tbuckley/cabot-search huggingface dataset:
De novo malignancies in patients after liver transplantation: A single centre experience
Authors: K. Chmelova, J. Spicak
Journal: Annals of Oncology (2018)

Introduction: De novo malignancy is a major cause of long term morbidity and mortality in patients after liver transplantation (LTx). The overall risk is estimated to be 2-4 times higher as compared to general population. Neither cancer screening protocols, nor universal recommendations have yet been established. The aim of this study was to evaluate incidence of de novo malignancies, identify potential risk factors and characterise the overall outcome of patients after LTx. Methods: We retrospectively reviewed adult 1295 patients (765 male and 530 female) who underwent LTx in IKEM between 1995 and 2016. Clinical characteristics and demographic data were collected in patients who survived at least one month post-transplant. Patients with non-melanoma skin cancer were excluded (as it does not affect mortality), as well as patients with recurrence of hepatocellular carcinoma. Results: In our cohort we identified 144 malignancies in 136 liver graft recipients (10.5%), 85 male and 51 female. The median time between LTx and diagnosis of the tumour was 64 months (range 4-234) at the age of 60 years (range 18-74). The most common malignancy was post-transplant lymphoproliferative disease – PTLD (2.2%), followed by lung cancer (1.77%) and head/neck cancer (1.62%). Mean age of cancer occurrence in these groups was lower as compared to general Czech population: 58, 63 and 58.5 years of age vs. 60, 74 and 62 years of age, respectively. Furthermore, only 9 cases of colon cancer were identified (2 of them in patients with ulcerative colitis). Smoking was identified as an independent risk factor for cancer development in the study cohort. Tumour was found in 81 non-smokers and 55 smokers compared to 269 smokers and 890 non-smokers in patients without any malignancy (p < 0.001). The most common cause of liver injury was alcoholic liver disease (47/136 patients), followed by viral hepatitis (35/136 patients) and primary sclerosing cholangitis (12/136 patients). Patients with de novo malignancy achieved 3-, 5- and 10-year survival of 91.1%, 78.1%, and 61.4%, which was comparable with patients without cancer (85.9%, 81.2%, and 62.9% respectively). Conclusion: Liver transplantation is related to increased occurrence of malignancy development. PTLD, lung cancer and head/neck cancer were most common malignancies in our study group. Future establishment of proper screening programs in patients after LTx is highly warranted.
DEV-13. PRELIMINARY RESULTS OF A BRAZILIAN CENTRAL NERVOUS SYSTEM GERM CELL TUMOR CONSORTIUM PROTOCOL
Authors: Andrea M Cappellano, Jonathan Finlay, Bruna Mançano, Daniela Barbosa, Sergio Cavalheiro, Patricia A Dastoli, Frederico A Silva, Simone S Aguiar, Elvis Valera, Nasjla Saba da Silva
Journal: Neuro-Oncology (2018)

Primary central nervous system (CNS) germ cell tumors (GCT) account for 2–3% of brain tumors in children/adolescents in Western hemisphere, being classified as germinomas and non-germinomatous GCT (NGGCT). Our objective is to report the results of a Brazilian CNSGCT consortium protocol. Since 2013, 28 patients with histologic and/or tumor marker (TM) diagnosis of germinoma with/without HCGβ levels ≤200mIU/ml (n=21) and NGGCT (n=7), received four/six cycles of carboplatin/etoposide/cyclophosphamide, followed by 18Gy ventricular field irradiation (VFI) and primary site(s) boost. Autologous bone marrow transplant (ABMT) was conducted for NGGCT low responders. Median age-13,5 years, 21 males. Diagnosis was made by TM (n=5), surgery (n=14), both (n=7). Two bifocal cases, TM(-) were treated as germinoma. Primary tumor location was pineal(n=14), suprasellar(n=7), bifocal (n=7). Nine had ventricular/spinal spread. Second-look surgery occurred in five patients. For the germinoma group, 18 patients achieved complete response (CR) after chemotherapy, the remaining 4 showed residual teratoma/scar. The NGGCT patients (n=7) showed partial responses(n=5), three with TM(-) and two CR after 4/6 cycles. Two patients were submitted to ABMT. Radiotherapy was performed as described except in two. No recurrences to date. One patient died of endocrinologic complications. Toxicity was mostly grade ¾ neutropenia/thrombocytopenia (NGGCT) following cyclophosphamide and in all patients for at least one cycle following carboplatin. At a median follow-up of 29,6 months, event-free and overall survival was 96,4%. Dose reduction of VFI to 18Gy seems to preserve efficacy. Further follow-up is warranted to better assess treatment efficacy especially among the slow responder patients.
Development of a PD-L1-Expressing Orthotopic Liver Cancer Model: Implications for Immunotherapy for Hepatocellular Carcinoma
Authors: Da-Liang Ou, Yu-Yang Lin, Chia-Lang Hsu, Yin-Yao Lin, Chia-Wei Chen, Jhang-Sian Yu, Shi-Chuen Miaw, Ping-Ning Hsu, Ann-Lii Cheng, Chiun Hsu
Journal: Liver Cancer (2018)

