tbuckley/cabot-search huggingface dataset:
Association Between Benzodiazepine Use With or Without Opioid Use and All-Cause Mortality in the United States, 1999-2015
Authors: Kevin Y. Xu, Sarah M. Hartz, Jacob T. Borodovsky, Laura J. Bierut, Richard A. Grucza
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Although overall rates of opioid use have been plateauing, coprescriptions of benzodiazepines and opioids have increased greatly in recent years. It is unknown whether this combination is an independent risk factor for all-cause mortality as opposed to being more frequently used by persons with a baseline elevated risk of death. <h3>Objective</h3> To evaluate whether benzodiazepine use, with or without opioid use, is associated with increased all-cause mortality relative to the use of low-risk antidepressants. <h3>Design, Setting, and Participants</h3> This retrospective cohort study used a large, nationally representative US data set (the National Health and Nutrition Examination Surveys [NHANES]) from 1999 to 2015. Eight cycles of NHANES data were used, spanning 37 610 person-years of follow-up time among 5212 individuals. Statistical analysis was performed from August 24, 2019, through May 23, 2020. <h3>Exposures</h3> The primary exposure variable was benzodiazepine and opioid coprescriptions. Individuals taking selective serotonin reuptake inhibitors (SSRIs) served as an active comparator reference group. <h3>Main Outcomes and Measures</h3> All-cause mortality was obtained via linkage of NHANES to the National Death Index. Propensity scores were calculated from covariates associated with sociodemographic factors, comorbidities, and medication use for more than 1000 prescription types. Propensity score–weighted mortality hazards were calculated from Cox proportional hazards regression models. <h3>Results</h3> Of 5212 participants aged 20 years or older (1993 men [38.2%]; mean [SD] age, 54.8 [16.9] years) followed up for a median of 6.7 years (range, 0.2-16.8 years), 101 deaths (33.0 per 1000 person-years) occurred among those receiving cotreatment, 236 deaths (26.5 per 1000 person-years) occurred among those receiving only benzodiazepines, and 227 deaths (20.2 per 1000 person-years) occurred among SSRI recipients taking neither opioids nor benzodiazepines. After propensity score weighting, a significant increase in all-cause mortality was associated with benzodiazepine and opioid cotreatment (hazard ratio, 2.04 [95% CI, 1.65-2.52]) and benzodiazepines without opioids (hazard ratio, 1.60 [95% CI, 1.33-1.92]). Subgroup analyses revealed an increased risk of mortality for individuals receiving cotreatment who were 65 years or younger but not for those older than 65 years; similar findings were observed for those receiving benzodiazepines without opioids. <h3>Conclusions and Relevance</h3> This study found a significant increase in all-cause mortality associated with benzodiazepine use with or without opioid use in comparison with SSRI use. Benzodiazepine and opioid cotreatment, in particular, was associated with a 2-fold increase in all-cause mortality even after taking into account medical comorbidities and polypharmacy burden.
BIOM-11. ENZYMATIC ASSAY USED TO MONITOR CHANGES IN ONCO-METABOLITE, D2HG, IN RESPONSE TO THERAPY
Authors: Rehan Saber, Masum Rahman, Ian E Olson, Karishma Rajani, Terry C Burns
