Neoadjuvant Chemotherapy With Oxaliplatin and Fluoropyrimidine Versus Upfront Surgery for Locally Advanced Colon Cancer: The Randomized, Phase III OPTICAL Trial.

PURPOSE: The role of neoadjuvant chemotherapy (NAC) in colon cancer remains unclear. This trial investigated whether 3 months of modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine and oxaliplatin (CAPOX) as NAC could improve outcomes in patients with locally advanced colon cancer versus upfront surgery. PATIENTS AND METHODS: OPTICAL was a randomized, phase III trial in patients with clinically staged locally advanced colon cancer (T3 with extramural spread into the mesocolic fat ≥5 mm or T4). Patients were randomly assigned 1:1 to receive six preoperative cycles of mFOLFOX6 or four cycles of CAPOX, followed by surgery and adjuvant chemotherapy (NAC group), or immediate surgery and the physician's choice of adjuvant chemotherapy (upfront surgery group). The primary end point was 3-year disease-free survival (DFS) assessed in the modified intention-to-treat (mITT) population. RESULTS: Between January 2016 and April 2021, of the 752 patients enrolled, 744 patients were included in the mITT analysis (371 in the NAC group; 373 in the upfront surgery group). At a median follow-up of 48.0 months (IQR, 46.0-50.1), 3-year DFS rates were 82.1% in the NAC group and 77.5% in the upfront surgery group (stratified hazard ratio [HR], 0.74 [95% CI, 0.54 to 1.03]). The R0 resection was achieved in 98% of patients who underwent surgery in both groups. Compared with upfront surgery, NAC resulted in a 7% pathologic complete response rate (pCR), significantly lower rates of advanced tumor staging (pT3-4: 77% v 94%), lymph node metastasis (pN1-2: 31% v 46%), and potentially improved overall survival (stratified HR, 0.44 [95% CI, 0.25 to 0.77]). CONCLUSION: NAC with mFOLFOX6 or CAPOX did not show a significant DFS benefit. However, this neoadjuvant approach was safe, resulted in substantial pathologic downstaging, and appears to be a viable therapeutic option for locally advanced colon cancer.

Serum metabolite signatures in normal individuals and patients with colorectal adenoma or colorectal cancer using UPLC-MS/MS method.

Colorectal cancer (CRC) is one of the main causes of cancer-related deaths worldwide. Sporadic CRC develops from normal mucosa via adenoma to adenocarcinoma, which provides a long screening window for clinical detection. However, early diagnosis of sporadic colorectal adenoma (CRA) and CRC using serum metabolic screening remains unclear. The purpose of this study was to identify some promising signatures for distinguishing the different pathological metabolites of colorectal mucosal malignant transformation. A total of 238 endogenous metabolites were elected. We found that CRA and CRC patients had 72 and 73 different metabolites compared with healthy controls, respectively. There were 20 different metabolites between CRA and CRC patients. The potential metabolites of tumor growth (including patients with CRA and CRC) were found, such as A-d-glucose, D-mannose, N-acetyl-D-glucosamine, L-cystine, Sarcosine, TXB 2, 12-Hete, and chenodeoxycholic acid. Compared with CRA, 3,4,5-trimethoxybenzoic acid was significantly higher in CRC patients. There results prompt us to use the potential serum signatures to screen CRC as the novel strategy. Serum metabolite screening is useful for early detection of mucosal intestinal malignancy. We will further investigate the roles of these promising biomarkers during intestinal tumorigenesis in future. SIGNIFICANCE: CRC is one of the main causes of cancer-related deaths worldwide. Sporadic CRC develops from normal mucosa via adenomas to adenocarcinoma, which provides a long screening window for about 5-10 years. We adopt the metabolic analysis of extensive targeted metabolic technology. The main purpose of the metabolic group analysis is to detect and screen the different metabolites, thereby performing related functional prediction and analysis of the differential metabolites. In our study, 30 samples are selected, divided into 3 groups for metabolic analysis, and 238 metabolites are elected. In 238 metabolites, we find that CRA patients have 72 different metabolites compared with health control. Compared with health control, CRC have 73 different metabolites. Compared with CRA and CRC patients, there are 20 different metabolites. The annotation results of the significantly different metabolites are classified according to the KEGG pathway type. The potential metabolites of tumor growth stage (including patients with CRA and CRC) are found, such as A-d-glucose, D-mannose, N-acetyl-D-glucosamine, L-cystine, sarcosine, TXB 2, 12-Hete and chenodeoxycholic acid. Compared with CRA patients, CRC patients had significantly higher 3,4,5-trimethoxybenzoic acid level. It is prompted to use serum different metabolites to screen CRC to provide new possibilities.