Background: Anti-programmed cell death-1(anti-PD1) treatment has shown promising antitumor efficacy in patients with advanced hepatocellular carcinoma (HCC). This study sought to explore the functional significance of programmed death ligand-1 (PD-L1) expression in tumor cells in the tumor microenvironment. Methods: The mouse liver cancer cell line BNL-MEA was transfected with PD-L1 plasmids and stable clones expressing PD-L1 were selected. An orthotopic HCC model was generated by implanting the cells into the subcapsular space of BALB/c mice. Cell growth features were measured by proliferation assay, colony formation, flow cytometry (in vitro), ultrasonography, and animal survival (in vivo). The changes in T-cell function were examined by cytokine assay, expression of T-cell related genes, and flow cytometry. The efficacy of anti-PD1 therapy was compared between the parental and PD-L1-expressing tumors. Results: PD-L1 expression did not affect growth characteristics of BNL-MEA cells but downregulated the expression of genes related to T-cell activation in the tumor microenvironment. Co-culture of PD-L1-expressing BNL-MEA cells with CD8+ T cells reduced T-cell proliferation and expression of cytokines IFNγ and TNFα. Tumors with PD-L1 expression showed better response to anti-PD1 therapy and depletion of CD8+ T cells abolished the antitumor effect. The difference in treatment response between parental and PD-L1-expressing tumors disappeared when a combination of anti-PD1 and sorafenib was given. Conclusions: PD-L1 expression in HCC cells may inhibit T-cell function in the liver tumor microenvironment. Anti-PD1 therapy appeared more effective in PD-L1-expressing than nonexpressing tumors, but the difference was diminished by the addition of sorafenib.
DIPG-11. TRANSCRIPTIONAL REGULATION OF NEURAL PROGENITOR CELL FATE BY DLX HOMEOBOX GENES - RELEVANCE TO DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)
Authors: David Eisenstat, Jamie Zagozewski, Sara Japoni, Xiaohua Song, Roseline Godbout, Alan Underhill, Oren Becher
Journal: Neuro-Oncology (2018)

