tbuckley/cabot-search huggingface dataset:
RARE-58. CONGENITAL METASTATIC CHORDOMA OF THE CLIVUS
Authors: Wieslawa Grajowska, Maria Stepaniuk, Joanna Trubicka, Katarzyna Wójcicka-Kowalczyk, Piotr Krych, Bozenna Dembowska-Baginska, Marta Perek-Polnik
Journal: Neuro-Oncology (2020)

Abstract Chordomas are rare midline axial skeletal neoplasms that typically present in adults. They are infrequent in childhood with typical localization in the spheno-occipital skull base. They are derived from remnants of the embryonic notochord. We present the case of 4 months old girl, who was born with „blueberry muffin” syndrome and was first negatively diagnosed for neuroblastoma and leukemia (two negative skin biopsies were performed) was admitted with axial laxity. In imaging testes there was a tumor of the scull base, metastases in the lungs and kidneys (that were not seen at previous assessments) and a small lesion in the heart. The third biopsy of skin lesion was performed and pathological examination revealed a neoplasm composed of cords, clusters, and chains of multivacuolated cells embedded within a myxoid matrix and separated by fibrous septa. No atypical and dedifferentiated features were present. Mitotic activity was not observed. Neoplastic cells showed the typical cytoplasmic immunostaining for EMA, S100 and cytokeratin AE1/AE3, strong nuclear brachyury expression, and retention of nuclear INI-1 expression. The diagnosis of chordoma was established. Neoplastic tissue and blood samples were obtained for molecular analysis using next generation sequencing, including germline mutations assessment (are ongoing). Chemotherapy as for soft tissue sarcomas was undertaken. Currently a patient is on treatment with improvement of neurological status.
Abstract P508: Association of Egg and Dietary Cholesterol Intake With Incident Cardiovascular Disease and All-cause Mortality
Authors: Guochong Chen, Li-Hua Chen, Yasmin Mossavar-Rahmani, Victor Kamensky, Aladdin Shadyab, Brian Silver, Robert A Wild, Yangbo Sun, Bernhard Haring, Marian Neuhouser, Lewis H Kuller, Barbara V Howard, Nazmus Saquib, Linda Snetselaar, Matthew A Allison, Linda VAN HORN, Joann E Manson, Sylvia W Wassertheil-Smoller, Qibin Qi
Journal: Circulation (2020)

Introduction: The association of egg or dietary cholesterol intake with risk of cardiovascular disease (CVD) and overall mortality remains a topic of active debate. Hypothesis: Higher egg or dietary cholesterol intake is associated with elevated risk of CVD and all-cause mortality. Methods: We analyzed data from 96,755 women aged 50-79 years who were free of CVD and cancer at baseline (1993-1998)(Women’s Health Initiative). Baseline dietary data were collected using a validated food frequency questionnaire. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals of CVD or mortality ascertained through February, 2018. Results: After multivariable adjustment (model 1 in Figure ), higher intakes of egg and dietary cholesterol both were associated with increased risk of CVD (HRs: 1.09 [1.06-1.13] for ½ eggs/day and 1.13 [1.09-1.17] for cholesterol intake of 100 mg/1000 Kcal/day) and all-cause mortality (HRs: 1.10 [1.07-1.12] for egg and 1.16 [1.12-1.19] for cholesterol intake). These associations persisted with further adjustment for other major food groups (e.g. red/processed meat) or nutrients (e.g. saturated fat), or for several potential intermediators (model 2 in Figure ). For both egg and cholesterol intakes, the positive associations with CVD were limited to obese individuals and the associations with all-cause mortality were more pronounced in individuals with diabetes (all P -interaction≤0.002). Among 9451 participants with blood cholesterol measurements, egg or cholesterol intake remained associated with increased CVD and mortality, and the associations were not altered by further adjustment for LDL and HDL cholesterol despite the expected associations of both lipid measures with CVD and mortality ( Figure ). Conclusions: A higher intake of eggs or dietary cholesterol was associated with higher risk of CVD in obese women and overall mortality predominantly in women diagnosed with diabetes. These associations appeared not attributable to blood cholesterol.
