bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between underlying causes of HCC and its complications.
Authors: Kyung Daniel , Perimbeti Stuthi , Adepoju Bolanle , Hanson Shaun Bryan , McCormack Michael Joseph , Ward Kristine Marie , Jain Maneesh Rajiv , Styler Michael
Published: May 2019

e13123

Background: Hepatocellular carcinoma (HCC) remains the 4th leading cause of cancer mortality in the US. While mortality varies by stage, the presence of certain HCC-related complications contribute to increased mortality. In this study, we assessed whether the underlying cause for HCC influenced the frequency of common complications. Methods: The National Inpatient Sample between 1999 and 2014 was analyzed using ICD-9 codes. The ICD-9 code for HCC was used to extract all admissions from the years 1999-2014 and weighted to approximate the full inpatient population of the US over the 16 year interval. The prevalence of HCC-related complications were calculated for portal vein thrombosis (PVT), erythrocytosis, peritonitis, esophageal variceal bleeding (EVB), portal hypertension (Portal HTN) and hepatic encephalopathy (HE). Bivariate analysis using Chi square test was performed to compare the percentages of each complication with underlying risk factors for HCC (HBV, HCV, NASH and alcohol). Results: Total of 131,115 admissions (weighted = 648,732) was identified to have HCC. Conclusions: Portal HTN was the most common complication associated with HCV and NASH, whereas hepatic encephalopathy was most frequently seen with alcohol and PVT with HBV, respectively. Alcohol was associated with the highest rate of HCC-complications with the exception of portal vein thrombosis. HBV was associated with the lowest frequencies of complications except for PVT, for which it was the highest. Future studies might look at whether disease modifying measures such as cessation of alcohol and eradication of active HBV, HCV would impact the natural history of HCC.[Table: see text][Table: see text]
Suspected and confirmed germline variants from tumor-only somatic sequencing of 864 gastrointestinal malignancies.
Authors: Khanna Shivani , Maron Steven Brad , Chase Leah , Lomnicki Samantha , Kupfer Sonia , Catenacci Daniel V.T.
Published: May 2019

e13131

Background: Targeted tumor-only somatic sequencing informs therapies and is becoming a routine part of cancer care. It also identifies patients with possible germline variants who require confirmatory genetic testing. The aim was to identify patients with suspected and confirmed germline variants whose GI tumors underwent somatic sequencing. Methods: 864 patients with GI tumors who had Foundation One (FO) somatic sequencing from 4/2003-3/2018 were evaluated. Inclusion criteria for suspected germline variants were: a) allele frequency ≥ 35% in hereditary cancer genes and b) pathogenic variants by FO and/or ClinVar. Variants in commonly mutated somatic genes ( TP53, KRAS, CDKN2A) were excluded in patients over age 40. Recommendation of genetic evaluation and germline test results were recorded. Patient, family, and tumor characteristics were compared using univariate analysis. Results: 199 of 864 patients had suspected germline pathogenic variants. 50 patients were recommended genetic evaluation, and 26 patients underwent genetic testing. A germline pathogenic variant was confirmed in 15 patients. Among all patients suspected to have germline variants, 8% were confirmed by genetic testing. Patients under age 40 and those with family cancer history were more often referred for testing (Table). Patients with variants in BRCA1, MLH1, MSH2, PMS2, POLE and TP53 were more often referred for testing. Conclusions: A quarter of patients carried a somatic pathogenic variant with allele frequency ≥35% in a hereditary cancer gene. 25% of these patients were recommended for genetic evaluation. Younger patients and those with family history were more often referred. 8% of patients with suspected germline variants were confirmed by genetic testing. These results provide “real world” experience in using somatic only tumor testing to identify patients with germline pathogenic variants who then might benefit from future cancer screening and genetic testing in family members. Comparison of characteristics by recommendation to undergo genetic testing based on somatic tumor sequencing results. [Table: see text]
Determination of the immunogenetic risk of developing cancer.
Authors: Miklós István , Toke Eniko Rita , Megyesi Mónika , Molnar Levente , Tóth József , Lőrincz Orsolya , Somogyi Eszter , Csiszovszki Zsolt , Pántya Katalin , Páles Péter , Lori Franco , Lisziewicz Julianna
Published: May 2019

e13132

Background: Association between certain HLA types and cancer is well known. We hypothesized that the number of epitopes of tumor antigens presented by autologous HLAs characterizes a patient’s capacity to kill tumor cells. These CD8+ T cell epitopes are presented by 6 out of >13,000 known HLA class I alleles and induce extremely variable tumor-specific T-cell responses. Methods: We predicted HLA-binding epitopes from 48 frequently expressed tumor antigens in subjects characterized with 6 HLA class I alleles. To develop the “HLA Score” cancer risk predictor we used epitopes binding to multiple HLAs of a subject. The predictor was trained on 5,789 non-American subjects. To identify populations with high and low immunogenetic risk to develop cancer we compared the HLA Score of American cancer subjects to a general population of American subjects (1,400 subjects). The performance of the predictor was characterized with AUC and Risk Ratio. Due to Bonferroni correction, AUC values with p-value p<0.007 was accepted as significant. Results: “HLA Score” predictor significantly separated cancer patients from the general population in six out of the seven investigated cancer types. The Risk Ratios between the most protected and most at risk subpopulations ranged between 2.38 and 5.67 (Table). Cancer risk prediction with HLA Score. Conclusions: Subjects with certain HLA class I alleles have high risk of developing cancer. The novel “HLA Score” predictor we introduced here could complement current testing used for determination of the genetic risk of cancer.[Table: see text]
Thank you, next: The impact of next-generation sequencing in clinical decision making.
Authors: Davis William , Makar Gabriel , Kubicek Greg J.
Published: May 2019

