Clinicopathological significance and impact on outcomes of the gene expression levels of IGF-1, IGF-2 and IGF-1R, IGFBP-3 in patients with colorectal cancer: Overexpression of the IGFBP-3 gene is an effective predictor of outcomes in patients with colorectal cancer.

The insulin-like growth factors (IGF) system is involved in tumor proliferation, invasion and metastasis in cancer. The current study investigated the association of IGF-1, IGF-2 and IGF-1 receptor (IGF-1R), IGF binding proteins type 3 (IGFBP-3) mRNA expression levels with clinicopathological characteristics and outcomes of 202 patients with untreated colorectal cancer (CRC). IGF-1, IGF-2, IGF-1R and IGFBP-3 mRNA expression levels were analyzed in surgical specimens of cancer tissues and adjacent normal mucosa cells using reverse transcription-quantitative polymerase chain reaction. The IGF-1R gene expression level was significantly higher in cancer tissue compared with adjacent normal mucosa. By contrast, IGF-1 gene expression levels were reduced in cancer tissue compared with normal mucosa. IGF-2 and IGFBP-3 gene expression levels did not differ significantly between cancer tissue and adjacent normal mucosa. As for the association of gene expression and clinicopathological characteristics, IGFBP-3 gene expression was significantly associated with lymph node metastasis. High IGFBP-3 gene expression was associated with poor 5-year overall survival compared with patients with low IGFBP-3 expression. Furthermore, IGFBP-3 gene expression was identified as an independent prognostic factor using multivariate analysis. Overexpression of the IGFBP-3 gene is considered an effective independent predictor of outcomes in patients with CRC.

Combining the Glasgow Prognostic Score and Serum Carbohydrate Antigen 19-9 Level Improves the Ability to Predict Early Recurrence in Resected Pancreatic Cancer Patients Receiving Adjuvant Gemcitabine.

AIM: The aim of this study was to confirm the predictive/prognostic value of the preadjuvant Glasgow Prognostic Score (GPS) and carbohydrate antigen (CA) 19-9 level in pancreatic cancer patients receiving adjuvant gemcitabine (GEM) after surgery. PATIENTS AND METHODS: A total of 67 resected pancreatic cancer patients, treated with adjuvant GEM, were included. The GPS and CA19-9 level were calculated prior to administration of adjuvant therapy and were found to correlate with the outcomes and rate of early recurrence. RESULTS: An elevated preadjuvant GPS or CA19-9 level was significantly associated with a shorter overall survival (OS) (p=0.003 and p<0.001, respectively). Either an elevated GPS or CA19-9 level predicted early recurrence and the combined use of these two factors improved the ability to predict early recurrence, with a specificity and accuracy up to 0.958 and 0.821, respectively. CONCLUSION: Both an elevated preadjuvant GPS and CA19-9 level, when used alone, are significant predictors of poor outcomes in pancreatic cancer patients receiving adjuvant GEM. The combined use of these parameters improves the ability to predict early recurrence in such patients.

Clinical significance of IGF1R gene expression in patients with Stage II/III gastric cancer who receive curative surgery and adjuvant chemotherapy with S-1.

PURPOSE: Curative resection and adjuvant chemotherapy is the standard treatment for Stage II/III gastric cancer, and S-1 is widely used for adjuvant chemotherapy. The type 1 insulin-like growth factor receptor (IGF1R) is involved in cell proliferation and prevention of apoptosis in many tumors. We evaluated the relative expression of the IGF1R gene to determine whether such expression correlates with outcomes in patients with Stage II/III gastric cancer. METHODS: We measured the expression levels of the IGF1R gene in specimens of cancer and adjacent normal mucosa obtained from 134 patients with Stage II/III gastric cancer who received curative resection and adjuvant chemotherapy with S-1. We then evaluated whether the IGF1R gene expression levels correlate with clinicopathological characteristics and outcomes. RESULTS: IGF1R mRNA expression levels tended to be higher in cancer tissue than in the normal adjacent mucosa (P = 0.078). Multivariate analysis showed that high IGF1R gene expression was a significant independent predictor of poor survival in Stage II/III gastric cancer after curative resection and adjuvant chemotherapy with S-1 (HR 3.681, P = 0.007). The overall survival rate was significantly lower in patients with high IGF1R gene expression than in those with low expression (P = 0.012). CONCLUSIONS: IGF1R overexpression is considered a useful independent predictor of outcomes in Stage II/III gastric cancer after curative resection and adjuvant chemotherapy with S-1.

