bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discordant Results Obtained for Different Methods of HER-2/Neu Testing in Breast Cancer – A Question of Standardization, Automation and Timing
Authors: Lüftner D. , Henschke P. , Kafka A. , Anagnostopoulos I. , Wiechen K. , Geppert R. , Stein H. , Wernecke K.D. , Kreienberg R. , Possinger K. 
Published: January 2018

Background HER-2/neu positivity is required for the selection of stage IV breast cancer patients for trastuzumab therapy. We compared the results of the recommended immunohistochemistry (IHC) evaluation with the automated ACIS™ IHC system and with fluorescence in situ hybridization (FISH). These HER-2/neu tissue results were correlated with the serum HER-2/neu (sHER-2/neu) levels at the time of metastatic spread. Patients and Methods A total of 61 IHC slides from 30 patients were stained using the HercepTest™. HER-2/neu gene amplification was determined using the Ventana™ FISH assay. sHER-2/neu levels were measured with the Oncogene Science” ELISA kit. The concordance of HER-2/neu results was determined using the concordance index Kappa (κ). Results The best concordance between any IHC and FISH was found for the automated ACIS system (88.5%, κ=0.68, category “good”). The comparison between the manual interpretations and the automated IHC was categorized as “very good” (95.1%, κ=0.85). The median sHER-2/neu level of FISH positive patients was significantly higher (67 ng/mL) than that of FISH negative patients (17 ng/mL, p=0.018). The increase in HER-2/neu positivity comparing tissue to stage IV serum was statistically significant (p=0.001). Conclusions The concordance between conventional IHC and computerized analysis was very good. The number of patients with stage IV breast cancer with an elevated sHER-2/neu level was much higher than HER-2/neu positivity in tissue. This discrepancy is only partially explained by the influence of tumor load. Patients with an elevated sHER-2/neu level and no tissue overexpression should be considered for retesting of tissue or a new biopsy.
ADVIA Centaur® Her-2/Neu Shows Value in Monitoring Patients with Metastatic Breast Cancer
Authors: Lüftner D. , Cheli C. , Mickelson K. , Sampson E. , Possinger K. 
Published: January 2018

Introduction The proteolytic breakdown product corresponding to the extracellular domain (ECD) of the HER-2/neu oncoprotein p185 is found in the circulation of healthy individuals and patients having cancers of epithelial origin. For the current evaluation we sought to determine the analytical performance as well as the clinical utility of the newly developed ADVIA Centaur® HER-2/neu assay (Bayer HealthCare LLC, Diagnostics Division, Tarrytown, NY, USA) in monitoring patients with metastatic breast cancer during the course of disease and treatment and to compare the obtained results with those of CA 15–3. Methods The analytical performance (including precision, normal range, interfering substances, minimum detectable concentration, dilution recovery, spiking recovery and high-dose hook effect) were determined. HER-2/neu and CA 15–3 values were measured in retrospective samples obtained from 59 patients with metastatic breast cancer undergoing treatment over a 6–12 month period. Serial changes in serum HER-2/neu and CA 15–3 were correlated with changes in clinical status on a visit-to-visit basis. For each pair of serial measurements, changes of equal to or greater than, or less than 15% for HER-2/neu and 21% for CA 15–3 were considered to indicate progression or lack of progression, respectively. Results The ADVIA Centaur HER-2/neu assay demonstrated within-run imprecision and total imprecision ranging from 3.0–5.6% and from 3.2–5.7%, respectively. The upper limit of normal was 15.2 ng/mL (90% CI: 14.2–17.0 ng/mL). No significant interference (<5%) was seen with bilirubins, hemoglobin, triglycerides and cholesterol or therapeutic drugs commonly present in the sera of breast cancer patients. The minimum detectable concentration (analytical sensitivity) was found to be 0.5 ng/mL. The patient population in the clinical study included breast cancer patients who responded to therapy (stable, partial or complete response) or had disease progression. HER-2/neu levels showed a concordance of 78.1% (82/105 restaging time points) with the clinical course of disease, whereas CA 15–3 levels showed a concordance of 76.2% (80/105 restaging time points). The concordance with clinical status increased to 85.7% (90/105 restaging time points) when both results were used in combination as a series test. Conclusions The ADVIA Centaur HER-2/neu assay provides excellent analytical performance for serial testing of serum HER-2/neu levels. The clinical data demonstrate the usefulness of serum HER-2/neu in monitoring metastatic breast cancer patients during treatment. Furthermore, the results indicate that serum HER-2/neu and CA 15–3 may be useful in identifying disease progression or therapeutic response in different subgroups of women with metastatic breast cancer.
Preoperative Plasma Soluble Urokinase Plasminogen Activator Receptor as a Prognostic Marker in Rectal Cancer Patients. An Eortc-Receptor and Biomarker Group Collaboration
Authors: Riisbro R. , Christensen I.J. , Nielsen H.J. , Brünner N. , Nilbert M. , Fernebro E. 
Published: January 2018

