Modeling Cardiotoxicity in Pediatric Oncology Patients Using Patient-Specific iPSC-Derived Cardiomyocytes Reveals Downregulation of Cardioprotective microRNAs.

Anthracyclines are widely used in the treatment of many solid cancers, but their efficacy is limited by cardiotoxicity. As the number of pediatric cancer survivors continues to rise, there has been a concomitant increase in people living with anthracycline-induced cardiotoxicity. Accordingly, there is an ongoing need for new models to better understand the pathophysiological mechanisms of anthracycline-induced cardiac damage. Here we generated induced pluripotent stem cells (iPSCs) from two pediatric oncology patients with acute cardiotoxicity induced by anthracyclines and differentiated them to ventricular cardiomyocytes (hiPSC-CMs). Comparative analysis of these cells (CTX hiPSC-CMs) and control hiPSC-CMs revealed that the former were significantly more sensitive to cell injury and death from the anthracycline doxorubicin (DOX), as measured by viability analysis, cleaved caspase 3 expression, oxidative stress, genomic and mitochondrial damage and sarcomeric disorganization. The expression of several mRNAs involved in structural integrity and inflammatory response were also differentially affected by DOX. Functionally, optical mapping analysis revealed higher arrythmia complexity after DOX treatment in CTX iPSC-CMs. Finally, using a panel of previously identified microRNAs associated with cardioprotection, we identified lower levels of miR-22-3p, miR-30b-5p, miR-90b-3p and miR-4732-3p in CTX iPSC-CMs under basal conditions. Our study provides valuable phenotype information for cellular models of cardiotoxicity and highlights the significance of using patient-derived cardiomyocytes for studying the associated pathogenic mechanisms.

First wave of COVID-19 impact on emergency general surgery in a Spanish tertiary hospital. A cohort study.

INTRODUCTION: The need to care for patients with emergency symptoms still continues during the COVID-19 pandemic. The number of emergency surgery procedures performed in Spanish hospitals decreased significantly during the first wave of COVID-19. PATIENTS AND METHODS: We performed a retrospective cohort study comparing the emergency surgery activity in a Spanish tertiary Hospital during the COVID-19 pandemic and emergency surgery activity registered in 2019 during the equivalent time period. RESULTS: A total of 1802 patients were included in control group (CG) versus 756 in pandemic group (PG). Mean number of patients who underwent emergency surgery during the control and pandemic periods was 3.42 patients per day, in contrast to 1.62 during the pandemic period, which represents a 52.6% decrease in emergency surgery activity. During the pandemic period, most of the patients consulted after more than 72 h of symptoms, representing a delay in presenting in the ER of 23.7% when compared to CG. Surgeries due to complications from previous elective procedures decreased (12% vs. 6.1%) in PG, probably because elective procedures are being postponed. We had a 13.1% COVID-19 positivity rate. Morbidity was higher during pandemic (52.5% vs. 35.2%). Mortality rates in patients undergoing emergency surgery was higher in PG (12.1% vs. 4.8%). CONCLUSIONS: The impact of the first wave of COVID-19 in emergency surgery activity has been profound. A significant reduction in emergency surgery was observed, along with longer time periods between patients' onset of symptoms and their arrival at the Emergency Department. Higher morbidity was also observed during the pandemic period.

Genomic mutation profile in progressive chronic lymphocytic leukemia patients prior to first-line chemoimmunotherapy with FCR and rituximab maintenance (REM).

Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia in Western countries and is notable for its variable clinical course. This variability is partly reflected by the mutational status of IGHV genes. Many CLL samples have been studied in recent years by next-generation sequencing. These studies have identified recurrent somatic mutations in NOTCH1, SF3B1, ATM, TP53, BIRC3 and others genes that play roles in cell cycle, DNA repair, RNA metabolism and splicing. In this study, we have taken a deep-targeted massive sequencing approach to analyze the impact of mutations in the most frequently mutated genes in patients with CLL enrolled in the REM (rituximab en mantenimiento) clinical trial. The mutational status of our patients with CLL, except for the TP53 gene, does not seem to affect the good results obtained with maintenance therapy with rituximab after front-line FCR treatment.