Systematic review and meta-analysis of histopathological predictive factors for lymph node metastasis in T1 colorectal cancer.

BACKGROUND: In this study we examined whether histopathological findings, specifically lymphatic vessel invasion identified by an anti-human podoplanin antibody, and several other factors are associated with lymph node metastasis in T1 colorectal cancer. METHODS: We searched PubMed and Cochrane Library, and also handsearched relevant journals, for reports written in English and published between 1998 and 2012, utilizing combination headings, such as 'colorectal cancer,' 'lymph node metastasis,' and 'risk factors.' For the report to be included in our study, the following criteria had to be met: (1) data on the frequency of lymph node metastasis in T1 colorectal cancer in relation to histopathological factors were reported; (2) patients had undergone bowel resection and had histologically diagnosed T1 colorectal cancer; (3) lymphatic vessel invasion was identified by immunohistochemistry with an anti-human podoplanin antibody rather than by hematoxylin and eosin staining; (4) univariate and multivariate analyses were conducted. Studies investigating molecular markers were excluded. The independent predictive factors were confirmed in at least one study included in the meta-analysis in the present systematic review. Microsoft Excel 2013 for Windows was used for the statistical analysis. RESULTS: Initially, 369 publications were identified in the database searches and handsearches, of which five ultimately met all of the inclusion criteria and selected for this systematic review. The meta-analysis revealed that only two factors were significantly associated with T1 colorectal cancer lymph node metastasis: (1) lymphatic vessel invasion identified by an anti-human podoplanin antibody [Mantel-Haenszel odds ratio (OR) 5.19; (95% confidence interval (CI) 3.31-8.15; P = 0.01]; (2) tumor budding (OR 7.45; 95 % CI 4.27-13.02; P = 0.0077). CONCLUSION: Our meta-analysis revealed that lymphatic vessel invasion identified by an anti-human podoplanin antibody and tumor budding were significantly associated with T1 colorectal cancer lymph node metastasis.

Risk factors for 6-month continuation of S-1 adjuvant chemotherapy for resected pancreatic cancer.

BACKGROUND: The factors which affect the 6-month continuation of adjuvant chemotherapy with S-1 have not been fully evaluated in pancreatic cancer. The objective of this retrospective study was to clarify the risk factors for the discontinuation of S-1 adjuvant chemotherapy after 6 months of treatment. METHODS: The study included patients who underwent curative surgery for pancreatic cancer, were diagnosed with stage II or III disease, had a serum creatinine level ≤1.2 mg/dl and received adjuvant S-1 between June 2007 and March 2014. RESULTS: Forty patients were eligible for the present study. A comparison of the 6-month continuation stratified by each clinical factor using the log-rank test revealed a significant difference in the creatinine clearance (CCr) between the patients who continued and discontinued the treatment. A CCr of 60 ml/min was regarded as a critical point. The uni- and multivariate Cox's proportional hazard analyses demonstrated that the CCr was the only significant independent predictive factor. The 6-month continuation rate was 70.8 % in the patients with a CCr ≥60 ml/min and was 25.0 % in patients with a CCr <60 ml/min (P = 0.008). The patients with a CCr <60 ml/min developed adverse events more frequently and earlier than those with a CCr ≥60 ml/min. CONCLUSIONS: A CCr < 60 ml/min was a significant risk factor for the 6-month discontinuation of S-1 adjuvant chemotherapy in pancreatic cancer patients, even though the renal function was judged to be normal based on the serum creatinine level. Careful attention is therefore required to improve the S-1 continuation in patients with a CCr < 60 ml/min.

Randomised phase III trial of adjuvant chemotherapy with oral uracil and tegafur plus leucovorin versus intravenous fluorouracil and levofolinate in patients with stage III colorectal cancer who have undergone Japanese D2/D3 lymph node dissection: final results of JCOG0205.