e13136

Background: Next Generation Sequencing (NGS) is increasingly used to identify actionable mutations for oncology treatment. We examined the results of NGS at our institution. Methods: We retrospectively reviewed the medical charts of 305 consecutive patients who had genomic testing performed on tumor samples from March 2014 to April 2017. Next Generation Sequencing was performed by Foundation One testing. Results: Of the 305 tissue samples sent to Foundation One, 189 reports were potentially usable. Reports were unusable due to an insufficient quantity of tissue (43), inadequate follow-up (32), cessation of oncologic care due to transferring to hospice or expiring (32), or a report not being generated due to the order being cancelled (4) or undocumented reasons (5). Of the 189 usable reports, 76 (40.21%) demonstrated an aberration targetable by on-label therapies, 126 (66.67%) via off-label therapies (66 of these had no available on-label treatment), and 170 (89.94%) revealed actionable aberrations via all potential avenues, including clinical trials. 19 (6.2%) yielded a change in management, 6 of these changes were utilizing on-label therapies, 6 were via off-label therapies, 3 were via enrollment in a clinical trial, and 4 involved discontinuing a medication with a predicted poor response. For the 6 patients with off-label use, median duration of treatment was 46 days and discontinued secondary to death (3 patients) or progression (3 patients). Conclusions: Only a minority of NGS assay results (6.2% percent of all tests ordered and 10% of useable tests) resulted in a management change. A small minority (6 patients, 1.9%) were started on off-label therapy based on NSG results and overall had poor responses to off-label treatment. While in theory NGS may improve oncology outcome, the results of our initial 305 patients who had NGS was poor.
Oncobox, gene expression-based second opinion system for predicting response to treatment in advanced solid tumors.
Authors: Poddubskaya Elena , Buzdin Anton , Garazha Andrew , Sorokin Maxim , Glusker Alex , Aleshin Alexey , Allina Daria , Moiseev Alexey , Sekacheva Marina , Suntsova Maria , Kim Ella L , Gaifullin Nurshat , Tkachev Victor , Giese Alf , Barbara Viktoria , Borger Pieter , Borisov Nikolay
Published: May 2019

e13143

Background: Anticancer Targeted Drugs (ATDs) specifically target one or a few types of tumor-related molecules in a cell. More than two hundred of ATDs were approved worldwide. They have different mechanisms of action and are effective for different cohorts of patients. However, many individual cases remain poorly responsive and it is of great importance to identify predictive markers of ATD efficacy. Our aim was to develop a platform enabling smart selection of the most efficient ATD therapies. Methods: We generated a second-opinion platform for clinical oncologists termed Oncobox. It is based on the analysis of gene expression profile of a cancer sample in comparison with the corresponding normal tissue biosamples in order to personalize selection of targeted drugs for individual cancer patients. Based on RNA-seq gene expression data, pathway activation levels are calculated and along with the concentrations of molecular target genes products used as predictors of tumor response to ATDs. Results: The Oncobox method was tested first on the retrospective samples of advanced tumors: gastric, renal cell, ovarian and colorectal cancers, thus showing ROC AUC values > 0.7. In currently ongoing prospective trial for advanced solid tumor patients, the Oncobox tests were completed for 239 patients, primary feedback information received for 144 patients. 25 patients (17%) died before prescription of the therapy, 19% received palliative care treatment, 39% received Oncobox-recommended therapies and 25% received other therapies (February 2019). Tumor responses were estimated for 30 patients (breast, colorectal, ovarian and other cancers) receiving therapies, with disease control rate of 71% for Oncobox-recommended ATDs (Bevacizumab, Crizotinib, Trastuzumab and others) and 44% for other therapies. Our results also suggest that cancer metastases and primary tumors may have different gene expression, molecular pathway activation and drug scoring patterns, thus pointing to the importance of testing multiple tumor sites. Conclusions: Our study suggests that profound analysis of gene expression profiles of tumor tissues may be useful for ATDs treatment of advanced and metastatic cancers. Clinical trial information: NCT03724097.
Specific clonal expansion at disease progression (PD) in solid cancers pinpointed by cell free DNA analysis.
Authors: Frullanti Elisa , Palmieri Maria , Baldassarri Margherita , Fava Francesca , Fabbiani Alessandra , Gelli Elisa , Tita Rossella , Torre Pamela , Petrioli Roberto , Hadijstilianou Theodora , Galimberti Daniela , Cinotti Elisa , Mencarelli Maria Antonietta , Pinto Anna Maria , Francini Edoardo , Marsili Stafania , Francini Guido , Renieri Alessandra
Published: May 2019

