bluuebunny/crossref_metadata_2025_split huggingface dataset:
Unexpected germline mutations in a pan-cancer analysis including sarcoma, renal, and other cancers.
Authors: Yang Shan , Michalski Scott T. , Holle Jennifer , Ekstein Tali , O'Leary Erin , Pardo Carolina , Heidari Nastaran , Anderson Michael , Ouyang Karen , Nussbaum Robert L. , Lincoln Stephen E , Esplin Edward D. 
Published: September 2018

1584 Background: Multi-gene testing for cancer predisposition is increasingly utilized in clinical care. Although the diagnostic yield and management implications of such testing in breast, ovarian and colorectal cancer are relatively well understood, data for other cancer types are still emerging. In this study we retrospectively examined 39,147 patients referred for hereditary cancer syndrome testing for pathogenic germline variants in 80 cancer risk genes, focusing on those patients with renal, sarcoma, paraganglioma, melanoma, and pancreatic cancers. Methods: Test results and personal/family history were extracted from a sequential series of de-identified clinical test reports. Data for genes not clinically ordered were analyzed under an IRB approved research protocol. Common low penetrance risk alleles were excluded. Results: Overall, 14.3% (5,589) of patients carried germline pathogenic mutations in 80 cancer risk genes. Of the 949 patients with renal cancer 20% (190) were positive, and 44% of these findings were “unexpected”, meaning they appeared in genes that are not commonly requisitioned in renal cancer patients. Of the 423 sarcoma patients, 16% (68) had positive findings, 45% of which were “unexpected”. For both cancer types, greater than 90% of these “unexpected” findings were in genes with published management recommendations. Similar results were observed in melanoma, paraganglioma and pancreatic cancer patients. A second or third pathogenic variant, many of which were also “unexpected”, were found in 3.6% of positive cases. Conclusions: In this series of patients we estimate almost 12% of pathogenic variants across cancer indications are “unexpected”. These data suggest many actionable pathogenic variants are being missed due to adherence to overly restrictive, narrowly constructed tumor-specific panels. Clinicians should expand the scope of their test panels in order to capture variants with the potential to impact patients and their family members by informing implementation of established management guidelines.
A phase II trial of temozolomide (TMZ) 1 week on/1 week off as initial treatment for high risk low grade oligodendroglial tumors: An AINO (Italian Association for Neuro-Oncology) study.
Authors: Ruda Roberta , Pellerino Alessia , Franchino Federica , Pace Andrea , Carapella Carmine Maria , Dealis Cristina , Caroli Manuela , Faedi Marina , Bomprezzi Chiara , Soffietti Riccardo 
Published: September 2018

2026 Background: The efficacy of dose-dense temozolomide (TMZ, 1 week on/1 week off ) in grade II gliomas is not well known and could depend on the molecular subtype. Methods: Between 2006 and 2010 a single arm phase II study on 60 patients with grade II oligodendroglial tumors was performed. Inclusion criteria were as follows: 1) age ≥ 18 years; 2) KPS ≥ 70; 3) biopsy-proven grade II oligodendroglioma or oligoastrocytoma ; 4) a measurable residual tumor after surgery. The primary endpoint was tumor response on MRI according to RANO criteria, while the secondary endpoints were progression-free survival (PFS), overall survival (OS), and seizure control. Most patients (65%) had seizures. Molecular factors (IDH 1-2 mutations, 1p19q codeletion, MGMT methylation) were available in 49/60 patients (81.7%). The median number of cycles was 11 (2-18). Median follow up was 64 months (7-112). Results: Response rate was PR in 21/60 (35%) patients, minor PR (mPR) in 14/60 (23%), SD in 21/60 (35%) and PD in 4/60 (7%). Most patients achieved the best tumor response within 6 months after the start of TMZ. Among patients with mPR and PR, 15/49 (30.6%) were IDH1-2 mutated with a PFS of 71.4% at 36 months and 28.6% at 60 months with a median value of 46 months while 11/49 (22.4%) were IDH 1-2 wild-type with a PFS of 45.8% at 36 months and 25% at 60 months with a median value of 34 months. OS was 90.5% at 36 months and 66.7% at 60 months with a median value of 76 months in the IDH1-2 mutated/1p19q codeleted subgroup, while OS was 66.7% at 36 months and 50% at 60 months with a median value of 60 months in the IDH1-2 wild-type subgroup. Responses were higher in MGMT methylated patients. Seizure improvement was achieved in 29/34 patients (85%): 17/33 (52%) patients at 12 months and 18/29 (62.1%) at 24 months were seizure-free. Time to maximal seizure response was earlier than that observed on MRI (3 vs 6 months). Conclusions: Dose-dense TMZ has shown a significant activity in terms of tumor and seizure control, especially in IDH1-2 mutated/1p19q codeleted patients. Seizure reduction could represent an early indicator of response to chemotherapy and maybe predict the duration of response. Clinical trial information: 2007-000386-38.
Comparison of high dose methotrexate treatments in CNS lymphoma patients: The Henry Ford experience.
Authors: Selim Ranya , Philip Joyce , Donthireddy Vijaya 
Published: September 2018

