bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II trial of bevacizumab and temozolomide for upfront treatment of elderly patients with newly diagnosed glioblastoma.
Authors: Nghiemphu Phioanh Leia , Bahng Hye Hyun , Lai Albert , Faiq Nadia , Yong William H. , Green Richard M. , Polikoff Jonathan , Spier Cynthia Elizabeth , Iwamoto Fabio Massaiti , Lassman Andrew B. , Cloughesy Timothy Francis 
Published: September 2018

2012 Background: Randomized clinical trials in newly diagnosed, elderly GBM patients have shown that treatment with temozolomide chemotherapy is at least equivalent to treatment with radiotherapy. Glioblastoma in elderly patients may also have high angiogenic activities. Bevacizumab is an antiangiogenic agent, a humanized monoclonal antibody directed against the vascular endothelial growth factor. We conduct a clinical trial of temozolomide and bevacizumab to evaluate the safety and efficacy of this combination in the treatment of elderly patients with newly diagnosed GBM, good performance status, and willing to forgo upfront treatment with radiation therapy. Methods: This is a phase II trial of newly diagnosed GBM patients age ≥70 with no prior treatments other than surgery and Karnofsky Performance Status (KPS) ≥60. Patients receive treatments 4-6 weeks after surgery with bevacizumab (10mg/kg every 2 weeks) and temozolomide (150-200 mg/m2 for 5 days out of 28 days, up to 12 cycles) until tumor progression. Primary outcome measures are overall survival and safety evaluations. Results: From June 2010 to January 2016, 50 GBM patients enrolled in this study. To date, all patients have tumor progression and 3 are still alive. The median age is 75 (range 70 - 87), and median KPS is 80 (range 60-100). 15 patients have a gross total resection. 26 out of 49 patients with tissues available for evaluation have methylation of the MGMT promoter, and no patient has IDH-1 mutation. Median overall survival is 12.3 months (14.8 months for those with methylation of MGMT, 10.0 months for unmethylated MGMT). Serious adverse events related to treatments include wound healing problems (2), CNS hemorrhage (3), pulmonary embolism (4), and bowel perforation (1). Serious hematological adverse events include thrombocytopenia (3) and neutropenia (5). Conclusions: For patients with newly diagnosed GBM age ≥70, KPS ≥60, treatment with temozolomide and bevacizumab may show promising survival benefits and have tolerable side effects. More detailed safety and efficacy analysis will be presented. Clinical trial information: NCT01149850.
Clinical and molecular features associated with long-term survival of elderly patients with glioblastoma.
Authors: Weller Michael , Sill Martin , Hentschel Bettina , Felsberg Joerg , Jones David T. W. , Gramatzki Dorothee , Kaulich Kerstin , Happold Caroline , Tonn Joerg , Herrlinger Ulrich , Schackert Gabriele , Westphal Manfred , Capper David , Kumar Rajiv , Hemminki Kari , Pietsch Torsten , Loeffler Markus , Pfister Stefan M. , von Deimling Andreas , Reifenberger Guido ,   German Glioma Network
Published: September 2018

2013 Background: Glioblastomas in elderly patients are associated with particularly poor outcome, with only few patients demonstrating long-term survival (LTS). Methods: To better characterize clinical and molecular correlates of LTS in elderly glioblastoma patients, we searched the German Glioma Network (GGN) database for patients aged 71 years or more with histological confirmation of glioblastoma and survival of at least two years after diagnosis. Results: Of 2071 glioblastoma patients enrolled in the GGN from 2004-2012, 425 patients were aged 71 years or more; of these, 27 patients (6.4%) survived for 2 years or more (median survival: 37.1 months, 95% confidence interval: 30.0-44.2 months). A comparison of these 27 patients with the 398 patients who survived shorter than 2 years (median survival: 6.2, 95% confidence interval: 5.2-7.2 months) revealed more intensive up-front treatment and a trend towards higher initial Karnofsky performance score as distinguishing clinical factors. Molecular analyses additionally showed more frequent O6-methylguanine-DNA methyltransferase ( MGMT) promoter methylation in the LTS patients. Isocitrate dehydrogenase (IDH) mutation was restricted to single patients and the frequency of telomerase reverse transcriptase ( TERT) promoter mutation did not differ between groups. Genome-wide DNA copy number and methylation profiling using 450k microarray analysis performed for 16 LTS patients and 40 control patients revealed limited differential DNA methylation and no specific copy number profiles linked to LTS. Conclusions: Collectively, our findings confirm that LTS is rare in elderly patients with glioblastoma and that clinical and tumor-associated molecular factors linked to LTS resemble those in standard age patients, except for less common IDH mutation.