UGT1A polymorphisms associated with worse outcome in colorectal cancer patients treated with irinotecan-based chemotherapy.

PURPOSE: To investigate the association between UDP-glucuronosyltransferase (UGT)1A polymorphisms and irinotecan-treatment efficacy in a Chinese population with metastatic colorectal cancer (mCRC). METHODS: The present study was based on a prospective multicenter trial of Chinese mCRC patients treated with irinotecan-based chemotherapy (NCT01282658, registered at http://www.clinicaltrials.gov ). Fifteen single-nucleotide polymorphisms (SNPs) in four UGT1A genes were selected for genotyping in 164 patients. Kaplan-Meier and Cox regression analyses were used to assess the association between potential signatures and survival outcome. RESULTS: We found that UGT1A1*28 variant genotype was significantly associated with decreased progression-free survival (PFS) [adjusted hazard ratio (HR), 1.803; 95% confidence interval (CI), 1.217-2.671] and overall survival (OS) (adjusted HR 1.979; 95% CI 1.267-3.091) compared with wild-type genotype. Patients carrying (TA)7 allele showed a median PFS of 7.5 (95% CI 5.5-9.6) months compared with 9.8 (95% CI 8.6-10.9) months for patients with wild-type genotype. Median OSs were 13.3 (95% CI 10.3-16.2), and 20.8 (95% CI 18.7-23.0) months for (TA)6/7 or (TA)7/7, and (TA)6/6 patients, respectively. Similarly but more significantly, the copy number of haplotype III (composed by rs3755321-T, rs3821242-C, rs4124874-G and rs3755319-C) constructed among the selected SNPs also correlated with survival outcome. CONCLUSIONS: UGT1A polymorphisms are predictive of survival outcome of irinotecan-treated Chinese mCRC patients. After validation, UGT1A polymorphisms might be helpful in facilitating stratification of mCRC patients for individualized treatment options.

A novel genetic score model of UGT1A1 and TGFB pathway as predictor of severe irinotecan-related diarrhea in metastatic colorectal cancer patients.

PURPOSE: UGT1A1*28/*6 as predictors of severe irinotecan-related diarrhea (SIRD) were duplicated by many studies. However, some patients of lower risk genotype (UGT1A1*1/*1) still suffered SIRD and the extremely low frequency of UGT1A1*6/*6 limited its clinical usage. Previous studies proved that the transforming growth factor (TGFB) family may have some effect on MTX-induced mucositis. However, the associations between TGFB gene variants and SIRD have never been reported so far. Our aim was to improve the predictive value of UGT1A1 gene variants on SIRD. METHODS: Six SNPs (TGFB1 rs1800469; TGFBR1 rs10733710, rs334354 and rs6478974; TGFBR2 rs3087465; UGT1A1*6) and UGT1A1*28 were selected for genotyping in 160 metastatic colorectal cancer patients treated with irinotecan in a prospective multicenter trial (NCT01282658). RESULTS: UGT1A1*6, UGT1A1*28, rs1800469 and rs3087465 were all associated with SIRD (p = 0.026, 0.014, 0.047 and 0.045 respectively). A novel genetic score model (with a cut off value of 1.5) based on them was created to predict SIRD (OR = 11.718; 95 % CI 2.489-55.157, p = 0.002). In patients of gene score > 1.5, the risk of SIRD was much higher (23.5 vs. 2.8 %, p = 2.24E-04) and continued in the first 6 cycles of chemotherapy, while in patients with gene score ≤1.5, the risk was much lower and none of them suffered SIRD after the first cycle of chemotherapy (p = 0.0003). CONCLUSIONS: The novel genetic score model improved the predictive value of UGT1A1 on SIRD. If validated, it will provide valuable information for clinical use of irinotecan.

Telomere length in peripheral blood leukocytes is associated with risk of colorectal cancer in Chinese population.

