tbuckley/cabot-search huggingface dataset:
P01.038 Drug resistance and recurrence in glioblastoma: molecular cytogenetic analysis in paired primary and recurrent form
Authors: Z Šporiková, M Megová Houdová, R Trojanec, O Kalita, J Vrbková, J Drábek, V Koudeláková, M Hajdúch
Journal: Neuro-Oncology (2018)

Glioblastoma (GBM) is the most common primary brain tumour in adults with nearly 100% mortality. Despite aggressive therapy, overall survival of GBM patients remains poor due to intrinsic or acquired resistance to maximal treatment modality based on combination of radiation and chemotherapy. The biological background behind GBM progression after first line therapy is mostly unknown and thus, there are only limited targeted therapeutic options for the second line treatment. The main goal of this study was to elucidate genetic landscape in paired samples of primary versus recurrent GBM and to validate prognostic and predictive value of the most significant differences in independent cohort of GBMs. The cohort consists of 43 paired samples obtained during 1st surgery followed by radiochemotherapy (at least 54 Gy plus 3 cycles of temozolomide) and during the second palliative surgery. The analysis comprises genome copy number variations (24/43 samples) and fluorescent in situ hybridization determined gene and chromosomal region statuses for EGFR, p53, RB1, MDM2, CDKN2A and 1p, 19q, 10p. Methylation-specific PCR was used for analysis of MGMT promoter methylation and competitive amplification of differentially melting amplicons PCR for IDH1/2 mutations detection. The validation of the most relevant alterations was performed on independent cohort of non-paired 104 tumors. Statistically the most significant differences of GBM progression induced by combination of chemo and/or radiotherapy were: EGFR amplification, CDKN2A loss, MDM2 gain, PDGFRA gain and GSTT1 loss in primary tumors and GSTM1 gain in recurrent tumors. Univariate analysis of overall survival for significant copy number alterations proofs significantly worse prognosis for patients harboring GSTT1 deletion in primary tumor. The analysis revealed trend of better prognosis in patients with CDKN2A deletion and GSTM1 amplification in recurrent tumors. Significantly worse prognosis had GBM patients harboring GSTT1 gene aberrations and was also confirmed in independent validation cohort of unpaired GBMs in multivariate analysis adjusted for age and Karnofsky score. Full data with statistical analysis will be presented in the poster. The molecular genetic background of paired samples of primary and recurrent form of GBM revealed association with glutathione S-transferases genes. The significance of GSTT1 gene aberration was validated in independent group of GBM and thus supports the theory of in involvement of redox enzymes in GBM chemoradiation response and tumor progression. The financial support of grants TACR TE02000058, IGA_LF_2018_005 is gratefully acknowledged. Authors thank the collaborating neurosurgical centers from Ostrava (CGB laboratory), Brno (CEITEC) and Prague (Faculty Hospital Královské Vinohrady).
Pathogen identification in prostate cancer biopsies using transcriptome sequencing.
Authors: Carisa M Shah, Rohan Bareja, Olivier Elemento
Journal: Journal of Clinical Oncology (2017)

e16545 Background: Tumor biopsies may frequently be associated with microbial species due to proximity with microbial communities or due to contamination during tissue processing. We examined sequencing data from tumor biopsies to explore the tumor-associated microbiome in prostate cancer. Methods: Patients were enrolled in a prospective Precision Medicine study to evaluate genomic alterations based on freshly obtained tissue biopsies. Total RNA was prepared for RNA sequencing using the standard Illumina mRNA sample preparation protocol. Paired-end RNA-sequencing at read lengths of 50 or 51 bp was performed with the HiSeq 2000 (Illumina). A total of ~268 million paired-end reads were generated, corresponding to 27 billion bases. Kraken and FusionCatcher were used to identify the metagenome that maps to microbial species. R was used to analyze the microbial pathogens and to create a heatmap of microbial abundance. We focused our analysis on prostate cancer. Results: From 1/30/2013 to 12/16/15, 83 patients with urothelial cancers were identified, of which 32 patients with prostate cancer (n = 23 from primary tumor, n = 9 metastatic prostate cancer) were sequenced. Of the 9 metastatic samples, 5 were metastatic prostate cancer to bone, 4 were other metastases. A giant cell tumor of bone was used as a control. The metagenome was identified and mapped to the Kraken pathogen database. 43 unique pathogens characterized the microbiome associated with prostate cancer, including Streptomyces species, Acinetobacter baumannii, Enterobacteriaceae, and Corynebacterium species. The most prevalent species in prostate cancer bone metastases were also the most prevalent in primary prostate tumors. Prostate cancer bone metastases clustered separately from the primary prostate cancer samples, the other metastases, and primary bone cancer. Conclusions: We have identified a putative microbiome signature associated with prostate cancer. Prostate cancer bone metastases appear to cluster separately from prostate cancer, suggesting a non-random association with microbial communities. Ongoing work is looking to (1) validate microbial association using orthogonal analyses and (2) determine the exact origin of the signature.
In vivo changes in the cutaneous antioxidant status during sorafenib, sunitinib and capecitabine treatment.
Authors: Sora Jung, Juergen Lademann, Jalid Sehouli, Maxim E. Darvin, Harald Fuss
Journal: Journal of Clinical Oncology (2017)

