Prevalence, phenotypic characteristics and prognostic role of apparent treatment resistant hypertension in the German Chronic Kidney Disease (GCKD) study.

Treatment resistant hypertension (TRH) appears of particular relevance in patients with chronic kidney disease (CKD). However, causes and consequences of TRH in CKD patients remain incompletely understood. Therefore, we analyzed the prevalence of apparent TRH (aTRH), and phenotypic characteristics and prognosis associated with aTRH among participants of the German Chronic Kidney Disease (GCKD) study. As insufficient medication adherence has been shown to be a frequent cause of pseudoresistance, we also assessed treatment adherence. Study participants were classified as having aTRH, controlled hypertension and uncontrolled hypertension based on study visit blood pressure and self-reported medication intake. Drug adherence was assessed by comparing self-reported antihypertensive medication with detectable urinary drug metabolites measured by mass spectroscopy. Out of 4901 individuals included in this study, 38% were classified as having aTRH. Male sex, older age, lower estimated glomerular filtration rate (eGFR), higher body mass index (BMI), higher urine albumin-to-creatinine ratio (UACR) and presence of diabetes mellitus were independently associated with higher prevalence of aTRH in a multivariable adjusted regression model. Patients classified as aTRH had higher risk for major adverse cardiovascular events and worsening of kidney disease compared to patients with no aTRH after multivariate adjustment for potential confounders. There was a high agreement between self-reported medication and detectable urinary drug metabolites. In conclusion, in a cohort of Caucasian patients with moderately severe CKD, aTRH was highly prevalent and, in most cases, likely not caused by low medication adherence. Furthermore, aTRH was linked to cardio-renal endpoints, emphasizing the need for improved management.

The Transmembrane Receptor TIRC7 Identifies a Distinct Subset of Immune Cells with Prognostic Implications in Cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a heterogeneous malignancy with a dismal prognosis. Therapeutic options are largely limited to surgery and conventional chemotherapy offers limited benefit. As immunotherapy has proven highly effective in various cancer types, we have undertaken a quantitative immunohistopathological assessment of immune cells expressing the immunoinhibitory T cell immune response cDNA 7 receptor (TIRC7), an emerging immunoinhibitory receptor, in a cohort of 135 CCA patients. TIRC7+ immune cells were present in both the tumor epithelia and stroma in the majority of CCA cases with the highest levels found in intrahepatic CCA. While intraepithelial density of TIRC7+ immune cells was decreased compared to matched non-neoplastic bile ducts, stromal quantity was higher in the tumor samples. Tumors exhibiting signet ring cell or adenosquamous morphology were exclusively associated with an intraepithelial TIRC7+ phenotype. Survival analysis showed intraepithelial TIRC7+ immune cell density to be a highly significant favorable prognosticator in intrahepatic but not proximal or distal CCA. Furthermore, intraepithelial TIRC7+ immune cell density correlated with the number of intraepithelial CD8+ immune cells and with the total number of CD4+ immune cells. Our results suggest the presence and prognostic relevance of TIRC7+ immune cells in CCA and warrant further functional studies on its pharmacological modulation.

Efficacy and Safety of CAP7.1 as Second-Line Treatment for Advanced Biliary Tract Cancers: Data from a Randomised Phase II Study.

CAP7.1 is a novel topoisomerase II inhibitor, converted to active etoposide via carboxylesterase 2 (CES2), with signals of efficacy in treatment-refractory solid tumours. In a Phase II trial, 27 patients with advanced biliary tract cancers (BTC) were randomised 1:1 to CAP7.1 plus best supportive care (BSC), or BSC alone, with crossover to CAP7.1 upon disease progression. The primary objective was disease control rate (DCR) following 28-day cycles of CAP7.1 (200/150 mg/m2; iv), or BSC until progression. Secondary objectives included progression-free survival (PFS), time-to-treatment failure (TTF), overall survival (OS) and safety. Fourteen patients received CAP7.1 and 13 BSC. DCR favoured CAP7.1 vs. BSC (50% vs. 20%; treatment difference: 30%, 95%CI -18.44, 69.22, full analysis set [FAS]), with disease progression in 40% vs. 70%, respectively. Significantly longer median PFS was achieved for CAP7.1 vs. BSC: 66 vs. 39 days, respectively (hazard ratio [HR] 0.31; 95%CI 0.11, 0.86; p = 0.009; FAS). Similar trends were observed for TTF and OS. CES2-positive patients had longer median PFS (158 vs. 56 days) and OS (228 vs. 82 days) vs. CES2-negative patients. Adverse events were predictable, dose-dependent and consistent with those previously observed with etoposide. These efficacy and safety findings in second-line BTC warrant further clinical investigation of CAP7.1.

A review of systemic therapy in biliary tract carcinoma.

