bluuebunny/crossref_metadata_2025_split huggingface dataset:
Male gender is associated with seizure risk in low-grade glioma (LGG) patients.
Authors: Jo Jasmin , Nevel Kathryn Sara , Sutyla Ryan , Smolkin Mark E , Lopes M. Beatriz , Schiff David 
Published: May 2019

e13520 Background: Up to 90% of LGG patients present with seizures, but the risk of developing seizure is not known. Our goal was to determine the association between clinical and molecular factors with seizure incidence in LGG patients. Methods: Retrospective study from 2/2002-1/2015 involving 291 patients ≥18 years old, with diagnosis of WHO grade II glioma. Intractable seizure was defined as patients needing ≥2 anti-epileptic drugs. Chi-square tests of association were used to test for associations between factors and outcome measures. Results: Study population was 54% men, median age of 51, with oligodendroglioma (47%), oligoastrocytoma (25%), astrocytoma (21%), NOS (7%). Among patients with molecular testing (87%), 32% had IDH mutation (IDHmt) and 1p/19q co-deletion, 37% IDHmt and 1p/19q intact and 18% IDH wildtype LGG. Sixty-eight percent of patients had seizures prior to LGG diagnosis; 41% intractable seizures. A trend toward higher incidence of pre-operative seizure was observed in IDHmt LGG patients (p = 0.09). On univariate analysis (Table), oligodendroglioma was significantly associated with a higher risk of intractable seizures. Male gender was strongly associated with the risk of seizure at presentation, seizure development after surgery, and intractable seizures. Conclusions: Consistent with historical data, the majority of our patients presented with seizure; oligodendroglioma with higher risk of intractable seizures. Unexpectedly, gross resection did not favorably predict seizure outcome, possibly due to our small study population. Our study only showed a trend towards higher seizure occurrence in IDHmt LGG patients. Our finding of association between male gender and seizure risk in LGG patients mirrors that of Pallud et al (Brain 2014) and warrants further investigation into the possible molecular basis of sex differences in epileptogenesis in LGG.[Table: see text]
Potential biomarkers for targeted and immunotherapy in gliomas.
Authors: Wu Jun , Chen Chen , He Zhengwen , Dai Pingping , Zhang Longbo , Liu Zhiqiang , Gao Jie , Guan Yan-Fang , Xia Xuefeng , Yang Ling , Yi Xin 
Published: May 2019

e13523 Background: Glioma is the most common malignant brain tumor among adults. To explore biomarkers for efficient therapy, we describe mutational features and hypermutated nature among glioma. Methods: Analysis was performed on 119 tissues from patients diagnosed with glioma using panel of 1021 genes. We defined hypermutation as TMB-20 (TMB>20 muts/Mb). Results: The most commonly observed alterations include mutations within promoter of TERT, catalytic domain of IDH1 and CDSs of TP53, EGFR, NOTCH1, CIC, ATRX, as well as amplifications of EGFR, 4q12 and deletions of 1p/19q, CDKN2A/B. Mutations in ATRX were mutually exclusive with TERT, but coexisted with TP53 mutations (p<0.001). Targeted drugs had been developed for EGFR, CDKN2A/B and 4q12. Among 114 evaluable cases, TMB ranged from 0 to 298 muts/Mb, with a median of 4.32. Only 6% cases displayed TMB-20. MSI-H was 2.6%, with only one case had a germline mutation in MLH1. 2.6% cases harbored mutations in Pol genes. Only one case was positive for all three criteria. MSI-H cases all displayed TMB-20. The two biomarkers were extremely statistically significant (p=0.001) in gliomas. The case with highest TMB (298 muts/Mb) harbored five mutations in Pol genes, and germline frameshift mutations in MSH6. This was consistent with previous reports that mut Pol genes contributed to high TMB. High TMB may occur spontaneously or be induced by treatment. In our study, hypermutated cases in de novo and post-treatment groups were 11.1% and 11.5%, respectively. In IDH wild-type and mut groups, hypermutated cases were both 6.3%. However, extremely high TMB (TMB>50) cases were all de novo and carried IDH mutations. While treatment-induced high TMB were always subclonal, which may not be sensitive to immunotherapy. This explained the limited efficiency of immunotherapy in gliomas to some extent. Conclusions: Most commonly observed mutations in gliomas may provide potential targets for targeted therapy. There is probably a trend that extremely higher TMB occurs in de novo patients, who may preferentially benefit from immunotherapy. Further research is needed on biomarkers for both effective targeted- and immuno-therapy.
Genomic analysis of paired IDHwt glioblastoma (GB) to reveal recurrent alterations of MPDZ at relapse after radiotherapy and temozolomide (RTCT).
Authors: Chanez Brice , Appay Romain , Guille Arnaud , Lagarde Arnaud , Adelaide José , Denicolai Emilie , Campello Chantal , Tchoghandjian Aurelie , Petrirena Gregorio , Colin Carole , Barrie Maryline , Baeza-Kallee Nathalie , Boucard Celine , Jiguet-Jiglaire Carine , Graillon Thomas , Nanni-Metellus Isabelle , Dufour Henry , Figarella-Branger Dominique , Chinot Olivier L. , Tabouret Emeline 
Published: May 2019

