tbuckley/cabot-search huggingface dataset:
Reintervention for stent occlusion after endoscopic ultrasound-guided hepaticogastrostomy with novel use of a precut needle-knife
Authors: Kosuke Minaga, Mamoru Takenaka, Ayana Okamoto, Shunsuke Omoto, Takeshi Miyata, Hajime Imai, Masatoshi Kudo
Journal: Endoscopy (2018)

Endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS) has gained popularity as an alternative biliary drainage method [1] [2]; however, reintervention after EUS-HGS remains to be elucidated. In EUS-HGS, use of a biliary stent that is longer than 100 mm is recommended in order to prevent stent migration [2] [3]. However, such stent placement occasionally makes reintervention challenging owing to the long length of the stent in the gastric lumen. A few reports have described technical efforts involved in reintervention after EUS-HGS [4] [5]. We describe a patient who underwent successful reintervention via a novel use of a precut needle-knife.
139PD Patient-reported outcomes from FLAURA: Osimertinib versus standard of care (SoC) epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC)
Authors: N. Leighl, N. Karaseva, K. Nakagawa, B.-C. Cho, J.E. Gray, T. Hovey, A. Walding, A. Rydén, S. Novello
Journal: Journal of Thoracic Oncology (2018)
A smartphone application supporting patients with psoriasis improves adherence to topical treatment: a randomized controlled trial
Authors: M.T. Svendsen, F. Andersen, K.H. Andersen, A. Pottegård, H. Johannessen, S. Möller, B. August, S.R. Feldman, K.E. Andersen
Journal: British Journal of Dermatology (2018)

Adherence to topical psoriasis treatments is low, which leads to unsatisfactory treatment results. Smartphone applications (apps) for patient support exist but their potential to improve adherence has not been systematically evaluated.To evaluate whether a study-specific app improves adherence and reduces psoriasis symptoms compared with standard treatment.We conducted a randomized controlled trial (RCT, clinicaltrials.gov registration: NCT02858713). Patients received once-daily medication [calcipotriol/betamethasone dipropionate (Cal/BD) cutaneous foam] and were randomized to no app (n = 66) or app intervention (n = 68) groups. In total, 122 patients (91%) completed the 22-week follow-up. The primary outcome was adherence, which was defined as medication applied ≥ 80% of days during the treatment period and assessed by a chip integrated into the medication dispenser. Secondary outcomes were psoriasis severity measured by the Lattice System Physician's Global Assessment (LS-PGA) and quality of life, measured using the Dermatology Life Quality Index (DLQI) at all visits.Intention-to-treat analyses using regression was performed. More patients in the intervention group were adherent to Cal/BD cutaneous foam than those in the nonintervention group at week 4 (65% vs. 38%, P = 0·004). The intervention group showed a greater LS-PGA reduction than the nonintervention group at week 4 (mean 1·86 vs. 1·46, P = 0·047). A similar effect was seen at weeks 8 and 26, although it did not reach statistical significance.This RCT demonstrates that the app improved short-term adherence to Cal/BD cutaneous foam treatment and psoriasis severity.
Final report of a pilot trial combining ipilimumab and adoptive cell therapy.
Authors: John Mullinax, Jeffrey S. Weber, Nikhil I. Khushalani, Zeynep Eroglu, Andrew Scott Brohl, Joseph Markowitz, Erica Royster, Allison Richards, Jonathan S. Zager, Vernon K. Sondak, James J Mule', Shari Pilon-Thomas, Amod Sarnaik
Journal: Journal of Clinical Oncology (2017)

