tbuckley/cabot-search huggingface dataset:
RADT-15. PREOPERATIVE SINGLE FRACTION RADIOSURGERY VERSUS POSTOPERATIVE FRACTIONATED RADIOSURGERY FOR RESECTED BRAIN METASTASES: A BI-INSTITUTIONAL ANALYSIS OF SAFETY AND CLINICAL OUTCOMES
Authors: Roshan Prabhu, Siyu Shi, Reshika Dhakal, Scott Soltys, Stuart Burri, Anthony Asher, Melanie Gephart, Matthew Ward, Gordon Li, John Heinzerling, Erqi Pollom
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Preoperative single fraction radiosurgery (SRS) and postoperative fractionated SRS delivered over 3–5 fractions have been shown to have favorable outcomes compared to postoperative single fraction SRS for resected brain metastases. No study has directly compared these 2 treatment approaches. METHODS Records for patients with resected brain metastases treated with either single fraction preoperative SRS or fractionated (3-5 fractions) postoperative SRS were reviewed. Preoperative SRS was 10-20% dose reduced compared to standard and surgery generally followed within 48 hours. Eligibility criteria included solid tumor metastases, 1 brain metastasis resected, and no previous cranial RT. Fine-Gray and Cox multivariable (MVA) and propensity score matched (PSM) analyses were used. RESULTS A total of 330 patients (137 preoperative; 193 postoperative) were included. Median dose was 15 Gy in 1 fraction and 24 Gy in 3 fractions, respectively. In MVA, preoperative SRS was significantly associated with higher risk of cavity local recurrence (LR, hazard ratio (HR) 2.04, p=0.002) and lower risk of leptomeningeal disease (LMD, HR 0.41, p=0.05). There was no difference in adverse radiation effect (ARE) or overall survival (OS) between groups. In the PSM analysis (65 matched pairs), 1-year outcomes for preoperative vs. postoperative SRS were as follows - cavity LR: 22.9% vs. 3.1%, p&amp;lt; 0.001, LMD: 4.2% vs. 15.5%, p=0.04, ARE: 3.2% vs. 7.9%, p=0.73, composite endpoint (cavity LR, symptomatic ARE, or LMD): 27.6% vs. 20.1%, p=0.33, OS: 56.3% vs. 62.3%, p=0.8. CONCLUSIONS Preoperative single fraction SRS and postoperative fractionated (3-5 fractions) SRS demonstrate distinct patterns of failure. Compared to postoperative SRS, preoperative SRS was associated with increased risk of cavity LR and lower risk of LMD in both multivariable and PSM analyses. There was no difference in risk of ARE or OS. Methods to reduce preoperative SRS cavity LR, such as with higher dose fractionated regimens, should be considered.
Incidental Finding of Bilateral Thalamic Glioma on 99mTc TRODAT-1 SPECT/CT
Authors: Ni-Chun Kuo, Chin Hu, Yu-Li Chiu, Nan-Jing Peng, Hung-Pin Chan
Journal: Clinical Nuclear Medicine (2020)

Abstract 99m Tc-TRODAT-1 SPECT/CT has been used to evaluate parkinsonian disorders. We present an interesting case of a 63-year-old woman with progressive tremulousness over the left side of the body for 6 months. Bilateral thalamic glioma with reduced uptake was shown on 99m Tc-TRODAT-1 SPECT/CT. Secondary parkinsonism was impressed in this case.
