Bunzo Nakata

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.

Microvessel quantitation in invasive breast cancer by staining for factor VIII-related antigen

The clinical importance of microvessel quantitation as a prognostic indicator in invasive breast cancer was examined. This study included 155 patients with invasive breast cancer, with a median follow-up of 82 months. Microvessels were identified by immunohistochemical staining for factor VIII-related antigen in formalin-fixed, paraffin-embedded primary tumours. For each tumour, microvessels were counted within a 200 x magnification field in the area of highest microvessel density. Microvessel counts (MVCs) had no correlation with tumour size, lymph node status or histological grade. When patients were classified by MVC, higher counts were associated with shorter disease-free survival and overall survival (P < 0.025 and P < 0.01 respectively). Multivariate analysis showed that MCV is an independent prognostic factor. Microvessel quantitation may be a useful predictor for identifying breast cancer patients at high risk for relapse and death.

Diagnostic usefulness of FDG PET for pancreatic mass lesions

The purpose of this study was to investigate the feasibility of [18F]2-deoxy-2-fluoro-d-glucose (FDG) positron emission tomography (PET) in patients with a pancreatic mass by comparing the results with those of X-ray computed tomography (CT) and magnetic resonance (MR) imaging.Methods: Eighty-six patients with pancreatic lesions, included 65 malignant tumors and 21 benign masses (55 masses were proven histologically and the others were diagnosed clinically), were studied. The diagnostic factors of CT and MR imaging were evaluated, and those of FDG PET were also evaluated for malignant and benign masses by visual interpretation and quantitative interpretation with the standardized uptake value (SUV) and SUV gluc which was designed to reduce the effects of a high blood sugar level. Visual interpretations were evaluated only in FDG PET images, and quantitative interpretations were evaluated by referring to CT and/or MR imaging. The correlation between SUV and the degree of histological differentiation in pancreatic ductal adenocarcinoma was investigated.Results: Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy for CT imaging were 91, 62, 88, 68 and 84%, and for MR imaging 78, 70, 88, 54 and 76%, respectively. In visual interpretation of FDG PET images, the sensitivity, specificity, PPV, NPV and accuracy were 82, 81, 93, 59 and 81%, respectively. Significant differences between malignant and benign lesions existed in SUV and SUV gluc (p<0.0001, each). With the cutoff value of SUV as 2.1 and SUV gluc as 2.2, the accuracy of diagnosis was maximal. With that cutoff value, the sensitivity, specificity, PPV, NPV and accuracy for SUV were 89, 76, 92, 70 and 86%, and for SUV gluc 91, 76, 92, 73 and 87%, respectively. The sensitivity and NPV of SUV gluc were higher than those of SUV, which suggests that SUV gluc may be more useful in reducing the number of overlooked malignant tumors. The specificity and PPV of FDG PET were superior to those of CT and MR imaging. There were no significant differences between the SUVs of moderately differentiated adenocarcinomas and those of well differentiated adenocarcinomas.Conclusion: To improve the diagnostic procedure for classifying masses, FDG PET with not only SUV but also SUV corrected by the blood sugar level is required in addition to morphological diagnosis by CT and/or MR imaging.

The detection of human pancreatic cancer‐associated antigen in the serum of cancer patients

A radioimmunoassay (RIA) test for human pancreatic cancer‐associated antigen (Span‐1) was developed to evaluate the diagnosis of various gastrointestinal disorders. Serum Span‐1 in normal subjects ranged from 5 to 275 U/ml, with a mean of 58.8 U/ml (±58.7, standard deviation). All control subjects had levels of less than 400 U/ml. Study subjects, 93% with pancreatic cancer, 59% with hepatobiliary cancers, 23% with gastric cancers, and 13% with colonic cancers had serum Span‐1 levels greater than 400 U/ml. Sensitivities of Span‐1, CA 19‐9, and Dupan‐2 for pancreatic cancer were 94%, 85%, and 38% respectively. Span‐1 in patients with Stage I pancreatic cancer showed a 50% positive rating but CA 19‐9 and Dupan‐2 showed only 0% and 25%. Although a positive rating of these three antibodies increased in advanced cases, Span‐1 showed the highest positive rating. Span‐1 reacted with colonic cancer tissues with Lewisa−b− phenotype. However, none of these tissues did not react against CA 19‐9. From these results, Span‐1 has a good predictive value for detecting pancreatic cancer compared with CA 19‐9 and Dupan‐2.

HER2 overexpression correlates with survival after curative resection of pancreatic cancer.

