bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value of 18FET positron emission tomography (18FET-PET) for the clinical course in newly diagnosed glioblastoma.
Authors: Tonn Joerg Christian , Suchorska Bogdana , Jansen Natalie , Linn Jennifer , Kretzschmar Hans A , Simon Matthias , Hentschel Bettina , Kreth Friedrich Wilhelm , Weller Michael , LaFougere Christian ,   for the German Glioma Network
Published: March 2020

2045 Background: Aim of this prospective longitudinal study was to evaluate whether 18FET-PET allow to monitor and quantify the therapeutic effects of surgery, radiotherapy and chemotherapy in newly diagnosed glioblastoma and whether 18FET-PET can provide additional prognostic information on response to therapy and outcome. Methods: 92 patients with newly diagnosed glioblastoma considered eligible for radiochemotherapy (RcX) were included; diagnosis was obtained by biopsy (n=46) or resection (n=46). Patients were to undergo 18FET-PET and cocomitant MRI scans prior to surgery, following RcX and as well as after three cycles of adjuvant temozolomide (TMZ). At each time point, biological tumor volume (BTV), maximal 18FET uptake as ratio to background (SUVmax/BG), and tumor uptake kinetics (TAC) were obtained. Overall survival (OS) was primary endpoint, progression-free survival (PFS) as defined by MRI using Macdonald criteria was a secondary endpoint. ROC analyses were done to determine optimal cut-off values of 18FET-PET parameters for survival outcome. To identify predictors for OS/PFS, Cox regression analysis was performed. Results: 79 patients were eligible for further evaluation. ROC analysis revealed cut-off values for pre-RCX BTV (9.5 ccm) and SUVmax/BG (2.95) with a sensitivity and specificity of both 70% for BTV and 68/73% for SUVmax/BG. Both pre-therapeutic BTV and SUVmax/BG were associated with PFS and OS (p<0.05). In contrast to MRI-based volume, the prognostic value of BTV remained highly significant in the multivariate Cox analysis independently of MGMT status.. Furthermore, 18FET TAC pattern and its changes were related to OS and PFS. Conclusions: Serial 18FET-PET imaging in glioblastoma before and after concomitant radio-/chemotherapy is a highly powerful tool to provide prognostic information for the outcome in newly diagnosed glioblastoma patients. These findings might help to personalize therapy and response evaluation in forthcoming clinical investigations. Clinical trial information: NCT01089868.
Clinical outcome of 1,968 cases of meningiomas from Kaiser Permanente Northern California.
Authors: Nguyen Nathalie T. , Lyon Liisa L , Moes Gregory S , Sahrakar Kamran , Villano John L. 
Published: March 2020

2062 Background: Meningioma is the most common primary brain tumor in the United States, but there is limited data on clinical outcomes. Methods: We performed descriptive and survival analysis of meningioma cases diagnosed 2001-2010 from the Kaiser Permanente Northern California Cancer Registry, which began inclusion of benign brain tumors in 2001. Datasets provided variables on gender, age at diagnosis, race, and vital status. Chart review extracted additional information on mortality, histology, imaging, tumor size, tumor site, and treatment. We used Kaplan Meier method to calculate overall survival (OS) and disease-free survival (DFS) and log-rank test to compare survival rates by variables. Cox proportional hazard models were used to analyze variables relative to endpoints. Results: 1968 cases in 1792 patients with meningioma were analyzed. 55% of cases had histological confirmation. 5- and 10-year OS and DFS for all groups were 76% & 61% and 89% & 82%. Disease progression and recurrence presented in 10% of cases at 10 years, resulting in 4% disease-specific mortality (DSM). Statistically significant prognostic factors of worse DFS were age >= 80, WHO grade 2-3, tumor size >= 18 mm, peritumoral edema on imaging, Simpson grades (SG) 4 or 5, and no surgery. Factors associated with significantly worse OS included age >= 60, male gender, tumor size >= 42 mm, peritumoral edema, SG 4 or 5, no histology and no treatment (NT). SG 1-3 groups provided statistically the highest OS and DFS. There was no significant difference in DFS or OS for definitive RT versus surgery and adjuvant RT groups. Definitive RT showed significantly better OS than NT (HR=0.46, 95% CI: 0.21-0.98). Cases with progression or recurrence had 51% DSM with 65% of deaths associated with lack of salvage therapy. Salvage RT provided better OS benefit compared to other salvage groups (HR=0.35, 95% CI: 0.14-0.91). Conclusions: We demonstrated favorable long-term outcome for meningiomas and confirmed the prognostic benefit of Simpson grading. We have identified additional adverse factors affecting outcome. While surgery remains standard, definitive RT demonstrates comparable outcome to cases not amenable to gross total resection. Salvage RT is effective, providing a survival benefit.
