tbuckley/cabot-search huggingface dataset:
FOLFIRINOX versus gemcitabine-cisplatin combination as first line therapy in treatment of pancreatic cancer
Authors: A. Ozet, N. Kayahan Satış, H. Satış
Journal: Annals of Oncology (2018)

Introduction: To purpose of this study was to compare efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) and gemcitabine-cisplatin as first-line therapy in patients with pancreatic cancer. Methods: We retrospectively evaluated pancreatic cancer patients with Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine plus cisplatin (gemcitabine at a dose of 1000 mg per square meter weekly for 1 and 2 week, cisplatin at a dose of 100 mg per square meter weekly for 1 week, every 3 weeks). Patients with at least three months chemotherapy given were included and primary end point was overall survival. Results: There were 32 patients in FOLFIRINOX group and 36 patients in gemcitabine-cisplatin group. The median overall survival was 18.1 months (7,5-28,7) in the FOLFIRINOX group as compared with 9.7 months (6,5-13) in the gemcitabine-cisplatin group (P:0.009). Median progression-free survival was 16.2 months ((9-23.4) in the FOLFIRINOX group and 6.9 months (6,1-7,6) in the gemcitabine-cisplatin group (P:0.001). More adverse events were noted in FOLFIRINOX group in terms of grade 3-4 neutropenia and diarrhea while in Gemcitabine-Cisplatin group more adverse events were noted in grade 3-4 thrombocytopenia and sensorineural neuropathy. Conclusion: As compared with gemcitabine-cisplatin combination, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is a safe and effective option for the first-line treatment of patients with pancreatic cancer and good performance status.
Influence of the visceral vessels structure variations on peculiarity of radical surgical treatment of stomach cancer
Authors: S. Khoshimov, S. Lukmonov
Journal: Annals of Oncology (2018)

Introduction: Optimization of the choice of diagnostic volume, adequate lymphodissection in patients with stomach cancer. Methods: On the basis of the Department of Oncology and Radiology of the Tashkent Medical Academy, multislice computed tomography is performed in angio-graphic mode for all patients suffering from stomach cancer, followed by a three-dimensional reconstruction of the main vessels. After the research, the preoperative planning of the operation is carried out. With the application of this method, 224 patients were examined. For radical surgical treatment, 125 patients were selected, while in 36 of them a variant anatomy of the visceral vessels of the upper abdominal wall was revealed. Given a thorough preoperative examination, all patients were radically operated in the volume of gastrectomy or distal subtotal resection of the stomach, lymphodissection in the volume of D2 and D2 + was performed. Results: In multislice computed tomography of the abdominal cavity in angiographic mode with subsequent three-dimensional modeling, one patient was identified with significant variations: all arteries of the celiac trunk separated from the aorta; the left hepatic artery (LHA) and the splenic artery moved away from the aorta, the right hepatic artery (RHA) retreated from the celiac trunk, the left gastric artery (LGA) receded from the LHA; The celiac trunk (СT) is represented by the RHA bifurcation and the splenic artery, the LHA moved away from the aorta, the LGA departed from the LHA; CT is represented by RHA bifurcation and splenic artery, LHA receded from the splenic artery, LGA departed from the LHA; The CT is represented by bifurcation of the LGA and splenic artery, the common hepatic artery (CHA) is receding from the superior mesenteric artery (SMA). In 1 case, a single celiac-mesenteric trunk was identified. In 2 patients, the CHA or splenic artery (1 patient) moved away from the aorta. In 4 patients, CT was represented by bifurcation of CHA and splenic artery, LGA departed from the aorta. In 4 cases, a cranial LHA was detected, which departs from the CT, followed by the withdrawal of the LGA. In 3 cases, the RHA was withdrawn from the SMA and there was an aberrant LHA that departed from the CT, followed by the withdrawal of the LGA. After all the operations, the lymph nodes were labeled according to the classification of the Japanese Association for the Treatment of Stomach Cancer (JGCA, 2010). In all operated patients, there were no specific complications associated with the volume of lymph node dissection. Conclusion: Performing multislice CT in angiographic mode at the preoperative stage is an effective way of visualization of the main vessels, which allows planning the volume and technique of surgical intervention depending on the revealed vascular variation, reducing the risks of intraoperative complications, more accurately performing lymphodissection and thus achieving greater radical surgical intervention.
QOL-16. ASSOCIATIONS BETWEEN SENSORY, PERCEPTUAL, AND COGNITIVE IMPAIRMENT IN THE VISUAL DOMAIN IN CHILDREN TREATED FOR OPTIC PATHWAY GLIOMA
Authors: Chiara Papini, Nicola Pitchford, Rob Dineen, David Walker
Journal: Neuro-Oncology (2018)