e21664 Background: A potential pathomechanism for doxorubicin-associated hand-foot syndrome (HFS) was shown based in particular on radical formation in the skin. Topically applied antioxidants (AO) have a therapeutic effect on HFS. Here, radical formation of orally administered sorafenib (Nexavar), sunitinib (Sutent) and capecitabine (Xeloda) was investigated. Methods: 26 patients were included in the study in total, including 13 patients receiving capecitabine (2-4 g/day), 7 patients receiving sunitinib (25-50 mg/day) and 6 patients sorafenib (400 mg/day). Cutaneous carotenoids serving as marker substance of the AO status of the epidermis were measured in vivo using a miniaturized measuring system based on multiple spatially resolved reflectance spectroscopy. Measurements were performed 1 day before the first oral administration and on the 10 th day during the first cycle of chemotherapy including an assessment of HFS skin lesions. Results: The mean AO status in capecitabine patients showed an insignificant decrease from 4.09±0.25 to 4±0.25 and in sunitinib patients an insignificant increase from 4.32±0.36 to 4.82±0.52. The AO status in patients treated with sorafenib was shown to increase significantly from 4.77±0.32 to 5.20±0.33, p = 0.028, along with an enhanced subjective vitality and well-being. Overall 3 patients, 1 in each treatment group, developed HFS grade I during the observational period of the first cycle. Conclusions: Sorafenib-, sunitinib- and capecitabine-associated HFS might not occur due to radical formation only, but due to different underlying pathomechanisms. As an AO decay was observed previously after intravenous, but not after oral administration of chemotherapeutics, the metabolisation of these agents after oral and intravenous intake might influence HFS development. Therefore, the application of topical AO might not have preventive effects for these orally applied chemotherapeutics, as shown for capecitabine previously. As therapeutic effects of topically applied AO in case of capecitabine and sorafenib induced HFS have been reported, it seems that although the pathomechanisms are different, radical formation can occur once HFS lesions have developed.
Transcriptional addiction in cancer cells is mediated by YAP/TAZ through BRD4
Authors: Francesca Zanconato, Giusy Battilana, Mattia Forcato, Letizia Filippi, Luca Azzolin, Andrea Manfrin, Erika Quaranta, Daniele Di Biagio, Gianluca Sigismondo, Vincenza Guzzardo, Pascale Lejeune, Bernard Haendler, Jeroen Krijgsveld, Matteo Fassan, Silvio Bicciato, Michelangelo Cordenonsi, Stefano Piccolo
Journal: Nature Medicine (2018)
Abstract 11974: Sestrin2 Prevents Age-related Intolerance to Ischemia and Reperfusion Injury via Modulating Substrate Metabolism
Authors: Nanhu Quan, Lin Wang, Dongyang Chu, Xu Chen, Courtney Cates, Quan Liu, Yang Zheng, Ji Li
Journal: Circulation (2016)

