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Background The role of platelets in the pathogenesis of venous thromboembolism (VTE) is receiving increasing attention; however, limited information is available on platelet function in the acute phase of the disease. Objective To characterize platelet function according to VTE phenotypes. Patients/Methods In total, 154 subjects (isolated pulmonary embolism [iPE], n = 28; isolated deep vein thrombosis [iDVT], n = 35; DVT+PE, n = 91) were included. In this study platelet function analyzer (PFA)-200, light transmission aggregometry (LTA), thrombin generation (TG) in presence (PRP) and absence (PFP) of platelets and platelet flow cytometry were investigated. LASSO regression was used to select clinical and platelet biomarkers that distinguish between VTE phenotypes. Results PFA-200 results did not differ between VTE phenotypes. LTA from DVT+PE subjects showed lowest maximum aggregation after epinephrine and adenosine diphosphate compared to iPE and iDVT. Lower % of PAC-1-positive platelets after in-vitro trigger were present in DVT+PE and iPE compared to iDVT. TG in PRP had lower peak height and velocity in DVT+PE and iPE against iDVT. The results of LASSO regression for the distinction between DVT+PE vs iDVT identified 18 variables (AUC =0.93) of which 72% were platelet biomarkers. For distinction between iPE and iDVT, 10 variables were selected (AUC = 0.96) of which 50% were platelet-related. Obesity was the only variable weakly discriminating between DVT+PE vs iPE (AUC = 0.66). Conclusion This explorative study suggests an important distinction between PE-related phenotypes and iDVT when considering clinical and platelet function data. Lower platelet-dependent TG along with reduced platelet reactivity suggest higher platelet degranulation in PE-dependent phenotypes compared to iDVT.

Aims Whether and how iron deficiency (ID) impacts patients with heart failure (HF) with preserved ejection fraction (HFpEF) remain unclear. The aim of our study was to investigate the impact of ID on functional status, exercise capacity, and prognosis in HFpEF. Methods and results The study population consisted of 300 HFpEF patients. ID was defined as serum ferritin

Background and objective The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable, and accurate prognostic markers are needed. KL-6 is a mucin-like glycoprotein (MUC1) expressed by type II pneumocytes, while CYFRA 21-1 is expressed by alveolar and bronchiolar epithelial cells. Both are released into the blood from cell injury. Methods Serum KL-6 and CYFRA 21-1 levels were measured in a retrospective (n = 189) and a prospective (n = 118) cohort of SSc patients. Genotyping of MUC1 rs4072037 was performed. Linear mixed-effect models were used to evaluate the relationship with change in lung function parameters over time, while association with survival was evaluated with Cox proportional hazard analysis. Results In both cohorts, KL-6 and CYFRA 21-1 were highest in patients with lung involvement, and in patients with extensive rather than limited ILD. KL-6 was higher in patients carrying the MUC1 rs4072037 G allele in both cohorts. In patients with SSc-ILD, serum KL-6, but not CYFRA 21-1, was significantly associated with DLCO decline in both cohorts (P = 0.001 and P = 0.004, respectively), and with FVC decline in the retrospective cohort (P = 0.005), but not the prospective cohort. When combining the cohorts and subgrouping by severity (median CPI = 45.97), KL-6 remained predictive of decline in DLCO in both milder (P = 0.007) and more severe disease (P = 0.02) on multivariable analysis correcting for age, gender, ethnicity, smoking history and MUC1 allele carriage. Conclusion Our results suggest serum KL-6 predicts decline in lung function in SSc, suggesting its clinical utility in risk stratification for progressive SSc-ILD.

The objective of this retrospective study was to determine the role of F-18-FDG PET/CT in a large cohort of 495 patients with metastatic neuroendocrine neoplasms (NENs) who were treated with peptide receptor radionuclide therapy (PRRT) with a long-term follow-up. Methods: The 495 patients were treated with Lu-177- or Y-90-DOTATOC/DOTATATE PRRT between February 2002 and July 2018. All subjects received both Ga-68-DOTATOC/TATE/NOC and F-18-FDG PET/CT before treatment and were followed 3-189 mo. Kaplan-Meier analysis, log-rank testing (Mantel-Cox), and Cox regression analysis were performed for overall survival (OS) and progression-free survival (PFS). Results: One hundred ninety-nine patients (40.2%) presented with pancreatic NENs, 49 with cancer of unknown primary, and 139 with midgut NENs, whereas the primary tumor was present in the rectum in 20, in the lung in 38, in the stomach in 8, and in other locations in 42. F-18-FDG PET/CT was positive in 382 (77.2%) patients and negative in 113 (22.8%) before PRRT, whereas 100% were Ga-68-DOTATOC/TATE/NOC-positive. For all patients, the median PFS and OS, defined from the start of PRRT, were 19.6 mo and 58.7 mo, respectively. Positive F-18-FDG results predicted shorter PFS (18.5 mo vs. 24.1 mo; P = 0.0015) and OS (53.2 mo vs. 83.1 mo; P

Objectives: To determine the accuracy of, and agreement among, EEG and aEEG readers' estimation of maturity and a novel computational measure of functional brain age (FBA) in preterm infants. Methods: Seven experts estimated the postmenstrual ages (PMA) in a cohort of recordings from preterm infants using cloud-based review software. The FBA was calculated using a machine learning-based algorithm. Error analysis was used to determine the accuracy of PMA assessments and intraclass correlation (ICC) was used to assess agreement between experts. Results: EEG recordings from a PMA range 25 to 38 weeks were successfully interpreted. In 179 recordings from 62 infants interpreted by all human readers, there was moderate agreement between experts (aEEG ICC = 0.724; 95%CI:0.658-0.781 and EEG ICC = 0.517; 95%CI:0.311-0.664). In 149 recordings from 61 infants interpreted by all human readers and the FBA algorithm, random and systematic errors in visual interpretation of PMA were significantly higher than the computational FBA estimate. Tracking of maturation in individual infants showed stable FBA trajectories, but the trajectories of the experts' PMA estimate were more likely to be obscured by random errors. The accuracy of visual interpretation of PMA estimation was compromised by neurodevelopmental outcome for both aEEG and EEG review. Interpretation: Visual assessment of infant maturity is possible from the EEG or aEEG, with an average of human experts providing the highest accuracy. Tracking PMA of individual infants was hampered by errors in experts' estimates. FBA provided the most accurate maturity assessment and has potential as a biomarker of early outcome.

Background The choice of treatment in laryngeal cancer is mainly based on tumor stage, post-treatment morbidity and quality of life. Biological tumor markers might also be of potential clinical relevance. Objective of the review The aim was to systematically review the value of published biological tumor markers to predict local control in laryngeal cancer patients treated with definitive radiotherapy. Type of review Systematic review. Search strategy PubMed, Embase, Cochrane Library. Evaluation method A literature search was performed using multiple terms for laryngeal cancer, radiotherapy, biological markers, detection methods and local control or survival. Studies regarding the relation between biological tumor markers and local control or survival in laryngeal cancer patients primarily treated with radiotherapy were included. Markers were clustered on biological function. Quality of all studies was assessed. Study selection, data extraction and quality assessment was performed by two independent reviewers. Results A total of 52 studies out of 618 manuscripts, concerning 118 markers, were included. EGFR and P53 showed consistent evidence for not being predictive of local control after primary radiotherapy, whereas proliferation markers (ie high Ki-67 expression) showed some, but no consistent, evidence for being predictive of better local control. Other clusters of markers (markers involved in angiogenesis and hypoxia, apoptosis markers, cell cycle, COX-2 and DNA characteristics) showed no consistent evidence towards being predictors of local control after primary radiotherapy. Conclusions Cell proliferation could be of potential interest for predicting local control after primary radiotherapy in laryngeal cancer patients, whereas EGFR and p53 are not predictive in contrast to some previous analyses. Large diversity in research methods is found between studies, which results in contradictory outcomes. Future studies need to be more standardised and well described according to the REMARK criteria in order to have better insight into which biomarkers can be used as predictors of local control after primary radiotherapy.

BackgroundThere is no effective prognostic signature that could predict the prognosis of nasopharyngeal carcinoma (NPC).MethodsWe constructed a prognostic signature based on five microRNAs using random forest and Least Absolute Shrinkage And Selection Operator (LASSO) algorithm on the GSE32960 cohort (N = 213). We verified its prognostic value using three independent external validation cohorts (GSE36682, N = 62; GSE70970, N = 246; and TCGA-HNSC, N = 523). Through principal component analysis, receiver operating characteristic curve analysis, and C-index calculation, we confirmed the predictive accuracy of this prognostic signature.ResultsWe calculated the risk score based on the LASSO algorithm and divided the patients into high- and low-risk groups according to the calculated optimal cutoff value. The patients in the high-risk group tended to have a worse prognosis outcome and chemotherapy response. The time-dependent receiver operating characteristic curve showed that the 1-year overall survival rate of the five-microRNA signature had an area under the curve of more than 0.83. A functional annotation analysis of the five-microRNA signature showed that the patients in the high-risk group were usually accompanied by activation of DNA repair and MYC-target pathways, while the patients in the low-risk group had higher immune-related pathway signals.ConclusionsWe constructed a five-microRNA prognostic signature, which could accurately predict the prognosis of nasopharyngeal carcinoma, and constructed a nomogram that could conveniently predict the overall survival of patients.

