Colorectal cancer genomics: evidence for multiple genotypes which influence survival

Colorectal cancer (CRC) is a leading cause of cancer death and the mechanism for variable outcome in this disease is not yet fully understood. It is hypothesized that differences in the genetic make-up of tumours may be partially responsible for the differences observed in survival among same staged individuals for this disease. In this study the tumour genomes of 29 consecutive patients undergoing surgery for Dukes' C CRC were assessed by comparative genomic hybridization (CGH). In addition, the CGH profiles from the tumours were compared with those from eight colorectal cell lines. Great variation in genetic grade (all detectable aberrations i.e., loss + gain) was observed in 29 Dukes' C colorectal tumours by CGH (median four aberrations per tumour, range 0–20). Gain was found in 76% and loss in 41% of tumours. The most frequently observed regions of gain were 13q (27.6%), 20q (27.6%), 7p (24.1%), 8q (24.1%), and 1q (20.7%) and loss were 18q (31%), 4q (20.7%), 17p (20.7%), 18p (20.7%), and 15q (20.1%). None of these specific genomic aberrations were associated with patient survival. However, patients with more than two aberrations had a better survival than patients with fewer regions of loss and gain (P = 0.02). CRC cell lines had similar regions of loss or gain as the tumours. However, the frequency of genomic aberrations was much greater in the CRC cell lines. Although genomic change in CRC is relevant to the survival of patients with Dukes' C CRC, careful analysis is required to identify cell lines which are representative models of CRC genomics.© 2001 Cancer Research Campaign  http://www.bjcancer.co

Topoisomerase I but not thymidylate synthase is associated with improved outcome in patients with resected colorectal cancer treated with irinotecan containing adjuvant chemotherapy

<p>Abstract</p> <p>Background</p> <p>Thymidylate synthase (TS) and Topoisomerase I (Topo I) are significant biomarkers in colorectal cancer (CRC). We aimed to study the expression of TS and Topo I in patients with resected CRC who received adjuvant chemotherapy and correlated it with clinical outcome.</p> <p>Methods</p> <p>All patients diagnosed with CRC between 1989 and 2007 and treated with adjuvant chemotherapy within Hellenic Cooperative Oncology Group's (HeCOG) protocols, were identified. Archival paraffin-embedded tumor tissues were used for immunohistochemical detection of TS and Topo I. Immunohistochemistry was performed on tissue microarray slides using monoclonal antibodies against TS and Topo I. The results were correlated with survival (OS) and disease free survival (DFS).</p> <p>Results</p> <p>A cohort of 498 patients with a median age of 61 years and Dukes' stage B (49%) and C (51%) fulfilled the criteria of the study. All patients received adjuvant 5-FU-based chemotherapy, 38% irinotecan-containing. Positive TS and Topo I expression was found in 43% and 48% of cases, respectively. Five-year OS was 74% and DFS was 68%. In univariate analysis no association of TS and Topo I expression with OS and DFS was identified. In multivariate analysis however, Topo I expression was associated with a reduced risk of death (HR = 0.61, 95% CI 0.42-0.88, p = 0.009). In the irinotecan-treated subgroup, those patients who expressed Topo I had a better OS (HR = 0.47, 95% CI 0.23-0.94, p = 0.033).</p> <p>Conclusion</p> <p>Patients with resected CRC expressing Topo I seem to benefit from irinotecan-containing adjuvant chemotherapy. However randomised prospective trials are needed to confirm these results.</p

Regional variation and determinants of vitamin D status in sunshine-abundant Thailand

<p>Abstract</p> <p>Background</p> <p>Vitamin D insufficiency is highly prevalent. Most of the studies concerning vitamin D status were generated from countries situated at temperate latitudes. It is less clear what the extent of vitamin D insufficiency is in countries situated in the tropics and how geographical regions within country would affect vitamin D status. In the present study, we investigated vitamin D status in Thais according to geographical regions and other risk factors.</p> <p>Methods</p> <p>Subjects consisted of 2,641 adults, aged 15 - 98 years, randomly selected from the Thai 4th National Health Examination Survey (2008-9) cohort. Serum 25 hydroxyvitamin D were measured by liquid chromatography/tandem mass spectrometry. Data were expressed as mean ± SE.</p> <p>Results</p> <p>Subjects residing in Bangkok, the capital city of Thailand, had lower 25(OH)D levels than other parts of the country (Bangkok, central, northern, northeastern and southern regions: 64.8 ± 0.7, 79.5 ± 1.1, 81.7 ± 1.2, 82.2 ± 0.8 and 78.3 ± 1.3 nmol/L, respectively; <it>p </it>< 0.001). Within each region, except for the northeastern part of the country, subjects living inside municipal areas had lower circulating 25(OH)D (central, 77.0 ± 20.9 nmol/L vs 85.0 ± 22.1 nmol/L, <it>p </it>< 0.001; north 79.3 ± 22.1 nmol/L vs 86.8 ± 21.8 nmol/L, <it>p </it>< 0.001; northeast 84.1 ± 23.3 nmol/L vs 87.3 ± 20.9 nmol/L, <it>p </it>= 0.001; south, 76.6 ± 20.5 nmol/L vs 85.2 ± 24.7 nmol/L, <it>p </it>< 0.001). Overall, the prevalence of vitamin D insufficiency was 64.6%, 46.7%, and 33.5% in Bangkok, municipal areas except Bangkok, and outside municipal area in other parts of the country, respectively. In addition, the prevalence of vitamin D insufficiency according to geographical regions was 43.1%, 39.1%, 34.2% and 43.8% in the central, north, northeast and south, respectively. After controlling for covariates in multiple linear regression analysis, the results showed that low serum 25(OH)D levels were associated with being female, younger age, living in urban and Bangkok.</p> <p>Conclusions</p> <p>Vitamin D insufficiency is common and varies across geographical regions in Thailand.</p

