bluuebunny/crossref_metadata_2025 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).
Albumin levels and Prognostic Nutritional Index in glioblastoma.
Authors: Saeed Bamashmos Anas , Barnett Addison , Ali Assad , Li Hong , Angelov Lilyana , Barnett Gene H. , Mohammadi Alireza Mohammad , Chao Samuel T. , Yu Jennifer S. , Murphy Erin Sennett , Suh John H. , Stevens Glen , Peereboom David M. , Ahluwalia Manmeet Singh , Wei Wei (Auston)
Published: May 2019

e13567

Background: Albumin levels are widely used to estimate patients’ nutritional status. Low perioperative albumin levels are associated with worse outcomes. Moreover, Prognostic Nutritional Index (PNI), which is calculated from serum albumin levels and peripheral blood lymphocyte count as follows: PNI = (Albumin x 10) + (0.005 x ALC), has been used to predict both short and long term outcomes in patients with wide variety of tumors. The primary objective of this study was to characterize perioperative albumin levels and PNI in newly diagnosed GBM patients. Secondary objectives included associations between albumin levels and PNI on progression free survival (PFS) and overall survival (OS). Methods: We retrospectively reviewed 568 newly diagnosed GBM patients who underwent surgery followed by standard of care chemoradiation. We analyzed the association between albumin and PNI on age, sex, MGMT methylation status, and extent of surgical resection on PFS and OS using a multivariate Cox proportional hazard model. Results: Of the 568 patients collected, 355 (62.5%) were males, 158 (27.8%) had gross total resection of the tumor, and 197(42.5%) were MGMT methylated. Both albumin and PNI were associated with OS but not PFS. The hazard ratio (HR) for OS among the top 2 quartiles of both albumin level and PNI were significantly higher than the bottom two quartiles. The median albumin level was 4.0 and the median PNI was 40. The point for significant high hazard ratio (HR) was around median value for both Albumin and PNI based on restricted cubic spine Cox regression models. The Kaplan-Meir (KM) estimated median OS was 15.2 months for albumin > 4, and 7.6 for albumin ≤4. The KM estimated median OS was 14.6 months for PNI > 40, and 5.7 for PNI≤40 (P logrank < 0.001 for both). While controlling for other factors that may also be associated with early death including age, gender, surgery type and MGMT status, HR = 1.9 (95% CI = 1.4- = 2.6) for Albumin < 4, and HR = 2.1 (95% CI = 1.5- 3.0) for PNI < 40 compared to their counterpart. Conclusions: Glioblastoma patients with perioperative albumin > 4 had a median OS of 15.2 months and 7.6 months for albumin ≤4, and a median OS of 14.6 months for PNI > 40 and 5.7 months for PNI≤40 (P logrank < 0.001 for both).
Impact of EGFR amplification status in newly diagnosed glioblastoma treated with Stupp protocol.
Authors: Barnett Addison , Saeed Bamashmos Anas , Ali Assad , Jia Xuefei , Wei Wei (Auston) , 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