2028 Background: The main backbone of therapy for CNS lymphoma involves systemic treatment with high dose methotrexate (HDMTX)-based regimens,with radiotherapy reserved only for cases that fail systemic therapy due to the significant cognitive toxicity of radiation. Over the last decade, rituximab and subsequently temozolomide were added to HDMTX chemotherapy regimens. Methods: Patients diagnosed with CNS lymphoma between 2009 and 2015 were identified. A retrospective cohort study was conducted of patients who received HDMTX alone (Cohort A), HDMTX and rituximab (Cohort B) and HDMTX, rituximab and temozolomide (Cohort C). Data collected included treatment related adverse events along with OS and PFS. Results: 31 patients were diagnosed with CNS lymphoma. 11, 10 and 6 patients were in cohorts A, B and C respectively. Median PFS and OS for the entire cohort were 14 and 25 months respectively. Cohort results were compared to the respective reference trials published in the literature. Cohort A had a PFS of 11 months and OS of 12 months compared to 12.8 months and 22.8+ months in the reference Phase II trial. Cohort B had a median PFS of 25+ months and OS of 41 months compared to 21 months and 33.5 months in the reference trial. Cohort C had a 2-year PFS of 0.50 compared to 0.57 in the reference trial. 3 (9.6%), 5 (16.1%), and 2 (6.4%) patients developed renal dysfunction in cohorts A, B and C respectively. 4 (12.9), 2 (6.4%), and 0 patients developed leukopenia in cohorts A, B and C respectively. 3 (9.6), 2 (6.4%), and 1 (3.2%) patients developed anemia in cohorts A, B and C respectively. 1 (3.2%), 1 (3.2%) and 1 (3.2%) patient developed thrombocytopenia in cohorts A, B and C respectively. Conclusions: The addition of Rituximab to HDMTX treatment for the treatment of CNS lymphoma increased the PFS and OS compared to HDMTX alone and is in concordance with the reference phase II trials reported in the literature if not better. In addition, our data at HFH shows no increased risk of adverse events with combination therapies compared to HDMTX alone. The addition of Temozolomide to Rituximab and High Dose methotrexate treatment showed a median 2 year PFS of 0.50 which is comparable to published reports of a 2-year PFS of 0.59.
Retrospective review of safety and efficacy of checkpoint inhibition in refractory high-grade gliomas.
Authors: Reiss Samantha , Yerram Prakirthi , Modelevsky Lisa , Grommes Christian 
Published: September 2018

