bluuebunny/crossref_metadata_2025_split huggingface dataset:
Use of CDK6 oncogene amplification and 17q gain to predict poor clinical risk groups in adult medulloblastoma
Authors: Pfister S. M. , Remke M. , Benner A. , Werft W. , Mendrzyk F. , Scheurlen W. , Kulozik A. , Lichter P. , Korshunov A. 
Published: August 2020

2030 Background: While in children medulloblastoma comprises the most common malignant brain tumor, it accounts for only 1% of intracranial malignancies in adults. The infrequent appearance of MB in adults poses the question, whether these tumors are the same in adults and children in terms of biological and clinical peculiarities. Methods: Array-CGH was performed for a total 34 adult medulloblastoma samples (>18 years) and results were compared with data from 101 pediatric patients. Selected genomic regions were further investigated by FISH analysis in an independent cohort of 415 samples (112 adult and 303 pediatric). All 146 adult patients received a standard treatment regimen consisting of tumor resection, irradiation of the neuroaxis with 36 Gy, a boost of 20–23 Gy to the posterior fossa, and eight cycles of vincristin, lomustine, and cisplatin. To identify novel prognostic markers, DNA copy-number information was correlated with survival data using log rank and chi-square tests. Results: Copy-number gains of chromosome 17q as well as high-level amplifications of CDK6 were identified as significant adverse prognostic markers in adult medulloblastoma. Apart from one exception, CDK6 amplifications were only observed in adult patients (9% in adults versus 0.2 % in children), whereas amplifications of MYC or MYCN were significantly overrepresented in the pediatric cohort, but when present were also associated with dismal prognosis in adults. Monosomy of chromosome 6, in contrast to the pediatric cohort, was not significantly associated with good prognosis, although nuclear ß-catenin accumulation was detected in most cases (r = 0.68). Based on these results, we propose a molecular staging system for adult medulloblastoma: i) cases with oncogene amplification (10% of cases, 5-year OS = 0%); ii) cases with chromosome 17q gain without oncogene amplification (25% of cases, 5-year-OS = 35%); and iii) cases without oncogene amplification or 17q gain (65% of cases, 5-year OS = 92%). Conclusions: We report on the largest cohort of adult medulloblastoma investigated for genomic imbalances to date. We propose a model for the molecular risk stratification of adult medulloblastoma comprising three distinct genomic risk groups with significantly different survival and tumor biology. No significant financial relationships to disclose.
A phase I trial of tumor-associated antigen-pulsed dendritic cell immunotherapy for patients with brain stem glioma and glioblastoma
Authors: Phuphanich S. , Rudnick J. , Chu R. , Mazer M. , Wang H. , Serrano N. , Francisco M. , Wheeler C. , Singh M. , Yu J. S. 
Published: August 2020

2032 Background: Previous immunotherapy trials for malignant glioma (Yu, J.,et al, Cancer Res. 2001;61:842–7 and 2004;64;4973–9) have demonstrated efficacy in generating a tumor specific immune response. Here we set out to determine feasibility and immunogenecity of dendritic vaccination with specific glioma-associated antigens. Methods: The goal of this study is to use tumor associated antigens (TAA) known to be expressed on gliomas and pulse dendritic cells with these antigens in an MHC compatible fashion using epitopes of HER-2, TRP-2, gp100, MAGE-1, IL13R alpha, and AIM-3. In this phase I trial, HLA-A1 and/or HLA-A2-positive patients with newly diagnosed or recurrent glioblastoma were eligible. Leukapheresis was used to isolate mononuclear cells which were differentiated into dendritic cells in culture, pulsed with tumor peptide, and then administered intradermally three times at 2-week intervals. Results: Twenty patients, 15 males and five females, were enrolled between November 2006 and December 2008 with one screen failure. The median patient age was 47 years (range: 26–65) and patients had a median Karnofsky performance status of 90% (range: 90–100). There were 16 newly diagnosed and three recurrent glioblastoma multiforme (GBM) patients, who underwent surgery prior to vaccination. Our data on 19 patients and 54 courses of dendritic cell vaccines demonstrate zero grade 3 /4 toxicities that were attributable to the vaccination. Thirteen patients continue to have stable disease (ranging from 15 to 115 weeks), six patients have demonstrated tumor progression. Median survival from surgery was 60 weeks (ranging from 26 to 115 weeks). Of 15 patients tested to date, six patients demonstrated an antigen-specific cytotoxic T-cell response to at least one antigen after vaccination. Only 17% of CTL responders (1/6) demonstrated tumor progression compared to 56% (5/9) of nonresponders to date. Conclusions: This phase I study demonstrated the feasibility, safety, and bioactivity of a TAA-pulsed dendritic cell vaccine for patients with glioblastoma progression free survival correlated with CTL response. [Table: see text]
Phase II trial of sunitinib malate in patients with temozolomide refractory recurrent high-grade glioma
Authors: Neyns B. , Chaskis C. , Dujardin M. , Everaert H. , Sadones J. , Nupponen N. N. , Michotte A. 