e13144

Background: More than 50% of solid cancers sooner or later escape control of standard treatments. Detection and analysis of cell free circulating DNA (cfDNA) now offer the possibility to detect key mutations of cancer driver genes which may play a major role in the therapy escaping mechanism. We sought to identify clones of solid tumors escaping standard treatments in order to assess personalized treatment at PD. Methods: A cohort of patients with 10 different solid tumors progressing after standard therapy were selected. CfDNA analysis was performed using PAXgene blood ccfDNA tubes (QIAGEN), MagMAX cell-free total nucleic acid isolation kit, and ION PROTON platform (ThermoFisher Scientific). Results: Next generation sequencing analysis of 52 cancer-driver genes of cfDNA samples of 39 patients allowed for picking up clones plausibly involved in the PD mechanism in 60% of cases. A mean of 1.3 mutated genes (range 1-3) for each tumor was found. Point mutations in TP53, PIK3CA, and CNV in FGFR3 were the most commonly observed, with a rate of 41%, 16%, and 13%, respectively. Increased copy number variations of FGF receptors were identified in patients with non-small cell lung, pancreatic, and gastric cancer, and cholangiocarcinoma. Other clones had mutations in ESR1 (breast), CTNNB1 (uterus), KRAS and CCND2 (pancreas), EGFR and BRAF (lung). Interestingly, retinoblastomas resistant to Melphalan showed expanding mutated clones in PTEN or SMAD4. Increased levels of cfDNA were observed in the plasma of all patients. Conclusions: The results presented here show that irrespective of the primary tumor mutational burden and subsequent complex clonal evolution, a simplified mutational load is present at PD. One or few “sniper” clones drive progression and the molecular profile has a weak correlation with the primary tumor. Single driver mutations in TP53 remain the main target of a not yet developed specific therapy in most tumors such as breast, ovarian, uterine, lung, gastric cancers and glioblastoma. Among the actionable mutations, PIK3CA were found, not only in breast cancers, but also in uterine carcinoma, Sezary syndrome and glioblastoma, pinpointing the needs of specific trials in these tumors.
Germline analysis of DNA-damage repair genes in men with advanced prostate cancer in comparison to women with breast cancer.
Authors: Kunz Amy , Tri Natalie , Samiei Arash , Mao Shifeng
Published: May 2019

e13147

Background: Women with breast cancer have traditionally been the population for genetic counseling. The association of hereditary cancer syndromes and the development of advanced prostate cancer have been established only since recent years. There has been increased utilization of germline analysis in men with prostate cancer since NCCN updated its guideline on genetic testing for DNA damage repair (DDR) genes in the homologous recombination (HR) pathway in this population. In this study, we analyzed the prevalence of genetic alterations in DDR genes in men with advanced prostate cancer in relevance to women with breast cancer in our institution. Methods: Patients who were referred to genetic counseling in 2018 and met NCCN criteria underwent genetic testing following pretest genetic counseling. Samples obtained from buccal mucosa or peripheral blood were analyzed for germline variants using commercially available multi-gene panels which included DDR genes in the HR pathway. Results: In 2018, 54 men with prostate cancer with relapsed disease following local therapy, or de novo metastasis, and 305 women with breast cancer were included. At least one pathogenic or likely pathogenic variant was identified in 9 men (16.7%), most frequently in BRCA2, ATM, and CHEK2, as compared to those in 30 women (9.8%), p = 0.137. 17 men (31.5%) had at least one variant of uncertain clinical significance (VUS) detected in a DDR gene as compared to those in 74 (24.3%) women with breast cancer, p = 0.261. Conclusions: Men with advanced prostate cancer have a statistically comparable but numerically trending higher frequency of pathogenic variants and VUS in DDR genes detected on germline testing in comparison to women with breast cancer. The high prevalence of VUS in prostate cancer is an intriguing finding. VUS represent a genetic alteration with undefined clinical outcome. With increasing genetic testing in prostate cancer, further correlation between VUS of DDR genes and clinical risk features from a larger population is warranted.
Auxiliary diagnosis of pulmonary nodules using liquid biopsy and deep learning/techniques.
Authors: Bai Li , Zhou Yanqing , Chen Yaru , Liu Quanxing , Zhou Dong , Zheng Hong , Dai Jigang
Published: May 2019

e13154

Background: Many people harbor pulmonary nodules. Such nodules can be detected by low-dose computed tomography (LDCT) during regular physical examinations. If a pulmonary nodule is small (i.e. < 10mm), it is very difficult to diagnose whether it is benign or malignant using CT images alone. To address this problem, we developed a method based on liquid biopsy and deep learning to improve diagnostic accuracy of pulmonary nodules. Methods: Thirty-eight patientsharboring one or more small pulmonary nodules were enrolled in this study. Twenty-nine patients were diagnosed as having cancer (stage I = 21, stage II = 1, stage III = 3, stage IV = 4) using tissue biopsy, while the other 9 patients were diagnosed as having benign tumors or lung diseases other than cancer. For each patient, a blood sample was obtained prior to biopsy, and the cell free DNA (cfDNA) was sequenced using a 451-gene panel to a depth of 20,000×. The unique molecular identifiers (UMI) technique was applied to reduce false positives. Seventeen patients also had full-resolution CT images available. A deep learning system primarily based on deep convolutional neural networks (CNN) was used to analyze these CT images. Results: Sequence analysis of blood samples revealed that 75.8% (22/29) of cancer patients had detectable cancer related mutations, and only 1 of 9 (11.1%) non-cancer patient was found to carry a TP53 mutation. The most frequent mutations seen in cancer patients involved genes TP53 (N = 11), EGFR (N = 7), and KRAS (N = 3) with mutant allele fractions varying from 0.08% to 74.77%. Deep learning analysis of the 17 available CT images correctly identified cancers in 88.2% (15/17) of patients. However, by combining the liquid biopsy and image analysis results, all 17 patients were correctly diagnosed. Conclusions: Deep learning-based analysis of CT images can be applied to early diagnosis of lung cancers; but the accuracy of image analysis, when used alone, is only moderate. Diagnostic accuracy can be greatly improved using liquid biopsy as an auxiliary method in patients with pulmonary nodules.
EMR documentation of genetics evaluations in patients with ovarian cancer.
Authors: Shah Payal Deepak , Symecko Heather , Batson Melissa , Pundock Stacy , Rustgi Neil , Haggerty Ashley Ford , Ko Emily Meichun , Martin Lainie P. , Nathanson Katherine , Domchek Susan M.
Published: May 2019

