bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/randomized phase II trial of either dasatinib or placebo combined with standard chemoradiotherapy for newly diagnosed glioblastoma multiforme (GBM): Final results of phase I study.
Authors: Laack Nadia N. , Galanis Evanthia , Leinweber Clinton , Buckner Jan C. , Giannini Caterina , Geoffroy Francois J. , Jaeckle Kurt A. , Sarkaria Jann Nagina ,   Alliance for Clinical Trials in Oncology
Published: March 2020

2032 Background: Dasatinib is a potent oral ATP competitive multi-targeted kinase inhibitor of multiple members of the Src kinase family, known to be involved in gliomagenesis and invasion. N0877 is a phase I/randomized phase II trial evaluating the combination of dasatinib, radiation (RT) and temozolomide (TMZ) in newly diagnosed GBM. The phase I portion has been completed and is the focus of this report. Methods: A cohorts-of-3 design was used to assess the safety of dasatinib in combination with RT and concomitant TMZ, and establish the phase II dose of the combination. Dasatinib was given orally for 42 days, beginning with the first day of RT (total dose 60 Gy) and first dose of TMZ (75 mg/m2/d). A 24 - 42 day rest (cycle 2) followed the RT/TMZ/dasatinib. Patients (pts) were observed for DLT to the end of cycle 2. Patients then received 6 cycles (28 day cycles) of dasatinib (once daily) and TMZ (days 1-5). At the completion of 6 cycles of TMZ + dasatinib, pts stay on dasatinib only (28 day cycles) until progressive disease. Results: Phase I component is complete with 13 patients (3 at dose level 0, 3 at dose level 0-A, 7 at dose level 1). One patient in dose level 1 had to be replaced due to the development of unrelated medical issues. One DLT (grade 4 pancytopenia) was observed in 1 patient at dose level 0 (50mg bid) and one DLT (grade 3 rash) was observed in 1 patient at dose level 1 (150mg qd). MTD of dasatinib was determined to be 150mg daily. Most common adverse events throughout the entire study period were hematologic with the most common toxicity being lymphopenia (grade 3 in 69% of patients, grade 4 in 8%). Other toxicities attributed to treatment and occurring in > 10% of patients included anemia (31%), neutropenia (15%), and fatigue(15%). Best response was stable disease in 10 patients, progressive disease in 1 patient, and not evaluable in 2. Conclusions: MTD for dasatinib in combination with TMZ and RT in newly diagnosed GBM patients is 150mg daily. Toxicity was primarily hematologic with minimal non-hematologic events. This dose is currently being used in the ongoing placebo-controlled, randomized phase II trial.
Final results of a randomized phase III trial of nimotuzumab for the treatment of newly diagnosed glioblastoma in addition to standard radiation and chemotherapy with temozolomide versus standard radiation and temoziolamide.
Authors: Westphal Manfred , Bach Ferdinand 
Published: March 2020

2033 Background: The receptor for epidermal growth factor (EGF-R) has consistently been found expressed or overexpressed in human malignant glioma disease. Therapeutic targeting of the EGF-R has shown mixed responses which appear to be restricted by specific features of the tumor cells.Nimotuzumab binds preferentially to highly over expressing cells, a phase III trial was initiated to test efficacy in glioma. Methods: Nimotuzumab was tested in an open label, randomized, multicenter Phase III trial in patients with histologically confirmed, newly diagnosed glioblastoma. 12 consecutive weekly infusions of 400mg during standard radiotherapy with Temozolomide followed by biweekly infusions of 400mg arm A was randomized against standard radio chemotherapy alone arm B. Primary endpoint was PFS as determined by centralized neuro-imaging review. OS as secondary endpoint with quality of life, safety as additional parameters.MGMT and EGF-R were assessed where sufficient materials could be retrieved as well as tumor hypoxia. Results: Between 2007 and 2010, 149 patients were randomized and 142 were available for analysis. Stratification according to resection status resulted in 40 pts in the treatment arm and 41 in the control arm with residual tumor and 31 vs 30 pts without residual tumor. PFS: 12 month was 25.5% arm A vs 20.3% in arm B (p = 0.78) and OS: 679 days vs 596 days. For non - methylated MGMT the difference was most notable: OS arm A 28 pats: 19.6 months vs arm B 28 pats 15.0 months EGF-R amplification, gave no clear signal, neither was there a statistically significant treatment effect between with or without residual tumor. Tumor hypoxia does not appear to have predictive value in the overall group but possibly in subgroups.AEs and SAEs did not reveal a new specific toxicity profile beyond the known side effects from glioma treatment with current standard. Conclusions: Nimotuzumab shows a clear trend towards efficacy in MGMT non-methylated glioblastoma patients. Safety profile and indications for subgroup efficacy potentially justify focused evaluation of antibody therapy against glioblastoma.
Toxicity profile of temozolomide in the treatment of 300 malignant glioma patients in Korea.
Authors: Kim Chae-yong , Bae So Hyun , Park Min-Jung , Lee Min Mi , Kim Tae Min , Kim Young-Hoon , Kim Yu Jung , Park Chul-Kee 
Published: March 2020

