tbuckley/cabot-search huggingface dataset:
DIPG-24. DIFFUSE INTRINSIC PONTINE GLIOMAS EXHIBIT HIGH BASAL DNA DAMAGE AND ARE VULNERABLE TO INHIBITION OF DNA DAMAGE REPAIR PATHWAYS
Authors: Sharmistha Pal, Jie Bian, Dipanjan Chowdhury, Daphne Haas-Kogan
Journal: Neuro-Oncology (2019)

BACKGROUNDL Diffuse intrinsic pontine gliomas (DIPGs) are fatal childhood gliomas and radiotherapy is the only modality that prolongs survival; however, all patients progress with no long term survivors, indicating an urgent need to develop new treatment approaches. METHODS: Genome wide CRISPR screen was used to identify the cellular pathway(s) critical for DIPG cell survival and doxycycline inducible shRNA were used for temporal knockdown of gene expression. Colony formation assays were performed to monitor effects on cell proliferation, comet assay and immunoflourescence based gamma-H2AX foci detection were used for DNA damage assessment, and caspase3/7 activity measured apoptosis. RESULTS: Our preliminary studies to understand radio- and chemo-resistance mechanisms in DIPGs uncovered high levels of persistent basal DNA double strand breaks (DSBs) in the majority of analyzed DIPG cell lines compared to neural stem cells and astrocytes, a phenomenon that promotes oncogenic potential. The basal increase in DSBs was independent of H3.3K27M mutational status. To pinpoint the molecular mechanism(s) that support proliferation and survival of DIPG cells with highly damaged DNA, we performed unbiased CRISPR screens in unperturbed cells and preliminary results suggest an addiction of DIPG cells to specific DSB repair factors. Further analyses confirmed this intrinsic reliance of DIPG cells on specific DSB repair pathways and the key role of DNA repair mechanisms in suppressing DNA damage induced apoptotic cell death. CONCLUSION: DIPG cells exhibit persistent DNA damage. To evade catastrophic genomic instability and cell death, DIPG cells hijack DNA repair pathways. Therefore, a promising therapy against DIPG would include inhibition of specific DNA damage response pathways that allow DIPGs to survive persistent DNA damage.
Evaluation of the Diagnostic Stability of the Early Autism Spectrum Disorder Phenotype in the General Population Starting at 12 Months
Authors: Karen Pierce, Vahid H. Gazestani, Elizabeth Bacon, Cynthia Carter Barnes, Debra Cha, Srinivasa Nalabolu, Linda Lopez, Adrienne Moore, Sunny Pence-Stophaeros, Eric Courchesne
Journal: JAMA Pediatrics (2019)

Universal early screening for autism spectrum disorder (ASD) in primary care is becoming increasingly common and is believed to be a pivotal step toward early treatment. However, the diagnostic stability of ASD in large cohorts from the general population, particularly in those younger than 18 months, is unknown. Changes in the phenotypic expression of ASD across early development compared with toddlers with other delays are also unknown.To examine the diagnostic stability of ASD in a large cohort of toddlers starting at 12 months of age and to compare this stability with that of toddlers with other disorders, such as developmental delay.In this prospective cohort study performed from January 1, 2006, to December 31, 2018, a total of 2241 toddlers were referred from the general population through a universal screening program in primary care or community referral. Eligible toddlers received their first diagnostic evaluation between 12 and 36 months of age and had at least 1 subsequent evaluation.Diagnosis was denoted after each evaluation visit as ASD, ASD features, language delay, developmental delay, other developmental issue, typical sibling of an ASD proband, or typical development.Diagnostic stability coefficients were calculated within 2-month age bands, and logistic regression models were used to explore the associations of sex, age, diagnosis at first visit, and interval between first and last diagnosis with stability. Toddlers with a non-ASD diagnosis at their first visit diagnosed with ASD at their last were designated as having late-identified ASD.Among the 1269 toddlers included in the study (918 [72.3%] male; median age at first evaluation, 17.6 months [interquartile range, 14.0-24.4 months]; median age at final evaluation, 36.2 months [interquartile range, 33.4-40.9 months]), the overall diagnostic stability for ASD was 0.84 (95% CI, 0.80-0.87), which was higher than any other diagnostic group. Only 7 toddlers (1.8%) initially considered to have ASD transitioned into a final diagnosis of typical development. Diagnostic stability of ASD within the youngest age band (12-13 months) was lowest at 0.50 (95% CI, 0.32-0.69) but increased to 0.79 by 14 months and 0.83 by 16 months (age bands of 12 vs 14 and 16 months; odds ratio, 4.25; 95% CI, 1.59-11.74). A total of 105 toddlers (23.8%) were not designated as having ASD at their first visit but were identified at a later visit.The findings suggest that an ASD diagnosis becomes stable starting at 14 months of age and overall is more stable than other diagnostic categories, including language or developmental delay. After a toddler is identified as having ASD, there may be a low chance that he or she will test within typical levels at 3 years of age. This finding opens the opportunity to test the impact of very early-age treatment of ASD.
Abstract 12405: Up to 39 Years of Follow-up After Repair of Truncus Arteriosus
Authors: Seiji Asagai, Kei Inai, Tokuko Shinohara, In Sam Park, Katsuhiko Mori, Mitsuki Nagashima, Toshio Nakanishi
Journal: Circulation (2012)

