tbuckley/cabot-search huggingface dataset:
EPEN-02. EVALUATION OF TREATMENT OUTCOMES AND EXPRESSION OF EMT-RELATED TRANSCRIPTION FACTORS AS NOVEL THERAPEUTIC TARGETS IN PEDIATRIC EPENDYMOMA
Authors: Keishi Makino, Jun-ichiro Kuroda, Naoki Shinojima, Kenji Fujimoto, Akira Takada, Akitake Mukasa
Journal: Neuro-Oncology (2020)

Abstract OBJECTIVE Intracranial ependymomas are common brain tumors in children. However, prognosis, especially in young children, remains poor because of the chemo- and radioresistant properties of intracranial ependymomas. Furthermore, effective treatments for intracranial ependymomas remain a challenge. The epithelial-to-mesenchymal transition (EMT) is important for invasion and metastasis in many cancers. This study aimed to evaluate and compare treatment outcomes with the expression of EMT-related transcription factors in pediatric ependymomas. MATERIAL AND METHODS Medical and radio-imaging data of 22 (11 boys, 11 girls) patients aged &amp;lt;15 years with intracranial ependymomas were reviewed from January 1983 to December 2018. Six cases were subdivided into clinicopathological-molecular subgroups and immunohistochemically analyzed for Slug and ZEB. RESULTS The median age at the start of treatment was 5 years (range 8 months–15 years) (9 cases were aged &amp;lt;3 years). The median progression-free survival (PFS) was 25.6 (range, 0.8–383.5) months; the median overall survival (OS) was 81.9 (range, 2.9–383.5) months. Extent of resection and malignant histology were significant prognostic factors for OS and PFS in multivariate analysis. There were 6 cases (2 cases of PFA, 2 of PFB, 1 of ST and 1 case of ST-RELA). Nuclear expression of ZEB1 was found in all tumors; however, that of Slug increased only in PFA and PFB tumors, which were associated with a poor prognosis. CONCLUSION Expression of EMT-related transcription factors was increased in pediatric ependymomas. These data suggest that EMT is a novel therapeutic target for treating pediatric intracranial ependymomas.
MBRS-66. COST-EFFECTIVE METHOD TO INCORPORATE MOLECULAR CLASSIFICATION OF MEDULLOBLASTOMA INTO A LATIN-AMERICAN CLINICAL TRIAL
Authors: Sidnei Epelman, Luis Henrique Sakamoto, Juliana Monte Real, Vijay Ramaswamy, Gregorio Pereira, Simone dos Santos Aguiar, Flavia Caldeira Queiroz
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND It is now widely accepted that medulloblastoma actually comprises four distinct molecular subgroups, requiring specific treatment strategies. Implementing routine subgrouping in a time and cost effective manner is a major challenge in Latin America, particularly the development of molecular informed clinical trials. Herein we describe the feasibility of reliable and rapid molecular stratification using a qPCR method integrated with immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH – c-myc, monosomy 6) from heterogeneously fixed, low-quality FFPE samples across Latin America. RESULTS Fifty-four FFPE samples were classified according to histologic and molecular criteria. Classic medulloblastoma was found in 53.7%, desmoplastic/extensive nodularity in 24.1%, NOS in 16,7% and anaplastic in 5,6%. IHC markers classified patients in three groups (WNT, SHH and non-WNT/non-SHH) in 98% of cases. PCR-based method confirmed results from IHC in 81,5%. Additionally, we were able to detect WNT activation in 2 patients, previously classified as SHH. For both cases, the presence of monosomy 6 further confirmed WNT subgroup. Integration of these three techniques resulted in the following frequencies: WNT (13.0%), SHH (38.9%), group 3 (9.3%), group 4 (20.3%) and non-WNT/non-SHH (18.5%). From 40 patients with clinical information available, 3-year overall survival (n=40) for low, intermediate and high-risk groups were 100%, 60% and 20%, respectively (p&amp;lt;0.05), based only in molecular criteria, which confirmed the prognostic importance of this method. CONCLUSIONS At an estimated cost of $220 per patient, we are able to implement central molecular diagnosis for the incorporation into a prospective clinical trial protocol in Latin America.
MODL-16. ABEMACICLIB, A SELECTIVE CDK4/6 INHIBITOR, RESTRICTS GROWTH OF PEDIATRIC GLIAL-LINEAGE TUMORS IN VITRO AND IN VIVO
Authors: Muh-Lii Liang, Tsung-Han Hsieh, Tai-Tong Wong
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Glial-lineage tumors constitute a heterogeneous group of neoplasms, comprising gliomas, oligodendrogliomas, and ependymomas, which account for 40%–50% of all pediatric central nervous system tumors. Advances in modern neuro-oncological therapeutics are aimed at improving neoadjuvant chemotherapy and deferring radiotherapy because radiation exposure may cause long-term side effects on the developing brain in young children. Despite aggressive treatment, more than half the high-grade gliomas (pHGGs) and one-third of ependymomas exhibit recurrence within 2 years of initial treatment. METHODS By using integrated bioinformatics and through experimental validation, we found that at least one gene among CCND1, CDK4, and CDK6 was overexpressed in pHGGs and ependymomas. RESULTS The use of abemaciclib, a highly selective CDK4/6 inhibitor, effectively inhibited cell proliferation and reduced the expression of cell cycle–related and DNA repair–related gene expression, which was determined through RNA-seq analysis. The efficiency of abemaciclib was validated in vitro in pHGGs and ependymoma cells and in vivo by using subcutaneously implanted ependymoma cells from patient-derived xenograft (PDX) in mouse models. Abemaciclib demonstrated the suppression of RB phosphorylation, downstream target genes of E2F, G2M checkpoint, and DNA repair, resulting in tumor suppression. CONCLUSION Abemaciclib showed encouraging results in preclinical pediatric glial-lineage tumors models and represented a potential therapeutic strategy for treating challenging tumors in children.
NCMP-09. POSTMORTEM STUDY OF ORGAN SPECIFIC TOXICITY IN GLIOBLASTOMA PATIENTS TREATED WITH A COMBINATION OF TEMOZOLOMIDE, BEVACIZUMAB AND IRINOTECAN
Authors: Jay-Jiguang Zhu, Guangrong Lu, Mayank Rao, Ping Zhu, Nadine Linendoll, Xuejun Tian, Monika Pilichowska, Julian Wu, William Glass, Meenakshi Bhattacharjee, Leomar Y Ballester, Lei Chen, Rongzhen Zhang, Anil Pillai, L Maximilian Buja, Robert Hunter
Journal: Neuro-Oncology (2020)