e13569

Background: Standard post-surgical glioblastoma (GBM) treatment, per Stupp protocol, includes six-weeks of concurrent Temozolomide chemoradiation followed by at least six cycles of adjuvant-Temozolomide. Previous investigations into epidermal growth factor receptor (EGFR) amplification as a prognostic factor in GBM have yielded contradicting results, requiring further investigation. The primary aim of this study was to determine the degree to which EGFR amplification, in newly diagnosed GBM, impacted progression free survival (PFS) and overall survival (OS). Methods: Data from 582 patients who underwent surgical intervention for GBM at a tertiary care institution between 2012 and 2018 were analyzed. Only adult patients who underwent treatment per Stupp protocol and had pathological analysis on EGFR and CEP7 were included. Amplification and non-amplification status was calculated by a ratio of EGFR/CEP7 > 2 and < 2, respectively. PFS and OS outcomes were compared using Cox proportional hazard models stratified by surgery type and sex. Results: Of the original 582 patients, 122 were treated per Stupp protocol and had documented EGFR analysis. Of patients who were EGFR amplified, 41 (58.5%) were male and 25 (48.1%) were female (p = 0.38) and median amplification was 1.07 and 1.16 (p < 0.001), respectively. EGFR non-amplified patients had a PFS hazard ratio, HR = 0.70 (95% CI = 0.44 – 1.12, p = 0.14); and an OS HR = 0.60 (95% CI = 0.35 – 1.03, p = 0.065). When the EGFR/CEP7 ratio was stratified by quartile, it was found that Q4 compared to Q1 (Q4 > 6.50 vs 0 < Q1 ≤ 1.06) had a PFS HR = 2.1 (95% CI = 1.11 – 4.07, p = 0.024); and an OS HR = 2.48 (95% CI = 1.10 – 5.60, p = 0.028). Conclusions: There was no statistical difference in prevalence of EGFR amplification by sex. However, despite statistical significance, there was minimal difference in median degree of amplification by sex (0.09). Trends begin to show that patients who were EGFR non-amplified had better PFS and OS outcomes than patients who were EGFR amplified, although this was not statistically significant. Patients with very high EGFR amplification (Q4) had significantly poorer PFS and OS outcomes than patients with very low EGFR amplification (Q1).
Avelumab in newly diagnosed glioblastoma multiforme: The SEJ study.
Authors: Jacques Francois Henri , Nicholas Garth , Lorimer Ian , Sikatifoko Victorine , Prévost Jasmine
Published: May 2019

e13571

Background: Glioblastoma Multiforme (GBM) has well documented systemic and local immunosuppressive mechanisms to escape immune surveillance and grow. GBM tumor cells as well as the microglia within it have a high PD-L1 surface expression which may make it susceptible to anti-PD-L1 antagonism and ADCC with avelumab therapy. Standard combination temozolomide/radiotherapy is associated with a median survival of 14.6 months and a median progression free survival of 6.9 months. Methods: This is a single center, phase 2, open label study of avelumab 10 mg/kg Q2W for 156 weeks duration in patients receiving standard therapy for newly diagnosed GBM. Thirty patients will be entered into the study within 3 weeks of completing combined radiotherapy/temozolomide. Here, we report the results of the first interim analysis completed when the first eight patients completed 52 weeks or an end of study visit. Results: To date 24 patients have started therapy. The median follow-up is 4.9 months (1-22 months). There has been overall no unexpected treatment emergent adverse event (TEAE). The most common TEAE was elevated liver or pancreatic enzymes. Two patients transiently withheld therapy because of immune related TEAE’s (both hepatitis) and none permanently. The objective response rate by iRANO criteria, at week 52 for the first eight patients was 4 (50%) with 2 (25%) having a complete response, 1 (12.5%) a partial response and 1 (12.5%) stable disease. The median progression free survival was 11.9 months. Conclusions: These preliminary results suggest that the addition of avelumab to standard combination therapy early on, in patients with GBM is safe. Efficacy trends look promising. Clinical trial information: NCT03047473.
Hyperprogressive disease in patients with recurrent high grade gliomas treated with immune checkpoint inhibitors or other therapies.
Authors: Donovan Laura , Gedailovich Samuel , Joanta-Gomez Adela , Schulte Jessica , Kreisl Teri Nguyen , Lassman Andrew B. , Welch Mary Roberta , Haggiagi Aya , Iwamoto Fabio Massaiti
Published: May 2019