DIPG is refractory to current therapies. The identification of histone H3.1/H3.3 K27M mutations in most DIPG has provided novel insights. DLX (distal-less) genes are expressed in the developing forebrain. The Dlx1/Dlx2 double knockout (DKO) mouse (dies at P0) has loss of tangential GABAergic interneuron migration to the neocortex. We have identified glutamic acid decarboxyase genes Gad1 and Gad2 as direct transcriptional targets of DLX1 and DLX2. In DIPG patients with H3.3 K27M there is decreased Dlx2 and increased expression of Myt1 (myelin transcription factor). We used bioinformatics and chromatin immunoprecipitation (ChIP) assays with embryonic ganglionic eminences to identify Olig2, Nkx2.2 and Myt1 promoter sequences as candidate DLX2 targets in vivo. DNA binding specificity was confirmed by electrophoretic mobility shift assays (EMSA). Co-expression of Dlx2 with luciferase reporter constructs of these ChIP-isolated promoter fragments of Olig2 and Nkx2.2 demonstrated repression of these gene targets in vitro. Assessment of target gene expression in the Dlx1/Dlx2 DKO forebrain by qPCR showed increased Olig2 and Nkx2.2 expression. Stable transfection of a murine HA-tagged DIPG cell line with Dlx2 increased expression of Gad1 and Gad2 and decreased expression of Olig2 and Nkx2.2. Of significance, using Western blotting we demonstrated decreased expression of H3.3 K27M and restoration of H3.3 K27 tri-methylation (me3). DLX transcription factors promote GABAergic interneuron differentiation and concomitant inhibition of oligodendroglial differentiation in neural progenitors by repression of a suite of genes including Olig2 and Nkx2.2. Restoration of H3 K27me3 expression in DIPG is a promising lead towards exploring differentiation as a therapeutic strategy for DIPG.
NFM-03. EFFECT OF NEUROFIBROMATOSIS TYPE 1 ON LONG-TERM HEALTH OUTCOMES IN ADULT SURVIVORS OF CHILDHOOD ASTROCYTOMA: A REPORT FROM THE CHILDHOOD CANCER SURVIVOR STUDY
Authors: Peter de Blank, Nan Li, Nicole Ullrich, Michael J Fisher, Smita Bhatia, Yutaka Yasui, Charles Sklar, Wendy Leisenring, Rebecca Howell, Kevin Oeffinger, Kristina Hardy, M Fatih Okcu, Todd Gibson, Les Robison, Gregory T Armstrong, Kevin Krull
Journal: Neuro-Oncology (2018)

The effect of neurofibromatosis type 1 (NF1) on incidence and severity of health outcomes in adult survivors of childhood astrocytoma is poorly understood. 1,617 >5yr survivors of childhood astrocytoma (147 NF1 survivors and 1,470 non-NF1 survivors matched on diagnosis and diagnosis decade) and 5,051 siblings were compared on self-reported chronic medical conditions (CTCAE v4.0) and cognitive impairment (defined as >90th percentile of siblings on the CCSS Neurocognitive Questionnaire) using logistic and Poisson regression adjusted for age at survey, age at diagnosis, sex, race, CNS radiation and other treatment exposures. Among astrocytoma survivors, NF1 survivors (mean age 6.6yr at diagnosis) received chemotherapy (24% vs 13%) and carboplatin (71% vs 40%) more frequently than non-NF1 survivors. Compared to non-NF1 survivors, NF1 survivors were more likely to report a serious health condition (grade 3-4, RR[95%CI] 1.9[1.5-2.4]) and multiple chronic medical conditions (grade 2-4, 1.7[1.4-2.1]). Specifically, NF1 survivors were at increased risk for vision loss (1.8[1.5-2.1]), gastrointestinal disease (1.8[1.5-2.1]), heart disease (1.5[1.2-2.0]), lung disease (1.4[1.2-1.6]), and motor (1.2[1.1-1.4]) and sensory (1.2[1.0-1.4]) impairments. Interestingly, compared to both non-NF1 survivors and siblings, diabetes (0.2[0.1-0.3] vs non-NF1; 0.3[0.2-0.5] vs siblings) and abnormal thyroid (0.2[0.2-0.3] vs non-NF1; 0.6[0.5-0.8] vs siblings) were less common in NF1 survivors. NF1 survivors reported more impairment on emotional regulation (OR 2.0[1.1-3.7]), task completion (2.0[1.2-3.5]) and learning/memory (1.5[1.3-1.8]), and attended college less frequently (0.5[0.2-0.9]) compared to non-NF1 survivors. NF1 impacts risk of health/cognitive outcomes in adult survivors of childhood astrocytoma. Further research should investigate the underlying mechanisms of these risks.
RONC-02. COMPARISON OF 3D PRINTED HEADREST FOR PEDIATRIC PATIENTS AND BRAINLAB® SRS STANDARD HEADREST IN RADIOTHERAPY
Authors: Longhui Luo, Wei Wu, Ping Zhang, Peng Dai, Qing Huang, Guanghua Deng, Xin Zhang, Weiping Hong, Xiao Xiao, MingYao Lai, Xingan Wang, Daqing Wang, Changguo Shan, Linbo Cai
Journal: Neuro-Oncology (2018)

