tbuckley/cabot-search huggingface dataset:
DIPG-77. INTRATUMORAL PHARMACOKINETICS OF CHEMOTHERAPY IN DIPG: XENOGRAFT AND INITIAL PHASE 0 CLINICAL TRIAL RESULTS
Authors: Adam Green, Patrick Flannery, Todd Hankinson, Brent O’Neill, John DeSisto, Rakeb Lemma, Lindsey Hoffman, Jean Mulcahy Levy, Jennifer Raybin, Molly Hemenway, Carl Koschmann, Michael Handler, Nicholas Foreman, Rajeev Vibhakar, Michael Wempe, Kathleen Dorris
Journal: Neuro-Oncology (2018)

Hundreds of chemotherapy trials have been conducted in diffuse intrinsic pontine glioma (DIPG) without survival improvement. One potential reason is a lack of intratumoral penetration, but this has not previously been assessed in humans. We used gemcitabine as a model agent to assess DIPG intratumoral pharmacokinetics (PK). We chose gemcitabine for its known blood-brain barrier penetration and established pediatric safety data. We first assessed intratumoral PK in a mouse orthotopic xenograft model of DIPG. We subsequently opened a phase 0 trial in which newly-diagnosed DIPG patients receive one intravenous gemcitabine dose immediately before biopsy. We measured gemcitabine concentration by liquid chromatography-tandem mass spectrometry. In the xenograft model, intraperitoneal gemcitabine showed a significantly greater tumor/normal brain penetration ratio in cortical compared to pontine tumors (p=0.032). Based on these results, we began our phase 0 trial. In the first patient enrolled, concentrations from four spatially heterogeneous tumor biopsies ranged from 4.8–9.7 µM. These compare favorably to intratumoral gemcitabine levels published from a similar study in adult glioblastoma (0.06–3.6 µM) and to our measured in vitro IC50 levels in three DIPG cell lines (44–162 nM). Levels were similar to those found in our xenograft pontine tumors (3.4–7.3 µM, p=0.24). We demonstrated adequate intratumoral chemotherapy penetration for therapeutic effect in DIPG, suggesting that this is not the reason for chemotherapy failure. We are now analyzing samples from a second trial subject, and from a xenograft study comparing penetration and clearance rate based on H3K27M mutant/wild-type status and tumor location.
Adrenal Suppression in Infants Treated with Topical Ocular Glucocorticoids
Authors: Regitze Bangsgaard, Katharina M. Main, Gøril Boberg-Ans, Morten la Cour, Julie Lyng Forman, Birgitte Haargaard, Jens Folke Kiilgaard
Journal: Ophthalmology (2018)
IMMU-08. PHASE I TRIAL (NCT02457845) SAFETY, TOLERABILITY AND PRELIMINARY EFFICACY OF IMMUNOVIROTHERAPY WITH HSV G207 IN CHILDREN WITH PROGRESSIVE MALIGNANT SUPRATENTORIAL BRAIN TUMORS
Authors: Gregory Friedman, Asim Bag, Avi Madan-Swain, Rong Li, Kara Kachurak, Diana Osorio, Juliette Hukin, Allison Martin, Devang Pastakia, Matthias Karajannis, Joshua Bernstock, John Fiveash, Alyssa Reddy, Richard Whitley, Yancey Gillespie, James Markert, James Johnston
Journal: Neuro-Oncology (2018)

Outcomes for children with progressive malignant supratentorial brain tumors are dismal. Preclinical evidence indicates that pediatric brain tumors are highly sensitive to genetically engineered oncolytic HSV-1 G207, which lacks genes essential for replication in normal brain. We report on this first-in-children oncolytic virotherapy brain tumor trial of G207. A 3 + 3 design was used to evaluate the safety, tolerability and preliminary efficacy of G207 at two doses (107 and 108 plaque-forming units). After informed consent, patients underwent biopsy to confirm viable tumor followed by placement of up to four silastic intratumoral catheters. The following day, G207 was infused by convection enhanced delivery over 6 hours. Patients were assessed for viral shedding and viremia by PCR and response by serial MRIs. Six subjects have been treated (5 glioblastoma; 1 anaplastic astrocytoma). No dose limiting toxicities, serious adverse events, or ≥ grade 2 toxicities related to G207 have occurred. No G207 shedding or viremia was detected in the saliva, conjunctiva or blood at any time. Evidence of radiographic responses to G207 were seen in 5 of 6 patients including a patient >12 months post-G207 with an ongoing response and improvement in performance score from 80 to 100. G207 delivered intratumorally is safe and tolerable in children with progressive malignant supratentorial brain tumors. Preliminary evidence of efficacy is very promising to date. The next phase of the study (NCT02457845) will test the safety of G207 combined with a single 5 Gy dose of radiation within 24 hours of virus inoculation.
Adapting liposomes for oral drug delivery
Authors: Haisheng He, Yi Lu, Jianping Qi, Quangang Zhu, Zhongjian Chen, Wei Wu
Journal: Acta Pharmaceutica Sinica B (2018)