e13575

Background: Hyperprogressive disease (HPD) has been described in solid tumor patients treated with immune checkpoint inhibitors (ICI). HPD is defined as a ≥2-fold increase in tumor growth rate (TGR) following initiation of ICI. HPD has not been explored in patients with high grade gliomas (HGG) on ICI or standard cytotoxic regimens. In advanced cancer patients receiving ICI, MDM2/4 amplification or EGFR alterations, both found in HGG, correlated with HPD. We compared the rate of HPD in recurrent HGG patients receiving ICIs to those treated with non-immunotherapy agents. Methods: Patients with HGG on ICIs for 1st or 2nd recurrence were compared to a control group receiving other therapies at 1st recurrence. Patients with prior or concurrent bevacizumab or anti-VEGFR were excluded due to pseudoresponse and decreased enhancement with these drugs. HPD was calculated by comparing TGR immediately before and after treatment. Results: 49 patients met inclusion criteria (27 ICI, 25 control). 25/27 patients treated with ICIs and 20/22 patients in the control group had complete imaging and were eligible for analysis. In the ICI group, 60% were men (15/25) and 88% (22/25) had a diagnosis of GBM. 68% were treated at first progression (17/25). Controls were 80% male (16/20) and all had a diagnosis of GBM. 30% (6/20) were 65 years or older at diagnosis in the control group compared to 28% (7/25) in the ICI group. In total, 7/25 patients met criteria for HPD in the ICI group (28%) compared to 4/20 patients in the control group (20%). 10/25 patients (5/7 with HPD) in the ICI group and 8/20 patients (2/4 with HPD) in the control group had next generation sequencing of their tumors. EGFR alterations and MDM2/4 amplifications were not associated with HPD whereas PTEN mutations were more common in the HPD group (71% HPD vs. 33.3% no HPD). Conclusions: HPD is observed in patients with HGG treated with ICI at comparable rates to those with other cancers, but was also observed in 20% of patients receiving other therapies. While the numbers are small, PTEN mutations may be associated with HPD in patients with HGG. In contrast to other solid tumors, EGFR alterations and MDM2/4 amplifications were not associated with HPD in HGG.
First-line stereotactic radiosurgery combined with systemic targeted and immune checkpoint inhibitor therapy in melanoma patients with newly diagnosed brain metastases.
Authors: Heumann Thatcher Ross , Wu Peter , Ye Rebecca , Sansosti Alexandra , Habibi Akram , Kryger Marc , Beaudreault Cameron , Bernstein Kenneth , Silverman Joshua Seth , Weber Jeffrey S. , Pavlick Anna C. , Kondziolka Douglas
Published: May 2019

e13577

Background: Of solid tumors, melanoma has the highest propensity for central nervous system spread with historic median survivals of 5-8 months following brain metastasis diagnosis. We evaluated the impact of systemic BRAF targeted and immune checkpoint inhibitor (ICI) therapies on survival outcomes in patients receiving stereotactic radiosurgery (SRS) for melanoma brain metastases (MBM) and assessed patient treatment burden associated with prolonged survival. Methods: We retrospectively reviewed the demographics, disease characteristics, therapeutic regimens, overall survival, and first-year cumulative incidence of comorbid disease for patients with de novo MBM treated between 2013 and 2017 at a major melanoma referral center. Results: Among 123 newly diagnosed MBM patients:65% were male, 24%were 50 years old or less, 50% were BRAF mutated, 63% had multiple intracranial lesions at diagnosis . Locally, 73% received SRS as first-line treatment.Systemically, 73% received ICI, 46% received BRAF targeted therapy, and 12% received neither. With median follow up of 11 months (mo), totalcohort median OS was 13.2 mo, 20.5 mo for BRAF mutated patients, 10.8 mo for BRAF wild-type patients. Median OS for first-line SRS was 31.0 mo (47% 3-year OS) when combined with both ICI and BRAF targeted therapy, 17.5 mo (31% 3-year OS) when combined with ICI monotherapy, and 6.1 mo (22% 3-yr OS) with neither systemic therapy. SRS and BRAF targeted therapy were associated with improved OS. BRAF status, ICI therapy, intratumoral hemorrhage were not significant prognosticators for OS.At one-year follow-up, comorbid conditions with the greatest cumulative incidence were fatigue, nausea, intracranial hemorrhage, deep vein thrombosis, major depressive disorder, and pneumonia. Patients averaged one inpatient visit every 4.5 mo (1 week average length of stay), and 2 advanced imaging studies (MR/CT/PET-CT) per month following MBM diagnosis. Conclusions: In one of the largest reported MBM series, survival has improved markedly for patients receiving first-line brain radiosurgery combined with BRAF targeted therapies and immunotherapies. Simultaneously, longer life expectancy comes with increasing incidences of comorbid conditions reflecting an evolving complexity of and need for coordination of care for patients with MBM.
Integrating salvage hypofractionated radiosurgery plus low-dose adjuvant bevacizumab for locally recurrent brain metastasis with high dose irradiation previously.
Authors: Guan Yun , Zhu Huaguang , Wang Chaozhaung , Li Jing , Xu Wenqian , Sun Lei , Pan Li , Dai Jiazhong , Wang Yang , Wang Enmin , Wang Xin
Published: May 2019