e13156

Background: Genetic testing for hereditary cancer predisposition has become increasingly complex yet impactful. Provider knowledge of test results influences risk management, implications for family members, and therapeutics. Currently, it’s unknown if genetic test (GT) results are appropriately recorded and accessible within the electronic medical record (EMR). Methods: We conducted a single-institution retrospective chart review to examine clinical diagnoses, family history of cancer, genetics referrals, and genetics services received at University of Pennsylvania’s Cancer Risk Evaluation Program (CREP) or elsewhere. The study cohort included new and prevalent cases of ovarian cancer (OC) seen by either a gynecologic or medical oncologist at the University of Pennsylvania in 2016. Analyses were conducted using SAS 9.4. Results: 667 women (83% white, 9% black, 4% Asian; mean age 61) with OC were included. 58% had a documented family history of breast, ovarian, prostate or pancreas cancer. 48% had documentation of referral to genetic testing and an additional 26% had documentation of testing outside of CREP. 26% had no documentation of referral or testing. Of those referred to CREP, 75% had genetic testing: in total 62% of the cohort had documented testing. 94% of those tested had a result documented in a provider note, and 64% had a scanned testing report uploaded into the EMR, including 74.3% of those tested through CREP and 25.7% of those tested outside. Among the 118 pathogenic mutations, 70% were documented on the EMR “problem list.” Conclusions: In this study, most, though not all, OC patients had documentation of a GT referral or testing in the EMR. Although GT results were routinely included in progress notes, these reports were less commonly scanned into the EMR (particularly for those tested outside Penn) or included in the EMR “problem list” which is both searchable and immediately visible. Capturing genetic data in a uniform and easily accessible manner within the EMR is necessary to maximize clinical utility of this information and should be a focus for EMR module development.
Effect of SSH1/SSH2 expression changes by shRNA in glioma cell lines on response to radiotherapy and cofilin-1 reactivation.
Authors: Xiao Hong
Published: May 2019

e13505

Background: Radiotherapy has become the most important treatment for malignant glioma following surgery. However, development of radioresistance in glioma cells limits therapeutic efficacy. The slingshot (SSH) family of phosphatases is a potent regulator of Cofilin-1 activation. Methods: We investigate the role of SSH1(slingshot protein phosphatase 1) and SSH2 in radioresistance via using shRNA to block SSH1/2 expression in U251 and U373 cells as well as established radioresistant U251 (RR-U251) and U373 (RR-U373) cells. Results: We found that both SSH1 and SSH2-shRNA efficiently sensitized glioma cells to radiation with a sensitization enhancement ratio (SER) of 1.01-1.73. In SSH1-silenced cells, the cell viability, migration, and invasion abilities following radiation were remarkably reduced and radiation induced cell apoptosis was markedly enhanced compared with control cells. While in SSH2-silenced cells, the alterations were not as significant. Furthermore, the result of Western-blot suggested that radiosensization of SSH1/SSH2 silencing was mediated by inhibiting reactivation of phosphorylated CFL-1. Conclusions: Our study demonstrated that SSH1 and SSH2 are valid radiosensitizing targets in not only normal glioma cells but radioresistant lines, suggesting a novel therapeutic strategy to improve the efficacy of radiotherapy in patients with glioma.
The effect of everolimus on CNS penetration and efficacy of dasatinib in the treatment of PDGFRA-driven glioma.
Authors: Miklja Zachary , Mullan Brendan , Siada Ruby , Stallard Stefanie , Yadav Viveka Nand , Bruzek Amy , Garcia Taylor , Leonard Marcia , Robertson Patricia , Paul Alyssa , Pai Manjunath , Phoenix Timothy , Marini Bernard , Koschmann Carl Johannes
Published: May 2019

e13508

Background: Pediatric and adult high-grade glioma (HGG) frequently harbor PDGFRA alterations. The CNS penetration of PDGFRA inhibitors, such as dasatinib, is limited by the tumor-efflux protein P-glycoprotein (P-gp). We hypothesized that co-treatment with everolimus, which has been shown to block P-gp, will increase CNS penetration and efficacy of dasatinib in in vitro and in vivo models as well as in human PDGFRA-driven glioma. Methods: Tumors were generated in mice using an intra-uterine electroporation (IUE) model [introduction of TP53, PDGFRA and H3K27M mutations in pre-natal cortex]. Dose response, synergism studies, P-GP inhibition and pharmacodynamics/pharmacokinetic studies were then performed on in vitro and in vivo models employing this IUE system. A phase 2 trial employing dasatinib and everolimus was established for children with HGG and diffuse intrinsic pontine glioma (DIPG) that contain PDGFRA alterations (NCT03352427). Paired CSF/plasma samples (before and after addition of everolimus) were collected from enrolled patients. Results: Dasatinib effectively treated mouse HGG cells with an IC50 of 100 nM. Dose-dependent reduction in PDGFRA and pPDGFRA was found. P-gp inhibitor assay confirmed that everolimus strongly blocks P-gp activity at 1 uM (p = 0.0028 vs untreated). Mice treated with dasatinib and everolimus had extended survival as compared to control. Two-hour exposure to everolimus resulted in sub-IC50 dasatinib concentration in cortex (23 nM) and tumor (65 nM). 24-hour exposure to everolimus resulted in greater cortex (235 nM) and tumor (509 nM) concentrations. Two trial patients, recurrent HGG ( PDGFRA-amplified) and recurrent DIPG ( PDGFRA D842V) respectively, survived 6 months and 9 months (ongoing) after progression, which compares very favorably to historical controls. A paired CSF sample from the PDGFRA-amplified patient showed a 50% increase in CSF dasatinib level after addition of everolimus. Conclusions: Dasatinib treatment of PDGFRA-driven HGG is improved with everolimus blockade of P-gp and represents a novel route for improving CNS penetration and efficacy of therapies for HGG. Clinical trial information: NCT03352427.
Circulating endothelial cells: Prognostic value in patients with glioblastoma.
Authors: Vaz Salgado María Ángeles , Earl Julie , Berrocal Victor Rodriguez , Salge Freddy , Gomez Ana , Corral de la Fuente Elena , Sepulveda Sanchez Juan Manuel Manuel , Perez-Núñez Angel , Muriel Alfonso , Lourido Daniel , Carrato Alfredo , Ley Luis
Published: May 2019