Paediatric optic pathway glioma (OPG) and its treatment often result in some degree of sight loss, ranging from mild deterioration to total blindness, in one or both eyes. Residual sight has been widely described through key ophthalmological measures (visual acuity, visual fields, and colour vision), but little is known about more complex processes that receive visual input. In this study, we used the three-level model of receptive processes by Hammill et al., (1993) to examine the associations between three levels of visual information processing: 1) sensation, measured through ophthalmological index of visual acuity (VA), 2) perception, assessed through the motor-reduced perception and visual-motor integration indices of the Developmental Test of Visual Perception (DTVP-2/DTVP-A) and 3) cognition, evaluated through the perceptual reasoning and processing speed IQ indices of the Wechsler scale (WISC-IV). Twelve OPG survivors (7 boys, 5 girls), aged between 6 and 13 years, were assessed on these measures. Results showed no significant correlations between VA in the best eye and the other behavioural measures, although all correlations were in the predicted direction. Strong associations were found between the two measures of perception and the two measures of cognition. Across perception and cognition, positive correlations were found, but the only significant association was between visual-motor integration and processing speed. Overall, these results show moderate to strong associations between sensation, perception and cognition within the visual domain for paediatric OPG patients, highlighting the need for clinical assessment at multiple levels of information processing. Further investigation is warranted with a larger sample.
EPEN-10. ROLE OF DNA METHYLATION ANALYSIS IN RECURRENT PAEDIATRIC EPENDYMOMA
Authors: Hazel A Rogers, Timothy A Ritzmann, Simon ML Paine, Lisa D Storer, Kristian W Pajtler, Martin Sill, Andrew M Donson, Nicholas K Foreman, Marcel Kool, Stefan M Pfister, Richard G Grundy
Journal: Neuro-Oncology (2018)

Ependymoma is the second most common malignant brain tumour in children. Relapse occurs in approximately 50% cases and is associated with a very poor prognosis. Recent studies highlighted the importance of DNA methylation in ependymoma. However, less is understood of its role at relapse. DNA methylation profiles were generated for 146 primary and 118 recurrent ependymoma samples using the Infinium HumanMethylation450 BeadChip arrays (Illumina). Samples were classified into previously defined subgroups with only 9 (6%) primary samples assigned to non-ependymoma groups. There was no significant difference in relapse risk between EPN_PFA and EPN_RELA cases. However, EPN_RELA cases relapsed significantly quicker. There was also no significant difference in survival between EPN_PFA and EPN_RELA relapsed cases. Radiotherapy given at relapse was associated with a significant improvement in survival for EPN_PFA cases but not EPN_RELA cases, although the number of cases investigated was low, limiting statistical power. The number of cases available for other ependymoma subgroups was too low for statistical analysis. However, in line with previous publications, EPN_PFB and EPN_SPINE cases displayed low relapse rates compared to other subgroups. 55 primary and matched relapsed cases were profiled. 53/55 (96%) cases, remained in the same subgroup at first relapse. Statistical comparisons suggested a low level of significant alterations in methylation levels at specific genes between primary and matched recurrent samples. In conclusion, relapse rates were very similar between common paediatric molecular subgroups and prognosis for relapsed cases was poor for all cases. Subgroups remained stable at relapse with little change in methylation levels.
Personalized Cancer Vaccine Platform for Clinically Relevant Oncolytic Enveloped Viruses
Authors: Erkko Ylösmäki, Cristina Malorzo, Cristian Capasso, Oona Honkasalo, Manlio Fusciello, Beatriz Martins, Leena Ylösmäki, Antti Louna, Sara Feola, Henrik Paavilainen, Karita Peltonen, Veijo Hukkanen, Tapani Viitala, Vincenzo Cerullo
Journal: Molecular Therapy (2018)