Background: Stroke is the second leading cause of death worldwide with heterogeneous characteristics. The subtypes of stroke are due to different pathophysiological regulations and causes. This study aimed to investigate the correlation of serum levels of apolipoprotein B 48, interleukin-1 beta and Homocysteine with BMI in patients with ischemic stroke (IS). Methods: Over one hundred controls (120) and an equal number of IS patients, including 31 women and 89 men, were recruited to participate in the case-control study conducted at Imam Reza Hospital (Tabriz, Iran) from February 2019 to March 2020. We measured serum levels of apolipoprotein B 48, interleukin-1 beta, and Homocysteine. Receiver operating characteristic analysis (ROC) was performed to evaluate the diagnostic value of these indices in patients and control groups. Results: The mean serum levels of apolipoprotein B 48, interleukin-1 beta, and Homocysteine, were significantly increased in the experimental group compared to the control group with a p-value of 0.001. The ROC curve analysis showed that the area under the curve for apo B48, IL-1 beta, hs-CRP, and Homocysteine serum levels were 0.94, 0.98, 0.99, and 1, respectively. Conclusions: The results of our current study show that the determination of serum levels of apolipoprotein B 48, interleukin-1 beta, and Homocysteine can potentially be used to monitor and diagnose IS patients. However, there was no statistically significant correlation between serum levels of apolipoprotein B 48, interleukin 1 beta and Homocysteine and BMI in the patient group. However, there was a statistically significant inverse correlation between serum levels of high-sensitivity C-reactive protein (hs-CRP) and BMI in the patient group., Research Vice-Chancellor of Tabriz University of medical sciences, Tabriz, IRAN [25992], The present study was supported by grants from the Research Vice-Chancellor of Tabriz University of medical sciences, Tabriz, IRAN grant no. 25992.

Purpose: To develop a prognostic model and cytogenetic risk classification for previously treated patients with chronic lymphocytic leukemia (CLL) undergoing reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT). Experimental Design: We performed a retrospective analysis of outcomes of 606 patients with CLL who underwent RIC allogeneic HCT between 2008 and 2014 reported to the Center for International Blood and Marrow Transplant Research. Results: On the basis of multivariable models, disease status, comorbidity index, lymphocyte count, and white blood cell count at HCT were selected for the development of prognostic model. Using the prognostic score, we stratified patients into low-, intermediate-, high-, and very-high-risk [4-year progression-free survival (PFS) 58%, 42%, 33%, and 25%, respectively, P < 0.0001; 4-year overall survival (OS) 70%, 57%, 54%, and 38%, respectively, P < 0.0001]. We also evaluated karyotypic abnormalities together with del(17p) and found that del(17p) or ≥5 abnormalities showed inferior PFS. Using a multivariable model, we classified cytogenetic risk into low, intermediate, and high (P < 0.0001). When the prognostic score and cytogenetic risk were combined, patients with low prognostic score and low cytogenetic risk had prolonged PFS (61% at 4 years) and OS (75% at 4 years). Conclusions: In this large cohort of patients with previously treated CLL who underwent RIC HCT, we developed a robust prognostic scoring system of HCT outcomes and a novel cytogenetic-based risk stratification system. These prognostic models can be used for counseling patients, comparing data across studies, and providing a benchmark for future interventions. For future study, we will further validate these models for patients receiving targeted therapies prior to HCT.

Low heart rate variability (HRV) is related to health problems that are known reasons for sick-leave or early retirement. A 1-minute-protocol could allow large scale HRV measurement for screening of health problems and, potentially, sustained employability. Our objectives were to explore the association of HRV with measures of health. Cross-sectional design with 877 Dutch employees assessed during a Workers’ Health Assessment. Personal and job characteristics, workability, psychological and mental problems, and lifestyle were measured with questionnaires. Biometry was measured (BMI, waist circumference, blood pressure, glucose, cholesterol). HRV was assessed with a 1-minute paced deep-breathing protocol and expressed as mean heart rate range (MHRR). A low MHRR indicates a higher health risk. Groups were classified age adjusted for HRV and compared. Spearman correlations between raw MHRR and the other measures were calculated. Significant univariable correlations (p < 0.05) were entered in a linear regression model to explore the multivariable association with MHRR. Age, years of employment, BMI and waist circumference differed significantly between HRV groups. Significant correlations were found between MHRR and age, workability, BMI, waist circumference, cholesterol, systolic and diastolic blood-pressure and reported physical activity and alcohol consumption. In the multivariable analyses 21.1% of variance was explained: a low HRV correlates with aging, higher BMI and higher levels of reported physically activity. HRV was significantly associated with age, measures of obesity (BMI, waist circumference), and with reported physical activity, which provides a first glance of the utility of a 1-minute paced deep-breathing HRV protocol as part of a comprehensive preventive Workers’ Health Assessment.Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat ivecommons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate redit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

The majority of patients with newly diagnosed chronic myeloid leukemia (CML) will enjoy a life expectancy equivalent to that of unaffected individuals, but will remain on life-long treatment with a concomitant requirement for on-going hospital interactions for molecular monitoring and drug dispensing. In order to determine more accurately the frequency of monitoring required, we performed a ‘real-life’ retrospective single-center cohort study of 450 patients with CML in at least major molecular remission (MR3) to analyze the risk of loss of MR3 [defined as at least 2 consecutive real-time quantitative polymerase chain reaction (RT-qPCR) results >0.1% International Scale (IS)]. Patients who achieved sustained MR4 (sMR4, BCR-ABL1 RT-qPCR

Background Inflammation scores based on general inflammation markers as leucocyte count or C-reactive protein have been evaluated as prognostic markers of inferior survival in several cancers. In small cell lung cancer (SCLC), however, inflammation scores are less studied. In the present study, we set out to perform a systematic review and meta-analysis investigating reported associations between inflammation scores and overall survival (OS) in SCLC. Methods A literature search was performed in PubMed, Embase, Scopus, and Web of Science following the Preferred Reporting Items for Systematic and Meta-Analyses (PRISMA) guidelines. Of the identified publications, only studies in English containing original data evaluating inflammation scores as a prognostic factor in SCLC patients were included. Hazard ratios (HRs) for OS were pooled in a random-effects model. Results In total, 33 articles were included evaluating eight different inflammation scores in 7762 SCLC patients. Seven of the identified scores were based on leucocyte count. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte (PLR) ratio were the most frequently evaluated scores (NLR: n = 23; PLR: n = 22). For NLR, a meta-analysis including 16 studies demonstrated that patients with a high NLR had a significantly shorter OS compared to patients with a low NLR (pooled HR = 1.39 (95% CI, 1.23–1.56)). For PLR, an association with survival could not be confirmed in a meta-analysis performed based on eight studies (pooled HR = 1.20 (95% CI, 0.96–1.51)). Conclusions This review identifies that inflammation scores based on general inflammation markers have some potential as prognostic biomarkers in SCLC. The meta-analyses indicated that NLR is associated with inferior OS, whereas an association between PLR and OS could not be confirmed. Thus, NLR could be a useful biomarker of OS in SCLC patients. Systematic review registration The protocol for the study was submitted to the PROSPERO database (registration number CRD42020188553).

Background: Carotid endarterectomy (CEA) has been associated with both postoperative cognitive dysfunction (POCD) and improvement (POCI). However, the prognostic significance of postoperative cognitive changes related to CEA is largely unknown. The aim of this study was to examine the associations between postoperative cognitive changes after CEA and long-term survival.Methods: We studied 43 patients 1 day before CEA as well as 4 days and 3 months after surgery with an extensive neuropsychological test array, and followed them for up to 14 years. POCD and POCI relative to baseline were determined with the reliable change index derived from 17 healthy controls. Associations between POCD/POCI and mortality within the patient group were studied with Cox regression analyses adjusted for confounders.Results: POCD in any functional domain was evident in 28% of patients 4 days after surgery and in 33% of patients 3 months after surgery. POCI was shown in 23% of patients at 4 days and in 44% of patients at 3 months. POCD at 3 months was associated with higher long-term mortality (hazard ratio 5.0, 95% CI 1.8–13.9, p = 0.002) compared with patients with no cognitive decline.Conclusions: Our findings suggest that POCD in a stable phase, 3 months after CEA predicts premature death. Evaluation of postoperative cognitive changes is essential, and POCD in a stable phase after CEA should prompt scrutiny of underlying factors and better adherence to therapies to prevent recurrences and to promote early intervention in imminent deterioration.

