tbuckley/cabot-search huggingface dataset:
Вікові особливості стану печінки у хворих на хронічні запальні захворювання кишечника за даними стеатометрії та зсувнохвильової еластометрії
Authors: M.V. Stoikevych, I.S. Konenko, N.V. Nedzvetskaya
Journal: GASTROENTEROLOGY (2018)

Актуальність. Стаття присвячена актуальній проблемі — вивченню вікових особливостей структурних змін печінки при хронічних запальних захворюваннях кишечника (ХЗЗК). Мета роботи: вивчити вікові особливості структурних змін печінки при неспецифічному виразковому коліті (НВК) та хворобі Крона (ХК). Матеріали та методи. Проведено обстеження 40 пацієнтів за допомогою неінвазивних методів дослідження — стеатометрії та зсувнохвильової еластометрії (ЗХЕ), у тому числі 27 хворих на НВК, 13 — на ХК. Усі хворі були розподілені на групи залежно від віку (відповідно до класифікації Всесвітньої організації охорони здоров’я: від 25 до 44 років — молодий вік, 45–59 років — середній вік). В обстеження включено 29 пацієнтів молодого та 11 пацієнтів середнього віку. Результати. Встановлено, що зміни печінки мали вікові відмінності. Так, за результатами стеатометрії печінки виявлені зміни, характерні для стеатозу печінки за шкалою NAS, у 32,5 % хворих на ХЗЗК, причому у пацієнтів середнього віку стеатоз печінки виявлявся в 1,8 раза частіше порівняно з хворими молодого віку. За даними ЗХЕ, виявлено зміни жорсткості паренхіми печінки у 14 (35 %) у хворих на ХЗЗК, у вигляді І і ІІІ стадії фіброзу — у 25 та 10 % відповідно. У пацієнтів середнього віку у 2,6 раза частіше зустрічалася І та ІІІ стадія фіброзу печінки. Висновки. Враховуючи отримані дані, хворим на ХЗЗК старшої вікової групи доцільно включати в стандарт діагностики проведення ультразвукового дослідження печінки з зсувнохвильовою еластометрією та стеатометрією, що дозволить своєчасно виявити ознаки жирового переродження печінки та визначити раціональну тактику ведення пацієнта, що буде сприяти зниженню ризику розвитку ускладнень захворювань.
HGG-23. DRUG SCREENING LINKED TO MOLECULAR PROFILING IDENTIFIES NOVEL DEPENDENCIES IN PATIENT-DERIVED PRIMARY CULTURES OF PAEDIATRIC HIGH GRADE GLIOMA AND DIPG
Authors: Alan Mackay, Valeria Molinari, Diana Carvalho, Helen Pemberton, Sara Temelso, Anna Burford, Matthew Clarke, Mariama Fofana, Jessica Boult, Elisa Izquierdo, Kathryn Taylor, Lynn Bjerke, Janat Fazal Salom, Ketty Kessler, Rebecca Rogers, Christopher Chandler, Bassel Zebian, Andrew Martin, Simon Stapleton, Samatha Hettige, Lynley Marshall, Fernando Carceller, Henry Mandeville, Sucheta Vaidya, Leslie Bridges, Safa Al-Sarraj, Jane Pears, Angela Mastronuzzi, Andrea Carai, Francesca del Bufalo, Carmen de Torres, Mariona Sunol, Ofelia Cruz, Jaume Mora, Andrew Moore, Simon Robinson, Christopher Lord, Angel Montero Carcaboso, Maria Vinci, Chris Jones
Journal: Neuro-Oncology (2018)

