The RECORD study evaluated the effects of rosiglitazone on cardiovascular outcomes. A 4-year observational follow-up was added to the study to monitor the occurrence of cancer and bone fractures. We present the cancer and bone fracture data aggregated across the main study and its observational follow-up.
RECORD was a multicentre, open-label trial in people with type 2 diabetes on metformin or sulfonylurea monotherapy randomly assigned to addition of rosiglitazone (n = 2,220) or to a combination of metformin and sulfonylurea (n = 2,227). At the end of the main study, patients stopped study drug and were invited to enter the observational follow-up during which glucose-lowering treatment was selected by the patient’s physician. Serious adverse events of cancer and serious and non-serious events of bone fracture were recorded. The study is registered with ClinicalTrials.gov, number NCT00379769.
Of the 4,447 patients comprising the intent-to-treat population, 2,546 entered the observational follow-up (1,288 rosiglitazone, 1,258 metformin/sulfonylurea) and added 9,336 patient-years experience to the main RECORD study, making an aggregate of 33,744 patient-years. Based on the totality of follow-up, malignancies were reported in 179 of 2,220 patients (8.1 %) in the group originally randomised to rosiglitazone and in 195 of 2,227 patients (8.8 %) in the group allocated metformin/sulfonylurea [relative risk, RR, 0.92 (95 % CI 0.76-1.12)]. More patients reported bone fractures in the rosiglitazone group (238, 10.7 %) than in the metformin/sulfonylurea control [151, 6.8 %; RR 1.58 (1.30-1.92)]. For women, the corresponding figures were rosiglitazone 156 (14.5 %), metformin/sulfonylurea 91 (8.5 %), RR 1.71 (1.34-2.18), and for men, the corresponding figures were rosiglitazone 82 (7.2 %), metformin/sulfonylurea 60 (5.2 %), RR 1.37 (0.99-1.90). Potentially high-morbidity fractures (hip, pelvis, femur, and spine) occurred in the same number of patients (31, 1.4 %) in the two treatment groups.
We conclude that data from a 4-year observational follow-up, combined with the main RECORD study data, do not suggest an increased risk of cancer in patients randomised to rosiglitazone combination use compared with those randomised to metformin/sulfonylurea. Consistent with the main study, rosiglitazone is associated with an increased risk of peripheral bone fracture in women, and probably in men, but the combined data do not suggest an increase in potentially high-morbidity (hip, pelvis, femur, and spine) fractures.

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Indoleamine-2,3-dioxygenase (IDO) is an immunosuppressive enzyme involved in tumor malignancy. However, the regulatory mechanism underlying its involvement remains largely uncharacterized. The present study aimed to investigate the hypothesis that NK4, an antagonist of hepatocyte growth factor (HGF), can regulate IDO and to characterize the signaling mechanism involved. Following successful transfection of the human ovarian cancer cell line SKOV-3 (which constitutively expresses IDO) with an NK4 expression vector, we observed that NK4 expression suppressed IDO expression; furthermore, NK4 expression did not suppress cancer cell growth in vitro [in the absence of natural killer (NK) cells], but did influence tumor growth in vivo. In addition, NK4 enhanced the sensitivity of cancer cells to NK cells in vitro and promoted NK cell accumulation in the tumor stroma in vivo. In an effort to clarify the mechanisms by which NK4 interacts with IDO, we performed investigations utilizing various biochemical inhibitors. The results of these investigations were as follows. First, c-Met (a receptor of HGF) tyrosine kinase inhibitor PHA-665752, and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 both suppress IDO expression. Second, enhanced expression of PTEN (a known tumor suppressor) via negative regulation within a PI3K-AKT pathway, inhibits IDO expression. Conversely, neither the MEK1/2 inhibitor U0126 nor the STAT3 inhibitor WP1066 affects IDO expression. These results suggest that NK4 inhibits IDO expression via a c-Met-PI3K-AKT signaling pathway.

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Angiogenesis inhibition by the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) inhibitor sorafenib provides survival benefit in hepatocellular carcinoma (HCC); however, angiogenic escape from sorafenib may occur due to angiogenesis-associated fibroblast growth factor receptor (FGFR) pathway activation. In addition to VEGFR and PDGFR, dovitinib inhibits FGFR. Frontline oral dovitinib (500 mg/day, 5 days on/2 days off; n = 82) vs sorafenib (400 mg, twice daily; n = 83) was evaluated in an open-label, randomized phase 2 study of Asian-Pacific patients with advanced HCC. Primary and key secondary endpoints were overall survival (OS) and time to tumor progression (TTP) per local investigator, respectively. Eligible patients had progressed after or were ineligible for surgical and/or locoregional therapies. Median OS (95% CI) was 8.0 (6.6-9.1) months for dovitinib and 8.4 (5.4-11.3) months for sorafenib. Median TTP (95% CI) per investigator assessment was 4.1 (2.8-4.2) and 4.1 (2.8-4.3) months for dovitinib and sorafenib, respectively. Common any-cause adverse events included diarrhea (62%), decreased appetite (43%), nausea (41%), vomiting (41%), fatigue (35%), rash (34%), and pyrexia (30%) for dovitinib, and palmar-plantar erythrodysesthesia syndrome (66%) and decreased appetite (31%) for sorafenib. Subgroup analysis showed higher median OS for patients on dovitinib, with baseline plasma soluble VEGFR1 (sVEGFR1) and hepatocyte growth factor (HGF) < median levels relative to ≥ median levels (median OS [95% CI]: sVEGFR1, 11.2 [9.0-13.8] and 5.7 [4.3-7.0] months, respectively [P = .0002]; HGF, 11.2 [8.9-13.8] and 5.9 [5.0-7.6] months, respectively [P = 0.0002]).
Dovitinib was well tolerated but activity was not greater than sorafenib as frontline systemic therapy for HCC. Based on these data, no subsequent phase 3 study is planned. This article is protected by copyright. All rights reserved.
© 2016 by the American Association for the Study of Liver Diseases.