e13517

Background: Glioblastoma (GB) is an aggressive tumor. Circulating Endothelial Cells (CECs) can be detected in peripheral blood and have been related to angiogenesis. CECs have an unclear prognostic value in patients with glioblastoma. The objective of this study was to quantify the presence and number of CECs in GB patients and determine its potential prognostic role. Methods: In this prospective, single center study, peripheral blood samples were obtained at the time of GB diagnosis. For the detection of CECs, 4 ml of blood was analyzed using the CellSearch system (Veridex). CEC blood samples were classified as CD146+, CD105+, CD45− and DAPI+. CEC detection was performed prior to surgery in a total of 26 patients and 22 patients with glioblastoma were included in the final analysis. We mesured progression free survival (PFS) and overall survival (OS). Results: Between 2014 and 2016, twenty two patients with histologically confirmed glioblastoma were studied. There were 14 males and 8 females with an average age of 63 years (range 42-81). A complete resection was achieved in 50% of cases, partial or subtotal resection in 31.8% and biopsy in 18%. The mean number of CECs was 59.3 cells/mL (range 0-954). Patients were classified into two groups depending on the number of CECs: group 1 had a CEC count below the mean and group 2 had a CEC count above the mean. A total of 17 patients (77.2%) were in group 1 and 5 patients (22.7%) were in group 2.The median OS was 14.4 months (range -0.36-33.36) for the entire study population. The median OS was 17.4 months (IC95% 11.47-23.37) for patients in group 1 and 8.12 months for patients in group 2 (IC 95% 4.38-11.85) p = 0.002. The median PFS was 8.94 m (IC95% 5.1-12.69) for group 1 and 3.95 for group 2 (IC 95% 2.91-4.98) p = 0.097. Conclusions: CECs can be detected in recently diagnosed GB patients. The present study demonstrates a possible prognostic value for CEC determination in GB cases at the time of diagnosis.
Ethics consultations in patients with neuro-oncologic diseases.
Authors: Sener Ugur , Neil Elizabeth C. , Carver Alan , Diamond Eli L. , Voigt Louis
Published: May 2019

e13519

Background: In patients with cancer, ethical issues regarding patient autonomy, surrogate decision making, and end-of-life care often arise. Ethics consultation can help clarify perspectives of different stakeholders involved in a patient’s care, facilitate communication, and resolve conflicts. Neurologic manifestations of cancer can cause impairment of cognition, communication, and functional independence. Ethical conflicts in the specific context of neuro-oncologic diseases have yet to be characterized. Methods: In this retrospective study, we reviewed 50 cases where ethics consultation was requested for patients with neurologic malignancies or neurologic complications of cancer treated at Memorial Sloan Kettering Cancer Center (MSK). Results: Of 50 patients (ages 4-76, 56% female) reviewed, 27 had a primary central nervous system (CNS) malignancy, 21 had CNS metastasis, one had a vascular malformation, and one had no clear diagnosis. Neurologic issues contributing to patients’ clinical status included toxic metabolic encephalopathy (14), leptomeningeal disease (10), intracerebral hemorrhage (10), hydrocephalus (9), seizures (6), cord compression (5), and ischemic stroke (3). At the time of ethics consultation, 39 patients lacked decision-making capacity, 47 did not have an advance directive, and 38 did not have a do not resuscitate (DNR) order. Ethical issues identified included surrogate decision making (20), DNR (18), capacity (6), refusal of treatment (5), futility (4), brain death (4), and research ethics (2). Contextual issues included staff-family conflict (22), cultural or religious considerations (10), intra-family conflict (7), intra-staff conflict (6), and physician attitude toward treatment (3). Conclusions: Neuro-oncologic diseases present a unique constellation of ethical conflicts, particularly about end-of-life care. Language and cognitive deficits, impaired decision-making, and sudden neurological decline are factors that shape ethical conflicts in this clinical setting. Further study of ethical issues in neuro-oncology may help patients receive care that is consistent with their goals and values.
RNA-sequencing and bioinformatic analysis to pre-assess sensitivity to targeted therapeutics in recurrent glioblastoma.
Authors: Kim Ella L , Buzdin Anton , Sorokin Maxim , Poddubskaya Elena , Poddubskiy Artem , Kantelhardt Sven R , Kalasauskas Darius , Sprang Bettina , Bikar Sven Ernoe , Giese Alf
Published: May 2019