Abstract Combined chemotherapy with temozolomide (TMZ), bevacizumab (BEV) and irinotecan (IRI) [TBI] has been used in patients with recurrent or progressive high-grade gliomas. Patients tolerated the regimen well with increased frequency of reversible clinical myelosuppression (CM), hypertension and proteinuria. However, organ-specific toxicities have never been evaluated by post-mortem examination. From 2009 to 2019, post-mortem examinations were performed in seventy-six decedents, including gliomas (N=68, 44/M and 24/F, median age: 59, ranging 23–80 years old) and brain metastases (N=8, 5/M and 3/F, ranging 39–75 years old). Twenty-four glioma subjects were treated with 1–25 cycles TBI (median 5.5) at glioma recurrence. All subjects’ clinical information, treatment histories and adverse events were collected. Five (7.7%, 5/65) glioma decedents (excluding three glioma patients who never received TMZ) permanently discontinued TMZ due to severe CM during concurrent chemoradiation therapy. There is no significantly elevated severity of CM from TBI when compared to standard of care therapies, nor when comparing extended TMZ treatment to the standard 12 cycles of TMZ. However, exposure to IRI significantly increased the CM occurrence (p&amp;lt; 0.05). Among glioma decedents, the most common cause of death was tumor progression (63.2 %, N=43), followed by aspiration pneumonia (48.5%, N=33). No deaths were attributed to acute toxicity from TBI. An electromicroscopic (EM) examination was performed in addition to routine autopsy procedures to investigate the cause of hypertension and proteinuria frequently developing in patients received BEV therapy. Ultrastructural evidence of thrombotic microangiopathy was observed in the kidneys among BEV users; however, it is difficult to conclude such changes were related to BEV due to rapid autolytic changes and artifacts. CONCLUSION: IRI, not the extended use of TMZ, significantly increased the frequency of reversible CM in recurrent glioma patients. There are no unexpected adverse events or organ-specific toxicities detected among glioma decedents who received the TBI regimen.
SURG-16. PREDICTORS OF LOCAL CONTROL FOLLOWING LASER INTERSTITIAL THERMAL THERAPY FOR GLIAL TUMORS
Authors: Sameah Haider, Jacob Pawloski, Hassan Fadel, Hesham Zakaria, Farhan Chaudhry, Seamus Bartlett, Michael Bazydlo, Steven Kalkanis, Ian Lee
Journal: Neuro-Oncology (2020)

