Molecular Pathological Classification of Colorectal Cancer

Colorectal cancer (CRC) shows variable underlying molecular changes with two major mechanisms of genetic instability: chromosomal instability and microsatellite instability. This review aims to delineate the different pathways of colorectal carcinogenesis and provide an overview of the most recent advances in molecular pathological classification systems for colorectal cancer. Two molecular pathological classification systems for CRC have recently been proposed. Integrated molecular analysis by The Cancer Genome Atlas project is based on a wide-ranging genomic and transcriptomic characterisation study of CRC using array-based and sequencing technologies. This approach classified CRC into two major groups consistent with previous classification systems: (1) ∼16 % hypermutated cancers with either microsatellite instability (MSI) due to defective mismatch repair (∼13 %) or ultramutated cancers with DNA polymerase epsilon proofreading mutations (∼3 %); and (2) ∼84 % non-hypermutated, microsatellite stable (MSS) cancers with a high frequency of DNA somatic copy number alterations, which showed common mutations in APC, TP53, KRAS, SMAD4, and PIK3CA. The recent Consensus Molecular Subtypes (CMS) Consortium analysing CRC expression profiling data from multiple studies described four CMS groups: almost all hypermutated MSI cancers fell into the first category CMS1 (MSI-immune, 14 %) with the remaining MSS cancers subcategorised into three groups of CMS2 (canonical, 37 %), CMS3 (metabolic, 13 %) and CMS4 (mesenchymal, 23 %), with a residual unclassified group (mixed features, 13 %). Although further research is required to validate these two systems, they may be useful for clinical trial designs and future post-surgical adjuvant treatment decisions, particularly for tumours with aggressive features or predicted responsiveness to immune checkpoint blockade

Gender differences in the use of cardiovascular interventions in HIV-positive persons; the D:A:D Study

Peer reviewe

Photoproduction of ηπ pairs off nucleons and deuterons

Quasi-free photoproduction of πη-pairs has been investigated from threshold up to incident photon energies of 1.4 GeV, respectively up to photon-nucleon invariant masses up to 1.9 GeV. Total cross sections, angular distributions, invariant-mass distributions of the πη and meson-nucleon pairs, and beamhelicity asymmetries have been measured for the reactions γp → pπ0η, γn → nπ0η, γp → nπ+η, and γn → pπ-n from nucleons bound inside the deuteron. For the γp initial-state data for free protons have also been analyzed. Finally, the total cross sections for quasi-free production of π0η pairs from nucleons bound in 3He nuclei have been investigated in view of final state interaction (FSI) effects. The experiments were performed at the tagged photon beam facility of the Mainz MAMI accelerator using an almost 4π covering electromagnetic calorimeter composed of the Crystal Ball and TAPS detectors. The shapes of all differential cross section data and the asymmetries are very similar for protons and neutrons and agree with the conjecture that the reactions are dominated by the sequential Δ*3/2- → ηΔ(1232) → πηN decay chain, mainly with Δ(1700)3/2- and Δ(1940)3/2-. The ratios of the magnitude of the total cross sections also agree with this assumption. However, the absolute magnitudes of the cross sections are reduced by FSI effects with respect to free proton data

Insertional mutagenesis identifies multiple networks of cooperating genes driving intestinal tumorigenesis

The evolution of colorectal cancer suggests the involvement of many genes. We performed insertional mutagenesis with the Sleeping Beauty (SB) transposon system in mice carrying germline or somatic Apc mutation. Analysis of common insertion sites (CISs) isolated from 446 tumors revealed many hundreds of candidate cancer drivers. Comparison to human datasets suggested that 234 CIS genes are also deregulated in human colorectal cancers. 183 CIS genes are candidate Wnt targets, and 20 are shown to be novel modifiers of canonical Wnt signaling. We also identified gene mutations associated with a subset of tumors containing an expanded number of Paneth cells, a hallmark of deregulated Wnt signaling, and genes associated with more severe dysplasia included members of the FGF signaling cascade. Some 70 genes showed pairwise co-occurrence clustering into 38 sub-networks that may regulate tumor development

Development and Validation of a Risk Score for Chronic Kidney Disease in HIV Infection Using Prospective Cohort Data from the D:A:D Study