Published: August 2020

2038 Background: High-grade gliomas (HGG) are characterized by neo-angiogenesis. Sunitinib is a small molecule tyrosine kinase inhibitor that inhibits multiple receptors (including VEGFR, PDGFR, and c-Kit). We investigated sunitinib for the treatment of patients (pts) with temozolomide (TMZ) refractory recurrent HGG. Methods: Pts were recruited according to a 2-stage phase II design and received a daily dose of 37.5 mg sunitinib. T1 ± Gd and T2 weighted MRI images were obtained after 4 and 8 weeks of sunitinib and q8 weeks thereafter. We assessed the antiangiogenic effect by calculating the cerebral blood volume (CBV) and cerebral blood flow (CBF) from dynamic susceptibility (DSC) based perfusion MRI and determined the lesion-to-normal-white matter CBV (CBVLTN) and CBF (CBFLTN) ratios. Uptake of fluorinated fenyl-methyl-alanine within the CNS was assessed by PET at baseline and reassessed in responding pts. Results: 21 pts were enrolled (median age 43 [range 34–71]; M/F 15/6; KPS 90–80: 11 pts, KPS 70–60: 10 pts). All pts had PD following surgery, RT and TMZ. A total of 142 treatment weeks (range 2–84) were evaluated; 81% of the administrations were at the 37,5 mg-, 19% at the 25 mg dose level. Most frequent AEs were: skin toxicity (gr2, n = 1; gr 3, n = 1), fatigue (gr 2, n = 4), hypertension (gr 2, n = 3), diarrhea (gr 2, n = 2), mucositis (gr 3; n = 1), afebrile- (gr 2, n = 3) and febrile neutropenia (gr 3, n = 1; gr 4, n = 1), thrombocytopenia (gr 2, n = 4; gr 3, n = 1; gr 4, n = 1), and lymphocytopenia (gr 2, n = 2; gr 3, n = 4). Decrease in CBVLTN and CBFLTN was observed in 6/14 evaluable pts after 4 weeks of sunitinib, 5/19 evaluable pts had SD on T1±Gd after 8 weeks; one pt experienced a marked clinical improvement with a reduction in the tumor metabolism on PET. After a median follow-up of 11 months, median TTP and -OS are1,6 and 3,8 months respectively. Three pts with a secondary glioblastoma (age <40 year) had an objective PR when administered CCNU at PD under sunitinib (with a TTP of 2, 8 and +9 mths respectively). Characterization of the VEGFR, PDGFR, and Kit gene copy numbers and protein expression in the tumors is ongoing. Conclusions: Sunitinib at a continuous daily dose of 37.5 mg has a transient antiangiogenic effect in pts with recurrent HGG but is of insufficient clinical benefit to warrant further investigation as a single agent. [Table: see text]
Pazopanib and lapatinib in patients with relapsed malignant glioma: Results of a phase I/II study
Authors: Frentzas S. N. , Groves M. D. , Barriuso J. , Harris D. , Reardon D. , Curtis M. C. , Suttle A. B. , Ma B. , Lager J. J. , de Bono J. S. 