Liposomes mimic natural cell membranes and have long been investigated as drug carriers due to excellent entrapment capacity, biocompatibility and safety. Despite the success of parenteral liposomes, oral delivery of liposomes is impeded by various barriers such as instability in the gastrointestinal tract, difficulties in crossing biomembranes, and mass production problems. By modulating the compositions of the lipid bilayers and adding polymers or ligands, both the stability and permeability of liposomes can be greatly improved for oral drug delivery. This review provides an overview of the challenges and current approaches toward the oral delivery of liposomes.
NORTH/HGCSG1003: A phase II study evaluating the safety and efficacy of FOLFOX as adjuvant chemotherapy for patients with stage III colon cancer: Comparison with medical oncologists and surgeons
Authors: I. Iwanaga, S. Yuki, Y. Kawamoto, H. Nakatsumi, N. Takahashi, T. Shichinohe, H. Okuda, A. Ishiguro, K. Harada, K. Hatanaka, K. Oomori, M. Nakamura, N. Senmaru, K. Iwai, M. Koike, Y.M. Ito, A. Taketomi, S. Hirano, N. Sakamoto, Y. Komatsu
Journal: Annals of Oncology (2018)
EMBR-12. IMPROVED DIAGNOSTIC ALGORITHM FOR DIFFERENTIAL DIAGNOSTICS OF CNS EMBRYONAL TUMORS (FORMER CNS-PNET) BY NEUROPATHOLOGICAL RE-EVALUATION OF 256 CASES AND CROSSVALIDATION BY METHYLATION CLASSIFICATION
Authors: Torsten Pietsch, Dominique Figarella-Branger, Felice Giangaspero, Marco Gessi, Cynthia Hawkins, Thomas Jacques, Andrey Korshunov, Charles Eberhart, Peter Burger, Katja von Hoff, Marcel Kool, Christine Haberler
Journal: Neuro-Oncology (2018)

Epigenetic profiling has shown that a proportion of cases diagnosed as CNS PNET in the past can be assigned to other tumour entities with similar morphological appearance. In an international effort to re-analyze CNS-PNET aiming for disease-specific re-evaluation of survival data and the development of diagnostic guidelines providing the basis for improved therapeutic approaches, 256 tumours diagnosed and treated as CNS-PNET in the last two decades in 17 countries were reviewed by a panel of neuropathologists according to today’s standards of clinical neuropathological diagnostics including immunohistochemical and molecular pathological assays. The majority of cases were also independently analyzed by methylation array hybridization and classified by random forest algorithm. In this unique cohort, we identified 20 different tumor entities including frequent high grade gliomas. 41% of cases were confirmed as CNS-PNET (now termed CNS-embryonal tumors (CNS-ET) according to the revised WHO-classification) representing two main entities: ETMR displayed typical histopathological features, LIN28A expression and/or C19MC alteration. The other represented a group of tumors with variable degrees of differentiation along neuroblastic/ganglionic lines, corresponding to the WHO diagnoses CNS-(Ganglio)-neuroblastoma or CNS-ET, NOS. The vast majority of these tumors could be assigned to the FOXR2 CNS-NB group by methylation array-based classification. Crossvalidation of neuropathological and epigenetic classification proved that methylation classification represents a useful complimentary tool in the differential diagnosis of CNS-ET. Re-evaluation of prototypic tumors and cases with discrepant diagnoses enabled us to develop an optimized diagnostic algorithm to securely delineate this tumor type from other entities with largely divergent clinical and biological behaviour.
Efficacy and safety of nivolumab monotherapy for metastatic gastric cancer
Authors: K. Akiyoshi, Y. Tsuboguchi, S. Ueda, S. Okazaki, A. Tsuya, S. Tokunaga, H. Daga
Journal: Annals of Oncology (2018)

