bluuebunny/crossref_metadata_2025_split huggingface dataset:
APG101_CD_002: A phase II, randomized, open-label, multicenter study of weekly APG101 plus reirradiation versus reirradiation in the treatment of patients with recurrent glioblastoma.
Authors: Bendszus Martin , Debus Jürgen , Wick Wolfgang , Kobyakov Grigory , Martens Tobias , Heese Oliver , Pichler Josef , Stupp Roger , Kunz Claudia , Fricke Harald 
Published: March 2020

2034 Background: Preclinical data indicate antiinvasive activity of APG101, an intravenous CD95 ligand-binding fusion protein, as well as synergistic activity together with radiotherapy in glioblastoma. Methods: Patients with recurrent glioblastoma after prior standard radiochemotherapy with temozolomide (± 1 second-line chemotherapy) were considered for re-irradiation provided a tumor diameter 1-4 cm and time since the end radiotherapy ≥ 8 months. Patients were randomized 1:2 between radiotherapy (36 Gy; 5 times 2 Gy per week) or radiotherapy plus APG101 at 400 mg weekly flat dose to be continued until progression. Radiotherapy plans were centrally evaluated. Primary endpoint was 6-months progression free survival (PFS-6). MRIs were performed every 6-weeks and centrally read. Sample size of the investigational treatment arm according to a two-stage design of Simon required 55 patients. A control arm of 28 patients was implemented to validate the assumptions on PFS-6 in a cohort of patients treated with reirradiation alone. Results: Between 12/09 and 09/11, 84 pts in 25 centers were randomized and treated, preliminary data of the current report are available on 71 patients (49 APG01 + irradiation, 22 irradiation alone). Median age was 57 years, median KPS 90%. The maximal tumor diameter was ≤ 2-5 cm in 34 patients and > 2.5 cm in 37 patients. No SUSARs have to be reported. Nine patients achieved PFS-6 in the APG101 arm and none in the radiotherapy arm. Conclusions: APG101_CD_002 is the first trial evaluating CD95-mediated pathway inhibition as a therapeutic strategy. This trial is also the prospective trial on reirradiation in glioblastoma. Side effects of the combination were minimal, and treatment could be delivered as planned. The experimental arm met the primary endpoint. The approach to block rather than stimulate the CD95 system is breaking a paradigm. Our data suggest that CD95 inhibition by APG101 should be evaluated in the management of newly diagnosed glioblastoma in combination with standard radiochemotherapy. Further molecular data and updated results will be presented.
Phase II trial of dose-dense temozolomide as initial treatment for progressive low-grade oligodendroglial tumors: A multicentric study of the Italian Association of Neuro-Oncology (AINO).
Authors: Ruda Roberta , Bertero Luca , Trevisan Elisa , Pace Andrea , Carapella Carmine Maria , Dealis Cristina , Caroli Manuela , Faedi Marina , Bomprezzi Chiara , Soffietti Riccardo 
Published: March 2020

2037 Background: Standard temozolomide has been shown to be active in progressive low grade gliomas after surgery, whereas few data are available on the impact of dose dense regimens. Thus, we developed a phase II single arm multicenter study to evaluate the efficacy and toxicity of a regimen of dose dense temozolomide in progressive low grade oligodendroglial tumors. Methods: The inclusion criteria of the study were as follows: 1)biopsy-proven supratentorial WHO grade II oligodendroglioma and oligoastrocytoma; 2)progressive disease, clinically (epileptic seizures)or radiologically; 3)measurable disease on MRI (at least 1 cm); 4)age ≥18 years; 5)Karnofsky Performance Status ≥70. Temozolomide was administered at 150mg/m2 1 week on/1 week off up to a maximum of 18 cycles or unacceptable toxicity. The primary end-point was response rate (RR) according to RANO criteria, whereas secondary end-points were clinical benefit in terms of reduction of epileptic seizures ≥50%, progression-free survival (PFS), quality of life and toxicity. Results: From January 2005 until December 2010 60 patients (median age 39 and median KPS 80) have been accrued and are now evaluable for response. Response rates on T2/FLAIR images were as follows: CR 0/60, PR 21/60 (35%), MR 14/60 (23%), SD 21/60 (35%) and PD 4/60 (7%). The clinical benefit was significant in 29/34 patients (85%). As for toxicity 5/60 (8%) patients stopped treatment for lymphopenia grade IV, whereas 11/31 patients (35%) were switched to the standard regimen of temozolomide. PET with methionine was added to MRI in 17 patients: in 10/17 (59%) a disappearance or a significant reduction of uptake was observed, being the reduction of seizures better correlated with the response on PET rather than that on MRI. 1p/19q codeletion was not associated with either the response or the clinical benefit, whereas the analysis of MGMT methylation and IDH1 mutations are ongoing. Thirty-nine (65%) patients are still free of tumor progression. Conclusions: Dose-dense TMZ seems to be active, especially in terms of clinical benefit, but the myelotoxicity could be a concern.
