Health Care Resource Utilization Costs Related to Anaemia Management in Chronic Kidney Disease Non-Dialysed Patients: A Retrospective Clinical and Administrative Database Analysis

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Insulin Glargine U100 Utilization in Patients with Type 2 Diabetes in an Italian Real-World Setting: A Retrospective Study

Background. This study is aimed at estimating the proportion of type 2 diabetes mellitus (T2DM) patients treated with basal insulin (insulin glargine U100) and at evaluating daily insulin dose, treatment pattern, and adherence to treatment of these patients. Methods. Data from administrative and laboratory databases of 3 Italian Local Health Units were retrospectively collected and analyzed. All patients with a diagnosis of T2DM between 01/01/2012 and 31/12/2012 were considered, and those with at least a prescription of insulin glargine between 01/01/2013 and 31/12/2014 were included and followed up for one year. For each patient, we evaluated HbA1c levels both at baseline and during the follow-up period and the daily average dose of insulin. Medication adherence was defined by using medication possession ratio (MPR) and reported as proportion of patients with MPR≥80%. Results. 7,422 T2DM patients were available for the study. According to the antidiabetic medication prescribed, patients were categorized into four groups: insulin glargine only, insulin glargine plus oral glucose-lowering drugs, insulin glargine plus rapid-acting insulin, and insulin glargine plus DPP-4 inhibitors. Median daily dose of insulin among insulin glargine only patients was higher than in other groups (35 IU vs. 20 IU, p<0.05), and a higher percentage of them achieved a target HbA1c value of less than 7.0% (53.8% vs. 30%, p<0.001). Adherence to insulin treatment was lowest (41%) in the insulin glargine only group compared to other groups (ranging from 58.4% to 64.4%), p<0.001. Conclusions. A large proportion of T2DM patients treated with insulin fail in achieving the glycemic target of HbA1c level<7%, irrespective of treatment regimen; however, basal insulin only is associated with lower therapeutic unsuccess. Adherence to antidiabetes medications is also suboptimal in these patients and should be addressed to improve long-term outcomes of reducing and preventing microvascular and macrovascular complications

hERG1 Potassium Channel Expression in Colorectal Adenomas: Comparison with Other Preneoplastic Lesions of the Gastrointestinal Tract

Preneoplastic lesions represent a useful target for early diagnosis and follow-up of gastrointestinal malignancies. hERG1 channel expression was tested by immunohistochemistry (IHC) in a cohort of colorectal adenoma samples belonging to Italian subjects. Overall, hERG1 was expressed in 56.5% of cases with both high staining intensity and a high percentage of positive cells. Moreover, hERG1 was expressed in a higher percentage of dysplastic adenomas with respect to hyperplastic lesions, and the proportion of positive samples further increased in patients with high-grade dysplasia. Comparing hERG1 expression in other preneoplastic lesions of the GI tract (gastric dysplasia and Barrett’s esophagus), it emerged that in all the conditions, hERG1 was expressed with a diffused pattern, throughout the cell, with variable staining intensity within the samples. The highest expression was detected in gastric dysplasia samples and the lowest in Barrett’s esophagus at similar levels observed in colorectal adenomas. Our results show that hERG1 is aberrantly expressed in human preneoplastic lesions of the gastrointestinal tract and has a different pattern of expression and role in the different sites. Overall, the detection of hERG1 expression in preneoplastic lesions could represent a novel diagnostic or prognostic marker of progression in the gastrointestinal tract

Reproducibility of histologic classification of gastric cancer

A panel review of histologic specimens was carried out as part of a multi-centre case-control study of gastric cancer (GC) and diet. Comparisons of diagnoses of 100 GCs by six pathologists revealed agreement in histologic classification for about 70-80% of the cancers. Concordance was somewhat higher when using the Lauren rather than the Ming or World Health Organization classification systems. Histologic types from reading biopsy tissue agreed with those derived from surgical specimens for 65-75% of the 100 tumours. Intra-observer agreement in histologic classification, assessed by repeat readings up to 3 years apart by one pathologist, was 95%. The findings indicate that, although overall concordance was good, it is important to standardise diagnoses in multi-centre epidemiologic studies of GC by histologic type