e13533

Background: This study developed molecular guided tools for individualized selection of chemotherapeutics for recurrent glioblastoma (rGB). A consortium involving clinical neurooncologists, molecular biologists and bioinformaticians identified gene expression patterns in rGB and quantitatively analyzed pathways involved in response to FDA approved oncodrugs. Methods: From2016 to 2018 biopsies from GB were collected using a multisampling approach. Biopsy material was used to isolate glioma stem-like cells and examined by RNA-sequencing. RNA-seq results were subjected to differential expression (DE) analysis and Oncobox analysis – a bioinformatic tool for quantitative pathway activation analysis. Results for newly diagnosed (nGB) and rGB (tissue samples and cell cultures) were compared. Oncobox analysis was further used to examine differential activation of pathways involved in response to existing chemotherapeutics. Results: 128 tissue samples and 28 cell cultures from a total of 44 GBs including 23 nGB, 19 rGB and 2 second-recurrent GBs were analyzed. 14 patient-matched pairs of nGB and rGB were obtained. DE analysis of nGB and rGB, showed a distinct “signature” associated with rGB. Oncobox analysis found down regulation of pathways related to cell cycle and DNA repair and upregulation of immune response pathways in rGB vs corresponding nGB. Specifically, pathways targeted by temozolomide, which is the first line chemotherapy for GB, were found down regulated in rGB. Among the top pathways upregulated in rGB were the pathways targeted by durvalumab and pomalidomide currently under investigation in phase II or III trials for GB. Conclusions: Specific pathway analysis revealed regional and clinical stage-associated differences in the transcriptional landscapes of nGB and rGB. Our results support a concept of treatment-induced resistance to cytotoxic therapeutics and indicate that temozolomide and radiation treatment have important impacts on gene expression changes associated with GB recurrence. Systematic molecular profiling of rGB is a promising avenue towards predicting sensitivity to targeted therapeutics in rGBs on an individual basis.
Mutations of H3.3 and H3.1 in a large cohort of glioma tumors.
Authors: Sumrall Ashley Love , Xiu Joanne , Eschbacher Jennifer M , Mittal Sandeep , Gatalica Zoran , Pandey Manjari K , Phuphanich Surasak , Korn Wolfgang Michael , Fuller Gregory N. , Heimberger Amy B.
Published: May 2019

e13540

Background: Mutations in the histone genes H3.3 and H3.1 are driver events in pediatric and adult gliomas and carry diagnostic and prognostic importance for tumors originating from midline structures. Patients with tumors affected by these mutations are notoriously difficult to treat, and the prevalence and molecular correlates of H3 mutations in a large glioma population have not been systematically reported. We aim to survey a large cohort of gliomas for H3-mutations. Methods: Consecutive gliomas submitted for tumor profiling at Caris Life Sciences from 2015- 2018 were analyzed. NextGen sequencing was done on 592 genes (NextSEQ Illumina); MGMT promoter methylation was tested by pyrosequencing; and EGFRvIII and gene fusions were tested by RNA-sequencing (ArcherDx FusionPlex). Results: Of the 1763 tumors analyzed, 41 harbored H3F3A alterations, including 33 with the K27M mutation (4 arose from the spinal cord, 1 from cerebellum, 1 from brain stem, 4 from thalamus, and 23 from brain, NOS). Eight G34R mutations were identified. A HIST1H3B-K27M was detected in a tumor from the brain stem. Overall, H3 mutations were more prevalent in pediatric tumors (8 of 26, 31%) than adult tumors (34 of 1737, 2%). All H3 mutations seen in pediatric tumors were from grade IV tumors. Among the 34 H3-mutated adult tumors, histology differed. There were 2 grade II tumors (diffuse astrocytoma), 1 low grade glioma from the spinal cord, 1 anaplastic ganglioglioma and 2 anaplastic astrocytomas. In the investigated cohort, H3-mutations were mutually exclusive of IDH1/2 mutations and EGFR alterations. Significantly higher mutation rates were seen in H3-mutated tumors for TP53 (69%. Vs. 37%), ATRX (46% vs. 24%), NF1 (23% vs. 12%) , PDGFRA (17% vs. 1%), FGFR1 (12% vs. 1%), FBXW7 (5% vs. 0), BLM (3% vs. 0) and TSC2 (2% vs.0) compared with H3-WT (p < 0.05). The H3-WT tumors were more enriched for MGMT-methylation (53% vs. 26%) and PTEN mutation (22% vs. 7%) (p < 0.05). In H3-mutated tumors that were MGMT-methylated (n = 10), most H3-mutations seen were G34R (n = 8) while K27M (n = 2) was largely exclusive. Conclusions: This survey of a large cohort of gliomas revealed a heterogeneous distribution of H3 mutations. The co-occurring molecular alterations seen in H3-mutated tumors further support the hypothesis that these tumors are a distinct molecular entity. By better characterizing these associations, we are closer to developing more insight into novel treatment strategies for a class of tumors with historically dismal prognosis.
Assessment of neurocognitive function in illiterate patients of high-grade glioma treated with chemoradiation.
Authors: Malik Monica , Valiyaveettil Deepthi , Ashalatha G , E Prathyusha , Joseph Deepa M.
Published: May 2019