Paediatric high grade glioma and diffuse midline glioma (including DIPG) are comprised of multiple biological and clinical subgroups, the majority of which urgently require novel therapies. Patient-derived in vitro primary cell cultures represent potentially useful tools for mechanistic and preclinical investigation based upon their retention of key features of tumour subgroups under experimental conditions amenable to high-throughput approaches. We established 21 novel primary cultures derived from patients in London, Dublin and Rome, and together with cultures shared from Barcelona, Brisbane and Stanford we assembled a panel of 42 models under 2D (laminin matrix) and/or 3D (neurospheres) conditions, fully credentialed by phenotypic and molecular comparison to the original tumour sample (methylation BeadArray, panel/exome sequencing, RNAseq). Screening against a panel of ~400 approved chemotherapeutics and small molecules, we identified specific dependencies associated with tumour subgroups and/or specific molecular markers. Examples included cells with sensitizing (HSJD-GBM-001, PDGFRA_A385ins; HSJD-DIPG-008, PDGFRA_D846N) or resistance (HSJD-GBM-002, PDGFRA_D842Y) mutations to a range of PDGFRA inhibitors, and individual models showing profound sensitivity to multiple FGFR (QCTB-R006) or EGFR (HSJD-DIPG-012) inhibitors. H3.3G34R cells were differentially sensitive to agents targeting the proteasome, whilst H3.3 K27M cells were responsive to crizotinib. MAPK-dysregulated PXA-like cultures differentially responded to inhibitors of upstream signalling via PKC and CK2. In total, 85% cells were found to have at least one drug screening hit in short term assays linked to the underlying biology of the patient’s tumour, providing a rational approach for individualised clinical translation.
CRAN-34. TRANSCRIPTOMIC AND PROTEOMIC COMPARISON OF PEDIATRIC AND ADULT ADAMANTINOMATOUS CRANIOPHARYNGIOMA
Authors: Eric Prince, Ros Whelan, Andrew Donson, Susan Staulcup, Kevin Lillehei, Nicholas Foreman, Luca Massimi, Michael Handler, Todd Hankinson
Journal: Neuro-Oncology (2018)

Adamantinomatous craniopharyngioma (ACP) is a biologically benign but clinically aggressive lesion that has a significant impact on quality of life. The incidence of the disease has a bimodal distribution with peaks occurring in children and adults. Our group previously published the results of a transcriptome analysis of pediatric ACPs that identified several genes that were consistently overexpressed relative to other brain tumors. We now present the results of a transcriptome analysis of both pediatric and adult ACP to identify biological differences between these groups that may provide novel therapeutic insights, or support the assertion that potential therapies identified through the study of pediatric ACP may also have a role in adult ACP. Following bulk RNA sequencing, we explored the differential expression of adult ACP versus pediatric ACPs via geneset enrichment analysis. Preliminary studies identified a decreased cytokine gene expression profile in adult ACP that may correspond to a reduced senescence-associated secretory phenotype (SASP), which has recently been described in pediatric ACP. Additionally, our results corroborate our previous work demonstrating an increase in IL-6 expression and overall inflammatory response in pediatric tumors. To further characterize age-associated transcriptomic differences, we performed immunohistochemistry, immunoblotting, and other proteomic studies. Our results demonstrate phenotypic similarities and differences between pediatric and adult ACP.
EAPH-09. POTENT CLINICAL AND RADIOLOGICAL RESPONSE TO LAROTRECTINIB IN FIRST CASE OF TRK FUSION HIGH GRADE GLIOMA
Authors: David Ziegler, Maria Tsoli, Vanessa Tyrell, Richard Cohn, Loretta Lau, Michael Cox, Mark Cowley, Paul Ekert, Glenn Marshall, Michelle Haber
Journal: Neuro-Oncology (2018)

Genes encoding neurotrophin receptor kinases (TRK) have recently been implicated as an oncogenic driver in multiple tumor types including congenital fibrosarcoma, papillary thyroid cancer and adult glioblastoma. TRK fusions have been found in up to 40% of non-brainstem infant high grade gliomas (HGG), and play a critical role in tumorigenesis. Larotrectinib is the first and only selective pan-TRK inhibitor in clinical development. Larotrectinib is available as a liquid formulation and has been shown in a Phase 1 trial to be well tolerated in children, with high response rates in TRK fusion solid tumors. Here we report the first case of a pediatric HGG treated with larotrectinib. The patient was initially diagnosed at 5 months of age with a high-grade, right parietal tumor and treated in another institution as an ependymoma with intensive chemotherapy. Following a localized recurrence and resection at 2 years, the diagnosis of HGG was confirmed and treated with focal radiation therapy. By age 3, she developed further primary site tumor progression, and multiple metastatic subependymal nodules. Tumor profiling confirmed an ETV6-NTRK3 fusion. Compassionate access to larotrectinib treatment was provided, and led to rapid clinical improvement with gains in all developmental milestones over 4–6 weeks. After 2 cycles, MRI imaging confirmed near total resolution of primary and metastatic lesions. The patient continues on therapy and updated clinical and radiological results will be presented. This case represents a new paradigm for the treatment for pediatric patients with TRK fusion HGG. Enrolment to a global phase 2 trial is ongoing.
Warshafsky did not intend to kill himself with fentanyl, coroner concludes
Authors: Clare Dyer
Journal: BMJ (2018)