Background and aims Since approximately 30% of patients with Dukes’ stage B colorectal cancer will experience disease recurrence within five years of primary treatment, current staging of patients with early colorectal cancer apparently fails to adequately predict patient outcome. It has previously been shown that the preoperative plasma concentration of soluble urokinase plasminogen activator receptor (suPAR) is associated with the survival of patients with early colorectal cancer. In this study we sought to confirm the independent prognostic value of suPAR in rectal cancer. Methods suPAR was retrospectively determined by two different versions of a suPAR ELISA in preoperatively collected plasma samples from a Swedish (n=354) and a Danish (n=255) cohort of rectal cancer patients. Results In both cohorts the suPAR concentration was significantly higher in Dukes’ stage D patients than in Dukes’ stage A-C patients (p<0.0001). Among Dukes’ stage A-C patients, no differences in median suPAR values were seen. In univariate analysis, continuous suPAR was found to be associated with survival (p<0.0001 in both cohorts). Of particular interest was that similar results were obtained for Dukes’ stage A and B patients when analyzed separately. In multivariate analysis, continuous suPAR was found in both cohorts to be independent of Dukes’ stage. Conclusions This study confirms that the preoperative concentration of plasma suPAR contains independent prognostic information on patients with rectal cancer. This result was independent of the two different versions of an in-house suPAR ELISA used to perform the analyses. The next step in the evaluation of suPAR as a prognostic parameter in rectal cancer will be to launch an appropriately dimensioned prospective study where the benefit of applying preoperative plasma suPAR measurement to clinical decision-making regarding adjuvant therapy is assessed.
Pancreatic Cancer Cells Invasiveness is Mainly Affected by Interleukin-1β not by Transforming Growth Factor-β1
Authors: Greco E. , Basso D. , Fogar P. , Mazza S. , Navaglia F. , Zambon C.-F. , Falda A. , Pedrazzoli S. , Ancona E. , Plebani M. 
Published: January 2018

Background We investigated in vitro whether IL-1β and TGF-β1 affect pancreatic cancer cell growth, adhesion to the extracellular matrix and Matrigel invasion. Materials and methods Adhesion to fibronectin, laminin and type I collagen, and Matrigel invasion after stimulation with saline, IL-1β and TGF-β1 were evaluated using three primary and three metastatic pancreatic cancer cell lines. Results Extracellular matrix adhesion of control cells varied independently of the metastatic characteristics of the studied cell lines, whereas Matrigel invasion of control cells was partly correlated with the in vivo metastatic potential. IL-1β did not influence extracellular matrix adhesion, whereas it significantly enhanced the invasiveness of three of the six cell lines. TGF-β1 affected the adhesion of one cell line, and exerted contrasting effects on Matrigel invasion of different cell lines. Conclusions IL-1β enhances the invasive capacity of pancreatic cancer cells, whereas TGF-β1 has paradoxical effects on pancreatic cancer cells; this makes it difficult to interfere with TGF-β1 signaling in pancreatic cancer treatment.
Matrix Metalloproteinase-19 is a Predictive Marker for Tumor Invasiveness in Patients with Oropharyngeal Squamous Cell Carcinoma
Authors: Velinov N. , Aebersold D. , Haeni N. , Hlushchuk R. , Weinstein F. , Sedlacek R. , Djonov V. 
Published: January 2018

