tbuckley/cabot-search huggingface dataset:
NCOG-61. A CASE OF LONG TERM SURVIVOR OF DISSEMINATED AND RELAPSED GERMINOMA. EIGHTEEN YEARS OF FOLLOW UP
Authors: Takamitsu Fujimaki, Akira Matsuno
Journal: Neuro-Oncology (2020)

Abstract Germinomas will respond to first-line treatment in general, but prognoses of disseminated and/or relapsed disease are sometimes poor and detailed course of those patients are not well documented. Here we report one of such cases. PATIENT: A 35-year-old man (at the time of abstract submission) initially had polyuria at the age of 15 and anorexia at 16. At the age of 17, MRI showed neurohypophyseal and disseminated tumor along lateral ventricular walls. He was diagnosed to have germinoma by partial resection of the tumor. ICE (Ifosfamide, Cisplatin, Etoposide) chemotherapy was given followed by 24 Gy whole ventricular irradiation. The tumor was well controlled for 22 months. However despite maintenance ICE chemotherapy, the tumor relapsed along the ventricular walls. With simultaneous BEP (Bleomycin, Etoposide, Cisplatin) chemotherapy and 40 Gy whole neuroaxis irradiation, all the tumor disappeared and he remains in complete remission now. He is receiving hormone replacement therapy. Eight years after the initial surgery, an MRI showed cavernous angioma in the cerebellum and the number has been increasing in follow-up scans. Asymptomatic minor bleeding occurred 14 and 15 years after the initial surgery. On MRA, no vasculopathy on major vessels has been identified. His wife gave birth to his first child through infertility treatment, when he was 34. He finished graduate school to obtain master degree and working as a company employee. CONCLUSION: Germinoma is a disease that can cause long-term survival even after recurrence. However, complications may occur and multimodality approaches are needed for the survivors.
Lifetime Risks, Life Expectancy, and Health Care Expenditures for Rheumatoid Arthritis: A Nationwide Cohort Followed Up From 2003 to 2016
Authors: Ying‐Ming Chiu, Yi‐Peng Lu, Joung‐Liang Lan, Der‐Yuan Chen, Jung‐Der Wang
Journal: Arthritis & Rheumatology (2020)

This study was undertaken to estimate the cumulative incidence rate of rheumatoid arthritis (RA) in the Taiwanese population ages 16-84 years, and life expectancy, loss of life expectancy, and lifetime health care expenditures for incident RA in Taiwan after 2003, when biologics began to be prescribed.We obtained all claims data for the period 1999 to 2016 from the National Health Insurance program of Taiwan, and validated the data against the Catastrophic Illness Registry to establish the study cohort. We estimated the survival function for RA and extrapolated to lifetime using a rolling-over algorithm. For every RA case, we simulated sex-, age-, and calendar year-matched referents from vital statistics and estimated their life expectancy. The difference between the life expectancy of the referent and the life expectancy of the RA patient was the loss of life expectancy for the RA patient. Average monthly health care expenditures were multiplied by the corresponding survival rates and summed up throughout the lifetime to calculate the lifetime health care expenditures.A total of 29,352 new RA cases were identified during 2003-2016. There was a decreasing trend in cumulative incidence rate in those ages 16-84 for both sexes. Mean life expectancy after diagnosis of RA was 26.3 years, and mean lifetime cost was $72,953. RA patients had a mean loss of life expectancy of 4.97 years. Women with RA survived 1-2 years longer than men with RA of the same age, which resulted in higher lifetime expenditures for the former. Since the life expectancy for women in Taiwan was 6-7 years higher than that for men, the loss of life expectancy for women with RA was higher than that for men with RA. Annual health care expenditures were similar for both sexes.Our findings indicate that since biologics became available, RA patients have lived longer and had higher lifetime expenditures, which should be monitored and evaluated for cost-effectiveness.
First-in-Human Phase I Study of MP0250, a First-in-Class DARPin Drug Candidate Targeting VEGF and HGF, in Patients With Advanced Solid Tumors
Authors: Richard D. Baird, Constanza Linossi, Mark Middleton, Simon Lord, Adrian Harris, Jordi Rodón, Christof Zitt, Ulrike Fiedler, Keith M. Dawson, Nicolas Leupin, Michael T. Stumpp, Andreas Harstrick, Analía Azaro, Stefanie Fischer, Aurelius Omlin
Journal: Journal of Clinical Oncology (2020)