A trainee anaesthetist who died after injecting himself with fentanyl did not kill himself intentionally, a coroner has concluded. Julien Warshafsky, 31, died from a drug related accident, said Karen Henderson, assistant coroner for Surrey.

The newly married trainee stole fentanyl at work and, after going on sick leave, obtained the drug over the internet with bitcoin. But employers, trainers, and other professionals dealing with him failed to recognise that he was addicted to the drug and thought he was using it, as he claimed, to self treat for his depression. He never received treatment for his addiction.1

On 28 June 2016 he was found by his wife, Mariana, slumped over a bed at their flat when she returned from work as an intensive care nurse. He had stopped breathing. He had been on sick leave since December 2015, when …
Characterisation of immunoparesis in newly diagnosed myeloma and its impact on progression-free and overall survival in both old and recent myeloma trials
Authors: Jennifer L. J. Heaney, John P. Campbell, Gulnaz Iqbal, David Cairns, Alex Richter, J. Anthony Child, Walter Gregory, Graham Jackson, Martin Kaiser, Roger Owen, Faith Davies, Gareth Morgan, Janet Dunn, Mark T. Drayson
Journal: Leukemia (2018)

We measured immunosuppression at myeloma diagnosis and assessed the impact on survival in 5826 UK myeloma trial patients. Polyclonal immunoglobulin levels were below normal in 85% of patients and above normal in only 0.4% of cases for IgA, 0.2% for IgM and no cases for IgG. Immunoparesis had a greater impact in recent trials: median overall survival (OS) was up to 3 years longer for patients without immunoparesis compared to the old trials, less than 1 year longer. Median progression-free survival (PFS) was 39%, 36% and 57% longer for patients with normal IgG, IgA and IgM levels, respectively. The depth of IgM suppression, but not the depth of IgG or IgA suppression, was prognostic for survival: the most severely suppressed IgM tertile of patients OS was 0.9 years shorter than those in the top tertile, and 2.6 years shorter than OS of those with normal IgM levels (p = .007). The degree of suppression of polyclonal IgM levels below normal was associated with worse PFS (p = .0002). Infection does not appear to be the main mechanism through which immunoparesis affects survival. We hypothesise that IgM immunoparesis impacts through a combination of being associated with more aggressive disease and reduced immune surveillance against relapse.
Constrained Mutational Sampling of Amino Acids in HIV-1 Protease Evolution
Authors: Jeffrey I Boucher, Troy W Whitfield, Ann Dauphin, Gily Nachum, Carl Hollins, Konstantin B Zeldovich, Ronald Swanstrom, Celia A Schiffer, Jeremy Luban, Daniel N A Bolon
Journal: Molecular Biology and Evolution (2019)

