bluuebunny/crossref_metadata_2025_split huggingface dataset:
BRAFv600e mutated gliomas: From biology to radiology and treatments.
Authors: Lhermitte Benoit , Guerin Eric , Chammas Agathe , Namer Izzie Jacques , Gauchotte Guillaume , Kremer Stephane , Roques Gaelle , Chenard Marie Pierre , Dontenwill Monique , Entz-Werle Natacha 
Published: May 2019

e13552 Background: BRAF V600E mutation is encountered in brain tumor, mostly low grade pediatric diffuse glioma (LGG) and epileptogenic glioneuronal tumor such as gangliogliomas (GG) or pleomorphic xanthoastrocytomas (PXA). Less frequently this mutation is present in high grade glial or glioneuronal tumors such as pleomorphic xanthoastrocytomas with anaplasia, anaplastic ganglioglioma, anaplastic diffuse astrocytomas or glioblastomas. Recently, few publications were highlighting differently the impact of BRAF mutation and CDKN2A deletion, as independent prognostic factors linked to a worst outcome in low grade forms. Methods: We studied retrospectively a monocentric cohort of 12 LGGs and 9 HGG with BRAFv600e positivity. The patients were aged from 1 to 47 years. Most of the LGG were under 25 years and only 3 patients with HGGs had less than 18 years old. We focused on extended biology assessment by Next generation sequencing of the tumors and their relapses, tumor metabolomics analyses, radiology comprising MRI, PET-scanning and spectroscopy and correlate them to tumor’s evolution and its treatment. Results: Among the LGGs, we had 9 GG and 3 pilocytic astrocytomas and only one had a CDKN2A deletion and one a gain on chromosome 5. 6 had a complete surgical resection, 2 had a minimal residue and 4 had chemotherapeutic treatment after partial surgery and underwent relapses. All HGGs had a surgical resection followed by chemotherapy (mainly Stupp protocol) and radiotherapy. 5 relapsed rapidly, benefit from targeted therapy with vemurafenib and are still in long term remission. In this HGG group, we had two subgroups: 4 patients with “de novo” tumors and 5 patients with a past history of LGG tumors in the same brain region. Both were responding well to targeted treatments and all had an additional CDKN2A deletion. Specific radiological and spectroscopic signs were linked to those two groups and seem to be associated to a specific metabolomic profile in each group. Currently, we are going further in the correlation between MAPK signaling pathway and metabolomic profile to be able to predict in LGG their potential evolution. Conclusions: BRAF mutated gliomas seem to have specific radiological and metabolomic correlations associated to their biology
A critical appraisal of the quality of glioma imaging guidelines using the AGREE II tool: A EuroAIM initiative.
Authors: Bisdas Sotirios , Romeo Valeria , Stanzione Arnaldo , Ugga Lorenzo , Cuocolo Renato , Cocozza Sirio , Brunetti Arturo , Shaikh Faiq , Roettger Diana 
Published: May 2019

e13553 Background: Following the EuroAIM initiative to assess the quality of medical imaging guidelines by using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument, we aimed to evaluate the quality of the current imaging guidelines in patients with gliomas. Methods: A literature search was conducted to identify eligible imaging guidelines considered in the management of adult patients with gliomas. The selected guidelines were evaluated using the AGREE II instrument by four independent appraisers. The agreement among the four appraisers was estimated using the intraclass correlation coefficient (ICC) analysis. Results: Seven guidelines were selected for the appraisal. Six out of the seven guidelines showed an average level of quality with only one showing a low quality. The highest scores were found in Domain 1 “Scope and purpose” (mean score = 81.2%) and Domain 4 “Clarity of presentation” (mean score = 77.6%). The remaining domains showed a low level of quality and, in particular, Domain 5 “Applicability” was the most critical with a mean score of 41.7%. The ICC analysis showed a very good agreement among the four appraisers with ICC values ranging from 0.907 to 0.993. Conclusions: The available guidelines on glioma imaging emerged as of average quality according to the AGREE II tool analysis. Based on these results, further efforts should be made in order to involve different professional bodies and stakeholders and increase patient and public involvement in any future guideline drafting as well as to improve the applicability of these guidelines into the clinical practice.
Exploiting metabolic susceptibilities in glioblastoma via glycolytic inhibition and ketogenic therapy.
Authors: Vallejo Frederic Anthony , Shah Sumedh , Walters Winston , Kostenko Katrina , Torrens Ingrid , Prince Jeffrey , Raez Luis E. , Khatib Ziad , Vanni Steven , Graham Regina M. 
Published: May 2019