BACKGROUND: NSABP C-06 demonstrated the non-inferiority of oral adjuvant uracil and tegafur plus leucovorin (UFT/LV) to weekly fluorouracil and folinate (5-FU/LV) with respect to disease-free survival (DFS) for stage II/III colon cancer. This is the first report of JCOG0205, which compared UFT/LV to standard 5-FU/levofolinate (l-LV) for stage III colorectal cancer patients who have undergone Japanese D2/D3 lymph node dissection. METHODS: Patients were randomised to three courses of 5-FU/l-LV (5-FU 500 mg/m(2), l-LV 250 mg/m(2) on days 1, 8, 15, 22, 29, 36 every 8 weeks) or five courses of UFT/LV (UFT 300 mg m(-2)day(-1), LV 75 mg/day on days 1-28 every 5 weeks). The primary end-point was DFS. The sample size was 1100 determined with one-sided alpha of 0.05, power of 0.78 and non-inferiority margin of hazard ratio of 1.27. This trial is registered with UMIN-CTR (C000000193). FINDINGS: Between February 2003 and November 2006, 1,101 patients (1092 eligible patients) were randomised to 5-FU/l-LV (n=550) or UFT/LV (n=551). Median age: 61 years, colon/rectum: 67%/33%, number of positive nodes ⩽3/>3: 73%/27%, stage IIIa/IIIb: 75%/25%. The hazard ratio of DFS was 1.02 (91.3% confidence interval, 0.84-1.23), demonstrating the non-inferiority of UFT/LV (P=0.0236). Five-year overall survival (87.5%) was higher than that in NSABP C-06 (69.6%). Grade 3/4 toxicities were 8.4% neutropenia in 5-FU/l-LV and 8.7% alanine aminotransferase elevation in UFT/LV, respectively. The incidences of diarrhoea (9.6% versus 8.5%) and anorexia (4.0% versus 3.7%) were similar between the two arms. No treatment-related deaths were reported. INTERPRETATION: Adjuvant UFT/LV is non-inferior to standard 5-FU/l-LV with respect to DFS. UFT/LV should be an oral treatment option for patients with stage III colon cancer who have undergone Japanese D2/D3 lymph node dissection.

Relation of INHBA gene expression to outcomes in gastric cancer after curative surgery.

Inhibin-ßA (INHBA), a ligand belonging to the transforming growth factor-ß superfamily, is associated with cell proliferation in cancer. We studied the relations of INHBA gene expression to clinicopathological factors and outcomes in 168 patients with gastric cancer who underwent curative surgery. Relative INHBA gene expression was measured in surgical specimens of cancer tissue and adjacent normal mucosa by quantitative real-time, reverse-transcription polymerase chain reaction. INHBA expression levels were significantly higher in cancer tissue than in adjacent normal mucosa and were related to TNM stage and venous invasion. High INHBA gene expression was associated with significantly poorer 5-year overall survival than was low expression. On multivariate analysis, INHBA gene expression was an independent prognostic factor. Overexpression of the INHBA gene is considered a useful independent predictor of outcomes in patients with gastric cancer after curative surgery.

Impact of overexpression of Sushi repeat-containing protein X-linked 2 gene on outcomes of gastric cancer.

BACKGROUND AND OBJECTIVES: Sushi repeat-containing protein X-linked 2 (SRPX2) was first described as a downstream target gene for E2A-HLA, which causes pro-B acute leukemia. SRPX2 is considered to promote cellular migration and adhesion in cancers. Our objective was to evaluate the relative expression of the SRPX2 gene and to determine whether such expression correlates with outcomes in patients with gastric cancer. METHODS: Surgical specimens of cancer tissue and adjacent normal mucosa obtained from 227 patients with previously untreated gastric cancer were examined. SRPX2 mRNA expression levels of cancer tissue and adjacent normal mucosa were measured by quantitative real-time polymerase chain reaction. We evaluated the clinicopathological significance of the relative expression of SRPX2 in patients with gastric cancer. RESULTS: SRPX2 expression was higher in cancer tissue than in adjacent normal mucosa (P < 0.001). On analysis of the relations between gene expression and clinicopathological factors, SRPX2 expression correlated with tumor size and distant metastasis. Overall survival was significantly lower in patients whose tumors had high SRPX2 expression than in those who had low SRPX2 expression (P = 0.003). Multivariate analysis showed that high SRPX2 expression was an independent predictor of survival (HR = 2.028, 95% CI = 1.265-3.251). CONCLUSIONS: SRPX2 expression was significantly higher in gastric cancer tissue than in adjacent normal mucosa, and overexpression of the SRPX2 gene is considered a useful independent predictor of outcomes in patients with gastric cancer.