2041 Background: Toxicity of temozolomide itself has been rarely reported in the field of neuro-oncology. In an attempt to explore the toxicity profiles of temozolomide we investigated the records of 300 glioma patients in two institutions in Korea. Methods: We reviewed the records of 300 glioma patients who were treated with temozolomide between Jan 2004 and May 2010 at two hospitals of our university at two medical centers in Seoul National University, Korea. The age range of patients was 17 ~ 84 years old with its median of 49 years old. Their pathologies were glioblastoma, anaplastic astrocytoma, anaplastic oligodendroglioma, anaplastic oligoastrocytoma, gliomastosis cerebri, gliosarcoma and others. Temozolomide was used as only concurrent manner with radiotherapy in 46 patients, as both concurrent and adjuvant manner in 93 patients, and as only adjuvant or palliative manner in 161 patients. We classified the side effects by Common Terminology Criteria for Adverse Events version 3.0(CTCAE). Results: We found 603 events of side effects of temozolomide. Nonhematolgic toxicities were most common (n=482). Especially, nausea(n=135), vomiting(n=110), and anorexia(n=40) were common among all kinds of toxicities. Hematologic adverse events(n=121), for example, thrombocytopenia(n=43), anemia(n=33), and neutropenia(n=20) were the second common toxicities. Some patients suffered from fatigue(n=31). None of our patient presented fatal Pneumocystis jiroveci pneumonitis. In our series, 512 cases(84.9%) of toxicity were grade 1 or 2, and 91 cases(15.1%) were grade 3 or 4. Grade 3 or 4 toxicity were 140 cases(15.1%). Only 27 cases(2.9%) presented grade 4 toxicity. There was no mortality due to temozolomide. Only 4 patients (1.3%) presented leukopenia, which is different pattern compared with the incidence reported in prior studies from western countries. Conclusions: Temozolomide had many kinds of toxicities. However, most of the toxicity was tolerable. This profile could be used to prevent toxic reactions more effectively and improve the patient’s quality of life. Furthermore, we could use these lessons for education of patients during the treatment with temozolomide.
Use of tumor-targeting salmonella typhimurium to eradicate human glioma in an orthotopic model in nude mice.
Authors: Momiyama Masashi , Zhao Ming , Kimura Hiroaki , Tran Benjamin , Chishima Takashi , Bouvet Michael , Endo Itaru , Hoffman Robert M. 
Published: March 2020

2044 Background: Prognosis remains poor for glioma and therefore requires new approaches. We have previously developed a genetically-engineered strain of Salmonella typhimurium, A1-R, that targets tumors without overt toxicity in mouse models (Proc. Natl. Acad. Sci. USA 102, 755-760, 2005; Cancer Research 66, 7647-7652, 2006; Proc. Natl. Acad. Sci. USA 104, 10170-10174, 2007; Expert Opinion on Drug Discovery 7, 73-83, 2012). In the present study, we demonstrated that Salmonella typhimurium A1-R can inhibit and eradicate human glioma in an orthotopic nude mouse model. Methods: S. typhimuirum A1-R was administered by injection through a craniotomy open-window or intravenously in nude mice. To establish the model, 2×105 U87 human glioma cells, expressing red fluorescent protein (RFP), were injected stereotactically into the mouse brain through the craniotomy open window. Two weeks after glioma-cell implantation, mice were treated with S. typhimurium A1-R (2×107 CFU / 200 μl intravenous injection [i.v.] or 1×106 CFU / 1 μl intracranial injection [i.c.]) once a week for 3 weeks. Results: Brain tumors were observed by fluorescence imaging through the craniotomy open window over time. S. typhimurium A1-R, administered i.c., inhibited brain tumor growth 7.6-fold compared with untreated mice (p = 0.009) and improved survival 73% (p = 0.001). Two of ten mice had their tumors eradicated. Intravenous administration of S. typhimurium A1-R was not effective. Conclusions: The results of the present study demonstrate that bacterial therapy of glioma is a novel, effective and safe treatment strategy in a highly treatment-resistance cancer in an orthothopic model, a first step toward clinical development.
A phase II multicentric study of sunitinib administered as upfront therapy in glioblastoma: A study by the GEINO group.
Authors: Balana Carmen , Gil Gil Miguel J. , Reynes Gaspar , Capellades Jaume , Ribalta Teresa , Gallego Oscar , Pérez Segura Pedro , Verger Eugenia 
Published: March 2020