Reparative cell therapy for the heart: critical internal appraisal of the field in response to recent controversies.

The concept that cell-based repair of myocardial injury might be possible was introduced almost two decades ago; however, the field of cardiovascular reparative medicine has been criticized as translation to clinically effective approaches has been slow. The recent retraction of a series of papers has further impacted perception of this area of research. As researchers, clinicians, and teachers in this field, we felt it incumbent to critically appraise the current state of cardiac cell repair, determine what can be learned from past mistakes, and formulate best practices for future work. This special communication summarizes an introspective assessment of what has fallen short, how to prevent similar issues, and how the field might best move forward in the service of science and patients.

Tumor pseudoprogression during nivolumab immunotherapy for lung cancer. / Pseudoprogresión tumoral en el tratamiento inmunoterápico con nivolumab en el cáncer de pulmón.

OBJECTIVES: Immunotherapy is a new treatment in advanced lung cancer that works by modulating the immune response against malignant cells. One aspect that is challenging for radiologists in the evaluation of the response to immunotherapy is the phenomenon of pseudoprogression, in which the infiltration of inflammatory cells causes lesions to increase in size or new lesions to appear and then decrease in size or disappear. Pseudoprogression actually represents a response to treatment. We aimed to determine the frequency of pseudoprogression in patients with advanced stages of lung cancer treated with nivolumab. PATIENTS AND METHODS: We included 56 patients with advanced stages of lung cancer treated with nivolumab as a second-line or later treatment. We analyzed CT studies done while patients were undergoing nivolumab treatment. Tumor pseudoprogression was defined as an increase in the size of lesions or appearance of new lesions followed by a decrease in size or disappearance of these lesions on follow-up CT studies 4 to 8 weeks later. We did a descriptive analysis. RESULTS: In 15 patients, it was impossible to evaluate possible pseudoprogression because a second CT study was unavailable due to change of treatment or death. Tumor pseudoprogression was observed in 5 (12.2%) of the 41 patients, in most cases within 12 weeks of treatment initiation (in the fourth cycle). A second episode of pseudoprogression occurred in 2 (40%) of the 5 patients with an initial episode; the second episode occurred more than 12 weeks after treatment initiation. CONCLUSION: Tumor pseudoprogression occurred in 12.2% of patients with advanced stage lung cancer treated with nivolumab. An increase in lesion size or the appearance of new lesions must be assessed over time to avoid mistaking pseudoprogression for true progression of disease.

Clinical Characteristics and Electrophysiological Mechanisms Underlying Brugada ECG in Patients With Severe Hyperkalemia.

Background Several metabolic conditions can cause the Brugada ECG pattern, also called Brugada phenotype (BrPh). We aimed to define the clinical characteristics and outcome of BrPh patients and elucidate the mechanisms underlying BrPh attributed to hyperkalemia. Methods and Results We prospectively identified patients hospitalized with severe hyperkalemia and ECG diagnosis of BrPh and compared their clinical characteristics and outcome with patients with hyperkalemia but no BrPh ECG. Computer simulations investigated the roles of extracellular potassium increase, fibrosis at the right ventricular outflow tract, and epicardial/endocardial gradients in transient outward current. Over a 6-year period, 15 patients presented severe hyperkalemia with BrPh ECG that was transient and disappeared after normalization of their serum potassium. Most patients were admitted because of various severe medical conditions causing hyperkalemia. Six (40%) patients presented malignant arrhythmias and 6 died during admission. Multiple logistic regression analysis revealed that higher serum potassium levels (odds ratio, 15.8; 95% CI, 3.1-79; P=0.001) and male sex (odds ratio, 17; 95% CI, 1.05-286; P=0.045) were risk factors for developing BrPh ECG in patients with severe hyperkalemia. In simulations, hyperkalemia yielded BrPh by promoting delayed and heterogeneous right ventricular outflow tract activation attributed to elevation of resting potential, reduced availability of inward sodium channel conductance, and increased right ventricular outflow tract fibrosis. An elevated transient outward current gradient contributed to, but was not essential for, the BrPh phenotype. Conclusions In patients with severe hyperkalemia, a BrPh ECG is associated with malignant arrhythmias and all-cause mortality secondary to resting potential depolarization, reduced sodium current availability, and fibrosis at the right ventricular outflow tract.