Response assessment of novoTTF-100A versus best physician’s choice chemotherapy in recurrent glioblastoma.
Authors: Wong Eric , Lok Edwin , Swanson Kenneth D. , Gautam Shiva , Engelhard Herbert H. , Lieberman Frank S. , Taillibert Sophie , Ram Zvi , Villano John L. ,   on behalf of the EF-11 Trial Investigators
Published: March 2020

2080 Background: The NovoTTF-100A device emits tumor treating electric fields and was tested against Best Physician’s Choice (BPC) chemotherapy in a randomized phase III trial. We analyzed post hoc the characteristics of responders and non-responders in both cohorts. Methods: Macdonald criteria were used to determine tumor response and progression. Kaplan-Meier and Chi-squared statistics were computed for time to response, response duration, progression-free survival (PFS) with and without Simon-Makuch correction, and overall survival (OS). Prognostic factors were compared using the Wilconox rank sum test. Relative hazard rates for responders and non-responders were plotted. Results: The median response duration was 7.3 versus 5.6 months for NovoTTF-100A and BPC chemotherapy respectively (p=0.0009). Five of 14 NovoTTF-100A responders but none of 7 BPC responders had prior low-grade histology. The mean cumulative dexamethasone dose was 35.9 mg for responders versus 485.6 mg for non-responders in the NovoTTF-100A cohort (p<0.0001) as compared to 525.6 mg for responders and 431.0 mg for non-responders in the BPC cohort (p=0.9520). Hazard rate analysis showed delayed tumor progression in responders compared to non-responders. The Simon-Makuch conditional plot, which adjusted for unequal progression-free states, still showed longer PFS in responders than non-responders treated with NovoTTF-100A (χ2=11.5, P=0.0007) or BPC chemotherapy (χ2=5.2, P=0.0222). The median OS was 24.8 months for responders that is longer than 6.2 months for non-responders treated with NovoTTF-100A (χ2=25.7, P<0.0001). In the BPC chemotherapy cohort, the median OS was 20.0 months for responders and 6.8 months for non-responders (χ2=5.1, P=0.0235). There was strong Pearson correlation between response and OS in NovoTTF-100A (P<0.0002) but not in BPC cohort (P=0.2952). Conclusions: Response duration, adjusted Simon-Makuch PFS and OS favor NovoTTF-100A over BPC chemotherapy. Data on prior low-grade histology and dexamethasone dose suggest potential genetic and epigenetic determinants of NovoTTF-100A response. Clinical trial information: NCT00379470.
Patterns of care study of adult medulloblastoma.