2045 Background: Sunitinib is a multitargeted tyrosine kinase inhibitor that has direct antitumor and antiangiogenesis activity through targeting VEGFR 1-2, PDGFR α-β, c-kit, bFGF, (CSF-1), FLT3 and RET. Experimental studies in GB mice showed angiogenic activity, prolonged survival and synergy with irradiation Methods: Eligible pts were ≤75 years with GB not amenable to resection, PS≥2, MMS ≥25. Treatment was sunitinib 37.5mg daily for 8 w before radiotherapy, during radiotherapy (60Gy, 6 w) and after radiotherapy until disease progression. Primary endpoint was overall response (OR) (RANO criteria) after 8 w of sunitinib treatment before radiotherapy. Secondary endpoints were % pts free of neurological deterioration before radiotherapy, % pts who completed radiotherapy, PFS, OS and 1-year survival. We used a Simon 2-stage design (12 →20) based on OR to calculate the number of patients needed to detect at least 10% of responses with α error of 0.05 and β error of 0.10. Twelve patients were included in the first phase and one response was needed to continue study accrual. Results: 12 pts were enrolled: 7 males, median age 65 years, PS≥1: 8pts, median MMS 26.5. Neurological deficit: 5pts, DXM treatment 10/12, non-EIDS 3/12. Treatment: 5 pts completed 8 w of therapy, 2pts completed 7 w, 4 pts ≤ 6w. Toxicity G3 and 4: diarrhea (1pt), asthenia (2pts), skin and EDDPP (2), mucositis (2), fatal CNS hemorrhage (1), hypercholesterolemia and hypertriglycemia (1). OR was 1/12 SD, 11/12 P; radiological response was SD in 5 pts but 4 pts progressed neurologically. Only 2 pts completed radiotherapy plus sunitinib. The only SD received treatment for 18 w. Median PFS was 7.5w (CI 95% 5.8-9.2), OS 16w (CI 95% 0.5-23.7), 1year OS: 0%. Conclusions: the trial was closed after the first stage due to lack of response. Sunitinib is an inactive agent in glioblastoma.
Anaplastic gliomas at first recurrence: Outcome analysis.
Authors: Franceschi Enrico , Bartolotti Marco , Dall'Occa Patrizia , Poggi Rosalba , Bartolini Stefania , Di Battista Monica , Marucci Gianluca , Ermani Mario , Brandes Alba Ariela 
Published: March 2020

2061 Background: Although anaplastic gliomas show a more favorable response to postsurgical therapy than glioblastoma, when recurs, salvage therapies offer only temporary benefit. Moreover, due to the rarity of these entities, no study exists to evaluate the clinical outcomes of anaplastic gliomas at first recurrence. Methods: A retrospective analysis was made using a database on 249 anaplastic glioma patients (pts) followed prospectively between 01/2000 and 12/2011. Eligibility criteria: age ≥18 years; PS 0-2; histological diagnosis at first surgery of anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), and anaplastic oligoastrocytoma (AOA); first recurrence after postsurgical treatments. Results: 163 pts (recurrent AA:52%, AOA:23%, AO: 25%, mean age: 45 years, range: 21–74) were enrolled. 1p deletion and MGMT methylation were found in 23% and 56% of evaluable specimens, respectively. At time progression, second surgery was performed in 51 pts (31%). Chemotherapy was delivered in 128 pts: temozolomide in 96 pts (75%), PCV regimen in 11 pts (9%), and other cytotoxic treatments in 21 pts (16%). Median PFS was 7.1 months (95% CI: 5.8–8.5), being PFS-6 57.8% (95%CI: 49.8%–65.8%), mOS: 18.3 months (95% CI: 13.9–22.8) and OS-12: 63% (95%CI: 55.4%-70.6%). 1p status was not significantly associated with PFS and OS measured from first recurrence to second progression or death, respectively (p=0.12 and p=0.08). In the Cox proportional hazard model, PFS at recurrence was significantly correlated with OS measured at the first disease recurrence (p<0.00001). Conclusions: our data represent the largest series that evaluated the outcome of anaplastic gliomas at first recurrence. In this setting, PFS should be considered as a worthy endpoint, being significantly correlated with OS.
Illness intrusiveness and subjective well-being in patients with glioblastoma multiforme.
Authors: Coate Linda E. , Edelstein Kim , Massey Christine , Jewitt Natalie C. , Mason Warren P. , Devins Gerald M. 
Published: March 2020