147 Background: We previously confirmed the feasibility of adoptive cell therapy (ACT) with tumor infiltrating lymphocytes (TIL) for patients with advanced melanoma. Patients successfully treated had a 38% response rate, but patient attrition due to progression before ACT (21%) resulted in a response rate of only 26% based on intent to treat (IIT) analysis. We hypothesized that combination immunotherapy would decrease attrition due to progression. Here we present the final report of a pilot trial combining ipilimumab (IPI) and ACT. Methods: Thirteen patients with metastatic melanoma were accrued to an IRB-approved trial. All had &gt;1 cm 3 of soft tissue/nodal metastases amenable to resection leaving residual disease. Patients received 3 mg/kg of IPI two weeks prior to tumor resection for TIL generation. One week following resection, a second dose of IPI was administered. ACT included pre-conditioning chemotherapy and TIL infusion followed by IL-2. Two additional doses of IPI were given 2 and 5 weeks after ACT. Feasibility was a primary endpoint and considered achieved if ≥ 2 doses of IPI and TIL were infused to at least 60% of all patients. The clinical responses were assessed by RECIST 1.1 criteria at 12 weeks following TIL transfer. Results: All patients received at least 2 doses of IPI, and 12 of the 13 patients (92%) received TIL. One patient (7%) dropped out due to progression before TIL infusion. TIL were expanded from 47.2% of tumor fragments and 58.7% of these fragments generated TIL reactive to autologous tumor. Median number of infused TIL was 6.5e10 (2.29e10-1.04e11) and median 85% were CD8+ (27-99). At 12 weeks following infusion, of the 13 patients enrolled, there were 6 responders (46%). Median progression-free survival was 7.4 months (1.4-42.2). Grade ≥3 immune-related adverse events included colitis (1), uveitis (1), and hypothyroidism (1). Conclusions: IPI combined with ACT with TILs for patients with advanced melanoma is feasible with decreased attrition due to progression and is associated with promising clinical results based upon ITT analysis. This combination approach of TIL cell therapy and co-inhibitory blockade serves as a model for future efforts to improve the efficacy of immunotherapy for patients with cancer. Clinical trial information: NCT01701674.
Appetite, Glycemia, and Entero-Insular Hormone Responses Differ Between Oral, Gastric-Remnant, and Duodenal Administration of a Mixed-Meal Test After Roux-en-Y Gastric Bypass
Authors: Daniel Gero, Robert E. Steinert, Hanna Hosa, David E. Cummings, Marco Bueter
Journal: Diabetes Care (2018)

OBJECTIVE To examine the effect of different feeding routes on appetite and metabolic responses after Roux-en-Y gastric bypass (RYGB). RESEARCH DESIGN AND METHODS A standard liquid meal was administered either orally, into the gastric remnant, or intraduodenally 6 months after RYGB. Changes in plasma glucose, insulin, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), peptide YY (PYY), and appetite were measured pre- and postprandially. RESULTS Postprandial GLP-1 and PYY responses were similar, whereas glucose, insulin, and GIP levels differed markedly after oral versus intraduodenal feeding. Intraduodenal feeding prompted an intermediate appetite response (i.e., between oral and intragastric). For postprandial glucose, insulin, and GIP levels, the intraduodenal route was more similar to the intragastric than the oral route. Intragastric administration did not evoke changes in appetite, glucose, or insulin; however, it slightly increased GLP-1 and PYY and moderately increased GIP. CONCLUSIONS Appetite and metabolic responses after RYGB depend on the route by which nutrients enter the gastrointestinal tract.
Correlation between dysthyroidism and efficacy in patients treated with anti PD-1 or anti PDL-1 agents.
Authors: Diego Signorelli, Maria Silvia Cona, Milena Vitali, Giuseppe Lo Russo, Claudia Proto, Martina Imbimbo, Nicoletta Zilembo, Marco Platania, Michele Del Vecchio, Ettore Seregni, Marina C Garassino, Massimo A. Di Nicola, Filippo G. De Braud
Journal: Journal of Clinical Oncology (2017)