Aims To evaluate the expression of matrix metalloproteinase-19 (MMP-19) in oropharyngeal squamous cell carcinoma along with its association with structural features of invasiveness. To investigate whether MMP-19 expression correlates with lymphatic or systemic metastasis and prognosis in patients who have received definitive radiotherapy. Methods and results The histological evaluation of the invasive front was based on Bryne's malignancy grading system. We correlated the immunohistochemical expression pattern with morphological parameters which characterize tumor invasiveness such as keratinization, nuclear polymorphism, invasion pattern, and the host inflammatory response. Local immunoreactivity for MMP-19 was positively correlated with tumor invasiveness as reflected in its structural characteristics and the degree of nuclear polymorphism, and negatively correlated with the inflammatory response of the host. No correlation existed between MMP-19 expression and clinicopathological features (TNM stage, grade of differentiation) or a patient's outcome and prognosis. Conclusions This latter finding probably reflects the unique change for MMPs from high immunoreactivity within healthy tissue areas and non-invasive tumor parts, through absence in the least invasive neoplastic regions, to strong re-expression at a highly invasive front of the same tumor. Our findings indicate that MMP-19 can be used as a marker for tumor invasiveness in patients with oropharyngeal squamous cell carcinoma.
Expression of Mina53 and its Significance in Gastric Carcinoma
Authors: Zhang Q. , Hu CM. , Yuan Y.S. , He C.H. , Zhao Q. , Liu N.Z. 
Published: January 2018

Aim To study the expression of Mina53 and its relationships with clinicopathological characteristics, antioncogene inactivation and tumor proliferation in human gastric carcinoma, and to explore the role of Mina53 in carcinogenesis and tumor progression. Methods Expression of Mina53 and proliferating cell nuclear antigen (PCNA) was determined in gastric carcinoma (n=79), gastric dysplasia (n=21) and normal gastric tissues (n=20), while p53 was measured in gastric carcinoma tissues by immunohistochemistry. Results Mina53 was negatively expressed in all normal mucosa tissues. Dysplasia specimens showed weakly positive staining for Mina53 in 3 of 21 cases. Elevated expression of Mina53 was observed in 72 (91.1%) of the gastric carcinomas. No significant associations were found between Mina53 and clinicopathological characteristics such as sex, age, histological differentiation, distant metastasis and lymph node metastasis (p>0.05). There was a significant association with depth of invasion (χ2=5.385, p<0.05) and TMN stage (χ2=6.255, p<0.05). In gastric carcinoma, positive staining for p53 was detected in 53 of 79 cases (67.1%), showing a significant association with Mina53 (χ2=5.161, p<0.05). The mean (± SD) PCNA labeling index for gastric carcinoma was 39.47±16.92%. Mina53 expression was positively associated with PCNA level (r=0.756, p<0.01). Conclusion Mina53 was overexpressed in gastric carcinoma and associated with tumor proliferation and antioncogene inactivation. Mina53 could therefore play an important role in the carcinogenesis and progression of gastric carcinoma.
PSA Doubling Time as a Predictor of the Outcome of Random Prostate Biopsies Prompted by Isolated PSA Elevation in Subjects Referred to an Outpatient Biopsy Facility in a Routine Clinical Scenario
Authors: Ciatto S. , Rubeca T. , Martinelli F. , Pontenani G. , Lombardi C. , Di Lollo S. 
Published: January 2018

Aim To assess the validity of PSA doubling time (PSADT) as a predictor of prostate sextant biopsy outcome in patients with PSA levels in the 4–10 ng/mL range. Material and methods A consecutive series of 355 sextant biopsies performed during 2001–2007 in subjects with negative digital rectal examination and transrectal ultrasonography was considered. Variables tested as possible predictors were age, total and free/total PSA value, PSA velocity and PSA doubling time. While PSA at time of biopsy and free/total PSA were determined with a standardized method undergoing strict quality control, previous PSA values used to assess velocity/doubling time came from other labs using different assays over widely varying intervals of time. The association with biopsy outcome (cancer vs non-cancer) was investigated by univariate and multivariate analysis. Results Apart from free/total PSA ratio, no other studied variable showed a statistically significant and independent association with biopsy outcome, either at univariate or multivariate analysis. No studied variable had a good performance as a biopsy indicator. Depending on the variable considered, 1.17 to 1.97 cancers would be missed to spare 10 benign biopsies. Conclusion When based on PSA data determined with different assays over widely varying intervals and in the absence of an underlying protocol for PSA surveillance, PSA velocity and doubling time should never discount a biopsy prompted by total PSA elevation.
Heat Shock Protein Expression Independently Predicts Survival Outcome in Schistosomiasis-Associated Urinary Bladder Cancer
Authors: El-Kenawy A. EL-Meghawry , El-kott A.F. , Hasan M.S. 
Published: January 2018

