tbuckley/cabot-search huggingface dataset:
IVOIRE: Results of a prospective multicentre cohort study in advanced renal carcinoma.
Authors: Eric Voog, Boris Campillo-Gimenez, Claude El Kouri, Frank Priou, Frederic Rolland, Brigitte Laguerre, Chaza Elhannani, Jacques Merrer, Florence Joly, Christian Pfister, Jean-pierre Malhaire, Remy Delva, Oana Cojocarasu, Isabelle Cumin, Catherine Ligeza-poisson, Friederike Schlurmann, Erik Monpetit, Delphine Deniel Lagadec, Fanny Marhuenda, Francoise Grude
Journal: Journal of Clinical Oncology (2017)

451 Background: Sequential targeted therapy is standard in patients (pts) with clear-cell renal carcinoma (CCRCC). Clinical Practice Guidelines exists only for first and second lines (ESMO recommendations). Exploratory recommendations for next treatments (ttt) have been proposed according to their MSKCSS risk. In 3 rd line, pts without prior everolimus were proposed to receive it. Pts who have failed 2 nd line ttt with everolimus were proposed to rechallenge Tyrosine Kinase Inhibitor only if they experimented a disease control ≤ 6 months in 1 st line. For 4 th line, TKI or everolimus were rechallenged according to the previously quoted criteria. Poor risk pts are not presented here. Methods: IVOIRE was a prospective multicentric study including pts treated according to these guidelines. Objectives were overall survival (OS) and for each line Best Objective Response (BOR - RECIST 1.1) and Disease Control Time (DCT: time from day 1 of ttt to the day before the next one). Results: 301 locally advanced/metastatic RCC pts have been included in 17 French centers between Sept 2011 and Sept 2014: 71% men; median age 66 years [35-90]; CCRCC: 89%; grade III-IV Führmann: 68%; tumor resection: 90%. Pts received between 2 and 8 ttt lines, including mainly TK and mTOR inhibitors, or rarely (&lt; 5%) immunotherapies in 1 st line (IFN, IL-2 and bévacizumab only). Median OS was 57 [51-70] months. Results are summarized in table. Important clinical benefit (L1: 79%; L2: 65%; L3: 59%; L4 : 38%; L5: 39%) and DCT could be observed until ttt line 5. A long DCT in 1 st line was predictive of a best OS (p=0.001). Indeed, pts with short 1 st line DCT (11 to 54 weeks) had a shorter median OS (32 months [23-61]] while pts with long DCT (&gt;54 weeks) had a longer median OS: 79 months [65-100]. Conclusions: Our results confirm that clinical benefit remained important to beyond the first lines and that DCT in the first line was predictive of the global OS. Ttt sequence analysis and tolerance will be shown at the meeting. [Table: see text]
The europrevall allergen library: a collection of high quality purified natural and recombinant allergens for in vitro diagnosis
Authors: K. Hoffmann-Sommergruber, A. Sanch, T. Holzhauser, P. Skov, S. Alessandri, J. Wal, N. Rigby, J. Marsh, H. Bernard, S. Gaier, I. Lauer, Y. Ma, C. Oberhuber, Vibeke Barkholt, U. Griesmeier, M. Bublin, C. Radauer, S. Scheurer, G. Reese, L. Zuidmeer, J. Akkerdaas, A. Neubauer, M. Fernandez-Rivas, B. Ballmer-Weber, S. Vieths, R. van Ree, P. Shewry, C. Mills
Journal: Allergy (2007)
Sustained induction of CYP1A1 gene expression by 3-methylcholanthrene in human hepatoma cells is mediated by persistent transcriptional activation of CYP1A1 promoter
Authors: Inayat Fazili, Lihua Wang, Weiwu Jiang, Bhagavatula Moorthy
Journal: Cancer Research (2008)