The evolution of HIV-1 protein sequences should be governed by a combination of factors including nucleotide mutational probabilities, the genetic code, and fitness. The impact of these factors on protein sequence evolution is interdependent, making it challenging to infer the individual contribution of each factor from phylogenetic analyses alone. We investigated the protein sequence evolution of HIV-1 by determining an experimental fitness landscape of all individual amino acid changes in protease. We compared our experimental results to the frequency of protease variants in a publicly available data set of 32,163 sequenced isolates from drug-naïve individuals. The most common amino acids in sequenced isolates supported robust experimental fitness, indicating that the experimental fitness landscape captured key features of selection acting on protease during viral infections of hosts. Amino acid changes requiring multiple mutations from the likely ancestor were slightly less likely to support robust experimental fitness than single mutations, consistent with the genetic code favoring chemically conservative amino acid changes. Amino acids that were common in sequenced isolates were predominantly accessible by single mutations from the likely protease ancestor. Multiple mutations commonly observed in isolates were accessible by mutational walks with highly fit single mutation intermediates. Our results indicate that the prevalence of multiple-base mutations in HIV-1 protease is strongly influenced by mutational sampling.
RONC-10. OUTCOMES OF STEREOTACTIC RADIOSURGERY FOR PILOCYTIC ASTROCYTOMA: AN INTERNATIONAL MULTICENTER STUDY
Authors: Erin S Murphy, Jason P Sheehan, Daniel M Trifiletti, David Mathieu, Hideyuki Kano, Fang Fang, John Y K Lee, Brendan McShane, Cheng-chia Lee, Huai-che Yang, Roberto Martinez Alvarez, Nuria Martinez Moreno, Gabriela Simonova, Roman Liscak, Douglas Kondziolka, Mayur Sharma, Gene H Barnett
Journal: Neuro-Oncology (2018)

The utility of radiosurgery is not well documented for pilocytic astrocytoma. We analyzed the efficacy and prognostic factors associated with Gamma Knife radiosurgery (GKRS) for pilocytic astrocytoma in an international multicenter trial. Nine medical centers from the International Gamma Knife Research Foundation provided data. Patients treated with single session GKRS with histologic diagnosis of pilocytic astrocytoma were eligible. Patient, tumor, and treatment variables were analyzed. 141 patients with a median age 13.9 years (range: 2-84) were included. Median follow up was 67.3 months. Twenty-one (15%) had radiotherapy (RT) and 11 (8%) had chemotherapy prior to GKRS. Median margin dose: 14 Gy (range: 4-22.5). Median tumor volume:3.45cc (range: 0.17-33.7). Overall survival at 3, 5 and 10 years from GKRS was 96.8%, 95.7% and 92.5%, respectively. Thirty-four patients progressed resulting in progression-free survival (PFS) at 3, 5, and 10 years of 80.8%, 74.0%, and 69.7%, respectively. For patients <18 years old, 3, 5, and 10 year PFS was 88.3%, 81.3%, and 77.0%, respectively. This was significantly improved (p=0.008) compared to patients ≥18 years old (3, 5, and 10 year PFS of 67.3%, 60.9%, and 56.8%, respectively). Similarly, patients without prior RT (p=0.001), or prior chemotherapy (p=0.003), and with tumor volume <4.5cc (p=0.012) had significantly better PFS. On multivariable analysis, only prior RT impacted PFS (p=0.001, HR=3.705, CI: 1.76-7.80). GKRS for pilocytic astrocytoma results in excellent long term survival and good local control. GKRS may be a particularly useful minimally invasive tool for younger patients with smaller tumor volumes.
Ethnic and racial disparities among young patients with noncardia gastric cancer
Authors: C. Hester, A. Yopp, P. Polanco, J. Mansour, S. Wang, M. Porembka
Journal: Annals of Oncology (2018)