e13579

Background: Treatment for recurrent brain metastasis remains uncertain. The purpose of this research was to evaluate the efficacy and toxicity of FSRS with adjuvant bevacizumab as a new salvage treatment for locally recurrent brain metastases with high dose irradiation previously. Methods: Patients with locally recurrent intracranial metastasis with irradiation previously were enrolled in this prospective study. Salvage FSRS dose ranged from 9.5 to 29 Gy in two to five sessions with 62–75% isodose line. Adjuvant bevacizumab was prescribed four cycles (5 mg/kg, q3w). Magnetic resonance imaging (MRI), Karnofsky Performance Scale (KPS), adverse events and clinical outcomes were recorded. The primary objective of this study was to identify the overall survival after salvage treatment. Secondary objectives included clinical response (KPS), imaging response (MRI) and adverse events. Results: From December 2009 to October 2016, 24 patients were enrolled. Of these patients, 9 received WBRT followed by SRS, and 15 underwent SRS. The median 1-year overall survival (OS) after salvage SRS was 87.5%. No treatment-related grade 4 adverse events were recorded. Grade 1/2 fatigue was observed in 8 (33%) patients followed by headache, hypertension and nausea. Grade 3 fatigue and headache occurred in 1 patient. No grade 4 toxicity was observed. Conclusions: Salvage FSRS with early use of low dose adjuvant bevacizumab treatment showed favourable clinical and radiologic control with manageable toxicity for locally recurrent brain metastasis patients who underwent high dose irradiation previously. The diagnosis of RN and LR after salvage FSRS merit further study. [Table: see text][Table: see text][Table: see text]
Effect of oligometastatic disease management with stereotactic body radiation therapy on survival in patients with metastatic lung cancer.
Authors: Raez Luis E. , Botero Ana , Castillo Miguel , Castellon Ignacio , Hunis Brian , Falchook Aaron
Published: May 2019