e13558 Background: Glioblastoma (GBM) remains one of the most lethal primary brain tumors in children and adults. Despite enormous efforts to elucidate the genetic and epigenetic drivers of this disease, the prognosis for patients diagnosed with GBM remains dismal. Because tumor cell metabolism differs greatly from that of normal non-cancerous cells, it is possible to develop therapies which more effectively target the cancer cell while sparing normal cells. Growing in popularity is the ketogenic diet, which is a high fat, very low carbohydrate diet resulting in the production of ketone bodies, acetoacetate (AA) and β-hydroxybutyrate (βHB) to generate ATP. Methods: Analysis conducted by open-access GBM patient database, mts assay, Western blot, neurosphere assay, and TEM. Results: Enzymes required for ketone metabolism (BDH1 and OXCT1) were significantly downregulated in GBM while glycolytic enzymes were significantly upregulated (HK2, HK1, SLC2A3, NAMPT, G6PD). GBM stem cell (GSC) markers (CD44, STAT3) positively correlated with glycolytic enzymes. Ultrastructural analysis of GSCs indicated that about half of the mitochondria were missing cristae, highly suggestive of an increased glycolytic dependency. Treatment of patient-derived GSC lines as well as non-stem cell lines SJGBM2 (pediatric) and U87 (adult) resulted in a dose-dependent decrease in viability in response to the glycolytic inhibitor 2-deoxy-D-glucose (2-DG). When cells were exposed to ketone bodies, AA but not βHB induced a dose-dependent decrease in cell viability with 10 mM reducing viability ranging from 20-80% of non-treated controls. Western blot analysis demonstrated robust caspase activation and PARP cleavage in response to AA. Furthermore, AA significantly reduced GSC neurosphere formation at 2.5 mM suggesting inhibition of GSC self-renewal pathways. Combined treatment of low dose 2-DG (50 μM) with increasing concentrations of AA resulted in more cell death than either treatment. The effect was more than additive at the low concentrations of AA (1- 5 mM) suggesting synergy. Conclusions: Glycolytic inhibition in conjunction with the ketogenic diet may be a promising therapeutic route for this difficult-to-treat cancer.
Low platelet counts in patients with glioblastoma.
Authors: Ali Assad , Barnett Addisson , Saeed Bamashmos Anas , Li Hong , Wei Wei (Auston) , Sagar Soumya , Barnett Gene H. , Angelov Lilyana , Mohammadi Alireza Mohammad , Peereboom David M. , Stevens Glen , Suh John H. , Yu Jennifer S. , Murphy Erin Sennett , Ahluwalia Manmeet Singh 
Published: May 2019

e13565 Background: Radiotherapy and concurrent chemotherapy with Temozolomide (TMZ) have myelosuppressive effect, and thrombocytopenia is commonly seen in this patient population seen in 5-10% of glioblastoma (GBM) patients. There is a lack of data analyzing the thrombocytopenia and it’s on the progression free survival (PFS) or overall survival (OS) of these patients. The primary objective of this study was to identify the degree of thrombocytopenia in newly diagnosed GBM patients receiving concurrent TMZ based chemoradiation (CRT). Secondary objectives included associations between thrombocytopenia PFS, and OS. Methods: We retrospectively reviewed 484 newly diagnosed GBM patients who underwent surgery followed by standard of care CRT. We also analyzed the association between platelet counts and age, sex, MGMT methylation status, and extent of surgical resection. Platelet count was collected at the time of surgery, CRT start date, and two, four, six, and ten weeks post-CRT start date. Patients were grouped into quartiles according to their platelets count. Results: Of the 484 patients collected, 308 were males, 139 had gross total resection of the tumor, 229 patients were older than 65 years, and 171 (42.1%) were MGMT methylated. In a univariate analysis, a platelet count less than 180,000 (lowest quartile) was associated with higher mortality (HR 1.63, P < 0.001) but had no significant association with PFS (HR 1.16, P = 0.48). Among the 118 patients who had platelet count lower than 180,000, 4 had platelets count less than 100,000 necessitating their TMZ to be stopped during CRT. In a multivariate analysis model adjusting for age, gender, MGMT status, and type of surgery, platelet counts less than 180,000 was also associated with significantly higher mortality (HR 1.60, P < 0.001). Conclusions: Our study concluded that patients who had platelet counts less than 180,000 at the time of surgery or CRT with TMZ had significantly higher mortality (HR 1.60, P < 0.001) but had no association with PFS (HR 1.16, P = 0.48).[Table: see text]
Using PIK3CB and connexin-43 inhibition to sensitize pediatric glioblastoma cells to temozolomide.
Authors: Shah Farah , Sheng Zhi 
Published: May 2019

