Yukio Nishiguchi

Combined analysis of p53 and vascular endothelial growth factor expression in colorectal carcinoma for determination of tumor vascularity and liver metastasis

Recent studies have demonstrated that the p53 tumor suppressor gene plays an important role in controlling tumor angiogenesis. We examined the expression of p53 and vascular endothelial growth factor (VEGF), a well‐characterized angiogenic inducer, together with microvessel density to investigate the role of p53 in the regulation of angiogenesis and its clinical significance in human colorectal carcinoma. Surgically resected specimens of 163 colorectal carcinomas were studied by immunohistochemical staining for p53 protein, VEGF and factor VIII‐related antigen. Positive p53 protein accumulation and VEGF expression was found in 41.7% and 49.1% of tumors, respectively. p53 and VEGF staining status was identical in 65.6% of tumors. The incidence of p53‐ or VEGF‐positive tumors was significantly higher in patients with venous invasion and liver metastases than in those without. The microvessel count (MVC) in p53‐ or VEGF‐positive tumors was significantly higher than that in negative tumors, and MVC in both p53‐ and VEGF‐positive tumors was significantly higher than that in the other subgroups. Neither synchronous nor metachronous hepatic metastases were found in patients with p53‐ and VEGF‐negative tumors, while 52.2% of patients with both‐positive tumors had liver metastases and had a poorer prognosis than those with both‐negative tumors. Our findings suggest the presence of a p53‐VEGF pathway regulating tumor angiogenesis in human colorectal carcinoma. Combined analysis of p53 and VEGF expression might be useful for predicting the occurrence of liver metastasis in patients with this disease. Int. J. Cancer 74:502–507, 1997.

Androgen receptor expression in breast cancer: relationship with clinicopathological factors and biomarkers

BackgroundBreast cancer is a hormone-dependent tumor. Most breast cancer cells have an androgen receptor (AR), but the clinical value of AR expression is unclear.MethodsAR expression was evaluated in 227 primary breast cancers using immunohistochemistry. The relation of AR expression to clinicopathological factors and biomarkers was analyzed. AR expression was assessed semiquantitatively, and tumors with more than 10% of stained cells were regarded as positive.ResultsThe AR-positive rate was higher in smaller tumors (P = 0.045), tumors with negative lymph node metastasis (P = 0.045), scirrhous-type tumors (P < 0.0001), tumors of low histological grade (P = 0.0001), and p53-negative tumors (P = 0.0097). Although AR had no relation to menopausal status, 79% of cases of high AR expression (>50% stained cells) were in postmenopausal women. AR was related to estrogen receptor (ER; P = 0.027) and progesterone receptor (PR; P = 0.016) expression, but showed no relation to human epidermal growth factor receptor type 2 (Her2) expression. Regarding the coexpression of these receptors, 18 of the 42 cases of triple-negative (ER/ PR/ Her2-negative) tumors (43%) were AR-positive.ConclusionAR expression is related to low malignancy in breast cancer. The assessment of AR expression may lead to new treatment strategies for breast cancer, especially in postmenopausal women and in women with tumors that show triple negativity for hormone receptors.

A Meta-analysis of the Short- and Long-Term Results of Randomized Controlled Trials That Compared Laparoscopy-Assisted and Conventional Open Surgery for Rectal Cancer

PurposeWe conducted a meta-analysis to evaluate and compare the short- and long-term results of laparoscopy-assisted and open rectal surgery for the treatment of patients with rectal cancer.MethodsWe searched MEDLINE, EMBASE, Science Citation Index, and the Cochrane Controlled Trial Register for relevant papers published between January 1990 and April 2011 by using the search terms “laparoscopy,” “laparoscopy assisted,” “surgery,” “rectal cancer,” and “randomized controlled trials.” We analyzed outcomes over short- and long-term periods.ResultsWe identified 12 papers reporting results from randomized controlled trials that compared laparoscopic surgery with open surgery for rectal cancer. Our meta-analysis included 2,095 patients with rectal cancer; 1,096 had undergone laparoscopic surgery, and 999 had undergone open surgery. In the short-term period, 13 outcome variables were examined. In the long-term period, eight oncologic variables, as well as late morbidity, urinary function, and sexual function were analyzed. Laparoscopic surgery for rectal cancer was associated with a reduction in intraoperative blood loss and the number of transfused patients, earlier resumption of oral intake, and a shorter duration of hospital stay over the short-term, but with similar short-term and long-term oncologic outcomes compared to conventional open surgery.ConclusionsLaparoscopic surgery may be an acceptable alternative treatment option to conventional open surgery for rectal cancer.

