tbuckley/cabot-search huggingface dataset:
A&amp;E consultant whose wife skipped triage and was treated at home is suspended for a month
Authors: Clare Dyer
Journal: BMJ (2019)

A consultant in emergency medicine who let his wife skip triage when she arrived at his A&E department, then took supplies from his hospital so that he could treat her at home, has been suspended from the medical register for one month.

Brian Flavin arranged for his wife, who is also a doctor, to skip the triage system and go immediately for radiography, the entire process from her registration to discharge lasting just 26 minutes. Later, he removed intravenous fluids and dressings from the hospital to treat her at home, then altered hospital records to create the impression that she had been treated there.

Royal Bournemouth and Christchurch Hospitals NHS …
GENE-20. MULTI-GENE MUTATION PROFILING OF PEDIATRIC MIDLINE GLIOMAS USING PATIENT LIQUID BIOPSY
Authors: Erin Bonner, Eshini Panditharatna, Madhuri Kambhampati, Michael Virata, Priyam Singh, Michael Prados, Sabine Mueller, Javad Nazarian
Journal: Neuro-Oncology (2019)

INTRODUCTION: Molecular profiling of the tumor genome is critical for diagnosis and clinical management of CNS tumors. In the case of pediatric diffuse midline gliomas (DMGs), the neuroanatomical location of the tumor precludes surgical resection. Moreover, when tumor resection or biopsy is permitted, serial monitoring of the tumor is limited to MR imaging. We have recently reported on detection of tumor associated somatic mutations in patient liquid biopsy specimens. While powerful, our current approach is limited to multiplexed detection of up to two somatic mutations, limiting comprehensive profiling. To address this, we developed a sensitive approach for profiling tumor genomic aberrations in circulating tumor DNA (ctDNA). RESULTS: We show successful detection of tumor-specific mutations in plasma, serum, and cerebrospinal fluid (CSF) of pediatric DMGs, using a targeted panel to sequence exons of 170 candidate genes. Our analysis indicates overlap of somatic tumor mutations in CSF and plasma with matched tissue; a higher number of mutations were detected in CSF compared to plasma. Patterns of tumor evolution were revealed in CSF analyzed at end-stage disease. For example, loss of a TP53 mutation at progression compared to initial diagnosis was confirmed in CSF collected at postmortem, indicating utility of our platform for identification of tumor evolution. Additionally, subclonal heterogeneity of DMGs was captured in CSF compared to tumor specimens. Low allelic frequency mutations in genes involved in DMG tumorigenesis, such as PI3K signaling and chromatin regulators, were exclusively detected in CSF, but not in matched tumor tissue. IMPACT: Our novel approach enables tumor exome monitoring of low frequency variants in liquid biopsy specimens. Our sensitive targeted sequencing panel provides opportunity for profiling somatic tumor mutations at initial diagnosis and at progression, for mapping tumor evolution in the context of clinical trials.
THER-27. ASSESSING CEREBROSPINAL FLUID FLOW IN PEDIATRIC PATIENTS WITH CENTRAL NERVOUS SYSTEM TUMORS TREATED WITH INTRAVENTRICULAR RADIOIMMUNOTHERAPY
Authors: Kim Kramer, Maria Donzelli, Emmanuela Nwora, Neeta Pandit-Taskar
Journal: Neuro-Oncology (2019)

BACKGROUND: Patients with primary or metastatic central nervous system (CNS) tumors may be treated with adjuvant intraventricular chemotherapy or radioimmunotherapy. Effectiveness of the drug may in part depend on adequate drug distribution throughout the thecal space. The incidence of normal, delayed, asymmetric or obstructed cerebrospinal fluid (CSF) flow in the pediatric population with CNS tumors prior to intraventricular therapy has not been described. METHODS: We performed a retrospective review of patients with primary or metastatic CNS tumors treated at MSK over a 15-year period (2003–2018). Patients underwent 111-indium diethylene triamine pentaacetic acid (DTPA) injection into the CSF with nuclear medicine imaging at 90 min-4 hours, 24 hours and 48 hours (if required). CSF flow studies were classified as normal, delayed, asymmetric or obstructed. RESULTS: 278 CSF flow studies were performed in 224 patients, 202 (90%) < 18 years of age. 116 (52%) of patients had metastatic CNS neuroblastoma, 57 (25%) had medulloblastoma and 51 (23%) had other CNS histologies. Of the 278 flow studies, 237 (85%) were normal, 9 (3%) were obstructed requiring neurosurgical intervention, 25 (9%) were delayed and 7(3%) were asymmetric. CONCLUSIONS: Abnormal CSF flow studies are noted in 15% of pediatric patients with CNS tumors; 3% of patients will require a procedure to improve adequate flow prior to receiving intraventricular therapy. These results have implications for successful delivery of intraventricular therapies.
Lung function in children with sickle cell disease from Central Africa
Authors: Michele Arigliani, Robert Kitenge, Luigi Castriotta, Pathy Ndjule, Vincenzo Barbato, Paola Cogo, Leon Tshilolo
Journal: Thorax (2019)

