Frequent k- ras -2 mutations and p16INK4Amethylation in hepatocellular carcinomas in workers exposed to vinyl chloride

Vinyl chloride (VC) is a know animal and human carcinogen associated with liver angiosarcomas (LAS) and hepatocellular carcinomas (HCC). In VC-associated LAS mutations of the K- ras -2 gene have been reported; however, no data about the prevalence of such mutations in VC associated HCCs are available. Recent data indicate K- ras -2 mutations induce P16 methylation accompanied by inactivation of the p16 gene. The presence of K- ras -2 mutations was analysed in tissue from 18 patients with VC associated HCCs. As a control group, 20 patients with hepatocellular carcinoma due to hepatitis B (n = 7), hepatitis C (n = 5) and alcoholic liver cirrhosis (n = 8) was used. The specific mutations were determined by direct sequencing of codon 12 and 13 of the K- ras -2 gene in carcinomatous and adjacent non-neoplastic liver tissue after microdissection. The status of p16 was evaluated by methylation-specific PCR (MSP), microsatellite analysis, DNA sequencing and immunohistochemical staining. All patients had a documented chronic quantitated exposure to VC (average 8883 ppmy, average duration: 245 months). K- ras -2 mutations were found in 6 of 18 (33%) examined VC-associated HCCs and in 3 cases of adjacent non-neoplastic liver tissue. There were 3 G → A point mutations in the tumour tissue. All 3 mutations found in non-neoplastic liver from VC-exposed patients were also G → A point mutations (codon 12- and codon 13-aspartate mutations). Hypermethylation of the 5′ CpG island of the p16 gene was found in 13 of 18 examined carcinomas (72%). Of 6 cancers with K- ras -2 mutations, 5 specimens also showed methylated p16. Within the control group, K- ras -2 mutation were found in 3 of 20 (15%) examined HCC. p16 methylation occurred in 11 out of 20 (55%) patients. K- ras -2 mutations and p16 methylation are frequent events in VC associated HCCs. We observed a K- ras -2 mutation pattern characteristic of chloroethylene oxide, a carcinogenic metabolite of VC. Our results strongly suggest that K- ras -2 mutations play an important role in the pathogenesis of VC-associated HCC. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

Applications of the ACGT Master Ontology on Cancer

In this paper we present applications of the ACGT Master Ontology (MO) which is a new terminology resource for a transnational network providing data exchange in oncology, emphasizing the integration of both clinical and molecular data. The development of a new ontology was necessary due to problems with existing biomedical ontologies in oncology. The ACGT MO is a test case for the application of best practices in ontology development. This paper provides an overview of the application of the ontology within the ACGT project thus far

Heparanase is a prognostic indicator for postoperative survival in pancreatic carcinoma

British Journal of Cancer (2002) 87, 689–689. doi:10.1038/sj.bjc.6600504 www.bjcancer.co

Sowing the seeds of doubt: a narrative review on metacognitive training in schizophrenia

AbstractThe present article provides a narrative review of empirical studies on metacognitive training in psychosis (MCT). MCT represents an amalgam of cognitive-behavioral therapy (CBT), cognitive remediation (CRT) and psychoeducation. The intervention is available in either a group (MCT) or an individualized (MCT+) format. By sowing the seeds of doubt in a playful and entertaining fashion, the program targets positive symptoms, particularly delusions. It aims to raise patients’ awareness for common cognitive traps or biases (e.g., jumping to conclusions, overconfidence in errors, bias against disconfirmatory evidence) that are implicated in the formation and maintenance of psychosis. The majority of studies confirm that MCT meets its core aim, the reduction of delusions. Problems (e.g., potential allegiance effects) and knowledge gaps (i.e., outcome predictors) are highlighted. The preliminary data suggest that the individual MCT format is especially effective in addressing symptoms, cognitive biases and insight. We conclude that MCT appears to be a worthwhile complement to pharmacotherapy

Sowing the seeds of doubt: a narrative review on metacognitive training in schizophrenia

