Koji Komori

Survival benefit of high ligation of the inferior mesenteric artery in sigmoid colon or rectal cancer surgery.

The aim of this study was to assess the impact of inferior mesenteric artery (IMA) root nodal dissection before high ligation of the artery on survival in patients with sigmoid colon or rectal cancer.

Association between an 8q24 locus and the risk of colorectal cancer in Japanese.

BackgroundA genome-wide association study (GWAS), which assessed multiple ethnicities, reported an association between single nucleotide polymorphisms in the 8q24 region and colorectal cancer risk. Although the association with the identified loci was strong, information on its impact in combination with lifestyle factors is limited.MethodsWe conducted a case-control study in 481 patients with colorectal cancer (CRC) and 962 sex-age matched non-cancer controls. Data on lifestyle factors, including diet, were obtained by self-administered questionnaire. Two 8q24 loci, rs6983267 and rs10090154, were assessed by the TaqMan method. Associations were then assessed by multivariate logistic regression models that considered potential confounders.ResultsWe found an increased risk of CRC with rs6983267 but not with rs10090154. An allelic OR was 1.22 (1.04-1.44, p for trend = 0.014), which remained significant after adjustment for confounders (OR = 1.25). No statistically significant interaction with potential confounding factors was observed.ConclusionThe polymorphism rs6983267 showed a significant association with CRC in a Japanese population. Further investigation of the biological mechanism of this association is warranted.

Characteristic methylation profile in CpG island methylator phenotype-negative distal colorectal cancers

Aberrant DNA methylation is involved in colon carcinogenesis. Although the CpG island methylator phenotype (CIMP) is defined as a subset of colorectal cancers (CRCs) with remarkably high levels of DNA methylation, it is not known whether epigenetic processes are also involved in CIMP‐negative tumors. We analyzed the DNA methylation profiles of 94 CRCs and their corresponding normal‐appearing colonic mucosa with 11 different markers, including the five classical CIMP markers. The CIMP markers were frequently methylated in proximal CRCs (p < 0.01); however, RASSF1A methylation levels were significantly higher in distal CRCs, the majority of which are CIMP‐negative (p < 0.05). Similarly, methylation levels of RASSF1A and SFRP1 in the normal‐appearing mucosae of distal CRC cases were significantly higher than those in the proximal CRC cases (p < 0.05). They were also positively correlated with age (RASSF1A, p < 0.01; SFRP1, p < 0.01). Microarray‐based genome‐wide DNA methylation analysis of 18 CRCs revealed that 168 genes and 720 genes were preferentially methylated in CIMP‐negative distal CRCs and CIMP‐positive CRCs, respectively. Interestingly, more than half of the hypermethylated genes in CIMP‐negative distal CRCs were also methylated in the normal‐appearing mucosae, indicating that hypermethylation in CIMP‐negative distal CRCs is more closely associated with age‐related methylation. By contrast, more than 60% of the hypermethylated genes in CIMP‐positive proximal CRCs were cancer specific (p < 0.01). These data altogether suggest that CpG island promoters appear to be methylated in different ways depending on location, a finding which may imply the presence of different mechanisms for the acquisition of epigenetic changes during colon tumorigenesis.

Negative serum carcinoembryonic antigen has insufficient accuracy for excluding recurrence from patients with Dukes C colorectal cancer: analysis with likelihood ratio and posttest probability in a follow-up study.

PURPOSEThis study was designed to determine the efficacy of carcinoembryonic antigen (CEA) monitoring for screening patients with colorectal cancer by using posttest probability of recurrence.METHODSFor this study, 348 (preoperative serum CEA level elevated: CEA+, n = 119; or normal: CEA−, n = 229) patients who had undergone potentially curative surgery for colorectal cancer were enrolled. After five-year follow-up with measurements of serum CEA levels and imaging workup, posttest probabilities of recurrence were calculated.RESULTSRecurrence was observed in 39 percent of CEA+ patients and 30 percent in CEA− patients, and CEA levels were elevated in 33.3 percent of CEA+ patients and 17.5 percent of CEA− patients. With obtained sensitivity (68.4 percent, CEA+; 41 percent, CEA−), specificity (83 percent, CEA+; 91 percent, CEA−) and likelihood ratio (test positive: 4.0, CEA+; 4.4, CEA−; and test negative: 0.38, CEA+; 0.66, CEA−), posttest probability given the presence of CEA elevation in the CEA+ and CEA− was 72.2 and 65.5 percent, respectively, and that given the absence of CEA elevation was 20 and 22.2 percent, respectively.CONCLUSIONSWhereas postoperative CEA elevation indicates recurrence with high probability, a normal postoperative CEA is not useful for excluding the probability of recurrence.