Clinical significance of SPARC gene expression in patients with gastric cancer.

PURPOSE: Secreted protein acidic and rich in cysteine (SPARC) is one of the first known matricellular proteins that modulates interactions between cells and extracellular matrix. Recent studies investigated the clinical significance of SPARC gene expression in the development, progression, and metastasis of cancer. The present study examined the relations of the relative expression of the SPARC gene to clinicopathological factors and overall survival in patients with gastric cancer. METHODS: We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 227 patients with previously untreated gastric cancer. The relative expression levels of SPARC mRNA in cancer tissue and in adjacent normal mucosa were measured by quantitative real-time, reverse-transcription polymerase chain reaction. RESULTS: The relative expression level of the SPARC gene was higher in cancer tissue than in adjacent normal mucosa. High expression levels of the SPARC gene were related to serosal invasion (P = 0.046). Overall survival at 5 years differed significantly between patients with high SPARC gene expression and those with low expression (P = 0.006). CONCLUSIONS: Overexpression of the SPARC gene may be a useful independent predictor of outcomes in patients with gastric cancer.

Well-differentiated papillary mesothelioma, possibly giving rise to diffuse malignant mesothelioma: a case report.

Well-differentiated papillary mesothelioma (WDPM) is a distinct subtype of mesothelial tumor from diffuse malignant mesothelioma (DMM), with an uncertain malignant potential. The relationship between WDPM and DMM, with regard to the ability of the former to develop into the latter, is also unknown. A 58-year-old woman, diagnosed with a rectal carcinoid tumor, underwent removal of the lymph nodes via the abdomen in 2004. A large number of white miliary nodules were identified on the mesentery and peritoneum, which were histologically diagnosed as WDPM. No further therapy was administered, but the patient was followed-up using imaging methods. Seven years later, an abdominal wall mass was discovered using positron emission tomography-computed tomography, and a laparotomy biopsy was performed. DMM was diagnosed, because mesothelioma with extended invasion had been histologically identified. Mesothelioma similar to papillary proliferation was present on the outer layer of the peritoneum, and an infiltrating lesion with continuous restiform or solid-like structures was noted. WDPM was believed to have undergone malignant transformation. Compared to DMM, WDPM has a good prognosis and is considered a benign or borderline neoplasm. Our findings suggest that WDPM does have malignant potential, however, because histological findings indicated a malignant transformation of WDPM to DMM.

Lymphatic invasion identified with D2-40 immunostaining as a risk factor of nodal metastasis in T1 colorectal cancer.

BACKGROUND: The management of T1 colorectal cancer after local resection is controversial. Regional lymph node metastasis often occurs, requiring subsequent colonic resection. The aim of this study was to reevaluate the risk factors of nodal metastasis of T1 colorectal cancer, especially to examine lymphatic vessel invasion in serially prepared hematoxylin and eosin sections and D2-40 immunostained sections to determine which is a better indicator of lymph node metastasis of T1 colorectal cancer. METHODS: The study investigated 120 patients who underwent bowel resection and were histologically diagnosed to have T1 colorectal cancer in Kanagawa Cancer Center Hospital from 1995 to 2005. Serially prepared paraffin sections were stained with hematoxylin and eosin, or immunostained with D2-40 antibody or von Willebrand factor, and reevaluated for lymphatic vessel invasion and other risk factors, including venous invasion, histological grade, depth of submucosal invasion, and budding. RESULTS: Lymphatic invasion diagnosed with either hematoxylin and eosin staining (p = 0.022), or D2-40 immunostaining (p = 0.001), and budding (p = 0.013) were significant risk factors for lymph node metastasis in the univariate analysis. Venous involvement, histological grade, or depth of submucosal invasion was not significant. The multivariate logistic regression analysis for the three risk factors found lymphatic invasion diagnosed with D2-40 as an independent risk factor (odds ratio 6.048, p = 0.018, CI 1.360-26.89). The sensitivity, specificity, positive predictive value, and negative predictive value were 58 %, 88 %, 35 %, and 95 %, respectively. CONCLUSIONS: Lymphatic vessel invasion diagnosed with D2-40 was a better indicator to evaluate the risk for lymph node metastasis by T1 colorectal cancer.