PURPOSE A first-in-human study was performed with MP0250, a DARPin drug candidate. MP0250 specifically inhibits both vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) with the aim of disrupting the tumor microenvironment. PATIENTS AND METHODS A multicenter, open-label, repeated-dose, phase I study was conducted to assess the safety, tolerability, and pharmacokinetics of MP0250 in 45 patients with advanced solid tumors. In the dose-escalation part, 24 patients received MP0250 as a 3-hour infusion once every 2 weeks at five different dose levels (0.5-12 mg/kg). Once the maximum tolerated dose (MTD) was established, 21 patients were treated with a 1-hour infusion (n = 13, 8 mg/kg, once every 2 weeks and n = 8, 12 mg/kg, once every 3 weeks) of MP0250 in the dose confirmation cohorts. RESULTS In the dose-escalation cohort, patients treated with 12 mg/kg MP0250 once every 2 weeks experienced dose-limiting toxicities. Therefore, MTD was 8 mg/kg once every 2 weeks or 12 mg/kg once every 3 weeks. The most common adverse events (AEs) were hypertension (69%), proteinuria (51%), and diarrhea and nausea (both 36%); hypoalbuminemia was reported in 24% of patients. Most AEs were consistent with inhibition of the VEGF and HGF pathways. Exposure was dose-proportional and sustained throughout the dosing period for all patients (up to 15 months). The half-life was about 2 weeks. Signs of single-agent antitumor activity were observed: 1 unconfirmed partial response with a time to progression of 23 weeks and 24 patients with stable disease, with the longest duration of 72 weeks and a median duration of 18 weeks. CONCLUSION MP0250 is a first-in-class DARPin drug candidate with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other anticancer therapies.
Abstract 10793: Alterations of the Ionic Current Profile Underlie the Defective Electromechanical Coupling of Old Myocytes
Authors: Kazuya Isobe, Sergio Signore, Andrea Sorrentino, Christian Arranto, Ramaswamy Kannappan, Fabio del Ben, Mehrdad Shafaie, Giorgia Palano, Ewa Wybieralska, Donato Cappetta, Anna Sanarico, Polina Goihberg, Annarosa Leri, Jan Kajstura, Piero Anversa, Marcello Rota
Journal: Circulation (2012)

Cardiac pathologies are characterized by prolongation of the action potential (AP) in myocytes, but whether a similar adaptation is present in the aging myocardium and impact on electromechanical c...
SURG-28. PRESENTATION OF A POSTERIOR FOSSA TUMOR AT A HOSPITAL IN WESTERN JAMAICA
Authors: Brandon Dixon, Renn Holness, Tasha-Kay Walker, Franz Pencle
Journal: Neuro-Oncology (2020)

Abstract The posterior cranial fossa is part of the cranial cavity, located between the foramen magnum and tentorium cerebelli that houses the cerebellum, pons and medulla oblongata. Commonly, tumors arising from this region in adults are cerebellar metastases or schwannomas of the vestibular nerve – the incidence of primary neoplasms is uncommon and more reserved for the pediatric population. A 28 year old female was in her usual state of health until last year when she started experiencing recurrent headaches with associated vomiting and intermittent loss of consciousness. A CT brain was done upon presentation to the hospital that revealed a 4th ventricle mass with obstructive hydrocephalus. A ventriculoperitoneal (VP) shunt was done thereafter to decompress the ventricular system, in anticipation for further surgical intervention for mass. Occipital craniotomy and resection of tumor was done and patient managed in a multidisciplinary manner in the intensive care unit. Post-operative course was marked by occipital pseudomeningocele with an associated CSF leak; a lumbar drain was placed in situ until complete resolution of leak. Histological analysis showed WHO Grade II Astrocytoma. Adult primary posterior fossa tumors are rare and can present with a constellation of symptoms. Although patient presented with findings in keeping with the diagnosis of an ependymoma, close clinical follow up will be required henceforth due to the refractory nature of such a low grade astrocytoma post-resection. Radiotherapy can also be considered in further management of case.
EPEN-16. TRANSCRIPTIONAL REGULATORY CIRCUITRIES AS MOLECULAR TARGETS IN EPENDYMOMA
Authors: Kelsey Bertrand, Stephen Mack, Donald W Parsons
Journal: Neuro-Oncology (2020)