e13535 Background: GB are highly aggressive tumors which systematically relapse. Our objective was to identify disease progression mechanisms and genomic drivers of GB treatment resistance. Methods: Ten paired frozen tumors from initial and recurrent surgery after RTCT were screened by CGH Array. Next, NGS of the selected genes was performed on 19 paired tumors (38 samples). Molecular alterations were correlated with patient data. TCGA was used to characterize the molecular profile of MPDZ. Results: Nineteen IDHwt GB patients with a median age of 54.5 years (37.2-72.8) were included. Using CGH array, unsupervised analysis clustered the whole samples by paired of initial and recurrent tumors. However only 44% of CGH Array alterations were shared between initial and recurrent tumors (amplifications: 55%; deletions: 30%). The new alterations detected at relapse were amplifications in 25% and deletions in 23% of tumors. Two regions corresponding to 171 genes were lost at relapse (p = 0.03): 19q13.33 and 19q13.41. Using DAVID genome, 3/171 genes (related to neutrophil chemotactic factors) were identified: FPR1, FPR2, FPR3. Moreover, 24 genes were lost (including MPDZ) and 2 genes were gained in 20% of recurrent tumors. Totally, 29 genes were analyzed by NGS and 4 genes showed pathogenic mutations shared by initial and recurrent tumors: FPR2, REL, TYRP1 and MPDZ. Only MPDZ showed, at relapse, an increasing rate of mutated variants and a new mutation affecting the splicing site. These alterations were independent from classical prognostic factors (age, sexe, karnofsky performans status, MMS and MGMT status) and from patient survivals. To explore MPDZ expression, we used TCGA initial dataset and observed that a lower RNA expression of MPDZ was associated with IDHwt ( p< 0.001) and grade IV ( p< 0.001) gliomas, reinforcing the potential pejorative impact of MPDZ loss. Conclusions: Our results suggest that MPDZ is frequently altered at initial diagnosis with increased alterations in recurrent IDHwt GB after RTCT, suggesting that MPDZ impairment could contribute to the resistance/relapse mechanisms. Further investigations are needed to validate these results.
Impact of PET-imaging during treatment planning on outcome in meningioma patients.
Authors: Combs Stephanie E , Fischer Hanna , Voglhuber Theresa , Diehl Christian , Straube Chistoph , Yakushev Igor , Kessel Kerstin 
Published: May 2019

