tbuckley/cabot-search huggingface dataset:
Abstract SY31-03: The future of combinations of immunomodulators with local radiation: toward a personalized immunotherapy approach
Authors: Sandra Demaria
Journal: Cancer Research (2016)

Abstract We have shown in multiple preclinical tumor models that ionizing radiation therapy can convert tumors refractory to immune checkpoint inhibitors and other immune modulators into responsive ones. Importantly, the elicited antitumor T cells rejected not only the irradiated tumor but also nonirradiated spontaneous metastases or synchronous palpable tumors (abscopal effect), demonstrating the potential of radiation to generate systemically effective antitumor immune responses. Investigations into the mechanisms underlying a successful response have highlighted a complex interaction between radiation and anti-CTLA-4 occurring at the priming and effector phase of the antitumor immune response. These data support a model whereby the irradiated tumor becomes a “live attenuated vaccine” resulting in marked expansion of a limited number of distinct T-cell clones within the tumor. Our data also suggest that generation of an in situ tumor vaccine by radiation is regulated by the intrinsic tumor immunogenicity, the host immune system, and the radiation regimen employed. The interaction of these three compartments determines the levels of immune modulating mediators in the tumor microenvironment, including interferon type I, transforming growth factor-b, and adenosine, which in turn control the number and state of activation of intratumoral dendritic cells, and the magnitude of the induced T-cell response. Thus, while radiation offers the promise of a simple treatment to achieve individualized vaccination against each patient's own tumor, success is likely to be achieved by a personalized combination of the most effective radiation regimen and immune modulator(s). We have recently shown in non-small cell lung cancer patients with chemotherapy-refractory metastatic disease that the synergy of radiotherapy and anti-CTLA-4 can be translated in the clinic (NCT02221739). Analysis of tumor and peripheral blood from responding and non-responding patients are beginning to provide clues to potential biomarkers and underlying mechanisms of response. Overall, local radiotherapy is showing the potential to be an ideal partner for immunotherapy. Because of its universal use in cancer treatment it is tempting to test standard of care radiotherapy in combination with any immunotherapy. However, rational use of radiation regimens and targeting of specific immune suppressive factors preexisting or elicited by radiation in a given tumor will be needed to truly reveal radiation's role in personalized immunotherapy. Citation Format: Sandra Demaria. The future of combinations of immunomodulators with local radiation: toward a personalized immunotherapy approach. [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 SY31-03.
Abstract 4224: Multiplexing single cell time lapse imaging of intra-cellular oxygen in cancer cells
Authors: Heiko Düssmann, Sergio Perez, Ujval Anil Kumar, Dmitri B. Papkovsky, Jochen HM Prehn
Journal: Cancer Research (2016)

Abstract Oxygen plays an important role in aerobic energy metabolism and signal transduction. The detection of intracellular or subcellular molecular oxygen (O2) levels is important for the understanding of cell physiology and mitochondrial energy metabolism, and the alterations correlated with cancer. Detection of O2 has recently been improved significantly with the development of live cell time lapse microscopy compatible oxygen sensitive probes. We here utilized nanoparticle probe MitoImageTM-MM2 with embedded poly(9,9-dioctylfluorene) (PFO) as an O2-independent component and Pt(II)-5,10,15,20-tetrakis-(2,3,4,5,6-pentafluorophenyl)-porphyrin (PtTFPP) to perform time lapse ratiometric measurements of intra-cellular oxygen levels. Loading of HeLa cervical cancer cells with MM2 enables us to image kinetics of intracellular O2 concentration in response to the mitochondrial respiratory chain inhibitors Antimycin A (complex III) or sodium azide (complex IV). These changes were detected in respiration-supporting medium equilibrated with 5% (53 μM) and 20% (225 μM)O2. Also exposing cells to varying extracellular oxygen concentrations (21 - 225 μM) showed strong dependence of the intracellular oxygen levels. The mitochondrial membrane potential was monitored by simultaneous imaging of Tetra-Methyl-Rhodamine-Methyl ester (TMRM) in the same sample. Multiplexing with GFP finally allowed us to monitor intracellular O2 during the apoptotic signaling process of mitochondrial outer membrane permeabilisation (MOMP) in HeLa expressing cytochrome-c-eGFP and stained with TMRM. In conclusion, the MitoImageTM-MM2 nanoparticle probe enables single-cell, time-lapse imaging of alterations in intracellular oxygen levels in cancer cells, and can be employed in multiplex assays to investigate alterations in intracellular oxygen levels relative to protein dynamics and mitochondrial function. Keywords: Intracellular oxygen; phosphorescent oxygen-sensitive nanoparticles; HeLa cells; MitoImage ratiometric probes; confocal microscopy. Citation Format: Heiko Düssmann, Sergio Perez, Ujval Anil Kumar, Dmitri B. Papkovsky, Jochen HM Prehn. Multiplexing single cell time lapse imaging of intra-cellular oxygen in cancer cells. [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 4224.
Abstract 299: Patient-derived tumor microenvironment models uncover non-autonomous TKI resistance mechanisms in NSCLC
Authors: Haichuan Hu, Matthew Niederst, Jeffrey Engelman
Journal: Cancer Research (2016)