TMOD-22. AKALUC BIOLUMINESCENCE OFFERS SUPERIOR SENSITIVITY TO TRACK IN VIVO GBM EXPANSION
Authors: Dominique Bozec, Anirudh Sattiraju, Alexandros Bouras, Joe Gerald Jesu Raj, Daniel Rivera, Yong Huang, Chrystian Junqueira Alves, Rut Tejero, Hongyan Zou, Constantinos Hadjipanayis, Roland H Friedel
Journal: Neuro-Oncology (2020)

Abstract Longitudinal tracking of tumor growth using non-invasive bioluminescence imaging (BLI) is a key approach for in vivo cancer studies, but the current method of firefly luciferase (Fluc) BLI has quantitative limitations, as it is only suited for detection of tumors of considerable sizes at advanced stage, typically in the order of &amp;gt;105 cells. Recently, Akaluciferase (Akaluc) has been developed as an alternative BLI system that offers higher signal strength and better light penetration of tissue due to its red-shifted emission. Here, we established Akaluc BLI as a new sensitive method for in vivo tracking of glioblastoma (GBM) expansion in intracranial transplant models. In multiple GBM cell lines, including the frequently used U87MG and GL261, as well as patient-derived glioma stem cells (GSC), we demonstrate that Akaluc-expressing GBM cells produced more than 50-times brighter BLI signals in vitro and up to 100-fold higher signal intensities in vivo over Fluc-expressing counterparts. The higher sensitivity of Akaluc BLI permits early in vivo detection of intracranial GBM transplants starting as early as 4 hours after implantation and with as little as 5,000 transplanted GSC. We also reveal a prolonged engraftment period in intracranial GSC transplants before wide dissemination into host brain parenchyma. Akaluc BLI is also advantageous for longitudinal monitoring of therapeutic effects of chemoradiation for GBM and detection of early phase of tumor relapse. Thus, Akaluc BLI offers an important addition to the tool box for cancer research. SIGNIFICANCE: The high sensitivity of Akaluc bioluminescence is a significant improvement for the non-invasive tracking of tumors in preclinical cancer studies, including detection of small incipient tumors and micro-metastasis.
RADT-47. A MULTICENTER OBSERVATIONAL STUDY OF SURGICALLY TARGETED RADIATION THERAPY (START) USING IMPLANTED CS-131 SEEDS IN A COLLAGEN-BASED CARRIER TILE IN INTRACRANIAL BRAIN NEOPLASMS - PROTOCOL IN PROGRESS
Authors: Peter Nakaji, David Brachman, Lisa Misell
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Post-resection radiotherapy (RT) is the most effective adjuvant treatment for brain tumors. However, there is no current consensus as to the “best” type of post-resection RT, either at diagnosis or recurrence. The use of internally placed radiation (brachytherapy) allows immediate initiation of RT when residual tumor burden is minimal, which theoretically should lessen the risk of recurrence. Brachytherapy placement intraoperatively allows more precise identification of the tumor margins than by postoperative imaging. Traditional brachytherapy methods have several drawbacks, including uneven dose distribution, long operating room times, a need for expensive equipment, and/or frequent adverse events (AE). To address these issues, a device with Cs-131 radiation seeds in a resorbable collagen-based carrier tile (GammaTile, GT Medical Technologies, Tempe AZ) was developed and is described as Surgically Targeted Radiation Therapy or STaRT. The device has demonstrated excellent safety and local control in early commercial use. OBJECTIVE The objectives of this registry study are to evaluate real-world clinical outcomes and patient reported outcomes that measure the effectiveness and safety of STaRT. METHOD Patients (N=600) with surgically resected (R) brain tumors of any pathology who have undergone STaRT are eligible. Accrual to start at 20+ sites in Q3 2020. Data collected includes local control, overall survival, QOL, neurocognition, functional decline, and surgical and radiation associated AE’s. Data will be collected at 1, 3, 6, 9, and 12 months, then every 6 months through 5 years. RESULT Data will be used to benchmark clinical outcomes of STaRT therapy and allow for comparisons to existing standard-of-care treatments. CONCLUSION This will be the first observational registry study of R+STaRT, delivered by Cs-131 sources in permanently implanted resorbable collagen tile carriers. The outcome measures captured will allow for evaluation of the potential risks and benefits of this treatment approach for patients in a real-world setting.