The clinical significance of SWI/SNF complex in pancreatic cancer.

Chromatin remodeling factors have been the subject of great interest in oncology. However, little is known about their role in pancreatic cancer. The objective of this study was to clarify the clinical significance of the SWItch/sucrose non-fermentable (SWI/SNF) complex in patients with pancreatic cancer. A total of 68 patients with pancreatic cancer who underwent R0, 1 resection were enrolled. Cancer tissues were processed to tissue microarray, then stained immunohistochemically by using antibody of SWI/SNF components; BRM, BRG1, BAF250a, BAF180 and BAF47. The correlation of expression levels and clinicopathological outcomes were analyzed, followed by the multivariate analysis of prognostic factors for overall survival. The expression levels of the SWI/SNF components were categorized as low or high according to the median value of Histoscore. Statistical analysis revealed that BRM expression was related to tumor size, T factor, M factor, lymphatic invasion and stage BRG1 expression to histology and stage BAF180 expression to tumor size and BAF47 expression to lymphatic invasion, respectively. Multivariate Cox proportional hazard analysis showed that high BRM and low BAF180 expression levels were independent predictors of worse survival in patients with pancreatic cancer. High BRM, and low BAF180 were also independent prognostic factors for poor survival in the subgroup with adjuvant gemcitabine. These results suggest that the specific cofactors of SWI/SNF chromatin remodeling complex certainly have roles in pancreatic cancer. High BRM, and low BAF180 are useful biomarkers for poor prognosis in pancreatic cancer.

The clinicopathological features of colorectal mucinous adenocarcinoma and a therapeutic strategy for the disease.

BACKGROUND: The guidelines established by the National Comprehensive Cancer Network do not describe mucinous histology as a clinical factor that should influence the therapeutic algorithm. However, previous studies show conflicting results regarding the prognosis of colorectal mucinous adenocarcinoma. In this study, we described the clinicopathological features of mucinous adenocarcinoma in Japan, to identify optimal therapeutic strategies. METHODS: 144 patients with mucinous and 2673 with non-mucinous adenocarcinomas who underwent primary resection in two major centers in Yokohama, Japan were retrospectively evaluated for clinicopathological features and treatment factors. A multivariate analysis for overall survival followed by the comparison of overall survival using Cox proportional hazard model were performed. RESULTS: Patients with mucinous adenocarcinoma had larger primary lesions, higher preoperative CEA levels, a deeper depth of invasion, higher rates of nodal and distant metastasis, and more metastatic sites. A multivariate analysis for overall survival revealed a mucinous histology to be an independent prognostic factor. In the subgroup analysis stratified by stage, Patients diagnosed as stageIII and IV disease had a worse survival in mucinous adenocarcinoma than non-mucinous, while survival did not differ significantly in patients diagnosed as Stage0-II disease. In stageIII, local recurrence in rectal cases and peritoneal dissemination were more frequently observed in patients with a mucinous histology. CONCLUSIONS: Our study indentified that mucinous adenocarcinoma was associated with a worse survival compared with non-mucinous in patients with stageIII and IV disease. In rectal StageIII disease with mucinous histology, additional therapy to control local recurrence followed by surgical resection may be a strategical alternative. Further molecular investigations considering genetic features of mucinous histology will lead to drug development and better management of peritoneal metastasis.

Comparison of the chemosensitivity of the primary lesion and a pancreatic metastasis of colon cancer: a case report.