e13543

Background: Although the role of chemo-radiation (CRT) in gliomas has been studied extensively, its effects on neurocognitive function (NCF) remain elusive. Assessment of NCF in illiterate patients is a challenge. Methods: Illiterate adults with histopathologically proven high grade gliomas planned for CRT following maximal safe resection were included. Temozolomide based CRT using standard protocols was planned. Neurocognitive function was assessed using the Addenbrooke’s Cognitive Examination (ACE-III) questionnaire prior to the start of CRT and at 3 and 6 months post RT. The subventricular zones (SVZ) and hippocampus were contoured using standard guidelines. The NCF scores were compared using the paired t test. Results: 32 patients were recruited. The median age was 40 years. M:F ratio was 1:1.16. IMRT to a dose 60 Gy with concurrent and adjuvant temozolomide was planned. Overall there was no significant difference in scores at 3 months and a significant decline in visuospatial scores at 6 months (p < 0.001). Mean doses to the ipsilateral and contralateral SVZ were 49.5 Gy and 35 Gy respectively. Based on mean ipsilateral SVZ dose, patients were divided into: Group I < 50 Gy (n = 18), group II ≥ 50 Gy (n = 14). At 3 months there was significant improvement in scores in Group I whereas a decline in scores in Group II. At 3 months, memory (18.73 vs 21.93; p = 0.021) and fluency (10.20 vs 11.67; p = 0.042) showed improvement in group I patients. In group II there was decline in visuospatial scores (14.41 vs 13.71; p = 0.016) at 3 months. At six months, there was improvement in memory (17.94 vs 22.94; p = 0.002), attention (14.78 vs 16.39; p = 0.031), fluency (10.11 vs 11.67; p = 0.018) and total ACE scores (80.83 vs 89.94; p = 0.008) in group 1 patients and a significant decline in visuospatial function, attention, memory and language scores in group II patients. Higher contralateral SVZ doses (> 35 Gy) correlated with a significant decline in visuospatial scores at 3 and 6 months. Lower mean dose to ipsilateral hippocampus (< 40 Gy) correlated significantly with improved memory scores. Doses to contralateral hippocampus did not correlate with scores. Conclusions: The Addenbrooke’s Cognitive Examination (ACE-III) questionnaire can be used to assess NCF in patients with gliomas including illiterate patients. Lower mean doses to the ipsilateral and contralateral SVZ and hippocampus resulted in improvement/preservation of memory, attention and fluency whereas higher doses were associated with a decline in scores.
Factors influencing the intracellular exposure of gemcitabine triphosphate in children with CNS tumors.
Authors: Campagne Olivia , Zhong Bo , Selvo Nicholas , Owens Thandranese S , Gajjar Amar J. , Robinson Giles W. , Stewart Clinton F.
Published: May 2019

e13547

Background: Gemcitabine (dFdC), a cytosine analog, is currently being evaluated as a therapy to treat children and young adults with central nervous systems (CNS) tumors in two clinical trials (NCT01878617 and NCT03434262). Once in the cell, dFdC undergoes complex and highly variable conversion to gemcitabine triphosphate (dFdCTP), which is responsible for its cytotoxic effects. Our objective is to identify the factors influencing dFdC and dFdCTP exposures in children. Methods: As part of treatment, patients with newly diagnosed medulloblastoma and patients with recurrent/refractory medulloblastoma or ependymoma receive 28-day cycles of dFdC, as a 30-minute IV infusion at 750, 1000 or 1250 mg/m2 on days 1 and 15 of each cycle. Patients with recurrent/refractory disease also receive concomitant ribociclib. Pharmacokinetic (PK) studies were performed after one dose of dFdC alone (day 1) and with ribociclib (day 15). dFdC and dFdCTP concentrations were measured in plasma and in peripheral blood mononuclear cells respectively, for up to 4h post-dose, using validated LC-MS/MS methods. The concentrations were analyzed using a population PK model. A preliminary covariate analysis was performed to evaluate the impact of factors (e.g., patient demographics and infusion rate) on dFdC and dFdCTP exposure (area under the curve). Results: dFdC and dFdCTP concentrations were fitted with a three-compartment linear model. dFdC infusion rate significantly influenced the drug exposures with a faster plasma dFdC elimination and higher dFdCTP formation observed at the lower infusion rate. On average, patients receiving dFdC as 25 or 33 mg/m2/min had a dFdCTP exposure of 526 µM·h vs 205 µM·h with a rate of 42 mg/m2/min (p < 0.001). Patient with lower body surface area also showed higher dFdC clearance. Significant intra-patient differences were observed in dFdCTP concentrations measured on days 1 and 15. Conclusions: This preliminary PK analysis shows a saturable formation of dFdCTP in children with CNS tumors, and suggests the need for longer infusion duration with higher dFdC dosages. Future work will evaluate potential drug-drug interaction with ribociclib and the effect of genotypic variants on dFdCTP exposure.
The prognosis of diffuse midline glioma H3 K27M mutant.
Authors: KIM Donghwan , Chung Chun Kee
Published: May 2019

e13548

Background: Diffuse Midline Glioma is rare spinal cord primary tumor. Unfortunately it is known that the prognosis is poor, and it was added to the WHO guidelines in 2016 as a grade IV. It is so rare that the prognosis of the diffuse midline glioma in spinal cord is not well known yet. So we want to analyze the prognosis of the spinal cord diffuse midline glioma and find out about the molecular profile. Methods: We retrospectively reviewed of 10 diffuse midline glioma H3-K27M mutant patients who underwent surgery in a single institute, 2015.09~2018.04. We analyzed the demographic data, overall survival, progression free survival and molecular profile which includes PTEN, BRAF, EGFR, MGMT methylation status, c-MET, IDH1, 1p/19q deletion. Results: Mean age was 44.8 yr; male to female ratio was 5:5. Tumor was located conus medullaris (8), CT Junction(1), Cervical(1). One was given gross total resection and the other was a partial resection or biopsy. All patient were treated with CCRT. Medial overall survival was 47.8 months, and median progression free survival was 21 months. One case each was found for BRAF, C-MET, IDH1, PTEN and EGFR. Conclusions: This study was conducted on patients collected for a relatively short period. This study reported survival analysis and molecular profile. These mutations are known to be mainly associated with MAPK pathway. So there may be a correlation between H3-K27M and MAPK pathway. Results indicating the association of MAPK and H3K27M can be found in some literature. Further research is needed.
DDR1 may be a good biomarker for brain tumors.
Authors: Erdem Dilek , Büyüksimsek Mahmut , Gunaldi Meral , Sahin Nilgun
Published: May 2019