67 Background: Immune checkpoints inhibitors have clearly improved patients’outcomes in different tumors, but definitive predictive biomarkers are still missing. Since thyroiditis have been reported, we have evaluated whether clinical responses are more frequent in patients who underwent anti PD-1 or anti PDL-1 agents and experienced dysthyroidism. Methods: We retrospectively evaluated 135 metastatic solid tumor patients, treated at our Institute with anti PD-1/PDL-1 antibodies since 2013. Thyroid toxicity was defined according to CTCAE version 4.0 and disease control (DC: CR+PR+SD) was chosen as efficacy endpoint. Correlation between dysthyroidism and DC rate was assessed by Fisher’s exact test. Results: Of 135 patients, 76 (56.3%) were treated by anti PD-1 and 59 (43.7%) by anti PDL-1 agents. Population was heterogeneous, including patients from the 1 st to the 9 th line of therapy, affected by the following cancers: 57 (42.2%) NSCLC, 18 (13.3%) melanoma, 13 (9.6%) RCC, 7 (5.2%) bladder and urothelial, 6 (4.5%) mesothelioma, 5 (3.7%) SCLC, 5 (3.7%) sarcoma, 5 (3.7%) biliary tract, 5 (3.7%) head and neck, 3 (2.2%) gastric, 3 (2.2%) colon, 2 (1.5%) Merkel cells and one each for thyroid, HCC, ovary, cervix, anal carcinoma and germ cells tumor. Median follow up was 8.6 months. Best responses were: 5 CR, 30 PR, 51 SD and 49 PD; 86 (63.7%) patients achieved DC. Overall, 38 patients developed dysthyroidism (subclinical, G1, G2 hypo/hyperthyroidism): 18/76 (23.7%) in anti PD-1, 20/59 (33.9%) in anti PDL-1 group; 31/38 (81.6%) of them achieved DC. The median time of dysthyroidism appearance was the 6 th cycle of therapy (range 1 st -22 th ). Of 97 patients who did not develop thyroid toxicity, 55 (56.7%) achieved DC. Dysthyroidism significantly correlated with DC rate (p=0.009). Conclusions: We found a significant correlation between dysthyroidism and clinical responses in solid tumor metastatic patients treated by anti PD-1 or anti PDL-1 antibodies. Our observation suggests that evaluation of thyroid function should be regularly performed during therapy with these agents. These retrospective findings must be confirmed in a prospective trial powered to see whether thyroid dysfunction is a surrogate marker of response.
Tumor uptake of pegylated diabodies: Balancing systemic clearance and vascular transport
Authors: Qing Li, Jason B. White, Norman C. Peterson, Keith W. Rickert, Christopher O. Lloyd, Kevin L. Allen, Kim Rosenthal, Xizhe Gao, Herren Wu, William F. Dall'Acqua, M. Jack Borrok, Ping Tsui
Journal: Journal of Controlled Release (2018)
ACE: A Workbench Using Evolutionary Genetic Algorithms for Analyzing Association in TCGA
Authors: Alan R. Gilmore, Matthew Alderdice, Kienan I. Savage, Paul G. O'Reilly, Aideen C. Roddy, Philip D. Dunne, Mark Lawler, Simon S. McDade, David J. Waugh, Darragh G. McArt
Journal: Cancer Research (2019)

Abstract Modern methods of acquiring molecular data have improved rapidly in recent years, making it easier for researchers to collect large volumes of information. However, this has increased the challenge of recognizing interesting patterns within the data. Atlas Correlation Explorer (ACE) is a user-friendly workbench for seeking associations between attributes in The Cancer Genome Atlas (TCGA) database. It allows any combination of clinical and genomic data streams to be searched using an evolutionary algorithm approach. To showcase ACE, we assessed which RNA sequencing transcripts were associated with estrogen receptor (ESR1) in the TCGA breast cancer cohort. The analysis revealed already well-established associations with XBP1 and FOXA1, but also identified a strong association with CT62, a potential immunotherapeutic target with few previous associations with breast cancer. In conclusion, ACE can produce results for very large searches in a short time and will serve as an increasingly useful tool for biomarker discovery in the big data era. Significance: ACE uses an evolutionary algorithm approach to perform large searches for associations between any combinations of data in the TCGA database.
Activity of CBT-501, a novel humanized anti-PD-1 antibody, in a humanized genetically engineered mouse model of colon carcinoma.
Authors: Qing Zhou, Weihong Nian, Ziyong Sun, Junzhuan Qiu, Zhun Wang, Gavin Choy, Sanjeev Redkar
Journal: Journal of Clinical Oncology (2017)