The approval of the first oncolytic virus for the treatment of metastatic melanoma and the compiling evidence that the use of oncolytic viruses can enhance cancer immunotherapies targeted against various immune checkpoint proteins has attracted great interest in the field of cancer virotherapy. We have developed a novel platform for clinically relevant enveloped viruses that can direct the virus-induced immune response against tumor antigens. By physically attaching tumor-specific peptides onto the viral envelope of vaccinia virus and herpes simplex virus 1 (HSV-1), we were able to induce a strong T cell-specific immune response toward these tumor antigens. These therapeutic peptides could be attached onto the viral envelope by using a cell-penetrating peptide sequence derived from human immunodeficiency virus Tat N-terminally fused to the tumor-specific peptides or, alternatively, therapeutic peptides could be conjugated with cholesterol for the attachment of the peptides onto the viral envelope. We used two mouse models of melanoma termed B16.OVA and B16-F10 for testing the efficacy of OVA SIINFEKL-peptide-coated viruses and gp100-Trp2-peptide-coated viruses, respectively, and show that by coating the viral envelope with therapeutic peptides, the anti-tumor immunity and the number of tumor-specific CD8+ T cells in the tumor microenvironment can be significantly enhanced.
Medication for Opioid Use Disorder After Nonfatal Opioid Overdose and Association With Mortality
Authors: Marc R. Larochelle, Dana Bernson, Thomas Land, Thomas J. Stopka, Na Wang, Ziming Xuan, Sarah M. Bagley, Jane M. Liebschutz, Alexander Y. Walley
Journal: Annals of Internal Medicine (2018)

Opioid overdose survivors have an increased risk for death. Whether use of medications for opioid use disorder (MOUD) after overdose is associated with mortality is not known.
EPEN-26. TO STUDY THE DEMOGRAPHIC CHARACTERISTICS OF PEDIATRIC EPENDYMOMA PATIENTS AND EVALUATE THE EFFICACY OF DIFFERENT TREATMENT MODALITIES AT KING FAHAD MEDICAL CITY (KFMC), RIYADH
Authors: Syed Nizam Hussain, Sadeq W Al Dandan, Muhammad Shuja, Ali Balbaid, Mohammad Salman, Musa Al Harbi
Journal: Neuro-Oncology (2018)

A retrospective review was performed for pediatric patients (< 14 years of age) with ependymoma who were treated at KFMC between 2006 and 2015. A total of 22 pediatric (< 14 years of age) patients with ependymoma were included (median age: 4 years, range: 1–9 years). Of these, four (18.2%) were < 3 years. Demographic, pathological and radiological features were not found to be of prognostic significance. Gross total resection (GTR) and subtotal resection (STR) was individually achievable in 9 (42.9%) cases, while near total resection (NTR) was performed in 14.3% of the cases. Median time from surgery to start of radiotherapy (RT) was 62 days. RT dose of 55.8 Gy (both mean and median) with median fractions of 30 days was given to 17 (77.3%) patients. Only 4 (18.18%) of the children received chemotherapy. With all modalities of treatment, median event-free survival (EFS) and overall survival (OS) from the first day of diagnosis were 1.57 years (range, 0.00–6.47) and 1.96 years (range, 0.01–7.37) respectively. At 4-year follow up, the overall EFS was about 34%, and OS was approximately 58%. This study is the first such kind of study from Kingdom of Saudi Arabia to describe the outcomes of 22 patients with childhood ependymoma and treated with surgical resection followed by chemotherapy or radiotherapy. KEY Ependymoma, Child, Surgery, Radiotherapy, Chemotherapy, Cancer treatment, Saudi Arabia
DIPG-75. INTERSECTION OF EPIGENETICS AND IMMUNITY IN DIPG
Authors: Allison Martin, Robert Bell, Charles Eberhart, Eric Raabe, Michael Koldobskiy
Journal: Neuro-Oncology (2018)