Neuraxis imaging in leptomeningeal metastasis: A retrospective case series.
Authors: Chamberlain Marc C. 
Published: March 2020

2046 Background: (and Objective) Leptomeningeal metastasis (LM) is a central nervous system metastatic complication of cancer that affects the entire neuraxis. Quantify imaging (brain and spine MRI and radio-isotope cerebrospinal fluid [CSF] flow study) abnormalities in a retrospective case series of patients with LM. Methods: 240 adult patients with LM (125 non-brain solid tumor patients with positive CSF cytology; 40 non-brain solid tumor patients with negative CSF cytology; 50 lymphoma and 40 leukemia patients with positive CSF flow cytometry) underwent prior to treatment brain and entire spine MRI and radio-isotope CSF flow studies (FS). Results: Neuraxis MRI in pathologically defined patients was more often normal in hematologic tumors (80-84%) compared to solid tumors (60%). Similarly, FS was more often normal in hematologic tumors (90-92%) compared to solid tumors (72-75%). However, neuraxis MRI and FS abnormalities (i.e. CSF flow obstruction; nodular subarachnoid or parenchymal disease; hydrocephalus) altered therapy by requiring CSF diversion, site specific radiotherapy, systemic chemotherapy or recommending no further therapy in one third of CSF cytology positive solid tumors and 15% of CSF flow cytometry positive hematologic tumors. Conclusions: Notwithstanding less frequent imaging abnormalities in hematologic tumors, similar to solid tumors imaging abnormalities frequently result in treatment alteration for patients with LM. Consequently, neuraxis imaging is recommended in both tumor categories in patients being considered for LM-directed and in particular intra-CSF chemotherapy treatment.
Predictive role of MGMT status in recurrent glioblastoma (GBM) patients (PTS) treated with antiangiogenic drug (AD) plus temozolomide (TMZ) or CPT-11.
Authors: Lombardi Giuseppe , Zustovich Fable , Farina Patrizia , Bertorelle Roberta , Della Puppa Alessandro , Gardiman Marina Paola , Fiduccia Pasquale , D'Avella Domenico , Zagonel Vittorina 
Published: March 2020

2049 Background: Methylation and silencing of MGMT promoter is a favourable predictive factor in PTS with GBM treated with single alkylating agent such as TMZ. Yet, MGMT is an important resistance determinant to CPT-11 activity. AD can be administered in second line treatment as single agent or in combination to cytotoxic drugs. We analyzed the predictive role of MGMT status in PTS treated with AD plus TMZ or CPT-11 as second line treatment. Methods: Retrospectively, 55 PTS were analyzed: 36 (65%) with unmethlyated MGMT, 19 (35%) with methylated MGMT; 3 (5%) PTS with IDH1 mutations. 17 (31%) PTS performed a reoperation before the second line treatment and MGMT status was changed in 2 (18%) PTS, IDH1 status was unchanged in all PTS. 32 PTS were treated with sorafenib 800mg/die plus TMZ 40mg/m2/die, 23 with bevacizumab 10mg/Kg plus irinotecan every two weeks. Tumor response was evaluated by clinician assessment and by MRI according to RANO criteria every two months or when clinically indicated. Results: Among all PTS, median PFS was 2.7 months (95%CI 1.5-3.5), median OS from start of AD was 7.3 months (95%CI 6.02-8.5), 6-month PFS was 32%; no significant differences were observed and MGMT status was balanced between the two AD groups (p>0.05). Analyzing MGMT status at first surgery, according to univariate analyses there were no significant differences in terms of PFS (3.5ms vs 2.1ms; p=0.2), OS (6.5ms vs 7.2ms; p=0.1) and 6-PFS (HR=0.2, CI95% 0.05-1.07) between PTS with unmethylated and methylated MGMT, respectively. On multivariate analysis, adjusted for performance status, age and cytotoxic drug, MGMT status was not statistically significant in terms of PFS (p=0.8) and OS (p=0.1). Yet, no significant differences emerged with MGMT status at second surgery as well as analyzing the two AD groups, separately. Conclusions: MGMT status might not be a predictive factor in recurrent GBM patients treated with AD plus TMZ or CPT-11 as second line treatment, although MGMT status may change in some PTS between first and second surgery. In conclusion, the outcome of patients with recurrent GBM receiving AD plus TMZ or CPT-11 is not significantly influenced by MGMT methylation status.