Radiomic analysis of pseudo-progression compared to true progression in glioblastoma patients: A large-scale multi-institutional study.
Authors: Abrol Srishti , Kotrotsou Aikaterini , Hassan Ahmed , Elshafeey Nabil , Hassan Islam , Idris Tagwa , El Salek Kamel , Elakkad Ahmed , Alfaro Kristin , Weathers Shiao-Pei S. , Moron Fanny E , Huse Jason , Weinberg Jeffrey S , Heimberger Amy B. , Sawaya Raymond , Kumar Ashok J , De Groot John Frederick , Law Meng , Zinn Pascal , Colen Rivka R. 
Published: September 2018

2015 Background: Treatment-related imaging changes are often difficult to distinguish from true tumor progression. Treatment-related changes or pseudoprogression (PsP) subsequently subside or stabilize without any further treatment, whereas progressive tumor requires a more aggressive approach in patient management. Pseudoprogression can mimic true progression radiographically and may potentially alter the physician’s judgment about the residual disease. Hence, it can predispose a patient to overtreatment or be categorized as a non-responder and exclude him from the clinical trials. This study aims at assessing the potential of radiomics to discriminate PsP from progressive disease (PD) in glioblastoma (GBM) patients. Methods: We retrospectively evaluated 304 GBM patients with new or increased enhancement on conventional MRI after treatment, of which it was uncertain for PsP versus PD. 149 patients had the histopathological evidence of PD and 27 of PsP. Remaining 128 patients were categorized into PD and PsP based on RANO criteria performed by a board-certified radiologist. Volumetrics using 3D slicer 4.3.1 and radiomics texture analysis were performed of the enhancing lesion(s) in question. Results: Using the MRMR feature selection method, we identified 100 significant features that were used to build a SVM model. Five texture features (E, CS, SA, MP, CP) were found to be most predictive of pseudoprogression. On Leave One Out Cross-Validation (LOOCV), sensitivity, specificity and accuracy were 97%, 72%, and 90%, respectively. Conclusions: 3D radiomic texture features of conventional MRI successfully discriminated pseudoprogression from true progression in a large cohort of GBM patients.
Low grade glioma patients with IDH mutation and 1p19q codeletion: To treat or not to treat?