Backgrounds: Long-term results of Rastelli operation for truncus arteriosus remain undetermined. Methods: At our institute, 55 Rastelli operations were performed for truncus arteriosus from1974 to 2002. Retrospective review of medical records was performed to assess long-term outcomes among 35 patients who survived the initial repair. The median age at the initial operation was 2.7 months, with the median body weight of 3.8 kg. In most cases, conduit made of equine pericardium with hand-made valve of either equine or autologous pericardium was used at the initial operation. Before the initial operation, truncal valve regurgitation was noted as follows: none (79%), mild (6%), moderate (15%), and severe (0%). Results: Mean age at the last follow-up was 22 years old, ranging 9.6 to 43 years. Mean follow-up duration was 21 years, ranging 9.4 to 39 years. There was only one late death, which was due to cerebral hemorrhage. Actuarial survival rate was 100% at 10 years, 95% at 20 years, and 95% at 30 years after...
Bone Marrow Stroma Protects FLT3 Acute Myeloid Leukemia (AML) through CYP3A4-Mediated Drug Metabolization of FLT3 Tyrosine Kinase Inhibitors (TKIs)
Authors: Yu-Ting Chang, Daniela Hernandez, Gabriel Ghiaur, Mark J. Levis, Richard J. Jones
Journal: Blood (2017)
LGG-09. PD-L1 EXPRESSION IN PEDIATRIC LOW GRADE GLIOMAS, AN OPPORTUNITY FOR INTERVENTION INDEPENDENT OF BRAF MUTATIONAL STATUS
Authors: Allison Martin, Robert Bell, Ming Yuan, Lauren Harris, Antje Arnold, Brad Poore, Laura Asnaghi, Eric Raabe, Charles Eberhart
Journal: Neuro-Oncology (2019)