Lung function in patients with sickle cell anaemia (SCA) living in sub-Saharan Africa is largely unknown. Anthropometry and spirometry were cross-sectionally evaluated in patients with SCA (HbSS) aged 6–18 years and in schoolchildren from the Democratic Republic of the Congo. The Global Lung Initiative 2012 spirometry reference values were used. A total of 112 patients and 377 controls were included. Twenty-six per cent of patients with SCA had spirometry findings suggestive of a restrictive pattern and 41% had a FEV 1 z-score &lt;5th percentile. Wasting, increasing age and female sex were independently associated with increased risk of restrictive spirometry pattern in patients with SCA. Longitudinal studies could clarify the prognostic meaning of these findings.
National Institutes of Health Pathways to Prevention Workshop: Research Gaps for Long-Term Drug Therapies for Osteoporotic Fracture Prevention
Authors: Albert Siu, Heather Allore, Darryl Brown, Susan T. Charles, Matthew Lohman
Journal: Annals of Internal Medicine (2019)

On 30 and 31 October 2018, the National Institutes of Health convened the Pathways to Prevention (P2P) Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention to assess the available evidence on long-term (>3 years) use of drug therapies to prevent osteoporotic fractures and identify research gaps and needs for advancing the field. The workshop was cosponsored by the NIH Office of Disease Prevention (ODP), National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute on Aging. A multidisciplinary working group developed the agenda, and an Evidence-based Practice Center prepared an evidence report through a contract with the Agency for Healthcare Research and Quality to facilitate the discussion. During the 1.5-day workshop, invited experts discussed the body of evidence and attendees had the opportunity to comment during open discussions. After data from the evidence report, expert presentations, and public comments were weighed, an unbiased independent panel prepared a draft report that was posted on the ODP Web site for 5 weeks for public comment. This final report summarizes the panel's findings and recommendations. Current gaps in knowledge are highlighted, and a set of recommendations for new, strengthened research to better inform the long-term use of osteoporotic drug therapies is delineated.
Polymersome nanoreactors with tumor pH-triggered selective membrane permeability for prodrug delivery, activation, and combined oxidation-chemotherapy
Authors: Jean Felix Mukerabigwi, Wei Yin, Zengshi Zha, Wendong Ke, Yuheng Wang, Weijian Chen, Abd Al-Wali Mohammed Mohammed Japir, Yi Wang, Zhishen Ge
Journal: Journal of Controlled Release (2019)
Abstract 17729: Multiple Reoperations on the Mitral Valve. Results and Risk Factors for Immediate and Long-term Outcomes
Authors: Jerome Jouan, Leonora Du Puymontbrun, Paul Achouh, Susanna Salvi, Philippe Menasché, Alain Carpentier, Christian Latremouille, Jean-Noël Fabiani
Journal: Circulation (2016)

Introduction: Operative mortality and long-term outcomes are keystones in the choice of valve substitute and operative strategy in multiple reoperations on the mitral valve (MV). At the dawn of per...
TAD fusion score: discovery and ranking the contribution of deletions to genome structure
Authors: Linh Huynh, Fereydoun Hormozdiari
Journal: Genome biology (2019)

Deletions that fuse two adjacent topologically associating domains (TADs) can cause severe developmental disorders. We provide a formal method to quantify deletions based on their potential disruption of the three-dimensional genome structure, denoted as the TAD fusion score. Furthermore, we show that deletions that cause TAD fusion are rare and under negative selection in the general population. Finally, we show that our method correctly gives higher scores to deletions reported to cause various disorders, including developmental disorders and cancer, in comparison to the deletions reported in the 1000 Genomes Project. The TAD fusion score tool is publicly available at https://github.com/HormozdiariLab/TAD-fusion-score .
IMMU-18. TARGETING H3.3 K27M MUTATION AS A SHARED NEOANTIGEN IN HLA-A*0201+ PATIENTS WITH DIFFUSE MIDLINE GLIOMAS – DEVELOPMENT OF A NOVEL MASS CYTOMETRY-BASED MONITORING OF VACCINE-REACTIVE, EPITOPE-SPECIFIC CD8+ T CELL RESPONSES
Authors: Jared Taitt, Payal Watchmaker, Neil Almeida, Kaori Okada, Maryam Shahin, Sabine Mueller, Hideho Okada
Journal: Neuro-Oncology (2019)