PATH-23. GENOMIC LANDSCAPE OF IDH-MUTANT PRIMARY GLIOBLASTOMAS SHOWS DISTINCT CLINICAL AND MOLECULAR FEATURES AND THAT CDKN2A SHOULD BE SUPPLEMENTED WITH MGMTp AND G-CIMP FOR PRECISE PROGNOSTICATION
Authors: Queenie Hoi-Wing Wong, Gabriel Chun-Hei Wong, Aden Ka-Yin Chan, Wai Sang Poon, Danny Tat-Ming Chan, Hong Chen, Zhen-yu Zhang, Houtan Noushmehr, Chris Jones, Yura Grabovska, Alan Mackay, Chit Chow, Johnny Sheung Him Kwan, Nellie Yuk-Fei Chung, Queenie Junqi Huang, Manix Fung-Man Poon, Zhi-feng Shi, Kay Ka-Wai Li, Ho-Keung Ng
Journal: Neuro-Oncology (2020)

Abstract There have only been rare studies of IDH-mutant primary glioblastomas (IDH-mutant astrocytoma IV); there were one or two studies on secondary glioblastomas. In a cohort of 70 cases, we conducted clinical analysis, methylation profiling, RNA sequencing, targeted sequencing, and TERTp seqeuncing on available FFPE tissues. Median follow-up was 58.2 months (n= 60). IDH-mutant primary glioblastomas had longer median OS (30.4 months) and median PFS (25.9 months) than IDH-mutant secondary glioblastomas as in the literature or established databases. MGMTp methylated cases had better OS (p= 0.001) and it was an independent prognosticator. We previously showed G-CIMP to be an independent prognostic marker for IDH-mutant glioblastomas (NOA 2019). Although CDKN2A deletion was an independent prognostic marker for poorer OS (p= 0.036) and PFS (p= 0.005), MGMTp methylation had a trend of superseding CDKN2A deletion (p= 0.055) for prognostication and G-CIMP subgroups could similarly partially supersede CDKN2A deletion (p= 0.582). Hence, CDKN2A deletion should be supplemented with these two biomarkers for finer prognostication. Targeted sequencing (n= 55) showed that there were more ATRX (35/55, 64%), TP53 (31/55, 56%), KMT2D (18/55, 33%), POLE (11/55, 20%) and MSH6 (7/55, 13%) mutations, but fewer TERTp (3/69, 4%) and PTEN (1/55, 2%) mutations than IDH-wildtype glioblastomas as from literature and databases. CNVs revealed by methylomes (n= 53) and mutations (n= 55) showed that there were more PDGFRA (amplification: 9/53, 17%, mutation: 10/55, 18%) alterations, but fewer MET (amplification: 3/53, 6%, mutation: 4/55, 7%) alterations and hypermutated (6/55, 11%) cases than IDH-mutant secondary glioblastomas from literature. GISTIC analysis revealed amplifications of CCND2, CDK4, MYC, and PDGFRA, deletions of CDKN2A, RB1, and chromosome 10q to be significant CNVs (q&amp;lt; 0.05). There were few EGFR amplifications (2/53, 4%), which was different from regular glioblastomas. RNA sequencing (n= 42) showed few fusions (4/42, 10%), which was different from IDH-mutant secondary glioblastomas.