2257  Polycyclic aromatic hydrocarbons (PAHs) are widely distributed environmental contaminants especially found in the byproducts of combustion processes such as coke ovens, cigarette smoke, and charcoalbroiled meats. Humans are constantly exposed to PAHs, many of which are carcinogens. Cytochrome P4501A (CYP1A) enzymes play important roles in the activation of PAHs such as 3-methycholanthrene (MC) to genotoxic metabolites, which could in turn lead to carcinogenesis. We reported earlier that exposure of rats to MC leads to persistent induction of hepatic microsomal cytochrome P450 (CYP)1A enzymes for up to 45 days. In this study, we tested the hypothesis that persistent induction of CYP1A1 gene expression by MC is mediated by sustained transcriptional activation of the CYP1A1 promoter in human hepatoma cells (HepG2). A plasmid containing the human CYP1A1 promoter (pGL3-1A1) and reporter (luciferase) gene was transiently transfected into HepG2 cells for 16 h, followed by MC (2.5 µM) or dimethylsulfoxide (DMSO) (solvent control) treatment, and luciferase expression was determined at 6, 12, 24, 48, 72 and 96 h after MC or DMSO exposure. Endogenous expression of CYP1A1 catalytic activity and apoprotein content was also determined in treated cell lysates. MC elicited 16 fold increase in luciferase activity at 24 h time point in transfected cells compared to DMSO-treated controls. There was signjficant induction of luciferase expression even at the 96 h time point, suggesting that persistent induction of reporter gene expression was mediated by sustained transcriptional activation of the CYP1A1 gene promoter. MC also caused sustained induction in the endogenous catalytic activity and apoprotein content of CYP1A1 for up to the 96 h time point in treated cells. Electrophoretic mobility shift assays revealed that persistent CYP1A1 induction by MC may have, in part, involved Ah receptor-independent mechanisms. These results support the hypothesis that persistent induction of CYP1A1 by MC in HepG2 cells may involve mechanisms other than persistence of MC in the cells. Future in-depth investigations are needed to elucidate the molecular mechanism of persistence of MC-inducible CYP1A1, a phenomenon that potentially has important implications for human carcinogenesis induced by PAHs.
Kinetics of the Human Papillomavirus Type 16 E6 Antibody Response Prior to Oropharyngeal Cancer
Authors: Aimée R. Kreimer, Mattias Johansson, Elizabeth L. Yanik, Hormuzd A. Katki, David P. Check, Krystle A. Lang Kuhs, Martina Willhauck-Fleckenstein, Dana Holzinger, Allan Hildesheim, Ruth Pfeiffer, Craig Williams, Neal D. Freedman, Wen-Yi Huang, Mark P. Purdue, Angelika Michel, Michael Pawlita, Paul Brennan, Tim Waterboer
Journal: JNCI Journal of the National Cancer Institute (2017)

In a European cohort, it was previously reported that 35% of oropharyngeal cancer (OPC) patients were human papillomavirus type-16 (HPV16) seropositive up to 10 years before diagnosis vs 0.6% of cancer-free controls. Here, we describe the kinetics of HPV16-E6 antibodies prior to OPC diagnosis.
Erratum: Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: A multicenter international myeloma working group study
Authors: S K Kumar, J H Lee, J J Lahuerta, G Morgan, P G Richardson, J Crowley, J Haessler, J Feather, A Hoering, P Moreau, X LeLeu, C Hulin, S K Klein, P Sonneveld, D Siegel, J Bladeé, H Goldschmidt, S Jagannath, J S Miguel, R Orlowski, A Palumbo, O Sezer, S V Rajkumar
Journal: Leukemia (2012)
MicroRNA landscape in non-small cell lung cancer (NSCLC).