The SRS standard headrest provided by BRAINLAB® frameless SRS system® was too big for pediatric patients. We applied 3D printing technology to produce a novel headrest for pediatric patients in radiotherapy. Our study aimed to compare the setup errors and transmittance between 3D printed headrest for pediatric patients and BRAINLAB® SRS standard headrest in radiotherapy. Thirty pediatric patients aged from 3 to 7 years old with cranial tumors were randomly selected from August 2016 to November 2017. These patients were divided into two groups equally. First group of patients was immobilized by 3D printed headrest with masks. Second group of patients were immobilized by BRAINLAB® SRS standard headrest with masks. The transmittance in both groups were recorded by DOSE1® with cc13 detector. The setup errors in VRT, LAT and AP directions were recorded by Exactrac® with Robotic® before radiotherapy. The average of transmittance was 98.891455% in group 1 and 98.51455% in group 2. The setup errors in VRT, LAT and AP directions were (0.040 ± 0.055) mm, (0.040 ± 0.055) mm and (0.10 ± 0.07) mm in group 1, as compared with (0.160 ± 0.055) mm, (0.08 ± 0.11) mm and (0.10 ± 0.10) mm in group 2. 3D printed headrest reduced setup errors in VRT direction (P<0.05) with no significant difference in the other two directions (P>0.05). Compared with BRAINLAB® SRS standard headrest, 3D printed headrest for pediatric patients showed higher transmittance and reduces the setup errors in VRT direction.
PHRM-01. PLASMA AND CEREBROSPINAL FLUID PHARMACOKINETICS OF THE DNA HYPOMETHYLATING AGENT, GUADECITABINE (SGI-110), FOLLOWING SUBCUTANEOUS ADMINISTRATION IN A NON-HUMAN PRIMATE MODEL
Authors: Cynthia M Lester McCully, Arman Odabs, Rafael Cruz, Cody Peer, William D Figg, John W Glod, Katherine E Warren
Journal: Neuro-Oncology (2018)

Guadecitabine, a potent hypomethylating agent currently being studied in clinical trials, is a dinucleotide that is resistant to degradation by cytidine deaminase resulting in an extended release of the active metabolite decitabine following subcutaneous (SC) administration. The CSF exposure of Guadecitabine following SC administration was evaluated via plasma and CSF pharmacokinetics (PK) in a nonhuman primate CSF Ventricular Reservoir or Lumbar Port model, which permits humane, rapid, serial CSF collection. Guadecitabine (2.3 mg/kg, Human Equivalent Dose 45 mg/m2) was administered to 4 rhesus macaques subcutaneously x 5 days. Following administration, multiple serial paired plasma and CSF samples were collected for 0-24 hours on day 1, prior to dosing on days 2-5, and at day 6 (24 hours post the final dose). Guadecitabine’s active metabolite, decitabine, was quantified via an LC-MS/MS assay and PK parameters calculated using noncompartmental methods. Mean peak plasma PK results were: Cmax 44.98 ng/ml ± 13.9; Tmax 0.75 hr ± 0.29, Half-Life 1.3 hr ± 0.41, AUC0-∞ 135.22 hr*ng/ml ± 32.9, and Clearance 381.60 L/hr/m2 ± 137.7. Guadecitabine CSF concentrations were detectable, but below the level of quantification (n=2) or undetectable (n=2). All macaques experienced a mild to moderate lymphocytopenia, but otherwise tolerated guadectabine. Lymphopenia resolved within 30 days. Systemic delivery of Guadecitabine does not provide adequate CSF exposure of decitabine when administered subcutaneously. The agent was well tolerated in the NHP. FUTURE Continuing studies will examine the PK and tolerability of the drug following intraventricular administration in this nonhuman primate model.
A rare case of spontaneous hepaticoduodenal fistula and management of biliary obstruction in metastatic cholangiocarcinoma
Authors: Andrew Kruger, Somashekar Krishna
Journal: Endoscopy (2018)

