Post-Operative Functional Outcomes in Early Age Onset Rectal Cancer

Background: Impairment of bowel, urogenital and fertility-related function in patients treated for rectal cancer is common. While the rate of rectal cancer in the young (<50 years) is rising, there is little data on functional outcomes in this group. Methods: The REACCT international collaborative database was reviewed and data on eligible patients analysed. Inclusion criteria comprised patients with a histologically confirmed rectal cancer, <50 years of age at time of diagnosis and with documented follow-up including functional outcomes. Results: A total of 1428 (n=1428) patients met the eligibility criteria and were included in the final analysis. Metastatic disease was present at diagnosis in 13%. Of these, 40% received neoadjuvant therapy and 50% adjuvant chemotherapy. The incidence of post-operative major morbidity was 10%. A defunctioning stoma was placed for 621 patients (43%); 534 of these proceeded to elective restoration of bowel continuity. The median follow-up time was 42 months. Of this cohort, a total of 415 (29%) reported persistent impairment of functional outcomes, the most frequent of which was bowel dysfunction (16%), followed by bladder dysfunction (7%), sexual dysfunction (4.5%) and infertility (1%). Conclusion: A substantial proportion of patients with early-onset rectal cancer who undergo surgery report persistent impairment of functional status. Patients should be involved in the discussion regarding their treatment options and potential impact on quality of life. Functional outcomes should be routinely recorded as part of follow up alongside oncological parameters

Radiation induced chromosomal instability in lymphocytes of cancer patients

Cytokinesis-blocked micronucleus (CBMN) assay has been extensively used to evaluate the radiation sensitivity of human individuals. Using the CBMN assay, Scott et al (1998, 1999)demonstrated that a fraction of radiosensitive individuals in breast cancer case population was larger than in normal individual population. However, Vral et al were very skeptical about the Scott et al\u27 s findings (2002). Under the approval from the ethical committee of NIRS, peripheral blood was obtained from 46 normal healthy females, 131 breast cancer patients, 32 cervical cancer patients and 7 female head and neck cancer patients. Radiosensitivity of T-lymphocytes was assessed by using a CBMN assay. The frequencies of MN per binucleated cell in healthy donors were 0.031 (+/-0.010) and 0.151 (+/-0.066) for cells treated before and after X-ray-irradiation (2Gy), respectively. Spontaneous MN frequencies in cancer patients were significantly higher than healthy donors (p<0.001). Radiation sensitivities of breast- and head and neck-cancer patients were significantly higher than normal individuals (p<0.001). Cervical cancer patients were more resistant to irradiation than healthy donors, though the number of cases for statistical analysis was small (p<0.001). We are considering that the HPV infection affected the radiosensitivity of cervical cancer cases. Because it is widely believed that one key mechanism which leads to spontaneous micronucleus formation involves an imbalance of chromosomal segregation and a chromosomal instability in patients\u27 lymphocytes might be greater than that in normal individuals\u27 lymphocytes. Recently, Kuschel et al (2002) demonstrated that ratios in two SNPs on XRCC3 were significantly different between cancer patients and healthy females. Then, we can suppose that the radiation-related genes with low penetrance may be involved in tumorigenesis of mammary- and head & neck-cells, and also, in patients\u27 radiation susceptibility.The 12th International Congress of Radiation Research(ICRR

Stepwise approach to SNP-set analysis illustrated with the Metabochip and colorectal cancer in Japanese Americans of the Multiethnic Cohort

Abstract Background Common variants have explained less than the amount of heritability expected for complex diseases, which has led to interest in less-common variants and more powerful approaches to the analysis of whole-genome scans. Because of low frequency (low statistical power), less-common variants are best analyzed using SNP-set methods such as gene-set or pathway-based analyses. However, there is as yet no clear consensus regarding how to focus in on potential risk variants following set-based analyses. We used a stepwise, telescoping approach to analyze common- and rare-variant data from the Illumina Metabochip array to assess genomic association with colorectal cancer (CRC) in the Japanese sub-population of the Multiethnic Cohort (676 cases, 7180 controls). We started with pathway analysis of SNPs that are in genes and pathways having known mechanistic roles in colorectal cancer, then focused on genes within the pathways that evidenced association with CRC, and finally assessed individual SNPs within the genes that evidenced association. Pathway SNPs downloaded from the dbSNP database were cross-matched with Metabochip SNPs and analyzed using the logistic kernel machine regression approach (logistic SNP-set kernel-machine association test, or sequence kernel association test; SKAT) and related methods. Results The TGF-β and WNT pathways were associated with all CRC, and the WNT pathway was associated with colon cancer. Individual genes demonstrating the strongest associations were TGFBR2 in the TGF-β pathway and SMAD7 (which is involved in both the TGF-β and WNT pathways). As partial validation of our approach, a known CRC risk variant in SMAD7 (in both the TGF-β and WNT pathways: rs11874392) was associated with CRC risk in our data. We also detected two novel candidate CRC risk variants (rs13075948 and rs17025857) in TGFBR2, a gene known to be associated with CRC risk. Conclusions A stepwise, telescoping approach identified some potentially novel risk variants associated with colorectal cancer, so it may be a useful method for following up on results of set-based SNP analyses. Further work is required to assess the statistical characteristics of the approach, and additional applications should aid in better clarifying its utility