Authors: Cosman Rasha , Brown Chris , DeBraganca Kevin , Khasraw Mustafa ,   Cooperative Trials Group for Neuro-Oncology
Published: March 2020

2086 Background: Medulloblastoma (MB) accounts for less than 1% of adult intracranial tumours. While pediatric MB has been investigated in several randomized studies, the evidence in adults is limited to case reports and retrospective series, with no accepted standard of care. The Australian Cooperative Trials Group for Neuro-Oncology (COGNO) sought to determine the range and consistency of clinicians’ approaches to management as a basis for future trials. Methods: We aimed to identify current treatment strategies for adult MB through an international electronic survey launched at the 2012 meeting of the Society of Neuro-Oncology and by email invitation. Clinicians who had treated at least 1 adult patient with MB, central primitive neuroectodermal tumor (cPNET), or pinealoblastoma in the preceding year were asked about their most recent patient and asked to discuss their approach to management of a typical clinical scenario. Results: Between Nov 2012 and Jan 2013, 45 clinicians (11 medical oncologists, 7 radiation oncologists, 5 pediatric oncologists, and 22 others) from Australia (n = 24), USA (n = 3), Europe (n = 4) and other countries (n = 14) completed the survey. Responding clinicians had treated 54 cases in the past 12 months. The commonest histological type was MB (64%), followed by cPNET (20%). Most patients were male (68%), and most had high-risk disease (65%). 56% had complete surgical resection and 32% had molecular testing. Radiotherapy was predominantly craniospinal (92%) and mostly post-resection (80%). Combination chemotherapy was more common than single agent. Vincristine, cisplatin, cyclophosphamide was the most common protocol (43%). Others included carboplatin, etoposide, ifosfamide (29%), vincristine, lomustine, cisplatin (19%), vincristine, lomustine, prednisone (5%). Further details will be presented at the 2013 ASCO Annual Meeting. Conclusions: Our study has shown substantial international variation in the treatment of adult MB, most pronounced in the choice of chemotherapeutic agents, highlighting the need for further collaborative research to guide evidence-based treatment strategies.
Bevacizumab in combination with TMZ in patients with recurrent GBM: Final OS and PFS analysis.
Authors: Sepulveda Juan Manuel , Belda-Iniesta Cristobal , Gil Miquel , Pérez Segura Pedro , Berrocal Alfonso , Reynes Gaspar , Gallego Oscar , Ordonez Jose Manuel , La Orden Beatriz , Balana Carmen 
Published: March 2020

2087 Background: BEV provides a consistent clinical benefit in the treatment of relapsing GBM in terms of a delayed progression and increased median overall survival compared to historical controls. The aim of this study is to evaluate the efficacy and toxicity profile of the combination of BEV with dose dense TMZ, reporting the final results of PFS, OS and the toxicity experienced. Methods: A phase II multicenter, national, open-label study in pts diagnosed of recurrent GBM treated with BEV 10 mg/kg day q2w and TMZ 150 mg/m2 days 1-7 and 15-21 q28d d until disease progression or unacceptable toxicity or medical decision, as first line of treatment all pts received radiotherapy and at least 3 cycles of adjuvant TMZ. This study evaluates efficacy by PFS as primary endpoint and as secondary endpoints: OS, RR based on the adapted MacDonald criteria and toxicity profile (NCI CTC v3.0). Results: From June 10 to July 11, 32 evaluable pts were recruited in 8 sites. The baseline characteristics were as follows: 17 males and 15 females, median age 57.5 y (29-74), ECOG PS 0: 25%, PS 1: 50% and PS 2: 25%, 44% patients had gross total resection, 50% had subtotal resection and 6% biopsy only, MGMT promotor was methylated in 12 pts, unmeth in 6 pts and missing in 14 pts. The median number of TMZ or BEV cycles administered across all patients was 4 (TMZ range 1-9 and BEV range 1-25) The median PFS was 4.4 m [IC 95% (3.7 – 5.6)]. The 6m-PFS probability was 29.25%. The median OS (75% events) was 7.5 m[IC 95% (5.98 – 9.11)]. No significant association with MGMT status was found in terms of OS or PFS. BEV related AEs have been reported in 56.2% of the population being most of them mild or moderate. Grade 3-4 most frequent toxicity: lymphopenia 31% and fatigue 12.5%. Six of 32 pts were long term survivors, in this population the median PFS was 9.8 m [IC 95% (8.2 – 24.4)] and median OS (50% events) was 15.9 m [IC 95 %( 9.2 – NA)], no differences in baseline characteristics were identified in comparison with total population. The median number of TMZ cycles administered was 4 and median BEV cycles were 9. Conclusions: Although the combination don’t met the previous reported activity of BEV, 19% of patients had longer survivals which suggest the need to identify patients that benefit for this treatment. Clinical trial information: NCT01115491.