PATH-25. GENOME-WIDE METHYLATION ANALYSIS CAN SEGREGATE RADIATION-INDUCED GLIOBLASTOMA FROM LATE RECURRENCE OF MEDULLOBLATOMAS
Authors: Takamasa Hiraki, Kohei Fukuoka, Yuko Matsushita, Yuko Hibiya, Satoko Honda, Makiko Mori, Yuki Arakawa, Koichi Ichimura, Masao Kobayashi, Yutaka Tanami, Atsuko Nakazawa, Jun Kurihara, Katsuyoshi Koh
Journal: Neuro-Oncology (2020)

Abstract It could be difficult to diagnose recurrent medulloblastoma with conventional diagnostic tools because other lesions mimic relapse of the tumor from both a morphological and radiological standpoint, particularly when it happens late. We report two medulloblastoma cases, both of which seemed to develop late-recurrence more than 5 years from the initial surgery. Genome-wide methylation analysis revealed that one of the recurrent tumors was in fact a radiation-induced glioblastoma. The first patient was a 6-year-old female patient who developed a posterior fossa tumor. The pathological diagnosis was medulloblastoma with focal desmoplasia. She was in complete remission for 9 years after the treatment but developed an intradural lesion in her thoracic spine. The lesion was biopsied and pathologically confirmed as recurrence of the tumor. The second patient was a female patient who developed non-metastatic medulloblastoma at the age of 10. She suffered local recurrence 5 years after the diagnosis. Biopsy was performed, and the pathological diagnosis was relapse of the tumor. We performed unsupervised hierarchical clustering of the methylation data from our cases and reference data. In contrast to consistency of methylation profiling and copy number abnormalities between primary and recurrent tumors of case 1, the analysis revealed that the recurrent tumor of case 2 was distinct from medulloblastomas and clustered with “IDH-wild type glioblastomas”, which suggested that the recurrent tumor was radiation-induced glioblastoma. This report highlights the clinical utility of molecular genetic/epigenetic approach to confirm diagnosis of brain tumor recurrence.
IMMU-06. T-CELL IMMUNOTHERAPY FOR PEDIATRIC BRAIN TUMORS: DIVERSITY IN CELL SURFACE ANTIGEN AND HLA EXPRESSION NECESSITATES A MULTI-PRONGED APPROACH
Authors: Haley Houke, Xiaoyan Zhu, Kimberly S Mercer, Jennifer L Stripay, Jason Chiang, Suzanne J Baker, Martine F Roussel, Stephen Gottschalk, Giedre Krenciute
Journal: Neuro-Oncology (2020)

Abstract Cell surface or intracellular antigens expressed in pediatric brain tumors are potential targets for chimeric antigen receptor (CAR) or ab (T-cell receptor) TCR T-cell immunotherapy. At present it remains unknown what cell surface antigens are suitable CAR targets for pediatric brain tumors; in addition, cell surface expression of HLA class I, a molecule critical for ab TCR T-cell recognition, has not been systemically studied in these tumors. Therefore, we set out to assess expression of five CAR targets (IL13Ra2, HER2, EphA2, B7-H3, GD2) and HLA class I. We established and validated a flow cytometry-based method to profile CAR targets and HLA class I expression from pediatric patient-derived xenograft (PDX) samples. To date, we profiled 53 PDX samples, including medulloblastoma, HGG, DIPG, ATRT, and ependymoma. We found that antigen expression has high intra- and inter-PDX sample variability with B7-H3 and IL13Ra2 being most consistently expressed. We confirmed these findings using conventional IHC for B7-H3 with PDX samples and patient tissue microarrays. HLA class I was present on the cell surface of HGGs and DIPGs, however significantly down-regulated in 26 out of 36 other brain tumor types. Finally, matched fresh tissue and PDX sample analysis revealed that cells derived from PDX models are indeed representative of fresh tissue. Our results indicate that more than one antigen needs to be targeted to achieve a more complete tumor clearance. In addition, variable expression of HLA class I suggests that pediatric brain tumors have developed immune evasion strategies to prevent recognition by conventional T cells.