e13557

Background: There are two important hardness in the treatment of central nerve system tumors; first of it is tumor heterogenity while the second is biomarker deficiency which can be target in the tumor tissue. For the reason we aimed to examine discoidin domain receptor (DDR1), a tyrosine kinase receptor , which may be thought to be effective in cell adhesion. Methods: 38 brain tumor were evaluated for tissue DDR1 messenger ribonucleic acid and blood DDR1 levels. We compared these with 10 control group tissue and blood levels of DDR1. Results: All brain tumor and control group tissues and blood samples were found DDR1 value positive. DDR1 levels of brain tumor tissues and blood samples were statistically higher when compared with DDR1 levels of control group tissue and blood samples. Conclusions: DDR1, found statistically higher among brain tumor tissues and blood samples may be a useful biomarker for the therapy and management of these patients.
Targeting of CD317 by the immunotoxin HM1.24-ETA’ to allow immunotherapy in glioblastoma patients.
Authors: Gramatzki Dorothee , Szabo Emese , Gramatzki Martin , Peipp Matthias , Weller Michael
Published: May 2019

e13560

Background: Glioblastoma is the most common primary malignant brain tumor with a poor prognosis. CD317 (HM1.24) is a transmembrane protein and may exist in differently spliced variants. It is highly expressed on plasma cells in multiple myeloma, as well as in certain solid tumor types. While several antibody drug conjugates are already in clinical practice, small immunotoxins with a different intracellular mode of action are only established in hairy cell leukemia. The immunotoxin HM1.24-ETA’ protein is a CD317 single chain Fv (scFv) antibody fused to a truncated version of Pseudomonas aeruginosa exotoxin A (ETA’). Methods: In vivo CD317 mRNA expression in human glioma of different grades and survival probabilities of glioblastoma patients based on CD317 mRNA expression were analyzed using the database of the Cancer Genome Atlas network (TCGA). CD317 protein expression was analyzed by immunohistochemistry in a human tissue microarray (TMA). In vitro CD317 mRNA expression was assessed by RT-PCR and CD317 protein levels by flow cytometry in several human glioblastoma cell lines. A cytotoxicity assay after treatment with HM1.24-ETA’ immunotoxin was performed in human glioblastoma cell lines. Results: Data on mRNA expression from the TCGA database demonstrated, that CD317 was upregulated in human glioblastomas compared to lower grade gliomas. In the group of glioblastoma patients increased CD317 mRNA expression was associated with decreased probability of survival ( p< 0.001). CD317 protein levels correlated directly with the tumor grade of astrocytic gliomas in the TMA. CD317 was expressed heterogeneously on mRNA and protein levels in the tested cell-lines in vitro. HM1.24-ETA’ induced cytotoxicity in CD317-positive glioblastoma cells in a concentration-dependent manner. Animal experiments currently performed suggest activity in glioblastoma xenografted mice. Conclusions: These data highlight CD317 as an interesting target antigen and HM1.24-ETA’ immunotoxin as a strategy for immunotherapy of glioblastoma patients.
Radiomics-based identification of peritumoral infiltration in de novo glioblastoma imaging presents targets amenable for potential targeted extended resection: A neurosurgical survey.
Authors: Sloan Andrew E. , Shukla Gaurav , Rathore Saima , Akbari Hamed , Gondi Vinai , Davatzikos Christos
Published: May 2019

e13573

Background: Radiomics-based machine learning tools have been developed to analyze preoperative multiparametric MR images of patients with glioblastoma (GBM) to predict various outcomes of clinical interest, such as survival, molecular mutation status, and subclinical peritumoral infiltration, all before initial surgical resection. Preoperative identification of regions containing the highest probability of subclinical tumor infiltration presents an opportunity for targeted extended resection in the setting of a clinical trial, but the willingness of neurosurgeons to perform such a procedure is not known. Methods: We selected five neurosurgeons from high volume centers ( > 20 GBM surgeries per year) and performed an in silico study of anonymized preoperative images of patients with GBM, with radiomics-based infiltration maps depicting high probabilities of peritumoral infiltration. With regards to these regions beyond the enhancing tumor, we surveyed them on their willingness to attempt biopsy, and asked them to rate whether they felt such a region could be resected. Results: Preoperative maps of 20 patients with GBM, containing 26 regions of interest depicting high-risk peritumoral infiltration regions (distributed among frontal, temporal, occipital, parietal, cerebellar, and deep loci) were presented to five expert neurosurgeons from different institutions. Of the 20 patients, a median of 90% were deemed to be safe to biopsy; a median of 55% were felt to be definitely resectable, and median 35% to be possibly resectable. 85% of the 20 subjects were felt to be good candidates for participation in a clinical trial assessing the feasibility, safety, and efficacy of targeted extended resection. Conclusions: In selected patients, experienced neurosurgeons are willing to attempt targeted extended resection using radiomics-based maps of peritumoral infiltration in the context of a clinical trial. Proceeding with development of such a trial is warranted.