tbuckley/cabot-search huggingface dataset:
KEYNOTE-045: Randomized phase 3 trial of pembrolizumab (MK-3475) versus paclitaxel, docetaxel, or vinflunine for previously treated metastatic urothelial cancer.
Authors: Joaquim Bellmunt, Guru Sonpavde, Ronald De Wit, Toni K. Choueiri, Arlene O. Siefker-Radtke, Elizabeth R. Plimack, Nicole M. Lewis, Holly Brown, Yabing Mai, Christine K. Gause, David Ross Kaufman, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2015)

TPS4571 Background: Paclitaxel, docetaxel, and vinflunine are commonly used as second-line therapy for advanced urothelial cancer, but median OS is only 7-9 months. The PD-1 pathway plays a key role in evading the tumor immune response. Pembrolizumab is a highly selective anti–PD-1 monoclonal antibody designed to block the interaction between PD-1 and its ligands PD-L1 and PD-L2. In KEYNOTE-012, pembrolizumab 10 mg/kg every 2 weeks (Q2W) provided a 24% ORR (RECIST v1.1, central review) and an acceptable safety profile in 33 pts with PD-L1–positive advanced urothelial cancer, 76% of whom received ≥ 1 prior therapy. Methods: In the international, open-label, phase 3 KEYNOTE-045 trial (ClinicalTrials.gov, NCT02256436), pts with confirmed metastatic or locally advanced/unresectable urothelial cancer (transitional cell or predominantly transitional cell histology) of the bladder, renal pelvis, ureter, or urethra that has recurred or progressed following platinum-based chemotherapy are randomized 1:1 to pembrolizumab 200 mg Q3W or investigator’s choice of paclitaxel 175 mg/m2 Q3W, docetaxel 75 mg/m2 Q3W, or vinflunine 320 mg/m2 Q3W. Key eligibility criteria include ≤ 2 prior chemotherapy regimens and measurable disease per RECIST v1.1. Randomization is stratified by ECOG PS (0/1 vs 2), liver metastases (presence vs absence), hemoglobin level ( < 10 vs ≥ 10 g/dL), and time from last chemotherapy dose ( < 3 vs ≥ 3 mo). All pts must provide a recently obtained biopsy sample for PD-L1 evaluation at a central laboratory. Pembrolizumab will be given for up to 24 mo or until disease progression, unacceptable toxicity, or investigator decision. Treatment may be continued beyond initial radiographic progression in select pts. Pts who achieve complete response may discontinue pembrolizumab. Response will be evaluated at wk 9 and every 12 wk thereafter. After discontinuation, pts will be followed for survival every 12 wk. Primary end points are OS and PFS assessed per RECIST v1.1 by independent central review. Secondary end points include ORR and duration of response. Enrollment began in Oct 2014 and will continue until approximately 470 pts are enrolled. Clinical trial information: NCT02256436.
Abstract 3622: Complete workflow for detection of low frequency somatic mutations from cell-free DNA using Ion Torrent™ platforms
Authors: Jian Gu, Dumitru Brinza, Ann Mongan, Richard Chien, Dalia Dhingra, Fiona Hyland, Kelli Bramlett
Journal: Cancer Research (2016)

Abstract Research detecting of somatic mutations in circulating cell-free DNA (cfDNA) using research blood samples from subjects previously diagnosed with cancer provides a potential non-invasive approach to monitor cancer status and evaluate cancer evolution in the future. However, most of the existing mutation detection methods show insufficient sensitivity to detect cfDNA mutations since only small amount of mutant gene fragments, derived from tumor cells, is present in a large amount of normal circulating DNA background. We demonstrated a complete workflow that includes blood collection, cfDNA isolation, library preparation, sequencing, and data analysis to enable detection of rare DNA variants in blood plasma samples. Blood samples were collected using Streck™ DNA tubes followed by plasma preparation and cfDNA isolation using MagMAX™ Cell-Free DNA Isolation Kit. Library preparation was performed using Oncomine™ lung cfDNA kit. Barcoded libraries were pooled and sequenced on Ion Torrent™ Next Generation Sequencing Platforms. Sequencing data was analyzed in Torrent Suite™ using variantCaller-cfDNA plugin. ∼150 biomarkers relevant to non-small cell lung cancer were interrogated in one sequencing run. We demonstrated detection sensitivity at 0.1% frequency using engineered mutants that were spiked into control DNA samples. The workflow was tested on a set of research samples from matched tumor FFPE and blood plasma collected from research subjects with non-small cell lung cancer (NSCLC). About 1 mL of plasma was processed using the workflow described above. RecoverAll™ Multi-Sample RNA/DNA Isolation Workflow was used to isolate DNA from FFPE samples, followed by library preparation, sequencing and data analysis using the same workflow described above. Summary of variant calls from matched cfDNA and FFPE tumor samples are presented here. Results indicate high sensitivity of the workflow and expected levels of concordance between variants detected in the two types of research samples. In this study, we developed a highly sensitive and reliable research workflow to detect rare somatic mutations in circulating cfDNA samples. Significant overlapping of mutations discovered in FFPE tumor and cfDNA samples suggests that this workflow may be used to monitor tumor dynamics in NSCLC and potentially other tumors in the future. Disclaimer: For research use only. Not for use in diagnostic procedures. Citation Format: Jian Gu, Dumitru Brinza, Ann Mongan, Richard Chien, Dalia Dhingra, Fiona Hyland, Kelli Bramlett. Complete workflow for detection of low frequency somatic mutations from cell-free DNA using Ion Torrent™ platforms. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3622.
Abstract 3341: Microarray analysis of gastrointestinal stromal tumor-originated spheroids
Authors: Hirotoshi Kikuchi, Shinichiro Miyazaki, Tomohiro Murakami, Tomohiro Matsumoto, Yusuke Ozaki, Yoshihiro Hiramatsu, Kinji Kamiya, Manabu Ohta, Takanori Sakaguchi, Hiroyuki Konno
Journal: Cancer Research (2016)