e13582

Background: Overall survival (OS) of metastatic non-small cell lung cancer (NSCLC) patients (pts) is improving with the development of targeted therapies (TARGET) and immunotherapy (IMMUNO), however is limited by disease progression (PD) which necessitates a change in systemic therapy. Stereotactic body radiation therapy (SBRT) can allow NSCLC pts to stay longer with the same therapy by eliminating oligometastatic progression (OMP) improving progression free survival (PFS) and OS. Methods: 100 pts with metastatic NSCLC undergoing chemotherapy (CHEMO), IMMUNO or TARGET that had OMP defined as less than 4 sites of metastasis and underwent SBRT were evaluated for PFS and OS. PFS1: Time between initiation of systemic therapy and development of OMP. PFS2: Time between OMP treated with SBRT and development of further PD requiring a change in systemic therapy. Pts received IMMUNO for second line and beyond. Robotic SBRT was delivered in 1-5 fractions on consecutive days or every other day. SBRT doses were determined based on the disease site and dose tolerance of the adjacent organs. Results: Brain metastasis (BM) were seen in 45 pts and 55 pts had extracranial metastasis (EM). 34 pts were receiving CHEMO, 34 Target and 32 IMMUNO at the time of OMP. Main endpoints (m) are shown (Table) Pts with BM that received SBRT were able to continue the same therapy for a period of 6.5-9 extra months due to the control of BM. Pts with EM that have developed PD were able to continue the same therapy 17-21 extra months due to the ablation of OMP by SBRT. Overall PFS was: 16.5m for BM and 34m for EM and the OS were: 31m and 53m respectively. Conclusions: Substantial prolongation was observed in PFS/OS compared with historical controls thanks to the use of SBRT in pts that develop OMP while on systemic therapy. SBRT allowed patients to continue with the same systemic treatment. Our CHEMO cohort is composed of long term survivors under therapy and may not represent the average PFS/OS of pts on CHEMO. Survival data from prospective trials will be essential in determining the value of this resource-intensive treatment.[Table: see text]
A new option in brain-metastases: Hippocampal-sparing whole-brain radiotherapy with simultaneous integrated boost VMAT-IGRT.
Authors: Marin Alicia , Martin Margarita , Gonzalez Emma , Torres Lisselott , Hernandez David , Casado Margarita , Montijano Miguel , Lopez Mario , Castro Pablo , Cerezo Laura , Perez Leopoldo , Murillo Maria Teresa
Published: May 2019

e13589

Background: We report our experience with volumetric modulated arc therapy (VMAT-IGRT) use to plan and deliver whole brain radiotherapy whit a simultaneous integrated boost in patients with brain metastases, using hippocampal sparing. Methods: In this retrospective study 57 patients with brain metastases were treated with radiotherapy VMAT-IGRT were administered in 12 daily fractions of 2.7Gy for a total of 32.4Gy (EBD 40Gy) to whole-brain and simultaneous integrated boost to brain metastases, multiple targets, in 12 fractions to 3.4Gy for a total dose of 40.8Gy (EBD 60Gy). The primary endpoint was intracranial progression-free survival (PFS) and secondary endpoints were preserves neurocognitive function and overall survival (OS). Survival rates were determined by Kaplan-Meier method. Differences between survival curves were analyzed by the log-rank test. Results: From January 2015 to December 2018, 57 patients were enrolled. The median follow-up time was 7 months. PFS6, PFS12 and PFS18 were 91.3%, 70.8% and 70.8% respectively. mOS, OS6, OS12 and OS18 were 10 months (95% IC 4.2-15.7 months), 67.2%, 48.6% and 35.3% respectively. Response rates were as follows: 29RC (50.9%), 21RP (36.8%), 7SD (12.3%) and 0PD (0%). Long progression-free survival patients: PFS > 12, 15 and 18 months for initial diagnosis 70%, 70% and 70% respectively. Conclusions: Whole-brain radiotherapy with simultaneous integrated boost to brain-metastases: VMAT-IGRT is safe and promising and possibly produces survival and tolerance benefits. Sparing the hippocampus during cranial irradiation poses important technical challenges with respect to contouring and treatment planning.
Active postmarketing surveillance: Results from a manufacturer's patient support program for patients under treatment with the first biosimilar trastuzumab (MYL-1401O) approved in Brazil.
Authors: Silva Allisson Monteiro da , Dib Gislaine Villarta Capeleti , Saraiva Emanuela Lopez Fernandes , Watanabe Thais Tiemi , Paulo Jaqueline Amália de
Published: May 2019