Introduction: A novel stress-inducible protein, Sestrin2, declines in the heart with aging. AMP-activated Protein Kinase (AMPK) has emerged as a pertinent stress-activated kinase shown to have cardioprotective capabilities against myocardial ischemic injury. We identified the interaction between Sestrin2 and AMPK in the ischemic heart. Hypothesis: The ischemic AMPK activation modulated by Sestrin2-AMPK complex in the heart is impaired in aging that sensitizes heart to ischemic insults. Methods: C57BL/6 young mice (4-6 months), middle age mice (10-12 months) and aged mice (24-26 months) were subjected to left anterior descending coronary artery occlusion for in vivo regional ischemia. The ex vivo working heart system was used for measuring substrate metabolism. Results: The protein level of Sestrin2 in the hearts were gradually decreased with aging. Intriguingly, ischemic AMPK activation was blunted in the aged hearts as compared with young hearts (p&lt;0.05), the AMPK downstream glucose uptake and the rate of glucose oxidation were significantly impaired in the aged hearts during ischemia and reperfusion (I/R) (p&lt;0.05 vs. young hearts). The myocardial infarction size was larger in the aged hearts (p&lt;0.05 vs. young hearts). The immunoprecipitation with Sestrin2 antibody revealed that cardiac Sestrin2 forms a complex with AMPK and upstream LKB1 during ischemia, intriguingly, the binding affinity between Sestrin2 and AMPK upstream LKB1 is impaired in the aged hearts during ischemia (p&lt;0.05 vs. young hearts). Furthermore, Sestrin2 knock out hearts demonstrate a similar cardiac phenotype and response to ischemic stress as the wild type aged hearts, i.e. impaired ischemic AMPK activation and higher sensitivity to I/R-induced injury. Adeno-associated virus 1 (AAV1)-Sestrin2 were delivered into the aged hearts via a coronary delivery approach significantly rescued the protein level of Sestrin2 and the ischemic tolerance of aged hearts. Conclusions: Sestrin2 is a scaffold protein that mediates AMPK activation in the ischemic myocardium via an interaction with AMPK upstream LKB1. The decreased Sestrin2 levels in aging lead to a blunted ischemic AMPK activation, alterations in substrate metabolism and an increased sensitivity to ischemic insults.
Trends in attention-deficit hyperactivity disorder medication use: a retrospective observational study using population-based databases
Authors: Sudha R Raman, Kenneth K C Man, Shahram Bahmanyar, Anick Berard, Scott Bilder, Takoua Boukhris, Greta Bushnell, Stephen Crystal, Kari Furu, Yea-Huei KaoYang, Øystein Karlstad, Helle Kieler, Kiyoshi Kubota, Edward Chia-Cheng Lai, Jaana E Martikainen, Géric Maura, Nicholas Moore, Dolores Montero, Hidefumi Nakamura, Anke Neumann, Virginia Pate, Anton Pottegård, Nicole L Pratt, Elizabeth E Roughead, Diego Macias Saint-Gerons, Til Stürmer, Chien-Chou Su, Helga Zoega, Miriam C J M Sturkenbroom, Esther W Chan, David Coghill, Patrick Ip, Ian C K Wong
Journal: The Lancet Psychiatry (2018)
Concordance, decision impact and guidelines adherence using artificial intelligence in high-risk breast cancer.
Authors: Zefei Jiang, Fengrui Xu, Martín-J. Sepúlveda, Jianbin Li, Haibo Wang, Zhenzhen Liu, Yongmei Yin, Min Yan, Yuhua Song, Jiakai Guo, M Christopher Roebuck, Cuizhi Geng, Jinhai Tang
Journal: Journal of Clinical Oncology (2018)

