Kaoru Kitamura

Clinical significance of vascular endothelial growth factor‐C (VEGF‐C) in breast cancer

Vascular endothelial growth factor‐C (VEGF‐C) is a specific ligand which induces lymphangiogenesis. We examined the expression of VEGF‐C protein to determine its role in the progression of breast cancer. Immunohistochemical analysis revealed that VEGF‐C was overexpressed in 39 of 98 breast cancer specimens (39.8%) but not in adjacent normal mammary glands. The expression of VEGF‐C showed a significant correlation with lymphatic vessel invasion (p=0.0004). It is noteworthy that the 5‐year disease free survival rate of the VEGF‐C positive group was significantly poorer than that of negative group (p=0.0356). We suggest that as expression of VEGF‐C is not implicated in lymphatic spread, it may prove to be a promising marker to predict the recurrence of breast cancer.

Relationship between preoperative assessment of organ function and postoperative morbidity in patients with oesophageal cancer

OBJECTIVE To find out if strict assessment of organ function preoperatively predicted morbidity and mortality in patients being operated on for oesophageal carcinoma. DESIGN Retrospective study. SETTING Teaching hospital, Japan. SUBJECTS 178 patients operated on for oesophageal cancer 1989-1993. INTERVENTIONS Oesophagectomy and reconstruction (using either stomach or colon) in one stage by a right thoracoabdominal approach in 173, and transhiatal resection in 5 with either poor pulmonary reserve or early lesions. MAIN OUTCOME MEASURES Correlation between preoperative assessment of organ function and postoperative development of complications. RESULT 79 patients (44%) developed complications and 6 died (3%). Pulmonary dysfunction preoperatively was significantly associated with the development of all complications (p=0.001) and of postoperative pulmonary complications (p=0.04). No other preoperative assessment correlated significantly with the development of postoperative complications. CONCLUSION Accurate preoperative assessment of pulmonary function is a valuable indicator of postoperative morbidity.

Endoscopic diagnosis of early carcinoma of the esophagus using Lugol's solution

Small esophageal lesions, particularly intraepithelial cancers, are extremely difficult to detect. We used Lugols iodine solution with panendoscopic examination to detect the presence and spread of small squamous cell carcinomas of the esophagus. Serial histologic specimens of the surgically removed esophagus from 32 patients with Lugols combined endoscopic diagnosis of early esophageal carcinoma were examined to determine the correlation between endoscopic and histologic findings. All of the early staged carcinomas clearly remained unstained by Lugols solution. We believe that the application of Lugols solution will greatly aid in instances when a suspicious mucosal lesion is noted, when the margin of the lesion is unclear, or when there is suspicion that a mucosal lesion may have been overlooked.

Diminished expression of ING1 mRNA and the correlation with p53 expression in breast cancers

p33(ING1) is a novel candidate tumor suppressor and its overexpression induces growth arrest or apoptosis in different cell lines. These functions of p33(ING1) depend largely on the activity of p53, and p53-dependent activation of the transcription from the p21/WAF1 promoter also requires p33(ING1). We examined the expression of ING1 mRNA in breast cancer cell lines and clinical breast cancer tissues, using quantitative RT-PCR and real time TaqMan technology. In breast cancer cell lines, ING1 mRNA was expressed at almost the same level. However, in a comparison between the cancer and matched normal tissues, a significant decrease in ING1 mRNA expression was found in 17 of 24 (70.8%) breast cancer tissues. We also examined the correlation between ING1 mRNA expression and p53 expression. There was a significant decrease of ING1 mRNA in nine of 15 tumors negative for p53 immunostaining, most of which were considered to have wild type p53. In these tumors, p53 may not function in case of a decreased expression of p33(ING1), and the lack of cell cycle regulation may correlate with the carcinogenesis and tumor progression.

Hyperthermia combined with chemotherapy and irradiation for patients with carcinoma of the oesophagus—A prospective randomized trial

From 1988 to 1990, 53 patients with squamous cell carcinoma of the thoracic oesophagus underwent subtotal oesophagectomy after either preoperative hyperthermo-chemoradiotherapy (HCR therapy) or chemoradiotherapy without hyperthermia (CR therapy), in a prospective randomized trial carried out to examine the effects of hyperthermia given preoperatively. The two groups (27 patients given HCR therapy and 26 given CR therapy) were found to be comparable with regard to prognostic factors of age, site of carcinoma, TNM stage, etc. Following preoperative evaluation by an upper GI series and endoscopy, a subtotal oesophagectomy was done for all 53 patients. All the resected specimens, including the lymph nodes, were histopathologically examined, and the effects of preoperative treatment were evaluated by findings in the upper GI series and endoscopy, as well as based on the histopathology of the excised tissues. There were no viable cancer cells in the resected specimens of seven patients in the HCR therapy group (26.9%) and of two patients in the CR therapy group (7.7%). In addition, no hyperthermia complications were observed. The study suggests that preoperative HCR therapy may be a more beneficial therapy than preoperative CR therapy in patients with squamous cell carcinoma of the oesophagus who undergo a subtotal oesophagectomy.

ENDOSCOPIC CORRECTION OF INTUSSUSCEPTION AND REMOVAL OF A COLONIC LIPOMA

Colonic lipomas are rare, but are the most common benign tumors except for adenomatous polyps.l Lipomas usually arise from the submucosa and range in size from a few millimeters to several centimeters. There is a similarity between the clinical presentation of some lipomas and other tumors. If the lesion can be confirmed to be benign and if the diameter of the base of the tumor is less than that of the lesion, endoscopic polypectomy can be an effective management. We report endoscopic polypectomy of a large lipoma in the colon following endoscopic correction of an intussusception.

