818Safety of ABT-450/r/Ombitasvir + Dasabuvir With or Without Ribavirin in HCV Genotype 1-infected Patients, by Baseline Demographics

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Specific (sialyl-)Lewis core 2 O-glycans differentiate colorectal cancer from healthy colon epithelium

Cells are covered with a dense layer of carbohydrates, some of which are solely present on neoplastic cells. The so-called tumor-associated carbohydrate antigens (TACAs) are increasingly recognized as promising targets for immunotherapy. These carbohydrates differ from those of the surrounding non-cancerous tissues and contribute to the malignant phenotype of the cancer cells by promoting proliferation, metastasis, and immunosuppression. However, due to tumor tissue heterogeneity and technological limitations, TACAs are insufficiently explored. Methods: A workflow was established to decode the colorectal cancer (CRC)-associated O-linked glycans from approximately 20,000 cell extracts. Extracts were obtained through laser capture microdissection of formalin fixed paraffin embedded tissues of both primary tumors and metastatic sites, and compared to healthy colon mucosa from the same patients. The released O-glycans were analyzed by porous graphitized carbon liquid chromatography-tandem mass spectrometry in negative ion mode. Results: Distinctive O-glycosylation features were found in cancerous, stromal and normal colon mucosal regions. Over 100 O-linked glycans were detected in cancerous regions with absence in normal mucosa. From those, six core 2 O-glycans were exclusively found in more than 33% of the cancers, carrying the terminal (sialyl-)LewisX/A antigen. Moreover, two O-glycans were present in 72% of the analyzed cancers and 94% of the investigated cancers expressed at least one of these two O-glycans. In contrast, normal colon mucosa predominantly expressed core 3 O-glycans, carrying α2-6-linked sialylation, (sulfo-)LewisX/A and Sda antigens. Conclusion: In this study, we present a novel panel of highly specific TACAs, based upon differences in the glycomic profiles between CRC and healthy colon mucosa. These TACAs are promising new targets for development of innovative cancer immune target therapies and lay the foundation for the targeted treatment of CRC

The prognostic and predictive value of Tregs and tumor immune subtypes in postmenopausal, hormone receptor-positive breast cancer patients treated with adjuvant endocrine therapy: a Dutch TEAM study analysis

Evidence exists for an immunomodulatory effect of endocrine therapy in hormone receptor-positive (HR+ve) breast cancer (BC). Therefore, the aim of this study was to define the prognostic and predictive value of tumor immune markers and the tumor immune profile in HR+ve BC, treated with different endocrine treatment regimens. 2,596 Dutch TEAM patients were treated with 5 years of adjuvant hormonal treatment, randomly assigned to different regimens: 5 years of exemestane or sequential treatment (2.5 years of tamoxifen–2.5 years of exemestane). Immunohistochemistry was performed for HLA class I, HLA-E, HLA-G, and FoxP3. Tumor immune subtypes (IS) (low, intermediate & high immune susceptible) were determined by the effect size of mono-immune markers on relapse rate. Patients on sequential treatment with high level of tumor-infiltrating FoxP3+ cells had significant (p = 0.019, HR 0.729, 95 % CI 0.560–0.949) better OS. Significant interaction for endocrine treatment and FoxP3+ presence was seen (OS p < 0.001). Tumor IS were only of prognostic value for the sequentially endocrine-treated patients (RFP: p = 0.035, HR intermediate IS 1.420, 95 % CI 0.878–2.297; HR low IS 1.657, 95 % CI 1.131–2.428; BCSS: p = 0.002, HR intermediate IS 2.486, 95 % CI 1.375–4.495; HR low IS 2.422, 95 % CI 1.439–4.076; and OS: p = 0.005, HR intermediate IS 1.509, 95 % CI 0.950–2.395; HR low IS 1.848, 95 % CI 1.277–2.675). Tregs and the tumor IS presented in this study harbor prognostic value for sequentially endocrine-treated HR+ve postmenopausal BC patients, but not for solely exemestane-treated patients. Therefore, these markers could be used as a clinical risk stratification tool to guide adjuvant treatment in this BC population

Longitudinal Serum Protein Analysis of Women with a High Risk of Developing Breast Cancer Reveals Large Interpatient Versus Small Intrapatient Variations:First Results from the TESTBREAST Study