Synthesis and biological activity of dehydrophos derivatives.

The synthesis of dehydrophos derivatives featuring modified peptide chains, characterized by the presence of substituents in the vinyl moiety, or possessing a phosphonic acid monoalkyl ester other than the monomethyl ester one, has been accomplished by a versatile procedure based on Horner-Wadsworth-Emmons olefination with suitable aldehydes and on the selective hydrolysis of the dialkyl phosphonate group. Such derivatives have been tested against a series of bacterial strains, using the naturally occurring peptide, dehydrophos, for comparison. Thus, the effects of the aforementioned structural variations on antimicrobial activity have been studied.

Methylation of WNT target genes AXIN2 and DKK1 as robust biomarkers for recurrence prediction in stage II colon cancer.

Stage II colon cancer (CC) still remains a clinical challenge with patient stratification for adjuvant therapy (AT) largely relying on clinical parameters. Prognostic biomarkers are urgently needed for better stratification. Previously, we have shown that WNT target genes AXIN2, DKK1, APCDD1, ASCL2 and LGR5 are silenced by DNA methylation and could serve as prognostic markers in stage II CC patients using methylation-specific PCR. Here, we have extended our discovery cohort AMC90-AJCC-II (N=65) and methylation was analyzed by quantitative pyrosequencing. Subsequently, we validated the results in an independent EPICOLON1 CC cohort (N=79). Methylation of WNT target genes is negatively correlated to mRNA expression. A combination of AXIN2 and DKK1 methylation significantly predicted recurrences in univariate (area under the curve (AUC)=0.83, confidence interval (CI): 0.72-0.94, P<0.0001) analysis in stage II microsatellite stable (MSS) CC patients. This two marker combination showed an AUC of 0.80 (CI: 0.68-0.91, P<0.0001) in the EPICOLON1 validation cohort. Multivariate analysis in the Academic Medical Center (AMC) cohort revealed that both WNT target gene methylation and consensus molecular subtype 4 (CMS4) are significantly associated with poor recurrence-free survival (hazard ratio (HR)methylation: 3.84, 95% CI: 1.14-12.43; HRCMS4: 3.73, 95% CI: 1.22-11.48). CMS4 subtype tumors with WNT target methylation showed worse prognosis. Combining WNT target gene methylation and CMS4 subtype lead to an AUC of 0.89 (0.791-0.982, P<0.0001) for recurrence prediction. Notably, we observed that methylation of DKK1 is high in BRAF mutant and CIMP (CpG island methylator phenotype)-positive cancers, whereas AXIN2 methylation appears to be associated with CMS4. Methylation of AXIN2 and DKK1 were found to be robust markers for recurrence prediction in stage II MSS CC patients. Further validation of these findings in a randomized and prospective manner could pave a way to identify poor prognosis patients of stage II CC for AT.

Candidate predisposing germline copy number variants in early onset colorectal cancer patients.

PURPOSE: A great proportion of the heritability of colorectal cancer (CRC) still remains unexplained, and rare variants, as well as copy number changes, have been proposed as potential candidates to explain the so-called 'missing heritability'. We aimed to identify rare high-to-moderately penetrant copy number variants (CNVs) in patients suspected of having hereditary CRC due to an early onset. METHODS/PATIENTS: We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRC patients (<50 years) without identifiable germline mutations in Mendelian genes related to this phenotype. Rare CNVs were selected by removing all CNVs detected at MAF >1% in the in-house control CNV database (n = 629 healthy controls). Copy number assignment was checked by duplex real-time quantitative PCR or multiplex ligation probe amplification. Somatic mutation analysis in candidate genes included: loss of heterozygosity studies, point mutation screening, and methylation status of the promoter. RESULTS: We have identified two rare germline deletions involving the AK3 and SLIT2 genes in two patients. The search for a second somatic mutational event in the corresponding CRC tumors showed loss of heterozygosity in AK3, and promoter hypermethylation in SLIT2. Both genes have been previously related to colorectal carcinogenesis. CONCLUSIONS: These findings suggest that AK3 and SLIT2 may be potential candidates involved in genetic susceptibility to CRC.