Ristola M. on työryhmien DAD Study Grp ; Royal Free Hosp Clin Cohort ; INSIGHT Study Grp ; SMART Study Grp ; ESPRIT Study Grp jäsen.Background Chronic kidney disease (CKD) is a major health issue for HIV-positive individuals, associated with increased morbidity and mortality. Development and implementation of a risk score model for CKD would allow comparison of the risks and benefits of adding potentially nephrotoxic antiretrovirals to a treatment regimen and would identify those at greatest risk of CKD. The aims of this study were to develop a simple, externally validated, and widely applicable long-term risk score model for CKD in HIV-positive individuals that can guide decision making in clinical practice. Methods and Findings A total of 17,954 HIV-positive individuals from the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) study with >= 3 estimated glomerular filtration rate (eGFR) values after 1 January 2004 were included. Baseline was defined as the first eGFR > 60 ml/min/1.73 m2 after 1 January 2004; individuals with exposure to tenofovir, atazanavir, atazanavir/ritonavir, lopinavir/ritonavir, other boosted protease inhibitors before baseline were excluded. CKD was defined as confirmed (>3 mo apart) eGFR In the D:A:D study, 641 individuals developed CKD during 103,185 person-years of follow-up (PYFU; incidence 6.2/1,000 PYFU, 95% CI 5.7-6.7; median follow-up 6.1 y, range 0.3-9.1 y). Older age, intravenous drug use, hepatitis C coinfection, lower baseline eGFR, female gender, lower CD4 count nadir, hypertension, diabetes, and cardiovascular disease (CVD) predicted CKD. The adjusted incidence rate ratios of these nine categorical variables were scaled and summed to create the risk score. The median risk score at baseline was -2 (interquartile range -4 to 2). There was a 1: 393 chance of developing CKD in the next 5 y in the low risk group (risk score = 5, 505 events), respectively. Number needed to harm (NNTH) at 5 y when starting unboosted atazanavir or lopinavir/ritonavir among those with a low risk score was 1,702 (95% CI 1,166-3,367); NNTH was 202 (95% CI 159-278) and 21 (95% CI 19-23), respectively, for those with a medium and high risk score. NNTH was 739 (95% CI 506-1462), 88 (95% CI 69-121), and 9 (95% CI 8-10) for those with a low, medium, and high risk score, respectively, starting tenofovir, atazanavir/ritonavir, or another boosted protease inhibitor. The Royal Free Hospital Clinic Cohort included 2,548 individuals, of whom 94 individuals developed CKD (3.7%) during 18,376 PYFU (median follow-up 7.4 y, range 0.3-12.7 y). Of 2,013 individuals included from the SMART/ESPRIT control arms, 32 individuals developed CKD (1.6%) during 8,452 PYFU (median follow-up 4.1 y, range 0.6-8.1 y). External validation showed that the risk score predicted well in these cohorts. Limitations of this study included limited data on race and no information on proteinuria. Conclusions Both traditional and HIV-related risk factors were predictive of CKD. These factors were used to develop a risk score for CKD in HIV infection, externally validated, that has direct clinical relevance for patients and clinicians to weigh the benefits of certain antiretrovirals against the risk of CKD and to identify those at greatest risk of CKD.Peer reviewe