e13572 Background: Glioblastoma (GBM) is one of the most common high grade gliomas in pediatric patients, accounting for 2.8% of central nervous system tumors. Standard of care for glioblastoma includes surgical resection, radiation, and temozolomide chemotherapy. However, many pediatric patients are not suitable candidates for surgery, and their tumors inevitably develop temozolomide resistance. Despite aggressive treatment, temozolomide (TMZ) resistance leads to tumor recurrence in 90% of patients. Thus, outcome for children with pediatric GBM remains poor with a 2-year survival rate ranging from 10-30%, highlighting the need for new therapeutic approaches. Connexin-43 (Cx43) and PIK3CB are proteins involved in conferring temozolomide resistance in glioblastoma. Combined inhibition of these proteins could improve temozolomide sensitivity and help develop a selective therapy that significantly improves quality of life and prognosis in pediatric glioblastoma patients. Methods: Primary GBM cells were plated in a 96-well plate and treated with vehicle (DMSO), TMZ (50 μmol/L), TGX-221 (20 μmol/L), αCT1 (30 μmol/L), or a combination of the latter three drugs. Cell viability was measured using the MTS assay. Primary pediatric GBM cell lines SJ-GBM2 and CHLA-200 were tested. These drug combinations were also tested in normal human astrocytes to make sure there were no off-target effects. Results: We found that targeting PIK3CB and Cx43 in primary pediatric GBM increases their sensitivity to TMZ. The triple combination of TMZ, TGX-221, and αCT1 significantly decreased cell viability than each drug alone while sparing normal human astrocytes. Conclusions: Our findings suggest that inhibiting PIK3CB and Cx43 enhances therapeutic response to TMZ and limits off-target effects in pediatric GBM. These findings closely mirror our results using the triple combination in adult glioblastoma as well, thus laying the groundwork for a novel combination therapeutic that can be used across age groups.
Study of a smartphone-based symptom assessment (OurBrainBank) for subjects with glioblastomas.
Authors: Morris Jessica , Hellman Bruce , Duprey Kelli , Ellen Jacob , Nayak Lakshmi , Iwamoto Fabio 
Published: May 2019

e13574 Background: Self-reports from patients done monthly or every few months in the doctor’s office have several limitations, including poor recall, under- or over-reporting of events, among other biases. Methods: We developed a glioblastoma specific app (OurBrainBank) using a platform designed by uMotif, which was previously used in other conditions but has been customized for glioblastoma. All data are sent to a HIPPA compliant database. The subject can view or export their own data as well and create data reports to their medical team. Inclusion criteria included age 18 years or older, diagnosis of glioblastoma, English-speaking subject, and availability of a smartphone or tablet. After electronic informed consent, patients completed baseline questionnaires about their treatment and validated surveys (EORTC-QLQ, EORTC-BN20). Certain parameters such as sleep quality, exercise, mood, and fatigue were captured for all patients. In addition, patients picked 6 additional symptoms most relevant to their clinical condition. Results: Since the study was IRB-approved and the app made available free of charge on app stores, there have been 305 individual patients who registered on this app. Recruitment has relied heavily on social media and patient run online support groups. The most commonly tracked symptoms were exercise, fatigue, mood, sleep quality, appetite, memory and concentration. Patients were alerted to capture symptoms at least weekly and more than 5,000 datapoints were captured. The median age was 48 (18-83). 53% of patients had received the GBM diagnosis < 1 year and 25% between 1-2 years. Most patients found symptom tracking useful (average rating of 7 in 0-10 scale). Conclusions: At this initial stage, OurBrainBank has shown that it can efficiently collect glioblastoma patients’ symptoms. In the next steps, we plan to collect passive data from smartphones and other device trackers. Additionally, OurBrainBank will enable patients to donate their medical records to a national and international database. The goal over the next few years is to create an unprecedented database of high quality and granularity with tens of thousands of de-identified glioblastoma patients, with open-access to qualified academic researchers. In addition, this powerful ‘real world experience’ database will be useful for pharma/biotech companies.
Access to clinical trials, multidisciplinary environment, and health care providers by facility type and outcomes of patients with newly diagnosed glioblastoma using SEER-Medicare dataset.
Authors: Zhu Ping , Du Xianglin L. , Esquenazi Yoshua , Zhu Jay-Jiguang 
Published: May 2019