Phase II study of PX-866 in recurrent glioblastoma.
Authors: Pitz Marshall W. , MacNeil Mary Valeria , Macdonald David R. , Kakumanu Ankineedu Saranya , Thiessen Brian , Tsao Ming Sound , Kamel-Reid Suzanne , Squire Jeremy , Sederias Joana , Walsh Wendy , Eisenhauer Elizabeth A. , Mason Warren P. 
Published: March 2020

2051 Background: Glioblastoma (GBM) is the most aggressive malignancy of the central nervous system. The majority of GBM have genetic changes that increase the activity of the phosphatidylinositol-3-OH kinase (PI3K) signal transduction pathway, critical for cell motility, proliferation, and survival. We present the interim results of PX-866, an oral PI3K inhibitor, in patients (pts) with recurrent GBM. Methods: Pts with histologically confirmed GBM at first recurrence after treatment with chemoradiation and adjuvant temozolomide are given PX-866 8 mg daily on this single-arm phase II study. MRI and clinical exam are done every 8 weeks to determine treatment response. The trial has a 2-stage design with dual endpoints of objective response and early progression (within 8 weeks). In Stage I, 15 pts are evaluated and if 0 responses and 10 or more early progressions are seen, enrolment will stop. Otherwise, Stage II will enrol another 15 pts for efficacy analysis. Tumour tissue is collected for analysis of potential markers of PI3K inhibitory activity (PTEN, EGFRvIII, PIK3CA mutations). Results: Seventeen pts have been enroled to date: 14 evaluable for response and 15 for toxicity. Median age was 54 years (range 35-70), with 7 females and 10 males. No pts had received treatment for recurrent GBM, and median time between initial diagnosis and study enrolment was 300 days (range: 113-447 days). Pts have received a median of one 8-week cycle of PX-866 (range: 1-4). Twelve pts have discontinued therapy, 9 due to disease progression and 3 due to grade 3/4 liver enzyme abnormalities. Other adverse effects have included fatigue (10 pts/1 grade 3), diarrhea (6 pts/3 grade 3), nausea (7 pts/0 grade 3), vomiting (6 pts/0 grade 3), lymphopenia (14 pts/3 grade 3). Stage I response data are premature; it is not yet known if the trial will continue to Stage II. Archival tissue is available on all patients and is undergoing analysis. Conclusions: This is one of the first trials of a PI3K inhibitor in pts with recurrent GBM. PX-866 has been relatively well tolerated. Stage I response data are premature; while it is not yet known if the criteria will be met to continue to Stage II, prolonged SD has been observed in some pts. The correlative biomarker assays underway will be important to understand this observation.
Effect of the integrin inhibitor cilengitide on TGF-beta signaling.