Constitutive nuclear factor-kappa B mRNA, protein overexpression and enhanced DNA-binding activity in thymidylate synthase inhibitor-resistant tumour cells

In this study, the gene copy number, mRNA and protein expression levels and nuclear DNA-binding activity of nuclear factor kappa B (NF-kappaB) were compared in a panel of five pairs of thymidylate synthase (TS) inhibitor-resistant and wild-type parent cancer cell lines. High constitutive NF-kappaB DNA-binding activity was detected in all chemoresistant cell lines. The upregulated NF-kappaB activity was composed of NF-kappaB subunits p50 and p65. Four out of five resistant cell lines constitutively overexpressed NF-kappaB p50 and p63 mRNA and protein. One resistant cell line with the highest NF-kappaB DNA-binding activity showed normal p50 and p65 protein expression. No NF-kappaB gene amplification was detected in resistant cell lines. Transient exposure of wild-type RKOWT and H630(WT) cells to 5-FU induced NF-kappaB DNA-binding activity but had no effect on NF-kappaB protein expression in these cells, Our results indicate that high constitutive NF-kappaB activity caused by its gene overexpression is an intrinsic character of TS inhibitor-resistant cells. NF-kappaB can antagonise anticancer drug-induced apoptosis. High NF-kappaB expression and nuclear activity in TS inhibitor-resistant cancer cells may play an important role in the chemoresistance

Pseudotumor Cerebri Appearing With Unilateral Papilledema After Trabeculectomy

We describe a patient with papilledema due to pseudotumor cerebri that was seen unilaterally following normalization of intraocular pressure (IOP) and discontinuation of systemic acetazolamide therapy following trabeculectomy. We hypothesize that the lamina cribrosa sclerae serves as a flexible barrier between intracranial pressure (ICP) and IOP and that alterations of the normal ICP/IOP ratio may lead to papilledema. To our knowledge, there have been no reports describing the development of unilateral papilledema following surgical reduction in IOP. REPORT OF A CASE. A 41-year-old obese white woman with a 9-year history of juvenile primary open-angle glaucoma underwent uncomplicated trabeculectomy in the left eye with supplemental 5-mg subconjunctival injections of 5-fluorouracil (50 mg/mL) because of progressive glaucomatous cupping. Preoperative IOP was 23 mm Hg in the right eye and 35 mm Hg in the left eye while receiving acetazolamide sequels, 500 mg twice daily, plus a combination of timolol maleate 0.5% an

Variations, trends and patterns of fish landings in large tropical reservoirs

Temporal variations of fish yields in four major reservoirs in Thailand (Ubolratana; Sirindhorn; Srinakarin; Vajiralongkorn) were investigated with the use of long-term fish landing data (&ge;20years). The long-term variations in fish yield, measured as the coefficient of variation of yearly yield, ranged mostly between 50% and 100%. For short-term variations, the means of the relative variation (85%) were larger than the absolute variation (63%). This finding indicates that short-term variations were inversely related to fish yield and that a higher uncertainty occurs when fish catches are low. The stocked exotic species exhibited higher variations than the indigenous species. The trend analyses indicated some species had sharply declined fish landings, while some species were quite stable (i.e. reservoir-adapted species). Stocked species tended to increase in relatively shallow reservoirs, compared to the deep reservoir. Fish landing data for each reservoir were patternized, using the self-organizing map, indicating temporal trends of chronological order. The differences among clusters in each reservoir were with respect to the weight of each species in the fish landings in each year, and temporal changes in species composition in the reservoirs, which would primarily be attributed to the environmental changes followed by anthropogenic pressures. The mean trophic level (&tau;) fluctuated, resulting from changes in species composition and weight of fish landing, as well as fish stocking programmes

Topoisomerase I protein expression in primary colorectal cancer and lymph node metastases

Topoisomerase I (topo I) is an important target for the treatment of malignant disease, especially colorectal cancer. Because there is little information on the expression of topo I in colorectal tumors, this study evaluated and characterized topo I protein expression in primary colorectal cancer and lymph node metastases and studied the association between topo I protein expression and clinicopathologic data, p53 status, and proliferating cell nuclear antigen (PCNA) status. Immunohistochemistry assay was performed for topo I protein expression in 249 primary human colorectal cancer and 42 paired lymph node metastasis samples. Topo I expression was described as the percentage of cells staining positive for topo I, along with the intensity and localization of the staining. Clinicopathologic data (sex, age, Dukes' stage, differentiation grade, survival status), p53 status, and PCNA status were statistically analyzed for association with topo I protein expression. Topo I expression in paired primary lymph node metastases were studied for concordance. Topo I protein expression was detected in 127 (51%) samples, including 24.4% with >50% positive tumor cells. The majority had nuclear (70.1%) or nuclear and cytoplasmic staining (17.3%). A higher percentage of cells expressing topo I in primary colorectal cancer was significantly associated with advanced age (P =.040). Patients with rectal cancer had greater topo I expression than those with colon tumors (P =.029). No significant correlation was found between topo I protein expression and sex, Dukes' stage, differentiation grade, survival status, p53 status, and PCNA status. Concordance in topo I staining between primary and lymph node metastases was observed in 33 of 42 cases (P =.029). This suggests that the activity of topo I inhibitors will not differ across various tumor stages, pathology, and patient gender. p53 and PCNA status do not appear to influence topo I expression, and topo I has no apparent association with the acquisition of a metastatic phenotype. Topo I expression now needs to be evaluated in patients undergoing topo I-inhibitor therapy, to better define the role of this protein as a predictive marker