Myocardial commitment from human pluripotent stem cells: Rapid production of human heart grafts.

Genome editing on human pluripotent stem cells (hPSCs) together with the development of protocols for organ decellularization opens the door to the generation of autologous bioartificial hearts. Here we sought to generate for the first time a fluorescent reporter human embryonic stem cell (hESC) line by means of Transcription activator-like effector nucleases (TALENs) to efficiently produce cardiomyocyte-like cells (CLCs) from hPSCs and repopulate decellularized human heart ventricles for heart engineering. In our hands, targeting myosin heavy chain locus (MYH6) with mCherry fluorescent reporter by TALEN technology in hESCs did not alter major pluripotent-related features, and allowed for the definition of a robust protocol for CLCs production also from human induced pluripotent stem cells (hiPSCs) in 14 days. hPSCs-derived CLCs (hPSCs-CLCs) were next used to recellularize acellular cardiac scaffolds. Electrophysiological responses encountered when hPSCs-CLCs were cultured on ventricular decellularized extracellular matrix (vdECM) correlated with significant increases in the levels of expression of different ion channels determinant for calcium homeostasis and heart contractile function. Overall, the approach described here allows for the rapid generation of human cardiac grafts from hPSCs, in a total of 24 days, providing a suitable platform for cardiac engineering and disease modeling in the human setting.

[Prevalence of multiple sclerosis in the Region of Murcia]. / Prevalencia de la esclerosis multiple en la Region de Murcia.

INTRODUCTION: Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system with immune-mediated pathogenesis. Recent research points to an increase in its prevalence, and a number of studies relate Epstein-Barr virus (EBV) with its aetiology. AIMS: This study seeks to analyse the prevalence of MS in the Region of Murcia, and includes a description of the clinical characteristics at the time of onset of the disease, and of the EBV serological status of patients with MS. PATIENTS AND METHODS: We conducted a retrospective epidemiological study based on a sample consisting of the population living within the central-west healthcare area of the Region of Murcia (257,865 inhabitants). Clinical and serological data extracted from different sources were analysed. RESULTS: Prevalence of MS in the population under study: 88 cases/100,000 inhabitants. Prevalence of MS together with isolated demyelinating syndrome: 98.4 cases/100,000 inhabitants. Mean incidence of MS: 5.8 cases/100,000 inhabitants/year. At the onset of MS, 67.8% were females, 81.9% presented a relapsing-remitting course, the mean age was 31.4 years, the sensory system was the most frequently compromised (45.1%), onset was monofocal in 55.4% and the degree of disability on the Expanded Disability Status Scale was 2.1 points. The seroprevalence of EBV was 99.3%. The reactivation of EBV infection was related to the clinical activity of MS in 10 patients (45.4%). CONCLUSIONS: Currently, the prevalence of MS in the Region of Murcia is similar to that estimated in other Spanish autonomous regions. The study confirms the trend of increased prevalence observed over the last few decades.

TITLE: Prevalencia de la esclerosis multiple en la Region de Murcia.Introduccion. La esclerosis multiple (EM) es una enfermedad inflamatoria desmielinizante del sistema nervioso central con patogenia inmunomediada. Recientes estudios indican un aumento de su prevalencia, y numerosos trabajos relacionan el virus de Epstein-Barr (VEB) con su etiologia. Objetivo. Analisis de prevalencia de la EM en la Region de Murcia, incluyendo la descripcion de las caracteristicas clinicas en el momento del inicio de la enfermedad, y del estado serologico del VEB de los pacientes con EM. Pacientes y metodos. Estudio epidemiologico retrospectivo, tomando como muestra la poblacion residente en el area sanitaria centro-oeste de la Region de Murcia (257.865 habitantes). Se analizan datos clinicos y serologicos extraidos de diferentes fuentes. Resultados. Prevalencia de la EM en la poblacion estudiada: 88 casos/100.000 habitantes. Prevalencia de la EM junto con el sindrome desmielinizante aislado: 98,4 casos/100.000 habitantes. Incidencia media de la EM: 5,8 casos/100.000 habitantes/año. En el inicio de la EM, el 67,8% eran mujeres, el 81,9% presentaba un curso recurrente-remitente, la edad media era de 31,4 años, el sistema funcional mas frecuentemente afectado era el sensitivo (45,1%), el inicio fue monofocal en el 55,4% y el grado de discapacidad en la Expanded Disability Status Scale era de 2,1 puntos. La seroprevalencia del VEB fue del 99,3%. La reactivacion de la infeccion por VEB se relaciono con actividad clinica de EM en 10 pacientes (45,4%). Conclusiones. Actualmente, la prevalencia de la EM en la Region de Murcia es similar a la estimada en otras comunidades autonomas españolas. El estudio confirma la tendencia de incremento de prevalencia observada en las ultimas decadas.