Authors: Weller Michael , Silginer Manuela , Goodman Simon L. , Hasenbach Kathy , Thies Svenja , Schraml Peter , Tabatabai Ghazaleh , Moch Holger , Tritschler Isabel , Roth Patrick 
Published: March 2020

2055 Background: Glioblastoma is the most malignant form of intrinsic brain tumors. One of its characteristic features, angiogenesis, is mediated by the expression of integrins αvβ3 and αvβ5 on tumor-associated vasculature. Cilengitide is a synthetic peptide which inhibits ligand binding to the αvβ3 and αvβ5 integrins. The addition of cilengitide to the standard treatment regimen of radiochemotherapy in patients with newly diagnosed glioblastoma demonstrated promising results without significant toxicity which led to the initiation of a randomized phase registration III trial. Besides other functions, av-integrins can be involved in the activation of the cytokine transforming growth factor (TGF)-β which contributes to the malignant phenotype of glioma cells. Methods: Integrin expression was examined by immunohistochemistry and flow cytometry. The effects of cilengitide on TGF-β signaling in glioma cells were investigated by PCR, immunoblot and ELISA. Further assessments included reporter assays and glioma xenografts in nude mice. Results: The target integrins of cilengitide are expressed in glioblastoma blood vessels and tumor cells. Exposure to cilengitide results in detachment and reduced phosphorylation of Smad2 in most glioma cell lines, including stem-like glioma cells. Furthermore, exposure of glioma cells to cilengitide is associated with reduced TGF-β-mediated reporter gene activity. Smad2 phosphorylation, but not attachment, can be rescued by co-exposure to recombinant TGF-β. Cilengitide results in decreased TGF-β1 and TGF-β2 mRNA and protein expression and loss of transcriptional activity of the TGF-β promoter. Blocking antibodies to integrins αv, αvβ3 or αvβ5, or silencing of integrins αv, β3, β5 or β8 by RNA interference mimics the effects of cilengitide on TGF-β expression. Intracranial LN-308 glioma xenografts in nude mice display reduced pSmad2 levels in response to cilengitide. Conclusions: This study demonstrate a novel mechanism which may in part mediate anti-glioblastoma activity of cilengitide. These anti-TGF-β properties of cilengitide might be exploited in future clinical trials.
Phase II study to evaluate the efficacy and safety of rilotumumab and bevacizumab (BEV) in subjects with recurrent malignant glioma (MG).
Authors: Affronti Mary Lou , Desjardins Annick , Friedman Henry S. , Peters Katherine B. , Herndon II James E , McSherry Frances , Lipp Eric S , Brickhouse Alise , Massey Woody C , Miller Elizabeth , Cheshire Sprague , Cone Christina , Kalinowski Katherine H , Kim Jung-Young , Lay Harry H , Poillucci Victoria , Southerland Cindy , Tetterton Jill , Vredenburgh James J 
Published: March 2020

2074^ Background: Prognosis of recurrent MG remains poor with a median survival of 3-9 months. Few evidence based treatments are available and response rates have been < 20% with 6 month progression–free survival (PFS) of < 9-16%. Poor prognosis is linked to the MG’s ability to induce vascular proliferation and invasion. MG’s have an abundance of neo-vascularization and high levels of vascular endothelial growth factor (VEGF). BEV, an antibody to VEGF, is the most active agent tested for recurrent MG with an overall response rate of 21.2%. Rilotumumab is a human monoclonal antibody that blocks human hepatocyte growth factor (HGF) and its receptor c-Met. HGF/c-Met signaling plays a role in MG tumorigenicity inducing angiogenesis and expression of additional angiogenic autocrine factors such as VEGF. The novel combination of rilotumumab (C-Met inhibitor) with an anti-VEGF drug (BEV) to block vascular invasion and tumor proliferation may demonstrate synergistic tumor growth inhibition. Methods: A two-stage design is used to assess radiographic response rate with > 3 responses required for the first stage. Secondary endpoints were PFS, overall survival (OS) and toxicity. Subjects with recurrent BEV-naïve MGs received rilotumumab at 20 mg/kg in combination with BEV at 10 mg/kg every two weeks ≥ 28 days after the last surgical procedure. A brain MRI was obtained after each 6-week cycle. Results: 15 of the 19 patients required for the first stage have been accrued. 10(67%) were male and ≥ 50 years. 73% received ≥ 2 prior regimens and 46% had ≥ 2 prior progressions. Best tumor response included 1(7%) complete response, 2 (13%) partial responses, 8 (53%) stable disease, 1 (7%) progressive disease with 20% (3/15) non-evaluable due to early termination secondary to toxicity. Median PFS was 3.9 months (95% CI: 1, 7.1) with a 6-month PFS of 25.4% (95% CI: 6.4, 50.5) and 6-month OS of 68.3% (95% CI: 34, 87.1). Toxicities are listed below. Maximum average weight increase over all cycles was 6.3 % (SD ± 6.09). Conclusions: Rilotumumab in combination with BEV is an active regimen in MG. Toxicity will need to be closely monitored. [Table: see text]
Phase II trial of bevacizumab and fotemustine in recurrent grade III gliomas.