The prospective, multicenter TESTBREAST study was initiated with the aim of identifying a novel panel of blood-based protein biomarkers to enable early breast cancer detection for moderate-to-high-risk women. Serum samples were collected every (half) year up until diagnosis. Protein levels were longitudinally measured to determine intrapatient and interpatient variabilities. To this end, protein cluster patterns were evaluated to form a conceptual basis for further clinical analyses. Using a mass spectrometry-based bottom-up proteomics strategy, the protein abundance of 30 samples was analyzed: five sequential serum samples from six high-risk women; three who developed a breast malignancy (cases) and three who did not (controls). Serum samples were chromatographically fractionated and an in-depth serum proteome was acquired. Cluster analyses were applied to indicate differences between and within protein levels in serum samples of individuals. Statistical analyses were performed using ANOVA to select proteins with a high level of clustering. Cluster analyses on 30 serum samples revealed unique patterns of protein clustering for each patient, indicating a greater interpatient than intrapatient variability in protein levels of the longitudinally acquired samples. Moreover, the most distinctive proteins in the cluster analysis were identified. Strong clustering patterns within longitudinal intrapatient samples have demonstrated the importance of identifying small changes in protein levels for individuals over time. This underlines the significance of longitudinal serum measurements, that patients can serve as their own controls, and the relevance of the current study set-up for early detection. The TESTBREAST study will continue its pursuit toward establishing a protein panel for early breast cancer detection

Colorectal carcinomas in MUTYH-associated polyposis display histopathological similarities to microsatellite unstable carcinomas

<p>Abstract</p> <p>Background</p> <p>MUTYH-associated polyposis (MAP) is a recessively inherited disorder which predisposes biallelic carriers for a high risk of polyposis and colorectal carcinoma (CRC). Since about one third of the biallelic MAP patients in population based CRC series has no adenomas, this study aimed to identify specific clinicopathological characteristics of MAP CRCs and compare these with reported data on sporadic and Lynch CRCs.</p> <p>Methods</p> <p>From 44 MAP patients who developed ≥ 1 CRCs, 42 of 58 tumours were analyzed histologically and 35 immunohistochemically for p53 and beta-catenin. Cell densities of CD3, CD8, CD57, and granzyme B positive lymphocytes were determined. <it>KRAS2</it>, the mutation cluster region (MCR) of <it>APC, p53</it>, and <it>SMAD4 </it>were analyzed for somatic mutations.</p> <p>Results</p> <p>MAP CRCs frequently localized to the proximal colon (69%, 40/58), were mucinous in 21% (9/42), and had a conspicuous Crohn's like infiltrate reaction in 33% (13/40); all of these parameters occurred at a higher rate than reported for sporadic CRCs. Tumour infiltrating lymphocytes (TILs) were also highly prevalent in MAP CRCs. Somatic <it>APC </it>MCR mutations occurred in 14% (5/36) while 64% (23/36) had <it>KRAS2 </it>mutations (22/23 c.34G>T). G>T tranversions were found in <it>p53 </it>and <it>SMAD4</it>, although the relative frequency compared to other mutations was low.</p> <p>Conclusion</p> <p>MAP CRCs show some similarities to micro-satellite unstable cancers, with a preferential proximal location, a high rate of mucinous histotype and increased presence of TILs. These features should direct the practicing pathologist towards a MAP aetiology of CRC as an alternative for a mismatch repair deficient cause. High frequent G>T transversions in <it>APC </it>and <it>KRAS2 </it>(mutated in early tumour development) but not in <it>P53 </it>and <it>SMAD4 </it>(implicated in tumour progression) might indicate a predominant MUTYH effect in <it>early </it>carcinogenesis.</p

Nuclear Localization of CXCR4 Determines Prognosis for Colorectal Cancer Patients

Chemokines and their receptors are implicated in formation of colorectal cancer metastases. Especially CXCR4 is an important factor, determining migration, invasiveness, metastasis and proliferation of colorectal cancer cells. Object of this study was to determine expression of CXCR4 in tumor tissue of colorectal cancer patients and associate CXCR4 expression levels to clinicopathological parameters. Levels of CXCR4 expression of a random cohort of patients, who underwent primary curative resection of a colorectal carcinoma, were retrospectively determined by quantitative real-time RT-PCR and semi-quantitative analyses of immunohistochemical stained paraffin sections. Expression levels were associated to clinicopathological parameters. Using RT-PCR we found that a high expression of CXCR4 in the primary tumor was an independent prognostic factor for a poor disease free survival (p = 0.03, HR: 2.0, CI = 1.1–3.7). Immunohistochemical staining showed that nuclear distribution of CXCR4 in the tumor cells was inversely associated with disease free and overall survival (p = 0.04, HR: 2.6, CI = 1.0–6.2), while expression in the cytoplasm was not associated with prognosis. In conclusion, our study showed that a high expression of nuclear localized CXCR4 in tumor cells is an independent predictor for poor survival for colorectal cancer patients

Variation in Structure and Process of Care in Traumatic Brain Injury: Provider Profiles of European Neurotrauma Centers Participating in the CENTER-TBI Study.