Pancreatic metastasis from colorectal cancer is rare, and accounts for less than 2% of all pancreatic metastases. There have been no studies that have reported the differences in the sensitivity to chemotherapy between the primary lesion and the pancreatic metastasis in colorectal cancer. We experienced a rare example of pancreatic metastasis from colorectal cancer, and report here the difference in the sensitivity to the antitumor drug. A 68-year-old female underwent colectomy for rectal carcinoma with a mass in the pancreatic tail and the liver. The patient also underwent a distal pancreatectomy and a segmental liver resection at the same time. v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and tumor protein 53 (TP53) gene mutation analyses, in addition to the histopathological examinations, revealed tumors of the liver and the pancreatic tail as being metastases from the primary carcinoma. We employed a collagen gel droplet-embedded culture drug sensitivity test for both the primary lesion and the pancreatic metastasis. The sensitivity to oxaliplatin and FOLFOX (5-flurouracil, folinic acid and oxaliplatin) were lower in the pancreatic metastasis compared to the primary lesion. In conclusion, pancreatic metastasis from colorectal malignancy is rare, and the present results suggest that there are potential differences in the sensitivity to chemotherapy between the primary colorectal tumor and its pancreatic metastasis.

The expression of the phosphatase regenerating liver 3 gene is associated with outcome in patients with colorectal cancer.

BACKGROUND/AIMS: The phosphatase of regenerating liver-3 (PRL-3) is over expressed in several human cancers and associated with tumor progression, invasion and metastasis. However, the correlation between PRL-3 expression and clinical outcome in colorectal cancer (CRC) has not been investigated. This study examined the relationship between the relative expression of the PRL-3 gene to the clinicopathological factors and outcomes in patients with CRC. METHODOLOGY: Surgical specimens of cancer tissue and adjacent normal mucosa were obtained from 202 patients with untreated CRC. The relative expression level of PRL-3 mRNA in cancer and in the normal adjacent mucosa was measured using the quantitative real-time reverse-transcriptase PCR. RESULTS: PRL-3 expression was higher in cancer tissue than in the adjacent normal mucosa. The tumor location and liver metastasis were found to be related to the PRL-3 expression level. The overall survival differed significantly between patients with high PRL-3 expression and those with low expression. CONCLUSIONS: High expression of the PRL-3 gene might be a useful predictor of poor postoperative outcome in patients with CRC.

Immunohistochemical analysis of human equilibrative nucleoside transporter-1 (hENT1) predicts survival in resected pancreatic cancer patients treated with adjuvant gemcitabine monotherapy.

BACKGROUND: Gemcitabine is a promising adjuvant treatment for patients with resected pancreatic cancer. Human equilibrative nucleoside transporter-1 (hENT1) is the major transporter responsible for gemcitabine uptake into cells. The aim of this study was to retrospectively determine the relationship between the outcome of pancreatic cancer after surgery followed by postoperative gemcitabine monotherapy and the expression of hENT1. METHODS: A total of 27 resected pancreatic cancer patients treated with adjuvant gemcitabine were analyzed for tumor hENT1 expression via an immunohistochemical analysis. The staining intensity and the percentage of positive tumor cells were scored, and the composite score (hENT1 score) was obtained by obtaining the sum of these two scores. RESULTS: There were 11 patients assigned to the low hENT1 expression group, and 16 patients to the high hENT1 group. The patients with tumors that had higher hENT1 expression had a significantly longer disease-free survival (DFS) (log rank, P = 0.022) and overall survival (OS) (P = 0.024). The hENT1 expression was indicated to be a significant and independent prognostic factor for OS by the univariate (P = 0.030) and multivariate analyses (P = 0.019). CONCLUSIONS: A high expression of hENT1 in pancreatic cancer was found to be significantly associated with a longer survival in patients who received adjuvant gemcitabine monotherapy after curative resection, and hENT1 immunohistochemistry may well serve as a significant prognostic factor for these patients.

The global histone modification pattern correlates with overall survival in metachronous liver metastasis of colorectal cancer.

Post-translational histone modifications are known to be altered in cancer tissues, and differences in the histone modification levels have recently been used to predict the clinical outcome in patients with certain types of cancer. In this study, we evaluated the immunohistochemical staining patterns of histone H3 dimethylation and acetylation in metachronous liver metastasis of colorectal carcinomas and examined its correlation with patient prognosis. Double 2 mm core tissue microarrays were made from 54 paraffin-embedded samples of liver metastasis from colorectal adenocarcinoma, and were examined by an immunohistochemical analysis of histone H3 lysine 4 (H3K4) dimethylation, histone, H3 lysine 9 (H3K9) dimethylation and histone H3 lysine 9 (H3K9) acetylation. Positive tumor cell staining for each histone modification was used to classify patients into low- and high-staining groups, which were then examined for correlations with the clinicopathological parameters and clinical outcome. Dimethylation of H3K4 correlated with the tumor histological type (P=0.043), and acetylation of H3K9 correlated with the tumor histological type (P=0.016). In addition, lower levels of H3K4 dimethylation correlated with a poor survival rate (P=0.035). The multivariate survival analysis showed that the H3K4 dimethylation status is an independent prognostic factor for colorectal cancer patients (P=0.011). We suggest that the pattern of histone modification as detected by immunohistochemistry may be an independent prognostic factor for metachronous liver metastasis of colorectal carcinomas.