e13576 Background: Prior studies demonstrated the superior outcomes among glioblastomas patients treated at academic facilities (ACs) verses non-academic facilities (non-AC). However, the factors contributed to the survival benefit observed at ACs remain unknown. Methods: Eligible GBM patients between 2004 and 2014 were derived from the SEER-Medicare database. Patients were categorized by treatment facility status (AC versus non-AC). Outcomes include overall survival (OS) and the receipt of surgery and adjuvant therapies. Kaplan-Meier and Cox proportional hazard model were applied for survival analysis, and multivariable binary/multinomial logistic regression models were performed to compare differences in treatments received and hospital characteristics by facility type. Results: A total of 3263 patients treated at 562 facilities were included. Significantly superior survival was observed at ACs [Hazard ratio (HR): 0.92, 95% CI: 0.85-0.99, P = 0.024], prior to and after adjusting all covariates. Radiation and chemotherapy were utilized more frequently at ACs. For the access to clinical trials, ACs were more likely to be NCI designated cancer center, Radiation Therapy Oncology Group (RTOG), and American College of Surgeons Oncology Group (ACSOG) compared to non-ACs (all P < 0.001). For multidisciplinary resources, ACs had higher probability to provide health care services in emergency, intensive care, inpatient care, nuclear medicine, operative room, and radiation treatment than non-ACs (all P < 0.01). Further, there were more sufficient health care provider resources (number of full-time registered nurses, physicians, and total beds) at ACs over non-ACs (all P < 0.001). Conclusions: This study identified factors that contributed to the superior outcomes when GBM patients are treated at ACs. An increased likelihood of undergoing adjuvant therapies, access to clinical trials, multidisciplinary environment, and available health care provider resources in ACs are important contributors to the improved GBM outcomes.
Single center, open and prospective evaluation of genomic sequencing on cerebro-spinal fluid, brain metastatic lesions and plasma from patients in non-small cell lung cancer with brain metastasis.
Authors: Ma Chunhua , Huang Chuoji , Li Zhi , Jiang Rong , Zhang Juncheng 
Published: May 2019

e13578 Background: Leptomeningeal metastases are observed in 9.4% non–small Cell Lung Cancer (NSCLC) patients with EGFR mutations. Depending on patient specific gene mutations, tumor cells may also have different proliferative activity, leading to differential metastatic potential. However, the clinical significance of observed gene mutation differences between CSF, plasma, primary pulmonary tumor and metastatic brain tumor samples remains unclear and should be further explored. Methods: From Apr. 2018 to Jan. 2019, plasma and CSF paired samples were drawn from consented NSCLC patients with diagnosed brain metastasis. Of these 21, brain lesion samples were obtained from 5 patients. All the samples were tested by next-generation sequencing. Patients were treated based on the detection results. Results: For this cohort, the detection rate of EGFR mutations in CSF cfDNA versus plasma cfDNA/CTC was 57.1% and 23.8% respectively (p < 0.05). For patients who had not received tyrosine kinase inhibitor (TKI) therapy, the CSF cfDNA EGFR mutation results were consistent with results for plasma, brain lesion and primary tumor samples. Conversely, for patients who had received TKI therapy, EGFR mutations detected in CSF were consistent with those from brain samples, but different from those observed in plasma or primary tumor samples. A high response rate (ORR, 70%; DCR, 90%) was observed in patients with EGFR positive detected in CSF after treatment with second orthird-generation TKI. Among the EGFR mutations detected in CSF, the EGFR uncommon mutation frequency was 58.3%(7/12), including G7I9A/L861Q/L703P/R776H/G575R/T790M 85.7% (6/7) of these occurred in LM patients. One patient who progressed from BM to LM had an uncommon mutation in the CSF sample. Among these five patients with EGFR G719A or L861Q positive and T790M negative, 4 patients had PR and 1 patient had SD after the second-generation TKI therapy. Conclusions: Differences in EGFR gene mutations were observed between CSF, plasma, primary pulmonary lesion and brain tissue samples in NSCLC patients with diagnosed brain metastasis after TKI therapy. The reasons for this discrepancy remain to be understood. Nevertheless, CSF may be a useful prognostic tool for patient monitoring and metastasis risk evaluation. The detection of uncommon EGFR mutations may increase the risk of LM in NSCLC patients. Clinical trial information: ChiCTR1800017499.
Effect and utility of targeted and immune therapy as single agent treatment for brain metastases in patients with non-small cell lung cancer.
Authors: Shalabna Hassan , Lokiec Alejandro , Haim Nissim , Wollner Mira 
Published: May 2019