BACKGROUND: Human telomeres, tandem repeats of TTAGGG nucleotides at the ends of chromosomes, are essential for maintaining genomic integrity and stability. Results of previous epidemiologic studies about the association of telomere length with risk of colorectal cancer (CRC) have been conflicting. METHODS: A case-control study was conducted in a Han population in Wuhan, central China. The relative telomere length (RTL) was measured in peripheral blood leukocytes (PBLs) using quantitative real-time polymerase chain reaction (PCR) in 628 CRC cases and 1,256 age and sex frequency matched cancer-free controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression models to evaluate the association between RTL and CRC risk. RESULTS: Using median RTL in the controls as the cutoff, individuals with shorter RTL were associated with a significantly increased risk of CRC (adjusted OR = 1.27, 95%CI: 1.05-1.55). When participants were further categorized into 3 and 4 groups according to the tertile and quartile RTL values of controls, significant relationships were still observed between shorter RTL and increased CRC risk (OR per tertile = 1.13, 95%CI: 1.00-1.28, P(trend) = 0.045; OR per quartile = 1.12, 95%CI: 1.03-1.23, P(trend) = 0.012). In stratified analyses, significant association between shorter RTL and increased CRC risk was found in females, individuals younger than 60 years old, never smokers and never drinkers. CONCLUSIONS: This study suggested that short telomere length in PBLs was significantly associated with an increased risk of CRC in Chinese Han population. Further validation in large prospective studies and investigation of the biologic mechanisms are warranted.

SLCO1B1 and SLC19A1 gene variants and irinotecan-induced rapid response and survival: a prospective multicenter pharmacogenetics study of metastatic colorectal cancer.

BACKGROUND: Rapid response to chemotherapy in metastatic colorectal cancer (mCRC) patients (response within 12 weeks of chemotherapy) may increase the chance of complete resection and improved survival. Few molecular markers predict irinotecan-induced rapid response and survival. Single-nucleotide polymorphisms (SNPs) in solute carrier genes are reported to correlate with the variable pharmacokinetics of irinotecan and folate in cancer patients. This study aims to evaluate the predictive role of 3 SNPs in mCRC patients treated with irinotecan and fluoropyrimidine-containing regimens. MATERIALS AND METHODS: Three SNPs were selected and genotyped in 137 mCRC patients from a Chinese prospective multicenter trial (NCT01282658). The chi-squared test, univariate and multivariable logistic regression model, and receiver operating characteristic analysis were used to evaluate correlations between the genotypes and rapid response. Kaplan-Meier survival analysis and Cox proportional hazard models were used to evaluate the associations between genotypes and survival outcomes. Benjamini and Hochberg False Discovery Rate correction was used in multiple testing. RESULTS: Genotype GA/AA of SNP rs2306283 of the gene SLCO1B1 and genotype GG of SNP rs1051266 of the gene SLC19A1 were associated with a higher rapid response rate (odds ratio [OR] =3.583 and 3.521, 95%CI =1.301-9.871 and 1.271-9.804, p=0.011 and p=0.013, respectively). The response rate was 70% in patients with both genotypes, compared with only 19.7% in the remaining patients (OR = 9.489, 95%CI = 2.191-41.093, Fisher's exact test p=0.002). Their significances were all maintained even after multiple testing (all p c < 0.05). The rs2306283 GA/AA genotype was also an independent prognostic factor of longer progression-free survival (PFS) (hazard ratio = 0.402, 95%CI = 0.171-0.945, p=0.037). None of the SNPs predicted overall survival. CONCLUSIONS: Polymorphisms of solute carriers' may be useful to predict rapid response to irinotecan plus fluoropyrimidine and PFS in mCRC patients.

The genetic variant on chromosome 10p14 is associated with risk of colorectal cancer: results from a case-control study and a meta-analysis.

BACKGROUND: A common single nucleotide polymorphism (SNP), rs10795668, located at 10p14, was first identified to be significantly associated with risk of colorectal cancer (CRC) by a genome-wide association study (GWAS) in 2008; however, another GWAS and following replication studies yielded conflicting results. METHODS: We conducted a case-control study of 470 cases and 475 controls in a Chinese population and then performed a meta-analysis, integrating the current study and 9 publications to evaluate the association between rs10795668 and CRC risk. Heterogeneity among studies and publication bias were assessed by the χ²-based Q statistic test and Egger's test, respectively. RESULTS: In the case-control study, significant association between the SNP and CRC risk was observed, with per-A-allele OR of 0.71 (95%CI: 0.54-0.94, P = 0.017). The following meta-analysis further confirmed the significant association, with per-A-allele OR of 0.91 (95%CI: 0.89-0.93, P(heterogeneity) >0.05) in European population and 0.86 (95%CI: 0.78-0.96, P(heterogeneity) <0.05) in Asian population. Besides, sensitivity analyses and publication bias assessment indicated the robust stability and reliability of the results. CONCLUSIONS: Results from our case-control study and the followed meta-analysis confirmed the significant association of rs10795668 with CRC risk.