Abstract Genomic sequencing has driven precision-based oncology therapy; however, genetic drivers remain unknown or non-targetable for many malignancies, demanding alternative approaches to identify therapeutic leads. Ependymomas comprise histologically similar tumor entities driven by distinct molecular mechanisms, such as fusion oncoproteins, genome-wide chromosomal instability, or disruption of DNA methylation patterns. Despite these differences, ependymomas resist chemotherapy and lack available targeted agents for clinical trial development. Based on our previous findings, we hypothesized that mapping chromatin landscapes and super enhancers (SE) could uncover transcriptional dependencies as targets for therapy (Mack, Pajtler, Chavez et al., Nature, 2018). To functionally test the requirement of these SE genes for ependymoma cellular growth, we designed a pooled RNA interference screen against 267 SE associated genes. Our screen was performed in one C11ORF95-RELA-fusion model and two PF-EPN-A models as controls in biological triplicates. As an indication that our screen was successful, positive controls scored among lead hits including KIF11, BUB1B, PHF5A and MYC. Importantly, we identified many subtype specific dependencies in both C11ORF95-RELA-fusion and PF-EPN-A models, thus revealing novel pathways that potentially govern subgroup-specific ependymoma cell growth. Further, several candidates detected across all ependymoma lines were also identified as pan-cancer dependencies or glioma/glioblastoma specific essential genes from the DepMap Cancer Dependency Gene Resource. Our findings reveal novel targets and pathways that are essential for ependymoma cell growth, which may provide new insight into therapeutic strategies against these aggressive brain tumors.
CTNI-14. A 3-ARM, PHASE IIA TRIAL OF SAFETY &amp; EFFICACY OF OLINVACIMAB, A MONOCLONAL ANTIBODY TO VEGFR2 IN PATIENTS WITH RECURRENT GLIOBLASTOMA MULTIFORME WITH IMAGING AND PK/PD ASSESSMENTS: FINAL REPORT
Authors: Lawrence Cher, Anna Nowak, George Iatropoulos, Samantha Bowyer, Hui Gan, Anne Poh Long, Michael Bynevelt, Graeme Jackson, Seon Young Lee, Weon Sup Lee, Jin-San Yoo
Journal: Neuro-Oncology (2020)

Abstract The VEGF pathway remains an important target in GBM given its vascularity and autocrine VEGF signalling. Olinvacimab (TTAC-0001) is a fully humanised VEGFR2 Mab that binds and inhibits the receptor. This report assesses the safety, dosing schedules and efficacy of Olinvacimab in recurrent GBM. We conducted a two-site, 3 arm, open-label study of Olinvacimab in recurrent GBM. Eligible patients were ≥18 years with RANO-measurable lesion, KPS ≥ 80, and had completed chemoradiotherapy without prior bevacizumab therapy. We assessed three arms, 8 mg/kg and 12mg/kg weekly for 3 of every 4 weeks, and 12 mg/kg weekly. Three patients were treated in arms 1 and 2 and 6 in arm 3. Safety assessments were performed prior to dose escalation. The main toxicity was development of grade 1 (67%) and 2 (8%%) cutaneous haemangiomas. Common toxicities seen with other VEGF directed therapies, including hypertension, impaired wound healing, and proteinuria were not seen in this cohort. Efficacy was assessed by MRI using RANO criteria. 6 month PFS was 17%, with disease control in 25%, with steroid dose reduction. The longest response was 15 months. On DCE MRI, there was no significant difference in perfusion parameters between baseline and 1st follow-up MRI comparing those with SD and PD. However, 6 of 12 patients showed decreased Ktrans &amp;gt; 20 % of baseline, consistent with an anti-angiogenic effect of Olinvacimab. Pharmacokinetics showed a decreased clearance rate and increased half-life of Olinvacimab compared to the prior Phase I study. Pharmacodynamic studies showed significantly higher levels of angiogenic markers, particularly VEGF-A in those treated at 12mg/kg vs arm 1. VEGF-A, C and D levels were elevated in patients with SD compared to those with PD. Conclusion: Olinvacimab was well tolerated with a different toxicity profile to other VEGFR directed therapies. There were promising responses in 25% of patients.
DDRE-34. TRIBBLES-1 (TRIB1) PSEUDOKINASE PROMOTES SURVIVAL OF GBM CELLS BY DECREASING RT/TMZ INDUCED APOPTOSIS
Authors: Karnika Singh, Chunhua Han, Jessica Fleming, Joseph McElroy, Erica Bell, Pierre Robe, S Jaharul Haque, Arnab Chakravarti
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Glioblastoma (GBM) is the most aggressive form of glioma with a mean survival of 12 to 15 months after diagnosis. The current therapy involves administration of radiation therapy and temozolomide (TMZ). Due to poor survival outcome, new druggable therapeutic targets need to be identified for drug development. TRIB1 is a Ser/Thr pseudokinase that acts as a scaffold protein to mediate proteasomal degradation of its substrate proteins in the cell. TRIB1 has been associated with tumorigenesis and therapy resistance of several cancers, including HCC, NSCLC among others. In the present study we show that TRIB1 can promote GBM by increasing survival of GBM cells and reducing RT/TMZ-induced cell death. MATERIALS AND METHODS We identified TRIB1 by statistical association (Cox regression analysis) of the patient-derived methylation data generated using 450K and EPIC methylation array. Functional validation of TRIB1 was done in vitro by overexpression and knockdown approaches. Doxycycline inducible system was used for TRIB1 knockdown. Stable cell lines were generated by puromycin selection. Western blotting was utilized to detect protein levels. RESULTS The global methylation analysis on a Utrecht GBM cohort showed that TRIB1 promoter methylation was associated with better OS of GBM patients (HR = 0.81 (0.62–1.05); p = 0.11). We also observed that TRIB1 overexpression caused a decrease in apoptosis of patient-derived GBM cell lines after RT/TMZ treatment. Additionally, an increase in the phosphorylation of ERK and Akt was also noted. However, TRIB1 knockdown only led to decreased Akt phosphorylation. CONCLUSION TRIB1 promotes GBM cell survival by upregulating survival signaling pathways like ERK and Akt, which leads to decreased effects of RT/TMZ therapy. Targeting TRIB1 would reduce oncogenic signaling in these cells and therefore may sensitize them towards RT/TMZ therapy.
Offline: The lessons of smallpox eradication for COVID-19
Authors: Richard Horton
Journal: The Lancet (2020)