Abstract Background: Tyrosine kinase inhibitors (TKI) have yielded great responses in non-small-cell lung cancer (NSCLC) with EGFR mutations and ALK translocations, however these and other targeted therapies are limited by intrinsic and acquired drug resistance. Previous studies looking into relapsed samples largely expanded our understanding of tumor autonomous resistance mechanisms. In this study, we aimed to decipher the non-autonomous mechanisms in vitro by recapitulating the in vivo tumor microenvironment from patient-derived models. Method: Cancer-associated fibroblast cells are isolated directly from EGFR mutant and ALK translocated NSCLC biopsies. Over 20 patient-derived fibroblast (PDF) models have been established for studying the tumor microenvironment's effect on TKI response. Result: We found that many, but not all, PDF cells exert significant resistance to TKIs. Furthermore, there is considerable variability in the degree and secreted factor / mechanism by which they are protecting the tumor cells. These variations are further correlated with patient in vivo response. Conclusion: Together, our results indicate that PDFs are clinically relevant models for deciphering non-autonomous resistance mechanisms, that they are heterogeneous in protecting cancer cells from TKI treatment, and that the resistance mediated by PDFs can be overcome by specific therapeutic combinations. Citation Format: Haichuan Hu, Matthew Niederst, Jeffrey Engelman. Patient-derived tumor microenvironment models uncover non-autonomous TKI resistance mechanisms in NSCLC. [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 299.
The Search for Better Patient Handoff Tools
Authors: Adam J. Schoenfeld, Robert M. Wachter
Journal: JAMA Internal Medicine (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Internal Medicine HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Internal Medicine journal
Comment on Schwartz et al. The Time Is Right for a New Classification System for Diabetes: Rationale and Implications of the β-Cell–Centric Classification Schema. Diabetes Care 2016;39:179–186
Authors: Sanjay Kalra, Manash P. Baruah
Journal: Diabetes Care (2016)

We appreciate the efforts by Schwartz et al. (1) to synthesize current scientific knowledge in a simple and lucid manner and hope that the following suggestions will help improve the utility of their proposed β-cell–centric classification.

It is less important to “classify” diabetes than it is to ensure appropriate treatment for the person with diabetes. This can be planned using a bipolar construct of the insulin-to-glucagon ratio (IGR) rather than a unipolar β-cell–centric model. A high IGR indicates insulin resistance and metabolic syndrome in a setting that can …
Association of Random Plasma Glucose Levels With the Risk for Cardiovascular Disease Among Chinese Adults Without Known Diabetes
Authors: Fiona Bragg, Liming Li, Derrick Bennett, Yu Guo, Sarah Lewington, Zheng Bian, Ling Yang, Junshi Chen, Yiping Chen, Rory Collins, Richard Peto, Baoyu Zhu, Jiyuan Yin, Ximin Hu, Liyuan Zhou, Yaxing Pan, Zhengming Chen
Journal: JAMA Cardiology (2016)