10–15% of all pediatric gliomas harbor a point mutation in the BRAF gene, BRAFV600E, and it is especially common in certain low grade subtypes. Targeting this mutation with BRAF inhibitors has generated impressive responses in pediatric brain tumor patients with multiple clinical trials ongoing. In melanoma, where BRAFV600E mutation is common, responses to BRAF inhibition have been robust but not durable. However, long term remission has been achieved with immune checkpoint inhibitors, including those of the programmed death (PD) pathway. Response to PD inhibition has been linked to the expression of PD-L1 on the surface of tumor cells. To evaluate a potential relationship between BRAFV600E mutation and PD-L1 expression, we examined the expression of PD-L1 in pediatric high and low grade glioma cell lines as well as a cohort of pediatric low grade glioma patient samples of diverse and rare histologic subtypes. Transient transfection of BRAF wild-type cell lines with a plasmid expressing mutant BRAFV600E increased baseline PD-L1 expression in 2 of 3 cell lines. Moreover, a BRAFV600E mutant cell line also had high baseline PD-L1 expression. All tumors in our cohort expressed PD-L1, and some cases had high levels, >50%. There was a trend toward increased PD-L1 in the BRAF mutant cases but some wild-type tumors also had robust expression. These findings suggest that the programmed death pathway may be active in subsets of pediatric low grade glioma as a mechanism of immune evasion regardless of BRAF mutational status. Although low grade gliomas often have excellent overall survival when they can be removed surgically, unresectable tumors are associated with significant morbidity and often present a treatment challenge for the neuro-oncologist. Clinical trials evaluating the effect of PD pathway inhibitors in pediatric low grade glioma patients will be critical in determining whether PD-L1 expression indicates a likely therapeutic benefit.
Letter to the Editor: Ductular Reaction in Acute Onset Autoimmune Hepatitis
Authors: Keiichi Fujiwara, Masayuki Nakano, Shin Yasui, Osamu Yokosuka, Naoya Kato
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. To the Editor: We read with interest the review article by Sato et al.,1 who summarized types, mechanisms, and pathways of ductular reaction (DR) in liver diseases. This concise and comprehensive review is valuable for understanding DR in liver diseases. For supporting this review, we present DR as a marker of liver regeneration in various severities of acute onset autoimmune hepatitis (A‐AIH) based on our previous publications.2 DR was observed by cytokeratin (CK) 7 immunostaining. DR consists of hepatic progenitor cells (HPCs), intermediate hepatocytes, and bile ductular reactions, and they could be distinguished by morphological characteristics. CK19 was positive in transitional cells in the bile ductular lineage and bile duct cells, and negative in HPCs, transitional cells in hepatocytic lineage, and hepatocytes with a lower intensity with fewer visualized cells than that of CK7; therefore, CK7 was superior to CK19, as a marker of DR.4 HPCs are single CK7‐positive small cells with an oval nucleus and small rim of cytoplasm located distal to bile ductular reactions and occasionally in sinusoids. Bile ductular reactions have poorly defined lumina located at the portal parenchymal interface, arranged in anastomosing cords, and lined with small CK7‐positive cells with little cytoplasm. Intermediate hepatocytes are defined as cells intermediate in size and with histochemical staining between HPCs and mature hepatocytes in periportal areas and occasionally with extension into lobular areas.2 In our analyses of A‐AIH patients, more intermediate hepatocytes and intralobular HPCs were found in nonsevere and recovered patients. On the other hand, marked formation of bile ductules were found at periportal areas, but intermediate hepatocytes and HPCs were not in fulminant and dead patients. We suppose that the differentiation from periportal HPC to intermediate and mature hepatocytes is maintained in nonsevere patients and survivors, but it is impaired in fulminant ones and nonsurvivors, resulting in the marked formation of bile ductules and resistance to immunosuppressive therapy.2 DR is also an important factor for liver regeneration in A‐AIH, although studies of DR are confusing depending on experimental conditions because of the complexity of DR as the researchers pointed out.
Reporting of Multi-Arm Parallel-Group Randomized Trials
Authors: Edmund Juszczak, Douglas G. Altman, Sally Hopewell, Kenneth Schulz
Journal: JAMA (2019)

<h3>Importance</h3> The quality of reporting of randomized clinical trials is suboptimal. In an era in which the need for greater research transparency is paramount, inadequate reporting hinders assessment of the reliability and validity of trial findings. The Consolidated Standards of Reporting Trials (CONSORT) 2010 Statement was developed to improve the reporting of randomized clinical trials, but the primary focus was on parallel-group trials with 2 groups. Multi-arm trials that use a parallel-group design (comparing treatments by concurrently randomizing participants to one of the treatment groups, usually with equal probability) but have 3 or more groups are relatively common. The quality of reporting of multi-arm trials varies substantially, making judgments and interpretation difficult. While the majority of the elements of the CONSORT 2010 Statement apply equally to multi-arm trials, some elements need adaptation, and, in some cases, additional issues need to be clarified. <h3>Objective</h3> To present an extension to the CONSORT 2010 Statement for reporting multi-arm trials to facilitate the reporting of such trials. <h3>Design</h3> A guideline writing group, which included all authors, formed following the CONSORT group meeting in 2014. The authors met in person and by teleconference bimonthly between 2014 and 2018 to develop and revise the checklist and the accompanying text, with additional discussions by email. A draft manuscript was circulated to the wider CONSORT group of 36 individuals, plus 5 other selected individuals known for their specialist knowledge in clinical trials, for review. Extensive feedback was received from 14 individuals and, after detailed consideration of their comments, a final revised version of the extension was prepared. <h3>Findings</h3> This CONSORT extension for multi-arm trials expands on 10 items of the CONSORT 2010 checklist and provides examples of good reporting and a rationale for the importance of each extension item. Key recommendations are that multi-arm trials should be identified as such and require clear objectives and hypotheses referring to all of the treatment groups. Primary treatment comparisons should be identified and authors should report the planned and unplanned comparisons resulting from multiple groups completely and transparently. If statistical adjustments for multiplicity are applied, the rationale and method used should be described. <h3>Conclusions and Relevance</h3> This extension of the CONSORT 2010 Statement provides specific guidance for the reporting of multi-arm parallel-group randomized clinical trials and should help provide greater transparency and accuracy in the reporting of such trials.
Abstract 18397: Higher Rates of Normal Coronaries and Nonobstructive CAD in Women Across Referral Indications Despite Similar Comorbidities
Authors: Michelle L Ouellette, Adrian I Loffler, Virginia K Workman, George A Beller, Jamieson M Bourque
Journal: Circulation (2016)