Diffuse midline glioma (DMG), including diffuse intrinsic pontine glioma (DIPG) constitutes up to 20% of pediatric brain cancer and has a median survival of less than one year. The ongoing development of immunotherapy has shown significant promise in many fields, including that of gliomas. Genetic studies have revealed that greater than 70% of DIPG cases harbor an amino acid substitution from lysine (K) to methionine (M) at position 27 of histone 3 variant 3 (H3.3). We have previously identified novel HLA-A*02:01-restricted neoantigen epitope encompassing the H3.3K27M mutation. Accordingly, we have implemented a clinical trial through the Pacific Pediatric Neuro-Oncology Consortium (PNOC). Newly diagnosed DIPG patients who are HLA-A2+ and H3.3K27M+ underwent radiation therapy, and then received the H3.3K27M peptide vaccine, combined with the tetanus toxoid (TT) peptide, emulsified in Montanide. The TLR3 agonist, Poly-ICLC, was given concurrently to improve therapeutic effects of the vaccine. Our objective is to characterize vaccine-induced H3.3K27M-specific T cells from peripheral blood at several time points of the study through the evaluation of a large number of analytes utilizing a novel H3.3K27M-specific dextramer-based mass cytometry method. The specificity of the H3.3K27M-specific dextramer was validated through significant binding to H3.3K27M TCR-transduced CD8 T cells and lack of non-specific binding. Subsequently, patient-derived PBMC samples were analyzed using this methodology, revealing a time course-dependent, progressive expansion of CD45RA+ effector memory cells with an inverse downregulation of CD45RO+ in H3.3K27M-specific CD8 T cells. Additionally, progressive upregulation of HLA-DR was observed in several myeloid-derived populations through the course of the trial. Future plans include the longitudinal quantification of IFN-γ and TNF-α expression as a response to the H3.3K27M peptide vaccine at each time point. The development of this methodology may greatly aid in the comprehensive evaluation of immunotherapeutic outcomes on the cellular basis.
MEDU-41. TARGETING GRANULOCYTE COLONY STIMULATION FACTOR RECEPTOR EXPRESSING MEDULLOBLASTOMA CELLS
Authors: Megan Paul, Jacqueline Lesperance, Peter Zage
Journal: Neuro-Oncology (2019)

Medulloblastoma can often be cured with resection, radiation, and chemotherapy, but recurrent disease has a dismal prognosis. Identifying mechanisms of disease recurrence is key to improving overall survival. Identifying sub-populations of medulloblastoma tumors with stem cell-like properties holds promise for reducing disease recurrence, but no unifying marker of medulloblastoma cancer stem cells has been found. The granulocyte stimulating factor receptor (GCSF-R or CD114) is well understood in the context of hematopoiesis. GCSF-R positive neuroblastoma and melanoma cells have cancer stem cell properties of chemoresistance and increased tumorigenicity, and are enriched after chemotherapy administration. GCSF-R is also expressed on a subpopulation of medulloblastoma cells. GCSF-R is particularly relevant as a cancer stem cell marker because its substrate, G-CSF, is used extensively in medulloblastoma treatment. GCSF-R exerts influence over the cell via the JAK-STAT pathway, presenting a potential therapeutic target. We show via flow cytometry that GCSF-R positive cells are identified in multiple medulloblastoma cell lines and PDX tumors, and that the GCSF-R+ subpopulation have a slower growth rate than GCSF-R- or mixed populations. In addition, GCSF selectively causes accelerated growth of GCSF-R+ cells in vitro. GCSF-R positive cells are more chemoresistant in vitro to vincristine, etoposide, and carboplatin. We also show that inhibitors of the JAK-STAT pathway have in vitro activity against medulloblastoma cell lines. We propose that GCSF-R represents a distinct subgroup of medulloblastoma cells which may evade traditional therapy. JAK-STAT inhibitors are already being used in other clinical contexts and may represent an adjunct therapy targeting overall tumor burden and specifically targeting GCSF-R+ cells via the JAK-STAT pathway.
THER-10. TELOMERE TARGETING BASED-THERAPIES TO TREAT THERAPY-RESISTANT PEDIATRIC BRAIN TUMORS
Authors: Satarupa Sengupta, Shiva Senthil Kumar, Deepak Mishra, Rachid Drissi
Journal: Neuro-Oncology (2019)