The announcement last week that Rochelle Walensky is President-elect Joe Biden's choice to lead the much-eroded Centers for Disease Control and Prevention was universally welcomed by the US medical community. A respected clinician and scientist, as well as a skilled communicator, she has every prospect of restoring credibility and leadership to the nation's foremost public health agency. Walensky recently co-authored an important paper in Health Affairs, which examined the future determinants of a successful COVID-19 vaccination campaign.
NIMG-38. NON-INVASIVE PREDICTION OF MGMT PROMOTER METHYLATION USING COMBINED FET PET/MRI RADIOMICS
Authors: Philipp Lohmann, Anna-Katharina Meissner, Jan-Michael Werner, Gabriele Stoffels, Martin Kocher, Elena Bauer, Gereon Fink, Nadim Shah, Karl-Josef Langen, Norbert Galldiks
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Recently, the Response Assessment in Neuro-Oncology (RANO) Working Group emphasized the additional diagnostic value of amino acid PET in addition to MRI. However, the number of studies using amino acid PET/MRI radiomics is still low. We investigated the potential of combined O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET/MRI radiomics for the non-invasive prediction of the O6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation status in glioma patients. METHODS Seventy-one patients with newly diagnosed glioma (predominantly WHO grade III and IV glioma, 82%) underwent a hybrid FET PET/MRI scan. Forty-six patients (65%) had a methylated MGMT promoter. The tumor and tumor subregions were manually segmented on conventional MRI. In total, 199 standardized features were obtained from FET PET, contrast-enhanced T1-weighted, T2-weighted, and fluid attenuated inversion recovery (FLAIR) MRI. After feature extraction and data normalization, patients were randomly assigned to a training and a test dataset for final model evaluation in a ratio of 70/30, with a balanced distribution of the MGMT promoter methylation status. Feature selection was performed by recursive feature elimination using random forest regressors. For the final model generation, the number of features was limited to seven to avoid data overfitting. Different algorithms for model generation were compared, and the model performance in the training data was assessed by 5-fold cross-validation. Finally, the best performing models were applied to the test dataset to evaluate the robustness of the models. RESULTS In the test dataset, the best radiomics signatures obtained from MRI or FET PET alone achieved diagnostic accuracies for the prediction of the MGMT promoter methylation of 64% and 70%, respectively. In contrast, the highest diagnostic accuracy of 83% was obtained by combining FET PET and MRI features. CONCLUSION Combined FET PET/MRI radiomics allows the non-invasive prediction of the MGMT promoter methylation status in patients with gliomas, providing more diagnostic information than either modality alone.
Antitumor effect of ZD6474 in a VEGF-producing primary gastric cancer model
Authors: Tokuzo Arao, Kazuyoshi Yanagihara, Misato Takigahira, Hisao Fukumoto, Fumiaki Koizumi, Kazuto Nishio
Journal: Cancer Research (2004)