Abstract Background: Although the main cause of gastrointestinal stromal tumor (GIST) is gain-of-function mutations in the c-kit gene in the interstitial cells of Cajal, concomitant genetic or epigenetic changes other than c-kit are thought to occur during tumor progression. Although sequential therapy with tyrosine kinase inhibitors (TKIs), imatinib mesylate, sunitinib malate and regorafenib, is an effective and standard treatment strategy for recurrent or metastatic GISTs, it is difficult to cure recurrent GISTs with TKIs alone. It has been reported that viable cells are often seen in tumors resected in response to imatinib therapy and they may cause refractory tumors after interruption of imatinib in responding patients with advanced GISTs. Therefore targeting these persistent clones, which may have stem cell characteristics, can be a novel treatment strategy to cure recurrent or metastatic GISTs. In this study, we generated spheroids from resected GIST and performed microarray analysis to identify gene sets typically expressed in GIST-originated spheroid (GISTOS). Methods: According to the previous report of cancer tissue originated spheroid (CTOS) (Kondo J et al. PNAS 108:6235-40, 2011), GISTOS was prepared from fresh samples of 6 primary gastric GISTs. Total RNAs were extracted from 6 GISTOS and their original tumors and utilized for cDNA microarray analysis. None of the patients had received imatinib therapy before surgery. Gene expression levels were compared between GISTOSs and their original tumors. Results: Hierarchical clustering revealed two distinct clusters, and distinguished GISTOS from original tumors. Gene set enrichment analysis (GSEA) revealed that the gene sets CISPLATIN_RESISTSNCE, METASTASIS_STROMAs and TUMOR_INVASIVENESS_2D were upregulated and gene sets CELL_CYCLE_G1_S and MIR21_TARGETS were downregulated in GISTOSs compared with original tumors. These gene sets appear to reflect distinctive features of GISTOS that consists of enriched stem cell populations. Conclusions: We generated GIST-originated spheroids. Microarray analysis revealed gene sets up-regulated and down-regulated in GISTOS. These gene sets appear to reflect distinctive features of GISTOS and may serve as novel molecular markers of stem cells in GIST. Citation Format: Hirotoshi Kikuchi, Shinichiro Miyazaki, Tomohiro Murakami, Tomohiro Matsumoto, Yusuke Ozaki, Yoshihiro Hiramatsu, Kinji Kamiya, Manabu Ohta, Takanori Sakaguchi, Hiroyuki Konno. Microarray analysis of gastrointestinal stromal tumor-originated spheroids. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3341.
Abstract 188: Isoform-specific AKT functions in thyroid carcinoma development
Authors: Michela Ranieri, Antonio Di Cristofano
Journal: Cancer Research (2016)