Diabetes is a known risk factor for cardiovascular disease (CVD). Substantial uncertainty remains, however, about the relevance to CVD risk for blood glucose levels below the diabetes threshold.To examine the association of random plasma glucose (RPG) levels with the risk for major CVD in Chinese adults without known diabetes.This prospective cohort study included 467 508 men and women aged 30 to 79 years with no history of diabetes, ischemic heart disease (IHD), stroke, or transient ischemic attack. Participants were recruited from 5 urban and 5 rural diverse locations across China from June 25, 2004, to July 15, 2008, and followed up to January 1, 2014.Baseline and usual (longer-term average) RPG level.Cardiovascular deaths, major coronary events (MCE) (including fatal IHD and nonfatal myocardial infarction), ischemic stroke (IS), major occlusive vascular disease (MOVD) (including MCE or IS), and intracerebral hemorrhage. Preliminary validation of stroke and IHD events demonstrated positive predictive values of approximately 90% and 85%, respectively. Cox regression yielded adjusted hazard ratios (aHRs) for CVD associated with RPG levels.Among the 467 508 participants (41.0% men; 59.0% women; mean [SD] age, 51 [11] years), a significant positive association of baseline RPG levels with CVD risks continued to 4.0 mmol/L (72 mg/dL). After adjusting for regression dilution bias, each 1-mmol/L (18-mg/dL) higher usual RPG level above 5.9 mmol/L (106 mg/dL) was associated with an 11% higher risk for cardiovascular death (6645 deaths; aHR, 1.11; 95% CI, 1.10-1.13). Similarly strong positive associations were seen for MCE (3270 events; aHR, 1.10; 95% CI, 1.08-1.13), IS (19 153 events; aHR, 1.08; 95% CI, 1.07-1.09), and MOVD (22 023 events; aHR, 1.08; 95% CI, 1.07-1.09). For intracerebral hemorrhage, the association was weaker, but also significant (4326 events; aHR, 1.05; 95% CI, 1.02-1.07). These associations persisted after excluding participants who developed diabetes during follow-up.Among adult Chinese without diabetes, lower RPG levels are associated with lower risks for major CVDs, even within a normal range of blood glucose levels.
Re: Christopher J.D. Wallis, Refik Saskin, Richard Choo, et al. Surgery Versus Radiotherapy for Clinically-localized Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol 2016;70:21–30
Authors: Ann A. Lazar, Tania L. Ceron Lizarraga, Mack Roach
Journal: European Urology (2016)
HYPERCOAGULABILITY PROMOTES ATRIAL FIBROSIS AND FIBRILLATION
Authors: Henri M. H. Spronk, Anne-Margreet de Jong, Hetty de Boer, Alexander Maass, Sander Verheule, Dennis Lau, Michiel Rienstra, Pieter Willem Kamphuisen, Hugo ten Cate, Harry Crijns, Isabelle van Gelder, Anton Jan van Zonneveld, Ulrich Schotten
Journal: American Journal of Hematology (2014)
P73 Impact of EBUS-TBNA on Modalities For Tissue Acquisition in Patients with Lung Cancer: A Study of 407 Patients: Abstract 73 Table 1
Authors: RJ José, M Taylor, A Ahmed, P Shaw, J Brown, G Hardavella, DR Lawrence, PJ George, SM Janes, N Navani
Journal: Thorax (2012)