"Assessment of RIFLE and AKIN criteria to define acute renal dysfunction for HIPEC procedures for ovarian and non ovarian peritoneal malignances".

BACKGROUND: The acute renal dysfunction (ARD) is a common complication in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Our aim is evaluate the ARD post-HIPEC procedures using the RIFLE and AKIN criteria. Evaluate the risk factors and analyze ARD's impact on postoperative course. METHODS: From 2011 to 2014, in a retrospective way using a prospective database were operated by HIPEC procedure. The ARD was analyzed by RIFLE and AKIN criteria. The perioperative features were analyzed and a multivariate analysis was performed to define the risk factors to develop the ARD. RESULTS: 141 patients were treated and analyzed. The ARD was detected in 30.5% (Injury 18.4% and Failure 12.1%) when RIFLE criteria were applied. The multivariate analysis detected that decrease of pH during HIPEC [OR = 29.39 (5.09-169.76)], PCI [OR = 1.07 (1.01-1.15)] and ureteral catheters [OR = 12.71 (1.44-111.85)] were associated to the development of acute renal injury (ARI) post-HIPEC. Decrease of Na during HIPEC [OR = 1.15 (1.01-1.30)], intraoperative inotrope use [OR = 3.83 (1.12-13.09)] and PCI [OR = 1.06 (1.0-1.14)] were associated to acute renal failure (ARF) post-HIPEC. The ARD was related to a higher length of stay hospital (17.2 ± 11 vs. 13.8 ± 8 days) (p = 0.05) but no impact in early survival was observed in ARD group. CONCLUSIONS: The widespread use of RIFLE criteria for ARD would have major benefits in terms of accurately diagnosing patients undergone HIPEC procedures. The ARD has a detrimental impact in length of stay hospital. The knowledge of risk factors helps us to prevent the ARD post-HIPEC by means of an aggressive and multidisciplinary perioperative management.

Incidence and Long-Term Prognosis of Cancer After Kidney Transplantation.

BACKGROUND: Malignancy is an important cause of mortality in renal transplants recipients. The incidence of cancer is increased by immunosuppressive treatment and longer kidney graft survival. The aim of this study was to evaluate the incidence, prognosis and survival of posttransplant malignancies: solid organ cancer (SOC), posttransplant lymphoproliferative disorder (PTLD), and nonmelanoma skin cancer (NMSC). METHODS: We retrospectively studied the development of cancers among kidney transplants patients in our hospital from January 1979 to January 2015. We analyzed demographic and clinical characteristics, risk factors, and patient survival after tumor diagnosis. RESULTS: We included 1450 kidney transplants recipients with a mean follow-up was 10 years; among them, 194 developed malignancies. The mean age at presentation was 59 ± 10 years. The SOC, PTLD, and NMSC incidences were 6.2%, 1.2%, and 6%, respectively. The most common tumors were kidney (16.6%), colon (11%), bladder (10%), breast (10%), prostate (10%), and lung (8.8%). The median times to development of a SOC, PTLD, and NMSC were 6.86 (range, 3.7-12), 4.43 (range, 1.8-5.7), and 8.19 (range, 3.8-12.2) years, respectively. Risk factors associated with developing SOC and PTLD were patient age (odds ratio [OR], 1.03; P < .001) and time posttransplant (OR, 1.05; P = .02), whereas for NMSC were to be male (OR, 3.61; P < .001), to take calcineurin inhibitors (OR, 2.17; P = .034), patient age (OR, 1.05; P < .001) and time posttransplant (OR, 1.15; P < .01). The mean survival time from the diagnosis of SOC, PTLD, and NMSC were 2.09 (range, 0.1-5.3), 0.22 (range, 0.05-1.9), and 7.68 (range, 3.9-10.5) years, respectively (P < .001). CONCLUSIONS: SOC occurs more frequently than other malignancies among renal transplant patients. NMSC has better survival and prognosis. Older patients and prolonged graft function have a greater risk of developing malignancies.

