Colorectal cancer screening: comparison of transferrin and immuno fecal occult blood test.

AIM: To evaluate the sensitivity and specificity of transfesrrin dipstick test (Tf) in colorectal cancer (CRC) screening and precancerous lesions screening. METHODS: Eight hundreds and sixty-one individuals at high-risk for CRC were recruited. Six hundreds and eleven subsequently received the three fecal occult blood tests and colonoscopy with biopsy performed as needed. Fecal samples were obtained on the day before colonoscopy. Tf, immuno fecal occult blood test (IFOBT) and guaiac fecal occult blood test (g-FOBT) were performed simultaneously on the same stool. To minimize false-negative cases, all subjects with negative samples were asked to provide an additional stool specimen for a second test even a third test. If the results were all negative after testing three repeated samples, the subject was considered a true negative. The performance characteristics of Tf for detecting CRC and precancerous lesions were examined and compared to those of IFOBT and the combination of Tf, IFOBT and g-FOBT. RESULTS: A total of six hundreds and eleven subjects met the study criteria including 25 with CRC and 60 with precancerous lesions. Sensitivity for detecting CRC was 92% for Tf and 96% for IFOBT, specificities of Tf and IFOBT were both 72.0% (95% CI: 68.2%-75.5%; χ² = 0.4, P > 0.05); positive likelihood ratios of those were 3.3 (95% CI: 2.8-3.9) and 3.4 (95% CI: 2.9-4.0), respectively. In precancerous lesions, sensitivities for Tf and IFOBT were 50% and 58%, respectively (χ² = 0.8, P > 0.05); specificities of Tf and IFOBT were 71.5% (95% CI: 67.6%-75.1%) and 72.2% (95% CI: 68.4%-75.8%); positive likelihood ratios of those were 1.8 (95% CI: 1.3-2.3) and 2.1 (95% CI: 1.6-2.7), respectively; compared to IFOBT, g-FOBT+ Tf+ IFOBT had a significantly higher positive rate for precancerous lesions (83% vs 58%, respectively; χ² = 9.1, P < 0.05). In patients with CRC and precancerous lesions, the sensitivities of Tf and IFOBT were 62% and 69% (χ² = 0.9, P > 0.05); specificities of those were 74.5% (95% CI: 70.6%-78.1%) and 75.5% (95% CI: 71.6%-79.0%); positive likelihood ratios of those were 2.5 (95% CI: 2.0-3.1) and 2.8 (95% CI: 2.3-3.5). Compared to IFOBT alone, combining g-FOBT, IFOBT and Tf led to significantly increased sensitivity for detecting CRC and cancerous lesions (69% vs 88%, respectively; χ² = 9.0, P < 0.05). CONCLUSION: Tf dipstick test might be used as an additional tool for CRC and precancerous lesions screening in a high-risk cohort.

Interactions between genetic variants in the adiponectin, adiponectin receptor 1 and environmental factors on the risk of colorectal cancer.

BACKGROUND: Metabolic syndrome traits play an important role in the development of colorectal cancer. Adipokines, key metabolic syndrome cellular mediators, when abnormal, may induce carcinogenesis. METHODOLOGY/PRINCIPAL FINDINGS: To investigate whether polymorphisms of important adipokines, adiponectin (ADIPOQ) and its receptors, either alone or in combination with environmental factors, are implicated in colorectal cancer, a two-stage case-control study was conducted. In the first stage, we evaluated 24 tag single nucleotide polymorphisms (tag SNPs) across ADIPOQ ligand and two ADIPOQ receptors (ADIPOR1 and ADIPOR2) among 470 cases and 458 controls. One SNP with promising association was then analyzed in stage 2 among 314 cases and 355 controls. In our study, ADIPOQ rs1063538 was consistently associated with increased colorectal cancer risk, with an odds ratio (OR) of 1.94 (95%CI: 1.48-2.54) for CC genotype compared with TT genotype. In two-factor gene-environment interaction analyses, rs1063538 presented significant interactions with smoking status, family history of cancer and alcohol use, with ORs of 4.52 (95%CI: 2.78-7.34), 3.18 (95%CI: 1.73-5.82) and 1.97 (95%CI: 1.27-3.04) for smokers, individuals with family history of cancer or drinkers with CC genotype compared with non-smokers, individuals without family history of cancer or non-drinkers with TT genotype, respectively. Multifactor gene-environment interactions analysis revealed significant interactions between ADIPOQ rs1063538, ADIPOR1 rs1539355, smoking status and BMI. Individuals carrying one, two and at least three risk factors presented 1.18-fold (95%CI:0.89-fold to 1.58-fold), 1.87-fold (95%CI: 1.38-fold to 2.54-fold) and 4.39-fold (95%CI: 2.75-fold to 7.01-fold) increased colorectal cancer risk compared with those who without risk factor, respectively (P(trend) <0.0001). CONCLUSIONS/SIGNIFICANCE: Our results suggest that variants in ADIPOQ may contribute to increased colorectal cancer risk in Chinese and this contribution may be modified by environmental factors, such as smoking status, family history of cancer and BMI.