e18566 Background: Concordance between breast cancer treatment recommendations from artificial intelligence (AI) systems and physicians or tumor boards, has been reported elsewhere. However, the impact of AI applications on clinician decision-making and adherence to treatment guidelines has not been reported. Methods: We conducted a cross-sectional observational study using the AI treatment advisor Watson for Oncology (WFO) to examine: a) concordance of recommended treatment between oncologists and WFO; b) changes to oncologists' treatment decisions after disclosure of WFO’s recommendations; and c) adherence to National Comprehensive Cancer Network or Chinese Society of Clinical Oncology (CSCO) treatment guidelines. To examine outcomes in complex treatment scenarios, the analysis included 1,997 breast cancer cases from the CSCO database which had metastatic disease or were at high risk of disease progression or metastasis. Four sets of oncology prescribers were consulted—WFO plus three groups of oncologists differing in level of oncology expertise (fellows, attending physicians, chief physicians). Results: Blinded assessment by prescribers showed a 55% treatment concordance rate with WFO. Oncology fellows exhibited higher concordance with WFO than attending and chief physicians (63% v. 51%, %53%; p < 0.001). Concordance by tumor stage and receptor status showed a significant difference between stages II and IV (66% v. 50%; p < 0.001), and highest concordance for triple negative tumors (69%). Disclosure of WFO recommendations resulted in prescriber treatment changes in 106 (5%) of cases. Attending physicians were less likely to alter their decisions (3%) than chief physicians (6%; p < 0.001) and fellows (7%; p < 0.001). Moreover, stage II and III cases were slightly more likely to be changed. Finally, although WFO treatment disclosures only modestly increased adherence to professional treatment guidelines overall (0.5%; p < 0.01), the adherence rate among the 106 cases where decision changes were made improved from 89% to 97% (p < 0.01). Conclusions: In a population of complex breast cancer cases, use of the WFO AI advisor in China confirmed previously reported lower concordance for metastatic disease, and was associated with a modest proportion of prescriber changes. When treatment decisions were altered, the newly selected therapies showed greater adherence to professional treatment guidelines
Immunohistochemical changes in ovaries caused by chemoimmunotherapy.
Authors: Evgeniya M. Nepomnyashchaya, Galina Andreevna Nerodo, Anna Ardzha, Inna Arnoldovna Novikova, Elena Petrovna Ulianova, Galina I. Zakora
Journal: Journal of Clinical Oncology (2017)

e17038 Background: The purpose of the study was to analyze morphological and immunohistochemical changes in patients with ovarian serous carcinomas under the influence of chemoimmunotherapy. Methods: The study included patients aged 52-76 years with stage IIIC-IV ovarian cancer with ascites. The patients were divided into two groups according to the treatment received: group A – 22 patients receiving neoadjuvant chemoimmunotherapy, 500 000 IU interferon-gamma (ingaron) on the 1 st day and 1 000 000 IU on days 2, 3 and 5, and chemotherapy (carboplatin AUC-6 and paclitaxel 175 mg/m 2 ) on day 4; group B – 24 patients receiving neoadjuvant chemoimmunotherapy and the same regimen of intraperitoneal interferon-gamma. The patients in two groups were similar in terms of disease stages, health condition and age. All patients received further surgery. Immunohistochemical study was performed on paraffin sections for the standard morphological study using Ki-67 rabbit monoclonal antibodies (Thermo scientific) and P-53 mouse monoclonal antibodies (Cell Marque). UltraVision Quanto Detection System HRP DAB was used for visualization. Results: Chemoimmunotherapy plus intraperitoneal interferon-gamma resulted in grade III-IV pathomorphosis, decreased apoptosis index and proliferation activity (р53 – 19.3±2.5%; Ki-67 – 6.2±0.58%) in comparison with the group receiving intramuscular interferon-gamma (р53 –27.6±3.11%; Ki-67 – 16.2±3.09%). The group with chemotherapy and intramuscular interferon-gamma showed grade II pathomorphosis. Conclusions: The study showed that chemotherapy with intraperitoneal interferon-gamma administration, compared with intramuscular one, resulted in more enhanced morphological changes.
Respectful Language and Care in Childhood Obesity
Authors: Fatima Cody Stanford, Theodore K. Kyle
Journal: JAMA Pediatrics (2018)

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Oligoclonal T cells transiently expand and express TIM3 and LAG3 following CD19 CAR t cell therapy.
Authors: Christopher Thomas Petersen, Neera Jagirdar, Edmund K. Waller
Journal: Journal of Clinical Oncology (2017)

