnosed during 2006 – 2008 and 2009 - present had a better OS/PFS (p = 0.01 and 0.003) than those who were diagnosed during 2000-2005. The impact of diagnosis date on PFS was not different in age groups. In OS outcomes, patient diagnosed during 2009 - present had a better OS than those who were diagnosed before 2005, and the impact is more prominent for patient who were younger than 65 years (p = 0.010). Conclusions: Aggressive treatment with chemo-radiation is associated with better outcomes in both young and older GBM patients. MGMT status did not have any impact on outcomes between the two groups although MGMT status was available for only a subset of patients. [Table: see text]
Identifying factors to predict benefit from bevacizumab in progressive glioblastoma multiforme (GBM).
Authors: Gleeson Jack Patrick , Alhusaini Abdullah , O'Halloran Philip , Harrold Emily , Keegan Niamh M. , Karadawi Nabeeha Eltag , Mammadov Emin , Kamel Dalia , Egan Keith , Molloy Susan , Hennessy Bryan T , Breathnach Oscar S. , Grogan William , Morris Patrick G. 
Published: September 2018

e13515 Background: Bevacizumab (BEV) has demonstrated activity in GBM, but the benefits have not been clearly defined in prospective randomised phase III trials. Some patients continue BEV for extended periods but little is known about predictors of clinical benefit. It has been suggested that a less intensive dose schedule might offer similar benefits. Methods: In a retrospective analysis of a National Neuro-Oncology centre database we examined biomarkers of BEV benefit on overall survival (OS), including age at diagnosis, time from diagnosis to BEV start, MGMT methylation and IDH-1 status. We compared those who derived clinical benefit (OS of ≥6-months) to those with limited clinical benefit (OS <6 months). At our Institution, there is variable practice between Neuro-Oncologists in terms of BEV dose schedule. In this homogeneous patient population, we examined whether OS was similar for patients who received standard BEV dosing (10mg/kg q 2wks or 15mg/kg q 3wks) or reduced intensity BEV (5mg/kg q 2wks or 7.5mg/kg q 3wks). Results: Between January 1st 2010 and Dec 31st 2016, 170 patients received BEV for progressive GBM. Median OS was 5.5 months (Range: 0.5-54). OS was 42%, 18% and 2% at 6-, 12- and 24-months, respectively. No significant predictors of clinical benefit were identified (table). Importantly, median OS was similar for patients who received standard (N=94) vs. reduced intensity (N=76) BEV (5.2 vs. 5.6mo respectively), p=0.74. Conclusions: In this large cohort of patients, we did not identify predictors of benefit from BEV. OS was similar in patients who received standard or reduced intensity BEV. Given the cost of BEV, these results have important implications for value in cancer care. [Table: see text]
Outcomes of primary central nervous system lymphoma in the era of immunotherapy: Cleveland Clinic experience.
Authors: Balasubramanian Suresh Kumar , Schmitt Philipp , Sadaps Meena , Karivedu Vidhya , Kangisser Debra , Chao Samuel T. , Murphy Erin Sennett , Suh John H. , Ahluwalia Manmeet Singh , Singh Arun D , Peereboom David M. 
Published: September 2018

e13516 Background: Primary central nervous system lymphoma (PCNSL), a form of extranodal non-Hodgkin lymphoma represents 3% of primary CNS tumors. It is aggressive but typically confined to the CNS. Despite improvements in the management of PCNSL, more than 50% of patients eventually relapse. There are limited data on PCNSL from larger cohort studies. Methods: With IRB approval, the Cleveland Clinic Neuro-Oncology Center database was used to identify patients treated between 2006-2015 for PCNSL. Overall survival (OS) from the diagnosis of PCNSL and progression free survival (PFS) were the primary and secondary end points respectively. Cox proportional hazards models were used for data analysis. Results: 86 PCNSL patients were included in the analysis. Only 5% (4/76) were HIV positive. The median age of diagnosis was 63 (range 15 - 86) and 50% were males. 88% of patients presented only with brain lesion, 8% only in eye and 4% had both brain and eye involvement. 15% of patients (12/81) had positive CSF findings. Treatment included: chemotherapy (CT) alone (39% of patients); chemoimmunotherapy (CIT) (32%); CIT with radiotherapy (RT) (13%); RT alone (11%); CT with RT (4%); and immunotherapy (IT) alone (1%). Among 23 patients (31%) who received RT upfront, 74% had WBRT (n = 17). The most common upfront therapy was high dose methotrexate (HD MTX) (44%), followed by HD MTX with rituximab (23%), RTOG 0227 (12%), RTOG 1114 (11%) and rest 14% included rituximab or temozolomide or other cytotoxic chemotherapy alone or in combinations. The most common relapse site was brain (72%), followed by eyes (12%) and spine (8%). The median follow-up was 26 months. At last follow up, 41% had died and 93% of which were PCNSL-related. The median PFS and OS were 17.7 months and 84 months, respectively. There was a trend towards superior PFS in upfront IT vs. no IT (20 vs. 14 months, p 0.08). Better performance status (KPS > 80 vs. < 80, HR 0.42 (p = 0.033)) and PFS ≥ 24 months compared to ≤ 24 months (p = 0.0012) were associated with improved OS. Conclusions: We report a large single institution cohort of PCNSL patients treated in the era of immunotherapy. In our cohort, better KPS (≥80) and PFS ≥ 24 months had improved OS. Upfront IT showed a trend towards improved PFS.
Visualisation of normal and abnormal brain vasculature with different ferumoxytol doses.
Authors: Varallyay Peter , Varallyay Csanad , Horvath Andrea , Szidonya Laszlo , Fu Rochelle , Toth Gerda , Neuwelt Edward A. 
Published: September 2018