[Impact of 5-fluorouracil on glucose metabolism and pancreatic pathology in rats].

OBJECTIVE: To explore the impact of 5-fluorouracil (5-FU) on glucose metabolism and pancreatic pathology. METHODS: Twenty Wistar rats were divided into 5-FU group(n=10, chemotherapy was administered intraperitoneally to animals at a dose of 20 mg/kg daily for continuous 5 days) and control group (n=10, sodium chloride was administered intraperitoneally to animals with the same dose at the same time ). Glucose tolerance was evaluated 2 and 7 days following 5-FU treatment by serial measurement of blood glucose before and after an oral glucose load. Plasma insulin concentration was determined by radioimmunoassay. Pancreatic pathology was examined with morphological method and the ultrastructural changes of ß cells were observed by transmission electron microscope. RESULTS: Fasting blood glucose level was significantly higher in the 5-FU group than that in the control group [(7.6±0.9) mmol/L vs. (4.6±0.6) mmol/L at day 2; (8.9±1.0) mmol/L vs. (4.7±0.6) mmol/L at day 7, P<0.01]. Insulin releasing test indicated that the early phase insulin response to glucose load was significantly diminished in animals treated with 5-FU at day 2. Insulin level was significantly lower in the 5-FU group than that in the control group at 30 min (P<0.01). The peak secretion time of plasma insulin in 5-FU group was at 60 min, similar to the control group; and plasma insulin level decreased more slowly. Plasma insulin level was higher in 5-FU groups than in control groups on 120 min and 180 min. At day 7, Insulin level was lower in the 5-FU group than that in the control group on 60 min, and the peak secretion time of plasma insulin was delayed to 120 min. Plasma insulin level was significantly increased in 5-FU group than that in control group on 180 min(P<0.01). No gross histopathological damage to the pancreas was observed at day 2 and 7 following administration of 5-FU. The structural changes of mitochondria were mainly the quantities of secretory granule diminished at day 7 under transmission electron microscope. Dilated rough endoplasmic reticula, swollen mitochondria, and the presence of adipose drops in lysosomes were found in few cells. CONCLUSIONS: 5-FU-induced hyperglycemia appears to be mediated in part by a relatively deficient insulin secretion to glucose stimulation. A relative deficiency in insulin secretion following 5-FU treatment appears to be related to ß cells function impairs with islet cell ultrastructural changes induced by 5-FU.

Rectal perforation after procedure for prolapse and hemorrhoids: possible causes.

PURPOSE: Our aim was to explore possible causes of rectal perforation occurring in patients who undergo the procedure for prolapse and hemorrhoids. METHODS: We evaluated data from cases of rectal perforation that occurred after the procedure for prolapse and hemorrhoids in China in conjunction with case reports from the international medical literature. RESULTS: We identified 7 patients from 5 hospitals in 2 provinces of China who had rectal perforation after the procedure despite having received prophylactic antibiotic treatment. Two patients had a disrupted staple line and 5 had perforations on the rectum wall above the intact staple line. Six patients presented with symptoms in the first 3 days after the procedure. Three patients had concomitant disease: 1 had concomitant constipation and internal rectal prolapse, 1 had concomitant constipation, and 1 had concomitant liver cirrhosis ascites that was not diagnosed preoperatively. Of the 15 cases of rectal perforation found in the literature, 3 patients had an intact staple line and 5 patients had a ruptured staple line. CONCLUSION: The cone-shaped tip of the anvil, concomitant rectal prolapse and pelvic floor descent, and concomitant ascites are possible causes of rectal perforation after the procedure for prolapse and hemorrhoids.

[Preliminary report about the screening program for colorectal cancer by sequential fecal occult blood in Wuhan area for 4 years].