2033 Background: Treatment options for refractory high grade gliomas (HGG) are limited. Programmed cell death ligand-1 (PD-L1) expression has been reported in 0-61% of HGGs and therefore might be a suitable target in HGG. The purpose of this study was to describe safety and efficacy of PD-1 inhibition in patients with refractory HGGs. Methods: This IRB approved single center retrospective study at Memorial Sloan Kettering Cancer Center included pathologically confirmed HGG with an age ≥18 years who received a PD-1 inhibitor between 9/2014 and 10/2016 outside of a clinical trial. Results: Twenty five HGGs were identified. All patients received the PD-1 inhibitor pembrolizumab (pembro) as part of compassionate use. Median age was 49 years (range 30-72); 44% were men; 13 had glioblastoma (52%), 7 anaplastic astrocytoma (28%), 2 anaplastic oligodendroglioma (8%), 2 unspecified HGG (8%), and 1 gliosarcoma (4%). Patients received a median of 4 prior lines of therapy (range 1-9). Nineteen (76%) previously failed bevacizumab. Median baseline KPS was 80 (range 50-100). Concurrent treatment included bevacizumab in 17 (68%) or bevacizumab and temozolomide in 2 (8%) patients. Median number of doses administered was 3 (range 1-14). Treatment toxicity and response was assessed in 24 patients. PD-1 inhibitor related adverse events (AEs) included LFT elevations (33%), hypothyroidism (17%), diarrhea (17%), myalgias/arthralgias (13%), and rash (8%). Other common AEs were hyperglycemia, fatigue, thrombocytopenia, lymphopenia, headache, and nausea in the setting of concomitant therapy and additional supportive care (dexamethasone). Grade 3 AEs included seizure (4%), headache (4%), nausea (4%), and vomiting (4%). Best radiographic response was partial response (n = 2), stable disease (n = 5), and progressive disease (n = 17). Median progression free survival (PFS) was 42 days (range 7-282) and median overall survival was 121 days (range 15-415). Three patients (12%) had a PFS > 90 days; of these, 2 received single agent pembro. Conclusions: Patients with HGG had low response rates. However, a small number of patients had prolonged PFS. Pembro was tolerated with few serious AEs, even in patients receiving concomitant therapy.
Clinical and molecular subgroups of ependymoma in adulthood: An analysis of the German Glioma Network.
Authors: Gramatzki Dorothee , Witt Hendrik , Hentschel Bettina , Pajtler Kristian W. , Schackert Gabriele , Westphal Manfred , Herrlinger Ulrich , Pietsch Torsten , Loeffler Markus , Reifenberger Guido , Pfister Stefan M. , Tonn Joerg , Weller Michael ,   German Glioma Network
Published: September 2018

2038 Background: Ependymoma is a subtype of glioma that is rare in adults. Its classification has remained entirely morphological until recently, and surgery and radiotherapy remain the mainstays of treatment. Here we characterized DNA methylation profiles and their clinical correlates in the prospectively assembled cohort of the German Glioma Network. Methods: The GGN cohort was screened for patients diagnosed with myxopapillary ependymoma, subependymoma, classic ependymoma and anaplastic ependymoma for whom clinical data and remaining tumor tissue were available. Tumors were subjected to DNA methylation profiling using the Illumina Infinium HumanMethylation450 BeadChip platform. Molecular data were correlated with morphological tumor and clinical patient characteristics. Results: One hundred and twenty-two ependymoma patients with available tumor tissue were identified. Each adult tumor could be assigned to one of the previously defined methylation classes of ependymoma. Molecular entities of ependymal brain tumors display distinct copy-number variations. PF-EPN-B and ST-EPN-RELA tumors tend to have a worse prognosis than other ependymal subtypes in adults. Conclusions: Molecular classification of adult ependymal methylation subclasses should be implemented in routine diagnostics. Patients with PF-EPN-B and ST-EPN-RELA subtypes might benefit from early treatment beyond surgery.
Changes in survival of primary central nervous system lymphoma based on a review of national databases over 40 years.
Authors: Mendez Joe Sammy , Quinn Ostrom T , Kruchko Carol , Barnholtz-Sloan Jill , Grommes Christian 
Published: September 2018

2040 Background: There has been significant improvement in treatment outcomes of Primary Central Nervous System Lymphoma (PCNSL) at specialized centers over past decades, and it is unclear if these changes have translated to benefits in the general population. In this study, we utilized national databases to examine survival trends over time. Methods: Incidence rates were obtained from the Central Brain Tumor Registry of the United States (CBTRUS, 2000 – 2013) and 18 Surveillance, Epidemiology and End Results (SEER, 1973 – 2013) registries. Data for survival analysis was obtained from SEER and analyzed using SEER*STAT. To focus on non-HIV-associated PCNSL, patients with “other infectious and parasitic diseases including HIV” as cause of death and follow up were excluded. CBTRUS identified 19,027 patients over 13 years and SEER 6,765 over 40 years. Results: The annual incidence of PCNSL in 2013 was 0.4 per 100,000 population (CBTRUS/SEER). Incidence increased from 0.1 per 100,000 in the 1970s to 0.4 per 100,000 in the 1980s, correlating with an increase in the diagnosis of elderly patients, ≥70 (1973:0.2 vs 2013:2.1 – SEER). Incidence rates differed greatly between young and elderly patients (20-29: 0.08 vs 70-79: 4.32 – CBTRUS). The median overall survival (mOS) of all patients is 17 months (m) with no survival benefit based on sex. Survival doubled from 12.5 m in the 1970s to 26 m in the 2010s. There was a significant difference in survival based on age: < 50: 83 m vs 50-69: 25 m vs ≥70: 6 m (p-value < 0.0001). In patients < 50, mOS increased from 35.5 m in the 1970s to 134 m in the 2000s (mOS not achieved in 2010s). In patients 50-69, mOS increased from 8 m in the 1970s to 35 m in the 2010s. However, mOS in the elderly population, ≥70, has not changed in the last 40 years (6 m in the 1970s vs 7 m in the 2010s, p-value = 0.1). Conclusions: PCNSL is a disease that more frequently affects the elderly. Although overall survival has increased over the past 4 decades, reflecting current literature in PCNSL, survival in the elderly has not changed since the 1970s. Identification of this vulnerable patient population highlights the need for clinical trials targeting the elderly in hopes of improving treatment strategies and ultimately outcomes.
Assessment of tumor hypoxia in BEV resistant GBM using FMISO 18F-PET and MRI.
Authors: Liu Yichu , Lee Eudocia Quant , Huang Shiliang , Muzi Mark , Reardon David A. , Wen Patrick Y. , Brenner Andrew Jacob 
Published: September 2018