<h3>Introduction</h3> NICE guidance for the diagnosis and treatment of lung cancer recommends choosing “investigations that give the most information about diagnosis and staging with the least risk to the patient”.<sup>[1]</sup> EBUS-TBNA is expanding as an important diagnostic modality in lung cancer and provides simultaneous information on lung cancer phenotype, genotype and nodal staging. The impact of the introduction of EBUS-TBNA on the use of diagnostic modalities for tissue acquisition in patients with lung cancer is unknown. <h3>Methods</h3> A retrospective review of 407 consecutive patients diagnosed with lung cancer at a university teaching hospital in 2007, 2009 and 2011. Data were collected on age, gender, FEV1, performance status, diagnostic modality, and pathological subtype. Patients where only a clinical diagnosis was made (n=21) were excluded. Data were analysed using the SPSS version 17 (Chicago, IL, USA). For comparison between categorical variables, Chi-square or Fisher’s exact test were used as appropriate. All reported <i>p</i>-values are two-tailed, and are considered statistically significant when <i>p</i>&lt;0.05. <h3>Results</h3> 386 patients were included in the analysis. The mean (SD) age (years) and FEV1 (L/min) were 69 (12) and 1.81 (0.80) for 2007, 67 (10) and 1.81 (0.79) for 2009 and 68 (12) and 2.07 (0.68) for 2011 respectively. In 2007, 2009 and 2011 57.9%, 51.4% and 62.7% were males. The results on diagnostic modalities, performance status, histological subtype and staging are listed in Table 1. Comparing 2007 to 2011 there has been a significant reduction in standard bronchoscopy (P=0.0001), CT guided biopsy of peripheral lesions (P=0.0008) and mediastinoscopy (P=0.0382). The proportion of cases diagnosed by EBUS-TBNA significantly increased from 0% in 2007 to 21.4% in 2009 and 25.4% in 2011 (P&lt;0.0001). There has been a significant increase in the proportion of patients going straight to surgery without pathological confirmation (p=0.002). <h3>Conclusions</h3> The use of diagnostic modalities that provide information on diagnosis and staging in a single intervention are increasing. At our hospital, the use of EBUS-TBNA has led to a significant reduction in CT guided biopsies, standard bronchoscopies and mediastinoscopies. These changes in practise have implications for future service provision, training and commissioning. <h3>Reference</h3> NICE Lung cancer. 2011.http://publications.nice.org.uk/lung-cancer-cg121/key-priorities-for-implementation.
Metastatic urothelial tumors progressing following first line chemotherapy: prognostic factors and importance of second line chemotherapy.
Authors: Mohammad Ma'koseh, Murad Salam, Rami Al-Wardat, Samer Salah
Journal: Journal of Clinical Oncology (2016)

e16036 Background: Data supporting the benefit from second-line chemotherapy in patients with metastatic urothelial carcinoma (UC) is limited. Furthermore, factors predicting survival following progression on first-line platinum based regimens in patients who are treated outside clinical trials are not clear Methods: We retrospectively reviewed patients with metastatic UC, who experience disease progression following first-line platinum-based regimens for the metastases, and were treated and followed up at a single institution. The effect of demographic, disease characteristics, and second-line therapy on overall survival (OS) was examined through univariate and multivariate cox-regression analysis. Results: 64 patients were included. Median age 62 years (range: 26- 78). Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 in 5 (8%), 1 in 32 (50%), and ≥ 2 in 27 patients (42%). Twenty-seven patients (42%) did not receive second-line chemotherapy (because of poor ECOG PS), twenty patients (31%) received combination chemotherapy (platinum-based in 17), and seventeen patients (27%) received single agent chemotherapy. The median OS from the date of documented progression after first-line therapy was 5.0 months. ECOG PS ≥ 1 (p= 0.002), ≥ 2 metastatic sites (p< 0.001), significant weight loss (p= 0.015), metastatic spread other than “lymph node only” (p = 0.005), WBC counts > 12000 (p= 0.001), serum albumin < 35 (p < 0.001), serum haemoglobin < 10 (p= 0.042), and treatment with best supportive care alone as opposed to second line chemotherapy (p < 0.001) were associated with inferior OS. In multivariate analysis, ECOG PS of ≥ 1 (HR: 5.74 (1.4 – 45.57, p= 0.036), no second-line chemotherapy (HR: 2.72, 95% CI: 1.39-5.31; p= 0.003), and ≥ 2 metastatic sites (HR: 5.19, 95% CI: 1.74-15.44; p <0.001), remained the only independent factors. Conclusions: Outside the clinical trial settings, significant proportion of patients with metastatic UC were not eligible for second-line chemotherapy. Use of second line chemotherapy was associated with improvement of OS. Performance status and number of metastatic sites were also important determinants of survival.
Reassuring results on birth outcomes in children fathered by men treated with azathioprine/6-mercaptopurine within 3 months before conception: a nationwide cohort study
Authors: B M Nørgård, B Magnussen, M D Larsen, S Friedman
Journal: Gut (2016)

