tbuckley/cabot-search huggingface dataset:
Ultraselective conventional transarterial chemoembolization: When and how?
Authors: Shiro Miyayama
Journal: Clinical and Molecular Hepatology (2019)

Ultraselective conventional transarterial chemoembolization (cTACE), defined as cTACE at the most distal portion of the subsubsegmental hepatic artery, is mainly performed for hepatocellular carcinoma (HCC) ≤5 cm. Distal advancement of a microcatheter enables injection of a larger volume of iodized oil into the portal vein in the limited area under non-physiological hemodynamics. As a result, the reversed portal flow into the tumor through the drainage route of the tumor that occurs when the hepatic artery is embolized is temporarily blocked. By adding gelatin sponge slurry embolization, both the hepatic artery and portal vein are embolized and not only complete necrosis of can be achieved. Ultraselective cTACE can cure small HCCs including less hypervascular tumor portions and replace surgical resection and radiofrequency ablation in selected patients. Keywords: Chemoembolization, Therapeutic; Hepatocellular carcinoma; Iodized oil; Gelatin sponge, Absorbable; Conebeam computed tomography
Diagnosis of genetic diseases in seriously ill children by rapid whole-genome sequencing and automated phenotyping and interpretation
Authors: Michelle M. Clark, Amber Hildreth, Sergey Batalov, Yan Ding, Shimul Chowdhury, Kelly Watkins, Katarzyna Ellsworth, Brandon Camp, Cyrielle I. Kint, Calum Yacoubian, Lauge Farnaes, Matthew N. Bainbridge, Curtis Beebe, Joshua J. A. Braun, Margaret Bray, Jeanne Carroll, Julie A. Cakici, Sara A. Caylor, Christina Clarke, Mitchell P. Creed, Jennifer Friedman, Alison Frith, Richard Gain, Mary Gaughran, Shauna George, Sheldon Gilmer, Joseph Gleeson, Jeremy Gore, Haiying Grunenwald, Raymond L. Hovey, Marie L. Janes, Kejia Lin, Paul D. McDonagh, Kyle McBride, Patrick Mulrooney, Shareef Nahas, Daeheon Oh, Albert Oriol, Laura Puckett, Zia Rady, Martin G. Reese, Julie Ryu, Lisa Salz, Erica Sanford, Lawrence Stewart, Nathaly Sweeney, Mari Tokita, Luca Van Der Kraan, Sarah White, Kristen Wigby, Brett Williams, Terence Wong, Meredith S. Wright, Catherine Yamada, Peter Schols, John Reynders, Kevin Hall, David Dimmock, Narayanan Veeraraghavan, Thomas Defay, Stephen F. Kingsmore
Journal: Science Translational Medicine (2019)

Automated phenotyping and interpretation of rapid whole-genome sequencing improve time to diagnosis of genetic diseases in hospitalized children.
HGG-19. MOLECULAR ANALYSIS UNCOVERS 3 DISTINCT SUBGROUPS AND MULTIPLE TARGETABLE GENE FUSIONS IN INFANT GLIOMAS
Authors: Ana Guerreiro Stücklin, Scott Ryall, Kohei Fukuoka, Michal Zapotocky, Alvaro Lassaletta, Anthony Arnoldo, Yvonne Zhong, Paul Kowalski, Claire Li, Michael Taylor, Uri Tabori, Cynthia Hawkins
Journal: Neuro-Oncology (2019)