Abstract Mammalian cells contain three genes that encode three AKT isoforms (AKT1-3). The three genes have &amp;gt;85% sequence identity, and possess conserved threonine and serine residues that are critical for full activation. All AKT isoforms seem to have identical or similar substrate specificity, and it is not clear whether they possess different functional specificities in vivo. Using conditional, organ-specific isoform deletion in a model of PI3K-dependent neoplastic transformation and progression, we are dissecting the molecular and biological roles of AKT1 and AKT2. Thyroid-specific deletion of Pten (Ptenthy-/− mice) results in thyroid hyperplasia at birth which then slowly progresses to solid nodular lesions and finally to invasive carcinomas. Simultaneous thyroid-specific deletion of Akt1 and/or Akt2 demonstrates that both AKT1 and AKT2 are necessary to confer proliferative ability to Pten−/- thyrocytes in an additive manner. However, with age, (Pten,Akt1)thy-/− mice have a significantly higher incidence of thyroid lesions compared to (Pten,Akt2)thy-/− mice. In addition, deletion of Akt2 is more effective than that of Akt1 to extend survival and reduce lesion aggressiveness in Ptenthy-/−/KrasG12D mice. Transcriptomic and proteomic analyses have revealed that AKT2 loss rescues most of the expression and activation changes induced, in vivo, by Pten deletion, while AKT1 loss has more restricted effects. Futhermore we have identified and are characterizing subsets of genes that are differentially regulated by AKT isoforms. These data point to the existence of dramatically different molecular pathways associated with each AKT isoform in the thyroid, and represent a strong rationale for the development of less toxic, more effective treatments based on isoform-specific inhibitors. Citation Format: Michela Ranieri, Antonio Di Cristofano. Isoform-specific AKT functions in thyroid carcinoma development. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 188.
Case 15-1967
Authors: Richmond Prescott, Benjamin Castleman
Journal: New England Journal of Medicine (1967)

Presentation of CaseA seventy-three-year-old man was admitted to the hospital because of fever and unresponsiveness.He had been in good health until two years previously, when he began to feel unwell but with no specific complaints. Six months later he entered another hospital, where diabetes was discovered, and he was told that he had suffered a "series of small strokes." A diet was prescribed, and tolbutamide, 0.5 gm. daily, was instituted. Five months before entry he was admitted to another hospital because of pneumonia and was reported to have had a severe stroke and possibly a myocardial infarct. Digitalis . . .
REDUCTION IN INFARCT SIZE, MORBIDITY AND SHORT-TERM MORTALITY BY EARLY INTRAVENOUS BETABLOCKADE
Authors: S Yusuf, D Ramsdale, P Rossi, R Peto, M Pearson, H Sterry, L Furse, R Motwani, S Parish, R Gray, D Bennett, C Bray, P Sleight
Journal: Journal of the American College of Cardiology (1983)
P53 Determination of specific IgE antibodies to mouse proteins in laboratory animal workers: Abstract P53 Table 1
Authors: J Canizales, J Welch, B Fitzgerald, Z Lightfoot, W Banya, J Feary, P Cullinan, M Jones
Journal: Thorax (2015)

<h3>Introduction</h3> Laboratory animal workers are at increased risk of developing specific IgE antibodies to laboratory animal proteins. The major allergen for mouse is Mus m 1 which is predominantly found in the urine. Specific IgE to mouse is determined using either a commercial skin prick test solution of mouse epithelium or ImmunoCAP for either mouse urine or epithelium. Specific IgE to Mus m 1 is used for routine diagnostic testing. The aim of this study was to compare sensitisation using both ImmunoCAP and skin prick test as well as compare mouse urine and epithelium as allergens. At present there is no gold standard for sensitisation to mouse allergens. <h3>Methods</h3> Laboratory workers exposed to mice were recruited to the SPIRAL (Safe Practice in Reduction of Allergy in Laboratories) study. Sensitisation was determined by the presence of specific IgE to Mus m 1 and mouse epithelium using ImmunoCAP (Phadia) (positive result ≥0.35 kU/l) and by skin prick test to mouse epithelium (positive result is a saline adjusted mean wheal diameter of ≥3 mm). <h3>Results</h3> Of the participants (321), 11 (3%) were positive by skin prick test, 34(11%) with specific IgE to Mus m 1 and 35 (11%) with a positive specific IgE to mouse epithelium. There were 25/321(8%) participants with a discordant results between SPT and specific IgE to Mus m 1 (Table 1). There were 14 participants with a discordant result between specific IgE to Mus m 1 and mouse epithelium (Table 1). <h3>Discussion</h3> Laboratory animal workers may have specific IgE antibodies to either Mus m 1 or mouse epithelium. Diagnostic tests for mouse sensitisation may require testing to both Mus m 1 and mouse epithelium to ensure we do not miss any sensitised cases. Skin prick tests appear higher rates of false negative than anticipated and are therefore less reliable in clinical practice if used alone.
Phase II Study of Alemtuzumab (CAMPATH-1) in Patients with HTLV-1–Associated Adult T-cell Leukemia/lymphoma
Authors: Kamal Sharma, John E Janik, Deirdre O'Mahony, Donn Stewart, Stefania Pittaluga, Maryalice Stetler-Stevenson, Elaine S Jaffe, Mark Raffeld, Thomas A Fleisher, Cathryn C Lee, Seth M Steinberg, Thomas A Waldmann, John C Morris
Journal: Clinical Cancer Research (2016)