The leptin gene family and colorectal cancer: interaction with smoking behavior and family history of cancer.

BACKGROUND: Pathologic condition associated with metabolic syndrome traits seems to increase the risk of colorectal cancer. One mechanism underlying this relationship may involve the growth-promoting effects of the circulation hormones associated with obesity and insulin resistance, such as leptin. METHODOLOGY/PRINCIPAL FINDINGS: A two-stage case-control study was used to explore the role of polymorphisms of Leptin (LEP) and Leptin receptor (LEPR), either alone or in combination with environmental factors in colorectal carcinogenesis. In stage 1, 20 single nucleotide polymorphisms (SNPs) that tag common SNPs in these two genes were genotyped among 470 cases and 458 controls. In stage 2, another population with 314 cases and 355 controls were genotyped for the two most promising SNPs from stage 1. LEPR rs12037879 only presented modestly increased colorectal cancer risk, with odds ratios of 1.41 (95% confidence interval [CI] 1.13-1.76) and 1.74 (95%CI 1.08-2.81) for GA and AA genotype when compared with GG genotype in combined population. Smokers carrying LEPR rs12037879 A allele presented 1.67-fold (95%CI 1.39-fold to 2.01-fold) increased colorectal cancer risk when compared with non-smokers carrying GG genotype in combined analysis. Individuals with family history of cancer harboring LEPR rs12037879 A allele showed 1.52-fold (95%CI: 1.24-fold to 1.86-fold) increased colorectal cancer risk, compared with individuals without family history of cancer harboring GG genotype. Multifactor gene-environment interaction analysis revealed significant interactions among LEPR rs12037879, LEPR rs6690625, smoking status and family history of cancer, exhibiting a gradient of increased colorectal cancer risk along with the increasing number of risk factors (P = 9.82 × 10(-10)). CONCLUSIONS/SIGNIFICANCE: Our research supports that polymorphisms in LEPR may be associated with marginal increase in the risk for colorectal cancer. Moreover, this association could be strengthened by cigarette smoking and family history of cancer.

Genetic variations in the TGFß signaling pathway, smoking and risk of colorectal cancer in a Chinese population.

Recent genome-wide association studies (GWAS) have reported multiple risk loci associated with risk of colorectal cancer (CRC), some of which are involved in the transforming growth factor beta (TGFß) signaling pathway. We systematically examined associations of common genetic variations in the TGFß signaling pathway and environmental factors with CRC risk using a two-staged case-control study in a Chinese population. A set of 77 single-nucleotide polymorphisms (SNPs) in 10 candidate genes involved in the TGFß signaling pathway and several environmental factors including sex, age, smoking and drinking were examined by random forest (RF) to capture the potential gene-gene and gene-environment interactions in stage 1 of the study with 443 CRC patients and 480 controls. Three promising SNPs (SMAD7 rs11874392, TGFBR1 rs10988706 and rs6478972) selected by the RF method were genotyped in stage 2 comprising 351 cases and 360 controls for validation. SMAD7 rs11874392 presented consistently significant associations with a risk of CRC at both stages, with odds ratio = 1.41 (95% confidence interval = 1.21-1.63) using additive modes in combined analyses. Moreover, the potential interactions between SMAD7 rs11874392, TGFBR1 rs10988706 and rs6478972 were indicated consistently in both stages of the study by using pair-wise interaction and multilocus genotype pattern analysis. Additionally, gene-smoking interactions for rs11874392, rs10988706 and rs6478972 were also found to enhance the risk of CRC at both stages, with P for multiplicative interaction equal to 1.162×10(-6), 8.574×10(-8) and 9.410×10(-8) in combined analyses, respectively. This study emphasized the substantial role of the TGFß signaling pathway in CRC, especially in interaction with smoking.

Association of estrogen receptor beta variants and serum levels of estradiol with risk of colorectal cancer: a case control study.