Characterization of glioblastoma (GBM) vasculature and protein expression of surrounding tumor cells on single FFPE sections with a multicycle multiplexed in situ immunofluorescent staining technology.
Authors: Zhang Jingyu , McCulloch Colin , Sui Yunxia , Dinn Sean , Li Qing , Santamaria-Pang Alberto , Sevinsky Christopher J , Graff Jeremy Richard , Weiss Lawrence , Ong Teng Jin , Ginty Fiona 
Published: March 2020

2097 Background: GBM is the most common brain tumor in humans and has a dismal prognosis. Although antiangiogenic therapy (bevacizumab) is an option for GBM, there is still unmet need to understand tumor pathophysiology and predictive biomarkers. We built a tissue based multiplexed immunofluorescent assays and developed algorithms to identify and quantify tumor vasculature, that enabled quantification, visualization, and colocalization of multiple protein in surrounding tumor cells at single cell and subcellular levels. This assay provides unique opportunity to explore tumor heterogeneity of tissue morphology and their relationships to vasculature, and is a novel tool for biomarker and treatment discovery. Methods: Tissue micro arrays (TMAs) were constructed from 141 GBM patients. Fluorescent dye labeled antibodies against 18 biomarkers were sequentially applied on single sections of these TMAs. Metrics were built to identify vessels, quantify distance of tumor cells to vessels, and analyze expression profiles of biomarkers, including signaling molecules in EGFR, PI3K/AKT, TGF-beta pathways, and hypoxia marker Glut1, in proximity to blood vessels. Results: CD31 was successfully used to identify blood vessels in GMB. Vessel segmentation and quantification were performed on all of the images. Biomarker profiling in the context of blood vessels demonstrated different patterns in close proximity to vessels, with some biomarkers showing increased levels (e.g. SMA, EGFR, pS6), some showing decreased levels (e.g. p4EBP), and others remain the same (FOXO3a, S6). Quantification of biomarkers showed heterogeneous expression within the same sample and across the cohort. In addition, co-localization of the above markers was visualized and demonstrated on single cell and subcellular levels. Conclusions: We were able to use a novel fluorescent multiplexing technology (MultiOmyx) to study GBM biology. This technology allowed the simultaneous analyses of multiple biomarkers of GBM, and provides new insights on the relationship of markers to each other, tumor heterogeneity and angiogenesis.
A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer.
Authors: Shapiro Geoffrey , Rosen Lee S. , Tolcher Anthony W. , Goldman Jonathan Wade , Gandhi Leena , Papadopoulos Kyriakos P. , Tolaney Sara M. , Beeram Muralidhar , Rasco Drew Warren , Kulanthaivel Palaniappan , Li Qian , Hu Tianle , Cronier Damien , Chan Edward M , Flaherty Keith , Wen Patrick Y. , Patnaik Amita 
Published: March 2020

2500 Background: Cyclin dependent kinases 4 and 6 (CDK4/6) act with D-type cyclins to inactivate the retinoblastoma (Rb) tumor suppressor protein and enable cell cycle progression from G1 to S phase. LY2835219 is a selective inhibitor of CDK4/6 that shows antitumor activity in preclinical models of human cancer and also distributes efficiently to the brain. We performed a phase 1 study to evaluate safety, pharmacokinetics, pharmacodynamics, and antitumor activity of LY2835219. Methods: 3+3 dose escalation was followed by expansions in 5 tumor types (brain metastases permitted): non-small cell lung cancer (NSCLC), glioblastoma, breast cancer, melanoma, and colorectal cancer. LY2835219 was taken orally every 12 or 24 hours (in escalation) and every 12 hours (in expansions) on days 1-28 of a 28-day cycle. Results: 55 patients (pts) received LY2835219. In escalation, 33 pts received LY2835219 on 1 of 2 schedules: 50, 100, 150, 225 mg every 24 hours (Q24H) or 75, 100, 150, 200, 275 mg every 12 hours (Q12H). On the Q24H schedule, the