BACKGROUND: Infants (< 1 year of age) with low (LGG)- and high-grade gliomas (HGG) have paradoxical survival outcomes when compared with older children. The association between tumor grade and outcome is less predictable, as is the response to classic LGG and HGG treatment. The clinical and molecular factors underlying these differences remain poorly characterized. METHODS: Multi-institutional collaborative retrospective study. We integrated genetic testing with morphologic characterization and detailed clinical outcome of 142 patients diagnosed with gliomas (WHO I-IV) in the first year of life with follow-up data spanning three decades (1985–2017). Novel oncofusions were further validated in vitro and in vivo. RESULTS: Infant gliomas comprise three unique groups of tumors; Group 1 are hemispheric receptor tyrosine kinase (RTK)-driven tumors, mostly but not exclusively HGG, and include gliomas harboring unreported ALK, ROS1 and NTRK1/2/3 fusions, analogous to alterations observed in adult tumors, such as lung cancer. Unlike in adult cancers, these alterations were often the only genetic drivers present. iNHA cells transduced with the most common ALK fusions were tumorigenic in vivo and susceptible to targeted agents. Group 2 are hemispheric Ras/MAPK-driven tumors, which show excellent long-term survival requiring minimal interventions post-surgery. Group 3 are midline Ras/MAPK-driven gliomas, enriched for LGG (optic pathway hypothalamic glioma) harboring BRAF alterations and with a surprisingly poor outcome. CONCLUSION: Most infant LGG and HGG showed single and actionable molecular drivers (BRAF, FGFR, ALK, ROS1, NTRK and MET), including novel oncofusions that are observed throughout pathological grades. This study broadens our understanding of cancers early in life and highlights the need for a change to clinical practice: early biopsy, routine molecular characterization, and the evaluation of targeted inhibitors in their treatment.
Image Gallery: Interaction between alcohol and topical tacrolimus as a cause of facial flushing
Authors: J. Sabater‐Abad, M. Matellanes‐Palacios, F. Millán Parrilla
Journal: British Journal of Dermatology (2019)

Funding sources: none. Conflicts of interest: none to declare. Dear Editor, A 66‐year‐old woman with no history of alcohol‐related facial flushing and predominantly facial vitiligo began treatment with two daily applications of topical tacrolimus 0·1%. After 3 months she reported self‐limited episodes lasting 30–60 min of facial erythema with a burning sensation, limited to the regions treated, 20 min after drinking alcoholic beverages (a, before and b, after). This reaction has been reported in 3·4% and 6·9% of patients treated with tacrolimus 0·03% and 0·01% ointment, respectively, and its physiopathogenic mechanism is unknown with accuracy. Patients should be informed of this potential adverse effect before starting treatment with topical tacrolimus.1,2
MEDU-37. NEURONAL DIFFERENTIATION AND CELL-CYCLE PROGRAMS MEDIATE RESPONSE AND RESISTANCE TO BET-BROMODOMAIN INHIBITION IN MYC-DRIVEN MEDULLOBLASTOMA
Authors: Pratiti Bandopadhayay, Federica Piccioni, Ryan O’Rourke, Patricia Ho, Elizabeth Gonzalez, Gabrielle Gionet, Kenin Qian, Jessica Clymer, Amanda Balboni-Iniguez, Fred Lam, Ofer Shapira, Noah Greenwald, Rumana Rashid, Hong Tiv, Shannon Coy, Michael Yaffe, Mark Kieran, Prafulla Gokhale, Kimberley Stegmaier, Sandro Santagata, Keith Ligon, Cory Johanneseen, Rameen Beroukhim
Journal: Neuro-Oncology (2019)

BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately of resistance, have not been fully defined. Using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA-driven rescue screens, and cell-based models of spontaneous resistance, we identified bHLH/homeobox transcription factors including NEUROD1, NEUROG1 and NEUROG3, and cell-cycle regulators CCND2 and CCND3 as key gene mediators of BETi’s response. Furthermore, these genes also mediated resistance, and were re-expressed in cells that acquire resistance to BETi through chronic dosing. Cells that acquired drug tolerance exhibit altered cell state, with an increase in neuronally differentiated cell-state and expression of lineage-specific bHLH/homeobox transcription factors. However, they did not terminally differentiate, maintaining the expression of SOX2 and the capacity to cycle through S-phase, re-instating expression of CCND2. Analysis of human medulloblastomas revealed heterogeneous populations of cell states, including those that expressed both neuronal and stem markers, and would be predicted to be less sensitive to BETi. Barcoding techniques to track evolution of cells through treatment indicated the existence of cells that are predetermined to acquire resistance to BETi. Finally, we found inhibition of cell-cycling with CDK4/CKD6 inhibition to delay acquisition of resistance, providing a rationale for combination treatments. These findings provide insights into the mechanisms of action of BETi as a therapeutic strategy for MYC-driven medulloblastoma that can be leveraged to increase efficacy in the clinical setting.
Small-bowel endoscopy
Authors: Hironori Yamamoto, Lars Aabakken
Journal: Endoscopy (2019)