Improved therapy for DIPG represents an urgent unmet clinical need. No meaningful improvement has been made in over 30 years, with palliative radiation leading to a median survival of just 1 year. Immune checkpoint inhibitors are an important new therapeutic modality, showing success in many adult cancers. Recently, immune checkpoint inhibitors targeting the PD-1 pathway were trialed in patients with DIPG with mixed preliminary results. The discovery that >80% of DIPGs harbor the H3K27M mutation leading to global loss of the repressive histone H3K27 trimethylation mark and DNA hypomethylation, has generated great interest in the use epigenetic modifying agents for therapy of DIPG. Hypomethylating drugs such as 5-azacytidine are well known to increase immune responsive elements in cancer cells, leading to expression of endogenous retroviral elements, neoantigens, and altered expression of major histocompatibility complexes and interferon response elements. We hypothesized that genome-wide DNA hypomethylation consequent to the H3K27M mutation may make DIPG cells more susceptible to immune modulation by hypomethylating agents. In this study we evaluated the expression of the PD-1 ligand, PD-L1, in human autopsy samples and DIPG human neurosphere cell lines. We find that in vitro, DIPG expresses PD-L1 and other immune molecules in response to epigenetic modifier drugs and interferons. Interestingly, we also find that DIPG human autopsy samples express PD-L1 primarily on infiltrating immune cells rather than tumor cells. These results highlight the complex relationship between the epigenetic state and immunogenicity of DIPG, and suggest the possibility of successful combination therapies in the future.
NSRG-15. FIRST IN HUMAN USE OF CANVAS IMAGING SYSTEM FOR VISUALIZATION OF TOZULERISTIDE-INDUCED TUMOR FLUORESCENCE
Authors: Amy Lee, Jason Hauptman, Bonnie Cole, Kimberly Starr, Sandra Poliachik, Jeffrey Ojemann, Sam Browd, Richard Ellenbogen, Dennis Miller, Laura Ishak, Carolyn Gombotz, Stacey Hansen, Jeff Perry, David Kittle, Julie Novak, Adam Mamelak, James Olson, Sarah Leary
Journal: Neuro-Oncology (2018)

Maximal safe surgical resection is a critical component of pediatric brain tumor treatment. Tozuleristide (BLZ-100) is an investigational imaging agent given 1-36 hours prior to surgery to facilitate fluorescence-guided tumor resection. We evaluated one commercially available device (Fluobeam) and two investigational imaging devices in a pediatric phase 1 clinical study. The Fluobeam was of limited use in neurosurgery due to inadequate resolution, black and white imaging, and disruption of surgical flow. The investigational Synchronized Infrared Imaging System (SIRIS) is an open-field, free-standing imaging device which improved resolution and color display, but still was not suitable for neurosurgery flow and required repositioning of the surgical microscope. The investigational Canvas imaging system was developed for potential use in pediatric neurosurgery, attaching directly to the surgical microscope. The Canvas acquired real-time imaging of tozuleristide-induced tumor fluorescence throughout neurosurgical tumor resection with minimal to no disruption of surgical procedure. Fluorescent, color images and white light/fluorescent overlay images were displayed on the Canvas monitor throughout neurosurgery without repositioning of the surgical microscope and in line with the microscope field of view. The Canvas system also captured video of tozuleristide-facilitated fluorescent tumor resection in a young child with a posterior fossa tumor. Tozuleristide used with the Canvas imaging system may provide a valuable tool to support safe neurosurgical tumor resection without disruption of surgical flow compared to other standard intra-operative tumor imaging options such as ultrasound or MRI. Further evaluation of the tozuleristide/Canvas combination is planned in a multi-institutional pediatric brain tumor clinical study.
Progress and challenges of selective Farnesoid X Receptor modulation
Authors: Vittoria Massafra, Roberto Pellicciari, Antimo Gioiello, Saskia W.C. van Mil
Journal: Pharmacology & Therapeutics (2018)