Background Heat shock proteins (HSPs) are synthesized by cells in response to various stress conditions, including carcinogenesis. These molecules have been studied in several malignancies, among which bladder carcinoma. This is the first study attempting to clarify the significance of HSP27 and HSP70 in schistosomiasis-associated bladder carcinoma and their relation to prognosis. Methods HSP27 and HSP70 were localized immunohistochemically in tissue sections from 75 schistosomiasis-associated bladder carcinomas. Their expression was correlated with clinical and pathological features and their impact on 5-year disease-free survival was studied with univariate and multivariate analysis. Results I N all, 45 and 51 patients were positive for HSP27 and HSP70 expression, respectively. A significant correlation was found between expression of both HSPs and tumor grade, stage, DNA ploidy and recurrence. In univariate analysis, a statistically significant association of HSP27 and HSP70 expression with 5-year disease-free survival was found. In a multivariate Cox proportional hazards model, both HSP27 and HSP70 maintained a statistically significant impact on survival. Conclusions The current results indicate that expression of HSP27 and HSP70 may have prognostic relevance in patients with schistosomiasis-associated bladder cancer. HSPs may be useful markers for patients with this type of bladder carcinoma and may be used for predicting disease progression.
CHFR Promoter Hypermethylation and Reduced CHFR mRNA Expression in Ovarian Cancer
Authors: Gao Ying , Lou Ge , Zhang Guang-Mei , Sun Xi-Wen , Ma Yu-Yan , Yang Yan-Mei , Liu Ge 
Published: January 2018

Background Ovarian cancer is one of the most common cancers and can be treated with microtubule-targeting drugs. Checkpoint with forkhead and ring finger domains (CHFR) is a protein implicated in cancer sensitivity to microtubule-targeting drugs. Whereas CHFR downregulation, often with CHFR promoter hypermethylation, has been identified in a large number of tumor types, it has not been in ovarian cancer. We therefore searched for CHFR downregulation in primary ovarian tumors. Methods Fresh ovarian cancer tissues from 53 patients (test) and normal ovarian tissues from 21 patients (control) were tested for CHFR promoter hypermethylation and CHFR mRNA levels. Results The CHFR promoter was hypermethylated in 20.75% (11/53) of the ovarian cancers and none (0/21) of the normal controls. The normal controls had a mean mRNA level of 1.89 relative fluorescence units (RFU) with a range of 0.04–24.78 RFU. The cancer tissues had a mean mRNA level of 0.77 RFU with a range of 0.00–68.75 RFU. The median value of the cancer group was significantly lower than that of the control group (p=0.0067). Those cancer samples that had hypermethylated CHFR promoters also had low (n=3) or undetectable (n=8) CHFR mRNA levels. Conclusions In contrast to previous reports, we found that alterations in CHFR mRNA and CHFR methylation can be frequently found in ovarian cancers. CHFR hypermethylation was strongly associated with the loss of CHFR mRNA expression. CHFR downregulation in ovarian tumors may be clinically relevant as a staging biomarker, as an indicator of sensitivity to microtubule-targeting drugs, and as a future drug target.
Risk factors associated with liver steatosis and fibrosis in chronic hepatitis B patient with component of metabolic syndrome
Authors: Cai Shaohang , Ou Zejin , Liu Duan , Liu Lili , Liu Ying , Wu Xiaolu , Yu Tao , Peng Jie 
Published: January 2018

BackgroundWe investigated whether metabolic syndrome exacerbated the risk of liver fibrosis among chronic hepatitis B patients and risk factors associated with liver steatosis and fibrosis in chronic hepatitis B patients with components of metabolic syndrome.MethodsThis study included 1236 chronic hepatitis B patients with at least one component of metabolic syndrome. The controlled attenuation parameter and liver stiffness, patient information and relevant laboratory data were recorded.ResultsControlled attenuation parameter was increased progressively with the number of metabolic syndrome components (p < 0.001). Multivariate analysis indicated younger age, high gamma‐glutamyltransferase level, high waist‐hip ratio, and high body mass index were independent risk factors associated with nonalcoholic fatty liver disease among chronic hepatitis B patients with metabolic syndrome. In the fibrosis and non‐fibrosis groups, most of blood lipid was relatively lower in fibrosis group. An increased proportion of chronic hepatitis B patients with liver fibrosis was found concomitant with an increasing number of components of metabolic syndrome. Male gender, older age, smoking, aspartate aminotransferase levels, high body mass index, and low platelet level were identified as independent risk factors associated with liver fibrosis.ConclusionsFor chronic hepatitis B patients with coexisting components of metabolic syndrome, stratification by independent risk factors for nonalcoholic fatty liver disease and fibrosis can help with management of their disease.
Thromboelastography-based anticoagulation management during extracorporeal membrane oxygenation: a safety and feasibility pilot study
Authors: Panigada Mauro , E. Iapichino Giacomo , Brioni Matteo , Panarello Giovanna , Protti Alessandro , Grasselli Giacomo , Occhipinti Giovanna , Novembrino Cristina , Consonni Dario , Arcadipane Antonio , Gattinoni Luciano , Pesenti Antonio 
Published: January 2018