Acellular human heart matrix: A critical step toward whole heart grafts.

The best definitive treatment option for end-stage heart failure currently is transplantation, which is limited by donor availability and immunorejection. Generating an autologous bioartificial heart could overcome these limitations. Here, we have decellularized a human heart, preserving its 3-dimensional architecture and vascularity, and recellularized the decellularized extracellular matrix (dECM). We decellularized 39 human hearts with sodium-dodecyl-sulfate for 4-8 days. Cell removal and architectural integrity were determined anatomically, functionally, and histologically. To assess cytocompatibility, we cultured human cardiac-progenitor cells (hCPC), bone-marrow mesenchymal cells (hMSCs), human endothelial cells (HUVECs), and H9c1 and HL-1 cardiomyocytes in vitro on dECM ventricles up to 21 days. Cell survival, gene expression, organization and/or electrical coupling were analyzed and compared to conventional 2-dimensional cultures. Decellularization removed cells but preserved the 3-dimensional cardiac macro and microstructure and the native vascular network in a perfusable state. Cell survival was observed on dECM for 21 days. hCPCs and hMSCs expressed cardiocyte genes but did not adopt cardiocyte morphology or organization; HUVECs formed a lining of endocardium and vasculature; differentiated cardiomyocytes organized into nascent muscle bundles and displayed mature calcium dynamics and electrical coupling in recellularized dECM. In summary, decellularization of human hearts provides a biocompatible scaffold that retains 3-dimensional architecture and vascularity and that can be recellularized with parenchymal and vascular cells. dECM promotes cardiocyte gene expression in stem cells and organizes existing cardiomyocytes into nascent muscle showing electrical coupling. These findings represent a first step toward manufacturing human heart grafts or matrix components for treating cardiovascular disease.

Short-term evolution of renal transplant with grafts from donation after cardiac death: Type III Maastricht category.

BACKGROUND: Kidney transplantation from donors after cardiac death (Type III Maastricht category) is a therapeutic option for patients with terminal renal failure. MATERIALS AND METHODS: We present a cohort of 8 patients who received a kidney transplant from donors after cardiac death (DCD). We analyzed the analytical results for the first 6 months after transplantation. RESULTS: We included 8 cases of kidney transplants with organs from DCD (Type III Maastricht category). The mean age of donors was 58.40 ± 4.39 years and 3 (60%) were male. The mean creatinine (Cr) level prior to death was 1.10 ± 0.36 mg/dL. The mean age of recipients was 59.88 ± 10.58 years and 7 (87.5%) were male. Seven patients (87.5%) were on hemodialysis, whereas only 1 (12.5%) was on peritoneal dialysis. The median time on renal replacement therapy was 18 months (range, 2-76). Mean total warm ischemia time (WIT) was 24.88 ± 6.72 minutes, whereas the mean real WIT was 20.13 ± 4.51 minutes. The mean cold ischemia time (CIT) was 6 hours and 12 minutes ± 2 hours. Preimplantation biopsy showed acute tubular necrosis (extensive 40%). Tubular atrophy was mild in 100% of cases. After transplantation, 6 patients (75%) had delayed graft function requiring dialysis sessions whereas 2 patients (25%) did not require renal replacement therapy. Mean Cr level at 1, 3, and 6 months after transplantation was 2.37, 1.75, and 1.17 mg/dL, respectively. CONCLUSION: Kidney transplantation with grafts from donors after cardiac arrest Maastricht Type III evolves favorably in the short term. According to preliminary results, controlled asystole donation could be an effective alternative to transplantation.

Index high insulin resistance in pancreas-kidney transplantation contributes to poor long-term survival of the pancreas graft.