Authors: Daniel Morgensztern, Siddhartha H. K. Devarakonda, Caroline Awh, Kalin Guebert, Christopher Maher, Leonard B. Maggi, Saiama Naheed Waqar, Danielle Carpenter, Gordon Robertson, Daniel C. Link, Ramaswamy Govindan
Journal: Journal of Clinical Oncology (2014)

e22194 Background: MicroRNAs (miRNAs) are a class of small non-coding RNAs that control gene expression and are involved in multiple processes including cancer initiation, proliferation, apoptosis and metastasis. miRNAs may function in cancer as either oncogenes or tumor suppressors. Each miRNA may have multiple target proteins. We evaluated The Cancer Genome Atlas (TCGA) data to estimate the frequency of miRNA somatic copy number alterations (SCNAs) in NSCLC. Methods: The latest version of putative SCNA (GISTIC thresholded) data was obtained for lung adenocarcinoma (LUAD) and squamous cell carcinoma (SQCC) through the Broad Firehose. A list of 178 SQCC (TCGA, Nature) and 230 LUAD (TCGA, in revision) samples sequenced by TCGA was obtained from cBioPortal for Cancer Genomics. SCNA data for all miRNA genes (“hsa-mir” or “hsa-let”) was subsequently extracted from the Firehose download. Alterations were classified into loss (low-level/heterozygous), deletion (homozygous), gain (low-level gain), and amplification (high-level gain). Online resources for miRNA target prediction (miRDB) and pathway classification (PANTHER) were queried for the top 10 amplified and deleted miRNAs. Results: SCNA information was available for 939 miRNAs. Amplification, gain, loss and deletion involving at least 1 miRNA were observed in 74.8%, 95.6%, 95.6% and 45.6% of LUADs and 88.8%, 99.4%, 97.8% and 57.9% of SQCCs respectively. The most common sites of miRNA amplification were 1q and 5p for LUAD, and 3q for SQCC. Deletions were most commonly seen at 9p in both histologies. Predicted targets for commonly amplified miRNAs included members of the EGFR, MAPK, PI3K, PDGF, FGF, Wnt, cell cycle regulation and apoptosis pathways. Conclusions: miRNAs are commonly altered in NSCLC and the evaluation of their target proteins may provide a new pathway for drug development.
Exome sequencing reveals a de novo POLD1 mutation causing phenotypic variability in mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome (MDPL)
Authors: Sahar Elouej, Ana Beleza-Meireles, Richard Caswell, Kevin Colclough, Sian Ellard, Jean Pierre Desvignes, Christophe Béroud, Nicolas Lévy, Shehla Mohammed, Annachiara De Sandre-Giovannoli
Journal: Metabolism (2017)
Correlation of hypoxia measured by fluorine-18 fluoroerythronitroimidazole (<sup>18</sup>F-FETNIM) PET/CT and the malignant progression of gliomas.
Authors: Man Hu, Yufang Zhu, Bingjie Fan, Wenwu Li, Dianbin Mu, Shuqiang Zhao, Dexian Zhang, Xiaorong Sun, Zheng Fu, Jinsong Zheng, Li Ma, Jujie Sun, Li Kong, Jinming Yu
Journal: Journal of Clinical Oncology (2014)

11100 Background: Hypoxia is important in the biology of human gliomas. PET offers a noninvasive method to differentiate individual tumor biology and modify treatment accordingly. The development of PET tracers provides further tools to evaluate the hypoxia of human tumors. The aim of this study was to determine whether hypoxia, as measured by fluorine-18 fluoroerythronitroimidazole (18F-FETNIM) PET/CT, was associated with malignant progression of gliomas. Methods: Fifteen patients with suspected primary glioma and who were referred for surgical treatment were enrolled prospectively in this study. All patients had 18F-FETNIM PET/CT studies before surgery. PET/CT imaging was performed at 120 min after 18F-FETNIM injection. For semi-quantitative analysis, the maximum standardized uptake value (SUVmax) was obtained by drawing regions of interest (ROI) on the PET images for tumor tissues. Hypoxia, angiogenesis, aggression, and cellular proliferation related markers hypoxia-inducible factors-1alpha (HIF-1a), vascular endothelial