2045 Background: Glioblastoma (GBM) is the most common malignant brain tumor in adults, and is characterized by poor survival and marked resistance to treatment. Hypoxic volume is directly correlated with poor outcome in GBM, with structural and functional tumor vasculature changes regarded as a primary driver of tumor hypoxia. As part of an ongoing clinical trial with a hypoxia activated prodrug, we sought to explore the correlation between abnormal tumor vasculature and hypoxia in bevacizumab (BEV) resistant GBM. Methods: MRI and 18F-FMISO PET scans were acquired at study entry. The MRI protocols include standard anatomical sequences as well as Dynamic Susceptibility Contrast (DSC/perfusion) imaging. Enhancing tumor ROIs were determined from Delta T1 maps, non-enhancing tumor ROIs were obtained from FLAIR images, ratio between enhancing and non-enhancing volumes were calculated, values from standardized rCBV maps were extracted from corresponding enhancing ROIs. Decay correction was applied to18F-FMISO images and converted to SUV units. After registration to MR images, cerebellar regions were used as surrogates for blood activity. The FMISO images were then normalized to generate tissue to blood ratio (TB). A threshold of TB > 1.2 was used in discriminating the hypoxia volume (HV). Correlation between parameters was assessed using Pearson correlation. Results: 7 patients from University of Texas Health Science center and 7 patients from Dana-Farber Cancer Institute had evaluable MR and PET imaging. We compared MRI parameters (enhancing and non-enhancing tumor volumes, srCBV) with hypoxia (HV and maxSUV). There was a positive correlation between HV and enhancing volume (R = 0.732, p = 0.0029) as well as between HV and ratio (R = 0.644, p = 0.013. The correlation between other pairs were not statistically significant (HV vs srCBV: p = 0.862, T1 vs maxSUV p = 0.492, srCBV vs maxSUV: p = 0.393, ratio vs maxSUV = 0.178). Conclusions: The hypoxic volume following bevacizumab failure correlates with both the volume of enhancement and the fraction of enhancement within the mass. The clinical implications of this is being assessed in an ongoing phase 2 study. Clinical trial information: NCT02342379.
A two-part safety and exploratory efficacy randomized double-blind, placebo-controlled study of a 1:1 ratio of the cannabinoids cannabidiol and delta-9-tetrahydrocannabinol (CBD:THC) plus dose-intense temozolomide in patients with recurrent glioblastoma multiforme (GBM).
Authors: Twelves Chris , Short Susan , Wright Stephen ,   Cannabinoid in Recurrent Glioma Study Group
Published: September 2018