Bile acids are amphipathic molecules that were previously known to serve as fat solubilizers in the intestine in postprandial conditions. In the last two decades, bile acids have been recognized as signaling molecules regulating energy metabolism pathways via, amongst others, the farnesoid X receptor (FXR). Upon bile acid activation, FXR controls expression of genes involved in bile acid, lipid, glucose and amino acid metabolism. In addition, FXR activation has been shown to limit the inflammatory response. The central role of FXR in various aspects of metabolism and inflammation makes FXR an attractive drug target for several diseases, such as obesity, metabolic syndrome, non-alcoholic steatohepatitis, cholestasis and chronic inflammatory diseases of the liver and intestine. However, most of the currently available compounds impact on all discovered FXR-mediated functions and may have, on top of beneficial effects, undesired biological actions depending on the disease. Therefore, research efforts are increasingly focused on the development of selective FXR modulators, i.e. selective bile acid receptor modulators (SBARMs), aimed at limiting the potential side-effects of conventional full FXR agonists upon chronic treatment. Here, we review the rationale for the design of SBARMs comprising dissociation between metabolic and inflammatory signaling, gene-selective and tissue-specific targeting. We discuss the potential structural mechanisms underlying the binding properties of dissociating ligands of FXR in light of ongoing efforts on the generation of dissociated ligands for otxher nuclear receptors, as well as their pharmacological and therapeutic potential.
EAPH-03. FINAL RESULTS OF THE PHASE II, SINGLE ARM TRIAL OF IRINOTECAN AND CISPLATIN IN CHILDREN WITH HIGH-RISK GLIAL TUMORS
Authors: Ofelia Cruz, Victoria Caloretti, Mariona Suñol, Carmen de Torres, Andres Morales, Antonio Guillen, Jordi Muchart, Eva Rodriguez, Veronica Celis, Hector Salvador, Joan Vinent, Sara Perez-Jaume, Jaume Mora
Journal: Neuro-Oncology (2018)