Authors: Soffietti Riccardo , Trevisan Elisa , Bosa Chiara , Bertero Luca , Ruda Roberta 
Published: March 2020

2075 Background: Bevacizumab (BV) has shown activity in recurrent grade III gliomas, and few data are available on the combination of BV and nitrosoureas. Fotemustine (FTM) is a nitrosourea with elevated lipophilic properties. Methods: In this phase II study patients with grade III gliomas recurrent after surgery, radiation therapy and concomitant/adjuvant temozolomide were eligible. The treatment consisted of an induction phase with BV at 10mg/kg intravenously on day 1 and 15 and FTM at 75mg/m2 intravenously on day 1 and 8, followed after a 3 week interval by a maintenance phase with BV 10mg/kg and FTM 75mg/m2 every 3 weeks until tumor progression or unacceptable toxicity. Patients had undergone clinical and MRI assessment 1 month after the start of treatment and thereafter every 2 months. The primary endpoint was progression-free survival at 6 months (PFS-6), whereas secondary end-points were response rate (RR), based on RANO criteria, progression-free survival (PFS), overall survival (OS), and safety. Results: From May 2008 to September 2011, 32 patients (males 23, females 9, median age 46) were enrolled. PFS-6, PFS -12 and median PFS were 31%, 7% and 5 months (range: 1-43+), respectively. OS-6, OS-12 and median OS were 78%, 37.8% and 8.6 months (3.5-43+), respectively. Response rates were as follows: 4 CR (12.5%), 12 PR (37.5%), 14 SD (44%) and 2 PD (6%). A significant neurological improvement was observed in 48% of symptomatic patients, being steroids reduced or withdrawn in 83% of patients. 29/32 (91%) patients have progressed and patterns of tumor progression were local in 20 (69%), multicentric in previous multicentrinc tumors in 5 (17%), gliomatosis-like in 3 (10%) and local plus leptomeningeal seeding in 1 (4%). 23/29 patients had salvage treatment after failure. Toxicities after BV were as expected; 5 patients interrupted FTM for grade III-IV myelotoxicity. We did not observe any additional toxicity from the combination. Conclusions: The combination of bevacizumab and fotemustine in grade III gliomas recurrent after standard treatment seems to have some activity.
High-dose chemotherapy (HDC) followed by autologous stem cell transplant (ASCT) for recurrent/progressive CNS lymphoma.