2063 Background: Glioblastoma multiforme (GBM) is the most common adult CNS malignancy. The quality-of-life (QOL) impact of its neurological sequelae and poor prognosis is poorly understood. In this study we examined relations between disease severity and mood in GBM patients. Methods: GBM patients (n=73) completed validated questionnaires examining depression (CESD), positive affect (ABS), illness intrusiveness (II), and health-related QOL (EORTC-QLQ30, BN-20). Median age was 53 years (range 26-75), median time since diagnosis was 1.1 years (range 0.1-12.4). 88% were on temozolomide. Questionnaire scores were compared to normative data from GI, GU, Breast, Head and Neck, Lymphoma, and Lung cancer groups using t-tests. Hierarchical multiple regression analyses tested the impact of disease severity indicators (ECOG; Symptoms, derived from QLQ30, BN20) and potential moderators on mood and whether II mediates those effects. Results: GBM patients reported less positive affect, more depression and greater II than other cancer patients (p<.05). Increase in symptoms correlated with greater II (β=.59; 95% CI [.31, .87], p<.0001) and depression (β=.37; 95% CI [.20, .55], p<.0001) and less positive affect (β=-.04; 95% CI [-.08, -.01], p=.02). Surprisingly, higher ECOG (i.e., poorer performance status) was associated with less II (β=-3.58; 95%CI [-7.06, -.10], p=.04) and depression (β=-2.20; 95%CI [-4.21, -.19], p=.03). II partially mediated the relations between disease severity and mood, evidenced by the change in the disease severity coefficient when II was added to the models (mean change measured by bootstrap sampling: CESD=.23, 95% CI [.06, .43]; ABS=.21, 95%CI [.02, .44]). The occurrence of other stressful life events was associated with II (β=2.73; 95% CI [.43, 5.02], p=.02), but there was no evidence of a moderating effect on this or any other relationship (p>.05). Conclusions: GBM patients are more distressed than other cancer patients. GBM-induced lifestyle disruptions partially mediate the association between disease severity and subjective well-being. Efforts to engage patients in valued activities and interests, despite the constraints, can help to preserve QOL.
Health-related quality of life (HRQOL) in patients with glioblastoma (GBM) and their caregivers in the end-of-life phase: A retrospective study.
Authors: Flechl Birgit , Sax Cornelia , Ackerl Michael , Crevenna Richard , Gaiger Alexander , Keilani Mohammad , Preusser Matthias , Dieckmann Karin , Widhalm Georg , Oberndorfer Stefan , Calabek Bernadette , Reijneveld Jaap , Sizoo Eefje , Marosi Christine 
Published: March 2020

2071 Background: Glioblastoma multiforme (GBM) still harbours an inevitably fatal prognosis. The specially course of this disease poses unique challenges in care provision to the relatives. We still lack data about the end-of-life phase of GBM patients to improve counseling and supporting GBM patients and their proxies. Methods: In this retrospecitve study we included 52 caregivers of deceased GBM patients treated in two hospitals in Vienna, Austria. We used a specially developed questionnaire by the Medical University of Amsterdam to explore and document the last three months of living of GBM patients. Results: Most of the included caregivers were the partners of the patients (88%) and two thirds were female. The most common symptom in GBM patients was fatigue (87%), followed by reduced consciousness (81%) and aphasia (77%). 22% of the patients were bedbound during their last three months increasing to 80% in the last week of life. 30% of the caregivers told that they felt incompletely informed for their task and about the illness of their loved one. They stated the quality of life (QOL) of the patients with 2.2 and their own with 2.8 on a scale of 1 to 7 whereas 7 displays the best possible answer. The majority of the patients (46%) died in hospitals and 38% at home, which was the most often expressed wish for place of death (45%)by patients. Regarding the caregivers’ symptoms, sadness (90%), fear (69%), burnout (60%), less interest in others (54%) and irritation (42%) were the leading ones and did not differ significantly in-between the places of death. Conclusions: The end-of-life phase of GBM patients is different from that of patients dying from other cancers. Most alarmingly, one thirds of their caregivers feels poorly informed. About two thirds of the caregivers fell overstrained and stresses thereby the urgent need for support and dedicated educational programs.
Adult low-grade gliomas: The Cleveland Clinic experience.
Authors: Robles Irizarry Lizbeth , Fawole Adewale Alade , Hashemi-Sadraei Neda , Patel Mital , Elson Paul , Tekautz Tanya M. , Murphy Erin Sennett , Recinos Violette , Chao Samuel T. , Suh John H. , Peereboom David M. , Stevens Glen , Weil Robert J. , Vogelbaum Michael A. , Barnett Gene H. , Ahluwalia Manmeet Singh 
Published: March 2020