A Meta-Analysis of the Short- And Long-Term Results of Randomized Controlled Trials That Compared Laparoscopy-Assisted and Open Colectomy for Colon Cancer

Purpose: We conducted a meta-analysis to evaluate and compare the short- and long-term results of laparoscopy-assisted colectomy (LAC) and open colectomy (OC) for colon cancer. Methods: We searched MEDLINE, EMBASE, Science Citation Index, and Cochrane Controlled Trial Register for relevant papers published between January 1990 and October 2011 by using the search terms “laparoscopy,” “laparoscopy-assisted,” “surgery,” “colectomy,” “colon cancer,” and “randomized clinical trials (RCTs)”. We analyzed the outcomes of each type of surgery over short- and long-term periods. Results: We selected 12 papers reporting RCTs that compared LAC with OC for colon cancer. Our meta-analysis included 4614 patients with colon cancer; of these, 2444 had undergone LAC and 2170 had undergone OC. In the short-term period, we found that the rates of overall postoperative complications and ileus in LAC were lower than in OC groups. LAC was associated with a reduction in intraoperative blood loss, a shorter duration of time to resumption and hospital stay, and lower rates of overall complication and ileus over the short-term, but with similar long-term oncologic outcomes such as overall and cancer-related mortality, overall recurrence, local recurrence, distant metastasis, and wound-site recurrence, compared to OC. Conclusions: It is suggested that LAC may be preferred to OC for colon cancer.

Cyclin D1 Overexpression and Prognosis in Colorectal Adenocarcinoma

Recently, it has been reported that cyclin D1 plays a major role in oncogenesis in various cancers; however, there have been few studies on the association of cyclin D1 overexpression and prognosis of patients with malignant tumors. We evaluated the prognostic significance of cyclin D1 overexpression in colorectal adenocarcinoma. One hundred twenty-three specimens resected from patients with colorectal adenocarcinomas were investigated by staining with a monoclonal antibody against cyclin D1. As a result, both overall survival and disease-free survival were significantly poorer in the patients with tumors strongly positive for cyclin D1 than in those with cyclin-D1-negative or weakly positive tumors. The 5-year survival rate of the patients with tumors strongly positive for cyclin D1 was 53.3%, while the 5-year survival rates of patients with cyclin-D1-negative and weakly positive tumors were 96.2 and 78.8%, respectively. Moreover, multivariate analysis indicated that cyclin D1 overexpression is an independent predictor of disease recurrence in our patients. In conclusion, cyclin D1 overexpression may be useful as a predictor of disease recurrence in colorectal adenocarcinoma.

Overexpression of cyclin D1 and p53 associated with disease recurrence in colorectal adenocarcinoma

Multiple genetic changes occur during the evolution of normal cells into cancer cells. It has been reported that both cyclin D1 and p53 genes play major roles in oncogenesis and/or cell cycle control in various cancers. In this study, we examined the overexpression of cyclin D1 and p53 by the immunohistochemical method and investigated the correlation between expression of these antigen and prognosis in patients with colorectal adenocarcinoma. Disease‐free survival was significantly lower in the patients with cyclin D1‐strongly positive tumors than in those with cyclin D1‐negative tumors. Similarly, disease‐free survival of the patients with p53‐strongly positive tumors was significantly lower than that of those with p53‐negative tumors. Moreover, multivariate analysis indicated that both cyclin D1 and p53 overexpression are independent prognostic factors in patients with colorectal adenocarcinoma. In conclusion, both cyclin D1 and p53 overexpression may be useful predictors of disease recurrence in patients with colorectal adenocarcinoma. Int. J. Cancer 74:310‐315, 1997.

Cronkhite-Canada syndrome containing colon cancer and serrated adenoma lesions.

We describe a case of Cronkhite-Canada syndrome associated with sigmoid colon cancer, and provide a literature review. A 77-year-old man was diagnosed with sigmoid colon cancer after presenting with hypoproteinemia, nail atrophy, loss of scalp hair, hyperpigmentation, and gastrointestinal polyposis. The findings were consistent with Cronkhite-Canada syndrome. The colon polyps were histologically serrated adenomas, whose crypts showed a saw-toothed growth pattern with dysplasia, or tubular adenoma. Cronkhite-Canada syndrome associated with colon cancer has been reported in 31 cases. The availability of histologic material permitted reexamination of 25 of these cases. Serrated adenoma of the polypoid lesions was retrospectively found in 10 (40%) of the 25 cases. By comparison, the incidence of serrated adenomas has been estimated to occur in about 1% of all general polyps. Taken together, it is suggested that Cronkhite-Canada syndrome associated with colorectal cancer frequently has polyps containing serrated adenoma lesions. In the case described here, microsatellite instability and overexpression of the p53 protein were found in the cancer lesion and serrated adenoma lesions, and none of the lesions showed a loss of heterozygosity of various genes or K-ras mutations. Thus, genetic alterations between the serrated adenoma and the colorectal cancer was correlated in this case. These findings suggested the possibility of a serrated adenoma-carcinoma sequence in this case of Cronkhite-Canada syndrome.