growth factor (VEGF), matrix metallo proteinase 9 (MMP-9), and Ki-67 expression were estimated in tissue specimens by immunohistochemistry. Results: SUVmax, HIF-1a, VEGF, MMP-9, and Ki-67 expression in high-grade gliomas were significant higher than those in low-grade (2.03 ± 0.49 vs.1.04±0.37, 40.63% ± 11.16% vs. 20.71% ± 12.05%, 71.88% ± 15.57% vs. 37.86% ± 13.5%, 68.13% ± 17.92% vs. 35% ± 10.8%, and 28.13% ± 18.11% vs. 3.7% ± 1.25%, respectively. p = 0.001, 0.006, 0.001, 0.001, 0.007, respectively). Furthermore, 18F-FETNIM uptake data were divided into 2 groups using the mean of SUVmax as a basis for the division. Significant differences were observed between high 18F-FETNIM uptake and low uptake in HIF-1a, MMP-9, VEGF, and Ki-67 expression (p= 0.004, 0.004, 0.001, 0.046, respectively). Conclusions: 18F-FETNIM PET/CT provides a noninvasive assessment of hypoxia in glioma. It is useful to understand the mechanisms by which hypoxia affect malignant progression of glioma. 18F-FETNIM PET/CT may have a role in evaluating novel therapeutic agent targeting tumor hypoxia in clinical trials.
iMYC: Proof-of-concept study of ibrutinib in c-MYC and HER2 amplified oesophagogastric carcinoma.
Authors: Michael Davidson, Irene Yu-Shing Chong, David Cunningham, Lauren Aronson, Hanna Bryant, Ruwaida Begum, John Swansbury, Andrew Wotherspoon, Nik Matthews, Ye Mong To, Eleftheria Kalaitzaki, Lina Yuan, David J. Watkins, Naureen Starling, Sheela Rao, Ian Chau
Journal: Journal of Clinical Oncology (2017)

TPS221 Background: The MYC proto-oncogene is among the most frequently dysregulated genes in human cancer and is amplified in 10-30% of oesophagogastric (OG) cancers. Such genes which code for transcription factors are challenging to target directly with small molecule inhibitors or monoclonal antibodies. High-throughput siRNA screening of OG cell lines has found silencing of Bruton’s tyrosine kinase (BTK) to result in selective lethality in the presence of MYC amplification. Sensitivity to the orally available BTK inhibitor ibrutinib has been confirmed in-vitro in MYC, HER2 and co-amplified OG cancer cell lines (Chong, Ann Onc 2014), suggesting it may be a potentially effective therapeutic strategy in both MYC and HER2 amplified OG cancer. Methods: i MYC is an open label, phase II non-randomised study to assess the efficacy of ibrutinib in advanced pre-treated OG cancer. A novel FISH assay for tumour MYC amplification has been developed and pts are pre-screened for MYC and HER2 amplification. Eligibility includes metastatic or locally advanced inoperable OG cancer (SCC or adeno), MYC (ratio &gt;2.5) and/or HER2 (ratio&gt;2) amplification, progression after at least 1 prior line of chemotherapy +/- trastuzumab for advanced disease, PS 0-2 and no history of significant cardiovascular or bleeding disorders. Of the first 9 pts, at least 4 will demonstrate MYC amplification and remaining 5 will show either MYC or HER2 amplification, or co-amplification of both. Pts will be treated with ibrutinib monotherapy until progression or unacceptable toxicity. A Simon 2 stage design will be used for the primary endpoint of response rate, with interim analysis after 9 pts and maximum recruitment to 17 pts. Secondary endpoints include PFS, OS and exploratory translational and imaging biomarker analysis. Mandatory biopsy will be obtained at baseline and optional biopsies will be undertaken at day 10-14, week 8 and progression. The trial represents the first attempt at targeting MYC amplification via synthetic lethal gene interactions in OG cancer through the novel application of an existing anti-cancer drug. As of September 2016, 61 patients have consented for pre-screening, 19 completed MYC analysis and first patient has started treatment. Clinical trial information: 02884453.
<sup>18</sup>F-FDG uptake for prediction EGFR mutation status in non-small cell lung cancer.