e13542 Background: Modern radiotherapy (RT) techniques such as IMRT combined with IGRT increased safety and precision over the years. However, during treatment planning, the definition of the planning target volume (PTV) remains challenging, and differentiation between healthy tissue, i.e., meninges, post-operative changes, and residual tumor can be difficult using MR and CT imaging alone. In this study, we evaluated the impact of additional PET-imaging on local control (LCR) and overall survival (OS). Methods: We analyzed 351 patients with primary RT of meningiomas treated between 1996 and 2018 and divided the cohort into low-grade (n = 283) and high-grade (n = 68) cases. All patients were treated with fractionated stereotactic radiotherapy (FSRT) with a median dose of 54.0 Gy and a median single dose of 1.8 Gy. A radiation oncologist delineated PTV based on diagnostic CT and MRI and, if available, additional PET-imaging. We used only PET-images acquired within 50 days before RT. In our clinic, PET-planned meningioma treatment started in 2000 with Methionine (2001-2010), between 2004 and 2011 F-18 FET tracer was used, and since 2011 only 68Ga-Dotanoc/Dotatoc PETs are acquired. This study is registered under the open science framework: DOI 10.17605/OSF.IO/RYX9D. Results: Median follow-up was 6.9 years (95%-KI: 6.3-7.4). For low-grade meningiomas, mean OS was 15.5 years (95%-KI: 14.7-16.2) and mean PFS was 15.7 years (95%-KI: 14.9-16.6); for high-grade cases, median OS was 13.8 years (95%-KI: 10.4-17.1), and median PFS was 8.9 years (95%-KI: 6.4-11.4). PET imaging had a significant impact on OS (p = 0.030) and PFS (p = 0.023) for low-grade meningiomas; however, in the multivariate analysis (with the prognostic factors age, gender, PTV, Karnofsky index, and time from resection to RT), it remained only significant for LCR. For high-grade cases, PET-imaging had no influence. Conclusions: PET-imaging improves the detection of tumor cells, especially during treatment planning. It showed a significant influence on OS and LCR. Further analyses will investigate the influence of PET regarding, e.g., residual tumor tissue, tumor size, and establish cut-off values for which tumors additional PET-imaging might be beneficial. With the further prognostic a weighted scoring system will be developed for prognostic assessment. [Table: see text]
Epidemiologic and histologic characteristics of central nervous system lesions: A 20-year experience of a single institution in Lebanon.
Authors: Eid Roland , Hage Stephanie , Antonios Ingrid , Moussa Rita , Khoury Makram , Haddad Fady , Kourie Hampig Raphael , Kesrouani Carole , Ghorra Claude , Abadjian Gerard , Kattan Joseph Gergi 
Published: May 2019

e13544 Background: Lesions of the central nervous system (CNS) are a heterogeneous group of tumoral and non-tumoral lesions, benign or malignant, primary or metastatic. The overall incidence rate of all brain tumors is estimated to be 10.82 per 100 000 person-years. There is no data in Lebanon characterizing the CNS lesions. The aim of our study is to report the epidemiologic and histologic characteristics of these lesions in a Lebanese tertiary center. Methods: This is a retrospective study evaluating the characteristics of the CNS lesions diagnosed in 20 years (from January 1998 to June 2017) in the pathology laboratory of Hôtel Dieu de France, Saint Joseph University hospital of Beirut, Lebanon. The data were extracted from the computerized records of the laboratory. Different variables were evaluated, from the samples types and epidemiologic characteristics, to the revealing symptoms and the histologic subtypes. Statistical analysis was performed using SPSS 24.0. Results: 2025 tumoral lesions over 20 years were interpreted. 25.4% of the samples were obtained by biopsy, 65% by surgical resection, 3.7% were cerebral spinal fluid and 5.9% were undetermined. 52.2% of the patients were men and 47.8% were women with a median age of 50 years, from 0 to 89 years. The most frequent revealing symptoms were epilepsy (22.5%), headache (20.6%) and motor impairment (19.9%). 90.7% of the CNS tumors were primary and 9.3% were metastatic. Lung (35.6%) and breast (16.5 %) were the two most frequent primaries of the metastatic lesions. 46.2% of primary CNS tumors were glial, 42.5% non-glial, 3.5% mixed neuroglial and 6.4% mesenchymal. The two most frequent glial tumors were astrocytic (56.4%) and oligodendroglial (17.9%) tumors, while the most frequent non-glial tumors were meningeal tumors (58%) and cranial nerve and paraspinal tumors (16.3%). Conclusions: The histological and epidemiological characteristics of brain tumors in Lebanon are consistent in many features with what is known in the literature, but the Lebanese population differs by a younger age of onset, a lower rate of meningiomas, and a higher rate of gliomas.
MGMT status through the ages, literally.
Authors: Ali Assad , Saeed Bamashmos Anas , Barnett Addisson , Li Hong , Sagar Soumya , Barnett Gene H. , Angelov Lilyana , Mohammadi Alireza Mohammad , Peereboom David M. , Stevens Glen , Suh John H. , Murphy Erin Sennett , Yu Jennifer S. , Ahluwalia Manmeet Singh 
Published: May 2019