Resistance to conventional therapies is the biggest challenge to cure high-risk pediatric brain tumors, the leading cause of cancer-related death in children. Therefore, developing effective therapies is an urgent unmet need. We recently reported in pediatric brain tumors the preclinical validation of 6-thio-dG, a telomerase substrate precursor analog*. Treatment with 6-thio-dG caused both telomeric and genomic DNA damage, G2/M cell cycle arrest and rapid cell death. In vivo treatment delayed tumor growth in mouse models of high-risk medulloblastoma and DIPG. Furthermore, 6-thio-dG crosses the blood-brain barrier and specifically targets tumor cells in an orthotopic mouse model of DIPG. In vitro, the effect of 6-thio-dG was sustained several days post-drug removal, suggesting that a short exposure time in a clinical setting may be sufficient to have a therapeutic effect. While the majority of the 6-thio-dG treated cells died by apoptosis, survivor cells emerged after prolonged drug holiday in both group 3 medulloblastoma and DIPG patient-derived cells. These findings suggest that in the long term, DIPG and medulloblastoma will likely resist to 6-thio-dG monotherapy. We will present preclinical data and discuss telomere targeting based-therapies in combination with radiotherapy (RT) and G2/M checkpoint inhibitors. Together, our data indicate that telomere targeting is an effective and a rapid therapy, and suggest that the combination with RT or G2/M checkpoint inhibitors will prevent the emergence of resistant cells and disease recurrence. *Sengupta, S. et al. Induced Telomere Damage to Treat Telomerase Expressing Therapy-Resistant Pediatric Brain Tumors, Mol Cancer Ther, 2018.
Effect of dexraoxane on impaired mitochondrial structure and function in doxorubicin-treated childhood ALL survivors.
Authors: Steven E. Lipshultz, Tracie L. Miller, Mariana Gerschenson, Donna S. Neuberg, Kristen Stevenson, Vivian I Franco, Lynn Anderson, Daniel LiButti, Lewis B. Silverman, Lynda M. Vrooman, Stephen E. Sallan
Journal: Journal of Clinical Oncology (2012)

9530 Background: Cardiotoxicity in doxorubicin (DOX)-treated long-term childhood cancer survivors is characterized by impaired cardiac function which is partly mediated by mitochondrial (mt) energy production. Preclinical studies show irreversible DOX-associated cardiac mt dysfunction. A response to impaired mt function is to increase the mtDNA copies/cell (mtDNA). We examined mtDNA and function in peripheral blood mononuclear cells (PBMCs) in childhood survivors of high-risk ALL who received DOX alone or DOX plus dexrazoxane (DOX/DEX). Methods: Patients with HR ALL treated on DFCI Childhood ALL protocols from 1987-2005 were eligible for this study. PBMCs mtDNA and oxidative phosphorylation (OXPHOS) NADH dehydrogenase (CI) and cytochrome c oxidase (CIV) activities were measured by RT-PCR and immunoassays respectively. A Wilcoxon rank-sum test was used to compare continuous measures between groups. Models for mitochondrial parameters were based on maximum likelihood variance component estimation and were adjusted for patient characteristics. Results: 64 patients provided samples at a median follow-up of 7.8 (2.9-30.2) years. 58% received DOX/DEX. Median cumulative DOX dose was 300 mg/m 2 . A significant difference was detected between groups for mtDNA (p=0.001, adjusted p=0.015). MtDNA medians for the DOX and DOX/DEX groups were 1106.3 and 310.5. No significant differences were found between groups for CI or CIV activities. Conclusions: DOX-treated survivors have increased mtDNA consistent with impaired mt function, which is abrogated by concurrent use of DEX. The use of DOX/DEX is associated with lower mtDNA. Due to a compensatory increase in mtDNA to augment mt function, overall mt function is not different between groups. This compensatory mechanism in 7.8-year survivors at risk for cardiac dysfunction is concerning over their subsequent lifespan. [Table: see text]
TMOD-15. SPATIOTEMPORAL LOSS OF SMARCB1 IN EARLY NEURAL CREST LINEAGE LEADS TO DIFFERENT MOLECULAR SUBTYPES OF RHABDOID TUMORS
Authors: Jeremie Vitte, Fuying Gao, Giovanni Coppola, Alexander R Judkins, Marco Giovannini
Journal: Neuro-Oncology (2019)