Authors: Jian Guan, Longhua Chen, Nanjie Xiao, Min Chen, Y Zhang, Lu Li, Mi Yang, Qinyang Li, Yongmei Dai, Chi Zhang, Laiyu Liu
Journal: Journal of Clinical Oncology (2015)

e22133 Background: EGFR mutation in NSCLC is a biomarker of tumor response to EGFR-TKI. However, lacking in sufficient tumor tissue has limitation to acquire EGFR mutation status in clinical practice. Previous studies showed that lower SUV was associated with better TKI treatment. The objective of this study was to predict EGFR mutation status of NSCLC patients based on a model consisting of 18F-fluorodeoxyglucose (FDG) uptake and supported by primary tumor size and smoking history. Methods: We retrospectively reviewed NSCLC patients undergoing EGFR mutation test and pretreatment PET/CT between March 2009 and December 2013. The relationship of EGFR mutations with both SUV uptake value of primary tumors and patient characteristics were evaluated, and a multivariate logistic regression analysis was constructed. The model was assessed by area under the receiver operating characteristic curve (AUC) and was prospectively validated during January to June 2014. Results: 316 patients meeting criteria were enrolled for model construction. The SUVmax were significantly lower in EGFR mutations (median, 8.8; range, 0-38.2) than in EGFR wild-type (median, 11.9; range, 0-39.3. P < 0.001). In subgroup analysis, we found patients harboring EGFR mutation in exon 19 (median, 8.8; range, 0-38.2) or exon 21 (median, 8.6; range, 0-23.6) had lower SUVmax than those of EGFR wide type (median, 11.9; range, 0-39.3, P < 0.001).Yet, we did not find similar trend in patients harboring exon 18 or 20. ROC curve analysis identified that the SUVmax cutoff point was 8.1, of which the AUC was 0.65 (95 % CI, 0.60–0.72). In addition, multivariate analysis also showed that low SUVmax ( ≤ 8.1) was statistically significant predictor of EGFR mutations, of which the AUC was 0.77, combining non-smoking history and primary tumor size ( ≤ 5cm). Eighty-five more patients were enrolled to validate the predictive model and the overall accuracy, sensitivity and specificity was 77.6%, 64.6% (95% CI 40.7–82.8) and 82.5% (95% CI 70.9–91.0) respectively. Conclusions: Specific FDG uptake value could be considered to effectively predict EGFR mutation status of NSCLC patients combing smoking history and primary tumor size when genetic test is not in place.
Erlotinib with sirolimus for advanced renal cell carcinoma: Preliminary efficacy results
Authors: T. W. Flaig, L. Costa, K. Breaker, M. Schultz, F. Crighton, F. J. Kim, H. A. Drabkin
Journal: Journal of Clinical Oncology (2009)

e16037 Background: The mammalian target of rapamycin (mTOR) is an important therapeutic target in the treatment of renal cell carcinoma (RCC). Temsirolimus, an analog of rapamycin, prolongs survival when used to treat high-risk RCC patients and is approved for the treatment of advanced RCC. Oral rapamycin (sirolimus/Rapamune) is less expensive than temsirolimus and plasma levels can be routinely monitored. Pre-clinical data indicate that the combined inhibition of the epidermal growth factor receptor (EGFR) and mTOR results in enhanced anti-cancer activity, especially in cell lines with wt-VHL. Methods: All patients on this study had metastatic or unresectable renal cell carcinoma with progression despite sunitinib and/or sorafenib. Treatment was started with erlotinib (Tarceva) 150 mg po daily. On day 8, sirolimus was begun with a single 6 mg loading dose and then given as 2 mg daily. Radiographic assessments were performed every 8 weeks. Results: The current data set was obtained through July of 2008. Enrollment started in July of 2006 with the last patient accrued in March 2008; 25 patients have been treated. The median subject age was 60 years with an average of 2.6 previous medical treatments. The unconfirmed median progression free survival (PFS) was 12 weeks (range 2–52) with 4 patients remaining on active treatment and included in this analysis. No confirmed complete or partial responses were observed, but meaningful stable disease (SD) (e.g., &gt; 6 months) was noted in a small group of patients. The most common adverse events were rash and diarrhea with the majority of these observed as a grade 1 event. Grade 3 and 4 toxicities included rash, mucositis, neurological motor weakness, dehydration, worsening cardiac function, non-ST elevation MI, and anemia. Additional efficacy, toxicity and pharmacokinetic data will be presented. Conclusions: The combination of erlotinib and sirolimus produces a median PFS of 12 weeks in a significantly pretreated RCC population, which is not dissimilar to recent results with other mTOR inhibitors in this setting. The toxicity profile of this combination is consistent with the expectations of this pre-treated patient population with advanced RCC. [Table: see text]
The network genomic medicine cost reimbursement model for implementation of comprehensive lung cancer genotyping in clinical routine.