Published: August 2020

2040 Background: Pazopanib (paz) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-kit; and lapatinib (lap) is an oral tyrosine kinase inhibitor of EGFR (ErbB1) and HER-2 (ErbB2). Combination of VEGFR, PDGFR, and ErbB1 inhibitors may provide synergistic antitumor activity in malignant glioma. Phase I determined the optimally tolerated regimen (OTR) of paz and lap when given with enzyme-inducing anticonvulsants (EIACs). Phase II, which evaluated the efficacy of daily paz/lap (400 mg/1000mg) in relapsed grade 4 glioma without EIACs, was previously reported. Methods: Patients (pts) with grade 3 or 4 glioma, on EIACs, and with adequate organ function were eligible. Doses of paz and lap were escalated in a 3 + 3 design. OTR was defined as the highest dose of paz/lap at which no more than 1 of 6 pts had dose limiting toxicity (DLT) and target concentrations were achieved. Results: 32 pts have been enrolled at doses of paz/lap (mg, daily unless specified) of 200/1500 (N = 4), 800/1500 (N = 6), 800/500 bid (N = 5), 800/750 bid (N = 7), 800/1000 bid (N = 6), and 600 bid/1000 bid (N = 4). Data on 28 pts: the most common adverse events (AEs) were: fatigue (25%); diarrhea (25%); headache (21%); ALT increase (18%); nausea (18%); and insomnia (14%). Hepatobiliary lab abnormalities were reversible, uncomplicated, and included: AST elevation (11%), hyperbilirubinemia (7%), ALT elevation (36%; 7% Gr 3), and Alk phos elevation (14%). DLTs were elevated liver enzymes (800/1500; 1 pt), elevated lipase (800/750 bid; 1 pt) and thrombocytopenia, fatigue, diarrhea, confusion (800/1000 bid; 1 pt). 2 pts dose reduced and 3 pts had a dose interruption. At 600 bid/1000 bid, the target paz Cmin of 17.5 μg/mL was achieved; median lap Cmin of 0.447 μg/mL approached the target of 0.5 μg/mL. Phase I best response (MacDonald criteria) was PR in 3 pts (11%) and SD ≥ 8 weeks in 5 pts (18%). Two pts remain on the phase II, at 21 months (PR) and 23 months (CR) of therapy. Conclusions: The paz/lap combination has a manageable safety profile with a preliminary OTR with EIACs of paz 600 mg bid/ lap 1000 mg bid. EIACs decreased plasma paz and lap concentrations. Responses and lengthy periods without disease progression were seen in some pts in phase I and II. [Table: see text]
A phase II trial of single-agent bevacizumab given every 3 weeks for recurrent malignant gliomas
Authors: Raizer J. J. , Grimm S. , Rice L. , Muro K. , Chandler J. , Tellez C. , Mellot A. L. , Newman S. , Nicholas M. K. , Chamberlain M. 
Published: August 2020

2044 Background: Increasingly target specific agents are used in the treatment of malignant gliomas (MG). Among targeted agents, bevacizumab appears most promising and when combined with CPT-11. As CPT-11 has limited activity in recurrent MG, a single agent phase II trial of bevacizumab given every 3 weeks in with recurrent MG was performed. Methods: All patients (pts) had to sign an IRB informed consent except six pts who were treated at a different site in a similar fashion. All pts had to have at least one relapse with the first sixteen required to have two relapses before protocol amendment. Inclusion criteria required > 18 year of age, KPS > 60, on a non-enzyme inducing anticonvulsant, adequate bone marrow, liver and renal function, and normal urine protein and creatinine. MRI with perfusion was done at baseline (if patient consented) and then every 6 weeks. Patients were assessed using Macdonald criteria and continued on trial until tumor progression or toxicity. Treatment was bevacizumab 15 mg/kg every 3 weeks. Results: 61 patients (35 male; 26 female; 50 GBM, 5 AA, 6 AO/AOA) with a median age of 51 were treated. Median number of doses given was 4 (range 1–18). PFS-6 was 32% (median PFS was 3.9 m; median OS was 6.6 m). Best radiographic response included 0% CR, 25% PR and 50% SD. Grade 3+ toxicities were non-fatal intracranial hemorrhage (1), fatal GI perforation (1), DVT (1), fatigue (4), rectal bleeding (1), weakness (1), and lack of drive (1). Conclusions: Bevacizumab as a single agent given every 3 weeks at 15 mg/kg is effective and safe for recurrent MG. The observed PFS-6 and OS is lower than reported bevacizumab regimens administered every 2 weeks; this difference may be related to patient selection. [Table: see text]
Phase II study of bevacizumab plus erlotinib for recurrent malignant gliomas
Authors: Sathornsumetee S. , Desjardins A. , Vredenburgh J. J. , Rich J. N. , Gururangan S. , Friedman A. H. , Friedman H. S. , Reardon D. A. 