108 Background: CBT-501 (Genolimzumab, GB-226) is a novel humanized mAb (IgG4k) against human Programmed Death-1 (PD-1). CBT-501 demonstrated highly specific binding to PD-1 of human (K D = 505 pM) and cynomolgus (K D = 7.2 nM). It did not completely block the binding of nivolumab or pembrolizumab, suggesting a novel epitope. CBT-501 efficiently inhibited the binding of PD-L1/L2 to PD-1 through a competitive action for both human and monkey. It enhanced human T-cell activation in the Mix Lymphocyte Reaction (MLR), as shown by increased release of IL-2 and INF-γ. The Fc-fragment bound to FcRn dose-dependently without any effector function. The PK/PD studies in cynomolgus showed a linear dose exposure, with a T 1/2 of 115-142 h for single and repeat dosing. The PD-1 receptor occupancy after a single dose was dose-dependent reaching 100% at peak, maintained after multiple dosing and continued for 6 wk after last dose. Single and repeat dose toxicology studies in cynomolgus showed weight gain of the thyroid and mild expansion of the thyroid follicles at the highest dose of 100 mg/kg which were reversible. No abnormal drug-related toxicity was found. In rhesus vaccinated with adenovirus-mediated Simian Immunodeficiency Virus, biweekly IV CBT-501 promoted the antigen-specific T-cell response, as shown by ELISPOT and intracellular staining of IL-2, INF-γ and TNF-α in PBMC and T-cell subpopulation. Due to lack of immunoselectivity to mouse PD-1, investigation of the in vivo anti-tumor activity in rodent model is challenging. Methods: Crown Bioscience has developed humanized genetically engineered mouse model expressing human PD-1 extracellular domain with a fully functional murine immune system. Subcutaneous colon adenocarcinoma MC38 syngeneic tumor draft was established in mice. Results: CBT-501 injected IP q2w×3wk demonstrated significant anti-tumor activity. The tumor growth reduction was dose dependent with comparable or improved activity over nivolumab, and with the highest inhibition rate at 83%. Conclusions: Based on the strong nonclinical data and differentiation, and an acceptable safety profile, a first in human Phase 1 trial is planned in the Asia-Pacific region.
Long-term risk of dementia among people with traumatic brain injury in Denmark: a population-based observational cohort study
Authors: Jesse R Fann, Anette Riisgaard Ribe, Henrik Schou Pedersen, Morten Fenger-Grøn, Jakob Christensen, Michael Eriksen Benros, Mogens Vestergaard
Journal: The Lancet Psychiatry (2018)
141PD A prospective study of molecular testing status in the EGFR mutation positive NSCLC patients with disease progression during EGFR TKI treatment (REMEDY study)
Authors: K. Kanai, N. Yamamoto, N. Nogami, S. Atagi, H. Saka, N. Tashiro, T. Seto
Journal: Journal of Thoracic Oncology (2018)
Abstract 12116: Exercise Parameters and Risk of Coronary Heart Disease and Mortality Among Obstructive Lung Disease Patients: The Henry Ford Exercise Testing Project [FIT]
Authors: Tolulope Adesiyun, Di Zhao, Sai Korada, Michael J Blaha, Clinton A Brawner, Steven J Keteyian, Mouaz H Al-Mallah, Erin D Michos
Journal: Circulation (2015)