Congratulations on the 50th anniversary of Endoscopy! We are honored to write an editorial on a landmark paper on small-bowel endoscopy. It is already nearly 50 years since “Endoscopy of the whole small intestine” was first described in Endoscopy by Deyhle et al. [1]. After successful total colonoscopy in 1969, it did not take too many years to achieve the total endoscopic inspection of the small intestine. Hideo Hiratsuka first accomplished this on March 29th in 1971 using the “ropeway” method [2]. Deyhle et al. also used a similar method to examine the whole of the small intestine in two patients with gastrointestinal blood loss of undetermined origin [1]. However, despite successful endoscopic investigation of the small bowel, these methods were not widely adopted because they were uncomfortable for the patient, complicated, and very time-consuming. Indeed, the guide-string for a subsequent enteroscopy could take several days to pass from mouth to rectum. Additionally, stretching of the string could damage the small-bowel mucosa and cause tremendous pain and discomfort that mandated the use of general anesthesia. Therefore “push enteroscopy” remained the standard enteroscopic procedure for about 30 years. However, push enteroscopy was incomplete, with a large area of the small intestine beyond the most proximal part still essentially uninvestigated.
Abstract 9972: Do Risk Models Accurately Predict the Coronary Artery Bypass Graft Mortality Risk in Patients of Southeast Asian Origin?
Authors: Sai Liang, Yan Zheng Daniel Lim, Ronald Ma, Ka Shing Yow, Jolane Eng, Bowen Li, Chuen Neng Lee, Theodoros Kofidis, Kristine Teoh, Oon Cheong Ooi, Hai Dong Luo
Journal: Circulation (2015)

Introduction: Cardiac surgery risk models have been developed based on predominantly Caucasian populations. This study is conducted to validate and evaluate these models for Southeast Asian patients. Methods: We analyzed a prospectively collected dataset of 1769 patients who underwent isolated CABG between 2009 and 2013 in an academic medical center: National University Heart Center, Singapore. Patients were scored by six risk models (Additive EuroSCORE, Logistic EuroSCORE, EuroSCORE II, Society of Thoracic Surgeons (STS), Northern New England Cardiovascular Disease Study Group, and Parsonnet). Discriminatory power was compared using ROC and C-statistics. Goodness of fit test was used to assess model calibration. Results: The overall observed mortality was 2.48% (n=44). C-statistics showed fair discriminatory power for all six risk scores, with STS (C-statistic 0.774, 95% CI 0.697 - 0.851) and EuroSCORE II (C-statistic 0.766, 95% CI 0.690 - 0.843) having the highest values. The optimal thresholds using Youden’s method were: STS threshold 1.33%, sensitivity 79.55%, specificity 68.04%; EuroSCORE II threshold 5.23%, sensitivity 54.55%, specificity 86.14%. Calibration testing revealed that only the STS (p=0.156) and EuroSCORE II (p=0.352) had a good fit with our data. However, EuroSCORE II and STS over-predict and under-predict mortality in high risk patients respectively. Conclusion: The STS and EuroSCORE II have the best predictive value for patients of Southeast Asian origin and can provide our surgeons with a suitable benchmark for outcome tracking. Inaccurate predictions for high-risk patients may be improved with recalibration.
Abstract 342: Differences in Inflammatory Dysregulation in TBI Versus Major Trauma
Authors: Holly E Hinson, Martin Schreiber, Cynthia Morris, Dennis Bourdette
Journal: Circulation (2014)

Introduction: Up-regulation of aseptic inflammation is a prominent feature of major trauma, with or without head injury. Observational studies in TBI often lack control groups with major trauma, obscuring the genesis of the reported biomarkers. We hypothesized that patients with TBI would display a unique inflammatory signature that would differ from patients with major trauma without brain injury, due to blood-brain-barrier compromise. Methods: We prospectively enrolled patients with major trauma with and without TBI from a busy level I trauma center ICU. TBI was defined as GCS&lt;13 not related to intoxication, or the presence of intracranial hemorrhage on admission CT scan. Plasma samples were obtained on admission (&lt;8 hours from the trauma), and banked at -80°C for subsequent analysis. Plasma was analyzed by the Stanford Human Immune Monitoring Center using a Luminex human 61-plex analyte platform that screens 61 secreted proteins using multiplex fluorescent immunoassay; samples were run in duplicate for confirmation, and the means reported. Measurements are reported in median [IQR] in pg/mL. P values of 0.05 or less were considered significant, though final data will be adjusted for multiple comparisons. Results: Forty patients were enrolled, 21 had TBI. Total injury severity scores (ISS) (26 [11-27 v. 14 [10-21] P=0.11) and APACHE (14 [12-24] v. 12 [10-14] P=0.07) scores were comparable between groups. Patients in the TBI group had a lower GCS on admission (15 [4-15] v. 15 [15-15]) P=0.04). While both groups had evidence of elevated cytokines, only TNF-alpha (72.23 [63.68-91.27] v. 63.52 [58.36-69.5], P=0.05) and interferon beta (19.31 [14.13-33.8] v. 14.79 [10.71-17.32], P=0.04) were statistically significantly different between the groups, both more elevated in the TBI group. Conclusion: Our data provides preliminary evidence of immunologic dissonance unique to TBI as compared to major trauma. Future studies using biomarkers in TBI must control for major trauma as a confounder.
Downregulation of survivin expression by SN-38 is preceded by altered expression of regulatory factors of the NF-kappa-B (NFkB) transcription complex
Authors: Hans Minderman, Jeffrey M. Conroy, Kieran L. O’Loughlin, Devin E. McQuaid, Paul K. Quinn, Norma J. Nowak, Maria R. Baer
Journal: Cancer Research (2005)

