Current treatment for localized anal carcinoma

PURPOSE OF REVIEW: Chemoradiation represents the standard of care for most patients with localized squamous cell carcinoma of the anal canal. This article reviews randomized trials and recent studies on chemoradiation for anal cancer. RECENT FINDINGS: A recent randomized trial showed that patients treated with induction 5-fluorouracil/cisplatin followed by concurrent 5-fluorouracil/cisplatin and radiotherapy had a higher colostomy rate than patients treated with concurrent 5-fluorouracil/mitomycin C and radiotherapy. It remains unclear whether this difference in the rate of colostomy was due to the chemotherapy agents, the use of induction therapy in the 5-fluorouracil/cisplatin arm, or other factors. Recent studies have started to evaluate intensity modulated radiation therapy for anal cancer, in an effort to reduce acute and long-term toxicity from radiotherapy. SUMMARY: The role of cisplatin in anal cancer is not completely clear, although an ongoing randomized trial (Anal Cancer Trial II) may help clarify the role of cisplatin. Studies on tumor biology and patient genetics are warranted to identify patients that are most likely to benefit from newer locoregional and systemic therapies. Intensity modulated radiation therapy appears to be a promising approach for reducing treatment-related toxicity in anal cancer patients. The Radiation Therapy Oncology Group (RTOG) is conducting a phase II trial evaluating the multi-institutional feasibility of intensity modulated radiation therapy for anal cancer.     

Elevated levels of somatic mutation in a manifesting BRCA1 mutation carrier

Homozygous loss of activity at the breast cancerpredisposing genes BRCA1 and BRCA2 (FANCD1) confers increased susceptibility to DNA double strand breaks, but this genotype occurs only in the tumor itself, following loss of heterozygosity at one of these loci. Thus, if these genes play a role in tumor etiology as opposed to tumor progression, they must manifest a heterozygous phenotype at the cellular level. To investigate the potential consequences of somatic heterozygosity for a BRCA1 mutation demonstrably associated with breast carcinogenesis on background somatic mutational burden, we applied the two standard assays of in vivo human somatic mutation to blood samples from a manifesting carrier of the Q1200X mutation in BRCA1 whose tumor was uniquely ascertained through an MRI screening study. The patient had an allele-loss mutation frequency of 19.4 x 10(-6) at the autosomal GPA locus in erythrocytes and 17.1 x 10(-6) at the X-linked HPRT locus in lymphocytes. Both of these mutation frequencies are significantly higher than expected from age-matched disease-free controls (P < 0.05). Mutation at the HPRT locus was similarly elevated in lymphoblastoid cell lines established from three other BRCA1 mutation carriers with breast cancer. Our patient's GPA mutation frequency is below the level established for diagnosis of homozygous Fanconi anemia patients, but consistent with data from obligate heterozygotes. The increased HPRT mutation frequency is more reminiscent of data from patients with xeroderma pigmentosum, a disease characterized by UV sensitivity and deficiency in the nucleotide excision pathway of DNA repair. Therefore, this BRCA1-associated breast cancer patient manifests a unique phenotype of increased background mutagenesis that likely contributed to the development of her disease independent of loss of heterozygosity at the susceptibility locus.     

Achievement of target cyclosporine concentrations as a predictor of severe acute graft versus host disease in children undergoing hematopoietic stem cell transplantation and receiving cyclosporine and methotrexate prophylaxis

This study evaluates our institution's target trough cyclosporine (CSA) concentrations as predictors of severe acute graft versus host disease (aGvHD) in children receiving either matched related or unrelated hematopoietic stem cell transplantation (HSCT). The outcomes of 87 consecutive children who underwent allogeneic HSCT and received CSA and methotrexate as prophylaxis against aGvHD between October 1, 1999 and September 30, 2002 were retrospectively evaluated. The proportion of time that each patient maintained a whole blood CSA concentration within or above the initial target range (105-155 ng/mL or 155-210 ng/mL) was calculated for each of the following time periods: in each week after HSCT from day 0 to +28; in the week preceding engraftment; and in the week preceding the onset of aGvHD. Patients were prospectively evaluated twice weekly for the presence and severity of aGvHD by senior attending physicians. The relationship between potential predictors and the development of severe aGvHD was examined using univariate logistic regression. The main variables of interest were the proportion of time that therapeutic or supratherapeutic CSA concentrations were maintained; median CSA concentrations; the number of methotrexate doses received; and the use of folinic acid rescue. Mean follow-up time was 3.0+/-1.9 years among children who survived beyond day +100. Three variables were significantly associated with the development of severe aGvHD on univariate analysis: initial CSA target concentration [odds ratio (OR), 0.24; P=0.03], proportion of time the target CSA concentration was achieved during the second week after transplant (OR, 0.16; P=0.02), and proportion of time the target CSA concentration was achieved during the week before engraftment (OR, 0.22; P=0.0489). Multivariable analysis demonstrated an inverse relationship between the median CSA concentration during the week before engraftment and the development of severe aGvHD (OR, 0.99; P=0.045). These results suggest that achievement of our CSA target concentrations is important to aGvHD outcomes.     

Epigenetic insight into effects of prenatal alcohol exposure on stress axis development: Systematic review with meta-analytic approaches

We conducted a systematic review with meta-analytic elements using publicly available Gene Expression Omnibus (GEO) datasets to determine the role of epigenetic mechanisms in prenatal alcohol exposure (PAE)-induced hypothalamic–pituitary–adrenal (HPA) axis dysfunctions in offspring. Several studies have demonstrated that PAE has long-term consequences on HPA axis functions in offspring. Some studies determined that alcohol-induced epigenetic alterations during fetal development persist in adulthood. However, additional research is needed to understand the major epigenetic events leading to alcohol-induced teratogenesis of the HPA axis. Our network analysis of GEO datasets identified key pathways relevant to alcohol-mediated histone modifications, DNA methylation, and miRNA involvement associated with PAE-induced alterations of the HPA axis. Our analysis indicated that PAE perturbated the epigenetic machinery to activate corticotrophin-releasing hormone, while it suppressed opioid, glucocorticoid receptor, and circadian clock genes. These results help to further our understanding of the epigenetic basis of alcohol's effects on HPA axis development.     

Eco-bioengineering tools in ecohydrological assessment of eutrophic water bodies

Ecotoxicology - Eutrophication of water bodies and deterioration of water quality are emerging environmental crises. The root causes and consequences of eutrophication are multidirectional. Thus,...     

Case-control and qualitative study of attrition in a community epilepsy programme in rural India.

Dropout from epilepsy programmes is a serious problem in developing countries and has not been systematically studied before. We set up a community-based programme for children with epilepsy in rural India. The aim of this study was to assess reasons for dropout. We assessed medical and sociodemographic variables for their effect on dropout at 12 months using an unmatched case-control design on 32 cases and 62 controls. We also interviewed the parents of 32 children who dropped out of treatment, using a topic schedule. Two-thirds of the dropouts occurred within the first 6 months of treatment. Severely impaired children were more likely to drop out (odds ratio 4.60, 95% CI: 1.0-21.0) and families who had tried AEDs before were less likely to do so (odds ratio 0.12, 95% CI: 0.015-0.88). Denial of diagnosis, access problems and symptom resolution were the other main reasons underlying attrition. Active ascertainment methods should be reconsidered in community programmes. Very poor families without a male head or with long journey times are at high risk of dropout. People with severe impairments need appropriate integrated rehabilitation.