Clinical Significance of the Mesorectal Extension of Rectal Cancer: A Japanese Multi-institutional Study

Objective:The aim of this study was to emphasize the importance of a subclassification in the TNM staging system of rectal cancer. Background:The clinical significance of the mesorectal extension of rectal cancer is unclear. Patients and Methods:Data from 463 consecutive patients with stage IIa disease (T3N0) undergoing curative surgery at 28 institutes were analyzed. The measurement of the distance of the mesorectal extension (DME) was histologically evaluated. Risk factors for recurrence, for the optimal cutoff point of the DME, independent prognostic factors, and for survivals were studied using receiver operating characteristic curve and logistic and Cox regression analyses. Survivals were calculated using the Kaplan-Meier method. Results:A value of 4 mm was determined as the optimal cutoff point. The patients were subdivided into 2 groups: DME ⩽ 4 mm and DME > 4 mm at the optimal cutoff point. DME > 4 mm had the greatest impact on recurrence-free survival [P = 0.00023, hazard ratio (HR): 2.26, 95% confidence interval (95% CI): 1.465-3.492, L/U ratio: 0.420] and was an independent adverse prognostic factor (P = 0.00323, HR: 1.97, 95% CI: 1.254-3.091). The distant metastasis rate in DME > 4 mm was higher 16.7% than that in DME ⩽ 4 mm (P = 0.00177, OR: 2.61, 95% CI: 1.430-4.761). The incidence of local recurrence was not influenced by DME. The recurrence-free 5-year survival rate in DME ⩽ 4 mm was significantly better than that in DME > 4 mm (86.6% vs 71.3%, P = 0.00015, HR: 0.44, 95% CI: 0.286-0.683). The cancer-specific survival rate in DME ⩽ 4 mm was also significantly better than that in DME > 4 mm (91.3% vs 82.2%, P = 0.000664, HR: 0.52, 95% CI: 0.325-0.843). Conclusions:A subclassification according to mesorectal extension based on a 4-mm cutoff point is needed for the TNM staging system. However, further prospective study is necessary to prove reproducibility and validity of the cutoff point.

Distinct Profiles of Epigenetic Evolution between Colorectal Cancers with and without Metastasis

Liver metastasis is a fatal step in the progression of colorectal cancer (CRC); however, the epigenetic evolution of this process is largely unknown. To decipher the epigenetic alterations during the development of liver metastasis, the DNA methylation status of 12 genes, including 5 classical CpG island methylator phenotype (CIMP) markers, was analyzed in 62 liver metastases and in 78 primary CRCs (53 stage I-III; 25 stage IV). Genome-wide methylation analysis was also performed in stage I-III CRCs and in paired primary and liver metastatic cancers. Methylation frequencies of MGMT and TIMP3 increased progressively from stage I-III CRCs to liver metastasis (P = 0.043 and P = 0.028, respectively). The CIMP-positive cases showed significantly earlier recurrence of disease than did CIMP-negative cases with liver metastasis (P = 0.030), whereas no such difference was found in stage I-III CRCs. Genome-wide analysis revealed that more genes were methylated in stage I-III CRCs than in paired stage IV samples (P = 0.008). Hierarchical cluster analysis showed that stage I-III CRCs and stage IV CRCs were clustered into two distinct subgroups, whereas most paired primary and metastatic cancers showed similar methylation profiles. This analysis revealed distinct methylation profiles between stage I-III CRCs and stage IV CRCs, which may reflect differences in epigenetic evolution during progression of the disease. In addition, most methylation status in stage IV CRCs seems to be established before metastasis.

Efficacy of mosapride citrate with polyethylene glycol solution for colonoscopy preparation

AIM To evaluate the efficacy and safety of adjunctive mosapride citrate for bowel preparation before colonoscopy. METHODS We conducted a randomized, double-blind, placebo-controlled study with mosapride in addition to polyethylene glycol (PEG)-electrolyte solution. Of 250 patients undergoing colonoscopy, 124 were randomized to receive 2 L PEG plus 15 mg of mosapride citrate (mosapride group), and 126 received 2 L PEG plus placebo (placebo group). Patients completed a questionnaire reporting the acceptability and tolerability of the bowel preparation process. The efficacy of bowel preparation was assessed by colonoscopists using a 5-point scale based on Aronchicks criteria. The primary end point was optimal bowel preparation rates (scores of excellent/good/fair vs poor/inadequate). RESULTS A total of 249 patients were included in the analysis. In the mosapride group, optimal bowel preparation rates were significantly higher in the left colon compared with the placebo group (78.2% vs 65.6%, P < 0.05), but not in the right colon (76.5% vs 66.4%, P = 0.08). After excluding patients with severe constipation, there was a significant difference in bowel preparation in both the left and right colon (82.4% vs 66.7%, 80.8% vs 67.5%, P < 0.05, P < 0.01). The incidence of adverse events was similar in both groups. Among the subgroup who had previous colonoscopy experience, a significantly higher number of patients in the mosapride group felt that the current preparation was easier compared with patients in the placebo group (34/72 patients vs 24/74 patients, P < 0.05). CONCLUSION Mosapride citrate may be an effective and safe adjunct to PEG-electrolyte solution that leads to improved quality of bowel preparation, especially in patients without severe constipation.