A 60-year-old woman with a history of breast cancer presented with jaundice, epigastric pain, and fever for 1 week. Laboratory results revealed a total bilirubin of 14.9 mg/dL and alkaline phosphatase of 365 U/L. Abdominal computed tomography revealed a 6.1 × 2.8-cm hilar liver mass with intrahepatic biliary dilatation ([Fig. 1]; [Video 1]); subsequent abdominal magnetic resonance imaging demonstrated an infiltrative soft tissue mass encasing the common hepatic and central intrahepatic ducts, suggestive of intrahepatic cholangiocarcinoma ([Fig. 2]).
HGG-15. PHASE 2 NESTED COHORT STUDY OF DEPATUXIZUMAB MAFODOTIN IN CHILDREN WITH HIGH GRADE GLIOMA AND DIFFUSE INTRINSIC PONTINE GLIOMA WITH EGFR AMPLIFICATION
Authors: Martin van den Bent, Winand Dinjens, Vassilis Golfinopoulos, Peter Ansell, Fiona Dungey, Jan Peter de Geus, Earle Bain, Jim Looman, Hao Xiong, Darren Hargrave
Journal: Neuro-Oncology (2018)

Pediatric high grade gliomas (HGGs) and diffuse intrinsic pontine gliomas have no adequate therapy and are almost universally fatal. Depatuxizumab mafodotin (depatux-m) is an antibody-drug conjugate, comprised of anti-EGFR antibody linked to a microtubule cytotoxin, monomethyl auristatin F, that has demonstrated promising antitumor activity in patients with EGFR gene-amplified tumors in two studies of adult glioblastoma. While EGFR amplification occurs in ~50% of adult glioblastomas, it occurs in only 1-3% of children. Due to this rarity, a nested pediatric cohort has been designed within the adult depatux-m phase 2 study in recurrent glioblastoma (NCT02343406). At least 6 patients will be enrolled globally. Eligible patients will be 3-17 years of age, tumors exhibiting EGFR amplification. Primary objectives include evaluating safety, tolerability, and pharmacokinetic profile. Secondary objective was to assesses tumor response per RANO criteria. To facilitate study access, we aim to analyze tumor specimens of at least 200 pediatric patients for EGFR amplification. Sites can use local or central EGFR testing. Additionally, tissue samples may also be sent to Erasmus Cancer Hospital, The Netherlands, for glioma-tailored next generation sequencing molecular panel/array, including EGFR amplification, by anyone (open to any HGG patient). Erasmus will provide these results directly to the physician. Physicians wishing to utilize this testing service (open to any patient) can contact h.dubbink@erasmusmc.nl. Of 98 patients pre-screened or began pre-screening: 75 were not EGFR amplified, 12 were not tested (e.g. insufficient tissue, progression), 3 are pending result, 8 are EGFR amplified, and 2 patients have been enrolled.
HGG-30. PEDIATRIC GLIOSARCOMA WITH AND WITHOUT NEUROFIBROMATOSIS TYPE 1: A WHOLE-EXOME COMPARISON OF TWO PATIENTS
Authors: Richard T Graham, Erica Hlavin Bell, Amy Webb, Cynthia Timmers, Nathan Robison, Joshua Palmer, Jonathan L Finlay, Arnab Chakravarti
Journal: Neuro-Oncology (2018)

Gliosarcoma is a WHO grade IV histologic variant of glioblastoma that occurs very rarely among pediatric patients, even more so amongst Neurofibromatosis Type 1 (NF1) individuals. Patients with NF1-associated high-grade gliomas (HGGs) reportedly have better clinical outcomes than others despite their germline tumor-suppressor mutation. Since molecular data to explain this are lacking, we compared tumor exomes from two pediatric gliosarcoma patients, one with NF1 (P1) and one without (P2). Two patients with gliosarcoma (ages 12 and 11 years), were treated with resection (gross total for P1 and near-total for P2), bevacizumab, temozolomide and irradiation. We performed whole-exome sequencing (WES, Agilent SureSelect V6 + Cosmic) on tumor and blood to determine both germline and somatic mutations. Tumor mutations were filtered based on predicted deleterious effects and a list of genes was compared to online pediatric tumor databases (PeCan and PedcBioPortal). P1 is alive without progression after 5.8 years. P2 developed tumor recurrence after 2 years, expiring 4.6 years from diagnosis. Tumor DNA revealed a lower mutational burden in P1 (NF1) than in P2 including some genes which have been previously reported in pediatric HGGs (e.g. IKBKB in P2). However, there was no overlap in specific gene mutations. This is the first report of WES in pediatric gliosarcoma. The differences in mutational burden between these patients might explain improved survival outcomes for HGG patients with NF1 as well as shedding light on the different mutational processes leading to their tumors. Further molecular analyses including methylation profiling are ongoing.
QOL-06. METHYLPHENIDATE IMPROVES HEALTH-RELATED QUALITY OF LIFE AND ATTENTIONAL IMPAIRMENT IN PAEDIATRIC NEURO-ONCOLOGY SURVIVORS
Authors: Sarah Jane Watts, Gail Halliday, Jade Ryles, Simon Bailey
Journal: Neuro-Oncology (2018)

