Hisanaga Horie

Periostin Is Expressed in Pericryptal Fibroblasts and Cancer-associated Fibroblasts in the Colon

Periostin is a unique extracellular matrix protein, deposition of which is enhanced by mechanical stress and the tissue repair process. Its significance in normal and neoplastic colon has not been fully clarified yet. Using immunohistochemistry and immunoelectron microscopy with a highly specific monoclonal antibody, periostin deposition was observed in close proximity to pericryptal fibroblasts of colonic crypts. The pericryptal pattern of periostin deposition was decreased in adenoma and adenocarcinoma, preceding the decrease of the number of pericryptal fibroblasts. Periostin immunoreactivity appeared again at the invasive front of the carcinoma and increased along the appearance of cancer-associated fibroblasts. ISH showed periostin signals in cancer-associated fibroblasts but not in cancer cells. Ki-67–positive epithelial cells were significantly decreased in the colonic crypts of periostin−/- mice (∼0.6-fold) compared with periostin+/+ mice. In three-dimensional co-culture within type I collagen gel, both colony size and number of human colon cancer cell line HCT116 cells were significantly larger (∼1.5-fold) when cultured with fibroblasts derived from periostin+/+ mice or periostin-transfected NIH3T3 cells than with those from periostin−/- mice or periostin–non-producing NIH3T3 cells, respectively. Periostin is secreted by pericryptal and cancer-associated fibroblasts in the colon, both of which support the growth of epithelial components.

Evaluation of venous invasion by Elastica van Gieson stain and tumor budding predicts local and distant metastases in patients with T1 stage colorectal cancer.

Evaluation of pathologic predictors of metastases in T1 stage colorectal cancer may be difficult with hematoxylin and eosin (HE) staining alone. The aim of this study was to clarify the role of pathologic predictors by using immunohistochemical staining and Elastica van Gieson (EVG) staining. One hundred and twenty-four patients who underwent bowel resection for single T1 stage colorectal cancer from 1990 to 2004 in 1 institution were studied. D2-40, EVG staining, and CAM5.2 were used to detect lymphatic invasion, venous invasion, and tumor budding, respectively. These 3 factors were separately evaluated based on HE staining. Histology was reviewed by 1 pathologist. Lymph node metastases in the surgical specimen were the standard reference, and distant metastases were identified by periodic computed tomography for 2 years or more after surgery. A logistic regression model was applied to analyze risk factors for lymph node metastases and a Cox regression model for distant metastases. In predicting lymph node metastases, univariate analysis demonstrated significance for all predictors except venous invasion by HE staining. Multivariate analysis showed that venous invasion by EVG and tumor budding by HE showed significance as predictors. In predicting distant metastases, univariate analysis showed significance for lymphatic invasion shown by D2-40, tumor budding shown by CAM5.2 and HE, and lymph node metastases. Multivariate analysis showed only venous invasion by EVG stain as being significantly associated with distant metastases (P=0.001). In conclusion, venous invasion evaluated shown by EVG staining is a useful pathologic predictor for metastases in T1 stage colorectal cancer.

A comparison of conventional endoscopy, chromoendoscopy, and the optimal-band imaging system for the differentiation of neoplastic and non-neoplastic colonic polyps