Background: In the general population, the exercise treadmill testing (ETT) variables of lower resting heart rate (HR) and higher peak HR, maximal age predicted HR (MPHR), and exercise capacity (METS) have favorable prognosis for mortality. Patients with obstructive lung disease have increased mortality risk. Furthermore, some pulmonary medications (i.e. beta agonists) can influence HR. We determined whether ETT parameters carry the same prognostic value in patients with lung disease on treatment compared to those without lung disease. Methods: We analyzed data on 69,855 patients (mean age 55 yrs) who completed a clinically indicated ETT. Patients were defined as “lung disease” if taking medications routinely used to treat obstructive lung disease (n=6145, 8.8%). ICD9 codes regarding type of lung disease were not available. Cox hazard models were used to determine risk of all-cause mortality, major adverse cardiac events (MACE) and myocardial infarction (MI) over a mean of 11 yrs follow-up. Results: Higher resting HR was associated with increased risk of all-cause mortality, while peak HR, achieving ≥85% MPHR, and higher METS were associated with decreased risk ( Table ). No significant interaction for lung disease status was seen for the HR variables, but slightly stronger protective effect for higher METS among lung patients (p-interaction 0.032). Similar results between lung and non-lung disease patients were observed for MACE and MI. Among lung patients stratified by the presence/absence of coronary artery disease (CAD), the prognostic significance for peak HR, MPHR, and METS was stronger among those without CAD (p-interaction &lt;0.05). Conclusion: HR-related parameters achieved on ETT are equally prognostic among patients with and without lung disease. Higher fitness (METS) was associated with improved clinical outcomes in both groups. However, the relative benefit of fitness on survival was even greater in patients with (versus without) lung disease.
214O Multiplexed proteomics biomarkers for malignant pleural mesothelioma detection in blood
Authors: F. Cerciello, M. Choi, S.L. Sinicropi-Yao, E. Felley-Bosco, R.A. Stahel, B. Robinson, J. Creaney, H.I. Pass, O. Vitek, D.P. Carbone
Journal: Journal of Thoracic Oncology (2018)
Monomeric TCRs drive T cell antigen recognition
Authors: Mario Brameshuber, Florian Kellner, Benedikt K. Rossboth, Haisen Ta, Kevin Alge, Eva Sevcsik, Janett Göhring, Markus Axmann, Florian Baumgart, Nicholas R. J. Gascoigne, Simon J. Davis, Hannes Stockinger, Gerhard J. Schütz, Johannes B. Huppa
Journal: Nature Immunology (2018)
Resolved versus confirmed ARDS after 24 h: insights from the LUNG SAFE study
Authors: Fabiana Madotto, Tài Pham, Giacomo Bellani, Lieuwe D. Bos, Fabienne D. Simonis, Eddy Fan, Antonio Artigas, Laurent Brochard, Marcus J. Schultz, John G. Laffey
Journal: Intensive Care Medicine (2018)
Chimeric antigen receptor (CAR) T cells genetically engineered to deliver IL-12 to the tumor microenvironment in ovarian cancer.
Authors: Oladapo O. Yeku, Terence Purdon, David R. Spriggs, Renier J. Brentjens
Journal: Journal of Clinical Oncology (2017)