Published: August 2020

2045 Background: Bevacizumab (B), a neutralizing VEGF monoclonal antibody, has anti-glioma activity as single agent and in combination with cytotoxic therapy. Erlotinib (E), an EGFR tyrosine kinase inhibitor, may exhibit anti-tumor activity in some malignant glioma (MG) patients. B plus E was associated with clinical benefit in several solid tumors. We performed a single-arm, phase II study to evaluate the efficacy of B and E in patients with recurrent MG. Methods: The primary endpoint was 6-month progression-free survival (PFS-6). Radiographic response, pharmacokinetics and correlative biomarkers were secondary endpoints. E was orally administered daily at 200 mg/day for patients not on enzyme-inducing anticonvulsants (EIAC) and 500 mg/day for patients on EIAC. All patients received 10 mg/kg of B intravenously every two weeks. Key eligibility criteria included: age ≥ 18 years; KPS ≥ 60; > 4 weeks from prior surgery, XRT or chemotherapy. Patients with either > 3 prior progressions, requirement for therapeutic anti-coagulation or acute hemorrhage on pre-treatment imaging were excluded. Results: Fifty-six patients with recurrent MG (n = 24 for glioblastoma multiforme [GBM] and n = 32 for anaplastic gliomas [AGs]) were assessable for outcome. The PFS-6 rates were 25% for GBM and 50% for AGs. There was no survival difference between EIAC and non-EIAC groups. Rash (54% grade 1–2 and 38% grade 3) was the most common side effect. Nausea, diarrhea, and fatigue were common but mostly grade 1–2. Serious side effects were rare and included two patients with pulmonary embolism, single patients with either intestinal perforation, ischemic stroke, gastric bleeding, or nasal septal perforation. Pharmacokinetic and tissue biomarker profiles are in preparation. Conclusions: Among heavily pretreated recurrent MG patients, bevacizumab plus erlotinib is tolerated and associated with encouraging anti-tumor benefit. No significant financial relationships to disclose.
A phase II study of XL184 in patients (pts) with progressive glioblastoma multiforme (GBM) in first or second relapse
Authors: De Groot J. F. , Prados M. , Urquhart T. , Robertson S. , Yaron Y. , Sorensen A. G. , Norton A. , Batchelor T. , Drappatz J. , Wen P. 