2076 Background: Low-grade gliomas account for 10-20% of all primary brain tumors. There is limited data on specific prognostic factors for patients with low-grade gliomas. Methods: After obtaining IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify patients with histologically confirmed grade 2 glioma at the time of diagnosis. Multivariable analysis was conducted with use of a Cox proportional hazards model and a stepwise selection algorithm that used p<0.10 as the criteria for entry and p<0.05 as retention in the model to identify independent predictors of survival. Results: Chart records of 478 patients (54% of whom were men) diagnosed between 1991 and 2010 were included for analysis. The median age at presentation was 41 years (range, 18-83 years). 42% of patients had biopsy only, 27% had gross total resection, 6% had near total resection, and 25% had subtotal resection. 22% of patients were initially treated with radiation, 30% with adjuvant chemotherapy, and 7% with concurrent chemotherapy. Median progression free survival and median overall survival (OS) were 5.1 years and 12.8 years, respectively. On multivariate analysis, independent of additional therapy, five factors were identified as independent predictors of OS: age at diagnosis (p=0.002), Karnofsky performance status (KPS, p<0.0001), histology (astrocytoma vs. other, p=0.001), hemispheric location (left or bilateral involvement vs. right, p=0.02) and gender (male vs. female, p=0.0003). Conclusions: Older age, male gender, poor performance status, astrocytic histology, and left hemispheric or bilateral involvement are associated with higher mortality. [Table: see text]
Utility of iron oxide nanoparticles in the radiographic diagnosis of CNS lymphoma and inflammatory diseases.
Authors: Farrell Brian T. , Hamilton Bronwyn E. , Dosa Edit , Rimely Endre , Nasseri Morad , Gahramanov Seymur , Lacy Cindy , Frenkel Eugene P. , Doolittle Nancy Diane , Jacobs Paula M. , Neuwelt Edward A. 
Published: March 2020

2077 Background: Ferumoxytol, an ultrasmall superparamagnetic iron oxide nanoparticle (USPIO), is approved for intravenous treatment of iron deficiency in chronic renal failure. The package insert warns of potential alterations of magnetic resonance imaging (MRI). Our initial animal studies provided evidence of USPIO uptake by macrophages and lymphoreticular cells suggesting its potential in CNS lymphoma (CNSL), post transplant lymphoproliferative disease, or CNS inflammation (i.e. multiple sclerosis). The mechanism of USPIO enhancement differs from gadolinium-based contrast agents (GBCA), which optimally image areas of increased vascular permeability. Methods: USPIO was administered as an MRI contrast agent to 20 patients with presumptive or de facto diagnosis of CNSL or CNS inflammation. Seventeen of 20 patients underwent both USPIO- and gadolinium-based MRI. Three patients received only USPIO due to risk of nephrogenic systemic fibrosis (NSF) with GBCA exposure. In the pilot phase of the study, patients were given the USPIO ferumoxtran-10 and subsequent patients were given a successor USPIO (ferumoxytol) which has improved pharmaceutical properties. All patients were monitored for adverse reactions. MRI scans were subsequently reviewed by a neuroradiologist. Results: No significant toxicities were seen. Thirteen of 17 patients who received both contrast agents showed equal numbers of enhancing lesions on postcontrast images. USPIO-based contrast revealed additional areas of enhancement in three of 17 patients that were not visible when GBCA was administered. In three patients more lesions were seen with GBCA. Examples of ferumoxytol utility include 1) improved targeting for surgical biopsy; 2) avoidance of NSF; 3) demonstrating enhancement related to macrophages within lesions; 4) correlating cerebral blood volume and CNS inflammation; 5) demonstrating pitfalls such as prolonged imaging changes (3 months) in one case due to intensive inflammation, which can simulate hemorrhage. Conclusions: These studies provide data about the utility and value of USPIO-based contrast imaging in CNSL and inflammatory CNS lesions that support a dual role for these agents beyond iron replacement.