Isolated tumor cell in lateral lymph node has no influences on the prognosis of rectal cancer patients

Background and aimsThe aim of this study was to determine the incidence of isolated tumor cells (ITC) and micrometastasis in lateral lymph nodes of patients with rectal cancer and its possible correlation with prognosis.Materials and methodsOne hundred seventy-seven rectal cancer patients who underwent curative resection with lateral lymph node dissection were enrolled. Dissected lymph nodes were examined using hematoxylin–eosin staining (HE) and immunohistochemistry (IHC) with anti-keratin antibody (AE1/AE3). States of lymph node metastasis were divisible into three groups: detectable with HE (HE+), detectable with only IHC (HE−/IHC+), and undetectable even with IHC (IHC−). Almost all the HE−/IHC+ group was classified as ITC consisting of a few tumor cells according to the UICC criteria (ITC+). Survival rates were compared among HE+, ITC+, and IHC−.ResultsITC+ were detected in 24.1% of patients with HE-negative lateral lymph nodes. No significant difference in overall 5-year survival was observed between ITC+ and IHC− patients (76.1 and 82.9%, respectively, p = 0.25). Multivariate analysis showed that perirectal HE+ lymph nodes, but not ITC+ lateral lymph nodes, was an independent prognostic factor.ConclusionsITC in lateral lymph nodes does not contribute to the prognosis of rectal cancer in patients who undergo extended lateral lymph node dissection, unlike HE+ lateral lymph node metastasis.

The Relationship of Lymph Node Evaluation and Colorectal Cancer Survival After Curative Resection: A Multi-Institutional Study

PurposeThis multicenter retrospective study aimed to clarify whether the number of lymph nodes retrieved influenced staging and survival in colorectal cancer.MethodsWe evaluated a total of 4538 patients who underwent curative resection for colorectal cancer with stage I, stage II, and stage III.ResultsThe median number of lymph nodes retrieved was 19. The 5-year actuarial disease-specific survival of colon cancer patients with stage I, stage II, and stage III was 99.0%, 94.1%, and 79.1%, respectively, and that for rectal cancer patients with stage I, stage II, and stage III was 98.2%, 88.3%, and 69.1%, respectively. After adjustment for confounders, the number of lymph nodes retrieved and the number of positive nodes were both significant in prognosis for patients with colon cancer and rectal cancer. Survival improved with an increasing number of nodes in stage II patients. In stage III, patients within strata of retrieval of fewer than 12 nodes with a cutoff based on quartiles had lower discriminative ability (c-index 0.683). Patients who were treated at the hospitals with higher average node counts (>23.4 nodes) and higher 12-node measure compliance (>80%) experienced better survival than those treated at the hospitals with lower average node counts for advanced T-stage.ConclusionThis study found that the number of lymph nodes retrieved and the number of positive nodes are both important prognostic factors. At least a 12-node threshold may be supported as a measure to improve a predictive capacity within individual patients and as a quality control parameter of hospital performance.

Predicting oncologic outcomes by stratifying mesorectal extension in patients with pT3 rectal cancer: a Japanese multi-institutional study

The goal of this study was to clarify the clinical significance of mesorectal extension in pT3 rectal cancer. This currently remains unclear. Data from 975 consecutive patients with pT3 rectal cancer that underwent curative surgery at 28 institutes were reviewed. The distance of the mesorectal extension (DME) was measured histologically. The optimal prognostic cut‐off point of the DME for oncologic outcomes was determined using the receiver operating characteristic curve and Cox regression analysis. When patients were subdivided into two groups according to the optimal cut‐off point, DME ≤ 4 mm and DME > 4 mm, DME was found to be a powerful independent risk factor for postoperative recurrence. A DME > 4 mm was significantly correlated with distant and local recurrences at Stage IIA and IIIB diseases. The recurrence‐free 5‐year‐survival rate was significantly higher in patients with a DME ≤ 4 mm [86.6% at Stage IIA (p = 0.00015), and 68.7% at Stage IIIB (p < 0.0001)] than in patients with a DME > 4 mm (71.3% at Stage IIA and 49.1% at Stage IIIB). No significant difference was noted in the oncologic outcomes between the two groups at Stage IIIC. A value of 4 mm provides the best prognostic cut‐off point for patient stratification and for the prediction of oncologic outcomes. A subclassification based on a 4‐mm cut‐off point may improve the utility of the TNM 7th staging system except for Stage IIIC. These findings warrant further prospective studies to determine the reliability and validity of this cut‐off point.