Published: August 2020

2047 Background: XL184 is a potent orally bioavailable inhibitor of MET, RET, KIT, and VEGFR2. Elevated levels of VEGFR2 and its ligand VEGF are found in GBM, and elevated levels of MET and KIT are correlated with poor prognosis in GBM pts. Treatment with XL184 results in potent inhibition of GBM in preclinical models. Methods: This is a phase II study of 46 pts with recurrent GBM who received XL184 175mg PO qd. Co-primary objectives are 6-month progression-free survival (PFS6) and safety. Secondary objectives include response rate (per MacDonald Criteria), duration of response, overall survival, pharmacodynamic and pharmacokinetic parameters, vascular imaging, and changes in steroid usage. Results: As of January 6, 2009, all 46 pts have been enrolled. At least 1 post-baseline tumor assessment at 4 weeks was available for 26 pts. Of these, 17 pts had not received prior therapy with an anti-angiogenic agent, whereas 9 pts had received prior therapy with bevacizumab (n = 6), vandetanib (n = 2), or VEGF-TRAP (n = 1). Safety: 6 pts have experienced a total of 9 possibly related grade 3/4 SAEs including increased troponin I and myocarditis (n = 1); dehydration, nausea, and fatigue (n = 1); elevated ALT (n = 1); pulmonary embolism (n = 2); and CNS hemorrhage (n = 1). 24/46 (52%) pts have required a dose interruption or reduction due to AEs or SAEs. Based on investigator assessment of bidimensional contrast-enhancing tumor measurements, 10 pts (38%) had a best radiologic response of >= 50% reduction from baseline (including 1 pt with a 100% reduction), 9 pts (35%) had tumor measurement changes ranging from +24% and -49%, and 7 pts (27%) had a >= 25% increase in tumor burden. Of the 17 anti-angiogenic-naïve pts, 9 (53%) had a best radiologic response of >= 50% reduction in tumor burden. 1 pt with prior vandetanib therapy has experienced a best radiologic response of >= 50%. Of the 4 pts with > 6 months follow-up, 3 remain on study with a sustained radiologic response. Conclusions: XL184 at a dose of 175 mg PO qd, has demonstrated substantial activity in pts with progressive or recurrent GBM. Updated safety and efficacy results including centrally reviewed PFS6 and response rate will be reported. [Table: see text]
Hematologic adverse events associated with temozolomide (TMZ)
Authors: Villano J. L. , Letarte N. , Yu J. M. , Shakir A. R. , Bressler L. 
Published: August 2020

2053 Background: Secondary acute myeloid leukemia (AML) is reported to occur in 3%-10% of patients treated with alkylating agents for Hodgkin's lymphoma, non-Hodgkin's lymphoma, ovarian cancer, breast cancer, and multiple myeloma. The incidence of secondary AML is greatest at 5–10 years after treatment, and AML often follows myelodysplastic syndrome (MDS). TMZ is a pro-drug of methyl-triazeno-imidazole-carboxamide (MTIC), an alkylating metabolite of dacarbazine. Chemotherapy induced aplastic anemia is usually dose-related versus an idiosyncratic mechanism. A small number of fatal cases of TMZ-induced aplastic anemia have been reported. The FDA, in a Drug Safety Newsletter, described 18 cases of aplastic anemia reported between 1999 and 2006. TMZ use in brain tumors and in melanoma is increasing, with little known on the incidence of severe hematologic adverse events. Methods: We searched the FDA MedWatch database for TMZ and obtained all entries submitted to the FDA from November 1, 1997 to September 3, 2008. We also obtained the number of aplastic anemia cases reported from Schering Plough's Global Pharmacovigilance department, as of December 13, 2007. Results: During this time period, 5,127 reports (on any side effect) on 3,490 patients were submitted to MedWatch. Among these patients, we identified 140 cases that we labeled as major hematologic adverse events: agranulocytosis (8 cases), aplasia (42), aplastic anemia (52), leukemia (26), MDS (6), and lymphoma (6). Gender was reported in 133 cases. Of these, 56 were male and 77 were female. The overall mean age in cases of major hematologic adverse events was 54 years. Schering Plough reports 25 cases of aplastic anemia and estimates the frequency to be 10.22 per 100,000 patients exposed to TMZ. Conclusions: TMZ's major hematologic adverse event profile seems to differ compared with other alkylating chemotherapy. Aplastic anemia is a significant concern with TMZ use and should be disclosed to patients. Risk of leukemia/MDS from our review may also be significant, but length of follow-up is insufficient and the real risk is likely still unknown. No significant financial relationships to disclose.
The infiltrative, diffuse pattern of recurrence in patients with malignant gliomas treated with bevacizumab
Authors: Potthast L. , Chowdhary S. , Pan E. , Yu D. , Zhu W. , Brem S. 