Authors: Anna Kostenko, Jan Peter Glossmann, Sebastian Yves Friedrich Michels, Juliane Sueptitz, Matthias Scheffler, Rieke Fischer, Birgid Markiefka, Andreas Scheel, Peter De Mary, Florian Kron, Reinhard Buettner, Juergen Wolf
Journal: Journal of Clinical Oncology (2015)

e12556 Background: The Network Genomic Medicine (NGM) Lung Cancer is a health care provider network offering comprehensive and centralized high-quality next generation sequencing (NGS)-based multiplex genotyping for all inoperable lung cancer patients (pts) and stands for the implementation of personalized cancer therapy into clinical routine in Germany. Since German catalogues of reimbursable procedures do not cover costs of NGS-based multiplex genotyping, NGM has successfully started a nationwide pilot-project for cost reimbursement. Methods: The AOK Rheinland/Hamburg, one of the largest German public health insurances, has contracted with NGM (integrated care contract (ICC) according to § 140 German Social Insurance Code) for a flat rate reimbursement of NGS-based multiplex genotyping of inoperable lung cancer pts in April 2014. Also, the ICC comprises optional second opinion consultation hours and a joint evaluation program with a strict focus on interdisciplinary and intersectoral cooperation. Other German public and private health insurances are currently negotiating to join the ICC. Results: In 2014 about 4500 lung cancer pts were genotyped. Since April 2014 126 pts, insured by the AOK Rheinland/Hamburg, received NGS-based molecular diagnostics of their tumors within the ICC. Based on the ICC model NGM has requested further insurance companies for reimbursement of multiplex testing for more than 800 publicly insured and 76 privately insured lung cancer pts tested since August 2014. Over 280 ( > 30 %) of these requests have been approved to date. 122 (14 %) requests were rejected but went in appeal. The reimbursement enables state of the art molecular testing strictly independent from pharmaceutical companies. Conclusions: NGM has established the first flat rate cost reimbursement model for NGS-based comprehensive lung cancer genotyping in Germany. A joint off-label database (NGM Cancer Information System) to evaluate personalized cancer therapy (including cost-effectiveness data) besides clinical trials will be launched in mid-2015. Our model of implementing personalized cancer care in broad clinical routine is currently transferred to other tumor entities.
Sedation vs Intubation for Patients With Acute Stroke Undergoing Thrombectomy—Reply
Authors: Julian Bösel, Silvia Schönenberger
Journal: JAMA (2017)

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Mastocarcinoma therapy synergistically promoted by lysosome dependent apoptosis specifically evoked by 5-Fu@nanogel system with passive targeting and pH activatable dual function
Authors: Xiandi Zhu, Yn Sun, Di Chen, Jingfeng Li, Xia Dong, Jie Wang, Huaiwen Chen, Ying Wang, Fulei Zhang, Jinaxin Dai, Rogério P. Pirraco, Shangjing Guo, Alexandra P. Marques, Rui L. Reis, Wei Li
Journal: Journal of Controlled Release (2017)