e13550 Background: It is known that in the setting of glioblastoma (GBM) having a methylated O6-Methylguanine Methyltransferase (MGMT) gene promoter confers a greater response to Temozolomide (TMZ) and an increased progression free survival (PFS) and overall survival (OS). Recent literature has uncovered interesting results when dichotomizing patients by demographics (i.e. age and gender) and analyzing response to the various available GBM therapies. Our primary objective is to analyze the effect of both age and MGMT status on OS and PFS in patients with newly diagnosed GBM. Understanding the role of MGMT on age in the setting of GBM can allow for a better understanding of disease course and treatment. Methods: 464 adult patients with newly diagnosed GBM and documented MGMT status were analyzed from a single major tertiary care institution between 2012 and 2018. Patients were stratified into four groups based on age (above or below 65 years) and MGMT status. A univariate Cox model was used to analyze the effect of age and MGMT status on PFS and OS, where our reference group was the group with the highest OS ( < 65/methylated). Results: The median age of the whole dataset was 63.4 years, and 65.2 years for patients who were MGMT methylated. Patients less than 65 years and were MGMT methylated had the best prognosis with a PFS and an OS of 10.9 months and 18.9 (Table), respectively. Patients above the age of 65 were more likely to be MGMT methylated (p = 0.002). There was an association between IDH1-mutant status and MGMT methylation (p = 0.006). Conclusions: Using MGMT status and age of the patient, our model predicts outcomes that can vary from 7.4 months to 18.9 months (HR = 3.41 p < 0.001).[Table: see text]
Spine stereotactic radiosurgery as a promising modality in patients with metastatic hepatocellular and cholangiocarcinoma.
Authors: Gjyshi Olsi , Kaseb Ahmed Omar , Ghia Amol J. 
Published: May 2019

e13551 Background: While stereotactic body radiation therapy (SBRT), a form of high-dose rate radiation therapy, is often used in the local management of early-stage hepatocellular carcinoma (HCC), its role in managing metastatic hepatobiliary malignancies is currently unclear. Here, we investigate the role of spine stereotactic radiosurgery (SSRS), a form of SBRT that targets spinal metastases, in the management of late-stage HCC or cholangiocarcinoma. Methods: We retrospectively reviewed a total of 28 patients with 43 HCC or cholangiocarcinoma metastases treated with SSRS between 2004 and 2017 at our institution. We used Kaplan-Meier curves to estimate overall survival (OS) and local control (LC), and Cox regression analysis to identify potential predictive factors of the two. Results: The median patient age was 63 (range 28 to 78) years old. Four patients had a histology-proven diagnosis of metastatic cholangiocarcinoma, while 39 had hepatocellular carcinoma. Of the patients with HCC, 47% had predisposing viral hepatitis, while 53% had either non-alcoholic steatohepatitis (NASH) or no known predisposing factors. Twenty-nine cases were treated with 24Gy in 1 fraction, 11 with 27Gy in 3 fractions, 2 with 18Gy in 2 fractions, and 1 with 30Gy in 5 fractions. The 1-year actuarial OS and LC rates were 23% and 75%, respectively. The median OS was 6.3 months, while the median time to local failure was not reached. On univariate modeling, negative predictors of LC included history of prior RT to the site of metastasis (p < 0.005) and tumor volume > 60cc (p = 0.03), while biologic equivalent dose (BED) > 52Gy was the only positive predictive factor (p < 0.05). Presence of epidural disease, Bilsky grade, presence of viral hepatitis, or type histology were not predictors of LC (all p > 0.05). In patients who had pain or neurologic findings at presentation, 56% reported improvement in their symptoms on follow up. Three patients (11%) developed compression deformity and one patient (4%) developed radiation-induced neuritis. Conclusions: SSRS provides promising and durable local control in patients with metastatic hepatobiliary disease, and early intervention with high BED are necessary to ensure high level of local control, improvement in symptoms, and a low rate of long-term toxicity.
Assessment of Leptomeningeal Carcinomatosis Diagnosis and Outcomes from 2005 to 2015 at Ohio State University.
Authors: Rinehardt Hannah , Morgan Evan , Kassem Mahmoud , Palettas Marilly , Miah Abdul , Alnahhas Iyad , Guillermo Prieto Eibl Pilar , Suresh Anupama , Ganju Akaansha , Williams Nicole Olivia , Puduvalli Vinay K. , Giglio Pierre , Lustberg Maryam B. , Wesolowski Robert , Sardesai Sagar D. , Stover Daniel G. , Vandeusen Jeffrey , Bazan Jose G. , Ramaswamy Bhuvaneswari , Noonan Anne M. 
Published: May 2019