2046 Background: Several plant-derived cannabinoids have shown efficacy in animal models of GBM, particularly when co-administered with temozolomide, a commonly-used treatment in both primary and recurrent disease. Methods: We conducted a two-part study in patients with recurrent GBM following standard chemo-radiotherapy treatment as described by Stupp et al. In Part 1 of the study, 6 patients were treated to an MTD of 1:1 CBD:THC oro-mucosal spray, as an adjunct to dose-intense temozolomide (DIT), to assess the safety of the combination. Part 2 was a double blind, randomized, placebo-controlled study in a planned 20 patients receiving either their individualized dose of 1:1 CBD:THC or placebo plus DIT. The primary endpoint was tolerability of 1:1 CBD:THC plus temozolomide. Results: There were no Grade 3 or 4 toxicities in Part 1 of the study. In Part 2, 12 patients were randomized to CBD:THC and 9 to placebo. Mean age was 58 years in both treatment groups, but there were more males in the placebo group (5 of 12 and 8 of 9, respectively). Baseline median Karnofsky score was 90 in both groups and median time from diagnosis of recurrence to start of treatment (day 1) was similar (3.6 and 3.0 weeks in the CBD:THC and placebo group, respectively). The median number of days of dosing with CBD:THC or placebo was similar (155 days [range: 50-356] and 134 days [range: 13-359]). Median survival in the placebo group was 369 days, and > 550 days in the CBD:THC treatment group (NS) and 1 year survival was 83% and 56% in the CBD:THC and placebo groups, respectively (p = 0.042). PFS6 was 42% in the CBD:THC group and 33% in the placebo group (NS). Overall, the commonest treatment related toxicities were dizziness (in 11/18 patients) and nausea (in 7/18 patients). Results of biomarker analyses are awaited. Conclusions: This randomized study provides preliminary evidence that 1:1 CBD:THC offers some efficacy in patients with recurrent GBM when used as an adjunct to dose-intense temozolomide and confirms the safety and feasibility of individualized dosing. Clinical trial information: NCT01812603.
Bevacizumab (Bev) to reduce the negative impact of glioblastoma (GBM) tumor size on survival from first recurrence.
Authors: Nguyen Huy Tram N. , Liu Liang Yen , Nguyen Nhung T , Lenchner Daniel , Dovek Laura , Harris Robert J. , Ellingson Benjamin M. , Ozer Byram H , Ravelo Arliene , Sommer Nicolas , Sim Myung Shin , Elashoff Robert M. , Green Richard M. , Nghiemphu Phioanh Leia , Cloughesy Timothy Francis , Lai Albert 
Published: September 2018

2052 Background: Bev was FDA approved for recurrent GBM in 2009. However, the survival benefit from Bev in GBM remains to be demonstrated. Methods: We retrospectively identified 168 primary GBM patients diagnosed between 2001-2015 at UCLA and Kaiser Permanente LA, who received upfront radio-chemotherapy, followed with Bev and/or Lomustine (CCNU) at 1st recurrence. We measured tumor size at 1st recurrent treatment initiation, using bi-dimensional (2D) and volumetric (3D) techniques. We analyzed overall survival (OS) from 1st recurrence by Kaplan-Meier analysis. Results: Three groups of patients diagnosed from 2009-2015 were identified: patients treated with Bev alone (n = 49), CCNU alone (n = 36), and concurrent Bev/CCNU (n = 53). Patients were statistically different in performance status at 1st recurrence and tumor size; the CCNU alone group had smaller tumor sizes at diagnosis compared to the Bev groups. The CCNU group showed substantially greater survival (median OS (mOS) = 14.1 mo) compared to the Bev and Bev/CCNU groups (mOS = 6.9 and 7.1 mo, respectively), which may be explained by the imbalance in tumor sizes among the groups, and high rate of crossover (69%) to Bev in subsequent recurrences. To minimize selection bias, we identified another control group (n = 30) diagnosed from 2001-2004 who received CCNU only (CCNU 01-04). These patients had tumor size and KPS more comparable to both Bev groups, and a low rate of crossover (7%). OS for CCNU 01-04 (mOS = 5.7 mo) was similar to the Bev groups. Across all patients, we observed poor OS associated with larger 2D size vs. those with small tumors (mOS = 6.7 vs. 8.8 mo; p = 0.003). In separate stratification of each treatment group by tumor size, this association was retained in the CCNU 01-04 group (mOS = 4.0 vs. 8.4 mo, p < 0.001), but not in either Bev (mOS = 6.7 vs. 7.3 mo) or BEV/CCNU (mOS = 7.0 vs. 8.8 mo). Analysis of effect of tumor size by 3D measurement yielded similar results. Conclusions: Bev appears to reduce the negative impact of large tumor size on GBM patient survival from 1st recurrence. 2D and 3D measurements were correlated, suggesting the adequacy of use of conventional tumor bi-dimensional measurement to predict benefit of Bev in patients based on tumor size.