5374   Irinotecan (CPT-11) interacts synergistically with a wide variety of anticancer agents, including thymidylate synthetase inhibitors, taxane derivatives, platinum compounds and anthracyclines, as well as immunotherapeutic agents. The wide variety of known mechanisms of action of these synergistic agents and the schedule-dependency of synergy suggest that synergistic interactions with CPT-11 are associated with a CPT-11-induced change in a general cellular process, such as the apoptotic response. Study of time kinetic changes in expression of apoptosis-associated genes studied by cDNA microarray analysis in HL60 cells following two-hour  in vitro  exposure to 0.3 μM SN-38, the active metabolite of CPT-11, revealed downregulation of the anti-apoptotic transcriptome survivin, with a nadir at six hours. In order to determine whether survivin downregulation was related to altered transcription regulation, expression profiles of factors controlling the NFkB transcription complex, which regulates survivin expression, were studied. NFkB/Rel proteins are bound and inhibited by IkB proteins. IKK complexes phosphorylate IkB proteins, freeing NFkB/Rel complexes which translocate to the nucleus where they induce target gene expression. Following SN-38 exposure, expression of NFKB1 and NFKB2 was slightly upregulated, whereas p65/RelA expression was unchanged, profiles which likely have no effect on transcription activity. However, expression of IkB proteins was upregulated (IkB-alpha immediately, IkB-epsilon peaking at 4h) and expression of IKK-epsilon was downregulated. All expression levels returned to normal by 12 hours after SN-38 exposure. The observed time kinetic changes in expression of IkB-alpha, IkB- epsilon and IKK-epsilon, preceding the time kinetic changes in expression of survivin, suggest that SN-38-induced downregulation of survivin results from inhibition of the activity of the NFkB transcription complex. Given the importance of dysregulation of transcription factors such as NFkB in cancer, the potential identification of the NFkB transcription complex as a CPT-11 target warrants further studies to identify the consequences of CPT-11 exposure on other NFkB controlled genes.
IMMU-09. LOCALLY ADMINISTERED CAR T CELLS DEMONSTRATE MOST FAVORABLE ROUTE OF ADMINISTRATION IN A MODEL OF ATRT
Authors: Johanna Theruvath, Claus Moritz Graef, Sabine Heitzeneder, Robbie Majzner, Louai Labanieh, Crystal Mackall
Journal: Neuro-Oncology (2019)