Decrease in ICAM-1 expression on gastric cancer cells is correlated with lymph node metastasis.

Background. Lymph node metastasis is a frequent type of metastasis in patients with gastric cancer. The mechanisms responsible for this type of metastasis, however, are not clearly understood. We hypothesize that the immunosurveillance system between cancer cells and lymphocytes may be associated with the lymph node metastatic process. In this study, we examined the correlation between lymph node metastasis and intercellular adhesion molecule-1 (ICAM-1), which mediates the immunosurveillance system between tumor cells and cytotoxic lymphocytes, in gastric cancer. Methods. One hundred and forty-three specimens resected from patients with gastric cancer were investigated by staining with a monoclonal antibody against ICAM-1. We studied the correlation between the expression of ICAM-1 and various clinicopathologic factors, as well as infiltration of tumor-infiltrating lymphocytes (TILs). Results. ICAM-1 expression on gastric cancer cells was significantly decreased in patients with lymph node metastasis. The infiltration of TILs was associated with ICAM-1 expression level. The prognosis of patients with ICAM-1-negative tumors was poorer than the prognosis of those with ICAM-1-positive tumors. Conclusions. These findings suggest that ICAM-1 expression on cancer cells is closely associated with lymph node metastasis in gastric cancer, under the influence of the host immunosurveillance system.

Correlation between vascular endothelial growth factor C expression and lymph node metastasis in T1 carcinoma of the colon and rectum

AbstractPurpose. Vascular endothelial growth factor C (VEGF-C) is known to be associated with the development of the lymphatic vessel system. Recently, VEGF-C is thought to be correlated with lymph node metastasis in some malignant tumors. In this study, we investigated the correlation between VEGF-C expression and lymph node metastasis in early carcinoma of the colon and rectum. Methods. Two hundred and twenty-one endoscopically biopsied specimens from patients with T1 colorectal carcinoma prior to operation were investigated by an immunohistochemical study. Results. VEGF-C expression was more frequently observed in the tumors with nodal metastasis than in those without metastasis. Moreover, a multivariate analysis indicated that VEGF-C expression is an independent predictor of lymph node metastasis. Conclusion. VEGF-C staining using endoscopically biopsied specimens prior to operation could be of use in the prediction of lymph node metastasis and in preoperative selection of treatment in patients with T1 colorectal carcinoma.

A novel high-specificity approach for colorectal neoplasia: Detection of K-ras2 oncogene mutation in normal mucosa.

There is an important need for a high‐specificity approach to colorectal cancer. Approximately 50% of colorectal tumors contain K‐ras gene mutations, which occur as an early step in carcinogenesis. K‐ras mutations were detectable not only in tumors but also in microscopically normal colorectal mucosa close to carcinomas in some patients with colorectal cancer. This is the first systematic analysis of K‐ras mutations in normal colonic mucosa at multiple consistently‐selected locations. A total of 480 normal colonic mucosal samples were obtained from 80 subjects, including 65 patients with sporadic colorectal cancer and 15 controls in whom a colorectal neoplasm was ruled out endoscopically. Normal mucosal samples were obtained at multiple consistently‐selected locations using biopsy forceps during colonoscopy. Mutant allele‐specific amplification (MASA)‐PCR was performed; this could detect a K‐ras mutation in normal colonic mucosa even though it was only sparsely present. The K‐ras mutation was found in histologically normal mucosa from colorectal cancer patients (20 of 65 cases; 41 of 390 loci) by MASA‐PCR, especially frequent (51%; 19 of 37 cases) when the tumor showed a K‐ras mutation. In contrast, no mutation was found in normal mucosa from 15 controls (90 loci). K‐ras mutation in normal mucosa showed a significant association with the presence of colorectal cancer (p = 0.008). The specificity of the MASA‐PCR method for colorectal neoplasms was thus 100%. We conclude that detection of K‐ras mutations in normal colonic mucosa might serve as a high‐specificity approach to colorectal cancer.