Genetic and epigenetic alterations of cdh1 regulatory regions in hereditary and sporadic gastric cancer

E-cadherin is a key player in gastric cancer (GC) and germline alterations of CDH1, its encoding gene, are responsible for Hereditary Diffuse Gastric Cancer (HDGC) syndrome. This study aimed at elucidating the role of genetic variants and DNA methylation of CDH1 promoter and enhancers in the regulation of gene expression. For this purpose, we analyzed genetic variants of the CDH1 gene through Next-Generation Sequencing (NGS) in a series of GC cell lines (NCI-N87, KATO-III, SNU-1, SNU-5, GK2, AKG, KKP) and the corresponding CDH1 expression levels. By bisulfite genomic sequencing, we analyzed the methylation status of CDH1 regulatory regions in 8 GC cell lines, in a series of 13 sporadic GC tissues and in a group of 20 HDGC CDH1-negative patients and 6 healthy controls. The NGS analysis on CDH1 coding and regulatory regions detected genetic alterations in 3 out of 5 GC cell lines lacking functional E-cadherin. CDH1 regulatory regions showed different methylation patterns in patients and controls, GC cell lines and GC tissues, expressing different E-cadherin levels. Our results showed that alterations in terms of genetic variants and DNA methylation patterns of both promoter and enhancers are associated with CDH1 expression levels and have a role in its regulation.This research and its authors were funded by IRCCS IRST (G.T., C.M., R.D. V.A., M.R., F.R., M.C., S.P., G.M., D.C., P.U.) and by FEDER-Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020–Operacional Programme for Competitiveness and Internationalization (POCI), Portugal 2020, and by Portuguese funds through FCT–Fundação para a Ciência e a Tecnologia/Ministério da Ciência, Tecnologia e Inovação in the framework of the project “Institute for Research and Innovation in Health Sciences” (POCI-01-0145-FEDER-007274) (C.S.J., R.B.-M., A.A., C.O.). This work was also financed by the project NORTE-01-0145-FEDER-000029 (CANCER)-supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF)–project POCI-01-0145-FEDER-016390 (CancelStem) and PTDC/BTM-TEC/30164/2017 (3DChroMe), funded by ERDF, POCI and FCT

hERG1 Channels Regulate VEGF-A Secretion in Human Gastric Cancer: Clinicopathological Correlations and Therapeutical Implications

Purpose: hERG1 channels are aberrantly expressed in several types of human cancers, where they affect different aspects of cancer cell behavior. A thorough analysis of the functional role and clinical significance of hERG1 channels in gastric cancer is still lacking. Experimental Design: hERG1 expression was tested in a wide (508 samples) Italian cohort of surgically resected patients with gastric cancer, by immunohistochemistry and real-time quantitative PCR. The functional link between hERG1 and the VEGF-A was studied in different gastric cancer cell lines. The effects of hERG1 and VEGF-A inhibition were evaluated in vivo in xenograft mouse models. Results: hERG1 was positive in69% of the patients and positivity correlated with Lauren's intestinal type, fundus localization of the tumor, G1-G2 grading, I and II tumor-node-metastasis stage, and VEGF-A expression. hERG1 activity modulated VEGF-A secretion, through an AKT-dependent regulation of the transcriptional activity of the hypoxia inducible factor. Treatment of immunodeficient mice xenografted with human gastric cancer cells, with a combination of hERG1 blockers and anti-VEGF-A antibodies, impaired tumor growth more than single-drug treatments. Conclusion: Our results show that hERG1 (i) is aberrantly expressed in human gastric cancer since its early stages; (ii) drives an intracellular pathway leading to VEGF-A secretion; (iii) can be exploited to identify a gastric cancer patients' group where a combined treatment with antiangiogenic drugs and noncardiotoxic hERG1 inhibitors could be proposed. © 2014 American Association for Cancer Research