Authors: Franceschi Enrico , De Biase Dario , Paccapelo Alexandro , Mura Antonella , Tosoni Alicia , Bartolini Stefania , Tallini Giovanni , Pession Annalisa , Danieli Daniela , Rossi Sabrina , Bartolini Daniela , Gardiman Marina Paola , Volpin Lorenzo , Ramponi Vania , Fioravanti Antonio , Foschini Maria Pia , Di Oto Enrico , Minichillo Santino , Pizzolitto Stefano , Brandes Alba Ariela 
Published: September 2018

2017 Background: Molecular characterization of low grade gliomas (LGG) is essential for diagnosis and treatment of these diseases. LGG patients (pts) with IDH mutation and 1p19q codeletion (codel) are characterized by a median OS (mOS) longer than 10 years. Thus, the role of treatments and side effects should be carefully evaluated. Methods: We evaluated LGG pts from our data warehouse (n=679 pts) who received surgery and had sufficient tissue to assess biomarkers characterization. Pts with gliomatosis were excluded. IDH1/2 assessment was performed on formalin-fixed paraffin-embedded samples by qPCR. In wild type cases we performed NGS. 1p/19 codel analysis was performed by FISH. Results: 93 consecutive LGG with IDH mutation and codel were included. The median follow up (FU) was 96.1 months. Mean age was 40 yrs (range: 25-66); 8 pts (8.6%) underwent biopsy, 61 pts (65.6%) partial resection, 24 pts (25.8%) complete resection. 84 pts (90.3%) were considered high risk using RTOG criteria (>40 years and/or incomplete resection). Fifty pts (53.7%) received only FU, 17 pts (18.3%) received chemotherapy (CT), 18 pts (19.4%) received radiotherapy (RT), 8 pts (8.6%) received RT + CT. Median PFS (mPFS) was 59.6 months (95%CI: 41.8-77.4) and was significantly longer in pts who received postsurgical treatments (79.5 months, 95%CI: 66.4-92.7) than pts who received FU (46.3 months, 95%CI: 36.0-56.5; P=0.001). mPFS was 50.8 months (95%CI: 17.4-84.3), 103.6 months (95%CI: 11.7-195.6) and 120.2 months (95%CI: 40.5-199.8) in pts treated with CT alone, RT alone and RT + CT, respectively. Multivariate analysis showed that receiving a post-surgical treatment (P<0.001), and the extent of resection (P=0.043) were significantly correlated with PFS. Conclusions: Our study evaluated the role of treatments in LGG pts assessed with NGS and FISH. Post-surgical treatments are crucial to extend PFS in pts with IDH mutation and codel. The choice of post-surgical treatments seems to have a role, being CT alone less effective than RT and RT+CT. Longer FU is needed to provide information about OS.
Association of aggressive resection with survival and progression-free survival in adult low-grade glioma: A systematic review and meta-analysis with numbers needed to treat.
Authors: Brown Timothy J , Bota Daniela Annenelie , Maher Elizabeth A. , Aregawi Dawit Gebremichael , Liau Linda M. , Brown Paul D. , Buckner Jan C. , Weller Michael , Van Den Bent Martin J. , Berger Mitchel S. , Glantz Michael J. 
Published: September 2018

2025 Background: Low-grade gliomas (LGG) account for 17-22% of all primary brain tumors. Optimal surgical management consists of optimum safe resection with the goal of complete resection. We performed a systematic review and meta-analysis to quantify the association of extent of resection with likelihood of survival, expressing our results in numbers needed to treat (NNT). Methods: A systematic review and study-level meta-analysis to determine the association of resection with overall survival and progression-free survival in newly diagnosed, supratentorial LGG in adults was performed by querying PubMed. Data were extracted to compare gross total resection (GTR) to subtotal resection (STR) and STR to biopsy (Bx) to determine relative risks (RR) of death and progression at 2, 5, and 10 years. Data were analyzed using a random effects model. NNT were calculated from significant comparisons and rounded up to the nearest whole number. Quality of evidence was determined by American Academy of Neurology criteria. Results: The systematic review resulted in 283 potential studies. Ultimately 29 studies were included in at least one comparison. There were no high quality (class I and II) or prospective studies discovered in the review. Comparing GTR to STR, RR with 95% confidence intervals (CI) of death at 2, 5, and 10 years, and NNT to avoid one death at 2, 5, and 10 years (GTR vs. STR) were 0.29 [0.17-0.52, p < 0.0001, NNT 17], 0.39 [0.29-0.51, p < 0.00001, NNT 6], and 0.50 [0.35-0.70, p < 0.0001 NNT 4]. RR and NNT for progression (GTR vs. STR) at 2, 5, and 10 years were 0.37 [0.24-0.57, p < 0.0001 NNT 7], 0.50 [0.39-0.64, p < 0.0001 NNT 4], and 0.67 [0.53-0.84, p = 0.0005 NNT 4]. Comparing STR to Bx, RR of death at 2, 5, and 10 years were 0.55 [0.34-0.88, p = 0.01 NNT 10], 0.9 [0.61-1.34], and 0.95 [0.73-1.23]. Conclusions: Increasing resection thresholds appear to be associated with improved overall and progression free survival, but the body of literature consists of low quality studies. Prospective studies are required to explore whether extent of resection matters or whether resectable tumors share a favorable biology associated with better outcome.