Therapeutic regimens for adult T-cell leukemia/lymphoma (ATL) are limited with unsatisfactory results, thereby warranting development of novel therapies. This study investigated antitumor activity and toxicity of alemtuzumab with regard to response, duration of response, progression-free survival, and overall survival in patients with human T-cell lymphotropic virus-1 (HTLV-1)-associated ATL.Twenty-nine patients with chronic, acute, and lymphomatous types of ATL were enrolled in a single-institution, nonrandomized, open-label phase II trial wherein patients received intravenous alemtuzumab 30 mg three times weekly for a maximum of 12 weeks.Twenty-nine patients were evaluable for response and toxicity. The overall objective response was 15 of 29 patients [95% confidence interval (CI), 32.5%-70.6%]. The 15 patients who responded manifested a median time to response of 1.1 months. Median response duration was 1.4 months for the whole group and 14.5 months among responders. Median progression-free survival was 2.0 months. Median overall survival was 5.9 months. The most common adverse events were 2 with vasovagal episodes (7%) and 3 with hypotensive episodes (10%), leukopenia (41%) grade 3 and (17%) grade 4, lymphocytopenia (59%) grade 3, neutropenia (31%) grade 3, anemia (24%), and thrombocytopenia (10%). All patients developed cytomegalovirus antigenemia (CMV). Three were symptomatic and all responded to antiviral therapy. Grade 3 or 4 infections were reported in 4 (14%) of patients.Alemtuzumab induced responses in patients with acute HTLV-1-associated ATL with acceptable toxicity, but with short duration of responses. These studies support inclusion of alemtuzumab in novel multidrug therapies for ATL. Clin Cancer Res; 23(1); 35-42. ©2016 AACR.
Dyspnea, Quality of Life and Walking Capacity during 1 Year Follow-up after a First Episode of Pulmonary Embolism: Results of the E.L.O.P.E. Study
Authors: Susan R Kahn, Andrew Hirsch, Margaret Beddaoui, Arash Akaberi, David Anderson, Philip S Wells, Marc Rodger, Susan Solymoss, Michael J. Kovacs, Lawrence Rudski, Avi Shimony, Carole Dennie, Chris Rush, William H. Geerts, Paul Hernandez, Shawn Aaron, John T Granton
Journal: Blood (2015)
A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection
Authors: Nicholas J. Barrows, Rafael K. Campos, Steven T. Powell, K. Reddisiva Prasanth, Geraldine Schott-Lerner, Ruben Soto-Acosta, Gaddiel Galarza-Muñoz, Erica L. McGrath, Rheanna Urrabaz-Garza, Junling Gao, Ping Wu, Ramkumar Menon, George Saade, Ildefonso Fernandez-Salas, Shannan L. Rossi, Nikos Vasilakis, Andrew Routh, Shelton S. Bradrick, Mariano A. Garcia-Blanco
Journal: Cell Host & Microbe (2016)
Brigatinib (BRG) in patients (pts) with crizotinib (CRZ)-refractory ALK+ non-small cell lung cancer (NSCLC): First report of efficacy and safety from a pivotal randomized phase (ph) 2 trial (ALTA).
Authors: Dong-Wan Kim, Marcello Tiseo, Myung-Ju Ahn, Karen L. Reckamp, Karin Holmskov Hansen, Sang-We Kim, Rudolf M. Huber, Howard Jack West, Harry J.M. Groen, Maximilian J. Hochmair, Natasha B. Leighl, Scott N. Gettinger, Corey J. Langer, Luis G. Paz-Ares, Egbert F. Smit, Edward S. Kim, William G Reichmann, David Kerstein, Frank G. Haluska, D. Ross Camidge
Journal: Journal of Clinical Oncology (2016)