High Prevalence of Advanced Liver Fibrosis Assessed by Transient Elastography Among U.S. Adults With Type 2 Diabetes
Authors: Stefano Ciardullo, Tommaso Monti, Gianluca Perseghin
Journal: Diabetes Care (2020)

OBJECTIVE Type 2 diabetes mellitus (T2DM) is an important risk factor for the progression of metabolic liver disease to advanced fibrosis. Here, we provide an estimate of the prevalence of steatosis and fibrosis in U.S. adults with T2DM on the basis of transient elastography (TE) and identify factors associated with these conditions. RESEARCH DESIGN AND METHODS This is a cross-sectional study of U.S. adults with T2DM participating in the 2017–2018 cycle of the National Health and Nutrition Examination Survey who were evaluated by TE. Hepatic steatosis and fibrosis were diagnosed by the median value of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively. RESULTS Among the 825 patients with reliable TE examination results, 484 (53.7%) were assessed using the M probe and 341 (46.3%) using the XL probe. Liver steatosis (CAP ≥274 dB/m), advanced fibrosis (LSM ≥9.7 kPa), and cirrhosis (LSM ≥13.6 kPa) were present in 73.8% (95% CI 68.5%–78.5%), 15.4% (95% CI 12.2%–19.0%), and 7.7% (95% CI 4.8%–11.9%) of patients, respectively. The mean ± SE age of patients with advanced fibrosis and cirrhosis was 63.7 ± 2.2 years and 57.8 ± 1.6 years, respectively. In the multivariable logistic regression model, BMI, non-Black race, and ALT levels were independent predictors of steatosis; and BMI, non-Black race, and AST and γ-glutamyltranspeptidase levels were independent predictors of advanced fibrosis. CONCLUSIONS Prevalence of both liver steatosis and fibrosis is high in patients with T2DM from the United States and obesity is a major risk factor. Our results support the screening of these conditions among patients with diabetes.
QOL-44. ASSESSMENT OF NEUROCOGNITIVE FUNCTION AND MRI PARAMETERS IN LONG-TERM SURVIVORS WITH POSTERIOR FOSSA TUMORS: A COMPARISON BETWEEN MEDULLOBLASTOMAS TREATED BY REDUCED-DOSE CRANIOSPINAL IRRADIATION AND OTHER TUMORS
Authors: Naoki Kagawa, Takako Miyamura, Ryuichi Hirayama, Chisato Yokota, Tomoyoshi Nakagawa, Noriyuki Kijima, Manabu Kinoshita, Yoshiko Hashii, Keiko Okada, Jyunichi Hara, Haruhiko Kishima
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Children with medulloblastoma cannot avoid chemoradiotherapy including craniospinal radiation, although prognosis of medulloblastoma has improved and previous studies have reported a significant risk of intellectual disturbance by these treatments. We retrospectively analysed neurocognitive functions, clinical MRI parameters of patients with posterior fossa tumors, especially medulloblastomas. MATERIALS AND METHODS Twenty-two patients (12 medulloblastomas, 5 ependymomas, 5 astrocytomas) treated in our institution were enrolled in this study. Mean age was 7.8 years and 6.5 years, percentage of hydrocephalus at onset was 66.7% and 60%, respectively in medulloblastoma group and in other tumor group (ependymoma and astrocytoma). Postoperative chemoradiotherapy including reduced-dose craniospinal irradiation (18Gy) was done for medulloblastoma group and local radiation or operation only was done for other group. Version 3 or 4 of Wechsler Intelligent Scale for Children (WISC) was used by neurocognitive function analysis. Ventricular size, white matter volume and other parameters were also was estimated based on MRI. Follow-up duration was 6–17 years (mean: 10.5 years). RESULTS Evaluations of neurocognitive functions based on WISC pointed out lower performance IQ than verbal IQ in long term survivor of both group, especially working memory (P=0.05). Both hydrocephalus and cranial nerve complications was influenced lower scores of WISC, but age at onset did not influence WISC scores. Comparison between both group showed there was no significant difference about cognitive function and white matter volume.