Identification of preneoplastic lesions as mucin-depleted foci in patients with sporadic colorectal cancer.

In experimental models, mucin-depleted foci (MDF), formed by dysplastic crypts devoid of mucin production have been recognized to be correlated with colorectal carcinogenesis and to serve as preneoplastic lesions of colorectal cancer (CRC). In humans, there is only one report of identification of MDF in patients with familial adenomatous polyposis and CRC; however, the histological characteristics of human MDF are not discussed extensively in the report. In the present study, colonic samples from 53 patients with sporadic CRC were stained with Alcian blue and examined for the presence of MDF. Subsequently, the samples were examined for the presence of aberrant crypt foci (ACF) by methylene blue staining. We classified MDF into two categories: flat-MDF and protruded-MDF (having the characteristics of both ACF and MDF). We found a total of 354, 41 and 19 colonic mucosal lesions with a mean multiplicity of 44, 38.9 and 66.9 crypts (ACF, flat-MDF and protruded-MDF, respectively). The density of MDF was 0.0082 lesions/cm(2) . The ACF identified in sporadic CRC patients corresponded to hyperplastic or non-dysplasic lesions. However, MDF identified in these patients corresponded to low-grade dysplasia. In addition, we found that Paneth cell metaplasia and inflammatory cell infiltration were specific histological features of MDF. These histological characteristics are reported to be associated with the development of CRC. Therefore, our results indicate that MDF might represent preneoplastic lesions in human colorectal carcinogenesis.

[Pancreatic resection for metastatic tumors to the pancreas].

We report 3 cases of resectable pancreatic metastasis. CASE 1: A 76-year-old woman was followed after nephrectomy for renal cell carcinoma for 13 years. CT examination demonstrated a high vascular lesion in the pancreatic body and tail. We conducted distal pancreatectomy and diagnosed with metastatic tumor from renal cell carcinoma. She died of liver metastasis 8 years after pancreatic resection. CASE 2: A 64-year-old man, who had undergone right lower lobectomy for lung cancer a year ago, was found to have a mass in the pancreatic tail. We performed distal pancreatectomy and diagnosed with metastatic tumor from lung cancer. He died of lung metastasis 12 months after pancreatic resection. CASE 3: A 62- year-old woman, who had undergone left nephrectomy for renal cell carcinoma 3 years ago, was found to have a mass in the pancreatic body. With a diagnosis of metastatic pancreatic tumor from renal cell carcinoma, distal pancreatectomy was done. She died of liver and lung metastases 15 months after pancreatic resection. Long-term survival can be achieved in patients undergoing a pancreatic standard resection including lymphadenectomy for isolated metastasis from nonpancreatic sites.

A case of adenomyomatous hyperplasia of the extrahepatic bile duct.

Adenomyomatous hyperplasia is rarely found in the extrahepatic bile duct. A 54-year-old man was referred to our center with a diagnosis of extrahepatic bile duct stenosis which had been detected by endoscopic retrograde choloangiopancreatography. Abdominal computed tomography revealed thickening of the wall of the middle extrahepatic bile duct, however no malignant cells were detected by cytology. Since bile duct carcinoma could not be ruled out, we performed resection of the extrahepatic duct accompanied by lymph node dissection. Histopathologically, the lesion was diagnosed as adenomyomatous hyperplasia of the extrahepatic bile duct. Present and previously reported cases showed the difficulty of making a diagnosis of adenomyomatous hyperplasia of the extrahepatic bile duct preoperatively or intraoperatively. Therefore, when adenomyomatous hyperplasia is suspected, a radical surgical procedure according to malignant disease may be necessary for definitive diagnosis.