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On April 16, 2016 Adaptive Biotechnologies, the leader in combining next generation sequencing (NGS) and expert bioinformatics to profile T- and B-cell receptors of the adaptive immune system, along with its collaborators from institutions around the world, will present data demonstrating how Adaptive’s immunosequencing platform can be used as a novel oncology diagnostic to accurately and reliably quantify the density and clonality of Tumor Infiltrating Lymphocytes (TILs) to assess disease prognosis and response to therapy (Press release, Adaptive Biotechnologies, APR 16, 2016, View Source [SID:1234511008]). Two oral presentations and eight posters will be presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, April 16-20, 2016, in New Orleans, Louisiana.

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Notably, many of the data to be presented explore the relevance of the immune repertoire in the blood as well as in the tumor tissue. The potential to identify blood-based immune molecular biomarkers of response to the growing class of immunomodulatory drugs may offer clinicians a more accessible sample source for widespread benefit to patients across many tumor types.

Select data presentations of interest include:

Dr. Robert Prins, et al. from UCLA will present data showing that in patients with glioblastoma undergoing immunotherapy, immunosequencing identified a potential biomarker of response and overall survival (Abstract 767).
Dr. Padmanee Sharma, et al. from MD Anderson Cancer Center will present data from a prostate cancer patient cohort receiving ipilumumab and androgen deprivation therapy correlating immune profiling data with adverse events which led to discovery of a potential predictive biomarker of patients who are at risk of grade 3 toxicities. (Abstract 1402).
Dr. Rebecca Gardner, et al. from Seattle Children’s Research Institute will present data on children with acute lymphoblastic leukemia (ALL) treated with a CART-19 therapy showing that high-throughput sequencing of patient samples had significantly greater sensitivity in detecting minimal residual disease (MRD) compared with samples analyzed by flow cytometry. Furthermore, in these patients, monitoring disease status by peripheral blood sampling is often more informative and far less invasive than bone marrow sampling. (Abstract 4893).
"These data being presented at AACR (Free AACR Whitepaper) demonstrate the utility of immunosequencing in both tissue and blood samples as a critical component in guiding clinicians’ approach to managing and treating cancer," said Harlan Robins, Chief Scientific Officer and Co-Founder of Adaptive Biotechnologies. "Ultimately incorporating immunosequencing into a potential blood-based biomarker for use in the clinic may help enhance the diagnosis, prognosis and monitoring of disease in cancer patients."

Representatives from Adaptive Biotechnologies will be exhibiting at AACR (Free AACR Whitepaper) booth #2530 to answer questions about their proprietary, transformative immunosequencing technology.

Oral Presentations:
Abstract #847: Molecular characterization of breast tumor T-cell infiltration in exome datasets
Date and Time: Sunday, Apr 17, 2016, 4:35 PM – 4:50 PM
Location: Room 243, Morial Convention Center
Presenter: Ricardo Armisen, Universidad de Chile, Santiago, Chile

Abstract #4362: T cell repertoire diversification is associated with immune related toxicities following immune checkpoint inhibition in metastatic cancer patients
Date and Time: Tuesday, Apr 19, 2016, 3:50 PM – 4:05 PM
Location: New Orleans Theater C, Morial Convention Center
Presenter: Lawrence Fong, University of California, San Francisco

Posters:

Abstract #767: TCR sequencing can identify and track tumor-specific T cell populations and is a predictive biomarker of response to DC vaccination in glioblastoma patients
Date and Time: Sunday, Apr 17, 2016, 1:00 PM – 5:00 PM
Location: Section 33, Poster Board #26
Author: Robert Prins, et al., University of California, Los Angeles

Abstract #1402: Exploratory biomarkers that predict for clinical outcomes in a Phase II trial with ipilimumab plus finite androgen deprivation therapy for metastatic non-castrate prostate cancer
Date and Time: Monday, Apr 18, 2016, 8:00 AM -12:00 PM
Location: Section 22, Poster Board #3
Author: Padmanee Sharma, et al., The University of Texas MD Anderson Cancer Center