Abstract not availableSteffen Moritz, Christina Andreou, Brooke C. Schneider, Charlotte E. Wittekind, Mahesh Menon, Ryan P. Balzan, Todd S. Woodwar

The Unique Clinical Phenotype and Exercise Adaptation of Fontan Patients With Normal Exercise Capacity

Background: Exercise limitation is almost universal among Fontan patients. Identifying unique clinical features in the small fraction of Fontan patients with normal exercise capacity (high-capacity Fontan [HCF]) provides potential to inform clinical strategies for those with low exercise capacity (usual Fontan). Methods: We performed a retrospective chart review of all patients with single-ventricle physiology palliated with a Fontan operation who underwent incremental cardiopulmonary exercise testing at Cincinnati Children’s Hospital Medical Center from 2013 to 2018. Comparison was between patients with peak oxygen uptake < vs ≥ 80% predicted. Results: A total of 22 of 112 patients were classified as HCF (68% were female; aged 18 ± 7 years). During incremental exercise, peak oxygen uptake (86.1% ± 6.1% vs 62% ± 12.2% predicted; P < 0.001) was greater in HCF vs usual Fontan despite similar chronotropic impairment, resulting in a greater oxygen pulse in HCF. Pulmonary function, breathing reserve, and ventilatory equivalent for CO2 output slope were not different between groups. Those in the HCF group were more likely to self-report exercise ≥ 4 days/week for at least 30 minutes (77% vs 10%, P < 0.001), have normal systolic function (95% vs 74%, P = 0.003), have fewer postoperative complications (8% vs 36%, P = 0.04), and have shorter post-Fontan length of stay (8 ± 2.8 vs 12.4 ± 0.9 days, P = 0.04). Conclusions: Approximately 1 in 5 Fontan patients who undergo cardiopulmonary exercise testing have normal exercise capacity despite chronotropic impairment. This implies a better preserved stroke volume, perhaps due to greater muscle pump-mediated preload. Additionally, a complicated perioperative Fontan course is associated with eventual impaired functional capacity

Inspiratory muscle warm-up does not improve cycling time-trial performance

Purpose: This study examined the effects of an active cycling warm-up, with and without the addition of an inspiratory muscle warm-up (IMW), on 10-km cycling time-trial performance

Imputation of missing values of tumour stage in population-based cancer registration

<p>Abstract</p> <p>Background</p> <p>Missing data on tumour stage information is a common problem in population-based cancer registries. Statistical analyses on the level of tumour stage may be biased, if no adequate method for handling of missing data is applied. In order to determine a useful way to treat missing data on tumour stage, we examined different imputation models for multiple imputation with chained equations for analysing the stage-specific numbers of cases of malignant melanoma and female breast cancer.</p> <p>Methods</p> <p>This analysis was based on the malignant melanoma data set and the female breast cancer data set of the cancer registry Schleswig-Holstein, Germany. The cases with complete tumour stage information were extracted and their stage information partly removed according to a MAR missingness-pattern, resulting in five simulated data sets for each cancer entity. The missing tumour stage values were then treated with multiple imputation with chained equations, using polytomous regression, predictive mean matching, random forests and proportional sampling as imputation models. The estimated tumour stages, stage-specific numbers of cases and survival curves after multiple imputation were compared to the observed ones.</p> <p>Results</p> <p>The amount of missing values for malignant melanoma was too high to estimate a reasonable number of cases for each UICC stage. However, multiple imputation of missing stage values led to stage-specific numbers of cases of T-stage for malignant melanoma as well as T- and UICC-stage for breast cancer close to the observed numbers of cases. The observed tumour stages on the individual level, the stage-specific numbers of cases and the observed survival curves were best met with polytomous regression or predictive mean matching but not with random forest or proportional sampling as imputation models.</p> <p>Conclusions</p> <p>This limited simulation study indicates that multiple imputation with chained equations is an appropriate technique for dealing with missing information on tumour stage in population-based cancer registries, if the amount of unstaged cases is on a reasonable level.</p