Author Correction: https://doi.org/10.1038/s41598-021-98620-6. The original version of this Article contained errors: The spelling of the author Monica Neri was incorrectly given as Neri Monica; Additionally, Affiliation 39 was incorrectly given as ‘National Institute of Health, Lisbon, Portugal’, the correct affiliation is listed below: National Institute of Health Doutor Ricardo Jorge, Porto, Portugal. The original Article has been corrected. [Abstract] The comet assay or single cell gel electrophoresis, is the most common method used to measure strand breaks and a variety of other DNA lesions in human populations. To estimate the risk of overall mortality, mortality by cause, and cancer incidence associated to DNA damage, a cohort of 2,403 healthy individuals (25,978 person-years) screened in 16 laboratories using the comet assay between 1996 and 2016 was followed-up. Kaplan–Meier analysis indicated a worse overall survival in the medium and high tertile of DNA damage (p

Background: Women are less likely to receive cardiac resynchronization therapy, yet, they are more responsive to the therapy and respond at shorter QRS duration. The present study hypothesized that a relatively larger left ventricular (LV) electrical dyssynchrony in smaller hearts contributes to the better cardiac resynchronization therapy response in women. For this, the vectorcardiography-derived QRS area is used, since it allows for a more detailed quantification of electrical dyssynchrony compared with conventional electrocardiographic markers. Methods: Data from a multicenter registry of 725 cardiac resynchronization therapy patients (median follow-up, 4.2 years [interquartile range, 2.7–6.1]) were analyzed. Baseline electrical dyssynchrony was evaluated using the QRS area and the corrected QRS area for heart size using the LV end-diastolic volume (QRSarea/LVEDV). Impact of the QRSarea/LVEDV ratio on the association between sex and LV reverse remodeling (LV end-systolic volume change) and sex and the composite outcome of all-cause mortality, LV assist device implantation, or heart transplantation was assessed. Results: At baseline, women (n=228) displayed larger electrical dyssynchrony than men (QRS area, 132±55 versus 123±58 μVs; P =0.043), which was even more pronounced for the QRSarea/LVEDV ratio (0.76±0.46 versus 0.57±0.34 μVs/mL; P P =0.003) and a lower occurrence of the composite outcome (hazard ratio, 0.59 [0.42–0.85]; P =0.004). A part of the female advantage regarding reverse remodeling was attributed to the larger QRSarea/LVEDV ratio in women (25-fold change in β from 0.12 to 0.09). The larger QRSarea/LVEDV ratio did not contribute to the better survival observed in women. In both volumetric responders and nonresponders, female sex remained strongly associated with a lower risk of the composite outcome (adjusted hazard ratio, 0.59 [0.36–0.97]; P =0.036; and 0.55 [0.33–0.90]; P =0.018, respectively). Conclusions: Greater electrical dyssynchrony in smaller hearts contributes, in part, to more reverse remodeling observed in women after cardiac resynchronization therapy, but this does not explain their better long-term outcomes.

Background Ribavirin is currently recommended for treating chronic hepatitis E virus (HEV) infection. This retrospective European multicenter study aimed to assess the sustained virological response (SVR) in a large cohort of solid organ transplant (SOT) recipients with chronic HEV infection treated with ribavirin monotherapy (N = 255), to identify the predictive factors for SVR, and to evaluate the impact of HEV RNA mutations on virological response. Methods Data from 255 SOT recipients with chronic HEV infection from 30 European centers were analyzed. Ribavirin was given at the median dose of 600 (range, 29–1200) mg/day (mean, 8.6 ± 3.6 mg/kg/day) for a median duration of 3 (range, 0.25–18) months. Results After a first course of ribavirin, the SVR rate was 81.2%. It increased to 89.8% when some patients were offered a second course of ribavirin. An increased lymphocyte count at the initiation of therapy was a predictive factor for SVR, while poor hematological tolerance of ribavirin requiring its dose reduction (28%) and blood transfusion (15.7%) were associated with more relapse after ribavirin cessation. Pretreatment HEV polymerase mutations and de novo mutations under ribavirin did not have a negative impact on HEV clearance. Anemia was the main adverse event. Conclusions This large-scale retrospective study confirms that ribavirin is highly efficient for treating chronic HEV infection in SOT recipients and shows that the predominant HEV RNA polymerase mutations found in this study do not affect the rate of HEV clearance. This large-scale retrospective study that included 255 solid organ transplant recipients confirms that ribavirin is highly efficient for treating chronic hepatitis E virus (HEV) infection and shows that HEV RNA polymerase mutations do not play a role in HEV clearance.

Background Emerging evidence indicates that an elevated C-reactive protein-to-albumin ratio (CAR) may be associated with a poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Further evidence showing that this ratio has significant prognostic value could contribute to current prediction models and clinical decision-making. Methods Data were analysed of consecutive patients who underwent curative pancreatic resection between 2013 and 2018 and were histologically diagnosed with PDAC. We investigated the relation between the ultimate preoperative CAR and overall survival. Results A total of 163 patients were analysed. Median overall survival was 18 months (IQR 9–36). Multivariate analysis demonstrated that a higher CAR (HR 1.745, P = 0.004), a higher age (HR 1.062, P P = 0.001), poor differentiation grade (HR 2.812, P P P = 0.003). Conclusion We demonstrated that an ultimate preoperative elevated CAR is an independent indicator of decreased overall survival after resection for PDAC. The preoperative CAR may be of additional value to the current prediction models.

BACKGROUND: Approximately 20–40% of patients diagnosed with breast cancer will experience a recurrence up to 20 years after their original diagnosis. 17?-hydroxysteroid dehydrogenase 1 and 2 (HSD17B1 and HSD17B2, respectively) regulate intratumoral concentrations of oestradiol, which promotes growth and proliferation of hormone dependent tumours. Breast carcinomas with increased HSD17B1, without a corresponding increase in HSD17B2, expression may become resistant to tamoxifen therapy by producing locally higher concentrations of oestradiol, which compete with tamoxifen and its metabolites for binding to the oestrogen receptor (ER). MATERIALS AND METHODS: In this population-based case-control study, we included women diagnosed with stage I–III breast cancer between 1985 and 2001, aged 35–69 years, registered in the Danish Breast Cancer Group. We identified 541 cases of breast cancer recurrence among women with ER positive disease who were treated with tamoxifen for at least 1 year (ER+TAM+). We also enrolled 300 breast cancer recurrence cases among women with ER negative disease, not treated with tamoxifen, who survived at least 1 year (ER?/TAM?). Controls were recurrence-free breast cancer patients at the time of case diagnosis, matched to recurrence cases on ER/TAM status, date of surgery, menopausal status, stage, and county or residence. Expression of HSD17B1 and HSD17B2 were measured by immunohistochemistry on tissue microarrays. We fit logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs) associating the HSD17B1:HSD17B2 ratio (>1 vs. ?1)—and each enzyme’s independent expression—with recurrence. RESULTS: We found no association between the HSD17B1:HSD17B2 ratio and breast cancer recurrence in either ER/TAM stratum (ER+/TAM+: OR=1.03, 95% CI: 0.78, 1.40; ER?/TAM?: OR=1.02, 95% CI: 0.77, 1.19). Associations for expression of each individual enzyme were also near null. CONCLUSION: The ratio of HSD17B1 expression to HSD17B2 expression was not associated with breast cancer recurrence in this study.

Diffuse malignant mesothelioma (DMM) of the pleura is a rare and aggressive disease, where the long-term survival (LTS) rate is low. The epithelioid subtype is the most prevalent form of DMM with the best prognosis. In order to study prognostic histopathologic factors associated with extended survival in epithelioid DMM, we examined 43 tumors from patients with survival over five years (long-term survivals [LTS]) and compared the findings with 84 tumors from a reference group with average survival (RG). We analyzed the tumors considering previously published histopathological prognostic features and attempted to identify additional morphological features predictive of extended survival. Most of the LTS tumors presented with nuclear grade I (n = 34,90%) and a tubulopapillary growth pattern (n = 30,70%). One LTS tumor had necrosis. In contrast, nuclear grade II (n = 49,61%) and solid growth pattern (n = 59,70%) were more frequent in RG, and necrosis was present in 16 (19%) tumors. We also evaluated the association of asbestos lung tissue fiber burden quantified from autopsy samples with histopathological features and found that elevated asbestos fiber was associated with higher nuclear grade (p

Introduction Viral remission after analytical treatment interruption (ATI), termed post-treatment control, has been described in a small proportion of HIV-positive patients. This phenomenon has been separately associated to both low levels of HIV-1 proviral DNA as well as cell-associated RNA. We investigated whether the combination of both parameters could help predict delayed viral rebound after treatment interruption (TI). Methods We conducted an open single-arm ATI study in four Belgian HIV reference centres from January 2016 to July 2018. Eligible participants were adults who had fewer than 50 HIV-1 RNA copies/mL for more than two years, more than 500 CD4 cells/mu L for more than three months, and were in general good health. Consenting participants who had fewer than 66 copies total HIV-1 DNA (t-DNA) and fewer than 10 copies cell-associated HIV-1 unspliced RNA (US-RNA) per million peripheral blood mononuclear cells (PBMCs), interrupted therapy and were monitored closely. Antiretroviral therapy (ART) was resumed after two consecutive viral loads exceeding 1000 copies or one exceeding 10,000 copies/mL. The primary outcome was the proportion of participants with fewer than 50 HIV-1 RNA copies/mL 48 weeks after TI. Secondary outcomes were time to viral rebound, the frequency of serious adverse events (AEs) and evolution of t-DNA and US-RNA after TI. Results All 16 consenting participants who interrupted therapy experienced rapid viral rebound two to eight weeks after TI. No serious AEs were observed. Levels of t-DNA and US-RNA increased after TI but returned to pre-ATI levels after treatment restart. None of the studied demographic, clinical and biological parameters were predictive of time of viral rebound. Conclusions The combination of low levels of t-DNA and US-RNA in PBMCs, corresponding respectively to a small and transcriptionally silent viral reservoir, is not predictive of viral remission after TI in patients on ART.