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Gliomas are the most common and deadly adult brain cancers with a median survival time of less than 18 months. Many therapeutics have failed translating into effective therapies due to incomplete understanding of the disease and heterogeneity of tumors between patients. There is a need for methods that allow for continual access and analysis of glioma biomarkers. We sought to establish a reliable method for quantifying the onco-metabolite, D2HG. After optimizing this method, we used microdialysate and microperfusate to test our hypothesis that analysis of D2HG in response to therapy can indicate therapeutic efficacy sooner than current methods permit. METHODS Microdialysate and microperfusate were collected from the tumor centers and lateral ventricles of athymic nude mice implanted with IDH1 mutant PDX line GBM196. We performed microdialysis and microperfusion on consecutive days to determine baseline D2HG concentration. Following a five day period of TMZ treatment, we collected another round of microdialysis and microperfusion one week after treatment and again two weeks after treatment. We then used our optimized D2HG enzymatic assay to quantify the changes in D2HG in response to therapy. RESULTS Using our enzymatic D2HG assay, we were able to quantify D2HG as low as 30nM (30fmol/uL). We found a ~20% decrease in D2HG concentration in the tumor center and right lateral ventricle after 1 week of TMZ treatment (n=2), and ~36% decrease after 2 weeks of TMZ treatment (n=2). CONCLUSION Using a D2HG quantification assay to monitor changes in concentration of D2HG in microdialysate/microperfusate can predict sensitivity to therapy.
EPEN-10. SPINAL MYXOPAPILLARY EPENDYMOMA AND METHYLATION-PROFILING: THE MD ANDERSON CANCER CENTER (MDACC) EXPERIENCE
Authors: Sumit Gupta, Xiangjun Tian, Jing Wang, Jason Huse, Laurence Rhines, Wafik Zaky, Claudio Tatsui, Soumen Khatua
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Spinal myxopapillary ependymoma (MPE) is a rare histological variant of ependymoma, classified as WHO grade I tumor. Further interrogation of the molecular and clinical profile is warranted, to better understand the biology and clinical phenotype. We summarize our institutional experience with spinal MPE including methylation-profiling. METHODS A retrospective analysis of charts during the period of 2001 to 2019 of histologically proven MPE was done. We performed methylation profiling for 12 patients by Infinium MethylationEPIC Kit. RESULTS 26 patients with spinal MPE were identified, median age of diagnosis was 34.2 years with a range of 11 to 59.9 years. Ten patients were below 30 years of age, lumbar spine location was commonest and 6 had leptomeningeal spread at diagnosis. All the patients underwent surgery and 11 received radiation following surgery. Eight patients below the age of 30 received radiation due to residual disease or metastases. Methylation profiling revealed 11,752 CpGs differentially methylated between the younger and older patients (p &amp;lt; 0.05), however only one CpG cg22496254 associated with gene NCAPG/DCAF16 (role in promoting mitosis) was detectable with FDR &amp;lt; 0.25 that overly methylated in the younger age group. This is a new finding in MPE. CONCLUSIONS Spinal MPE is a rare spinal tumor. Our study though limited by numbers, showed younger patients had aggressive phenotype, most requiring radiation. Methylation profiling reaffirmed this finding and trend in the younger patients. Prospective studies in a larger cohort of patients with methylation profiling are needed to identify prognostic variables and new targets for treatment.
Case 38-2020: A 52-Year-Old Man with Cancer and Acute Hypoxemia
Authors: Lucas X. Marinacci, F. Joseph Simeone, Andrew L. Lundquist, David J. Kuter, Grace K. Mahowald
Journal: New England Journal of Medicine (2020)