BACKGROUND The diagnostic accuracy of conventional endoscopy for small colonic polyps is not satisfactory. Optimal band imaging (OBI) enhances the contrast of the mucosal surface without the use of dye. OBJECTIVE To evaluate the diagnostic accuracy for the differentiation of neoplastic and non-neoplastic colorectal polyps by using magnified OBI colonoscopy. DESIGN An open prospective study. SETTING Jichi Medical University, Japan. PATIENTS A total of 133 colonoscopy cases. MAIN OUTCOME MEASUREMENT A comparative study of the overall accuracy, sensitivity, and specificity for the differentiation of neoplastic and non-neoplastic colorectal polyps < or =5 mm in size by capillary-pattern diagnosis by using conventional colonoscopy, capillary-pattern diagnosis in OBI, and pit-pattern diagnosis in chromoendoscopy with low magnification. RESULTS A total of 107 polyps, composed of 80 neoplastic and 27 non-neoplastic polyps, were evaluated. OBI clearly showed the capillary network of the surface mucosa of neoplastic polyps at low magnification, whereas the surface mucosa of non-neoplastic polyps showed up as a pale lesion. The capillary pattern in conventional colonoscopy had 74% accuracy, 71% sensitivity, and 81% specificity for neoplastic polyps. The accuracy and sensitivity were significantly lower than those that used the capillary pattern in OBI (accuracy 87% and sensitivity 93%) and the pit pattern in chromoendoscopy (accuracy 86% and sensitivity 90%). There were no significant differences in specificity (OBI 70% and chromoendoscopy 74%). The kappa analysis indicated good agreement in both OBI and chromoendoscopy. CONCLUSIONS Capillary-pattern diagnosis in OBI is superior to that in conventional endoscopy and is not significantly different from pit-pattern diagnosis for predicting the histology of small colorectal polyps.

Favorable Effects of Preoperative Enteral Immunonutrition on a Surgical Site Infection in Patients with Colorectal Cancer Without Malnutrition

PurposeA prospective study was conducted to ascertain the effects of preoperative enteral immunonutrition on a surgical site infection (SSI) in patients with colorectal cancer without malnutrition.MethodsPatients with colorectal cancer undergoing elective surgery without malnutrition, bowel obstruction, severe cardiopulmonary complications, diabetes, collagen disease, or renal failure were sequentially divided into an immunonutrition group (n = 33) and a control group (n = 34). In the immunonutrition group, an enteral diet supplemented with arginine, dietary nucleotides, and ω-3 fatty acids was administered for 5 days (750 ml/day) prior to surgery.ResultsThe mean age was slightly higher in the immunonutrition group (69 ± 9 years) than in the control group (63 ± 11 years; P < 0.05), but no significant differences between the groups were noted for the body mass index, total protein, albumin, hemoglobin, surgical methods, operation time, or volume of intraoperative bleeding. The frequencies of superficial incisional SSI, deep incisional SSI and organ/space SSI in the immunonutrition and control groups were 0% and 11.8% (4/34; P < 0.05), 0% and 0%, and 0% and 2.9% (1/34), respectively.ConclusionPreoperative enteral immunonutrition appears to be effective for preventing SSI in patients with colorectal cancer without malnutrition.

Chromosome copy number analysis in screening for prognosis-related genomic regions in colorectal carcinoma

Colorectal carcinoma (CRC) remains the major cause of cancer death in humans. Although chromosomal structural anomaly is presumed to play an important role in the carcinogenesis of CRC, chromosomal copy number alterations (CNA) and loss of heterozygosity (LOH) have not yet been analyzed extensively at high resolution in CRC. Here we aim to identify recurrent CNA and LOH in human CRC with the use of single nucleotide polymorphism‐typing microarrays, and to reveal their relevance to clinical outcome. Surgically resected CRC specimens and paired normal mucosa were obtained from a consecutive series of 94 patients with CRC, and both of them were subjected to genotyping with Affymetrix Mapping 50K arrays. CNA and LOH were inferred computationally on every single nucleotide polymorphism site by integrating the array data for paired specimens. Our large dataset reveals recurrent CNA in CRC at chromosomes 7, 8, 13, 18, and 20, and recurrent LOH at chromosomes 1p, 4q, 5q, 8p, 11q, 14q, 15q, 17p, 18, and 22. Frequent uniparental disomy was also identified in chromosomes 8p, 17p, and 18q. Very common CNA and LOH were present at narrow loci of <1 Mbp containing only a few genes. In addition, we revealed a number of novel CNA and LOH that were linked statistically to the prognosis of the patients. The precise and large‐scale measurement of CNA and LOH in the CRC genome is efficient for pinpointing prognosis‐related genome regions as well as providing a list of unknown genes that are likely to be involved in CRC development. (Cancer Sci 2008; 99: 1835–1840)