An impaired immune response could play a role in the acquisition of secondary infections in critically ill children. Human leukocyte antigen-DR expression on monocytes (mHLA-DR) has been proposed as marker to detect immunosuppression, but its potential to predict secondary infections in critically ill children is unclear. We aimed to assess the association between mHLA-DR expression at several timepoints and the change of mHLA-DR expression over time with the acquisition of secondary infections in critically ill children. In this prospective observational study, children Conclusions: Our results confirm that infectious critically ill children have significantly lower mHLA-DR expression than controls. mHLA-DR expression was not associated with the acquisition of secondary infections. What is Known:• An impaired immune response, estimated by mHLA-DR expression, could play an essential role in the acquisition of secondary infections in critically ill children.• In critically ill children, large studies on the association of mHLA-DR expression with secondary infections are scarce. What is New:• Our study confirms that critically ill children have lower mHLA-DR expression than healthy controls.• mHLA-DR expression and change in mHLA-DR was not associated with the acquisition of secondary infection.

Purpose Patients are referred to exercise-based cardiac rehabilitation (ECR) to increase exercise capacity and health-related quality of life (HRQOL) and thereby reduce risk of morbidity and mortality. The purpose of this study was to examine the correlation between exercise capacity and HRQOL. Furthermore, this study examined whether improvements in HRQOL were directly related to improvements in exercise capacity. Methods The study included 277 patients participating in ECR. HRQOL was assessed using the Medical Outcomes Study 36-item Short Form Health Survey (SF-36), and exercise capacity was measured as peak oxygen uptake ((Equation is included in full-text article.)O2peak) and oxygen uptake ((Equation is included in full-text article.)O2) at the ventilatory threshold (VTh). Patients were examined before and after completion of an 8-wk ECR program. Results Analyses at baseline showed a significant correlation between (Equation is included in full-text article.)O2peak and VTh and physical functioning (PF), role limitations because of physical problems (RP), general health perceptions (GH), vitality (VT), and physical component summary (PCS) on the SF-36; PF was the only dimension showing a moderate correlation (>0.40 Spearman ρ) with (Equation is included in full-text article.)O2peak. The follow-up analyses demonstrated a significant correlation between changes in (Equation is included in full-text article.)O2peak and changes in PF, RP, VT, and MH. Changes in (Equation is included in full-text article.)O2 peak explained 4% of the changes in the PF and VT scores. Conclusion The correlations between exercise capacity and HRQOL were weak and varied considerably among patients. The ECR program improved both exercise capacity and HRQOL, but it was not necessarily the same patients who improved both parameters. Therefore, it is recommended to use separate objective measures and patient-reported outcomes when evaluating the effect of ECR.

Background: Stopping nucleos(t)ide analogues (NA) after hepatitis B e antigen (HBeAg) seroconversion is associated with high relapse rates in Asian patients, but data in Caucasian cohorts are scarce. Clinical course, outcomes and immunological aspects of chronic hepatitis B infections differ substantially between distinct ethnicities. Aim: The aim of this study was to determine relapse rates, factors predicting relapse and clinical outcomes after nucleos(t)ide analogue cessation in a large, predominantly Caucasian cohort of chronic hepatitis B patients with nucleos(t)ide analogue-induced HBeAg seroconversion. Methods: This is a nationwide observational cohort study including HBeAg positive, mono-infected chronic hepatitis B patients with nucleos(t)ide analogue-induced HBeAg seroconversion from 18 centres in Belgium. Results: A total of 98 patients with nucleo(s)tide analogue-induced HBeAg seroconversion were included in the study. Of the 62 patients who stopped treatment after a median consolidation treatment of 8 months, 30 relapsed. Higher gamma-glutamyl transferase levels at both treatment initiation (HR 1.004; P = 0.001 per unit increment) and HBeAg seroconversion (HR 1.006; P = 0.013 per unit increment) were associated with an increased risk of clinically significant relapse in a multivariate Cox regression model. Treatment cessation led to liver-related death in 2 patients, of whom one showed a severe flare. Of the patients who continued treatment after HBeAg seroconversion, none relapsed or developed severe hepatic outcomes. Conclusion: Treatment withdrawal in Caucasian chronic hepatitis B patients after nucleos(t)ide analogue-induced HBeAg seroconversion results in viral relapses in more than half of patients with potential fatal outcomes. These real-world data further lend support to preferentially continue NA treatment after HBeAg seroconversion until HBsAg loss. Foundation Against Cancer Belgium, Grant/Award Number: 2014-087

CPNE3, a member of a Ca2+‐dependent phospholipid‐binding protein family, was identified as a ligand of ERBB2 and has a more general role in carcinogenesis. Here, we identified the prognostic significance of CPNE3 expression in acute myeloid leukemia (AML) patients based on two datasets. In the first microarray dataset (n = 272), compared to low CPNE3 expression (CPNE3 low), high CPNE3 expression (CPNE3 high) was associated with adverse overall survival (OS, P < 0.001) and event‐free survival (EFS, P < 0.001). In the second independent group of AML patients (TCGA dataset, n = 179), CPNE3 high was also associated with adverse OS and EFS (OS, P = 0.01; EFS, P = 0.036). Notably, among CPNE3 high patients, those received allogenic hematopoietic cell transplantation (HCT) had longer OS and EFS than those with chemotherapy alone (allogeneic HCT, n = 40 vs chemotherapy, n = 46), but treatment modules played an insignificant role in the survival of CPNE3 low patients (allogeneic HCT, n = 32 vs chemotherapy, n = 54). These results indicated that CPNE3 high is an independent, adverse prognostic factor in AML and might guide treatment decisions towards allogeneic HCT. To understand its inherent mechanisms, we investigated genome‐wide gene/microRNA expression signatures and cell signaling pathways associated with CPNE3 expression. In conclusion, CPNE3 high is an adverse prognostic biomarker for AML. Its effect may be attributed to the distinctive genome‐wide gene/microRNA expression and related cell signaling pathways.

Supplemental Digital Content is available in the text., Background: Long QT syndromes (LQTS) arise from many genetic and nongenetic causes with certain characteristic ECG features preceding polymorphic ventricular tachyarrhythmias (PVTs). However, how the many molecular causes result in these characteristic ECG patterns and how these patterns are mechanistically linked to the spontaneous initiation of PVT remain poorly understood. Methods: Anatomic human ventricle and simplified tissue models were used to investigate the mechanisms of spontaneous initiation of PVT in LQTS. Results: Spontaneous initiation of PVT was elicited by gradually ramping up ICa,L to simulate the initial phase of a sympathetic surge or by changing the heart rate, reproducing the different genotype-dependent clinical ECG features. In LQTS type 2 (LQT2) and LQTS type 3 (LQT3), T-wave alternans was observed followed by premature ventricular complexes (PVCs). Compensatory pauses occurred resulting in short-long-short sequences. As ICa,L increased further, PVT episodes occurred, always preceded by a short-long-short sequence. However, in LQTS type 1 (LQT1), once a PVC occurred, it always immediately led to an episode of PVT. Arrhythmias in LQT2 and LQT3 were bradycardia dependent, whereas those in LQT1 were not. In all 3 genotypes, PVCs always originated spontaneously from the steep repolarization gradient region and manifested on ECG as R-on-T. We call this mechanism R-from-T, to distinguish it from the classic explanation of R-on-T arrhythmogenesis in which an exogenous PVC coincidentally encounters a repolarizing region. In R-from-T, the PVC and the T wave are causally related, where steep repolarization gradients combined with enhanced ICa,L lead to PVCs emerging from the T wave. Since enhanced ICa,L was required for R-from-T to occur, suppressing window ICa,L effectively prevented arrhythmias in all 3 genotypes. Conclusions: Despite the complex molecular causes, these results suggest that R-from-T is likely a common mechanism for PVT initiation in LQTS. Targeting ICa,L properties, such as suppressing window ICa,L or preventing excessive ICa,L increase, could be an effective unified therapy for arrhythmia prevention in LQTS.