Biliary tract carcinoma (BTC) has a poor prognosis and is increasing in incidence. Although surgery, chemotherapy and other treatment modalities have improved, surgery remains the only potential curative treatment and is appropriate for only those few patients who present with localized, resectable disease. However, for the majority of patients, unresectable disease is evident at diagnosis and about 95% of patients die within 10 years, despite the majority receiving chemotherapy. Long-term survival is significantly greater for patients with resected BTC compared to those with unresectable disease. In unresected disease, life expectancy is limited, with first-line gemcitabine/cisplatin (GEM/CIS) accepted as standard of care. Currently no standard second-line regimen which provides significant improvement of clinical outcomes exists for those who present with refractory disease or who relapse after first-line treatment. Of particular importance is establishing the impact of best supportive care (BSC) as a benchmark for survival outcomes to which the impact of treatment modalities can be compared. Survival outcome often differs significantly for patients with different prognostic factor profiles even when receiving the same therapy so that it can be difficult to predict which patient subgroup might benefit most from which therapy. Therefore, the influence of prognostic factors on survival under different therapies as well as under BSC needs to be further assessed in order to arrive at truly evidence-based, best therapeutic decisions for individual patients. Encouraging new research into the genomic landscape of BTC may help to further subdivide the BTC population into molecular-genetic clusters likely to be sensitive to different targeted therapy approaches leading to further improvements in survival. Consequently, an unmet need exists not only to develop new and more effective therapies for this devastating disease, but also to integrate original research findings into a more complex, dynamic, individualized therapeutic decision model to aid clinicians in making evidence-based, best therapeutic decisions for individual patients.

Hydroxyoctadecadienoic acids: Oxidised derivatives of linoleic acid and their role in inflammation associated with metabolic syndrome and cancer.

Linoleic acid (LA) is a major constituent of low-density lipoproteins. An essential fatty acid, LA is a polyunsaturated fatty acid, which is oxidised by endogenous enzymes and reactive oxygen species in the circulation. Increased levels of low-density lipoproteins coupled with oxidative stress and lack of antioxidants drive the oxidative processes. This results in synthesis of a range of oxidised derivatives, which play a vital role in regulation of inflammatory processes. The derivatives of LA include, hydroxyoctadecadienoic acids, oxo-​octadecadienoic acids, epoxy octadecadecenoic acid and epoxy-keto-octadecenoic acids. In this review, we examine the role of LA derivatives and their actions on regulation of inflammation relevant to metabolic processes associated with atherogenesis and cancer. The processes affected by LA derivatives include, alteration of airway smooth muscles and vascular wall, affecting sensitivity to pain, and regulating endogenous steroid hormones associated with metabolic syndrome. LA derivatives alter cell adhesion molecules, this initial step, is pivotal in regulating inflammatory processes involving transcription factor peroxisome proliferator-activated receptor pathways, thus, leading to alteration of metabolic processes. The derivatives are known to elicit pleiotropic effects that are either beneficial or detrimental in nature hence making it difficult to determine the exact role of these derivatives in the progress of an assumed target disorder. The key may lie in understanding the role of these derivatives at various stages of development of a disorder. Novel pharmacological approaches in altering the synthesis or introduction of synthesised LA derivatives could possibly help drive processes that could regulate inflammation in a beneficial manner. Chemical Compounds: Linoleic acid (PubChem CID: 5280450), 9- hydroxyoctadecadienoic acid (PubChem CID: 5312830), 13- hydroxyoctadecadienoic acid (PubChem CID: 6443013), 9-oxo-​octadecadienoic acid (PubChem CID: 3083831), 13-oxo-​octadecadienoic acid (PubChem CID: 4163990), 9,10-epoxy-12-octadecenoate (PubChem CID: 5283018), 12,13-epoxy-9-keto-10- trans -octadecenoic acid (PubChem CID: 53394018), Pioglitazone (PubChem CID: 4829).

Kindergarten attendance may reduce developmental impairments in children: results from the Bavarian Pre-School Morbidity Survey.

BACKGROUND: The relative risks and benefits of children attending kindergarten or pre-school remain uncertain and controversial. We used data from the Bavarian Pre-School Morbidity Survey (BPMS) to look at the prevalence of developmental impairments in pre-school children entering primary school and to assess if these were correlated with the duration of kindergarten attendance. METHODS: We collected data from all school beginners in the district of Dingolfing, Bavaria from 2004 to 2007 (n = 4,005) and utilised a retrospective cross-sectional study design to review the information. The children were assessed for motor, cognitive, language and psychosocial impairments using a standardized medical assessment. Point prevalence of impairments of speech, cognition, motor functioning and psychosocial functioning were compared by chi(2)-test for the variable of time spent in kindergarten. RESULTS: We detected a high incidence of impairments, with boys showing higher rates than girls in all the areas assessed. Longer length of time spent in kindergarten was associated with reduced rates of motor, cognitive and psychosocial impairments. There was no clear correlation between length of kindergarten attendance and speech disorders. CONCLUSIONS: Kindergarten attendance may have a positive effect on a number of domains of development including motor, cognitive and psychosocial development, but no significant effect on speech impairments. Implications for public health policies are discussed.