A 52-year-old man with back pain was admitted to the hospital with a vertebral mass, multiple lytic bone lesions, and severe hypercalcemia. MRI showed an enhancing, marrow-replacing mass involving the T1 vertebral body. On the fifth hospital day, the oxygen saturation decreased acutely. A diagnosis was made.
The mRNA Binding Proteome of Proliferating and Differentiated Muscle Cells
Authors: Monika Hiller, Miriam Geissler, George Janssen, Peter van Veelen, Annemieke Aartsma-Rus, Pietro Spitali
Journal: Genomics Proteomics & Bioinformatics (2020)

Abstract Muscle formation is a coordinated process driven by extensive gene expression changes where single cells fuse together to form multinucleated muscle fibers. Newly synthesized mRNAs are then regulated by RNA binding proteins (RBPs), affecting post-transcriptional transcript metabolism. Here, we determined how large-scale gene expression changes affect the catalog of RBPs by studying proliferating and differentiated muscle cells in healthy and dystrophic conditions. Transcriptomic analysis showed that the expression of more than 7000 genes was affected during myogenesis. We identified 769 RBPs, of which 294 were muscle-specific and 49 were uniquely shared with cardiomyocytes. A subset of 32 RBPs (half of which were muscle-specific) was found to be preferentially associated with target mRNAs in either myoblasts (MBs) or myotubes (MTs). A large proportion of catalytic proteins were bound to mRNAs even though they lack classical RNA binding domains. Finally, we showed how the identification of cell-specific RBPs enabled the identification of biomarkers that can separate healthy individuals from dystrophic patients. Our data show how interactome data can shed light on new basic RNA biology as well as provide cell-specific data that can be used for diagnostic purposes.
IMMU-37. DIRECT REPROGRAMMING OF GLIOBLASTOMA TO ANTIGEN PRESENTING-LIKE CELLS BY MASTER REGULATORS PREDICTED FROM AN ARTIFICIAL INTELLIGENCE PLATFORM
Authors: Dan Jin, Mathew Sebastian, Son Le, Dongjiang Chen, Nagheme Thomas, Changwang Deng, David Tran
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is the most common and lethal malignant brain cancer in adults. Immunotherapy has emerged as a potentially powerful approach to achieve long-term survival in patients with GBM. Antigen presenting cells (APCs) play a central role in priming cancer-specific immune responses due to their ability to sample and present tumor neoantigens to the immune system. We hypothesis that antigen presenting cells could be induced by transdifferentiated from GBM in-situ so that these locally created APC will find themselves pre-planted in the tumor microenvironment (TME) with full access to tumor neoantigens. Top ten ranked candidate fate determinants for the GBM-DC transdifferentiation were predicted by NETZEN, an integrated deep-learning and gene network-based ranking artificial intelligence (AI) platform for precision medicine. We successfully transdifferentiated the murine GBM cell line GL261 into CD45+ immune cells accompanying morphological changes to less adhering cells by a combination of four factors (PU.1, IRF8, BATF3, ID2). Of these induced CD45 positive cells, a significant fraction also expresses high levels of the myeloid marker CD11b and antigen presenting molecules MHCII and MHCI by flow cytometry, suggesting these induced CD45+ cells are myeloid lineage APCs (iAPC).These iAPC exhibit phagocytic property, tested by incubating pHrodo Red bioparticles conjugated with Zymosan, an antigen found on the surface of fungi. More importantly, these induced iAPC appear to have lost their proliferative capacity characteristic of the parental GBM cells. Total live cell numbers were significantly reduced in 4F-induced culture compared to the EV control. In conclusion, we successfully transdifferentiated mouse GBM cells into APC-like cells based on NETZEN prediction and our work can potentially provide a novel therapeutic approach for developing an in-situ APC vaccine immunotherapy for GBM, and for other cancers.
CTNI-63. PROGNOSTIC FACTORS IN PATIENTS WITH BASAL GANGLIA GERM-CELL TUMORS: A RETROSPECTIVE ANALYSIS OF THE SINGLE CHINESE INSTITUTE EXPERIENCE FROM 2009 TO 2019
Authors: Qingjun Hu, Juan Li, Mingyao Lai, Cheng Zhou, Zhaoming Zhou, Changguo Shan, Linbo Cai
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE To evaluate the clinical factors related to the prognosis of basal ganglia germ cell tumors. METHODS A retrospective analysis of 52 cases of the basal ganglia germ cell tumors treated from January 2009 to January 2019 in the department of oncology of Guangdong Sanjiu Brain Hospital. The median age: 12 years (range: 5–32), The median course of disease: 11.7 months (range: 1–54). Thirteen cases were diagnosed by biopsy and 39 cases were diagnosed by elevated tumor markers. There were 31 patients (59.6%) diagnosed with germinomas and 21 patients (40.4%) with non-germ germ cell tumors. Univariate and multivariate survival analysis was performed. RESULTS To October 15, 2019, the median follow-up time was 30.4 months (range 2–124 months). The 5-year survival rate was 85%, and the 5-year progression-free survival rate was 84%. Multivariate analysis found whether serum AFP was greater than 100mIU / ml, (with HR: 11.441,95% CI: 2.09–47.66, P = 0.005),the degree of surgical resection(with HR 5.323 (1.19–23.812), P = 0.029), PD as the effect of radiotherapy (HR: 16.53, (1.19–23.81), P = 0.001) were independent prognostic factor affecting survival. CONCLUSION The pathological type, degree of surgical resection, and response to initial treatment can all affect survival.
DDRE-25. NOVEL TEMOZOLOMIDE ANALOGS TO IMPROVE ANTI-TUMOR EFFICACY AND OVERCOME RESISTANCE IN GLIOBLASTOMA MULTIFORME
Authors: Ariana Waters, Nozomi Tomimatsu, Ivan Babic, Elmar Nurmemmedov, Annamarie Allnutt, Yueqin Quan, Natsuko Nomura, Sandeep Burma, Santosh Kesari, Venkata Yenugonda
Journal: Neuro-Oncology (2020)