A cellular platform to enable targeted brain delivery of T cells to glioblastoma.
Authors: Samaha Heba , Pignata Antonella , Fousek Kristen , Byrd Tiara , Lam Fong , Stossi Fabio , Marelli Sean , Shum Thomas , Joseph Sujith , Hegde Meenakshi , Ahmed Nabil M. 
Published: September 2018

2053 Background: Poor T cell homing hinders the development of effective cell therapy for central nervous system (CNS) malignancies. Lessons learnt from inflammatory brain diseases can give insight into how to overcome the blood brain barrier (BBB) blockade created by cancer. Activated Leukocyte Cell Adhesion Molecule (ALCAM; CD166) is a pathological adhesion molecule upregulated in the endothelium of a number of inflammatory/infiltrative CNS diseases, such as multiple sclerosis. Antibodies blocking ALCAM decrease leukocyte access to the brain and are currently being tested in a clinical trial for MS. Methods: We studied the difference in the dynamic signature of adhesion molecules in the “anergic” brain tumor endothelium and that of infiltrative brain conditions. Consequently, we mapped the ALCAM minimal binding region to domain 3 (D3) of CD6 and created an artificial molecule with the intent of creating a novel cellular platform to reverse endothelial anergy, through ALCAM specific binding. Results: GBM endothelium fails to launch the second wave of adhesion molecules necessary for firm T leukocyte capture and effective BBB transmigration. Engineered D3 on the T cell crosslinked to ALCAM on endothelial cells in proximity ligation assays (PLA; < 40nm) during TEM. Under shear stress, D3 T cells showed a global improved ALCAM specific trafficking kinetics: higher capture on ALCAM+ endothelium, rolling with slower velocity, and better TEM. In an ex vivo model of BBB, D3 T cells exhibited higher transmigratory ability. We discovered that signaling through the D3 endodomain phosphorylated pZAp70 recruiting Talin that enables LFA-1 (ICAM-ligand) open confirmation, mediating effective TEM. Lastly, in an orthotopic model of GBM, D3 T cells homed more and accumulated at the tumor site compared to NT controls. And, testing Her2 CAR T cells on D3 platform showed an advantageous homing after IV administration which was reflected in tumor control and better survival. Conclusions: We created a cellular platform that enables targeted brain delivery of T cells. This platform serves as a gateway to the effective cellular therapeutics for brain malignancies but potentially as a delivery system for complex biologics for other pathological conditions.
Activity of cabazitaxel in temozolomide refractory glioblastoma: Final results of a phase 2 study (C-GBM study; EudraCT 2013-001550-98 NCT 01866449).