Authors: Welch Mary Roberta , Sauter Craig Steven , Matasar Matthew J. , Moskowitz Craig , Omuro Antonio Marcilio Padula 
Published: March 2020

2089 Background: In two reports by Soussain et al, promising efficacy was observed in recurrent primary CNS lymphoma with induction cytarabine/VP-16 (CYVE) followed by HDC-ASCT (busulfan, thiotepa and cyclophosphamide [BTC]), but significant toxicity, mainly from CYVE, has limited widespread use. We report our experience with HDC-ASCT with alternative induction regimens. Methods: Retrospective review of pts with recurrent/refractory non-Hodgkin lymphoma (NHL) with CNS involvement treated with HDC-ASCT (2000-present). Results: Seventeen pts met inclusion criteria: med age= 58 (41-65); 9 were women; med KPS prior to transplant= 90 (range 70-100). At initial presentation, 10 had primary CNS lymphoma (ocular: 1); 7 had systemic NHL without CNS involvement; 1 had both systemic and CNS disease. Pts had been heavily pre-treated. Among those with PCNSL, high dose MTX was used in all pts and WBRT in 4. Two pts had received a previous HDC-ASCT. Among systemic NHL pts, various regimens were used, mostly R-CHOP(4), but also R-EPOCH (1), CVP (1), ICE (1) and CODOX-M (1). At CNS recurrence, pts received various induction regimens prior to HD-ASCT: high-dose methotrexate (MTX)-based chemotherapy (N= 13), cytarabine-based regimens (N=2), and other (N= 2). All pts achieved a CR or near CR prior to HDC-ASCT. Harvesting was obtained with G-CSF alone in 9 pts; 8 required plerixafor. Two pts failed mobilization N=15 received HDC-ASCT. The HDC consisted of BTC (N=13); 1 received BEAM and 1 received reduced intensity fludarabine, melphalan and alemtuzumab. Eight pts experienced a grade III or IV toxicity – most commonly fatigue, febrile neutropenia, and infection. One previously transplanted pt died from sepsis. With a med follow-up of 11 months, post-transplant med-PFS has not been reached. The 12m PFS was 92% (95% CI 56-98). Because no patient has progressed, the OS was identical to PFS. Conclusions: HDC-ASCT was a highly effective salvage approach in this population of recurrent/refractory CNS lymphoma. To reduce the risk of harvesting failure at the time of recurrence, harvesting stem cells at the time of initial treatment could be considered in pts with high risk for relapse.
Poor prognostic factors of post-CNS recurrence survival in breast cancer patients.
Authors: Castaneda Altamirano Carlos , Gomez Henry Leonidas , Pinto Joseph A. , Schwarz Luis Jesus , Vigil C. E. , Vallejos Carlos 
Published: March 2020

2097 Background: Survival after the onset of metastases in the central nervous system is very short. However, some variables could indicate subsets of worse prognosis. Our aim was to determine the value of clinicopathological characteristics and prognostic scores in the post-SNC recurrence survival. Methods: We evaluated a retrospective cohort of 2597 breast cancer patients treated at the Instituto Nacional de Enfermedades Neoplasicas (Lima-Peru) between 2000-2005. Clinicopathological data was retrieved, RPA and GPA brain metastases prognostic scores were constructed and phenotypes were categorized according to the IHC expression in [HR+,HER2-], [Any HR, HER2+] and Triple Negative. Survival was calculated according to the Kaplan Meier methodology and cases were stratified by variables evaluated. The log-rank or Breslow tests were used when appropriate and multivariate analysis was done by the cox regression. A P<0.05 was considered statistically significant. Results: One hundred and fifty seven cases developed CNS metastasis, from which 23 developed leptomeningeal metastases. The post recurrence CNS survival was 0.405 years. There were not differences according to phenotype (P=0.102), histological grade (P=0.647), number of brain metastases (P=0.695) and metastases volume (P=0.155). We found statistic differences in regard to leptomeningeal carcinomatosis (present, 0.249ys vs absent 0.436ys; P=0.033); CSF infiltration (present, 0.115ys vs absent, 1.044ys; P=0.022); status of primary tumor (controlled, 0.501ys vs uncontrolled, 0.263ys; P<0.001); ECOG performance status (<2, 0.504ys vs ≥2, 0.288ys; P=0.030); and time from BC diagnosis to SNC metastases (<8 moths, 0.115 vs ≥8 months, 0.425ys; P=0.023). Cox regression identifies to CSF infiltration as statistically significant (HR=9.77; P=0.025). In regard to Prognostic scores, we found differences when cases were stratified according to RPA score (Class I, 0.564ys vs Class II, 0.455ys vs Class III, 0.288ys; P=0.049) and GPA score (0-1, 0.26ys vs 1.5-3, 0.455ys vs 3.5-5, 0,564; 0.048). Conclusions: RPA and GPA scores are more accurate to identify poor survival subsets in this group of patients than other tumor features (phenotype or histology).