Abstract
Background
There is no consensus on the management of anticoagulation during extracorporeal membrane oxygenation (ECMO). ECMO is currently burdened by a high rate of hemostatic complications, possibly associated with inadequate monitoring of heparin anticoagulation. This study aims to assess the safety and feasibility of an anticoagulation protocol for patients undergoing ECMO based on thromboelastography (TEG) as opposed to an activated partial thromboplastin time (aPTT)-based protocol.

Methods
We performed a multicenter, randomized, controlled trial in two academic tertiary care centers. Adult patients with acute respiratory failure treated with veno-venous ECMO were randomized to manage heparin anticoagulation using a TEG-based protocol (target 16–24 min of the R parameter, TEG group) or a standard of care aPTT-based protocol (target 1.5–2 of aPTT ratio, aPTT group). Primary outcomes were safety and feasibility of the study protocol.

Results
Forty-two patients were enrolled: 21 were randomized to the TEG group and 21 to the aPTT group. Duration of ECMO was similar in the two groups (9 (7–16) days in the TEG group and 11 (4–17) days in the aPTT group, p = 0.74). Heparin dosing was lower in the TEG group compared to the aPTT group (11.7 (9.5–15.3) IU/kg/h vs. 15.7 (10.9–21.3) IU/kg/h, respectively, p = 0.03). Safety parameters, assessed as number of hemorrhagic or thrombotic events and transfusions given, were not different between the two study groups. As for the feasibility, the TEG-based protocol triggered heparin infusion rate adjustments more frequently (p < 0.01) and results were less frequently in the target range compared to the aPTT-based protocol (p < 0.001). Number of prescribed TEG or aPTT controls (according to study groups) and protocol violations were not different between the study groups.

Conclusions
TEG seems to be safely used to guide anticoagulation management during ECMO. Its use was associated with the administration of lower heparin doses compared to a standard of care aPTT-based protocol.
Trial registration ClinicalTrials.gov, October 22,2014. Identifier: NCT02271126.
The peer review process for awarding funds to international science research consortia: a qualitative developmental evaluation
Authors: Gregorius Stefanie , Dean Laura , Cole Donald C , Bates Imelda 
Published: January 2018

Background: Evaluating applications for multi-national, multi-disciplinary, dual-purpose research consortia is highly complex. There has been little research on the peer review process for evaluating grant applications and almost none on how applications for multi-national consortia are reviewed. Overseas development investments are increasingly being channelled into international science consortia to generate high-quality research while simultaneously strengthening multi-disciplinary research capacity. We need a better understanding of how such decisions are made and their effectiveness.Methods: An award-making institution planned to fund 10 UK-Africa research consortia. Over two annual rounds, 34 out of 78 eligible applications were shortlisted and reviewed by at least five external reviewers before final selections were made by a face-to-face panel. We used an innovative approach involving structured, overt observations of award-making panel meetings and semi-structured interviews with panel members to explore how assessment criteria concerning research quality and capacity strengthening were applied during the peer review process. Data were coded and analysed using pre-designed matrices which incorporated categories relating to the assessment criteria.Results: In general the process was rigorous and well-managed. However, lack of clarity about differential weighting of criteria and variations in the panel’s understanding of research capacity strengthening resulted in some inconsistencies in use of the assessment criteria. Using the same panel for both rounds had advantages, in that during the second round consensus was achieved more quickly and the panel had increased focus on development aspects.Conclusion: Grant assessment panels for such complex research applications need to have topic- and context-specific expertise. They must also understand research capacity issues and have a flexible but equitable and transparent approach. This study has developed and tested an approach for evaluating the operation of such panels and has generated lessons that can promote coherence and transparency among grant-makers and ultimately make the award-making process more effective.