maximum tolerated dose (MTD) was not identified. On the Q12H schedule, the MTD was 200mg Q12H with dose limiting toxicity of G3 fatigue at 200 mg (1/6 evaluable pts) and 275 mg (2/3 evaluable pts). At 200mg Q12H, the mean Cmax and AUC0-24hr at steady state were 285 ng/mL and 5502 ng-hr/ml, respectively. In skin, LY2835219 induced pharmacodynamic inhibition of both Rb phosphorylation and topoisomerase IIα expression. In the ongoing expansions, 22 pts have received LY2835219. Across the study, the most common related adverse events were diarrhea (52%, including 5% G3), nausea (30%, 4% G3), fatigue (21%, 7% G3), vomiting (18%, 2% G3), and neutropenia (16%, 7% G3). 15 pts have reached ≥4 cycles for stable disease or better with 3 pts achieving 8, 16, and 26 cycles. One pt with ovarian cancer had a durable CA-125 response with >50% decrease for 16 cycles. One pt with KRAS mutant NSCLC had a 27% decrease by RECIST. One pt with CDKN2A-/- NRAS mutant melanoma had a confirmed partial response. Early clinical activity has been observed in ovarian cancer, NSCLC, breast cancer, and melanoma. Conclusions: LY2835219 shows acceptable safety and early clinical activity as a single agent for patients with advanced cancer. Clinical trial information: NCT01394016.
Phase I study of REGN421 (R)/SAR153192, a fully-human delta-like ligand 4 (Dll4) monoclonal antibody (mAb), in patients with advanced solid tumors.
Authors: Jimeno Antonio , LoRusso Patricia , Strother Robert Matthew , Diamond Jennifer Robinson , Plato Leah , Younger Anne , Messersmith Wells A. , Kittaneh Muaiad , Sawyer Doug , Adriaens Lieve , Liu Liming , Kao Richard J. , DiCioccio A Thomas , Brownstein Carrie M. , Lowy Israel , Trail Pamela , Chiorean E. Gabriela 
Published: March 2020

2502 Background: Dll4, a Notch receptor ligand, may have a role in tumor angiogenesis and is an emerging anticancer target. REGN421 (R) is a fully human IgG1mAb that binds human Dll4 and disrupts Notch-mediated signaling. Methods: Primary objectives of the dose escalation (3+3 design) trial were to determine safety and a recommended phase II dose (RP2D) of R in patients (pts) with advanced cancer. R was given IV at doses of 0.25, 0.5, 1, 2 and 4mg/kg every 3 weeks (Q3W) or 0.75, 1, 1.5, and 3mg/kg every 2 weeks (Q2W). Secondary objectives were PK, immunogenicity, and antitumor activity. Results: 53 pts (M/F=22/31, ECOG 0/1=18/35) were enrolled; 31 pts were treated Q3W at doses of 0.25 - 4 mg/kg; 22 pts were treated Q2W at doses of 0.75 - 3 mg/kg. Two DLTs occurred: Grade 3 (Gr3) nausea (0.5mg/kg Q3W) and Gr3 abdominal pain (1 mg/kg Q2W). A maximum tolerated dose was not reached on either schedule. Grade 3/4 AEs occurred in 29 pts; nausea, abdominal pain, dyspnea, hypoxia, and hypertension (HTN) were reported in ≥ 5%. Most frequent treatment related AEs were fatigue (30%), headache (26%), HTN (26%), and nausea (15%). Six treatment related SAEs (all reversed off treatment) were reported in 4 patients: BNP increase (0.25mg/kg, Gr1), troponin I increase (4mg/kg, Gr3), right ventricular dysfunction (1.5mg/kg, Gr3), left ventricular dysfunction (3mg/kg, Gr3) and 2 events of pulmonary HTN (1.5mg/kg, Gr 3, and 3mg/kg Gr3). Laboratory abnormalities (≥ Gr3) were neutropenia (3) and anemia (2), and elevated ALP (7), ALT (3), bilirubin (3), AST (2), and decreased albumin (1). Anti-tumor activity included 2 PRs (NSCLC BAL-type with a beta-catenin mutation and ovarian cancer [OvCa]), and 16 pts with SD (3 pts had SD > 6 months). Two of 8 pts with OvCa had CA125 responses. R had non-linear target-mediated PK without accumulation. The half-life of R at 3mg/kg Q2W was 7 days. No immunogenicity was observed. Conclusions: REGN421 had an acceptable safety profile, and RP2Ds of 4mg/kg Q3W and 3mg/kg Q2W. Responses and prolonged SD were noted in OvCa pts and other solid tumors. Dose escalation has concluded and disease specific expansion cohorts are ongoing. Clinical trial information: NCT00871559.