e13517 Background: Ferumoxytol is an iron oxide nanoparticle, marketed for iron replacement therapy. Off label use as an MRI contrast agent allows visualization of cerebral vasculature in the early blood pool phase without early contrast enhancement obscuring the vessels as seen with small molecular gadolinium. This study tested the optimal ferumoxytol dose for visualization of normal and abnormal cerebral vasculature. Methods: MRI images of 75 subjects enrolled in imaging research protocols were analyzed. Vascular visualization was tested in high resolution gradient echo T2*-weighted images acquired after 1mg/kg, 3mg/kg and 7mg/kg (up to 510mg) ferumoxytol doses. Visualization of normal and abnormal vasculature was separately evaluated as “poor, moderate or clear”. Degree of blooming artifact was graded as “none, mild and marked”. Overall clarity of the image was visually assessed as “poor, moderate and very clear”. The probability of abnormal vasculature visualization being “moderate” or “clear” was tested among the three Fe dosages with a mixed effects model while taking correlation among different dosages into account. Results: Visualization of normal brain vasculature was poor with 1mg/kg, moderate with 3mg/kg and very clear with 7mg/kg in 97% of the cases. However, blooming with 7 mg/kg was already marked for all cases causing confluence of larger veins and even smaller vessels close to each other, while images with 3mg/kg showed only mild blooming in all cases, resulting in altogether a better quality/clarity of the images (very clear in 93.3%) with good contrast between normal vessels and brain parenchyma. Not all subjects had abnormal vasculature due to prior surgery. However, when considering all subjects, visualization of abnormal vasculature was moderately or clearly visible in 23% of subjects when using1mg/kg, significantly less than 3mg/kg (42.7%, P = 0.0012) and 7mg/kg (43.9%, P = 0.0007). Conclusions: 3mg/kg ferumoxytol allows adequate visualization of normal and abnormal vasculature with acceptable degree of blooming artifact. Visualization of tumor vasculature may help targeting the most malignant area for surgery/radiotherapy and may help differentiating tumor progression from pseudoprogression. Clinical trial information: NCT00659776, NCT02359097.
Constitutive IFN signaling to modulate the immunogenicity of glioma cells.
Authors: Roth Patrick , Nagy Sara , Happold Caroline , Schneider Hannah , Weller Michael , Silginer Manuela 
Published: September 2018

e13528 Background: Interferons (IFN) are cytokines that might be constitutively expressed also in the absence of acute infection and thereby regulate various physiological processes such as cellular proliferation and differentiation, cell viability or immune cell function. Alterations in IFN signaling have been observed in numerous malignancies, but their role in glioblastoma, particularly in glioma-initiating cells, has not been investigated in detail. Methods: We characterized constitutive type I IFN signaling and its functional impact in glioma cells using expression analyses, RNA interference-mediated silencing of various genes involved in the IFN signaling pathway and immune cell lysis assays. Results: We found constitutive expression of pSTAT1 and Myxovirus A (MxA), a classical IFN-response marker, in the absence of exogenous IFN-β in vitro and higher MxA expression in gliomas than in normal tissue in vivo, indicating that IFN signaling is constitutively active in these tumors. Silencing of the type I IFN receptor, IFNAR1/2, or its ligands, IFN-α or IFN-β, decreased MxA levels, providing evidence for the existence of an autocrine type I IFN signaling loop. On a functional level, we observed reduced PD-L1, MHC class I and class II expression and increased susceptibility to immune cell-mediated lysis upon disruption of IFN signaling, suggesting that constitutive IFN signaling in gliomas contributes to the immune evasion of glioma cells. Conclusions: Our findings point to an important role of constitutive IFN signaling in glioma cells in the regulation of anti-tumor immune responses.
Health-related quality of life in patients with recurrent glioma treated with bevacizumab plus daily temozolomide as the salvage therapy.
Authors: Liu Yong , Wang Liang 
Published: September 2018