141 Background: Chimeric antigen receptor (CAR) T cell therapy for solid tumor malignancies has not shown the same degree of clinical efficacy observed in hematologic malignancies such as B-ALL. The presence of an immunosuppressive cellular and cytokine microenvironment has been hypothesized as one reason for the failure of adoptive immunotherapy for solid tumors. In ovarian cancer, myeloid derived suppressor cells (MDSC) and immunosuppressive cytokines in the ascitic microenvironment have been reported. IL-12 is a proinflammatory cytokine produced by macrophages, dendritic cells (DC), and NK cells, and it has been shown to increase proliferation of T cells, induce differentiation of type 1 T helper cells, inhibit regulatory T cells, promote maturation of DCs, and enhance antigen presentation by macrophages. We hypothesize that CAR T cells genetically modified to constitutively secrete IL-12 will overcome a hostile tumor microenvironment in a peritoneal carcinomatosis model of ovarian cancer. Methods: CAR T cells were generated from retroviral transduction of second generation and IL-12 modified CAR’s directed to either an irrelevant CD-19 antigen or Muc16 ecto . C57BL/6 mice were inoculated i.p with syngeneic ovarian cancer cells and treated with various CAR T cells. Results: Here we report increased production of IL-12, improved proliferation and cytotoxic activity of 4H1128ζ-IL12 CAR T cells. Further, we show increased levels of inflammatory cytokines at 24 and 48hrs after treatment of tumor-bearing mice, leading to increased survival at advanced stages of disease. Animals treated with 4H1128ζ-IL12 CAR T cells had decreased levels of F4/80 + CD11b + MDSCs. Genetic analysis of recovered MDSCs from the ascites of treated animals showed skewing towards an M1-phenotype via upregulation of cytokines, chemokines, MHC-II, and downregulation of Arg1. Furthermore, clodronate-mediated depletion of TAM’s further enhanced survival in mice treated with 4H1128ζ-IL12 CAR T cells. Conclusions: These results demonstrate the mechanisms of efficacy of localized delivery of IL-12 to the tumor microenvironment by 4H1128ζ-IL12 CAR T cells.
Fracking and Climate Change
Authors: Howard Frumkin, Jonathan Patz
Journal: JAMA (2018)

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Ion-Dan Edeleanu
Authors: Hugh Edeleanu, Louise Edeleanu
Journal: BMJ (2018)

Ion-Dan Edeleanu was born to Ion and Marie Edeleanu in Bucharest, Romania, on 14 June 1925. He came to the UK in 1937 and attended Morrison’s Academy in Crieff, followed by the Bedford School. He graduated from Christ’s College, Cambridge, in 1946 and studied medicine at the London Hospital. After qualifying in 1950 he joined the British …
Targeting the TNFR2 oncogene on tumor cells and tregs of the tumor microenvironment via dominant TNFR2 antagonism.
Authors: Denise L. Faustman, Heather Torrey, John Butterworth, Toshi Mera, Yoshiaki Okubo, Limei Wang, Danielle Baum, Sara Warden, Sarah Plager, Daniel Huang, Eva Vanamee, Rosemary Foster
Journal: Journal of Clinical Oncology (2017)

106 Background: A major barrier to cancer immunotherapy is lack of selective inhibitors of the regulatory T cells (Tregs) of the cancer microenvironment and methods to directly kill tumors through novel surface oncogenes. Tumor necrosis factor receptor 2 (TNFR2) is a target protein with restricted expression on the most potent Tregs of the tumor infiltrate and newly identified as a broadly expressed oncogene on human tumors. Methods: We characterized the effect of TNFR2 antibody antagonists via TNFR2 in human samples from ovarian ascites compared to healthy controls. Results: TNFR2 antagonists potently inhibited Treg proliferation with exponential potency and selectivity for tumor microenvironment Tregs. Furthermore, common ovarian cancer cell lines such as OVCAR3 expressed the TNFR2 oncogene and were rapidly and completely killed by TNFR2 antagonistic antibodies. TNFR2 antagonistic antibodies were dominant because they succeeded even in the presence of TNF agonism. Remarkably, these antibodies worked as well in killing Treg cells as F(ab’)2 fragments, but not as well as Fc fragments. TNFF2 antagonists were not dependent on ADCC mechanisms for activity. Conclusions: Dominant TNFR2 antagonistic antibodies demonstrate tumor-specific Treg depletion. Blocking TNFR2 signaling with antagonist antibodies also creates a novel tool to possibly eliminate tumors expressing the TNFR2 oncogene and to more potently suppress Tregs of the tumor microenvironment.