Abstract Glioblastoma (GBM) is considered one of the most lethal forms of human cancers, and despite considerable advances in multimodality treatments, it remains an incurable disease with an overall survival of 14 to 16 months after diagnosis. Even in the era of personalized medicine and immunotherapy, temozolomide (TMZ), an oral alkylating agent, remains the standard-of-care for GBM. However, intrinisic or acquired resistance to TMZ due to over expression of O6-methylguanine-DNA methyltransferase (MGMT) results in initial treatment inefficacy or tumor relapse, highlighting the significant need for improved treatment strategies. Recently, much effort has been directed towards creating novel TMZ analogs to address the clinical barriers associated with TMZ. While some reported TMZ analogs showed improved brain permeability and anticancer effects in preclinical models, none of them have progressed to testing in humans. There is therefore significant room to improve the brain permeability and anticancer effect profiles of TMZ by incorporating yet unexplored functional groups into new analogs. We have designed and synthesized a series of novel C8-substituted TMZ analogs and have evaluated their anticancer potency against a panel of GBM cell lines with variable levels of MGMT expression. Encouragingly, our analogs demonstrated promising anti-cancer effect in both MGMT low and high expressing lines. We then evaluated our analogs in a variety of cell based assays to compare their activity with TMZ, and performed in vivo brain permeability and anti-tumor efficacy assays in mouse flank models. Our results demonstrated that several of our analogs clearly display improved anti-cancer effects and increased brain permeability over TMZ. This work points to a new direction for the development of novel TMZ analogs for improved patient survival.
IMMU-48. CD4+ T CELLS RESTRICT MEDULLOBLASTOMA GROWTH AND DISSEMINATION
Authors: Tanja Eisemann, Robert Wechsler-Reya
Journal: Neuro-Oncology (2020)

Abstract The immune system serves as a powerful defense not only against pathogens and parasites but also against neoplastic cells. Emerging immunotherapies that boost the activity of tumor-reactive immune cells or counteract immune suppressive mechanisms have shown promising effects in certain types of cancer. However, the success of immunotherapy for brain tumors has been limited, highlighting the need for a better understanding of the immune microenvironment in these tumors. Our previous studies have shown that T cells critically affect growth of the pediatric brain tumor medulloblastoma. In particular, depletion of CD4+ T cells results in more aggressive growth of medulloblastoma cells and allows these cells to metastasize to the spinal cord. The anti-tumoral effects of CD4+ T cells are not due to their function as helpers for CD8+ cytotoxic T cells, since CD8+ T cell depletion did not enhance tumor growth to the same extent as CD4+ T cell depletion. To test whether CD4+ T cells can recognize MHC class II molecules on tumor cells and attack these cells directly, we generated tumors from MHC class II knockout mice. Surprisingly, depletion of CD4+ cells in these animals still enhanced tumor growth and metastasis. These results suggest that CD4+ T cells regulate medulloblastoma growth and metastasis in a manner that is independent of CD8+ T cells and independent of MHC-II on tumor cells. Ongoing studies are aimed at elucidating the mechanisms by which CD4+ T cells regulate medulloblastoma growth, including the antigen-presenting cells that activate them and the effector cells responsible for killing tumor cells following their activation. These studies will advance our understanding of the immune microenvironment in medulloblastoma and allow us to design more effective therapies for controlling tumor growth and metastasis.
SURG-24. NOVEL MALLEABLE FORCIPES FOR ENDOSCOPIC ASSISTED TECHNIQUE IN PEDIATRIC BRAIN TUMORS
Authors: Yukiko Nakahara, Hiroshi Ito, Fumitaka Yoshioka, Kohei Inoue, Atsushi Ogata, Jun Masuoka, Tatsuya Abe
Journal: Neuro-Oncology (2020)

Abstract Recent advances in optical devices and surgical instruments have been applied to neurosurgery. Even with modifications, one of the most serious risks is injury of neuronal and vascular structure caused by operation of surgical instruments in a narrow surgical field. Fixed instruments are not practical for pediatric brain tumor surgeries because the length of the curved or angled tip portion is limited because of the narrow entrance. We developed a novel malleable forceps to resolve the difficulties related to microsurgical procedures. The malleable forceps has two shafts with a sharp cup at the tip. The entire forceps was made of stainless steel, with a silver and nickel alloy inserted between 10 and 40 mm from the tip. In the alloy part, the surgeon can flex the forceps freely using a special cylinder. The special cylinder is useful to prevent from slipping of the cups of tip. The maximum angle that can be bent is 70 degrees vertically. We also developed a monoshaft malleable forceps. We used these flexible forcipes in the case of various pediatric brain tumors including craniopharyngioma. We performed tumor resection by anterior interhemispheric trans-lamina terminalis approach. After procedure of tumor resection using microscope, endoscope inserted around the pituitary stalk. The piece of calcified tumor could be easily removed without any complications. These forcipes can be deformed to an appropriate angle and can be applied to various cases, especially pediatric brain tumors.
Paraneoplastic Multicentric Reticulohistiocytosis on 18F-FDG PET/CT Breast Carcinoma Follow-up
Authors: Matthieu Dietz, Sebastien Debarbieux, Morgane Righetti, Olivier Harou, Jeremie Tordo
Journal: Clinical Nuclear Medicine (2020)

