Gastrointestinal Toxicity of Pelvic Radiotherapy: Are We Letting Women Down?

For all cancers there are four areas of importance: prevention, early diagnosis, optimising therapy and living with and beyond. For women diagnosed with gynaecological cancers, progress in these first three areas has been immense. However, living with and beyond has largely been ignored as a significant issue. As a group, patients treated for gynaecological cancer are more often young and more often suffer the most difficult long-term issues. Despite the growing number of long-term survivors, little has been done to ensure appropriate assessment and treatment of side-effects of cancer therapies, especially when radiotherapy has been used. For many affected patients their symptoms become part of everyday life, 'normality' is adjusted and these changes are tolerated even when severely limiting activities. Data show that even expert clinicians frequently do not appreciate the true impact of these problems and the focus of treatment and of follow-up remains fixed on 5-year survival and cancer recurrence, respectively. Many clinicians are unaware of what experts can do for toxicity and do not know where to refer their patients. However, rapid identification of patients with significant symptoms can lead to earlier diagnosis of treatable pathologies and improvement in patients' quality of life. In addition, the underlying pathophysiology of radiation-induced damage is potentially amenable to disease-modifying therapies. This review focuses on the factors that contribute to patients developing pelvic radiation disease, what can be done to mitigate the toxicity of treatment and highlights the challenges that must be addressed to reduce the gastrointestinal toxicity of pelvic radiotherapy.

Investigation of genetic susceptibility to Mycobacterium tuberculosis (VDR and IL10 genes) in a population with a high level of substructure in the Brazilian Amazon region.

OBJECTIVES: Tuberculosis (TB) is an infectious and contagious disease that has been very influential in human history and presents high rates of mortality. The objective of this study was to investigate the association of VDR, IL10, and SLC11A1 gene polymorphisms with susceptibility to the presence of Mycobacterium tuberculosis infection. METHODS: A total of 135 patients with confirmed TB and 141 healthy individuals were included in the analysis. Blood samples were collected for DNA extraction. Genotyping of the polymorphisms in the VDR and IL10 genes was performed by real-time PCR, and genotyping of the polymorphisms in the SLC11A1 gene by conventional PCR, followed by visualization in polyacrylamide gel. The genomic ancestry was obtained using an autosomal panel with 48 insertion/deletion ancestry-informative markers. RESULTS: Polymorphisms TaqI (TT, p=0.004), FokI (CC and CC+CT, p=0.012 and p=0.003, respectively), and BsmI (GG, p=0.008) in the VDR gene, as well as A-592C (GC+AG, p=0.001) in the IL10 gene, were significantly associated with susceptibility to TB In addition, high production of VDR combined with low production of IL10 showed protection for the TB group (p=0.035). CONCLUSIONS: The VDR polymorphisms may confer an increased risk and the IL10 haplotype may be a protection factor for the presence of M. tuberculosis infection in the Brazilian population.

N-acetyl transferase 2 and cytochrome P450 2E1 genes and isoniazid-induced hepatotoxicity in Brazilian patients.

SETTING: Isoniazid (INH) is related to the development of hepatotoxicity in some patients. OBJECTIVE: To investigate the role of N-acetyl transferase 2 (NAT2) and cytochrome P450 2E1 (CYP2E1) in the hepatotoxicity of patients treated with INH in an Amazonian Brazilian population. DESIGN: Patients undergoing anti-tuberculosis treatment were investigated. Hepatotoxicity was defined as an increase of more than three times the upper limit of normal in serum alanine aminotransferase levels after treatment. NAT2 genotypes were identified by sequencing, whereas CYP2E1 alleles were detected using polymerase chain reaction based methods. RESULTS: Of the 270 individuals included in the study, 18 (6.7%) developed drug-related hepatotoxicity. A high association was found between slow acetylators and hepatotoxicity, particularly with regard to allele *5. The adjusted risk of developing hepatotoxicity was significant in individuals carrying two slow acetylation alleles (P = 0.036, OR 3.05, 95%CI 1.07-8.64). In all of the CYP2E1 markers examined, wild homozygous genotypes were more prevalent in subjects with hepatotoxicity than in controls; however, the difference was not statistically significant. Joint evaluation of the genes revealed a high risk of developing hepatotoxicity in slow acetylators with CYP2E1 wild alleles (adjusted OR 4.26; 95%CI 1.47-12.37, P = 0.008). CONCLUSIONS: Large-scale screening for NAT2 and CYP2E1 genotypes can prove useful in predicting the risk of adverse effects.