OBJECTIVE: To evaluate the sequential fecal occult blood test (SFOBT) program for the screening of colorectal cancer and elucidate the prevalence of colorectal cancer in Wuhan area. METHODS: At 19 screening sites, 63,961 residents were recruited as target population according to random cluster and stratified sampling for four years (between 2005 and 2008). Residents aged over 40 years old received SFOBT. Those with positive SFOBT underwent colonoscopy. RESULTS: The target population was 63,961. There were 25,837 people whose age was over 40. Finally, 7784 participants received the SFOBT screening, with a medium age of 56 years old. The positive rate of SFOBT was 12.3% (956 persons). Of the 956 persons, 240 participants underwent colonoscopy. Colorectal cancer was found in 14 cases (6.5%), gastric cancer in 2 cases (0.9%), colorectal adenoma in 53 cases(24.8%), colorectal inflammation in 80 cases (37.3%) and hemorrhoids in 65 cases (30.4%). CONCLUSIONS: The prevalence of colorectal cancer is relatively high in Wuhan area. The SFOBT is available and feasible in screening early changes of colorectal cancer.

[Expression of cyclooxygenase-2 and relationship with mismatch repair gene and microsatellite instability in hereditary non-polyposis colorectal cancer].

OBJECTIVE: To investigate the expression of Cyclooxygenase (COX)-2 and the relationship between cox-2, mismatch repair gene (MMR) proteins and microsatellite instability (MSI) in HNPCC. METHODS: Twenty-eight cases of adenomas and 14 cases of carcinomas were collected from 33 HNPCC families patients by colonoscopy. Sporadic adenomas (n = 32) and carcinomas (n = 24) were used as a control group. The expressions of COX-2 and mismatch repair gene hMLH1, hMSH2, hMSH6 proteins were examined by immunohistochemistry. MS1 were analyzed by using PCR with BAT25, BAT26, D2S123, D5S346 and D17S250 loci. RESULTS: The COX-2 high-expression rates were 53.6% (15/28) and 42.9% (6/14) in HNPCC adenomas and carcinomas, and were 62.5% (20/32) and 91.7% (22/24) in sporadic adenomas and carcinomas. COX-2 expression was lower in HNPCC carcinomas than that of sporadic carcinomas (P < 0.05). MMR deficiency rate and positive rate of MSI-H were both 71.4% (10/14) respectively in HNPCC carcinomas. It was higher than that in sporadic colorectal carcinomas [both 12.5% (3/24)]. Eight (80.0%) COX-2 low-expression were observed in 10 HNPCC carcinomas with MMR-deficient system while 4 cox-2 high-expression cases were observed in 4 HNPCC carcinomas with MMR-proficient system. COX-2 expression was lower in HNPCC carcinomas and adenomas, sporadic carcinomas with MMR-deficient system than that of MMR-proficient (P < 0.05). The COX-2 low-expression rates were 80.0% (8/10), 66.7% (12/18) and 66.7% (2/3) in HNPCC adenomas, HNPCC carcinomas and sporadic carcinomas with MSI-H. Cox-2 expression was lower in HNPCC and sporadic carcinomas (adenocarcinomas) with MSI-H than that of MSS (P < 0.05). CONCLUSION: Compared with sporadic carcinomas, the COX-2 expression was lower in HNPCC carcinomas. There was negative correlation between COX-2 expression and MMR-deficient (MSI-H). The detection of COX-2, MMR protein and MSI is of important significance in further studying the pathogenesis and interventional therapy of colorectal neoplasms.

Association between two functional polymorphisms of insulin-like growth factor binding protein 3 and colorectal cancer risk in a Chinese population.

Circulating levels of insulin-like growth factor binding protein 3 (IGFBP3) are modulated by functional variants of IGFBP3 and therefore may be associated with higher risk of colorectal cancer development. However, few studies have investigated the role of IGFBP3 polymorphisms in colorectal cancer in Chinese individuals. In this study, two common polymorphisms of IGFBP3 were determined by the Taqman genotyping platform in 202 Chinese colorectal cancer cases diagnosed between 2006 and 2008 and 212 cancer-free population controls. Data showed that the genotype distribution of G2133C (rs2864746), but not A-202C (rs2864744), was significantly different between cancer cases and controls. Unconditional logistic regression analyses revealed that participants carrying the G2133C GC heterozygote or CC homozygote had a significant 1.55-fold increased risk of colorectal cancer development in an allele dose-responsive manner. However, there was no evidence of a dose-effect relationship between number of variants and risk for CRC occurrence. Data suggest that the exon 1 G2133C missense variant of IGFBP3 may be a susceptibility factor for colorectal cancer in Chinese subjects. Larger studies are warranted to validate our findings in a Chinese population.

[Study on the prognostic factors of colorectal cancer and on suggested model for prediction].