Background: Hepatocellular carcinoma is the most common innate liver tumor. Due to improved surgical techniques, even extended resections are feasible, and more patients can be treated with curative intent. As the liver is the central metabolic organ, preoperative metabolic assessment is crucial for risk stratification. Sarcopenia, obesity and sarcopenic obesity characterize body composition and metabolic status. Here we present the impact of body composition on survival after liver resection in patients with hepatocellular carcinoma.Methods: A retrospective database analysis of 70 patients who were assigned for liver resection due to hepatocellular carcinoma was conducted. For assessment of sarcopenia and obesity, skeletal muscle surface area was measured at lumbar vertebra 3 level (L3) in preoperative four-phase contrast enhanced abdominal CT scans, and L3 muscle index and body fat percentage were calculated.Results: Univariate analysis comparing the survival curves using the score test demonstrated superior postoperative overall survival for sarcopenic (P=0.035) and sarcopenic obese (P=0.048) patients as well as a trend favoring obese (P=0.130) subjects. Whereas multivariate analysis could not identify significant difference in postoperative survival regarding sarcopenia, obesity or sarcopenic obesity. Only large tumor size, multifocal disease and male gender were risk factors for long-term survival.Conclusions: Sarcopenia, obesity and sarcopenic obesity are indeed no risk factors for poor postoperative survival in this study. Our data do not support the evaluation of sarcopenia, obesity and sarcopenic obesity before liver resection in hepatocellular carcinoma patients. (C) 2018 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.

Transient proteinuria and acute kidney injury (AKI) are characteristics of Puumala virus (PUUV) infection. Albuminuria peaks around the fifth day and associates with AKI severity. To evaluate albuminuria disappearance rate, we quantified albumin excretion at different time points after the fever onset. The study included 141 consecutive patients hospitalized due to acute PUUV infection in Tampere University Hospital, Finland. Timed overnight albumin excretion (cU-Alb) was measured during the acute phase in 133 patients, once or twice during the convalescent phase within three months in 94 patients, and at six months in 36 patients. During hospitalization, 30% of the patients had moderately increased albuminuria (cU-Alb 20&ndash, 200 &mu, g/min), while 57% presented with severely increased albuminuria (cU-Alb &gt, g/min). Median cU-Alb was 311 &mu, g/min (range 2.2&ndash, 6460) &le, 7 days after fever onset, 235 &mu, g/min (range 6.8&ndash, 5479) at 8&ndash, 13 days and 2.8 &mu, g/min (range 0.5&ndash, 18.2) at 14&ndash, 20 days. After that, only one of the measurements showed albuminuria (35.4 &mu, g/min at day 44). At six months, the median cU-Alb was 2.0 &mu, g/min (range 0.6&ndash, 14.5). Albuminuria makes a flash-like appearance in PUUV infection and returns rapidly to normal levels within 2&ndash, 3 weeks after fever onset. In the case of AKI, this is a unique phenomenon.

OBJECTIVE Patients with type 1 diabetes and diabetic nephropathy are targets for intervention to reduce high risk of end-stage renal disease (ESRD) and deaths. This study compares risks of these outcomes in four international cohorts. RESEARCH DESIGN AND METHODS In the 1990s and early 2000s, Caucasian patients with type 1 diabetes with persistent macroalbuminuria in chronic kidney disease stages 1–3 were identified in the Joslin Clinic (U.S., 432), Finnish Diabetic Nephropathy Study (FinnDiane) (Finland, 486), Steno Diabetes Center Copenhagen (Denmark, 368), and INSERM (France, 232) and were followed for 3–18 years with annual creatinine measurements to ascertain ESRD and deaths unrelated to ESRD. RESULTS During 15,685 patient-years, 505 ESRD cases (rate 32/1,000 patient-years) and 228 deaths unrelated to ESRD (rate 14/1,000 patient-years) occurred. Risk of ESRD was associated with male sex; younger age; lower estimated glomerular filtration rate (eGFR); higher albumin/creatinine ratio, HbA1c, and systolic blood pressure; and smoking. Risk of death unrelated to ESRD was associated with older age, smoking, and higher baseline eGFR. In adjusted analysis, ESRD risk was highest in Joslin versus reference FinnDiane (hazard ratio [HR] 1.44, P = 0.003) and lowest in Steno (HR 0.54, P < 0.001). Differences in eGFR slopes paralleled risk of ESRD. Mortality unrelated to ESRD was lowest in Joslin (HR 0.68, P = 0.003 vs. the other cohorts). Competing risk did not explain international differences in the outcomes. CONCLUSIONS Despite almost universal renoprotective treatment, progression to ESRD and mortality in patients with type 1 diabetes with advanced nephropathy are still very high and differ among countries. Finding causes of these differences may help reduce risk of these outcomes.

ObjectivesTo validate cut-offs of the Juvenile Arthritis Disease Activity Score 10 (JADAS10) and clinical JADAS10 (cJADAS10) and to compare them with other patient cohorts.MethodsIn a national multicentre study, cross-sectional data on recent visits of 337 non-systemic patients with juvenile idiopathic arthritis (JIA) were collected from nine paediatric outpatient units. The cut-offs were tested with receiver operating characteristic curve-based methods, and too high, too low and correct classification rates (CCRs) were calculated.ResultsOur earlier presented JADAS10 cut-offs seemed feasible based on the CCRs, but the cut-off values between low disease activity (LDA) and moderate disease activity (MDA) were adjusted. When JADAS10 cut-offs for clinically inactive disease (CID) were increased to 1.5 for patients with oligoarticular disease and 2.7 for patients with polyarticular disease, as recently suggested in a large multinational register study, altogether 11 patients classified as CID by the cut-off had one active joint. We suggest JADAS10 cut-off values for oligoarticular/polyarticular disease to be in CID: 0.0–0.5/0.0–0.7, LDA: 0.6–3.8/0.8–5.1 and MDA: >3.8/5.1. Suitable cJADAS10 cut-offs are the same as JADAS10 cut-offs in oligoarticular disease. In polyarticular disease, cJADAS10 cut-offs are 0–0.7 for CID, 0.8–5.0 for LDA and >5.0 for MDA.ConclusionInternational consensus on JADAS cut-off values is needed, and such a cut-off for CID should preferably exclude patients with active joints in the CID group.

BACKGROUND: Ablating left atrial (LA) ganglionated plexi (GP), identified invasively by high-frequency stimulation (HFS) during pulmonary vein isolation (PVI), may reduce atrial fibrillation (AF) recurrence. 123I-metaiodobenzylguanidine (123I-mIBG) solid-state SPECT LA innervation imaging (LAII) has the spatial resolution to detect LAGP non-invasively but this has never been demonstrated in clinical practice. METHODS: 20 prospective patients with paroxysmal AF scheduled for PVI underwent 123I-mIBG LAII. High-resolution tomograms, reconstructed where possible using cardiorespiratory gating, were co-registered with pre-PVI cardiac CT. Location and reader confidence (1 [low] to 3 [high]) in discrete 123I-mIBG LA uptake areas (DUAs) were recorded and correlated with HFS. RESULTS: A total of 73 DUAs were identified, of which 59 (81%) were HFS positive (HFS +). HFS + likelihood increased with reader confidence (92% [score 3]). 64% of HFS-negative DUAs occurred over the lateral and inferior LA. Cardiorespiratory gating reduced the number of DUAs per patient (4 vs 7, P = .001) but improved: HFS + predictive value (76% vs 49%); reader confidence (2 vs 1, P = .02); and inter-observer, intra-observer, and inter-study agreement (κ = 0.84 vs 0.68; 0.82 vs 0.74; 0.64 vs 0.53 respectively). CONCLUSIONS: 123I-mIBG SPECT/CT LAII accurately and reproducibly identifies GPs verified by HFS, particularly when reconstructed with cardiorespiratory gating.