Abstract INTRODUCTION Laser Interstitial thermal therapy (LITT) is a minimal-access procedure for intracranial tumors that are either refractory to standard treatment paradigms or difficult to access via conventional open surgery. OBJECTIVE To evaluate predictors of local disease control following LITT in patients with primary and secondary brain tumors. METHODS Single-center retrospective cohort study of all consecutive LITT ablations between 2014 and 2019. Demographic and procedural characteristics analyzed with respect to local disease control at 6 months. Chi-square tests for categorical variables, T-tests/Wilcoxon Rank-Sum tests for continuous variables for parametric and non-parametric data, respectively. Poisson regression models were used to approximate relative risk (RR) with 95% confidence intervals. RESULTS A total of 76 patients underwent LITT with a median follow up of 12.3 months; pathology at time of ablation was glioblastoma multiforme (GBM, 36%), WHO grade III primary CNS (24%), low grade CNS (20%), and metastatic lesions (19%) with respective local control rates of 26%, 20%, 29%, and 26%. Pathology of GBM (RR 0.46, 0.21-1.02, p=0.055) and a 5-year increase in age at the time of ablation (RR 0.91, 0.83-0.99, p=0.028) were associated with a lower likelihood of local control at 6 months. Preoperative Karnofsky performance status (KPS) of 100 (RR 2.04, 1.13-3.69, p=0.019) was associated with a higher likelihood of local control. Extent of ablation (EOA) demonstrated a direct relationship with local control; when EOA=100% local control was 59%, with this rate dropping down to 21% when EOA=90%. Tumor location, lesion volume, gender, BMI, ethnicity, or whether there existed multiple foci of disease at the time of ablation had no strong association with local control. CONCLUSION Our series demonstrates that preoperative performance status and age were strong predictors of local disease control following LITT. Incomplete ablation and histology of high-grade glioma portended a higher risk of local recurrence.
DDRE-18. DEVELOPMENT OF EGFRvIII AND EGFR DIRECTED CHIMERIC ANTIGEN RECEPTOR T CELL THERAPY FOR THE TREATMENT OF GLIOBLASTOMA MULTIFORME
Authors: Michael Ruff, Reona Sakemura, Claudia Manriquez-Roman, Mehrdad Hefazi-Torghabeh, Kendall Schick, Cox Michelle, Ismail Can, Paulina Horvei, Elizabeth Siegler, Erin Tapper, Saad Kenderian
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Chimeric antigen receptor T cell (CART) therapy has revolutionized the treatment landscape for hematological malignancies, its efficacy remains limited in solid tumors. EGFRvIII is a truncated version of the wild type EGFR in which deletion of exons 2–7 of the extracellular domain leads the variant (EGFRvIII) that is strongly antigenic and is mostly expressed on tumor cells. EGFR amplification (tEGFR) almost uniformly precedes the presence of EGFRvIII on tumor cells. The heterogeneity of surface receptor expression and immunosuppressive stromal microenvironment underscore the need to develop CART strategies to target multiple tumor antigens simultaneously. METHODS we generated tEGFR/EGFRvIII directed CAR construct by cloning a clinically relevant tEGFR and EGFRvIII specific scFv into a second generation CAR construct (41BB stimulated) in a third generation lentivirus backbone. This was used to transfect 293T cells and the generated lentivirus particles were used to transduce T cells and generate EGFRvIII/tEGFR CART cells. GBM primary patient derived cell lines were used in these experiments. These cells were passaged and maintained in patient derived xenograft models. RESULTS EGFRvIII/tEGFR directed CART cells exhibited potent antitumor activity against EGFRvIII/tEGFR + GBM cell lines: with 100% killing at 1.25:1, 2.5:1, 5:1 and 10:1 E:T ratio on multiple PDX cell lines with EGFRvIII expression and EGFR over-expression (greater than five copies of EGFR gene) at 24 hours of incubation. Conclusion: We demonstrate that targeting EGFRvIII and over-expressed EGFR with CART cells is feasible, efficacious and represents a promising therapeutic strategy to target GMB. Data from in vivo and combinatorial CART experiments will be reported at the meeting.
Pancreatitis, Panniculitis, and Polyarthritis Syndrome Detected on 99mTc-MDP Bone Scan
Authors: Limeng He, Yan Deng, Ying Deng, Zijuan Rao, Wei Zhang
Journal: Clinical Nuclear Medicine (2020)