We report the case of a 60-year-old woman who underwent 18F-FDG PET/CT to evaluate a metastatic breast carcinoma. Follow-up 18F-FDG PET/CT showed progressive disease with 18F-FDG increased in primary tumor, axillary lymph nodes, and pleural and bone diffuse metastases but also a concomitant uptake in multiples joints. The anatomopathological analysis from skin biopsy revealed a multicentric reticulohistiocytosis, considered paraneoplastic in the context. Second follow-up PET/CT after treatment showed a decrease of 18F-FDG uptake in previously affected joints, consistent with the symptoms evolution. 18F-FDG PET/CT could be helpful in the detection and the evaluation of such rare systemic disorder.
HGG-47. DECREASED GROWTH VELOCITY WITH LONG TERM USE OF BRAFV600e AND MEK INHIBITION IN A PATIENT WITH ANAPLASTIC GANGLIOGLIOMA
Authors: Hung Tran, Robert Cooper
Journal: Neuro-Oncology (2020)

Abstract PURPOSE To describe decreased growth velocity with long term use of BRAFV600e and MEK inhibition in a patient with anaplastic ganglioglioma. RESULTS 4-year-old patient was found to have a 6 x 4.6 x 5 cm mass in the hypothalamus. Pathology consistent with anaplastic ganglioglioma and chromosomal microarray revealed a BRAFV600e mutation. Patient started on dabrafenib and trametinib and tumor decreased 85% after 3 months. She is stable without significant toxicities 39 months on therapy, and is now 8 years old. Patient had been growing at the 25% for weight and 12% for height but is now 65% for weight and 0.5% for height. It is difficult to tease out the relationship between the tumor, the location of the tumor, and the BRAF and MEK inhibitors and their effect on growth. Discussions with the family and endocrinology are ongoing but being &amp;lt;1% for height will lead to decrease in quality of life. CONCLUSIONS Further follow-up study is needed to determine if this is truly a long-term toxicity, or if this may just be a direct result of the location of the tumor. Would supplementation with growth hormone in this patient lead to losing control of a high grade tumor, or would it simply replace a hormone that is not produced?
EPEN-54. ACNS0831, PHASE III RANDOMIZED TRIAL OF POST-RADIATION CHEMOTHERAPY IN PATIENTS WITH NEWLY DIAGNOSED EPENDYMOMA AGES 1 TO 21 YEARS
Authors: Amy Smith, Arzu Onar-Thomas, David Ellison, Emily Owens-Pickle, Shengjie Wu, Sarah E S Leary, Maryam Fouladi, Thomas Merchant, Amar Gajjar, Nicholas Foreman
Journal: Neuro-Oncology (2020)

Abstract PURPOSE The primary objective of this study is to determine the EFS and OS of children with gross total and near totally resected ependymoma (EPN) treated with post-operative focal radiation therapy (RT) followed by randomization to either RT alone or RT + 4 cycles of maintenance chemotherapy with vincristine, cisplatin, cyclophosphamide and etoposide. Secondary objectives include estimating the EFS and OS of children not randomized, evaluation of neurobehavioral and quality of life (QoL) endpoints, and EPN biomarkers. RESULTS 479 patients enrolled, 451 were eligible. Of 325 eligible randomized patients, 161 were randomized to RT alone and 164 to RT + maintenance chemotherapy. Age range (1–21 years, median 4.9 years). The planned primary analysis was based on intent-to-treat, irrespective of actual treatment received. Based on the data available as of 12/31/2019, estimated 3-year EFS in the RT + maintenance chemotherapy vs. RT arms were 78% vs. 72%, respectively, which did not meet statistical criteria to establish the benefit of maintenance chemotherapy post RT (1-sided log-rank p-value=0.074). Due to significant noncompliance (30.5% in the RT + maintenance vs 4.3% in the RT arm), a planned secondary “as treated” analysis was performed. With median follow-up of 42.6 months among patients without events, the 3 year EFS estimates for patients who received any chemotherapy (n=114) vs. those who received RT only (n=196) were 80% vs. 71%, respectively (1-sided p-value = 0.0121). CONCLUSION Early results in this randomized trial suggest that there may be some EPN patients who benefit from maintenance chemotherapy. Genomic analyses are ongoing.
In non–low back musculoskeletal injuries, NSAIDs and acetaminophen reduce acute pain
Authors: Joel M. Schectman
Journal: Annals of Internal Medicine (2020)

Source Citation Busse JW, Sadeghirad B, Oparin Y, et al. Management of acute pain from non-low back, musculoskeletal injuries: a systematic review and network meta-analysis of randomized trials. Ann Intern Med. 2020;173:730-8. 32805127