GHEP-ISFG collaborative exercise on mixture profiles of autosomal STRs (GHEP-MIX01, GHEP-MIX02 and GHEP-MIX03): results and evaluation

One of the main objectives of the Spanish and Portuguese-Speaking Group of the International Society for Forensic Genetics (GHEP-ISFG) is to promote and contribute to the development and dissemination of scientific knowledge in the area of forensic genetics. Due to this fact, GHEP-ISFG holds different working commissions that are set up to develop activities in scientific aspects of general interest. One of them, the Mixture Commission of GHEP-ISFG, has organized annually, since 2009, a collaborative exercise on analysis and interpretation of autosomal short tandem repeat (STR) mixture profiles. Until now, three exercises have been organized (GHEP-MIX01, GHEP-MIX02 and GHEP-MIX03), with 32, 24 and 17 participant laboratories respectively. The exercise aims to give a general vision by addressing, through the proposal of mock cases, aspects related to the edition of mixture profiles and the statistical treatment. The main conclusions obtained from these exercises may be summarized as follows. Firstly, the data show an increased tendency of the laboratories toward validation of DNA mixture profiles analysis following international recommendations (ISO/IEC 17025:2005). Secondly, the majority of discrepancies are mainly encountered in stutters positions (53.4%, 96.0% and 74.9%, respectively for the three editions). On the other hand, the results submitted reveal the importance of performing duplicate analysis by using different kits in order to reduce errors as much as possible. Regarding the statistical aspect (GHEP-MIX02 and 03), all participants employed the likelihood ratio (LR) parameter to evaluate the statistical compatibility and the formulas employed were quite similar. When the hypotheses to evaluate the LR value were locked by the coordinators (GHEP-MIX02) the results revealed a minor number of discrepancies that were mainly due to clerical reasons. However, the GHEP-MIX03 exercise allowed the participants to freely come up with their own hypotheses to calculate the LR value. In this situation the laboratories reported several options to explain the mock cases proposed and therefore significant differences between the final LR values were obtained. Complete information concerning the background of the criminal case is a critical aspect in order to select the adequate hypotheses to calculate the LR value. Although this should be a task for the judicial court to decide, it is important for the expert to account for the different possibilities and scenarios, and also offer this expertise to the judge. In addition, continuing education in the analysis and interpretation of mixture DNA profiles may also be a priority for the vast majority of forensic laboratories.Fil: Sala, Adriana Andrea. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Servicio de Huellas Digitales Genéticas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Crespillo, M.. Instituto Nacional de Toxicología y Ciencias Forenses; EspañaFil: Barrio, P. A.. Instituto Nacional de Toxicología y Ciencias Forenses; EspañaFil: Luque, J. A.. Instituto Nacional de Toxicología y Ciencias Forenses; EspañaFil: Alves, Cíntia. Universidad de Porto; PortugalFil: Aler, M.. Servicio de Laboratorio. Sección de Genética Forense y Criminalística; EspañaFil: Alessandrini, F.. Università Politecnica delle Marche. Department of Biomedical Sciences and Public Health; ItaliaFil: Andrade, L.. Instituto Nacional de Medicina Legal e Ciências Forenses, Delegação do Centro. Serviço de Genética e Biologia Forenses; PortugalFil: Barretto, R. M.. Universidade Estadual Paulista Julio de Mesquita Filho; BrasilFil: Bofarull, A.. Instituto Nacional de Toxicología y Ciencias Forenses; EspañaFil: Costa, S.. Instituto Nacional de Medicina Legal y Ciencias Forenses; PortugalFil: García, M. A.. Servicio de Criminalística de la Guardia Civil. Laboratorio Central de Criminalística. Departamento de Biología; EspañaFil: García, O.. Basque Country Police. Forensic Genetics Section. Forensic Science Unit; EspañaFil: Gaviria, A.. Cruz Roja Ecuatoriana. Laboratorio de Genética Molecular; EcuadorFil: Gladys, A.. Corte Suprema de Justicia de la Nación; ArgentinaFil: Gorostiza, A.. Grupo Zeltia. Genomica S. A. U.. Laboratorio de Identificación Genética; EspañaFil: Hernández, A.. Instituto Nacional de Toxicología y Ciencias Forenses; EspañaFil: Herrera, M.. Laboratorio Genda S. A.; ArgentinaFil: Hombreiro, L.. Jefatura Superior de Policía de Galicia. Brigada de Policía Científica. Laboratorio Territorial de Biología – ADN; EspañaFil: Ibarra, A. A.. Universidad de Antioquia; ColombiaFil: Jiménez, M. J.. Policia de la Generalitat – Mossos d’Esquadra. Divisió de Policia Científica. Àrea Central de Criminalística. Unitat Central de Laboratori Biològic; EspañaFil: Luque, G. M.. Instituto Nacional de Toxicología y Ciencias Forenses; EspañaFil: Madero, P.. Centro de Análisis Genéticos; EspañaFil: Martínez Jarreta, B.. Universidad de Zaragoza; EspañaFil: Masciovecchio, M. Verónica. IACA Laboratorios; ArgentinaFil: Modesti, Nidia Maria. Provincia de Córdoba. Poder Judicial; ArgentinaFil: Moreno, F.. Servicio Médico Legal. Unidad de Genética Forense; ChileFil: Pagano, S.. Dirección Nacional de Policía Técnica. Laboratorio de Análisis de ADN para el CODIS; UruguayFil: Pedrosa, S.. Navarra de Servicios y Tecnologías S. A. U.; EspañaFil: Plaza, G.. Neodiagnostica S. L.; EspañaFil: Prat, E.. Comisaría General de Policía Científica. Laboratorio de ADN; EspañaFil: Puente, J.. Laboratorio de Genética Clínica S. L.; EspañaFil: Rendo, F.. Universidad del País Vasco; EspañaFil: Ribeiro, T.. Instituto Nacional de Medicina Legal e Ciências Forenses, Delegação Sul. Serviço de Genética e Biologia Forenses; PortugalFil: Santamaría, E.. Instituto Nacional de Toxicología y Ciencias Forenses; EspañaFil: Saragoni, V. G.. Servicio Médico Legal. Departamento de Laboratorios. Unidad de Genética Forense; ChileFil: Whittle, M. R.. Genomic Engenharia Molecular; Brasi