Introduction: In Japan, nivolumab was approved in September 2017 ahead of the rest of world, so that patients with metastatic gastric cancer were able to receive nivolumab monotherapy refractory to, or intolerant of, at least two previous chemotherapy. Methods: We retrospectively reviewed metastatic gastric cancer patients in our hospital who received nivolumab monotherapy since September 2017. All patients received 3 mg/kg nivolumab intravenously every 2 weeks. Results: Between September 26, 2017, and January 31, 2018, 13 patients were received nivolumab. Baseline patient characteristics were as follows: median age (range), 70 (52-84) years; male/female, 8/5; Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2, 0/10/3; previous gastrectomy yes/no, 7/6; histology intestinal/diffuse, 9/4; previous treatment regimens 2/3/≥4, 6/4/3; organs with metastases 1/2/≥3, 6/6/1. The median cycles of nivolumab was three (range 2-7). With respect to disease responses by CT scan, no patient had partial response, one patient had stable disease, 8 patients had progressive disease and 4 were not yet evaluated. After progression, 2 patients received post-treatment (one in capecitabine plus oxaliplatin, one in S-1 plus oxaliplatin plus trastuzumab) and 4 patients received best supportive care. All grade toxicities included fatigue (69%), decreased appetite (38%), nausea (31%), diarrhea (8%), rash (8%), ALT increased (8%), hypothyroidism (8%) and intestinal lung disease (8%). No patients had Grade3/4 toxicities. Conclusion: Although these data included some patients with an old age or PS 2 due to real world, we show that nivolumab monotherapy for metastatic gastric cancer has been well tolerated. At this point, we have not yet confirmed responder, but we will accumulate cases to report further efficacy and feasibility.
Recanalization method for pancreatic duct stricture complicated by a huge pancreatic stone
Authors: Takeshi Ogura, Rieko Kamiyama, Masanori Yamada, Shinya Fukunishi, Kazuhide Higuchi
Journal: Endoscopy (2018)

Chronic pancreatitis is sometimes complicated by both pancreatic stones and pancreatic duct stricture [1] [2] [3]. In such situations, stone fragmentation may be needed before a stent can be placed. Electrohydraulic lithotripsy is one of the treatment methods used to achieve stone fragmentation. However, if the pancreatic stone is located in the pancreatic head, pancreatoscope insertion is sometimes challenging. We describe herein technical tips for a recanalization method for pancreatic duct stricture complicated by a huge pancreatic duct stone.
RONC-12. SPECTRUM OF INTRACRANIAL IMAGING FINDINGS POST PROTON BEAM THERAPY IN A PEDIATRIC PATIENT COHORT: THE GOSH EXPERIENCE
Authors: Debarata Bhattacharya, Kshitij Mankad, Darren Harvrave, Jenny Gains, Rahul Lakshmana
Journal: Neuro-Oncology (2018)

Proton Beam Therapy (PBT) is now well accepted for the treatment of certain pediatric brain tumours. The intrinsic properties of proton radiation are said to theoretically reduce long term negative effects of photon radiation such as cognitive deficits, endocrine and vascular abnormalities, among others. We designed a study to retrospectively describe the imaging changes in a cohort of 45 children with brain tumors followed up for more than 7 years, with clinical correlation. In addition to the now established and well described imaging phenomena such as pseudoprogression and radiation induced changes, we also found instances of large vessel cerebral arteriopathy, usually associated with photon radiotherapy. Also, there were significant clinical symptoms and morbidities in some patients as a result of these imaging changes, not previously reported in literature. We feel that these findings argue for closer long term monitoring of similar patients treated with PBT, to enable us to have a better understanding of the long term treatment effects.
Transcriptional profiling and biomarker identification reveal tissue specific effects of expanded ataxin-3 in a spinocerebellar ataxia type 3 mouse model
Authors: Lodewijk J. A. Toonen, Maurice Overzier, Melvin M. Evers, Leticia G. Leon, Sander A. J. van der Zeeuw, Hailiang Mei, Szymon M. Kielbasa, Jelle J. Goeman, Kristina M. Hettne, Olafur Th. Magnusson, Marion Poirel, Alexandre Seyer, Peter A. C. ‘t Hoen, Willeke M. C. van Roon-Mom
Journal: Molecular Neurodegeneration (2018)