Published: August 2020

2057 Background: There is no standard of care for recurrent gliomas; however, bevacizumab is often used as a salvage chemotherapy regimen. A diffuse, infiltrative pattern of recurrence, as evidenced by MR imaging, was seen manifesting as multifocal disease or presumed CSF dissemination with subependymal spread. Methods: We conducted a retrospective analysis of 40 recurrent glioma patients followed at Moffitt Cancer Center from September 2006 through December 2008 treated with bevacizumab alone or in combination with irinotecan. Histologies included glioblastoma (GB), anaplastic astrocytomas (AA), anaplastic oligodendrogliomas (AO), anaplastic oligoastrocytomas (AOA), and low-grade astrocytomas. Rate of diffuse, infiltrative recurrence, progression free survival (PFS) and overall survival (OS) were analyzed and correlated with respect to specific prognostic variables. Results: 38% (15) of the patients were female and 63% (25) were male. The median (range) age was 51 (20–72) years. The median (range) KPS was 80 (50–100). Twenty-six (65%) patients had GB, 8 (20%) AA, 2 (5%) AO, and 3 (8%) AOA and 1 (3%) had LGA. Five (13%) patients had a gross total resection (GTR), 23 (58%) a subtotal resection (STR) and 12 (30%) had biopsy only. The median (range) number of prior therapies was 2 (1–7). At time of analysis 28 (70%) patients had died. Incidence of diffuse, infiltrative recurrence was seen in 8 (20%) of patients (95% CI: [9%, 36%]). This recurrence seems to be negatively associated with age: rate for age<=50: 6/18 (33%); (95% CI: [13%, 59%]) while rate for age>50: 2/22 (9%); (95% CI: [1%, 29%]), with an odds ratio (OR) of 5.0. Conclusions: There appears to be an increase in a diffuse, infiltrative pattern of recurrence among recurrent glioma patients treated with bevacizumab as a salvage regimen. In our experience, this appears most prevalent in patients less than 50 years of age. It is unclear why the disparity among this subset of patients occurs, however, we hypothesize that this may once again highlight the distinct tumor biology among young glioma patients. The impact of this observation on clinical decision making on whether to utilize bevacizumab in young recurrent glioma patients warrants further investigation. [Table: see text]
Prognostic significance of early changes in the apparent diffusion coefficient that occurs after treatment of patients with glioblastoma multiforme with bevacizumab
Authors: Paldino M. , Desjardins A. , Friedman H. S. , Vredenburgh J. J. , Barboriak D. P. 
Published: August 2020

2058 Background: To determine the prognostic significance of changes in parameters derived from diffusion tensor imaging (DTI) that occur in response to combination chemotherapy with the antiangiogenesis agent bevacizumab (BEV) in patients with recurrent glioblastoma multiforme (GBM). Methods: 16 patients (10 men, 6 women; age range 38–62 years) with recurrent GBM underwent serial 1.5T MR imaging. Axial single-shot echo planar DTI (TR/TE 6000/100; flip angle 90 degrees; voxel: 1.72 x 1.72 x 5mm; b value of 1000 sec/mm2; 12 directions) was obtained on scans performed 3 days and 1 day prior to and 1 day after initiation of therapy with BEV and irinotecan (CPT-11). Clinical follow-up and survival status was documented up to 20 months after the date of initial MR imaging. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were aligned to whole brain contrast-enhanced 3D FLASH and 3D FLAIR image volumes (1 mm isotropic voxels) using a rigid body normalized mutual information algorithm. Based on two pre-treatment scans, the 95% confidence limits for change (95%CL) in ADC and FA were calculated in volumes of tumor-related contrast-enhancement (TRE) and FLAIR signal abnormality (FSA). A patient was considered to have a change in FA or ADC after therapy if the difference between the pre- and post-treatment values was greater than the 95% CL for that parameter. Progression was defined on contrast-enhanced MRI using MacDonald criteria by neuro-oncologists blinded to the DTI findings. Survival was compared using the log rank test. Results: DTI detected a change in ADC within FSA after therapy in three patients (2 increased, 1 decreased). Patients with a change in ADC within FSA had significantly shorter overall (p < 0.0012) and progression free (p < 0.015) survival than those with no change. Median survival in the patient group with a change in ADC was 24.7 (95% CI [17.3, 39.4]) weeks and 56.4 (95% CI [41.7, 96]) weeks in those patients with no change. Conclusions: In patients with GBM treated with BEV and CPT-11, a change in ADC after therapy in areas of FSA is associated with decreased survival. Parameters derived from DTI may, therefore, potentially serve as early markers of treatment failure in patients with GBM. [Table: see text]