Risperidone plasma levels, clinical response and side–effects

Assessment of the relation between oral risperidone dose, serum drug levels and clinical response may provide important information for rational treatment decisions. Inter–individual differences in the liver cytochrome P450 system, especially in the CYP2D6 subsystem, which account for a significant portion of risperidone metabolism, may also influence plasma drug levels and alter clinical response parameters. We thus prospectively investigated risperidone serum concentrations in relation to clinical efficacy and side–effects and genotyped major CYP2D6 polymorphisms to determine their effect upon these parameters.Neuroleptic monotherapy with risperidone was administered to schizophrenia patients in a 6–week open dose clinical trial. Weekly assessments including CGI and PANSS ratings to assess psychopathology; SAS to assess medication side effects; and blood draws to quantify steady state plasma levels of risperidone and 9–OH–risperidone were carried out. In addition, major CYP2D6 polymorphisms including alleles *4, *6 and *14 were genotyped.Eighty–two patients were recruited. Mean oral dose of risperidone was 4.3 ± 0.9mg. Mean plasma level of both risperidone and 9–OH–risperidone together (“active moiety”) was 41.6 ± 26.6 ng/ml. Significant improvements in PANSS scales and the various subscales ensued. There was a positive linear correlation between active moiety plasma levels and dose (r = 0.291, p = 0.015) and between risperidone and 9–OH–risperidone levels (r = 0.262; p = 0.016). Nonresponders to pharmacotherapy (PANSS–Improvement < 30%) showed significantly higher active moiety plasma levels (49.9 ± 30.7 ng/ml) than responders (38.2 ± 17.0 ng/ml; p = 0.045) without significantly higher oral doses (p = 0.601). Patients with longer illness duration (≥ 3 years) had significantly higher plasma drug levels than those with a shorter course (< 3 years; p = 0.039). Extrapyramidal side effects (EPS) and plasma levels were not correlated (r = 0.028; p = 0.843), but higher plasma levels at week 2 predicted an incidence for EPS (p < 0.050). Accordingly, patients initially receiving higher oral doses of risperidone were significantly more likely to respond with EPS in the trial course. Eight patients (9.8%) were heterozygous carriers of the CYP2D6 allele *4. CYP2D6 polymorphisms did not predict clinical response, but predicted a tendential increase in the plasma risperidone to 9–OH–risperidone ratio (0.5 ± 0.6 vs. 1.9 ± 1.8; p = 0.120).The major finding was that responders to risperidone treatment had significantly lower blood levels of risperidone and 9–OH risperidone than patients who did not respond to the treatment despite administration of similar oral doses. The observed CYP2D6 polymorphisms did not contribute to altered clinical efficacy, but affected risperidone to 9–OH–risperidone ratios. Increased plasma levels of the active moiety in patients with longer illness may represent general aging effects. Conversely, the observed higher plasma levels in nonresponders may derive from unaccounted genetic metabolism abnormalities or Phase II metabolism disturbances. Patients initially receiving higher oral risperidone doses were more likely to respond with extrapyramidal side effects which reaffirms the need for careful titration. The high inter–individual variability in risperidone and 9–OH–risperidone metabolization and the relationship between clinical outcome and plasma levels warrants regular plasma level monitoring of both compounds to assess for the clinically relevant active moiety

Risperidone Plasma Levels, Clinical Response and Side-Effects

Introduction: Assessment of the relation between oral neuroleptic dose, serum drug levels and clinical response may provide important information for rational treatment decisions. Methods: Risperidone mono-therapy was administered to 82 schizophrenia patients in a 6-week open dose clinical trial. Weekly assessments including CGI and PANSS ratings to assess psychopathology; SAS to assess medication side effects; and blood draws to quantify steady state plasma levels of Risperidone and 9-OH-Risperidone were carried out. Additionally, major CYP2D6 polymorphisms were genotyped. Results: Mean oral dose of risperidone was 4.4±1.0mg. Mean plasma level of both risperidone and 9-OH-Risperidone together („active moiety“) was 41.6±26.6 ng/ml. There was a positive linear correlation between risperidone plasma levels and dose (r=0.308, p≤.05). Therapy non-responder (PANSS improvement <30%) showed significantly higher plasma levels (p=.032) than responder (PANSS improvement ≥30%) without higher dosages (p=.258). Patients with a duration ≥ 5 years had significantly higher plasma levels than those with a duration <5 years (p=.028). EPS and plasma levels were not correlated (r=.028; p=.843). Patients initially receiving higher oral doses of risperidone were significantly more likely to develop extrapyramidal side effects later in the trial course. Eight of the patients (9.8%) were heterozygous for the CYP2D6 polymorphism. CYP2D6 polymorphisms did not predict clinical response, but tended to predict an increase in the Risperidone/9-OH-Risperidone-Ratio (p=0.095). Discussion: Several aspects of our study have an important implication for the clinical use: The higher incidence of EPMS is related to a faster up-titration of Risperidone and higher plasma levels; Non-responders to risperidone treatment showed higher plasma levels, indicating that a further increase in the daily dose is not recommended; patients with a longer duration of illness showed higher plasma levels, although receiving the same oral dose. The therapeutic monitoring of risperidone and 9-OH-risperidone blood levels is thus highly recommended