RBIO-01. PROSPECTIVE OBSERVATIONAL STUDY TO DETERMINE THE IMMUNE SYSTEM RESPONSE TO GAMMA KNIFE RADIOSURGERY FOR VESTIBULAR SCHWANNOMAS
Authors: Joshua S Silverman, Jason Gurewitz, Courtney Gunter, Benjamin Cooper, Amy Palermo, Lynda Boulio, Jessica Schafrick, Whei Ying Lim, Ece Karhan, Stephanie Renzullo, Lina Kozhaya, John Golfinos, Erik Sulman, Derya Unutmaz, Douglas Kondziolka
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION The effects of radiosurgery for primary intracranial tumors on systemic immune response are unknown. Vestibular schwannomas (VS) treated with Gamma Knife (GK) have high control rates and low risk of adverse effects. This study examines if radiosurgery for VS is associated with an immune response detectable by peripheral blood sampling, and if that response can be correlated with tumoral expansion and/or toxicity. METHODS 50 patients treated with GK for VS were enrolled on an IRB-approved, prospective study at initial consultation. Blood samples were drawn preceding GK and 6 months and 1 year follow-up. Neurological and hearing outcomes were assessed. Tumor volume was measured at treatment, 6 months, and 1 year follow-up. Tumoral expansion (TE) was defined by volumetric increase &amp;gt;20%. Immunophenotyping via multicolor flow cytometry panels evaluated lymphoid and myeloid differentiation, phenotypic characterization, activation, tissue homing, and immune exhaustion. RESULTS Median volume at radiosurgery was 0.55cc (range 0.04-11.94) and median margin dose was 12.5Gy (11.5-13) prescribed to the 50% isodose line (50-60). 22 tumors exhibited TE, 20 at six months and 2 at one year. No VS with TE grew at median follow-up of 30.8 months (9.8-52.8). 1 tumor, non-expanding (NE) post-GK, showed progression at 24 months. Presence of cranial neuropathy and hearing decline was similar in both groups. Immunophenotyping showed numerous significant (p&amp;lt; .05) changes in the TE group, not seen in NE, at 6 months and 1 year follow-up compared to baseline. Major changes were observed in cytokine secretion (e.g. IFNg, TNF or IL-17) of CD4+ and CD8+ memory T cells, frequencies of regulatory T cells, increased death of CD8+ effector cells in culture, suggesting chronic activated state. CONCLUSION Vestibular schwannomas that expand after GK are associated with a peripherally measurable change in systemic immune response that is absent from non-expanding tumors. The biologic underpinnings of these findings require further study.
EMBR-08. CORRELATION OF HISTOPATHOLOGY, CHROMOSOMAL MICROARRAY, AND NANOSTRING BASED 22-GENE ASSAY FOR MEDULLOBLASTOMA SUBGROUP ASSIGNMENT ON “HEAD START” 4 CLINICAL TRIAL
Authors: Girish Dhall, Parth Patel, Megan Blue, Jaclyn Biegel, Isabel Almiraz-Suarez, Eugene Hwang, Christopher Pierson, Daniel Boue, Jonathan Finlay
Journal: Neuro-Oncology (2021)

Abstract “Head Start” 4 (HS 4) is a prospective randomized clinical trial that tailors treatment based on medulloblastoma molecular subgroups and response to induction chemotherapy to compare the efficacy of one versus three (tandem) cycles of myeloablative therapy. Advances in RNA and DNA profiling have identified four core molecular subgroups of medulloblastoma with prognostic significance: Sonic Hedgehog (SHH) subtype, WNT subtype, Group 3, and Group 4. In HS 4 trial, we utilize a combination of histopathology and immunohistochemistry (pathology/IHC), as well as chromosomal microarray analysis (CMA) utilizing OncoScanTM (Thermo Fisher) to classify medulloblastoma samples into either SHH, WNT, or non-WNT/non-SHH (Group 3/4) subgroups at the time of diagnosis. NanoString based 22-gene assay is performed retrospectively to test concordance. We have pathology/IHC, CMA, and NanoString data on 26 infants and young children with medulloblastoma enrolled on HS 4. Pathology/IHC was able to assign samples to SHH, WNT, and non-WNT/non-SHH subgroups in all but two cases: one case was classified as Group 3, and the second as SHH by both CMA and NanoString. CMA was indeterminate in six cases, of which, pathology/IHC was able to assign all six samples aforementioned three subgroups. NanoString was indeterminate in two cases: one case was classified as SHH by CMA and pathology/IHC, and the second case was indeterminate by CMA but was assigned as non-WNT/non-SHH on pathology/IHC. There is excellent correlation between NanoString and combination of histopathology and CMA for core medulloblastoma subgrouping on HS 4. Methylation studies are ongoing.