<h3>Objective</h3> Information on the safety of paternal use of azathioprine (AZA) and 6-mercaptopurine (6-MP) prior to conception is limited. Based on nationwide data from the Danish health registries, we examined the association between paternal use of AZA/6-MP within 3 months before conception and adverse birth outcomes. <h3>Design</h3> This nationwide cohort study is based on data from all singletons born in Denmark from 1 January 1997 through 2013. Children fathered by men who used AZA/6-MP within 3 months before conception constituted the exposed cohort (N=699), and children fathered by men who did not use AZA/6-MP 3 months prior to conception constituted the unexposed cohort (N=1 012 624). The outcomes were congenital abnormalities (CAs), preterm birth and small for gestational age (SGA). We adjusted for multiple covariates and performed a restricted analysis of men with IBD. <h3>Results</h3> There were no significantly increased risks of CAs, preterm birth or SGA in exposed versus unexposed cohorts of children. The adjusted ORs were 0.82 (95% CI 0.53 to 1.28) for CAs, 1.17 (95% CI 0.72 to 1.92) for preterm birth and 1.38 (95% CI 0.76 to 2.51) for SGA. Restricting our analysis to fathers with IBD showed similar results with no significantly increased risk of adverse birth outcomes. <h3>Conclusions</h3> This nationwide study is the largest to date, examining the effect of preconceptual paternal use of AZA/6-MP on birth outcomes in live born singletons. The results of no significantly increased risks of adverse birth outcomes are reassuring and support the continuation of paternal AZA/6-MP treatment during conception.
Abstract 3392: Lung cancer cell derived extracellular vesicles carrying DNAs, RNAs and proteins that may trigger oncogenic signals and promote angiogenesis
Authors: Chien-Chung Lin, Wei-Lun Huang, Wu-Chou Su
Journal: Cancer Research (2016)

Abstract Extracellular vesicles (EVs) secreted from tumor cells have been implicated in modulating the tumor microenvironment changes. In this study, we demonstrated that EVs secreted by lung cancer cell are loaded with several cargos, such as DNA, RNA, cytokines, and growth factors. After the EVs had been taken up by recipient cells, the cargos might activate oncogenic pathways. We firstly isolated EVs from cell-free medium of lung cancer cells lines (AS2, PC9) and malignant pleural effusion (MPE) from patients with lung cancer. Isolated EVs were confirmed by the morphology and size in transmission electron microscopy (TEM) and the presentation of specific EV markers (Alix, CD63, and Tsg101). We found that several RNA species with enrichment of small RNAs and mutated EGFR DNA in the EVs of PC9 cells. After labeling with the green fluorescent dye Cellvue, the uptake of EVs by AS2 cells was imaged by the fluorescent microscopy. With these data, we further investigated the role of EVs in regulating the tumor microenvironment. We found the content of IL-6 in EVs, secreted from AS2 and CL1-5 cells, increased gradually after changing culture medium. And after uptake of EVs by recipient cells the cargos induced higher phsophorylation of Stat3 and AKT compared to the treatment with serum-free medium. Previously, we have shown that IL-6/Stat3/tissue factor (TF)/VEGF pathway enhances lung cancer angiogenesis, metastasis and the generation of MPE. In the current study, we demonstrated that EVs from lung cancer cells and in the MPE contain high level of VEGF and TF. And treatment with the EVs, containing high VEGF and TF, induced more prominent extravasation than cell free medium did in Miles assays. In conclusion, we successfully isolated EVs not only from culture supernatants but also from MPE of lung cancer patients. The EVs contain many biologically active molecules that may modulate behaviors of cancer cells and cells in tumor microenvironment. Citation Format: Chien-Chung Lin, Wei-Lun Huang, Wu-Chou Su. Lung cancer cell derived extracellular vesicles carrying DNAs, RNAs and proteins that may trigger oncogenic signals and promote angiogenesis. [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 3392.