HER2 overexpression has been linked to clinical outcomes in several solid tumors, such as breast cancer. However, the correlation between HER2 overexpression and survival in pancreatic carcinoma remains unclear. The impact of HER2 overexpression on survival in pancreatic ductal cancer was examined. Immunohistochemical staining of 129 pancreatic cancers without hematogenous metastases or peritoneal dissemination treated by macroscopically curative resection were analyzed in association with survival data. To determine HER2 overexpression in this pancreatic cancer series, the polyclonal antibody included in HercepTest, which is used worldwide for clinical examination of HER2 overexpression in breast cancer, was used. Immunoreactivity was classified according to the scale presented in the HercepTest Scoring Guidelines. Twenty‐two cases (17.1%) had a score of 0, 28 cases (21.7%) had of a score of 1+, 41 cases (31.8%) had a score of 2+, and 38 cases (29.4%) had a score of 3+. Therefore, HER2 overexpression (score 2+ or 3+) was observed in 79 cases (61.2%). Patients with HER2 overexpression tumors had significantly shorter survival times than those with HER2 normal expression (score 0 or 1+) tumors (median survival time, 14.7 vs 20.7 months, respectively; P = 0.0078 on the log‐rank test). On multivariate survival analysis, HER2 overexpression remained an independent prognostic factor (hazard ratio, 1.806; P = 0.0258). A significant percentage of pancreatic cancers were demonstrated to have HER2 overexpression, and overexpression of this tyrosine kinase receptor proved to be an independent factor for a worse prognosis. These results should encourage further investigation of treatments using new molecular targeting agents against HER2 protein to improve the survival of pancreatic cancer patients. (Cancer Sci 2009; 100: 1243–1247)

Expression of p53 and Vascular Endothelial Growth Factor Associated with Tumor Angiogenesis and Prognosis in Gastric Cancer

Recently, it has been reported that p53 tumor suppressor gene plays an important role in controlling tumor angiogenesis by regulating expression of vascular endothelial growth factor (VEGF), which is a well-characterized angiogenic inducer. In this study, we investigated these antigens’ expression together with microvessel density, and investigated their clinical importance. One hundred twenty specimens resected from patients with gastric carcinoma were investigated using immunohistochemical methods. p53 and VEGF expression was observed in 42 and 35% tumors, respectively. p53 and VEGF staining status was coincided in 72% tumors, and a significant correlation was found between p53 and VEGF status. The microvessel density, determined by immunostaining for factor VIII-related antigen, was significantly higher in p53-positive or VEGF-positive tumors. According to prognosis, patients with p53-positive tumors had significantly worse survival than those with p53-negative tumors. There was also a significant worse survival in the patients with VEGF-positive tumors than those with VEGF-negative tumors. Moreover, the 5-year survival rate was lowest in the patients with p53-positive and VEGF-positive tumors, while it was highest in the patients with p53-negative and VEGF-negative tumors. In conclusion, both p53 and VEGF significantly correlated with tumor vascularity and prognosis in patients with gastric carcinoma.

Combined analysis of vascular endothelial growth factor and platelet-derived endothelial cell growth factor expression in gastric carcinoma

Solid tumours require neovascularization for growth and metastasis. Both vascular endothelial growth factor (VEGF) and platelet‐derived endothelial cell growth factor (PD‐ECGF) are well‐characterized inducers of angiogenesis. In this study we examined the expressions of these antigens and their relationship with microvessel density and also determined their prognostic significance. Ninety‐five specimens resected from patients with gastric carcinoma were investigated using immunohistochemical methods. Microvessel density, determined by immunostaining for factor VIII‐related antigen, was significantly higher in tumours that were both VEGF+ and PD‐ECGF+ than in tumours that were both VEGF− and PD‐ECGF−. According to prognosis, patients with VEGF+ tumours had a significantly worse prognosis than did those with VEGF− tumours. Although there was no significant correlation between PD‐ECGF expression and prognosis, patients with PD‐ECGF+ tumours tended to have a shorter survival than did those with PD‐ECGF− tumours. Moreover, the frequency of hepatic recurrence was significantly higher in patients with tumours that were both VEGF‐positive and PD‐ECGF+ than in all other patients. Int. J. Cancer 74:545–550, 1997.

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.

Immunohistochemical Assessment for Estrogen Receptor and Progesterone Receptor Status in Breast Cancer : Analysis for a Cut-off Point as the Predictor for Endocrine Therapy

BackgroundAn immunohistochemical (IHC) method is commonly used for determining estrogen receptor (ER) and progesterone receptor (PR) status in breast cancer. However, the proper cut-off points of IHC have not been established. Cut-off points for ER and PR status as predictive factors for endocrine therapy are needed.MethodsA total of 249 cases of female breast cancer were enrolled. ER and PR status by IHC were analyzed using the proportion of stained cells and staining intensity by Allred’s score.ResultsProportion score (PS) and intensity score (IS) were related to enzyme immunoassay (EIA) titers, for both in ER and PR(p < 0.0001, all). PS correlated with IS in both ER and PR (R=0.47 and 0.41,respectively). ER status by IHC was related to tumor size and lymph node status, while PR was related to tumor size and menopausal status. In 152 patients who received endocrine therapy with a median follow-up term of 38 months, differences in disease-free survival were most significant using a cut-off point of PS 3 which indicated more than 10% of cells stained positively for both ER and PR(p = 0.0007 and 0.0087, respectively). In addition, combination analysis of ER and PR using this cut-off point revealed a notable prognostic difference.ConclusionA 10% staining proportion may be an acceptable cut-off point for both ER and PR status by IHC, in terms of predicting response to endocrine therapy in breast cancer.