e13581 Background: Brain metastases are estimated to occur in approximately 30% of patients with metastatic non-small cell lung cancer (NSCLC). Patients with brain metastases experience significant morbidity, often with neurological dysfunction and cognitive impairment. While brain radiation therapy was the foundation of management, it is associated with delays in systemic drug therapy and neurocognitive impairment. The use of immunotherapy or targeted therapy (TKIs) in well-selected patients may be effective in all tumor sites, including the central nervous system with a low toxicity profile.Therefore, this study aims to examine the clinical and radiological effect and efficacy of biological treatment or immunotherapy on brain metastases in patients with NSCLC and to present a new therapeutic approach. Methods: This retrospective/prospective study includes all patients referred to Oncology department- Rambam Medical Center from Oct. 2008 till Jul. 2016, and prospective for one year started from 01 Aug. 2016. The patients were diagnosed with NSCLC with brain metastases, and treated with immunotherapy or targeted therapy as single agent without radiotherapy. Treatment response was defined as symptomatic improvement and/or radiologic regression. Results: Overall, 16 patients were included. 12 patients (75%) with EGFR mutation or ALK TRANSLOCATION. 11 patients were treated with targeted therapy, and 5 were treated with immunotherapy. 7 patients (43%) had neurological symptoms and 5 of these had clinical response lasted 3 to 11 months. Of the 11 patients receiving biological therapy, 9 (82%) had a good response with tolerable treatment. Of the 5 patients treated with immunotherapy, 2 patients had a radiologic response. 6 patients with no smoking history had EGFR mutation or ALK TRANSLOCATION and received biological therapy, all of them had radiologic response, accounting for 55% of the total of patients who responded. However, only 5 out of 10 patients who are active smokers or had smoking history, had a response. This implies that all patients who did not respond to the treatment are either current or past smokers. (P = 0.09). There was no difference in response to targeted therapy or immunotherapy in patients who received brain radiation therapy in the past compared to patients who were not radiated previously. Conclusions: There is an intracranial effect of targeted therapy or immunotherapy in NSCLC patients. These treatments can delay or prevent radiation therapy to the brain and all its related neurological damage.
Molecular profiling using the 92-gene assay for tumor classification of brain metastases.
Authors: Brenner Andrew Jacob , Collazo Raul , Schnabel Catherine A. , Greco F Anthony 
Published: May 2019

e13583 Background: Nearly 200,000 patients are diagnosed with brain metastases in the US annually. Advances in targeted therapies make definitive diagnosis of the primary tumor type important but can be challenging in many patients. The 92-gene assay is a validated gene expression classifier of 50 tumor types/subtypes for patients with uncertain diagnoses. Results from a clinical series of brain biopsies and potential impact on treatment were evaluated. Methods: An IRB-approved, de-identified database of clinical and molecular information from biopsies (N = 24,486) submitted for testing with the 92-gene assay (CancerTYPE ID, Biotheranostics, Inc.) as part of routine care were reviewed. Descriptive analysis included patient demographics and molecular diagnoses. Results: Analysis included 464 brain biopsies. A molecular diagnosis was provided in 433 (93.3%) tested ( < 5% assay failure rate) with 24 different tumor types. Six primary tumor types made up the majority (67.4%) with almost one-third of the molecular predictions being Lung (31.2%), followed by Neuroendocrine (NET) (9.9%), Sarcoma (7.9%), Skin (6.4%), Gastroesophageal (6.2%), and Urinary bladder (5.8%). All of these 6 tumor types, for which activity in the CNS has been documented, have immune checkpoint inhibitors or other targeted therapies approved in selected cases by the US Federal Drug Administration (FDA) (Table). Conclusions: Molecular classification of brain metastases can identify distinct tumor types for which there are FDA approved targeted medications. Improving diagnostic precision with the 92-gene assay helps identify a subset of therapy-responsive metastatic brain tumors, thus improving therapy and possibly providing better outcomes and survival. [Table: see text]