Treatment for paediatric brain tumour (BT) is increasingly effective in preserving life but is associated with lifelong neurocognitive sequelae. Most frequently documented domains of impairment include executive function and its components: processing speed, working memory, and attention. Deficits impact on the child’s ability to take in and consolidate new material, leading to failure to make age-expected intellectual gains. In addition to intellectual impairments, cranial radiation survivors report decreased Health-Related Quality of Life (HRQoL) comparative to other BT patients. As part of a tailored treatment package, pharmacological interventions have been introduced to maximise the intellectual potential of these patients. To explore the impact of methylphenidate (MPH) upon HRQoL in survivors of childhood BT with learning impairments. Participants (N=12) with paediatric BT with a history of radiotherapy or hydrocephalus and current learning impairment received MPH. Cognitive impact of MPH was evaluated using measures of selective and sustained attention, inhibition, set shifting, response and processing speed using a common test battery (TEA-Ch 2), and parent and teacher response questionnaires (SNAP-18). HRQoL subjective impact was assessed using parent and participant response questionnaires (PEDSQL) and clinical interview. All patients showed a significant increase in raw scores on all psychometric measures excepting measures of response inhibition. All participants reported increased HRQoL in a number of areas, specifically in improved self-esteem, confidence, and peer interactions, and improved speed of processing and selective attention. 4 participants noted a reduction in fatigue. MPH provides HRQoL and cognitive improvement in this participant group with limited side-effects.
Autophagy orchestrates the regulatory program of tumor-associated myeloid-derived suppressor cells
Authors: Themis Alissafi, Aikaterini Hatzioannou, Konstantinos Mintzas, Roza Maria Barouni, Aggelos Banos, Sundary Sormendi, Alexandros Polyzos, Maria Xilouri, Ben Wielockx, Helen Gogas, Panayotis Verginis
Journal: Journal of Clinical Investigation (2018)

Myeloid-derived suppressor cells (MDSCs) densely accumulate into tumors and potently suppress antitumor immune responses, promoting tumor development. Targeting MDSCs in tumor immunotherapy has been hampered by lack of understanding of the molecular pathways that govern MDSC differentiation and function. Herein, we identify autophagy as a crucial pathway for MDSC-mediated suppression of antitumor immunity. Specifically, MDSCs in patients with melanoma and mouse melanoma exhibited increased levels of functional autophagy. Ablation of autophagy in myeloid cells markedly delayed tumor growth and endowed antitumor immune responses. Notably, tumor-infiltrating autophagy-deficient monocytic MDSCs (M-MDSCs) demonstrated impaired suppressive activity in vitro and in vivo, whereas transcriptome analysis revealed substantial differences in genes related to lysosomal function. Accordingly, autophagy-deficient M-MDSCs exhibited impaired lysosomal degradation, thereby enhancing surface expression of MHC class II molecules, resulting in efficient activation of tumor-specific CD4+ T cells. Finally, targeting of the membrane-associated RING-CH1 (MARCH1) E3 ubiquitin ligase that mediates the lysosomal degradation of MHC II in M-MDSCs attenuated their suppressive function, and resulted in markedly decreased tumor volume followed by development of a robust antitumor immunity. Collectively, these findings depict autophagy as a molecular target of MDSC-mediated suppression of antitumor immunity.
Abstract 14786: Effect of Left Ventricular Dyssynchrony on Vortex Formation Assessed With Vector Flow Mapping
Authors: Toshiki Kamimukai, Kasumi Masuda, Hitomi Adachi, Yuki Sakakibara, Marie Stugaard, Toshihiko Asanuma, Satoshi Nakatani
Journal: Circulation (2016)

Background: Vortex in the left ventricle (LV) has been suggested to contribute to effective blood transport. Since vortex formation during diastole is influenced by LV structure and function, its q...