Patient mortality after surgery on the surgeon’s birthday: observational study
Authors: Hirotaka Kato, Anupam B Jena, Yusuke Tsugawa
Journal: BMJ (2020)

Abstract Objective To determine whether patient mortality after surgery differs between surgeries performed on surgeons’ birthdays compared with other days of the year. Design Retrospective observational study. Setting US acute care and critical access hospitals. Participants 100% fee-for-service Medicare beneficiaries aged 65 to 99 years who underwent one of 17 common emergency surgical procedures in 2011-14. Main outcome measures Patient postoperative 30 day mortality, defined as death within 30 days after surgery, with adjustment for patient characteristics and surgeon fixed effects. Results 980 876 procedures performed by 47 489 surgeons were analyzed. 2064 (0.2%) of the procedures were performed on surgeons’ birthdays. Patient characteristics, including severity of illness, were similar between patients who underwent surgery on a surgeon’s birthday and those who underwent surgery on other days. The overall unadjusted 30 day mortality on the operating surgeon’s birthday was 7.0% (145/2064) and that on other days was 5.6% (54 824/978 812). After adjusting for patient characteristics and surgeon fixed effects (effectively comparing outcomes of patients treated by the same surgeon on different days), patients who underwent surgery on a surgeon’s birthday exhibited higher mortality compared with patients who underwent surgery on other days (adjusted mortality rate, 6.9% v 5.6%; adjusted difference 1.3%, 95% confidence interval 0.1% to 2.5%; P=0.03). Event study analysis of patient mortality by day of surgery relative to a surgeon’s birthday found similar results. Conclusions Among Medicare beneficiaries who underwent common emergency surgeries, those who received surgery on the surgeon’s birthday experienced higher mortality compared with patients who underwent surgery on other days. These findings suggest that surgeons might be distracted by life events that are not directly related to work.
Covid-19: Pfizer vaccine efficacy was 52% after first dose and 95% after second dose, paper shows
Authors: Elisabeth Mahase
Journal: BMJ (2020)

Covid-19: Pfizer vaccine efficacy was 52% after first dose and 95% after second dose, paper shows Elisabeth MahaseThe Pfizer and BioNTech covid-19 vaccine may provide some early protection, starting 12 days after the first dose, the peer reviewed results of a phase III trial have found.The study, published in the New England Journal of Medicine, 1 found that vaccine efficacy between the first and second doses was 52% (95% credible interval 29.5% to 68.4%), with 39 cases of covid-19 in the vaccine group and 82 cases in the placebo group.Seven or more days after the second dose, vaccine efficacy then rose to 95% (90.3% to 97.6%), with eight covid-19 cases reported in the vaccine group and 162 cases in the placebo group.
EPCO-22. IDENTIFYING NEOANTIGENS FOR A PERSONALIZED MUTATION-DERIVED GENOMIC VACCINE IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMA
Authors: Julia Kodysh, Alex Rubinsteyn, Ana Blazquez, John Mandeli, Nina Bhardwaj, Adilia Hormigo
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glioblastomas (GBM) are known for having a lower mutational burden than many other tumor types. Nevertheless, somatic variants that occur in GBM mutational processes may give rise to neoantigens, which can be targeted in a personalized genomic vaccine to elicit a patient-specific anti-tumor response. METHODS Normal and tumor DNA and tumor RNA are extracted from tumor specimens and PBMCs. Exome and RNA sequencing and HLA typing is performed for each patient. Neoantigens are identified using the OpenVax computational pipeline, which calls somatic variants in the DNA and prioritizes corresponding candidate neoantigens for vaccination based on tumor RNA expression and predicted MHC class I binding affinity for each of the patient’s HLA alleles. This work is the base for a phase I trial of personalized neoantigen vaccines in combination with Tumor Treating Fields for GBM (NCT03223103). RESULTS For each of the 9 patients enrolled in the trial, an average of 1005 somatic mutations were identified (range 299–2441), of which 118 were coding variants (range 52–198), 20 were coding and expressed in the tumor RNA (range 9–45), and 16 were coding, expressed and resulted in predicted MHC class I ligands (range 7–33). An average of 2.3% of all somatic variants identified in each tumor gave rise to predicted neoantigens. Sufficient numbers of neoantigens were identified in all tumor samples of the patients enrolled in the study. The overall somatic mutation landscape for the tumors revealed 4/9 PIK3R1 deletions, 2/9 IDH1 substitutions, as well as disruptions in PTEN, TP53, and ATRX, among others. CONCLUSIONS Identifying sufficient neoantigens for inclusion in the personalized genomic vaccine is computationally feasible despite a typically low GBM mutational burden. Driver and passenger mutations can be identified through the same computational pipeline utilized for other tumor types.