BACKGROUND: Pancreas-kidney transplantation (PKT) is the best therapeutic option for diabetic patients with end-stage renal failure. Peripheral insulin resistance and the percentage of remaining ß-cells in the PKT have been little studied in medical literature. METHODS: We analyzed PKT performed in our hospital from January 1992 to January 2014, with follow-up for 5 years. Metabolic values related to glycemic were studied, namely, proteinuria, peptide C, glucose, insulin, and glycosylated hemoglobin. We analyzed insulin resistance (homeostatic model assessment [HOMA]-IR), the percentage of remaining ß-cells (HOMA-ß), and the influence of these variables on the glycemic profile and graft survival. RESULTS: In the study period, 156 simultaneous PKT were performed in our center. At 2 years posttransplantation, the median value of HOMA-IR kidney-pancreas was 4. We compared transplantation with lower HOMA-IR (<4) and higher HOMA-IR (>4). HOMA-ß (36 [26-67] vs 29 [14-42]; P = .04), glucose (86 [80-90] vs 81 [74-89]; P = .018), and body mass index (BMI; 24 [21-27] vs 21 [19-24]; P = .013) were greater in the group HOMA-IR>4 versus HOMA-IR<4 group, respectively, after 3 months. These differences in glycemic profile were maintained until the first year after transplantation. At 2 and 5 years of follow-up, the HOMA-IR>4 group showed higher glucose levels and greater BMI, but not differences in HOMA-ß. At 1 and 5 years posttransplantation, pancreatic graft survival in the HOMA-IR>4 group (82.9% vs 92.5%) was lower compared with the HOMA-IR<4 group (67% vs 87.5%; P = .016). CONCLUSIONS: PKT exhibit an altered glycemic profile in the posttransplantation follow-up associated with the percentage of remaining ß-cells and peripheral insulin resistance. PKT patients with peripheral insulin resistance showed decreased pancreatic graft survival.

Effect of oral anticoagulants on the outcome of faecal immunochemical test.

BACKGROUND: We aimed to evaluate whether oral anticoagulants (OACs) alter faecal immunochemical test (FIT) performance in average-risk colorectal cancer (CRC) screening. METHODS: Individuals aged 50-69 years were invited to receive one FIT sample (cutoff 75 ng ml(-1)) between November 2008 and June 2011. RESULTS: Faecal immunochemical test was positive in 9.3% (21 out of 224) of users of OAC and 6.2% (365 out of 5821) of non-users (P-trend=0.07). The positive predictive value (PPV) for advanced neoplasia (AN) in non-users was 50.4% vs 47.6% in users (odds ratio, 0.70; 95% CI, 0.3-1.8; P=0.5). The PPV for AN in OAC more antiplatelets (aspirin or clopidogrel) was 75% (odds ratio, 2; 95% CI, 0.4-10.8; P=0.4). CONCLUSIONS: Oral anticoagulant did not significantly modify the PPV for AN in this population-based colorectal screening program. The detection rate of advanced adenoma was higher in the combination OAC more antiplatelets.

A genome-wide association study on copy-number variation identifies a 11q11 loss as a candidate susceptibility variant for colorectal cancer.

Colorectal cancer (CRC) is a complex disease, and therefore its development is determined by the combination of both environmental factors and genetic variants. Although genome-wide association studies (GWAS) of SNP variation have conveniently identified 20 genetic variants so far, a significant proportion of the observed heritability is yet to be explained. Common copy-number variants (CNVs) are one of the most important genomic sources of variability, and hence a potential source to explain part of this missing genetic fraction. Therefore, we have performed a GWAS on CNVs to explore the relationship between common structural variation and CRC development. Phase 1 of the GWAS consisted of 881 cases and 667 controls from a Spanish cohort. Copy-number status was validated by quantitative PCR for each of those common CNVs potentially associated with CRC in phase I. Subsequently, SNPs were chosen as proxies for the validated CNVs for phase II replication (1,342 Spanish cases and 1,874 Spanish controls). Four common CNVs were found to be associated with CRC and were further replicated in Phase II. Finally, we found that SNP rs1944682, tagging a 11q11 CNV, was nominally associated with CRC susceptibility (p value = 0.039; OR = 1.122). This locus has been previously related to extreme obesity phenotypes, which could suggest a relationship between body weight and CRC susceptibility.