Authors: Heinrich Bernhard , Schlenk Richard F , Brudler Olaf Lothar , Edenhofer Simone , Scheuerle Angelika , Naumann Ralph , Mayer-Steinacker Regine , Bangerter Markus , Bullinger Lars 
Published: September 2018

2056 Background: Following progression on Temozolomide (TMZ) glioblastoma (GBM) is a therapeutic challenge with a 6 month survival rate of only ~20-30% and no well-established 2nd line treatments. Methods: We designed a phase II study to assess the efficacy of cabazitaxel, a second generation taxoid, in TMZ-refractory GBM pts (pts). Primary enpoint was response at 12 weeks of treatment. Secondary endpoints were overall survival (OS), quality of life, and pharmacokinetics. The study population were pts with progressive GBM during or within 6 months after TMZ treatment, in whom radiotherapy and surgery was no treatment options. Exclusion criteria were signs of inflammation, an ECOG performance score (PS) > 2, as well as impaired organ function. Patient characteristics: In total, between 2014 and 2016 8 female and 16 male pts were included with a median age of 55 years (range 32-76 years) and a median of 3 previous therapies (range 1-9). Treatment: Cabazitaxel was given at 25mg/m² q3w with G-CSF prophylaxis. Every two cycles response assessment was performed (MRI). Treatment was discontinued in case of i) progressive disease (RANO criteria), ii) PS≥3, or iii) persistent toxicity. Results: Five pts went off study prior to the first MRI assessment due to progressive disease, while 19 of 24 of pts could be evaluated for response after 2 cycles. We did not observe any objective response (i.e. complete or partial remission). In 7 pts a stable disease (SD) was obtained; 12 pts had progressive disease. Of the 7 SD pts, 4 progressed after 4 cycles of treatment and the remaining pts remained in SD for 6, 10 and 12 cycles, respectively. The median OS was 155 days. Toxicity was manageable by G-CSF application in pts with CTC grade 3/4 neutropenia/leukopenia in 12 pts. Non-hematological toxicity CTC grade 3/4 comprised infection (n = 2), diarrhea (n = 2), vaginal bleeding (n = 1) and hypokalemia (n = 1). Conclusions: Cabazitaxel shows only marginal activity in TMZ refractory GBM with a disease stabilization rate following 4 cycles of only 12.5% in heavily pretreated GBM pts and median OS of 155 days. Clinical trial information: NCT 01866449.
Quantifying the benefit of chemotherapy and radiation in low-grade glioma: A systematic review and meta-analysis of numbers needed to treat.
Authors: Brown Timothy J , Bota Daniela Annenelie , Maher Elizabeth A. , Aregawi Dawit Gebremichael , Liau Linda M. , Brown Paul D. , Buckner Jan C. , Weller Michael , Van Den Bent Martin J. , Berger Mitchel S. , Glantz Michael J. 
Published: September 2018

2057 Background: The optimal role of chemotherapy and radiation (RT) in adult low-grade glioma (LGG, WHO grade 1 & 2) is unclear. We conducted a systematic review and study-level meta-analysis of the literature on overall survival (OS) and progression free survival (PFS) in patients with LGG. Methods: Pubmed was queried with MeSH terms. All comparative studies of adults with newly diagnosed, supratentorial LGG were included. Comparisons of interest were OS and PFS at 2, 5, and 10 years in chemotherapy versus no chemotherapy and early RT versus delayed or no RT. Data were extracted from studies and synthesized with a random effects model. Quality of evidence was determined by American Academy of Neurology criteria and further analysis was performed, separating high quality (class I and II) from low quality (class III and IV) evidence. Numbers needed to treat (NNT) were determined from the risk difference. Results: 1531 articles were screened; 18 studies were included. Chemotherapy was not associated with a significant survival advantage compared to control. However, an analysis of high quality data revealed a survival advantage at 10 years associated with chemotherapy compared to control with NNT 5 (relative risk death chemo vs control 0.69 [0.56-0.86] p = 0.0006). Furthermore, NNT to prevent one progression with chemotherapy at 5 and 10 years was 6 and 3, respectively. Early RT was not associated with an OS advantage compared to control. However, early RT had progression benefit at all time points, with NNT of 10, 6, and 5 at 2, 5, and 10 years. Conclusions: Further study will be needed to confirm the optimal role of chemotherapy and RT. Caution must be used in interpretation as much of the literature consists of low-quality studies. [Table: see text]
Effect of treating glioblastoma with a cytokine inhibitor, ibudilast, in combination with temozolomide on survival in a patient-derived xenograft model.