The study’s aim was to image severe alcoholic hepatitis (SAH) using 111In-labelled leucocytes with two objectives in mind: firstly for non-invasive diagnosis and secondly to provide a platform for experimental therapies aiming to inhibit intrahepatic neutrophil migration. 111In-leucocyte scintigraphy was performed 30 min and 24 h post-injection in 19 patients with SAH, 14 abstinent patients with alcohol-related cirrhosis and 11 normal controls. Eleven with SAH and seven with cirrhosis also had 99mTc-nanocolloid scintigraphy. Change in hepatic 111In radioactivity was expressed as decay-corrected 24 h:30 min count ratio and, in SAH, compared with histological grading of steatohepatitis and expression of granulocyte marker, CD15. Hepatic microautoradiography on biopsy specimens obtained 24 h post-injection of 111In-leucocytes was performed in one patient. Median 24 h:30 min hepatic 111In activity ratio was higher in SAH (2.5 (interquartile range (IQR): 1.7–4.0) compared with cirrhotics and normal controls (1.0 (0.8–1.1) and 0.8 (0.7–0.9) respectively, P

BACKGROUND: Vitamin K antagonist (VKA) therapy is safer and more effective when patients have a high time within the therapeutic range and low international normalised ratio variability. The SAMe-TT2R2 score aims to identify those at risk for poor VKA control.OBJECTIVES: To evaluate the predictive value and clinical usefulness of the SAMe-TT2R2 score to identify those at risk for poor VKA control.METHODS: We performed a systematic review in MEDLINE and Embase for original research papers assessing the SAMe-TT2R2's relation to poor TTR. We performed a meta-analysis where scores ≥ 2 and ≥ 3 predicting TTR < 70%. When studies evaluated other cutoffs for TTR or SAMe-TT2R2, they were harmonised by multiple simulations with patient characteristics from the individual studies, if the data were available.RESULTS: 16 studies were identified and used in the meta-analysis: 4 and 2 times directly, 8 and 8 times harmonised for scores ≥ 2 and ≥ 3, respectively (not all studies provided information about both cutoffs). The sensitivities and specificities were too heterogeneous to pool. The positive likelihood ratios were 1.25 (1.14-1.38) for a score ≥ 2, and 1.24 (1.09-1.40) for a score ≥ 3; the negative ones were 0.87 (0.82-0.93) and 0.96 (0.91-1.02), respectively. This shows that the post-test probabilities hardly differ from the prior probability (prevalence).CONCLUSION: The SAMe-TT2R2 score does predict low TTR, but the effect is small. Its effect on individual patients is too limited to be clinically useful.

This study aimed to validate the prognostic value of baseline whole-body metabolic active tumor volume (WB-MATV) and total lesion glycolysis (WB-TLG) measured with [18F]fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) in a large cohort of chemorefractory metastatic colorectal cancer (mCRC) patients treated with multikinase inhibitors (MKI). The secondary objective of this study was to compare WB-MATV and WB-TLG respective prognostic values to commonly used clinical prognostic factors. Methods: Out of 238 patients pooled from two successive prospective multicenter trials investigating MKI in chemorefractory mCRC, 224 were considered suitable for analysis. The patients were retrospectively randomly assigned to a development set (n = 155 patients) and a validation set (n = 69 patients). WB-MATV and WB-TLG optimal cutoffs for prediction of overall survival (OS) were determined by Contal and O'Quigley's method. Univariate analyses were performed to assess the prognostic values of WB-MATV and WB-TLG. Multivariate analyses were performed for WB-MATV and WB-TLG along with clinical factors to identify the independent prognostic factors of OS. The prognostic weight for each parameter was obtained from the Cox's model. Results: WB-MATV and WB-TLG optimal cutoffs for OS prediction were 100 cm3 and 500 g, respectively. Univariate analyses showed that WB-MATV and WB-TLG parameters were strongly related to outcome in both the development and validation sets. In the validation set, the median OS was 5.2 months vs 12.8 months for high vs low WB-MATV (HR: 3.12, P < 0.001), and 4.7 months vs 13.9 months for high vs low WB-TLG (HR: 3.67, P < 0.001). The multivariate analyses identified that both high WB-MATV and WB-TLG were independent negative prognostic parameters for OS, with the highest prognostic weight among the well-known clinical prognostic factors (HR: 2.46 and 2.23, respectively, P < 0.001). Conclusion: Baseline WB-MATV and WB-TLG parameters were validated as strong prognosticators of outcome in a large cohort of chemorefractory mCRC patients treated with MKI. These parameters were identified as independent prognostic imaging biomarkers with the highest prognostic values among the commonly used clinical factors. These biomarkers should therefore be used to support the optimal therapeutic strategy., info:eu-repo/semantics/published

Purpose: To review the safety of hepatic radioembolization (RE) in patients with high (>= 10%) hepatopulmonary shunt fraction (HPSF) using various prophylactic techniques. Materials and Methods: A review was conducted of 409 patients who underwent technetium 99m-labeled macroaggregated albumin scintigraphy before planned RE. Estimated pulmonary absorbed radiation doses based on scintigraphy and hepatic administered activity were calculated. Outcomes from dose reductions and adjunctive catheter-based prophylactic techniques used to reduce lung exposure were assessed. Results: There were 80 patients with HPSF >= 10% who received RE treatment (41 resin microspheres for metastases, 39 glass microspheres for hepatocellular carcinoma). Resin microspheres were used in 17 patients according to consensus guideline-recommended dose reduction; 38 patients received no dose reduction because the expected lung dose was

Item does not contain fulltext BACKGROUND: In patients treated for early-stage squamous cell vulvar carcinoma local recurrence is reported in up to 40% after ten years. Knowledge on prognostic factors related to local recurrences should be helpful to select high risk patients and/or to develop strategies to prevent local recurrences. OBJECTIVE: This systematic review aims to evaluate the current knowledge on the incidence of local recurrences in vulvar carcinoma related to clinicopathologic and cell biologic variables. DATA SOURCES: Relevant studies were identified by an extensive online electronic search in July 2017. STUDY ELIGIBILITY CRITERIA: Studies reporting prognostic factors specific for local recurrences of vulvar carcinoma were included. STUDY APPRAISAL AND SYNTHESIS METHODS: Two review authors independently performed data selection, extraction and assessment of study quality. The risk difference was calculated for each prognostic factor when described in two or more studies. RESULTS: Twenty-two studies were included; most of all were retrospective and mainly reported pathologic prognostic factors. Our review indicates an estimated annual local recurrence rate of 4% without plateauing. The prognostic relevance for local recurrence of vulvar carcinoma of all analyzed variables remains equivocal, including pathologic tumor free margin distance

Background: Graft right ventricular (RV) function is compromised directly posttransplant, especially in heart transplantation (HTx) recipients with pretransplant pulmonary hypertension (PH). Graft RV size and systolic function, and the effect of the recipient's pulmonary haemodynamics on the graft extracellular matrix are not well characterised in the patients long-term after HTx. Aim: Comparison of RV size and systolic function in HTx recipients' long-term posttransplant stratified by the presence of pretransplant PH. Methods: HTx survivors >/=2 years posttransplant were divided into group I without pretransplant PH (pulmonary vascular resistance, PVR /=2.5Wood units, n=16). RV size and systolic function were measured using cardiac magnetic resonance imaging (CMR). The collagen content was assessed in septal endomyocardial biopsies obtained at HTx and at study inclusion. Results: Mean posttransplant follow-up was 5.2+/-2.9 years (group I) and 4.9+/-2.2 years (group II) (p=0.70). PVR was 1.5+/-0.6 vs 4.1+/-1.7Wood units pretransplant (p/=0.07). Collagen content at transplantation and at follow-up were not different (p always >/=0.60). Conclusion: Posttransplant normalisation of pretransplant PH is associated with normal graft RV function long-term after HTx.

Patients with tetralogy of Fallot and combined right ventricular outflow tract obstruction (RVOTO) and pulmonary regurgitation (PR) have a less dilated right ventricular (RV) and better RV function compared with patients without RVOTO. It is not known whether RVOTO is associated with improved exercise capacity. We compared cardiac magnetic resonance imaging, echocardiography, and exercise tests in 12 patients with RVOTO (Doppler peak RVOT gradient ≥30 mm Hg) and 30 patients without RVOTO. RV end-systolic and end-diastolic volumes were smaller in patients with RVOTO compared with patients without RVOTO (50 ± 16 vs 64 ± 18 ml/m(2) and 117 ± 24 vs 135 ± 28 ml/m(2), respectively) and patients with RVOTO had a higher RV mass (52 ± 14 vs 42 ± 11 ml/m(2)), p0.05. RV ejection fraction was marginally significantly different between both groups (58 ± 8% vs 53 ± 7%), p = 0.051. Degree of PR, left ventricular volumes, and function did not differ significantly between both groups. Peak oxygen uptake in patients with RVOTO was significantly lower (25 ± 3 vs 32 ± 8 ml/kg/min) than in patients without RVOTO, as was the percentage of predicted peak oxygen uptake (63 ± 7% vs 79 ± 14%), p0.001. Multivariate analysis showed that the peak RVOT gradient was the only independent predictor of exercise capacity. In conclusion, exercise capacity is lower in patients with RVOTO compared with those without RVOTO despite a less dilated RV and comparable degree of PR. Therefore, exercise capacity may be of importance and should additionally be taken in consideration to RV volumes and function in patients with tetralogy of Fallot and PR.