Effects of a Diverting Stoma on Symptomatic Anastomotic Leakage after Low Anterior Resection for Rectal Cancer: A Propensity Score Matching Analysis of 1,014 Consecutive Patients

BACKGROUND Routine creation of a diverting stoma (DS) in every patient who undergoes low anterior resection (LAR) remains controversial. We aimed to investigate the effect of DS on symptomatic anastomotic leakage (AL) after LAR. STUDY DESIGN Patients with rectal cancer within 10 cm from the anal verge were eligible for this prospective, multicenter, cohort study (UMIN-CTR, number 000004017). Propensity score matching (PSM) was used to compare groups of patients with and without DS. RESULTS One thousand fourteen consecutive patients were registered, of whom 936 patients who underwent LAR were analyzed. Before PSM, the overall rate of symptomatic AL was 13.2% (52 of 394) in patients with DS vs. 12.7% (69 of 542) in cases without DS (p = 0.84). Symptomatic AL requiring re-laparotomy occurred in 4.7% (44 of 936) of all patients, occurring in 1.0% (4 of 394) of patients with DS vs. 7.4% (40 of 542) of patients without DS (p < 0.001). After PSM, the 2 groups were nearly balanced, and the incidence rates of symptomatic AL in patients with and without DS were 10.9% and 15.8% (p = 0.26). The incidences of AL requiring re-laparotomy in patients with and without DS were 0.6% and 9.1% (p < 0.001). Multivariate analysis identified male sex (p < 0.001; odds ratio [OR] 3.2; 95% confidence interval [CI] 1.8 to 5.7) and tumor size (p < 0.001; OR 1.2; 95% CI 1.1 to 1.4) as independent risk factors of symptomatic AL. CONCLUSIONS Diverting stoma did not have a significant relationship with symptomatic AL before and after PSM. However, DS does seem to mitigate the consequences of leakage, reducing the need for urgent abdominal reoperation.

Pathological Predictors for Lymph Node Metastasis in T1 Colorectal Cancer

PurposeTo clarify pathological predictor for lymph node metastasis in T1 colorectal cancer.MethodsOne hundred and sixty-four patients who underwent surgery for single T1 colorectal cancer were reviewed. The pathological differentiations of non-well differentiation, invasion depth (≥2 000 μm), lymphatic channel involvement, venous invasion, and tumor budding were selected as candidate predictors. Tumor budding was estimated according to the definition proposed by Ueno et al. (Gastroenterology 2004; 127:385–394). The lymph node status was set for the endpoint. Logistic regression model was applied to analyze the predictors.ResultsLymph node involvement was observed in 9.8%. The positive rates were 13.4% for the pathological differentiations of non-well differentiation, 51.8% for invasion depth (≥2 000 μm), 6.1% for lymphatic channel involvement, 8.5% for venous invasion, and 14.6% for tumor budding. The pathological differentiations of non-well differentiation (P < 0.001) and tumor budding (P = 0.002) were significantly associated with lymph node metastasis in multivariate analysis. When either two significant factors was adopted for the prediction of the lymph node metastasis, the sensitivity, specificity, positive predictive value, and negative predictive value were 94%, 82%, 36%, and 99%, respectively.ConclusionThe pathological differentiations of non-well differentiation and tumor budding are useful predictors for lymph node metastasis in T1 colorectal cancer.