Efficient trafficking and infiltration of CAR T cells to brain tumors is an important determinant of treatment success. Data comparing the route of delivery for CAR-T cells in CNS malignancies is limited, but crucial for successful clinical trial design. We therefore investigated differences in CAR-T cell efficacy, trafficking, toxicity and persistence in intratumoral (IT), intracerebroventricular (ICV) and intravenous (IV) administered CAR-T cells targeting the immune checkpoint B7-H3 in a xenograft model of Atypical teratoid/rhabdoid tumor (ATRT). In order to detect CAR-T cells in vivo we fused a nano-luciferase protein to the CAR construct to simultaneously track tumor growth and CAR-T cell expansion and location. In terms of efficacy, we found that systemic treatment took longer and required a tenfold higher dose to cure the mice compared to locoregional treatment. Tracking of CAR-T cells revealed after 5 days of treatment expansion of CAR-T cells within the tumor of locoregional (IT, ICV) treated mice but not systemic treated mice. Furthermore, 13 days after treatment a significant fraction of locally administered (IT, ICV) CAR-T cells were found in spleen and liver of the mice, demonstrating the migratory potential. No significant differences in CAR-T cell numbers were found in the spleens between the different treatment groups. Regarding toxicity, intravenous administration led to high levels of circulating inflammatory cytokines which were undetectable following local administration. Independent of the route of administration CAR-T cells persisted in brain and spleen. We re-challenged previously treated mice and all groups effectively rejected flank and orthotopic tumors. In summary, local delivery might be favorable in terms of efficacy, trafficking and toxicity, whereas persistence may not depend on the route of delivery. These findings have direct valuable implications for a clinical trial design for CAR-T cell based immunotherapies for ATRT and other CNS malignancies.
IMMU-21. DEVELOPMENT OF PET TRACERS FOR NON-INVASIVE IMAGING OF IMMUNOTHERAPY IN DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Shubhanchi Nigam, Lauren McCarl, Carolyn Anderson, Ashok Panigrahy, Ian Pollack, Barry Edwards, Gary Kohanbash
Journal: Neuro-Oncology (2019)

DIPG is an incurable brain tumor with median overall survival times of less than 10 months, with current treatment. Immunotherapy is an attractive approach for some DIPG patients based on promising clinical and preclinical studies. However, due to surgical inaccessibility, intratumoral heterogeneity, and lack of biomarkers, patient stratification and real-time monitoring of immunotherapy is challenging. Furthermore, radiologic enlargement of tumors, due to immune cell infiltration (pseudoprogression) may result in premature removal from effective clinical trials. Molecular imaging of immunologic markers may allow for non-invasive quantification of tumor antigen levels, activated T-cells within tumors, and differentiation of tumor progression from pseudoprogression. Based on our previous experience, receptor densities/cell, cell type specificity, and analysis of publicly available gene expression data we selected EphA2, CD69, and CD45, for development of antibodies radiolabeled with Zr-89 to quantify receptor levels by positron emission tomography (PET). EphA2, a tumor antigen, could be used to stratify patients for therapy. CD69, a marker on activated lymphocytes, could be used to quantify activated NK and T-cells within the tumor. Finally, quantification of CD45, a highly expressed marker on immune cells, could be used to measure immune infiltrates to distinguish tumor growth from pseudoprogression. We have developed an immunotherapy sensitive syngeneic orthotopic cell injection DIPG model (SB-DIPG-11), using tumor cells isolated from de novo tumors induced by sleeping beauty transposon-mediated integration of DIPG-relevant oncogenic genes. Intravenous injection of radiotracers into SB-DIPG-11 tumor-bearing mice demonstrated standard uptake values (SUVs) of 3.9, 2.5, and 2.2 for Zr-89-labeled anti-EphA2, anti-CD69, and anti-CD45, in the tumors, respectively. All SUVs were dramatically reduced by pre-blocking of targets with unlabeled antibody. Biodistribution analysis and flow cytometry validated the SUVs. Overall, our data suggest that immunoPET quantification of tumor antigen and immune cell markers may be promising for stratification and monitoring of DIPG patients for immunotherapy.
Statutory Restrictions on Advance Care Planning and Pregnancy
Authors: Anne Drapkin Lyerly
Journal: JAMA (2019)

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Conbase: a software for unsupervised discovery of clonal somatic mutations in single cells through read phasing
Authors: Joanna Hård, Ezeddin Al Hakim, Marie Kindblom, Åsa K. Björklund, Bengt Sennblad, Ilke Demirci, Marta Paterlini, Pedro Reu, Erik Borgström, Patrik L. Ståhl, Jakob Michaelsson, Jeff E. Mold, Jonas Frisén
Journal: Genome biology (2019)

Accurate variant calling and genotyping represent major limiting factors for downstream applications of single-cell genomics. Here, we report Conbase for the identification of somatic mutations in single-cell DNA sequencing data. Conbase leverages phased read data from multiple samples in a dataset to achieve increased confidence in somatic variant calls and genotype predictions. Comparing the performance of Conbase to three other methods, we find that Conbase performs best in terms of false discovery rate and specificity and provides superior robustness on simulated data, in vitro expanded fibroblasts and clonal lymphocyte populations isolated directly from a healthy human donor.