Conclusions BMI-1 is an upstream repressor of tumor suppressor p16 and their inverse expression patterns have been linked with patient survival in OPSCC. In this material only p16 remained a relevant prognostic marker in OPSCC. Objectives HNSCC tumors carry variable phenotypes and clinical outcomes depending on their anatomical location. In OPSCC, expression of tumor suppressor p16 is used as a surrogate marker of HPV infection and has prognostic value. There are no good prognostic biomarkers for HNSCC tumors of other anatomical locations. Aim To study the expression patterns of p16 and BMI-1 in not only oropharyngeal but also oral, hypopharyngeal, and laryngeal squamous cell carcinomas and to clarify their putative connections with clinical parameters, survival, and each other. Method Hospital records on 130 patients (59 OPSCC, 18 OSCC, 20 HPSCC, and 33 LSCC) diagnosed between 1997-2008 at the Helsinki University Hospital, Finland, were reviewed. BMI-1 and p16 expressions were studied by immunohistochemistry. Results Sixty-eight per cent of OPSCC expressed p16 and expression correlated with lower age, lower T- and higher N-category, and with improved OS and DFS. BMI-1 expression was most prevalent in OPSCC and LSCC, but had no clinical correlations. No correlation between p16 and BMI-1 expression was found.

Background Non-operative management (NOM) is the standard of care in hemodynamically stable patients with blunt splenic injury after trauma. Splenic artery embolization (SAE) is reported to increase observation success rate. Studies demonstrating improved splenic salvage rates with SAE primarily compared SAE with historical controls. The aim of this study was to investigate whether SAE improves success rate compared to observation alone in contemporaneous patients with blunt splenic injury. Methods We included adult patients with blunt splenic injury admitted to five Level 1 Trauma Centers between January 2009 and December 2012 and selected for NOM. Successful treatment was defined as splenic salvage and no splenic re-intervention. We calculated propensity scores, expressing the probability of undergoing SAE, using multivariable logistic regression and created five strata based on the quintiles of the propensity score distribution. A weighted relative risk (RR) was calculated across strata to express the chances of success with SAE. Results Two hundred and six patients were included in the study. Treatment was successful in 180 patients: 134/146 (92 %) patients treated with observation and 48/57 (84 %) patients treated with SAE. The weighted RR for success with SAE was 1.17 (0.94–1.45); for complications, the weighted RR was 0.71 (0.41–1.22). The mean number of transfused blood products was 4.4 (SD 9.9) in the observation group versus 9.1 (SD 17.2) in the SAE group. Conclusions After correction for confounders with propensity score stratification technique, there was no significant difference between embolization and observation alone with regard to successful treatment in patients with blunt splenic injury after trauma.

Acute kidney injury (AKI) is associated with progression to advanced chronic kidney disease (CKD). We tested whether patients who survive AKI and are at higher risk for CKD progression can be identified during their hospital admission, thus providing opportunities to intervene. This was assessed in patients in the Department of Veterans Affairs Healthcare System hospitalized with a primary diagnosis indicating AKI (ICD9 codes 584.xx). In the exploratory phase, three multivariate prediction models for progression to stage 4 CKD were developed. In the confirmatory phase, the models were validated in 11,589 patients admitted for myocardial infarction or pneumonia during the same time frame that had RIFLE codes R, I, or F and complete data for all predictor variables. Of the 5351 patients in the AKI group, 728 entered stage 4 CKD after hospitalization. Models 1, 2, and 3 were all significant with ‘ c ' statistics of 0.82, 0.81, and 0.77, respectively. In model validation, all three were highly significant when tested in the confirmatory patients, with moderate to large effect sizes and good predictive accuracy (‘ c ' 0.81–0.82). Patients with AKI who required dialysis and then recovered were at especially high risk for progression to CKD. Hence, the severity of AKI is a robust predictor of progression to CKD.

Background Epidemiologic evidence for the association between types of fatty acid and risk of type 2 diabetes is inconsistent This may in part be due to the limitations of fatty acid measurement methods Objective The objective was to use 3 different measures of fatty acid to estimate the prospective association between fatty acid composition and development of incident diabetes Design We analyzed 199 cases of clinically incident diabetes and 184 noncases aged 40-79 y at baseline in the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk study Fatty acids were derived from a food frequency questionnaire (FFQ) and measured in plasma phospholipid (P FA) and erythrocyte membrane phospholipid (Ery FA) fractions by gas chromatography Results There were stronger associations with diabetes risk with the use of objectively measured tatty acids (P FA and Ery-FA) than with the FFQ in analyses adjusted for age sex and potential confounders Positive associations with diabetes were greater in magnitude with the use of P FA than with Ery FA (highest lowest tertiles) for example the palmitic acid odds ratios (ORs) were 247 (95% CI 1 37 4 46) and 1 96 (95% CI 1 10 3 49) respectively Inverse associations with diabetes were also stronger with the use of P FA than with Ery FA for example the OR for linoleic acid was 050 (95% CI 028 0 91) compared with 0 77 (95% CI 043 1 37) respectively Conclusions The objective measurement of fatty acids with the use of either P-FA or Ery-FA identifies important associations with diabetes Incidence that may be missed when assessed by FFQ Fatty acids measured in P-FA appear to be more strongly associated with diabetes incidence These findings endorse the use of objective measurement of fatty acids for nutritional-epidemiologic studies and the apparently stronger findings for the plasma fraction should be confirmed in larger studies and in different populations Am J Clin Nutr 2010 92 1214-22

The use of A1C for the identification of persons with undiagnosed diabetes has been investigated for a number of years (1–3). A1C better reflects long-term glycemic exposure than current diagnostic tests based on point-in-time measures of fasting and postload blood glucose (4,5) and has improved test-retest reliability (6). In addition, A1C includes no requirement for fasting or for the oral glucose tolerance test's 2-h wait. These advantages should lead to increased identification and more timely treatment of persons with diabetes. Recently, an American Diabetes Association (ADA)-organized international expert committee recommended the adoption of the A1C assay for the diagnosis of diabetes at a cut point of 6.5% (7). This cut point was primarily derived from a review of studies that examined the association of A1C values with incident retinopathy, and some of the most influential data were obtained from recently published prospective studies. Retinopathy was chosen as the ultimate criterion because it is among the main complications of diabetes. Identification of the point on the A1C distribution most closely related to future retinopathy will identify persons in the greatest need of interventions for the prevention of diabetes complications. In addition to utility and convenience, A1C could help identify persons at increased risk of developing diabetes. This is an important public health priority since a structured lifestyle program or the drug metformin can reduce the incidence of diabetes by at least 50 and 30%, respectively (8). Ideally, selection of diagnostic cut points for pre-diabetes would be based on evidence that intervention, when applied to the high-risk group of interest, results not only in the prevention of diabetes but also later complications. However, currently there are no trials that can provide data to determine the ideal method for defining cut points. In the absence of such data, expert committees had to rely on information about the shape of risk curves for complications such as retinopathy. Previous expert committees assembled to address this issue have noted that there is no clear difference in retinopathy risk between different levels of impaired glucose tolerance (7). We are unaware of published prospective studies of adequate sample size or duration that have followed people in various pre-diabetic categories across the full span of time until complications developed. In the absence of informative trials (as well as prospective studies), the studies that measure A1C at baseline and incident diabetes may provide the definitions of high-risk states. To better define A1C ranges that might identify persons who would benefit from interventions to prevent or delay type 2 diabetes, we carried out a systematic review of published prospective studies that have examined the relationship of A1C to future diabetes incidence.

Iron and (stainless) steel are potent platelet aggregation activators, and may be involved in stent thrombosis, a serious complication after intracoronary stenting. Current platelet function tests are suboptimal, because of inappropriate agonists and/or lack of reproducibility. We tested the feasibility and reproducibility of a novel platelet function test using stainless steel as an agonist and compared it with other platelet function tests.In 111 patients with acute ST segment elevation myocardial infarction (STEMI), duplo measurements of iron (Fe)-induced platelet aggregation (FIPA) were performed after clopidogrel, acetylsalicylic acid and/or tirofiban treatment. Within 1 h, citrated blood samples drawn from the femoral sheath before primary percutaneous coronary intervention were added to 100 mg of low carbon steel and after 5 s mixing with vortex, the samples were incubated for 15 min. The ratio between the non-aggregated platelets in the agonist sample and platelets in a reference sample was calculated as the platelet aggregation inhibition.FIPA measurement was highly reproducible (correlation coefficient (R) = 0.942, P This study showed good reproducibility of a novel platelet function test using stainless steel as an agonist and showed correlation with validated platelet function tests. We found that the novel platelet function test is a suitable test for measurement of platelet aggregation inhibition in patients undergoing stenting for STEMI, even when they are taking multiple antiplatelet regimens.Eur J Clin Invest 2009; 39 (2): 103-109.