OBJECTIVE: To explore the factors related to the prognosis of colorectal cancer (CRC) and to establish a prognostic model for evaluating the prognosis of the patients with CRC. METHODS: 370 cases with CRC were selected in the study and clinical/pathological factors were collected and patients were followed. Kaplan-Meier method was used to calculate survival rate. Log-rank test and proportional-hazards regression model (Cox model) were used for univariate and multivariate analysis. Log cumulative hazards function plot was used to test Cox model proportional-hazards assumption (PH assumption). Prognostic index (P1) was calculated based on the results of multivariate analysis. RESULTS: (1) One-year, three-year and five-year survival rates were 90.5%, 78.3% and 76.5% respectively. (2) Lymphatic metastasis, Duckes classification and therapeutic measure were independent prognostic factors of CRC and all passed PH assumption. (3) Patients with different PI were classified into 3 groups and there were significant differences noticed in survival rates (P < 0.001). (4) Individual survival rate was evaluated based on the prognostic Cox model and PI. CONCLUSION: Lymphatic metastasis, Duckes classification and therapeutic measure were independent prognostic factors of CRC. To test PH assumption of the factors, selection of Cox model was essential. Cox model and PI seemed to be available in predicting the long term survivrate of patients with CRC.

[Comparative study on the exfoliative cytology of intraoperative peritoneal lavage in patients with rectal cancer pre- and post-tumor resection].

OBJECTIVE: To investigate the clinical value of sequential intraoperative peritoneal lavage in reducing the positive rate of peritoneal exfoliated tumor cells. METHODS: Six sequential intraoperative peritoneal lavages were performed in each of the 63 patients with rectal cancer, with three before resection and three post resection, which were then compared by using cytological smear examination. RESULTS: Exfoliated tumor cells were positive in the first three intraoperative peritoneal lavages of all the 63 patients before resection. The cytological smear examination of the three peritoneal lavage fluids after excision revealed that 40 cases were positive at the first lavage, 33 at the second and 13 at the third. The positive rate between the first and the second post-resection peritoneal lavages showed no significant difference (P>0.05), while the positive rate of the third lavage was significantly lower than the second after resection (P<0.01). CONCLUSION: Sequential intraoperative peritoneal lavages is a useful method in reducing the positive rate of peritoneal exfoliated tumor cells in patients with rectal cancer.

Microsatellite instability and novel mismatch repair gene mutations in northern Chinese population with hereditary non-polyposis colorectal cancer.

OBJECTIVE: Hereditary non-polyposis colorectal cancer (HNPCC) syndrome is the most common cause of hereditary colorectal cancer with an early age of onset. Microsatellite instability (MSI) and germline mutation in one of the DNA mismatch repair (MMR) genes are found in the majority of HNPCC families and provide an opportunity for genetic diagnosis and prophylactic screening. The MMR gene mutation spectrum may vary across different populations and be influenced by founder mutations that prevail in specific ethnic groups. China is a big and ancient nation with enormous genetic diversity, which is especially notable between the northern and southern Chinese populations. A MMR gene mutation database for the southern Chinese population based in Hong Kong has been previously established. This study compares the MMR gene mutation spectrum and the MSI of HNPCC between the northern and southern Chinese populations. METHODS: Twenty-five HNPCC families from northern China were systematically analyzed. The MSI analysis was performed using five loci in the USA National Cancer Institute (NCI) panel (D2S123, D5S346, BAT-25, BAT-26 and BAT-40) by PCR from the tumor and normal tissue. MSH2, MSH6 and MLH1 were performed using immunohistochemical staining. Two founder mutations of MSH2 and MLH1 were examined by PCR base analyses using primers flanking the two deletion sites (c.1452_1455delAATG in MSH2 and 1.8 kb deletion involving exon 11 of MLH1). RESULTS: Of the 25 families collected, 19 met Bethesda guideline (BG) 1 and six met BG3. Twenty-two (15.7%) were extra-colonic cancers with gastric cancer (in seven patients) being the most common cancer type. Of the 25 tumors analyzed, 21 (84%) were high level microsatellite instability (MSI-H) and four (16%) were microsatellite stable (MSS). Eighteen (86%) of the 21 MSI-H tumors showed loss of either the MLH1 or the MSH2 protein. Three MSI-H tumors and all four MSS tumors showed no loss of expression of the three MMR proteins. Out of the 21 patients with MSI-H tumors, 12 (57%) showed pathogenic germline mutations in either MLH1 (n = 8) or MSH2 (n = 4). Overall, three novel mutations (in patients H22, H17 and H29) have been identified. One of them, c.503_4insA, caused a frameshift mutation in the MLH1 gene. The other two were found in the MSH2 gene, including a frameshift (c.899_890insAT) and a splice junction (IVS7-1G-->A, SA of Exon 8) mutation. CONCLUSIONS: The results suggest a distinctly different mutation spectrum of MMR genes between northern and southern Chinese populations and call for a systematic, nationwide study to facilitate the design of a MMR gene mutation detection strategy tailored for individual populations in China.