29P ALLELE study: A multicenter, open label, phase III study of tabelecleucel for solid organ or allogeneic hematopoietic cell transplant subjects with Epstein-Barr virus-driven post-transplant lymphoproliferative disease (EBV+ PTLD) after failure of rituximab or rituximab and chemotherapy
Authors: N. Worel, J.A. Perez-Simon, P. Barba, D. Dierickx, M. Hiremath, W. Ye, L. Gamelin, W.H. Navarro, S. Choquet
Journal: Annals of Oncology (2020)
Heart Failure Hospitalization and Guideline-Directed Prescribing Patterns Among Heart Failure With Reduced Ejection Fraction Patients
Authors: Pratyaksh K. Srivastava, Adam D. DeVore, Anne S. Hellkamp, Laine Thomas, Nancy M. Albert, Javed Butler, J. Herbert Patterson, John A. Spertus, Fredonia B. Williams, Carol I. Duffy, Adrian F. Hernandez, Gregg C. Fonarow
Journal: JACC Heart Failure (2020)
Abstract 12682: Accuracy of Expert Electrocardiography versus ST-Segment Elevation Myocardial Infarction Criteria for Diagnosis of Acute Coronary Occlusion Myocardial Infarction
Authors: Harvey P Meyers, Alexander Bracey, Daniel Lee, Andrew Lichtenheld, Wei Li, Daniel Singer, Jesse Kane, Kenneth W Dodd, Kristen Meyers, Gautam R Shroff, Adam Singer, Stephen W Smith
Journal: Circulation (2020)

Introduction: In the current STEMI paradigm of Acute Myocardial Infarction (AMI), many NonSTEMI patients have unrecognized acute coronary occlusion. Such patients do not receive emergent reperfusion and are known to have higher mortality than NSTEMI patients without occlusion. Thus, we have proposed a new Occlusion MI vs. Non-Occlusion MI (OMI vs. NOMI) paradigm. We sought to compare the diagnostic accuracy for OMI of blinded expert ECG interpretation vs. STEMI criteria advocated in the fourth Universal Definition of MI. We hypothesized that blinded expert ECG interpretation would be more accurate than STEMI criteria for the diagnosis of OMI, and that STEMI(-) OMI patients would have similar characteristics to STEMI(+) OMI but greater delays to cardiac catheterization. Methods: Retrospective case-control study of patients with suspected acute coronary syndrome, collecting demographics, laboratory results, ECGs, angiographic data, and outcomes. The primary definition of OMI was defined as either 1) acute TIMI 0-2 flow culprit or 2) TIMI 3 flow culprit with peak troponin T &gt;1.0 ng/mL or troponin I &gt;10.0 ng/mL. Results: 808 patients were included, of whom 49% had AMI (33% OMI; 16% NOMI). Sensitivity, specificity, and accuracy of STEMI criteria vs Expert 1 for OMI among all 808 patients were 41% vs 86%, 94% vs 91%, and 77% vs 89%, and for Expert 2 among 250 patients were 36% vs 80%, 91% vs 92%, and 76% vs 89%. When experts outperformed STEMI criteria (55% of OMI), they diagnosed OMI a median of 1.5 hours earlier than STEMI criteria. Seven key ECG findings were identified by experts as important signs of OMI in STEMI(-) cases. STEMI(-) OMI patients had similar infarct size and mortality as STEMI(+) OMI patients, but greater delays to angiography. Conclusions: Blinded expert ECG interpretation was superior to STEMI criteria for the ECG diagnosis of Occlusion MI. STEMI(-) OMI patients had greater delays to catheterization but similar outcomes to STEMI(+) OMI patients. These data support the OMI vs. NOMI paradigm and suggest that STEMI(-) OMI patients could be identified rapidly and noninvasively for emergent reperfusion using expert ECG interpretation.