Rhabdoid tumor predisposition syndrome 1 (RTPS1) results from inactivation of the tumor-suppressor SMARCB1, a core component of the BAF (hSWI/SNF) complex. Rhabdoid tumors (RTs) are a highly malignant group of neoplasms that usually occur in children less than 2 years of age, which have no effective medical treatment. We discovered that the myelin protein zero (P0) gene serves as a lineage marker to trace the developmental origin of RT neoplastic cells. Ablating Smarcb1 in the P0+early neural crest lineage was necessary and sufficient to initiate tumorigenesis in cranial nerves and meninges, faithfully recapitulating histological features and molecular profiles of human RTs. About 65% of P0-CreC;Smarcb1flox/floxmice developed tumors between 1.5 and 5 months of age with an overall median survival of 3.2 months. These mice developed aggressive tumors emanating from cranial nerves, meninges, with variable extent of brain invasion, and spinal nerve roots. This genetically engineered mouse model opens the doors for deciphering the origin and evolution of RTs to identify effective therapies.
TMOD-05. IN VIVO REPROGRAMMING OF POSTMITOTIC NEURONS INDUCES MEDULLOBLASTOMA
Authors: Giuseppe Aiello, Luca Tiberi
Journal: Neuro-Oncology (2019)

Abstract It is widely accepted that the “cell of origin” of tumors has to possess a proliferative capacity. Particularly for brain cancer, the transition of neural progenitors to differentiated postmitotic neurons is considered irreversible in physiological and pathological conditions. Therefore, postmitotic neurons have not been considered as suitable cell-of-origin for brain cancer. Here, we show that neurons reprograming may occur upon Shh activation and it leads to medulloblastoma (MB) formation in vivo. Shh MB is a cerebellar tumor, found in infants and adults that is thought to originate from cerebellar granule neuron progenitors. More recently, it was discovered that the two different forms of SHH MB are distinguished by different transcriptome/methylome levels suggesting that the adult SHH MB may originate from a different cell-of-origin. Relying on these data, we take advantage of a conditional Cre-Lox recombination system to recapitulate the human adult medulloblastoma pathogenesis in mice and demonstrate that post-migratory mature granule neurons can be reprogrammed in vivo. Furthermore, to define the contribution of chromatin changes in granule neurons dedifferentiation in response to Shh activation, we profiled changes in chromatin accessibility by ATAC-seq both in mouse tissue samples and also in human neurons. Upon Shh pathway activation we detected the presence of hyper-accessible chromatin regions corresponding to cis-regulatory elements specifically favouring activation of enhancers and super-enhancers. Our novel model of cancer development could explain the human SHH medulloblastoma onset in adult individuals where granule neuron progenitors are no more present. We strongly believe that our model represents an important starting point to study other tissues where postmitotic cells might originate cancer and therefore open a new field in cancer and stem cell biology.
Immune Checkpoint Blockade in PD-L1–Positive Platinum-Refractory Cervical Carcinoma
Authors: Krishnansu S. Tewari
Journal: Journal of Clinical Oncology (2019)

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 36-year-old white married mother of two small children presented with intermenstrual bleeding, dyspareunia, and pelvic pain. Because of significant lapses in health care coverage, she had had only sporadic screening for cervical cancer over the past 15 years. On evaluation with a vaginal speculum, her cervix was found to have been replaced by a friable lesion 5 cm in diameter. Biopsy revealed poorly differentiated, squamous cell carcinoma. Bimanual pelvic and rectovaginal examination, as well as radiographic imaging studies, were consistent with an International Federation of Gynecology and Obstetrics (FIGO) stage IB3 squamous cell carcinoma of the cervix. She was treated with cisplatin-based chemoradiation (40 mg/m2 body surface area once per week with a planned total dose of 50 Gy using intensity modulated radiotherapy) plus high-dose-rate intracavitary brachytherapy (to bring the total dose to point A to 80 to 85 Gy). Despite missing eight radiotherapy sessions because of transportation issues, she had a complete clinical response. Fourteen months later, she developed severe pelvic and right flank pain. In the clinic, she was cachectic and reported significant abdominal discomfort that kept her from eating well over the past several months. She was no longer able to work as a medical assistant and spent most of her time confined to her apartment. Physical examination demonstrated a fixed, firm pelvic mass; a computed tomography-guided biopsy confirmed recurrent carcinoma, and staging scans disclosed a pulmonary metastasis.