e13541 Background: The therapeutic methods of recurrent glioma are limited. Most studies evaluating treatment effect for brain tumor mainly focused on overall survival and progression-free survival. It is increasingly recognized that the health related quality of life (HRQL) is of great value in clinical practice when choices of treatment for recurrent glioma have to be made. We retrospectively analyzed the HRQL and treatment response of patients with recurrent glioma treated by bevacizumab (BEV) plus daily temozolomide (TMZ). Methods: Twenty patients with recurrent glioma were treated with BEV (5-10mg/kg, i.v. every 2 weeks) plus daily TMZ (daily, 50 mg/m2). The treatment response was evaluated via the RANO criteria. HRQL was measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (QLQ-C30) and Brain Module (QLQ-BN20). HRQL was assessed at the baseline (before salvage therapy) and after every two cycles of BEV. Results: Twenty patients totally received 85 cycles of BEV with the median number of 4 cycles (range: 2-10). There was no patient with complete response (CR), 12 patients with partial response (PR), 5 patients with stable disease (SD), and 3 patients with progressive disease (PD). Objective response rate (CR+PR) was 60.0%. The clinical benefit rate (CR+PR+SD) was 85.0%. In the functioning domains of QLQ-C30, physical functioning, cognitive functioning and emotional functioning were significantly improved after the second cycle of BEV compared to baseline. In the symptom scales, the scores of pain and nausea/vomiting were significantly decreased. Score of global health status was significantly increased. In the QLQ-BN20, motor dysfunction, weakness of legs, headache, and drowsiness after the second cycle of BEV were also significantly improved. Conclusions: BEV plus daily TMZ could improve HRQL in patients with recurrent glioma. BEV plus daily TMZ as the salvage therapy is an effective treatment for recurrent glioma.
Analysis of chemo-predictive assay for targeting cancer stem cells in 41 glioblastoma patients.
Authors: Howard Candace M , Alberico Anthony , Valluri Jagan , Griswold Michael , Claudio Pier Paolo 
Published: September 2018

e13544 Background: We have developed a drug response assay (ChemoID) that identifies effective chemotherapy against cancer stem cells (CSCs) vs. bulk of tumor cells from of a panel of potential treatments. A prospective study was conducted evaluating the use of the CSC drug response assay in glioblastoma patients treated with standard-of-care. Methods: 41 glioblastoma patients were enrolled in an IRB-approved protocol. Patients were all treated with standard-of-care TMZ plus radiation with or without maximal surgery. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Results: For every 5% increase in in-vitro CSC cell kill by TMZ, 12-month patient response (non-recurrence of cancer) increased 2-fold, OR=2.2 (p=0.016). Similar associations with the bulk tumor test were seen, OR=2.75 (p=0.07) for each 5% bulk tumor cell kill by TMZ. Combining CSC and bulk tumor assay results in a single model yielded a statistically supported CSC association, OR=2.36 (p=0.036) but a much attenuated remaining bulk tumor association, OR=1.46 (p=0.472). Areas under the curve (AUC) and [sensitivity/specificity] at optimal outpoints (>40% CSC cell kill and >55% bulk tumor cell kill) were AUC=0.989 [Sens=100/Spec=97], 0.972 [100/89] and 0.989 [100/97] for the CSC only, bulk tumor only, and combined models, respectively. Risk categorization of patients was improved by 11% when using the CSC test in conjunction with the bulk test (risk reclassification non-event NRI and overall NRI = 0.111, p=0.030). Median recurrence time was 20 months for patients with a positive (>40% cell kill) CSC test versus only 3 months with a negative CSC test, whereas median recurrence time was 13 months versus 4 months for patients with a positive (>55% cell kill) bulk test versus negative. Similar favorable results for the CSC test were observed for PFS and OS. Results across 14 potential other treatments indicated that 34/41 (83%) and 27/41 (66%) potentially more optimal alternative therapies may have been chosen using CSC results and Bulk results, respectively. Conclusions: The ChemoID assay has the potential to increase the accuracy of bulk tumor assays.