e14000

Background: The development of biosimilars is increasing around the world, and facilitates patient’s access to these high-tech therapies. Active pharmacovigilance is considered one of the main tools for monitoring the safety of biologics and biosimilars, especially in post marketing. In 2017, trastuzumab (MYL-1401O) became the first trastuzumab biosimilar approved in Brazil. A program to support patients under trastuzumab (MYL-14010) treatment was sponsored by the manufacturer in order to closely monitor adverse events (AE). Methods: This is a prospective observational study based in data from a manufacturer’s patient support program. Patient diagnosed with initial or advanced HER2+ breast cancer (BC) and HER2+ gastric cancer (GC) who received prescription for trastuzumab (MYL-1401O) were invited to participate. They are followed by periodical phone calls after each infusion and up to 3 months after the last infusion of trastuzumab. Treatment related data and AEs were collected. Results: A total of 21 female patients with HER2+ BC receiving trastuzumab (MYL-14010) were enrolled in the program between May 2018 and January 2019. 16 (76,2%) out of these patients with median age 52 years (range 33 to 76) reported 101 AEs (all-causality): 94 (93,1%) non-serious (73 expected / 21 unexpected) and 7 (6,9%) serious (5 expected / 2 unexpected). Considering all unexpected AEs causality assessment was unlikely in 47,8% AEs. The most frequently reported AEs according SOC (system organ classification) were general disorders and administration site conditions (18,8%), nervous system disorders (14,9%) and gastrointestinal disorders (14,9%). The most reported symptoms were nausea, asthenia, infusion reactions, paresthesias and pain in the body. Conclusions: Safety data for biosimilar trastuzumab (MYL-1401O) is consistent with original trastuzumab in female patients with HER2+ BC. Most of the reported AEs were non-serious (93,1%) and expected (77,2%). No new safety signals were detected.
Potent targeting of B cell lymphoma and plasma cell tumors by a tetravalent, Fc-engineered antibody directed against the glycoantigen CD75s.
Authors: Klausz Katja , Karimzadeh-Tabrizi Amir , Buck Malena , Otte Anna , Krohn Steffen , Kellner Christian , Klapper Wolfram , Peipp Matthias , Gramatzki Martin
Published: May 2019

e14004

Background: Monoclonal antibodies are established treatment options for B cell-derived malignancies, but relapse is still the major challenge. Novel target structures may open alternative avenues to develop effective antibody therapies. Here, we characterized the novel tetravalent antibody ‘EBU-141 Tetra’ and identified the glycoantigen CD75s (α-2,6-sialylated lactosamines) as suitable target structure for antibody-based therapy. CD75s was detected on most B cell lymphomas, including Burkitt’s lymphoma, FL, DLBCL, MCL, CLL, and plasma cell tumors. Classical Hodgkin lymphomas were consistently negative while reactivity on individual cases of peripheral T cell lymphoma was seen. To evaluate CD75s as a target for antibody therapy, we generated a tetravalent, Fc-engineered chEBU-141 IgG1 antibody with enhanced avidity for CD75s and potent effector functions. Methods: ‘EBU-141 Tetra’ was produced by transient transfection and purified by affinity chromatography. Direct anti-tumor effects and Fc-mediated effector functions were investigated in cell proliferation assays, by fluorescence microscopy and in 51Cr release experiments using lymphoma and myeloma cell lines and patient-derived tumor cells. Peripheral blood mononuclear cells and monocyte-derived macrophages of healthy donors were used as human effector cells in the experiments. Results: ‘EBU-141 Tetra’ showed improved binding to CD75s on cell surface of mature B cell lymphoma as well as myeloma plasma cells compared to the conventional chimeric antibody chEBU-141 IgG1. The higher avidity for CD75s resulted in markedly improved ADCC activity of ‘EBU-141 Tetra’ against Daudi Burkitt’s lymphoma, U266 plasma cells and CLL patient-derived tumor cells with EC50 values in the low nanomolar range. In addition, ‘EBU-141 Tetra’ demonstrated efficient phagocytosis of Burkitt’s lymphoma and myeloma cell lines. Thus, the novel tetravalent, chimeric, Fc-engineered antibody ‘EBU-141 Tetra’ efficiently recruits immune effector cells for tumor cell lysis. Conclusions: Our findings further demonstrate that highly potent IgG-like antibodies against glycan-structures can be generated from mouse IgM antibodies and may open a new therapeutic window for therapy of patients with mature B cell lymphomas and multiple myeloma.