Introduction: A high rate of normal coronary arteries in patients referred for invasive coronary angiography (ICA) has been reported previously. We sought to evaluate gender differences in clinical characteristics, referral indications, stenosis severity, and appropriateness in consecutive patients referred for index ICA for ischemia evaluation. Methods: We retrospectively analyzed data on 925 patients who underwent non-emergent index ICA. Stenosis severity was defined as normal (≤20%), nonobstructive (21-49%), and obstructive (≥50%). Clinical data was abstracted from the medical record and compared by gender using chi-square analysis and logistic regression. Results: The study cohort was 44.4% women. Stenosis severity varied significantly by gender (p<0.001). Women had more normal coronaries (37.7% vs. 25.7%) and less obstructive CAD (46.5% vs. 62.7%). Women had lower rates of obstructive CAD across all referral indications as shown in the Figure. This pattern persisted in the stress imaging subgroup des...
DIPG-28. NTRK FUSIONS IN PEDIATRIC DIFFUSE INTRINSIC PONTINE GLIOMAS
Authors: Nathan Dahl, Andrew Donson, Dong Wang, Nicholas Foreman, Suzanne Baker, Christopher Tinkle, Chris Jones, Simon Bailey, Rajeev Vibhakar, Lindsey Hoffman
Journal: Neuro-Oncology (2019)

Diffuse intrinsic pontine gliomas (DIPGs) are effectively incurable brainstem tumors with extraordinarily limited treatment options. Decades of clinical trials of largely nonspecific, cytotoxic chemotherapies have failed to improve these outcomes, demonstrating the need to identify and validate druggable biologic targets within this disease. NTRK1/2/3 fusions are found in a broad range of pediatric cancers, including high-grade gliomas and a subset of DIPGs. Phase 1/2 studies of TRK inhibitors have demonstrated good tolerability, effective CNS penetration, and promising objective responses across all patients with TRK-fusion-positive cancers, but their use has not been explored in NTRK-positive DIPG. We describe the clinical and molecular features of four patients with biopsy-proven DIPG found to harbor NTRK fusions. Next generation sequencing was used to define TRK breakpoints and characterize co-mutations in these patients. We employed single-cell RNA-seq on a single patient tumor to examine the heterogeneity of the NTRK-fusion-positive cells within the bulk tumor population. Recognition of NTRK fusions in a subset of DIPGs and demonstration of the in silico relevance of these fusions highlights the ongoing need for broad molecular characterization of these tumors and may justify inclusion of NTRK-positive DIPG patients in ongoing TRK-inhibitor trials.
HGG-06. PODOPLANIN POSITIVE MYELOID CELLS PROMOTE GLIOMA DEVELOPMENT BY IMMUNE SUPPRESSION
Authors: Tanja Eisemann, Barbara Costa, Heike Peterziel, Peter Angel
Journal: Neuro-Oncology (2019)