Spinocerebellar ataxia type 3 (SCA3) is a progressive neurodegenerative disorder caused by expansion of the polyglutamine repeat in the ataxin-3 protein. Expression of mutant ataxin-3 is known to result in transcriptional dysregulation, which can contribute to the cellular toxicity and neurodegeneration. Since the exact causative mechanisms underlying this process have not been fully elucidated, gene expression analyses in brains of transgenic SCA3 mouse models may provide useful insights.Here we characterised the MJD84.2 SCA3 mouse model expressing the mutant human ataxin-3 gene using a multi-omics approach on brain and blood. Gene expression changes in brainstem, cerebellum, striatum and cortex were used to study pathological changes in brain, while blood gene expression and metabolites/lipids levels were examined as potential biomarkers for disease.Despite normal motor performance at 17.5 months of age, transcriptional changes in brain tissue of the SCA3 mice were observed. Most transcriptional changes occurred in brainstem and striatum, whilst cerebellum and cortex were only modestly affected. The most significantly altered genes in SCA3 mouse brain were Tmc3, Zfp488, Car2, and Chdh. Based on the transcriptional changes, α-adrenergic and CREB pathways were most consistently altered for combined analysis of the four brain regions. When examining individual brain regions, axon guidance and synaptic transmission pathways were most strongly altered in striatum, whilst brainstem presented with strongest alterations in the pi-3 k cascade and cholesterol biosynthesis pathways. Similar to other neurodegenerative diseases, reduced levels of tryptophan and increased levels of ceramides, di- and triglycerides were observed in SCA3 mouse blood.The observed transcriptional changes in SCA3 mouse brain reveal parallels with previous reported neuropathology in patients, but also shows brain region specific effects as well as involvement of adrenergic signalling and CREB pathway changes in SCA3. Importantly, the transcriptional changes occur prior to onset of motor- and coordination deficits.
LGG-57. FUNCTIONAL CHARACTERIZATION AND EFFECTIVE TARGETING OF NRF1-BRAF AND ATG7-RAF1 FUSIONS IDENTIFIED IN ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA PATIENTS WITHOUT BRAF p.V600E MUTATION
Authors: Poonam Sonawane, Patrick Diviney, Joanna Phillips, Payal Jain, Phillip Storm, Adam Resnick, Angela Waanders
Journal: Neuro-Oncology (2018)

Pleomorphic xanthoastrocytoma (PXA) is a type of astrocytic glial neoplasm classified as WHO grade II and anaplastic PXA as WHO grade III. These tumors are known to commonly harbor BRAF (p.V600E, c.1799T>A) mutation leading to dysregulation of mitogen-activated protein kinase (MAPK) pathway. Using targeted next-generation sequencing analysis, two gene fusions ATG7-RAF1/CRAF and NRF1-BRAF were identified in BRAF p.V600 wild-type anaplastic PXA patients. We sought to functionally characterize above two fusions using the heterologous cell model systems, which stably expressed ATG7-RAF1 and NRF1-BRAF. Immunoblot analysis showed increased phosphorylation of PI3K/mTOR and MAPK pathways in both the cell lines expressing ATG7-RAF1 and NRF1-BRAF fusions. In protein-protein interaction analysis of ATG7-RAF1 and NRF1-BRAF by co-immunoprecipitation we found both fusions to dimerize suggesting activation of PI3K/mTOR and MAPK pathways due to dimerization. ATG7-RAF1 and NRF1-BRAF preferred homo dimerization compared to hetero dimerization to the full form CRAF and BRAF partners. Soft agar proliferation assay showed significant increase in colony formation in both the fusion expressing cell lines compared to the control (p<0.0005) which was significantly inhibited by PLX8394 RAF inhibitor in the NRF1-BRAF fusion but not in the ATG7-RAF1. By combinatorial inhibition of both MAPK and PI3K/mTOR using trametinib (MEK inhibitor) and everolimus (mTOR inhibitor) we found suppressed phospho-ERK and phospho-S6 expression in both fusions. In summary, our preliminary data suggests differential responsiveness to targeted therapies in the BRAF and CRAF fusions. Our study suggests that further functional characterization of BRAF and CRAF fusions may provide a better therapeutic intervention for the PXA patients.
27 Percutaneous endoscopic gastrostomy tubes; a retrospective analysis in patients with head and neck cancer over 5 years
Authors: E Mc Auliffe, C Murphy, E Clifford, L Perrott, A Heavers, D O’Hanlon
Journal: Gut (2017)