e13554 Background: Leptomeningeal carcinomatosis (LMC) is a complication of advanced malignancies wherein primary tumors metastasize to the leptomeninges surrounding brain and spinal cord. LMC complicates 4-15% of malignant solid tumors with incidence increasing as survival of patients with advanced cancer improves. Diagnostic methods include magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) cytology. MRI findings may be nonspecific, and the gold standard of diagnosis is malignant cytology on CSF analysis. We assessed detection methods, incidence, and outcomes of LMC at The Ohio State University Comprehensive Cancer Center from 2005-2015. Methods: This was an IRB-approved single-institution retrospective study of 160 patients with confirmed diagnosis of LMC who were treated at the OSUCCC-James between Jan 1, 2005 and Dec 31, 2015. Patients with hematologic and central nervous system malignancies were excluded. Descriptive statistics were used to summarize demographic and clinical characteristics. Overall survival (OS) was defined as time from LMC diagnosis to death or last known follow-up, and was generated using Kaplan-Meier methods. Results: Median age of LMC diagnosis was 55.8 years (range: 48, 62.5). 69 (43%) patients had primary breast cancer, 41 (26%) had lung cancer, and 17 (11%) had melanoma. 73 patients (46%) presented with stage IV disease at initial diagnosis of the primary cancer, 41 (26%) with stage III disease, and 26 (16%) with stage II disease. Median time from diagnosis of primary cancer to diagnosis of LMC was 2 years (range: 0, 31.2). 158 (99%) patients had metastases at the time of LMC diagnosis, predominantly in bone (36%) or brain (36%). Median OS was 1.9 months (CI: 1.3, 2.5). 160 (100%) patients had an MRI of the brain or spine and 155 (97%) had MRI findings consistent with LMC. 75 (47%) patients underwent lumbar puncture, and 39 (52%) had CSF cytology positive for malignancy. Conclusions: Patients with LMC commonly presented with stage IV breast cancer, lung cancer, or melanoma with metastases to the brain or bone. Despite treatment, prognosis remains poor and confirmation of diagnosis can be challenging. Clinicians should have a low threshold for investigating LMC in high risk patients presenting with neurologic signs or symptoms.
Absolute lymphocyte count in patients with glioblastoma treated with temozolomide chemoradiation.
Authors: Saeed Bamashmos Anas , Ali Assad , Barnett Addison , Sagar Soumya , Rybicki Lisa A. , Barnett Gene H. , Mohammadi Alireza Mohammad , Angelov Lilyana , Chao Samuel T. , Murphy Erin Sennett , Suh John H. , Yu Jennifer S. , Peereboom David M. , Stevens Glen , Ahluwalia Manmeet Singh , Wei Wei (Auston) 
Published: May 2019

e13564 Background: Standard glioblastoma (GBM) management includes radiotherapy, chemotherapy, and steroids; all of which can result in immunosuppression and a low absolute lymphocyte count (ALC). Previous literature identified an association between low CD4 and worse progression free survival (PFS) and overall survival (OS). There remains a lack of research addressing predictors of immunosuppression in patients with GBM. The primary objective of this study is to identify the degree of immunosuppression, measured by ALC, in GBM patients receiving concurrent temozolomide chemoradiation (CRT). Secondary objectives include associations between ALC, PFS, and OS, and whether there are any predictors of immunosuppression in patients with GBM. Methods: We retrospectively reviewed 231 newly diagnosed GBM patients who underwent surgery followed by standard of care CRT. We also analyzed the association between ALC and age, sex, MGMT methylation status, and extent of surgical resection. ALC was collected at the time of surgery, CRT start date, and two, four, six, and ten weeks post-CRT start date. Common Terminology Criteria for Adverse Events (CTCAE) protocol version 5.0 was then used to grade low ALC as grade 0, 1, 2, 3, or 4. Results: Of the 231 patients analyzed, 139 were males, 74 underwent gross total resection of the tumor, 129 patients were less than 65 years, and 79 (42.5%) were MGMT methylated. 37 patients had grade 3-4 low ALC. In a univariate analysis, grade 3-4 low ALC at 4 weeks (±14 days) post-CRT start was associated with higher mortality (HR 1.54, P = 0.028) but had no significant association with PFS (HR 1.22, P = 0.29). Logistic regression analysis was used to identify risk factors for grade 3-4 low ALC and its association with survival. None of the risk factors that we tested such as age, gender, type of surgery, or molecular markers including MGMT, IDH, or EGFR were associated with low ALC. Conclusions: Our study demonstrated that patients with ALC grade 3 or 4 at 4 weeks (±14 days) of CRT had a significantly higher mortality (HR 1.54, P = 0.028) but had no significant association with PFS (HR 1.22, P = 0.29).