Authors: McDonald Kerrie Leanne , Ha Wendy , Sevim Hatice , Matsuda Kazuko , Khasraw Mustafa 
Published: September 2018

2062 Background: Recurrence in patients with glioblastoma (GBM) is inevitable, even in patients with O-6-Methylguanine-DNA Methyl Transferase ( MGMT) methylation. We identified increased expression of the inflammatory cytokine, Macrophage Inhibitory Factor (MIF) and its receptor CD74 in patients with recurrent tumors. High levels of MIF and CD74 were associated with poor overall survival in GBM patients. This study aims to determine efficacy of Ibudliast (MN-166; 3-isobutyryl-2-isopropylpyrazolo-[1,5-a]pyridine) to block MIF expression and decrease tumor burden. Ibudilast is an anti-inflammatory drug that was developed for the treatment of bronchial asthma. Methods: The patient derived cell lines (PDCLs) RN1 ( MGMT unmethylated), BAH1 ( MGMT methylated), and HW1 ( MGMT methylated) were treated in vitrowith different concentrations of ibudilast in combination with temozolomide (TMZ). Patient derived xenograft (PDX) models of GBM were developed and treated with the combination of ibudilast and TMZ. Overall survival was calculated. Results: Regardless of MGMT status, significant synergism between ibudilast and TMZ was observed in the PDCLs. Efficacy was associated with significantly decreased expression of its targets, MIF and CD74. Downstream proteins such as Src and Akt were also significantly inhibited. The combination induced apoptosis. RN1 tumors were established intracranially in Balb/c nude mice. Significant increases in survival times of the mice were recorded when treated with the combination. Conclusions: Ibudilast in combination with TMZ resulted in significant blockage of MIF expression, increased apoptosis and longer survival in vivo. A human pilot study for recurrent GBM patients is underway.
The value of 18F-fluordesoxyglucose positron emission tomography (FDG-PET/CT) in the detection of the primary lesion and for staging in brain metastasis (BM) patients with cancer of unknown primary site (CUPS).
Authors: Le Rhun Emilie , Weller Michael , Berghoff Anna Sophie , Rushing Elisabeth Jane , Fuereder Lisa , Petyt Gregory , Leske Henning , Andrastschke Nicolaus , Regli Luca , Neidert Marian Christoph , Stupp Roger , Dummer Reinhard , Frauenfelder Thomas , Roth Patrick , Reyns Nicolas , Kaufmann Philipp Antonio , Preusser Matthias , Wolpert Fabian 
Published: September 2018

2076 Background: Brain metastasis (BM) are the first clinical presentation of cancer in around 30% of patients. They are then referred as BM from cancer of unknown primary site (BM-CUPS). The value of 18F-fluordesoxyglucose positron emission tomography (FDG-PET)/CT has not yet be determined for the management of these patients. Methods: A total of 566 patients were operated for BM at the University Hospital Zurich between 2004 and 2014, of whom 127 were identified as BM-CUPS patients. Two cohorts from other independent centers (n = 100 and 120) were used for the validation of data. Results: No difference in determining the localization of the primary lesion was observed between FDG-PET/CT and CT (FDG-PET/CT: 73/78, 93.6%; CT: n = 70/78, 89.7%; p = 0.25, McNemar’s test). The same pattern of primary lesion and other extracranial lesions was observed in 36 of 64 patients (56.3%). Additional suspicious extracranial metastases were identified by FDG-PET/CT in 28 patients (43.7%). The median graded prognostic assessment (GPA) scores were 2.5 determined according to FDG-PET/CT and 3 according to CT alone (p = 3.8x10-5), resulting in predicted survival times of 3.8 versus 5.3 months (p = 6.1x10-5; Wilcoxon’s test). Conclusions: A similar sensitivity of FDG-PET/CT and chest CT was observed for the detection of the primary tumor in BM-CUPS, however, FDG-PET/CT significantly improved the accuracy of staging. FDG-PET/CT should be preferred for the management of BM-CUPS and may help to avoid redundant CT imaging.