Background  Weight loss and malnutrition are common side effects of disease process and treatment of head and neck cancer. The use of PEG tubes to aid nutrition has been shown to be effective in previous studies and suggest patients benefit from PEGs.  Aim  1) To determine the rate of insertion and use of PEGs  2) To determine complication rates  Method  This study assessed 175 patients who had PEG tubes inserted from 2012 to 2016. Data was collected and extracted from patient dietitian record and analysed using SPSS.  Results  175 patients had PEGs placed from January 2012  t o December 2016. 39% of PEGs were inserted prophylactically. 67% of patients in the cohort had a diagnosis of oropharyngeal cancer. 27% of patients had laryngeal cancer. 3% had salivary gland cancer. Of all patients who received PEGs from 2012-2016, 25% gained weight and 6% of patients’ weight remained stable. 68% did not experience any complication (n=119). 5% experienced a major complication of PEG infection (n=9), while the remaining 11.5% had minor complications of PEG leakage 7.5% and granuloma formation (4%).  Conclusions  Weight loss is almost ubiquitous in head and neck cancers. This study demonstrated that PEGs are a useful aid for patients undergoing treatment for cancer allowing 31% of patients to gain and/or maintain weight. PEGs had relatively low rates of complications with only 5% of patients experiencing a serious complication. This study highlights that patients may benefit from PEG placement during treatment and benefits may outweigh risks.
LGG-29. RESIDUAL TUMOUR SIZE AS A PREDICTOR OF PROGRESSION FOR PAEDIATRIC LOW-GRADE GLIOMA
Authors: Neelakshi Ghosh, Karen Manias, Christopher D Bennett, Adam Oates, Martin English, Andrew Peet, Jenny Adamski
Journal: Neuro-Oncology (2018)

Paediatric low-grade glioma can progress or recur following primary surgical/non-surgical treatment and require further therapy. Studies have identified clinical characteristics predictive of disease progression. This study aims to determine whether size of residual disease following primary treatment is a prognostic indicator for predicting progression. A retrospective analysis of 61 children with histopathologically confirmed low-grade glioma treated at Birmingham Children’s Hospital between 2004 and 2015 was performed. Residual tumour size following primary treatment was measured from MR imaging and analysed in context of clinical characteristics. 47.5% (29/61) children progressed during the follow-up period. A residual tumour size of ≤1cm3 was predictive of better progression free survival for the entire cohort (p<0.001). Age at diagnosis (p=0.377), gender (p=0.619) and Ki-67 index (p=0.234) were not associated with tumour progression. Cerebellar tumours had a longer progression-free interval compared to supratentorial, midline tumours, including the hypothalamic optic pathway tumours (p=0.001). Children with larger residual disease (>2cm3) progressed earlier (minimum 0.36 years) than those with smaller residuals (<2cm3) (minimum 1.1 years). The majority (75.8%) of children with disease progression were asymptomatic and detected on surveillance imaging only. Asymptomatic disease progression occurs following primary treatment for low-grade glioma. Children with smaller residual disease are less likely to progress, with disease progression occurring later after initial treatment. Surveillance neuroimaging is needed to detect disease progression, and optimal timing of imaging may be tailored based on the size of residual disease.
GERM-18. RELAPSE PATTERN AND TREATMENT OUTCOME OF RECURRENT CENTRAL NERVOUS SYSTEM GERM CELL TUMORS
Authors: Takaaki Yanagisawa, Tomonari Suzuki, Kohei Fukuoka, Junichi Adachi, Kazuhiko Mishima, Ryo Nishikawa, Takamitsu Fujimaki, Masao Matsutani, Masayoshi Yamaoka, Wataru Ohyama, Kentaro Yokoi, Masaharu Akiyama, Ai Masumoto, Yuichiro Nonaka, Yasuharu Akasaki, Yuichi Murayama
Journal: Neuro-Oncology (2018)

Central nervous system germ cell tumors (CNS-GCT) are a heterogeneous group of diseases. The management of CNS-GCT remains controversial. Objective: To clarify the relapse pattern and outcome of patients with recurrent CNS-GCT in order to find problems with current initial management. Chart review of patients with recurrent CNS-GCTs treated in two institutions from 2007 to 2017. There were 19 germinomas and six non-germinomatous germ cell tumors (NGGCT), referred to us for the first (n=19), second (n=4), third (n=1) and fourth (n=1) relapse. The time from the diagnosis to the first relapse was within three years for 15 patients (range 6- 24 months) and over three years (range 36 -144 months) for 10 patients. The site of recurrence was outside the irradiation field for 13 germinoma cases, and inside for six germinoma and six NGGCT patients. Thirteen patients with first recurrent germinoma survived with chemotherapy and re-irradiation, and one failed with high-dose chemotherapy only. Two patients with second relapse of germinoma were successfully treated with high-dose chemotherapy only. One patient with second relapse of germinoma refractory to chemotherapy and re-irradiation is alive with oral metronomic etoposide for nine years. Only one of six NGGCT patients survived in spite of intensive treatments. Germinoma patients treated with reduced radiotherapy and chemotherapy can relapse both within and outside irradiation fields, very early and very late in longer follow-up. These results can teach us not only the optimal management of recurrent disease, but also suggest possible novel management of initial disease.