Introduction: Although up to 15% of patients with gastric cancer present at young age, the characteristics of these patients are not well described. We sought to determine the clinical and pathologic characteristics of young noncardia gastric cancer patients in the United States to identify differences between ethnicities. Methods: Patients with noncardia gastric cancer younger than 50 years were selected from the National Cancer Database between 2004 and 2013. We analyzed patient, tumor-, and treatment-related factors as well as overall survival using standard statistical methods. Results: 7,036 patients younger than 50 were identified with 38% Non-Hispanic Whites (NHW), 28% Hispanics (HS), 22% Non-Hispanic Black (NHB) and 12% Asians (AS). HS patients presented at a younger age compared to other ethnicities (37.6% were 18-39 years vs 27% NHW, 28% NHB, and 31% AS p < 0.01). HS was more likely to be uninsured (24% vs 7% NHW, 13% NHB, and 10% AS, p < 0.001) and presented with metastatic disease (47% vs 38% NHW, 41% NHB, and 37% AS, p < 0.001). After adjusting for early stage, NHB and HS were less likely to undergo resection compared to NHW and AS (68% and 70% vs 82% and 77%, p < 0.001). AS had longer median overall survival of 34.4 months compared to 19.7 months for NHW, 19.1 months for HS and 18.3 months for NHB (p < 0.01). Independent variables associated with favorable survival included HS or AS ethnicity (HR 0.76 95%CI 0.7-0.9 and 0.78 95%CI 0.7-0.9), low Charlson Comorbidity Index, private insurance, early clinical stage, and receipt of treatment. Conclusion: There is ethnic and racial variability in disease presentation, treatment delivery, and outcomes in young noncardia gastric cancer patients. HS patients present earlier with more advanced disease. Resection was underutilized in minority patients (NHB and HS). Despite presentation and receipt of therapy, HS race is independently associated with improved survival. Additional studies are warranted to determine underlying biologic and socioeconomic/geographic factors influencing these disparities.
QOL-56. QUALITY OF LIFE IN SURVIVORS OF CHILDHOOD BRAIN TUMORS
Authors: Jessica Channell, Jennifer Raybin, Nicholas Foreman, Christa Hutaff-Lee
Journal: Neuro-Oncology (2018)

As survival rates for children with pediatric central nervous tumors (CNS) improve, long term quality of life is increasingly salient. Between June 2003 and November 2017, patients with intracranial tumors, at least 5 years off therapy, and their parents were approached during follow up visits. After completing informed consent, children and parents completed a quality of life scale (Health Status Index). 64 participants (M=17.95 years, SD=3.99) and 65 parents completed the questionnaires. Average age at diagnosis was 9 years (range: 2 months-20 years). Average number of years off therapy was 8.5 years (range: 5-19 years). Forty-two (72%) subjects received radiation. Participants endorsed difficulties with recalling information (63%) and learning/remembering schoolwork (46%). A smaller percentage (32%) reported cognitive problems involving thinking and solving everyday problems. Parent rating revealed similar concerns regarding their child’s ability to recall information (36%) and cognitive difficulties (29%). Both parents and children rated concerns regarding gross (12%) and fine motor concerns (10% and 18%, respectively), social interactions (13% and 44%, respectively), and cosmetic problems (15%). Interestingly, parent and child ratings significantly differed (p = <.01) in three areas: pain management (parents = 24%, child = 9%), level of pain (parents = 24%, child = 9%), and hearing problems (parents= 6 %, child= 10%). Similar to the literature, cognition and memory were the highest reported concerns by parents and children followed by motor and social-related issues; however, other concerns differed between the two groups. Further work is needed comparing survivor’s concerns versus their caretakers.
Long term survival in advanced esophageal cancer, treated with a French modality of hypofractionated radiotherapy + chemotherapy with or without surgery, the experience at the Instituto Nacional de Cancerología, México
Authors: J. Zamora Moreno, V. Aiello-Crocifoglio, B García Pantoja, E. Ruiz-Garcia, G. Estrada, F. Baillet
Journal: Annals of Oncology (2018)