4537  Vascular endothelial growth factor (VEGF) is a multifunctional cytokine that plays a key role in the angiogenic process. VEGF secretion occurs in human cancers and correlates with increased tumor neovascularization. ZD6474 is an orally available inhibitor of VEGFR-2 (KDR) tyrosine kinase inhibitor, which also has activity against epidermal growth factor receptor tyrosine kinase and is currently in clinical development. The antitumor effects of ZD6474 have been assessed in a novel in vivo model of VEGF-secreting signet ring cell human gastric cancers 44As3 (that express VEGF-A and -C) and 58As1 (that express VEGF-A). When implanted into the murine gastric wall, tumors develop and metastasize into the peritoneum. ZD6474 treatment (50 or 100 mg/kg/day p.o. for 2 weeks) administered 3 days after implantation resulted in tumor regression in a dose-dependent manner and prolonged survival compared with control mice. Survival was determined by the appearance of ascites. To examine whether ZD6474 affects peritoneal dissemination, the level of VEGF (A, B, C and D) was examined by RT-PCR of ascites using human-specific VEGF primers and ELISA. ZD6474 decreased intraperitoneal VEGF levels (as determined by ELISA), suggesting that ZD6474 effectively decreased intraperitoneal dissemination. These results suggest that ZD6474 is active against VEGF-secreting gastric cancers with dissemination. Ongoing experiments are examining whether ZD6474 exerts differential antitumor activity depending on the isotypes of VEGF secreted by the tumors.
Endocytic pathway inhibition attenuates extracellular vesicle-induced reduction of chemosensitivity to bortezomib in multiple myeloma cells
Authors: Chenggong Tu, Zhimin Du, Hui Zhang, Yueyuan Feng, Yujun Qi, Yongjiang Zheng, Jinbao Liu, Jinheng Wang
Journal: Theranostics (2020)

Extracellular vesicles (EVs), including exosomes and microvesicles, derived from bone marrow stromal cells (BMSCs) have been demonstrated as key factors in the progression and drug resistance of multiple myeloma (MM). EV uptake involves a variety of mechanisms which largely depend on the vesicle origin and recipient cell type. The aim of the present study was to identify the mechanisms involved in the uptake of BMSC-derived small EVs (sEVs) by MM cells, and to evaluate the anti-MM effect of targeting this process. Methods: Human BMSC-derived sEVs were identified by transmission electron microscopy, nanoparticle tracking analysis, and western blot. The effects of chemical inhibitors and shRNA-mediated knockdown of endocytosis-associated genes on sEV uptake and cell apoptosis were analyzed by flow cytometry. The anti-MM effect of blocking sEV uptake was evaluated in vitro and in a xenograft MM mouse model. Results: sEVs derived from BMSC were taken up by MM cells in a time- and dose-dependent manner, and subsequently promoted MM cell cycling and reduced their chemosensitivity to bortezomib. Chemical endocytosis inhibitors targeting heparin sulphate proteoglycans, actin, tyrosine kinase, dynamin-2, sodium/proton exchangers, or phosphoinositide 3-kinases significantly reduced MM cell internalization of BMSC-derived sEVs. Moreover, shRNA-mediated knockdown of endocytosis-associated proteins, including caveolin-1, flotillin-1, clathrin heavy chain, and dynamin-2 in MM cells suppressed sEV uptake. Furthermore, an endocytosis inhibitor targeting dynamin-2 preferentially suppressed the uptake of sEV by primary MM cells ex vivo and enhanced the anti-MM effects of bortezomib in vitro and in a mouse model. Conclusion: Clathrin- and caveolin-dependent endocytosis and macropinocytosis are the predominant routes of sEV-mediated communication between BMSCs and MM cells, and inhibiting endocytosis attenuates sEV-induced reduction of chemosensitivity to bortezomib, and thus enhances its anti-MM properties.
Case 39-2020: A 29-Month-Old Boy with Seizure and Hypocalcemia
Authors: Yamini V. Virkud, Neil D. Fernandes, Ruth Lim, Deborah M. Mitchell, William T. Rothwell
Journal: New England Journal of Medicine (2020)

A 29-month-old boy with a history of febrile seizure, atopic dermatitis, and multiple environmental and food allergies was transferred to the hospital because of a seizure and a blood calcium level of 5.0 mg per deciliter (reference range, 8.5 to 10.5). He had a pes planus deformity. A diagnostic test was performed.