Abstract #1405: Vesigenurtacel-L stimulates tumor infiltration of unique polyclonal T cell clones in non-muscle invasive bladder cancer patients
Date and Time: Monday, Apr 18, 2016, 8:00 AM -12:00 PM
Location: Section 22, Poster Board #6
Author: Melissa Price, et al., Heat Biologics, Inc., Durham, NC

Abstract #2392: Genomic and immune heterogeneity in synchronous melanoma metastases is associated with differential tumor growth and response to therapy
Date and Time: Monday, Apr 18, 2016, 1:00 PM -5:00 PM
Location: Section 28, Poster Board #22
Author: Jennifer A. Wargo, et al., MD Anderson Cancer Center, Houston, TX

Abstract #4159: Characterization of the T-cell receptor (TCR) repertoire in extensive disease small cell lung cancer (ED SCLC)
Date and Time: Tuesday, Apr 19, 2016, 1:00 PM – 5:00 PM
Location: Section 31, Poster board #26
Author: Cory Batenchuk, et al., Bristol-Myers Squibb, NJ

Abstract #4903: Multimodal therapy with a potent vaccine, metronomic cyclophosphamide and anti-PD-1 enhances immunotherapy of advanced tumors by increasing activation and clonal expansion of tumor infiltrating T cells
Date and Time: Wednesday, Apr 20, 2016, 7:30 AM – 11:00 AM
Location: Section 23, Poster board #14
Author: Genevieve Weir, et al., Immunovaccine, Inc., Halifax, NS, Canada

Abstract #4893: Molecular detection of ALL in the peripheral blood is more sensitive than flow cytometric analysis of the bone marrow in patients with treatment-related hypocellularity
Date and Time: Wednesday, Apr 20, 2016, 8:00 AM -12:00 PM
Location: Section 23, Poster board #4
Author: Rebecca Gardner, et al., Seattle Children’s Research Institute, Seattle, WA

Abstract #4897: First evidence of changes in the TCRβ repertoire from a cutaneous melanoma patient immunized with the CSF-470 vaccine.
Date and Time: Wednesday, Apr 20, 2016, 8:00 AM -12:00 PM
Location: Section 23, Poster board #8
Author: José Mordoh, et al., Centro de Investigaciones Oncológicas-Fundación Cáncer, Ciudad Autónoma de Buenos Aires, Argentina

About the immunoSEQ Platform
Adaptive’s immunoSEQ Platform helps researchers make discoveries in areas such as oncology, autoimmune disorders, infectious diseases and basic immunology. The immunoSEQ Assays can identify millions of T- and B-cell receptors from a single sample in exquisite detail. Offered as a Service or Kit, immunoSEQ Assays provide quantitative, reproducible sequencing results along with access to powerful, easy-to-use analysis tools. The immunoSEQ Assays are for research use only and are not for use in diagnostic procedures.

About Minimal Residual Disease
Minimal residual disease (MRD) refers to cancer cells that may remain in the body of a person with lymphoid cancer after treatment. These cells are present at levels undetectable by traditional microscopic examination (also called morphologic examination) of blood, bone marrow or a lymph node biopsy. Sensitive molecular technologies, such as the next-generation sequencing utilized by Adaptive’s clonoSEQ MRD Test, are needed for reliable detection of very low levels of MRD. Learn more at knowMRD.com.

About the clonoSEQ Process
Adaptive’s clonoSEQ Process enables physicians to utilize sequencing-based minimal residual disease (MRD) detection as an aid to clinical decision making for patients with lymphoid cancers (blood cancers). With its ability to detect cancer cells at a level as low as one per one million white blood cells, the clonoSEQ MRD Test is one to two orders of magnitude more sensitive than the other methods of MRD detection, such as ASO-PCR and flow cytometry.

The Giens 2015 Workshop Round Table entitled "What specifications for a centre or network of excellence in clinical research?" took a viewpoint distinct from earlier work and studies on changes in clinical research activities in France. The purpose of the present work was to identify, starting from concrete examples, the main strengths and advantages of clinical research activity in France related, in part, to the background environment and also to the specific characteristics of the investigation centres considered to be among the most high-performance units in activity. The criteria retained were grouped into a set of specifications that could be used to establish a "label of excellence" upon which the different teams and clinical research centres could model themselves. It was thus considered that belonging to a centre or structured network with at least a national configuration, when this is possible for the medial topic in question, constitutes a real advantage. Four benchmarks were identified: the scientific and clinical expertise of the head investigator, as well as the qualification and operational capacity of the centre’s team; definition and measurement of performance using clearly displayed indicators and evaluation procedures; the quality of the overall trial "process" and of each of its component steps; communication, because know-how and promotion go hand in hand, with the main objective of informing the professional and general public about the value of the research centre meeting the above-mentioned criteria, about its networks of competencies, and more generally, about the important assets of the background of clinical research in France. This sector of research is funded by the public authorities via calls for public grants, financial aids for structures supporting clinical research in the University Hospital Centres and other healthcare institutions allowing for a professionalization of the research occupations, and the national public health plans (cancer, rare disease, HIV).
Copyright © 2016. Published by Elsevier Masson SAS.

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