Introduction: Esophageal cancer, it is an aggressive malignancy with an increasing incidence. Its virulence, in terms of symptoms, mortality, and its geographic variation with a worst prognostic in developing countries, justifies a continued search for optimal therapy. In our country more of the 80% of the patients presents at first time with an advanced disease and a large proportion of them abandon the conventional treatment due to its toxicity. The aim of this retrospective study was to investigate the efficiency and toxicity of an hypofractionated radiotherapy regime, concurrent with a basic scheme of chemotherapy. Methods: From February 2000 to January 2011, 85patients were treated. Radiotherapy was delivered with an hypofractionated Split course scheme of 5 Gy + 5Gy (days 1 and 3) and 6.5 Gy + 6.5 Gy (days 15 and 17) to a total radiation dose of 23 Gy in 3 weeks with a Split of 1 week+ concurrent chemotherapy with 5 Fu + CDDP for one or two cycles. Results: The median age was 59.81 years (range: 30-85 years), female 25.9% (22) patients, <40y (3.5%) >70y (7.1%) male 74.1% (63) patients, <40y (5.9%) > 70y (20%), the tumor location was supracarinal in 37.6% (32) patients and infracarinal in 62.4% (53) patients, histology; squamous cell carcinoma 60% (51) patients, adenocarcinoma 36.5% (31) patients, unknown 3.5% (3) patients, obstruction ≥ 80% was observed in 57.64% (49) patients, and the length of the tumor was >70 mm in 37.6% (32) patients. The clinical stages (AJCC2002) stage II 1.2% (1) patient, stage III 44.7% (38) patients, stage IV 51.8% (44) patients, unknown III or IV 2.4% (2) patients. The median follow-up time was 17.44 months (range 3-184.31), and the overall survival (OS) at 5, 10, and 15 years was 23,%, 18% and 18%, respectively. The most common nonhematologic toxicity was esophagitis, toxicities grades 3 and 4, were not observed. Conclusion: As retrospective study, it has several limitations, but the clinical benefit to be alive not, there are limitations inherent to the model of biological equivalent dose, no allowances can be made for any time gaps in Split course treatments. At our knowledge, this is the first report of advanced esophagus cancer with survival at 15 years, treated with an hypofractionated scheme of radiotherapy with concurrent chemotherapy ± surgery. This yielded satisfactory survival outcomes with minimum costs and toxicities. Randomized studies are warranted to further clarify this issue.
LGG-40. EX VIVO TISSUE METABOLITE PROFILES PREDICT PROGRESSION-FREE SURVIVAL IN PAEDIATRIC CEREBELLAR PILOCYTIC ASTROCYTOMAS
Authors: Christopher Bennett, Sarah Kohe, Simrandip Gill, Neelakshi Ghosh, Karen Manias, Adam Oates, Martin English, Jenny Adamski, Daniel Tennant, Andrew Peet
Journal: Neuro-Oncology (2018)

Pilocytic astrocytomas are the most common brain tumours arising in children, accounting for ~18% of primary brain tumours. 42% are cerebellar in origin and, whilst they have an excellent 10-year overall survival rate of >90%, progression-free survival for these tumours is variable. Identifying tumours more likely to progress will help determine those requiring more aggressive treatment. Metabolite profiles were obtained from 23 cerebellar pilocytic astrocytomas using High Resolution Magic Angle Spinning NMR (HR-MAS). Cox regression tested the ability of individual metabolites to predict progression-free survival. Progression was defined as the time point at which the local multi-disciplinary team decided to further treat the tumour. Low normalised tissue glutamine concentration was found to be associated with a worse progression-free survival (HR=4.58; P<0.05). Glutamine was found to significantly negatively correlate with glutamate (R2=-0.48; P<0.05), suggesting a metabolic link between the metabolites and a mechanism for low glutamine in high-risk tumours. Greater post-surgical residual was associated with poorer progression-free survival (log-rank P<0.05) in this cohort; however, there was no significant correlation between the size of residual tumour and glutamine. This study has shown that metabolite concentrations obtained from tissue samples are associated with progression-free survival of cerebellar pilocytic astrocytoma patients. Low glutamine has previously been associated with worse overall survival in children’s brain tumours. Knowledge of a high risk of progression may have altered the clinical management of one patient in our cohort with disease progression. HR-MAS acquires data in minutes and could detect high-risk tumours intraoperatively.
ATRT-07. MURINE SOX2-POSITIVE EARLY PRECURSOR CELLS GIVE RISE TO RHABDOID TUMORS WITH FEATURES OF THE HUMAN ATRT-MYC GROUP
Authors: Natalia Moreno Galarza, Dörthe Holdhof, Marta Interlandi, Viktoria Melcher, Monika Graf, Dennis Kastrati, Michael Meisterernst, Pascal Johann, Marcel Kool, Michael Frühwald, Ulrich Schüller, Kornelius Kerl
Journal: Neuro-Oncology (2018)