e19017 Background: CAR T therapies targeted towards the CD19 antigen have shown tremendous promise in the treatment of multiple B cell malignancies. However, not all B cell malignancies show the same degree of response; B cell lymphomas such as DLBCL have been more resistant to CAR T-mediated lysis. The reasons for the higher treatment failures and relapse rates in this setting are poorly understood which prompts investigation into the dynamics of T cell responses following CAR T infusion. Methods: Peripheral blood was collected from a single DLBCL patient enrolled on a single-patient compassion-use CAR T cell protocol utilizing a single chain CD19 with 4-1BB co-stimulatory signaling domain (NCT02445248 IND 16130). Blood samples were obtained prior to and on day 1, 8, 17, 24, 31, and 58 post-CAR T infusion. A bone marrow aspirate was collected on day 58. Mononuclear cells were collected by ficoll gradient and cryopreserved. Flow cytometry was performed on thawed samples to identify CAR T cells and surface markers. TCR sequencing was performed using the ImmunoSeq platform on an additional sample from each time point. Results: TCR sequencing revealed distinct waves of oligoclonal T cells within the first two months following CAR T therapy. A population of T cells expressing Vβ 20 appeared early following CAR T infusion and contracted by day 17. Additionally, a population of cells expressing Vβ 27.1 also expanded at the peak of the response (D8), but remained at a high frequency up to two months post-treatment. A third wave of T cells expressing Vβ 7.3 expanded in the blood and marrow on day 58. The expression of TIM3 and LAG3 also changed over time. TIM3 was expressed predominantly in the CD8 compartment while LAG3 expression was limited to the CD4 compartment. Expression of both increased at peak and decreased over time. Low levels of PD-1 expression were detected in contrast to the much higher levels of TIM3. Conclusions: The waves of oligoclonal T cell expansion and dynamic expression of TIM3 and LAG3 provide further insight into the CAR T response and may provide new possible targets for supportive therapies that can enhance the overall response. Clinical trial information: NCT02445248.
CD38-targeted therapy in glioblastoma: A step forward.
Authors: Sonikpreet Aulakh, Alak Manna, Paula Schiapparelli, Sikander Ailawadhi, Aneel Paulus, Steven Rosenfeld, Asher Alban Akmal Chanan-Khan, Alfredo Quinones-Hinojosa
Journal: Journal of Clinical Oncology (2018)

e14030 Background: Glioblastoma (GBM) is the primary malignant tumor of the brain with a dismal outcome. Current management includes maximal safe surgical resection, radiation therapy with concomitant and adjuvant temozolomide (TMZ). Its recurrence is inevitable with limited available therapies. In the era of targeted therapeutics, CD38 can be a potential target especially with the availability of Daratumumab; an FDA approved Anti-CD38 monoclonal antibody. CD38 is expressed on 25% of tumor-microglia macrophages that form 40% of the bulk of glioma. In vivo data suggests decreased glioma growth and prolonged survival of GL261 bearing C57BL CD38 -/- and K-rhein treated CD38 wild-type syngeneic mice. Hence, we further explored the potential for a CD38 targeting strategy with DARA in our in vitro studies. Methods: We used the human 965 and 1A primary GBM cell lines. CD38 expression was determined via flow cytometry. IC50s of DARA and TMZ were calculated. Cells were treated with DARA+ DMSO (control) and DARA+TMZ. Calcein-AM labeled GBM cells were co-cultured in vitro with healthy human peripheral blood mononuclear cells (PBMCs) or plasma as a source of immune cells or complement, respectively, to perform antibody dependent cell mediated cytotoxicity (ADCC) and complement mediated cytotoxicity (CDC). These cells were treated with TMZ alone, DARA alone and DARA+TMZ combination. Results: 9% of 965 cells and 7% of 1 A cells expressed CD38 with very high Mean Fluorescent Intensity. DARA IC50 for 965 and 1A, respectively, was 75 µg/ml and 150 µg/ml. TMZ IC50 for 965 and 1 A, respectively, was 700µM and 3000 µM. In vitro viability experiment illustrated enhanced cell death with the combination of DARA+TMZ vs DARA+DMSO. DARA+TMZ combination has direct apoptotic effect on GBM cells in vitro more than DARA and TMZ alone. DARA +/- TMZ also exerts its effect via ADCC and CDC when co-cultured with healthy donor PBMCs. All of the results were statistically significant. Conclusions: DARA +/- TMZ causes direct apoptosis, ADCC and CDC on human derived GBM cells in our in vitro experiments. This data requires further understanding of CD38 linkage to glioma progression and invasion.