BACKGROUND: Endogenous estrogens may play a vital role in colorectal tumorigenesis. Estrogen receptor beta is the predominant subtype which mediates the biological effect of estrogens, while loss of expression of estrogen receptor beta has been indicated as a common step in the development of colorectal cancer (CRC). Epidemiological studies have revealed several functional polymorphisms of estrogen receptor beta (ESR2) for cancer risk, but relevant study in CRC is limited, particularly in men. This study aimed to investigate the association of circulating estradiol and variations of ESR2 with CRC risk in men. METHODS: We initiated a case-control study consisting of 390 patients with CRC and 445 healthy controls in men only. We genotyped ESR2 single nucleotide polymorphisms (SNPs) rs1256049 and rs4986938 and measured serum estradiol concentration using chemilluminescence immunoassay. Multivariable logistic regression model was performed to evaluate the associations between these variables and CRC risk. RESULTS: ESR2 rs1256049 CT/TT genotypes were associated with reduced risk of CRC (odds ratio [OR], 0.7, 95% confidence interval [CI], 0.5-1.0), while rs4986938 CT/TT genotypes were associated with increased risk of CRC (OR, 1.5, 95% CI, 1.0-2.1). In addition, the CRC risk increased with the number of risk genotypes of these two SNPs in a dose-response manner (Ptrend, 0.003). Specifically, subjects carrying risk genotypes of both SNPs had the highest risk of CRC (OR, 2.0, 95% CI, 1.3-3.3.). Moreover, serum estradiol concentration alone was associated with risk of CRC in men (OR, 1.2, 95% CI, 1.0-1.3). However, individuals presenting both rs4986938 CT/TT genotypes and high level of serum estradiol had a high risk of CRC (OR, 2.3, 95% CI, 1.4-3.9), compared with those presenting CC genotype and low level of serum estradiol. The similar joint results were not observed for SNP rs1256049. CONCLUSIONS: These results suggest that endogenous estrogen and genetic variations in ESR2 may individually, or more likely jointly, affect CRC risk in male Han Chinese population, while larger studies are needed to validate our findings.

Polymorphisms in TP53 and MDM2 contribute to higher risk of colorectal cancer in Chinese population: a hospital-based, case-control study.

The murine double minute 2 protein (MDM2) and TP53 interact in regulating cell cycle, DNA repair and apoptosis process, which is crucial in carcinogenesis. Since functional variations in these two genes were shown to change gene expression and function, we hypothesized that potentially functional polymorphisms in these genes may contribute to colorectal cancer (CRC) susceptibility. A hospital-based case-control study consisting of 444 patients and 569 controls was conducted to explore the associations between TP53 Arg72Pro and MDM2 T309G and CRC risk in Chinese. The combined effect of TP53 Arg72Pro and MDM2 T309G was significant in a gene dose-response increasing CRC risk (trend test: P = 0.02). Individuals carrying 3 or more potential risk alleles had 1.78 times risk (95 % CI: 1.13-2.80) to develop CRC compared with individuals without potential risk allele. This increased cancer risk was more pronounced in smokers who carried 3-4 potential risk alleles (OR = 2.75, 95 % CI: 1.14-6.60) and in young subjects (OR = 2.05, 95 % CI: 1.08-3.88). The gene-gene interaction between TP53 Arg72Pro and MDM2 T309G may interact in carcinogenesis of CRC in Chinese, especially in smokers, and this kind of interaction is associated with onset age of CRC.

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.

[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.

Transferrin dipstick as a potential novel test for colon cancer screening: a comparative study with immuno fecal occult blood test.

Recent proteomic studies identified Transferrin (Tf) as a potential biomarker for cancer. We examined the efficacy of the newly developed Tf dipstick for detecting colorectal cancer and premalignant lesions, and compared that to Immuno Fecal Occult Blood test (IFOBT). Fecal samples from 110 patients including 40 colorectal cancer, 36 premalignant subjects (including 16 with high-risk adenomas and 20 with ulcerative colitis), and 34 low-risk subjects were collected before colonoscopic examination. Compared with IFOBT, Tf had a significantly higher positive rate in patients with colorectal cancer and premalignant lesions (76% for Tf versus 61% for IFOBT, respectively; chi(2) = 4.38; P < 0.05). The difference of positivity was mainly observed in patients with premalignant lesions (72% for Tf versus 44% for IFOBT; chi(2) = 5.71; P < 0.05), whereas the positive rates in cancer group and in low-risk group were similar (both P > 0.05). Combining Tf with IFOBT together (either/or) had 90% positive rate in cancer patients, 78% in premalignant patients, and 29% in low-risk subjects. The overall accuracy of IFOBT and Tf tests for detecting colorectal cancer and premalignant lesion was 69.0% and 76.4%, respectively. Tf dipstick test seems to be a highly sensitive test for detecting not only cancer, but also premalignant lesions, and provides an additional tool for colorectal cancer screening.

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.