Association of Plasma Leucine-Rich α-2 Glycoprotein 1, a Modulator of Transforming Growth Factor-β Signaling Pathway, With Incident Heart Failure in Individuals With Type 2 Diabetes
Authors: Jian-Jun Liu, Sharon L.T. Pek, Jiexun Wang, Sylvia Liu, Keven Ang, Yi Ming Shao, Justin I.-Shing Tang, Resham L. Gurung, Subramaniam Tavintharan, Wern Ee Tang, Chee Fang Sum, Su Chi Lim
Journal: Diabetes Care (2020)

OBJECTIVE Leucine-rich α-2 glycoprotein 1 (LRG1) is a circulating protein potentially involved in several pathways related to pathogenesis of heart failure (HF). We aimed to study whether plasma LRG1 is associated with risks of incident HF and hospitalization attributable to HF (HHF) in individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 1,978 individuals with type 2 diabetes were followed for a median of 7.1 years (interquartile range 6.1–7.6). Association of LRG1 with HF was studied using cause-specific Cox regression models. RESULTS In follow-up, 191 incident HF and 119 HHF events were identified. As compared with quartile 1, participants with LRG1 in quartiles 3 and 4 had 3.60-fold (95% CI 1.63–7.99) and 5.99-fold (95% CI 2.21–16.20) increased risk of incident HF and 5.88-fold (95% CI 1.83–18.85) and 10.44-fold (95% CI 2.37–45.98) increased risk of HHF, respectively, after adjustment for multiple known cardiorenal risk factors. As a continuous variable, 1 SD increment in natural log-transformed LRG1 was associated with 1.78-fold (95% CI 1.33–2.38) adjusted risk of incident HF and 1.92-fold (95% CI 1.27–2.92) adjusted risk of HHF. Adding LRG1 to the clinical variable–based model improved risk discrimination for incident HF (area under the curve [AUC] 0.79–0.81; P = 0.02) and HHF (AUC 0.81–0.84; P = 0.02). Conclusions Plasma LRG1 is associated with risks of incident HF and HHF, suggesting that it may potentially be involved in pathogenesis of HF in individuals with type 2 diabetes. Additional studies are warranted to determine whether LRG1 is a novel biomarker for HF risk stratification.
Advancing digital health: FDA innovation during COVID-19
Authors: Kushal Kadakia, Bakul Patel, Anand Shah
Journal: npj Digital Medicine (2020)

Digital health products have played an important role in the COVID-19 response, from supporting the remote monitoring of patients to enabling continuity in data collection for clinical trials. The U.S. Food and Drug Administration (FDA) has issued a number of temporary policies to support digital health innovation during the pandemic, such as guidance documents to expand the use of digital therapeutics for psychiatric disorders and medical devices for remote patient monitoring. In this article, we contextualize these policies to the agency's existing regulatory framework for digital health, outline key considerations for patients and health care providers, and identify implications for the future of digital health innovation.
Recent updates on the management of autoimmune hepatitis
Authors: Atsumasa Komori
Journal: Clinical and Molecular Hepatology (2020)

Autoimmune hepatitis (AIH) is an immunoinflammatory chronic liver disease with dynamic and rather heterogeneous disease manifestations. A trend of increasing prevalence of AIH has been observed worldwide, along with a relative increase in the percentage of male patients. AIH is characterized and diagnosed based on serum biochemistry and liver histology: elevated aminotransferases and serum immunoglobulin G (IgG), the presence of serum anti-nuclear antibody or anti-smooth muscle antibody, and interface lympho-plasmacytic hepatitis. Clinical manifestations differ among disease subtypes with distinct time-frames, i.e., AIH with a chronic insidious onset, and acute-onset AIH (the diagnosis of which is often challenging due to the lack of typical serum findings). The absence of disease-specific biomarkers or histological findings may expand the disease phenotype into drug-induced AIH-like liver injury. Corticosteroids and azathioprine are recommended first-line treatments for AIH. The complete normalization of aminotransferases and serum IgG is an essential treatment response to ensure long-term overall survival. An incomplete response or intolerance to these drugs is considered an indication for second-line treatment, especially with mycophenolate mofetil. Life-long maintenance treatment is required for the majority of patients, but the few who achieve prolonged and stringent biochemical remission with lower alanine aminotransferase and IgG within the normal range may be able to discontinue the medications. In the future, the quality of life of AIH patients should be managed by personalized medicine, including the appropriate selection and dosing of first-line therapy and perhaps alternating with potential therapeutics, and the prediction of the success of treatment withdrawal.