A Case-Crossover Analysis of Indoor Heat Exposure on Mortality and Hospitalizations among the Elderly in Houston, Texas
Authors: Cassandra R. O’Lenick, Amir Baniassadi, Ryan Michael, Andrew Monaghan, Jennifer Boehnert, Xiao Yu, Mary H. Hayden, Christine Wiedinmyer, Kai Zhang, Peter J. Crank, Jannik Heusinger, Paige Hoel, David J. Sailor, Olga V. Wilhelmi
Journal: Environmental Health Perspectives (2020)

Despite the substantial role indoor exposure has played in heat wave-related mortality, few epidemiological studies have examined the health effects of exposure to indoor heat. As a result, knowledge gaps regarding indoor heat-health thresholds, vulnerability, and adaptive capacity persist.We evaluated the role of indoor heat exposure on mortality and morbidity among the elderly (≥65 years of age) in Houston, Texas.Mortality and emergency hospital admission data were obtained through the Texas Department of State Health Services. Summer indoor heat exposure was modeled at the U.S. Census block group (CBG) level using building energy models, outdoor weather data, and building characteristic data. Indoor heat-health associations were examined using time-stratified case-crossover models, controlling for temporal trends and meteorology, and matching on CBG of residence, year, month, and weekday of the adverse health event. Separate models were fitted for three indoor exposure metrics, for individual lag days 0-6, and for 3-d moving averages (lag 0-2). Effect measure modification was explored via stratification on individual- and area-level vulnerability factors.We estimated positive associations between short-term changes in indoor heat exposure and cause-specific mortality and morbidity [e.g., circulatory deaths, odds ratio per 5°C increase=1.16 (95% CI: 1.03, 1.30)]. Associations were generally positive for earlier lag periods and weaker across later lag periods. Stratified analyses suggest stronger associations between indoor heat and emergency hospital admissions among African Americans compared with Whites.Findings suggest excess mortality among certain elderly populations in Houston who are likely exposed to high indoor heat. We developed a novel methodology to estimate indoor heat exposure that can be adapted to other U.S.In locations with high air conditioning prevalence, simplified modeling approaches may adequately account for indoor heat exposure in vulnerable neighborhoods. Accounting for indoor heat exposure may improve the estimation of the total impact of heat on health. https://doi.org/10.1289/EHP6340.
Abstract 15913: Novel Dual MTOR Inhibitors/AMPK Activators Attenuate Doxorubicin-Induced Cardiotoxicity
Authors: Anindita Das, Arun Samidurai, Laura G Corral, Leah Fung, Robert W Sullivan, Kyle W Chan, Cathy A Swindlehurst, Fadi N Salloum
Journal: Circulation (2019)

Background: Doxorubicin (DOX) is among the most widely used and highly efficacious anticancer drugs for the treatment of breast cancer, however, its therapeutic application is limited by its life-t...