Risk of hospitalization for heart failure in patients with type 2 diabetes newly treated with DPP-4 inhibitors or other oral glucose-lowering medications: A retrospective registry study on 127,555 patients from the Nationwide OsMed Health-DB Database

Aims Oral glucose-lowering medications are associated with excess risk of heart failure (HF). Given the absence of comparative data among drug classes, we performed a retrospective study in 32 Health Services of 16 Italian regions accounting for a population of 18 million individuals, to assess the association between HF risk and use of sulphonylureas, DPP-4i, and glitazones. Methods and results We extracted data on patients with type 2 diabetes who initiated treatment with DPP-4i, thiazolidinediones, or sulphonylureas alone or in combination with metformin during an accrual time of 2 years. The endpoint was hospitalization for HF (HHF) occurring after the first 6 months of therapy, and the observation was extended for up to 4 years. A total of 127 555 patients were included, of whom 14.3% were on DPP-4i, 72.5% on sulphonylurea, 13.2% on thiazolidinediones, with average 70.7% being on metformin as combination therapy. Patients in the three groups differed significantly for baseline characteristics: age, sex, Charlson index, concurrent medications, and previous cardiovascular events. During an average 2.6-year follow-up, after adjusting for measured confounders, use of DPP-4i was associated with a reduced risk of HHF compared with sulphonylureas [hazard ratio (HR) 0.78; 95% confidence interval (CI) 0.62-0.97; P = 0.026]. After propensity matching, the analysis was restricted to 39 465 patients, and the use of DPP-4i was still associated with a lower risk of HHF (HR 0.70; 95% CI 0.52-0.94; P = 0.018). Conclusion In a very large observational study, the use of DPP-4i was associated with a reduced risk of HHF when compared with sulphonylureas