We conducted an open label, single arm phase II clinical trial with with irinotecan and cisplatin (I/C) for pediatric patients with glial tumors (EudraCT:2009-010742-59). Patients diagnosed with high-risk (HR) gliomas at diagnosis (HGG, ependymomas, DIPG, or HR-LGG) received sixteen weekly outpatient iv. cycles of Cisplatin(30mg/m2) and Irinotecan(65mg/m2). Malignant gliomas received radiation at progression. Objective response was assessed with MRI plus volumetric analysis. Clinical and neurological changes were assessed. Since November/2009 until December/2012, 39 patients (66,7% females), aged 7m-17y (mean=84-months), diagnosed with DIPG(n=7), HGG(n=5), anaplastic-ependymoma(n=6), atypical neurocytoma(n=1), LGG n=20: Pilocytic Astrocytoma(n=7), Pilomyxoid A.(n=1), Astrocytoma NOS(n=5), Grade-II astrocytoma (n=2), Ganglioglioma(n=2), LGG-NF1(n=3) were included. Most frequent events were nausea/vomiting, mostly grade 1–2, only 5/39 grade >2; 17 patients (43,6%) developed grade-1 diarrhea. At the end of follow-up 3/31 patients developed hypoacusia, all grade 1 (9,7%). Five (45.5%) patients with HGG, 1 relapsed HGG(100%), 7 DIPG(100%) and 3 LGG(15.0%) progressed during treatment, ending prematurely the study. Objective response rate (ORR) at the end of therapy (week 21), was by ITT / PP, of 54,4% for HGG, 0% for DIPG, and 85% for HR-LGG After a median follow-up time of 67.5 months, OS/EFS was 0/0% for relapsed HGG and DIPG, 62%/23% for High-grade glial tumors, and 95%/43% for HR-LGG. Radiation was avoided in 19/20 HR-LGG patients. The I/C regimen was acceptably tolerated and shows activity for some children with HR-gliomas, mainly HR-LGG.
A natural killer–dendritic cell axis defines checkpoint therapy–responsive tumor microenvironments
Authors: Kevin C. Barry, Joy Hsu, Miranda L. Broz, Francisco J. Cueto, Mikhail Binnewies, Alexis J. Combes, Amanda E. Nelson, Kimberly Loo, Raj Kumar, Michael D. Rosenblum, Michael D. Alvarado, Denise M. Wolf, Dusan Bogunovic, Nina Bhardwaj, Adil I. Daud, Patrick K. Ha, William R. Ryan, Joshua L. Pollack, Bushra Samad, Saurabh Asthana, Vincent Chan, Matthew F. Krummel
Journal: Nature Medicine (2018)
EPEN-34. HIGH-THROUGHPUT DRUG SCREENING OF PRIMARY CULTURES REVEALS IRREVERSIBLE ERBB2 INHIBITION AS NOVEL THERAPEUTIC VULNERABILITY OF EPENDYMOMAS
Authors: David Pauck, Sevgi Sarikaya-Seiwert, Viktoria Marquardt, Daniel Picard, Jasmin Bartl, Lena Blümel, Mara Maue, Christian Dimitriadis, Michaela Kuhlen, Ute Fischer, Hans-Jakob Steiger, Guido Reifenberger, Arndt Borkhardt, Thomas Beez, Marc Remke
Journal: Neuro-Oncology (2018)

Ependymoma is the third most common brain tumor in children. Subsets of ependymomas, in particular RELA fusion-positive supratentorial ependymomas and posterior fossa type A ependymomas, are associated with frequent recurrence and dismal outcome. Neurosurgical resection and radiotherapy are the main therapeutic options, while response to conventional chemotherapy is limited. We aimed to establish a high-throughput drug screening (HTS) pipeline for comprehensive individualized testing of patient-derived primary cultures to identify novel therapeutic targets for ependymomas. Ependymoma primary cultures (n=6) were established following tumor resection and underwent HTS in 1536-well plates to allow large-scale drug screening despite limited cell numbers. We generated dose-response data with 9 dilution steps (dose range 32.5nM to 25µM) for a clinical inhibitor library (n=196) comprising established chemotherapeutic agents and novel anti-cancer compounds currently in phase III and IV studies. The Infinium MethylationEPIC Array was used to characterize primary tumors and matched primary cultures genomically and epigenetically. DNA methylation and copy number profiles revealed that short-term primary cultures faithfully recapitulate the genomic and epigenetic landscape of the corresponding primary tumors. Comparison of drug response data from ependymomas, other pediatric brain tumors (n=25) and controls (i.e. non-neoplastic neural progenitor cells) confirmed extraordinary chemoresistance of ependymomas but also revealed promising selectively active drugs, such as neratinib, an irreversible ERBB2 inhibitor. Thus, our data demonstrate the feasibility of HTS in primary cultures derived from pediatric brain tumors and provide preclinical evidence suggesting inhibition of ERBB2 as a promising therapeutic option in a subset of otherwise highly chemoresistant ependymomas.