Arginine Vasopressin Receptor Antagonists for Heart Failure: A Winter Climbing to the Everest’s Tip?⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Gian Paolo Rossi
Journal: Journal of the American College of Cardiology (2007)
EPCO-06. MOLECULAR DETERMINANTS OF EVOLUTION AND PROGNOSIS AMONG DIFFUSE LOWER GRADE ASTROCYTOMAS
Authors: Mehul Kumar, Gregory Cairncross, Michael Blough, Pinaki Bose
Journal: Neuro-Oncology (2020)

Abstract Gliomas with wild type (WT) isocitrate dehydrogenase (IDH) are considerably more aggressive than those with mutant IDH. To identify putative drivers of the distinct progression trajectories of IDH WT and mutant disease, we analyzed transcriptomes of lower grade astrocytomas (LGAs; grade 2–3) with retention of 1p and 19q from The Cancer Genome Atlas (TCGA; n = 347). Compared to IDH mutant LGAs, we found that PDGF signaling was significantly enriched in IDH WT LGAs and that PDGFA was the top overexpressed gene in this pathway. We identified copy number gains of chromosome 7 in WT LGAs, and methylation of the PDGFA promoter in mutant LGAs, as candidate mechanisms for the differential expression of PDGFA. High PDGFA expression and low PDGFA promoter methylation were significantly associated with poor survival in all LGAs. We also found that PDGFA expression was positively associated with aneuploidy and extracellular matrix-related immunosuppressive features in WT LGAs, underscoring the role of PDGFA as a secreted mitogen. Finally, we show that the proportion of p53 pathway mutations increase significantly with grade in IDH WT gliomas. Taken together, our findings suggest that IDH WT LGAs evolve to higher grades, and ultimately to GBM, by progressive inactivation of the p53 pathway - functioning in concert with a background of increased PDGFA expression. These data emphasize the scope of genomic reprogramming that occurs in gliomas in relation to IDH mutations and further highlight the role of PDGFA in glioma formation, progression, and prognosis. Going forward, this work provides critical biological insight that may inspire new therapeutic strategies to suppress the transformation of IDH WT LGAs to higher-grade cancers.
Steering Transplant Immunosuppression by Measuring Virus-Specific T Cell Levels: The Randomized, Controlled IVIST Trial
Authors: Thurid Ahlenstiel-Grunow, Xiaofei Liu, Raphael Schild, Jun Oh, Christina Taylan, Lutz T. Weber, Hagen Staude, Murielle Verboom, Christoph Schröder, Ruxandra Sabau, Anika Großhennig, Lars Pape
Journal: Journal of the American Society of Nephrology (2020)

Background Pharmacokinetic monitoring is insufficient to estimate the intensity of immunosuppression after transplantation. Virus-specific T cells correlate with both virus-specific and general cellular immune defense. Additional steering of immunosuppressive therapy by virus-specific T cell levels might optimize dosing of immunosuppressants. Methods In a multicenter, randomized, controlled trial, we randomized 64 pediatric kidney recipients to a control group with trough-level monitoring of immunosuppressants or to an intervention group with additional steering of immunosuppressive therapy by levels of virus-specific T cells (quantified by cytokine flow cytometry). Both groups received immunosuppression with cyclosporin A and everolimus in the same target range of trough levels. Primary end point was eGFR 2 years after transplantation. Results In the primary analysis, we detected no difference in eGFR for the intervention and control groups 2 years after transplantation, although baseline eGFR 1 month after transplantation was lower in the intervention group versus the control group. Compared with controls, patients in the intervention group received significantly lower daily doses of everolimus and nonsignificantly lower doses of cyclosporin A, resulting in significantly lower trough levels of everolimus (3.5 versus 4.5 µ g/L, P &lt;0.001) and cyclosporin A (47.4 versus 64.1 µ g/L, P &lt;0.001). Only 20% of patients in the intervention group versus 47% in the control group received glucocorticoids 2 years after transplantation ( P =0.04). The groups had similar numbers of donor-specific antibodies and serious adverse events. Conclusions Steering immunosuppressive therapy by virus-specific T cell levels in addition to pharmacokinetic monitoring seems safe, results in a similar eGFR, and personalizes immunosuppressive therapy by lowering exposure to immunosuppressive drugs, likely resulting in lower drug costs. Clinical Trial registry name and registration number: IVIST trial, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2009-012436-32 and ISRCTN89806912