Pancreatitis, panniculitis, and polyarthritis syndrome is a rare disease. A 49-year-old man recently complained of bilateral ankle and epigastric pain. An ankle x-ray showed subcutaneous soft tissue swelling. Subsequent 99mTc-MDP bone scan showed foci of abnormal activity around joints in all extremities, especially in the knees and ankles. In addition, multiple nodular calcifications in the head of the pancreas were found in the abdominal CT scan. The patient also had increased blood amylase and lipase. The symptoms were resolved after the treatment of his pancreatitis.
27P Methodology for identification of clinically relevant targets for TCR-immunotherapy in hepatocellular carcinoma
Authors: P. Maravelia, A.P. Potti, T. Sekine, D.S.N. Silva, K. Healy, M. Chrobok, C. Jorns, M. Sällberg, M. Buggert, A. Pasetto
Journal: Annals of Oncology (2020)
Abstract 15998: Relation Between Periarterial Neovascularization and Progression of Coronary Allograft Vasculopathy: A Serial IVUS Study of Cardiac Transplant Patients
Authors: Hideki Kitahara, Ryotaro Yamada, Kenji Sakamoto, Katsuhisa Waseda, Paul G Yock, Alan C Yeung, Hannah A Valantine, William Fearon, Peter J Fitzgerald, Yasuhiro Honda
Journal: Circulation (2013)

Background: A number of studies have correlated vasa vasorum proliferation with arterial inflammation and plaque progression. A recent study also reported that periarterial small vessels (PSV) were...
Noninvasive strategies in COVID-19: epistemology, randomised trials, guidelines, physiology
Authors: Martin J. Tobin, Amal Jubran, Franco Laghi
Journal: European Respiratory Journal (2020)

<b>Two recent <i>ERJ</i> articles demonstrate dramatic benefit with CPAP in COVID-19 patients, highlighting problems with the landmark trial of CPAP (and related guidelines) and illustrating the danger of believing that trials capture the truth of clinical practice</b>https://bit.ly/3pVp78e
T-cell activation profiles distinguish hemophagocytic lymphohistiocytosis and early sepsis
Authors: Vandana Chaturvedi, Rebecca A. Marsh, Adi Zoref-Lorenz, Erika Owsley, Vijaya Chaturvedi, Trung C. Nguyen, Jordana R. Goldman, Michael M. Henry, Jay N. Greenberg, Stephan Ladisch, Michelle L. Hermiston, Michael Jeng, Ahmed Naqvi, Carl E. Allen, Hector R. Wong, Michael B. Jordan
Journal: Blood (2020)
Challenges and Opportunities in Marginal Zone Lymphoma: Implications of Biology on Treatment
Authors: Stephen D. Smith
Journal: Journal of the National Comprehensive Cancer Network (2020)

Although sharing some common features in terms of etiology and even clinical presentation, marginal zone lymphoma is a heterogeneous group of diseases, with subtypes that can present in unexpected ways, especially with regard to autoimmune disease. There’s a proven role of antimicrobial therapy for both Helicobacter pylori and hepatitis C virus, and 10-year overall survival is high. Because this disease requires continuous treatment, therapy should be properly sequenced, with consideration given to patient comorbidities and age. Finally, B-cell receptor signaling inhibitors and immunomodulatory agents can provide responses and disease control.
Celastrol targets adenylyl cyclase-associated protein 1 to reduce macrophages-mediated inflammation and ameliorates high fat diet-induced metabolic syndrome in mice
Authors: Yuyu Zhu, Ning Wan, Xinni Shan, Guoliang Deng, Qiang Xu, Hui Ye, Yang Sun
Journal: Acta Pharmaceutica Sinica B (2020)

Metabolic syndrome is a clustering of metabolic disorder with unclear molecular mechanism. Increasing studies have found that the pathogenesis and progression of metabolic syndrome are closely related to inflammation. Here, we report celastrol, a traditional Chinese medicine, can improve high fat diet-induced metabolic syndrome through suppressing resistin-induced inflammation. Mechanistically, celastrol binds to adenylyl cyclase associated protein 1 (CAP1) and inhibits the interaction between CAP1 and resistin, which restrains the cyclic adenylate monophosphate (cAMP)–protein kinase A (PKA)–nuclear factor kappa-B (NF-κB) signaling pathway and ameliorates high fat diet-induced murine metabolic syndrome. Knockdown of CAP1 in macrophages abrogated the resistin-mediated inflammatory activity. In contrast, overexpression of CAP1 in macrophages aggravated inflammation. Taken together, our study identifies celastrol, which directly targets CAP1 in macrophages, might be a promising drug candidate for the treatment of inflammatory metabolic diseases, such as metabolic syndrome.
Recent advances in supramolecular antidotes
Authors: Hang Yin, Xiangjun Zhang, Jianwen Wei, Siyu Lu, David Bardelang, Ruibing Wang
Journal: Theranostics (2020)