Regulatory SNP in the RBP4 Gene Modified the Expression in Adipocytes and Associated With BMI

Retinol‐binding protein 4 (RBP4) is a recently identified adipokine that was involved in insulin resistance. RBP4 is predominantly expressed from the liver in normal metabolic state to transport retinoids throughout the body, but the exact physiological function and the regulatory mechanisms of adipocyte‐derived RBP4 have not been revealed. We conducted the genetic analysis about metabolic parameters in Japanese and Mongolian; the minor allele carriers of regulatory single‐nucleotide polymorphism (SNP −803G>A) showed significantly higher BMI in Japanese men (P = 0.009) and women (P = 0.017), and in Mongolian women (P = 0.009). Relative quantification of RBP4 transcripts in −803GA heterozygotes showed that the minor allele–linked haplotype‐derived mRNA was significantly more abundant than the transcript from major allele. RBP4 promoter assay in 3T3L1 adipocytes revealed that the minor allele increased the promoter activity double to triple and the administration of 9‐cis‐retinoic acid (RA) and 8‐bromo‐cyclic adenosine monophosphate (8‐Br‐cAMP) enhanced the activity. Multiple alignment analysis of human, mouse, rat, and cattle RBP4 promoter suggested conserved seven transcription factor binding motifs. Electrophoretic mobility shift assay showed the −803G>A SNP modulate the affinity against unidentified DNA‐binding factor, which was assumed to be a suppressive factor. These results collectively suggested that the minor allele of RBP4 regulatory SNP enhanced the expression in adipocytes, which may be associated with the adipogenesis.

Prevalence of Synchronous Colorectal Neoplasms Detected by Colonoscopy in Patients with Gastric Cancer

PurposeOur purpose was to study the characteristics of colorectal neoplasms in patients with gastric cancer (GC).MethodsThe study group comprised GC patients who underwent colonoscopy before resection of their GC. We examined the prevalence, site, and histology of colorectal neoplasms, as well as the clinicopathological features and treatment of the patients who had synchronous colorectal cancers (CRC). The logistic regression model was applied to investigate the features of the GC patients with concurrent CRC.ResultsWe studied 466 GC patients (mean age 64.5 years; 147 women, 319 men), 143 (31%) of whom had a family history of gastrointestinal cancer. Synchronous colorectal adenoma and cancer were detected in 182 (39%) and 18 (4%) patients, respectively. Among the 18 synchronous CRCs, 11 were in the early stages and 10 of these were resected endoscopically. The other eight required simultaneous open radical surgery. All the GC patients with synchronous CRC were older than 50 years. Statistical analysis did not show a significant difference between the features of the patients with and those without concurrent CRC.ConclusionsThe possibility of synchronous colorectal neoplasms in GC patients cannot be disregarded in clinical practice; however, screening of the large bowel may not be necessary in GC patients younger than 50 years.

Preoperative T Staging of Colorectal Cancer by CT Colonography

PurposeThis study was designed to estimate the accuracy of CT colonography for the assessment of T stage in colorectal cancer.MethodsCT colonograms obtained from 246 lesions were reviewed by 3 investigators. Intestinal wall deformity on shaded-surface display and rough appearance around the intestine were studied to assess their relations to T stage. Intestinal wall deformity was classified into arc type, trapezoid type, and apple-core type, defined as a trapezoidal wall deformity involving ≥50 percent of the circumference of the lumen.ResultsAs for intestinal wall deformity, the rate of arc type was higher in Tis/T1 than in T2 (74 percent: 17/23 vs. 24 percent: 8/34, P < 0.0001); the rate of trapezoid type was 17 percent (4/23) in Tis/T1, 59 percent (20/34) in T2, and 15 percent (28/189) in T3/T4 (Tis/T1 vs.T2, P < 0.0001; T2 vs. T3/T4, P < 0.0001); and the rate of apple-core type was lower in T2 than in T3/T4 (18 percent: 6/34 vs. 81 percent: 154/189, P < 0.0001). Arc type, trapezoid type, and apple-core type were primarily associated with T1, T2, and T3/T4, respectively. When these criteria were used, the overall accuracy for T stage was 79 percent. Rough appearance was specific for T3/T4, but insensitive.ConclusionsCT colonography can provide important information for the preoperative assessment of T stage in colorectal cancer.