Aims To investigate the influence of interlead distance and lead positioning on success of cardiac resynchronization therapy (CRT) in patients with advanced chronic heart failure and electrical dyssynchrony. Despite application of established selection criteria, 20-40% of the patients do not respond to CRT.Methods and results We examined consecutive patients in whom CRT was implanted. Response to CRT was defined as a decrease in the left ventricular end-systolic volume >= 10% after 6 months. A comparison was made between patients who were responders to CRT and those who were non-responders. A univariate and stepwise multivariate logistic regression was performed with regard to predictors for response. Between January 2004 and January 2008, 174 patients who were treated with CRT were classified as responders [n = 95 (55%)] or non-responders [n = 79 (45%)]. Responders had a significantly larger horizontal interlead distance on the lateral thoracic X-ray [odds ratio (OR) 2.8 (1.2-6.6), P = 0.01], a septal-to-lateral delay > 60 ms [OR 4.9 (2.0-11.4), P Conclusion Larger interlead distance on the lateral thoracic X-ray, associated with positioning of the left ventricular lead in the posterior position, is associated with response after 6 months of follow-up. Furthermore, diminishing the septal-to-lateral delay is predictive for response.

Background: Protein kinase C beta (PKC beta), a pivotal enzyme in B-cell signaling and survival, is overexpressed in most cases of mantle cell lymphoma (MCL). Activation of PI3K/AKT pathway is involved in pathogenesis of MCL. Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKC beta/PI3K/AKT pathways, induces apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis.Patients and methods: Patients with relapsed/refractory MCL, and no more than four regimens of prior therapy, received 500 mg enzastaurin, orally, once daily.Results: Sixty patients, median age 66 years (range 45-85), Eastern Cooperative Oncology Group performance status of zero to two (48% had baseline International Prognostic Index of 3-5), were enrolled. Most patients had prior CHOP-like chemotherapy and/or rituximab (median = 2 regimens). No drug-related deaths occurred. There was one case each of grade 3 anemia, diarrhea, dyspnea, vomiting, hypotension, and syncope. Fatigue was the most common toxicity. Although no objective tumor responses occurred, 22 patients (37%, 95% CI 25% to 49%) were free from progression (FFP) for >= 3 cycles (one cycle = 28 days); 6 of 22 were FFP for >6 months. Two patients remain on treatment and FFP at >23 months.Conclusion: Freedom from progression for >6 months in six patients and a favorable toxicity profile with minimal hematological toxicity indicate that enzastaurin warrants evaluation as maintenance therapy and combination chemotherapy in MCL.

Patients with chronic lymphocytic leukemia (CLL) harboring TP53 aberrations (TP53abs; chromosome 17p deletion and/or TP53 mutation) exhibit an unfavorable clinical outcome. Chromosome 8 abnormalities, namely losses of 8p (8p-) and gains of 8q (8q+) have been suggested to aggravate the outcome of patients with TP53abs. However, the reported series were small, thus hindering definitive conclusions. To gain insight into this issue, we assessed a series of 101 CLL patients harboring TP53 disruption. The frequency of 8p- and 8q+ was 14.7% and 17.8% respectively. Both were associated with a significantly (P < 0.05) higher incidence of a complex karyotype (CK, ≥3 abnormalities) detected by chromosome banding analysis (CBA) compared to cases with normal 8p (N-8p) and 8q (N-8q), respectively. In univariate analysis for 10-year overall survival (OS), 8p- (P = 0.002), 8q+ (P = 0.012) and CK (P = 0.009) were associated with shorter OS. However, in multivariate analysis only CK (HR = 2.47, P = 0.027) maintained independent significance, being associated with a dismal outcome regardless of chromosome 8 abnormalities. In conclusion, our results highlight the association of chromosome 8 abnormalities with CK amongst CLL patients with TP53abs, while also revealing that CK can further aggravate the prognosis of this aggressive subgroup., This work has been supported by the following grants: PI11/01621, PI15/00437, RD09/0076/00036, RD12/0036/0044, RD12/0036/0069 and PT13/0010/0005 FEDER, Instituto de Salud Carlos III, Spanish Ministry of Economy and Competitiveness; 2014/SGR585 from Generalitat de Catalunya; “Xarxa de Bancs de tumors” sponsored by Pla Director d'Oncologia de Catalunya (XBTC) and Fundació La Caixa; the Swedish Cancer Society, the Swedish Research Council, the Lion's Cancer Research Foundation, and Selander's Foundation, Uppsala; H2020 “AEGLE, An analytics framework for integrated and personalized healthcare services in Europe” by the EU.

Objective Current data suggest that individual genetic predisposition may influence the magnitude of cytokine response and the degree of organ dysfunction after cardiopulmonary bypass. Lipoprotein lipase S447X polymorphism has been shown to be protective against atherosclerosis. The aim of the study was to investigate the effect of lipoprotein lipase S447X polymorphism on cytokine release and early outcome after cardiopulmonary bypass. Methods Forty patients who underwent coronary artery bypass grafting with cardiopulmonary bypass were included. Genotyping for lipoprotein lipase S447X polymorphism was performed by polymerase chain reaction. Levels of interleukins 6 and 8 were measured before induction and 6, 24, and 72 hours after operation by enzyme-linked immunosorbent assay. Clinical data were collected prospectively. Daily assessment of organ dysfunction was done according to the cardiac surgery scoring (CASUS) system. Results The allele frequency of lipoprotein lipase S447X stop codon was 17.5%. S447X carriers revealed significantly lower interleukin 8 levels at the sixth and 24th postoperative hours than the noncarrier group ( P = .005 and P = .041, respectively). Patients in the S447X carrier group had significantly shorter ventilation times than the noncarrier group ( P = .048). Also, the S447X carrier group revealed significantly lower postoperative 6-hour lactate levels, operative day, and postoperative day 1 organ dysfunction scores than the other group ( P = .001, .005 and .002, respectively). Conclusion Lipoprotein lipase S447X stop codon mutation is associated with lower levels of interleukin 8 after coronary artery bypass grafting. Identification of high-risk patients for cardiopulmonary bypass–related systemic inflammation by detecting lipoprotein lipase S447X stop codon polymorphism may improve early postoperative outcome, especially in patients with limited organ reserves.

Sensitive and quantitative detection of minimal residual disease (MRD) in bone marrow (BM) samples of children with acute lymphoblastic leukemia (ALL) is essential for evaluation of early treatment response. In this study, we evaluated whether the traumatic BM samplings can be replaced by peripheral blood (1313) samplings. MRD levels were analyzed in follow-up samples of 62 children with precursor-B-ALL (532 paired BM-PB samples) and 22 children with T-ALL (149 paired BM-PB samples) using real-time quantitative PCR (RQ-PCR) analysis of immunoglobulin and T cell receptor gene rearrangements with sensitivities of 10(-3) to 10(-5) (one ALL cell in 103 to 105 normal cells). In 14 of the 22 T-ALL patients, detectable MRD levels were found in 67 paired BM-PB samples: in 47 pairs MRD was detected both in BM and 1313, whereas in the remaining pairs very low MRD levels were detected in BM (n = 11) or PB (n = 9) only. The MRD levels in the paired BM-PB samples were very comparable and strongly correlated (r(s) = 0.849). Comparable results were obtained earlier by immunophenotyping in 26 T-ALL patients (321 paired BM-PB samples), which also showed a strong correlation between MRD levels in paired BM and PB samples (r(s) = 0.822). In 39 of the 62 precursor-B-ALL patients, MRD was detected in 107 BM-PB pairs: in 48 pairs MRD was detected in both BM and PB, in 47 pairs MRD was solely detected in BM (at variable levels), and in 12 pairs only the 1313 sample was MRD-positive at very low levels (less than or equal to10(-4)). Furthermore, in the 48 double-positive pairs, MRD levels in BM and PB varied enormously with MRD levels in BM being up to 1000 times higher than in the corresponding PB samples. Consequently, BM samples cannot easily be replaced by PB sampling for MRD analysis in childhood precursor-B-ALL, in line with their BM origin. In T-ALL, which are of thymic origin, BM sampling might be replaced by PB sampling, because the dissemination of T-ALL cells to BM and PB appears to be comparable.

Major depressive disorder (MDD) is characterized by a heterogeneous course and identifying patients at risk for an unfavorable course is difficult. Neuroimaging studies may identify brain predictors of clinical course and may help to further unravel the neurobiological processes underlying an unfavorable course. We investigated whether brain activation during an emotional memory paradigm is associated with depressive course. To this end, we followed 74 MDD patients and 45 healthy controls (HCs) for 2 years. At baseline, participants performed an emotional word-encoding and -recognition task during functional magnetic resonance imaging. Activation patterns were compared between patients with fast remission (n=22), remission with recurrence (n=23), non-remission (n=29), and HCs. Additionally, linear relations of brain activation and time to remission during the follow-up period were investigated across patients. We observed that during encoding of negative words, non-remitters showed higher activation of the left insula than HCs. Groups also differed in activation of the right hippocampus and left amygdala during negative encoding, with a trend for higher activation in non-remitters compared with HCs. Furthermore, hippocampal activation during negative word encoding was significantly and positively correlated with time to remission, irrespective of illness severity. Our findings suggest that higher activation in the left insula could serve as a neural marker of a naturalistic non-remitting course, whereas higher hippocampal activation is associated with delayed remission. Longitudinal analyses should clarify whether abnormal activation progresses further as a function of time with depression or may serve as load-independent markers of MDD course.