Phase I study of oral selective c-Met inhibitor EMD 1214063 in pts with advanced solid tumors.
Authors: Falchook Gerald Steven , Hong David S. , Amin Hesham M. , Fu Siqing , Piha-Paul Sarina Anne , Janku Filip , Subbiah Vivek , Naing Aung , Wheler Jennifer J. , Klevesath Manfred B. , Köhler Karola , Johne Andreas , Bladt Friedhelm , Kurzrock Razelle 
Published: March 2020

2506^ Background: To perform the first-in-human study of EMD 1214063, a highly selective, reversible, ATP-competitive c-Met inhibitor that causes growth inhibition and regression of hepatocyte growth factor-dependent and -independent tumors in preclinical models. Methods: Primary objective of this dose-escalation study (3+3 design) was to establish the EMD 1214063 MTD (NCT01014936). Secondary endpoints included safety, PK, antitumor effect, and pharmacodynamics (Pd). Eligible pts had advanced solid tumors not amenable to standard therapy. Pts received once daily (QD) oral EMD 1214063 on 1 of 3 regimens (all 21-d cycles): d 1–14 followed by 7-d rest (R1), continuous 3 times weekly (R2), or d 1–21 (R3). An optimized formulation (OF) was introduced in Aug 2011. Results: 100 pts were treated (R1:42; R2:41; R3:17). On the initial formulation, doses were escalated from 30–230 mg/d in R1, and 30–115 mg/d in R2. OF data are available for 30–400 mg/d in R1, 60–175 mg/d in R2, and up to 500 mg/d in R3. Cmax and AUC increased with dose; OF showed higher bioavailability. 4 pts experienced DLTs: G4 lipase and G3 amylase increase (R1; 115 mg/d), G3 lipase increase (R2; 60 and 115 mg/d), and G3 nausea and vomiting (R2; 130 mg/d OF). Other G3 drug-related AEs included G3 peripheral edema (1 pt in R3, 300 mg/d OF). G2 drug-related AEs (R1-3) included fatigue (n=8), lipase increase (n=3), nausea (n=2), decreased appetite (n=2), vomiting (n=2), and neutropenia (n=2). 80% pts had no drug-related AE >G1. Pre- and on-treatment tumor biopsies showed inhibition of phospho-c-Met levels in 13/15 evaluable pts. 2 unconfirmed partial responses were observed (NPC and NSCLC). SD >4 mo was observed in 15 pts. 1 pt with sarcomatoid bladder cancer and multiple MET copies due to Chr 7 polysomy had SD for >32 mo. PK/Pd analysis suggested that 500 mg QD was sufficient for target inhibition, consistent with preclinical models. In the 500 mg QD cohort, which was expanded to 12 pts, no DLTs were observed. 500 mg QD was confirmed as the recommended phase 2 dose (RP2D). A formal MTD was not identified despite dose escalation beyond 500 mg. Dose escalation above 1000 mg is not anticipated. Conclusions: EMD 1214063 was safe and demonstrated antitumor activity. 500 mg QD was determined as the RP2D. Clinical trial information: NCT01014936.