INTRODUCTION: The strength of evidence underpinning care and treatment recommendations in traumatic brain injury (TBI) is low. Comparative effectiveness research (CER) has been proposed as a framework to provide evidence for optimal care for TBI patients. The first step in CER is to map the existing variation. The aim of current study is to quantify variation in general structural and process characteristics among centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. METHODS: We designed a set of 11 provider profiling questionnaires with 321 questions about various aspects of TBI care, chosen based on literature and expert opinion. After pilot testing, questionnaires were disseminated to 71 centers from 20 countries participating in the CENTER-TBI study. Reliability of questionnaires was estimated by calculating a concordance rate among 5% duplicate questions. RESULTS: All 71 centers completed the questionnaires. Median concordance rate among duplicate questions was 0.85. The majority of centers were academic hospitals (n = 65, 92%), designated as a level I trauma center (n = 48, 68%) and situated in an urban location (n = 70, 99%). The availability of facilities for neuro-trauma care varied across centers; e.g. 40 (57%) had a dedicated neuro-intensive care unit (ICU), 36 (51%) had an in-hospital rehabilitation unit and the organization of the ICU was closed in 64% (n = 45) of the centers. In addition, we found wide variation in processes of care, such as the ICU admission policy and intracranial pressure monitoring policy among centers. CONCLUSION: Even among high-volume, specialized neurotrauma centers there is substantial variation in structures and processes of TBI care. This variation provides an opportunity to study effectiveness of specific aspects of TBI care and to identify best practices with CER approaches

Variation in general supportive and preventive intensive care management of traumatic brain injury: a survey in 66 neurotrauma centers participating in the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study

Abstract Background General supportive and preventive measures in the intensive care management of traumatic brain injury (TBI) aim to prevent or limit secondary brain injury and optimize recovery. The aim of this survey was to assess and quantify variation in perceptions on intensive care unit (ICU) management of patients with TBI in European neurotrauma centers. Methods We performed a survey as part of the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. We analyzed 23 questions focused on: 1) circulatory and respiratory management; 2) fever control; 3) use of corticosteroids; 4) nutrition and glucose management; and 5) seizure prophylaxis and treatment. Results The survey was completed predominantly by intensivists (n = 33, 50%) and neurosurgeons (n = 23, 35%) from 66 centers (97% response rate). The most common cerebral perfusion pressure (CPP) target was > 60 mmHg (n = 39, 60%) and/or an individualized target (n = 25, 38%). To support CPP, crystalloid fluid loading (n = 60, 91%) was generally preferred over albumin (n = 15, 23%), and vasopressors (n = 63, 96%) over inotropes (n = 29, 44%). The most commonly reported target of partial pressure of carbon dioxide in arterial blood (PaCO2) was 36–40 mmHg (4.8–5.3 kPa) in case of controlled intracranial pressure (ICP) < 20 mmHg (n = 45, 69%) and PaCO2 target of 30–35 mmHg (4–4.7 kPa) in case of raised ICP (n = 40, 62%). Almost all respondents indicated to generally treat fever (n = 65, 98%) with paracetamol (n = 61, 92%) and/or external cooling (n = 49, 74%). Conventional glucose management (n = 43, 66%) was preferred over tight glycemic control (n = 18, 28%). More than half of the respondents indicated to aim for full caloric replacement within 7 days (n = 43, 66%) using enteral nutrition (n = 60, 92%). Indications for and duration of seizure prophylaxis varied, and levetiracetam was mostly reported as the agent of choice for both seizure prophylaxis (n = 32, 49%) and treatment (n = 40, 61%). Conclusions Practice preferences vary substantially regarding general supportive and preventive measures in TBI patients at ICUs of European neurotrauma centers. These results provide an opportunity for future comparative effectiveness research, since a more evidence-based uniformity in good practices in general ICU management could have a major impact on TBI outcome

Biomimetic strategy to improve haemo- and biocompatibility of PET

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