Poisons always have fascinated humankind. Initially considered as deleterious or hazardous substances, the modern era has witnessed the controlled utilization of dangerous poisons in medicine and cosmetics. Simultaneously, antidotes have become crucial as reversal agents to counteract the effects of a poison, and they are also used today to positively cancel the benefits of a poison after use. Currently, the majority of poisons are composed of small molecules. This review focuses on recent developments to reverse or prevent toxic effects of poisons by encapsulation in host molecules. Cyclodextrins, cucurbiturils, acyclic cucurbituril derivatives, calixarenes, and pillararenes, have been reported to largely impact the effects of toxic compounds, thus extending the current paradigm of small molecule antidotes by adding a new family of macrocyclic compounds to the current arsenal of antidotes. Along this line of research, endogenous "harmful" species are also sequestered by one or more of these supramolecular host molecules, expanding the potential of supramolecular antidotes to diverse therapeutic areas.
Comment on “The natural history of progressive fibrosing interstitial lung diseases”
Authors: Yuben P. Moodley, Christopher Zappala, Chantalia Tedja, Britt Clynick, Dino B.A. Tan, Eugene Haydn Walters
Journal: European Respiratory Journal (2020)

We have read with great interest the paper titled "The natural history of progressive fibrosing interstitial lung diseases" by Brown et al . [1]. This elegant study has used data from the INBUILD and INPULSIS trials to investigate the natural history of progressive fibrosing interstitial lung diseases (ILDs). The controversy around lung function testing in IPF to predict progression of the disease <https://bit.ly/34E2JGW>
Macrophages Come To The Rescue
Authors: Robert P. Coppes
Journal: Cancer Research (2020)

Abstract The study by Zhao and colleagues, in this issue of Cancer Research, builds on previous work where they showed that transient activation of Hedgehog signaling within the murine submandibular gland rescued radiation-induced salivary gland dysfunction. The current study provides mechanistic insight into this phenomenon by showing that restoration of radiation-depleted resident macrophages through prorepair paracrine interactions with endothelial cells and epithelial progenitors rescued salivary function. See related article by Zhao et al., p. 5531
TAMI-01. NEOADJUVANT PD-1 ANTIBODY BLOCKADE REMODELS THE IMMUNE MICROENVIRONMENT OF METASTATIC BRAIN TUMORS
Authors: Lu Sun, Jenny Kienzler, Alexander Lee, Frances Chow, Carolina Chavez, William Yong, Richard Everson, Won Kim, Willy Hugo, Robert Prins
Journal: Neuro-Oncology (2020)

Abstract Brain metastases (BM) commonly arise in patients with melanoma, lung, and breast cancer. Currently, there are limited options for GBM and BM patients who have failed the first-line standard treatment, underscoring the importance of developing new therapeutic strategies. Last year, we and other groups evaluated the neoadjuvant timing of anti-PD-1 checkpoint blockade therapy in recurrent GBM (rGBM) patients, which resulted in a modest survival benefit. In light of the known effectiveness of anti-PD-1 as a systemic therapy to control melanoma and non-small cell lung cancer BM, we set out to study the anti-tumor immune response of BM patients to anti-PD-1 in the neoadjuvant setting. We posited that neoadjuvant anti-PD-1 in patients with BM would result in a stronger antitumoral immune response, which could be quantified at the single cell level. To test this, we made use of contemporary single cell techniques, including multiplex immunofluorescence, time-of-flight mass cytometry (CyTOF) and single-cell RNA sequencing (scRNAseq), to characterize the intratumoral immune cell populations and their transcriptomic profiles. We found that neoadjuvant anti-PD-1 significantly increased the number of tumor infiltrating T lymphocytes in BM compared to rGBM (2.5 fold in BM, p= 0.02 vs. 1.4 fold in rGBM, p= 0.19). Multiplex immunofluorescence analysis of T cells in BM samples revealed a change from T cell exclusion to a diffusely infiltrating phenotype after anti-PD-1 treatment. Importantly, BM showed a higher fraction of effector/cytotoxic T cells compared to rGBM (7.3% vs. 0.9% of lymphoid cells, p= 0.005) and anti-PD-1 further enhanced this population. In the myeloid compartment of BM, neoadjuvant anti-PD-1 increased the frequency of HLA-DR+CD206- M1-like macrophages, implicating a pro-inflammatory microenvironment. In summary, our study delineated the immune cell subtypes altered by neoadjuvant anti-PD-1 and offers insights into new combination therapies that can help understand the clinical efficacy of immunotherapy for BM and GBM patients.