9007 Background: We report the first results of a pivotal ph 2 trial of BRG in pts with ALK+ NSCLC. BRG, an investigational oral tyrosine kinase inhibitor (TKI) with preclinical activity against rearranged ALK and CRZ-resistant mutants, yielded promising clinical activity in CRZ-treated ALK+ NSCLC pts in a ph 1/2 study. As responses and AEs varied with starting BRG dose, two BRG regimens are being evaluated in this ongoing randomized study. Methods: Pts ≥18 y with advanced ALK+ NSCLC whose disease progressed on CRZ and who had received no other ALK TKI were eligible. Pts were stratified by presence of brain metastases at baseline and best response to prior CRZ and randomized 1:1 to receive oral BRG at 90 mg qd (arm A) or 90 mg qd for 7 d followed by 180 mg qd (arm B). Primary endpoint was investigator-assessed confirmed ORR per RECIST v1.1. Key secondary endpoints included PFS and IRC-assessed confirmed ORR and CNS response/PFS. Results: 222 pts were randomized (arm A/B, n=112/n=110; last pt enrolled 21 Sept 2015): median age was 51 y/57 y; 71%/67% had brain metastases. As of 7 Dec 2015, 63%/74% (A/B) were ongoing; median time on treatment was 25 wk/23 wk. Investigator-assessed ORR in A: 46% (95% CI 36–55%; 39 confirmed responses + 12 single responses awaiting confirmation), including 1 confirmed complete response (CR); ORR in B: 54% (95% CI 44–63%; 49 confirmed responses + 10 single responses awaiting confirmation), including 5 confirmed CRs. Median PFS in A/B: 8.8 mo/11.1 mo (events per arm [A/B]: 44/25). Most common grade ≥3 treatment-emergent AEs (A/B) included: increased CPK (3%/8%), hypertension (4%/5%), pneumonia (3%/5%), rash (1%/4%), increased lipase (3%/2%), and pneumonitis (2%/3%). Early-onset pulmonary events (within first 7 d) occurred in 6% of pts (3% grade ≥3); no such events occurred within 7 d of escalation to 180 mg in arm B. Discontinuations and dose reductions due to AEs (A/B) were 3%/6% and 7%/18%, respectively. Conclusions: In each arm, BRG yielded substantial responses and robust PFS, with an acceptable safety profile. A ph 3 study of BRG at 90 mg qd for 7 d followed by 180 mg qd vs CRZ in TKI-naive, advanced ALK+ NSCLC is planned. Clinical trial information: NCT02094573.
Characterization of tumor-infiltrating CD8+ T lymphocytes in malignant lymphoma
Authors: Mutsunori Murahashi, Taichi Matsumoto, Hiroshi Hamana, Hiroo Katsuya, Yosuke Ikari, Kenji Ishitsuka, Shujji Hara, Hiroyuki Kishi, Yasushi Takamatsu, Kazuo Tamura
Journal: Annals of Oncology (2015)
Abstract 4383: SOCRATES: integrating ex vivo and in silico analysis to identify optimal drug combinations for patients
Authors: Elizabeth A. Coker, Adam Stewart, Anna Minchom, Mary O’Brien, Timothy Yap, Paul Workman, Udai Banerji, Bissan Al-Lazikani
Journal: Cancer Research (2016)

Abstract Recent work on cancer heterogeneity and evolution has greatly enhanced our understanding of drivers of drug resistance, but this has also highlighted the need to move away from generic, “one-size-fits-all” treatment regimes. It is clear that we should tailor therapy to individual patients at different stages of disease based on the current behaviour of their tumour cells, yet detailed experimental characterisation and analysis of patient tissue is impractical and costly. Predictive computational models that can produce patient-specific recommendations of drug combinations would therefore be of great value to the field of personalised medicine. In silico modelling has already been used to successfully predict synergistic drug combinations in single cell lines in the lab, but such approaches have not yet been translated to dynamic, real patient data in the clinic. The SOCRATES project (Signalling output to rationalise combinations of targeted anticancer therapies) integrates experimental data and computational analysis to predict context-specific synergistic drug combinations. Here we present ambitious computational modelling of dynamic signalling network changes in response to ex vivo exposure of seven targeted drugs used singly at clinically appropriate concentrations. We also apply our adaptive modelling to genomics and proteomics data from 54 proteins in over 30 non small-cell lung cancer cell lines and ten patient samples to predict and experimentally validate personalised, context specific drug combinations. We will describe our adaptive, in silico modelling for predicting response to drug combinations, including novel methods utilizing network topology. We have predicted over 50 synergistic drug combinations and will present our predictions alongside initial results of experimental validation in the lab. We will also illustrate the differences observed in various cell lines and patient derived cells depending on genetic context. SOCRATES is, to our knowledge, the first project of its kind and is a prototype for the future of adaptive, individualised cancer treatment. Citation Format: Elizabeth A. Coker, Adam Stewart, Anna Minchom, Mary O’Brien, Timothy Yap, Paul Workman, Udai Banerji, Bissan Al-Lazikani. SOCRATES: integrating ex vivo and in silico analysis to identify optimal drug combinations for patients. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4383.