The diverse tumor microenvironment is a significant parameter in tumor development and therapy response. One compartment of the tumor microenvironment that has gained growing interest is the immune system. As endogenous defense machinery the immune system has the capacity to fight against cancer cells. However, tumor cells frequently engage immune-regulatory mechanisms to disable tumor-directed immune responses. Thus, in order to unleash the immune system against cancer cells, it is crucial to characterize in great detail individual tumor-associated immune cell populations and their role in immune evasion. In this study we investigated the function of a tumor-associated myeloid cell subpopulation characterized by podoplanin (PDPN) expression on the development of high-grade glioma tumors. The cell surface protein PDPN has frequently been associated with malignant progression in glioma and other cancer entities. In addition to tumor cells, multiple cell types in the glioma microenvironment have been reported to express PDPN, including glioma-associated myeloid cells. Interestingly, although PDPN expressing inflammatory macrophages have been shown to critically regulate inflammation during sepsis and acute respiratory distress syndrome, the function of PDPN-positive macrophages in cancer has remained unexplored. Here, we show that the deletion of Pdpn in myeloid cells results in increased CD3+ and CD8+ T-cell infiltrates and significantly prolonged survival in a syngeneic transplantation model of high-grade glioma. In vitro co-culture of glioma cell lines and macrophages revealed that PDPN transcriptionally regulates arginase-1, a well-known player in myeloid cell-mediated immune suppression. These findings identify PDPN-positive myeloid cells as one novel mediator of glioma-induced immune suppression. More detailed in vivo studies will be required to identify the underlying mechanisms and determine whether targeted ablation of PDPN-positive myeloid cells could be included in combinatorial cancer therapies to enhance immune-mediated elimination of highly aggressive and difficult to treat glioma tumors.
DIPG-29. DFMO AND PANOBINOSTAT TARGET LIN28 AND HDAC IN DIPG DECREASING CELL VIABILITY
Authors: Tyler Maser, Joseph Zagorski, Elizabeth VanSickle, Abhinav Nagulapally, Giselle Saulnier Sholler
Journal: Neuro-Oncology (2019)

BACKGROUND: Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric cancer with a poor prognosis of < 10% overall survival at 2 years from diagnosis. Due to their location DIPG presents a therapeutic challenge with radiation as the mainstay of therapy. Over 80% of DIPG tumors harbor a K27M mutation in genes encoding H3 histone variants, causing epigenetic dysregulation. Previous work has shown that treatment with the histone deacetylase (HDAC) inhibitor Panobinostat decreases DIPG tumor growth and viability in preclinical studies. In addition, LIN28 and MYCN have been shown to portend poor prognosis in CNS tumors. DFMO (α-difluoromethylornithine) has been shown to reverse this Lin28/let-7 axis and suppress MYCN in neuroblastoma cells and improve overall survival in neuroblastoma patients. Therefore, we hypothesize this may be effective in DIPG and combined with panobinostat. METHODS: DNA/RNA sequencing of 11 DIPG cell lines were evaluated for mutation and pathway analysis. High-throughput drug testing of 88 drugs was completed in DIPG cell lines which identified Panobinostat and DFMO as potential therapies for DIPG. Testing of these in combination studies using CellTiter-Glo, western blots and flow cytometry was performed to evaluate response and mechanism. RESULTS: RNA sequencing of 11 DIPG cell lines identified upregulation of HIST1H3B, HMGA2, LIN28 and MYCN. DFMO reduces cell viability of DIPG cells in a time and dose dependent manner as shown by cell viability assay and flow cytometry. This reduction in viability is further enhanced with the addition of Panobinostat. Western blot and flow cytometry confirm that DFMO suppresses LIN28 in DIPG. CONCLUSION: Due to the importance of epigenetic dysregulation and the upregulation of the LIN28 pathway in DIPG tumors we demonstrated that the combined treatment of Panobinostat and DFMO is a viable therapeutic option for DIPG and will be tested in an upcoming clinical trial.
HIGH DIAGNOSTIC ACCURACY OF ENDOSCOPIC ULTRASONOGRAPHY IN PATIENTS WITH SUSPECTED CHOLEDOCHOLITHIASIS
Authors: B Keczer, Z Dubravcsik, A Szepes, L Madácsy, L Harsányi, A Szijártó, I Hritz
Journal: Endoscopy (2019)

The likelihood of common bile duct (CBD) stones can be prognosticated by various clinical predictors, however the sensitivity and specificity of these factors is moderate. Endoscopic ultrasonography (EUS) has been shown to be a non-invasive precise test for the detection of CBD stones. Our aim was to assess the diagnostic accuracy of EUS in patients with suspected choledocholithiasis in two centers during the period of 1 year.