Frequency of Microsatellite Instability inBreast Cancer Determined by High-Resolution Fluorescent Microsatellite Analysis

In breast cancer, the rates of positivity for microsatellite instability (MSI), vary greatly in the literature. Using high-resolution fluorescent microsatellite analysis (HFRMA), we studied microsatellite alterations in 75 patients with sporadic breast cancer. In this system, several devices were prepared to improve reproducibility of polymerase chain reaction products, migration accuracy of electrophoresis, and characteristics of the detection system. Precise and objective analyses of microsatellite alterations are made feasible using HRFMA. Seven of the 75 cases were judged to be positive for MSI, the rate of positivity being 9.3%. This rate is relatively low compared to the data in the literature. All the microsatellite changes observed in this system can be classified into two types: type A with relatively small changes in microsatellite sequences observed in limited loci and type B with drastic and widely dispersed changes. The former was thought to be connected to abnormal activity in DNA mismatch repair (MMR). Among the 7 cases, 6 (8.0%) had type A alterations, which means that the tumors may have an abnormal MMR activity. Application of precise and objective systems for microsatellite analysis is expected to be clinically useful to detect patients at high risk for cancers.

Prognostic factors in patients with submucosal carcinoma of the oesophagus

To clarify the prognostic factors in patients with submucosal carcinoma of the oesophagus, we examined the results of surgical treatment for 78 cases over the last decade. The clinicopathological factors including age, sex, location of the tumour, length of the tumour, histological differentiation, subclassification of depth, lymphatic or blood vessel invasion, intramural metastasis and lymph node metastasis were all analysed. Then the correlation between these factors and prognosis was investigated. As a result, significant differences were observed in the survival rates between the groups regarding lymphatic vessel invasion (P = 0.0003), intramural metastasis (P = 0.0051) and lymph node metastasis (P = 0.0026). According to a multivariate analysis, intramural metastasis (P = 0.0038, relative risk 9.17), vessel invasion (P = 0.0033, relative risk 6.25) and lymph node metastasis (P = 0.0187, relative risk 3.62) were found to be independent prognostic factors. The prognosis of the patients with at least one of these factors was significantly poorer than that without. The five-year survival rate of the patients without these factors was as good as that with mucosal carcinoma of the oesophagus. Based on our findings, vessel invasion, intramural metastasis and lymph node metastasis are thus considered to be significant prognostic factors in patients with submucosal carcinoma of the oesophagus.

Proliferative activity of cancer cells in front and center areas of carcinoma in situ and invasive sites of esophageal squamous‐cell carcinoma

Intraepithelial carcinoma contiguous with invasive squamous‐cell carcinoma is a conspicuous feature of esophageal cancer. However, whether the mechanism of intraepithelial spreading is due to cell proliferation or field carcinogenesis has yet to be clarified. This study investigated the mechanism of intraepithelial spreading by measuring the cell proliferative activity using argyrophilic nucleolar organizer region (AgNOR) and proliferating cell nuclear antigen (PCNA)‐positive cell counting. We examined the AgNOR number and PCNA‐positive ratio (PCNA ratio) in the center and outer edge of intraepithelial carcinoma and in the center and deep margin of invasive squamous‐cell carcinoma of the esophagus in 50 specimens from 18 cases of esophageal squamous‐cell carcinoma concomitant with contiguous intraepithelial carcinoma. The proliferative activity was thus found to differ between the normal epithelium and cancerous lesions (p < 0.001), between intraepithelial carcinoma and invasive cancer (p < 0.001) and between deep margin and center areas of invasive cancer (p < 0.005). On the other hand, such activity was observed to be similar in the center and outer edge of the intraepithelial spread. These findings suggest that cell proliferation is the main mechanism of tumor progression at the invasive site of cancer, whereas in intraepithelial carcinomatous areas, “field carcinogenesis” or a paracrine mechanism, and not cell proliferation, is thought to be the cause of intraepithelial spread of esophageal cancer. These results therefore support the concept of field carcinogenesis. Int. J. Cancer 78:149–152, 1998.© 1998 Wiley‐Liss, Inc.

Improved surgical results after combining preoperative hyperthermia with chemotherapy and radiotherapy for patients with carcinoma of the rectum

PURPOSE: The aim of this study is to evaluate long-term results of preoperative hyperthermia combined with chemotherapy and irradiation (HCR therapy) in patients with carcinoma of the rectum. METHODS: Postoperative prognoses were compared among 36 patients with carcinoma of the rectum, who were given preoperative HCR therapy followed by surgery, and 52 patients undergoing surgery alone without any preoperative therapy. RESULTS: There were significant differences in the prognosis between patients given preoperative HCR therapy plus surgery and those having surgery alone, and five-year survival rates were 91.3 and 64 percent, respectively. Particularly, for patients with tumors invading beyond the muscularis propria and/or with positive lymph node metastasis, a significantly longer survival was obtained with HCR plus surgery than in surgery alone (86.5vs.50.9 percent and 92.9vs.51.7 percent, respectively). However, no significant differences were observed in the postoperative prognosis for cases with no lymph node metastasis and/or with tumors limited to the muscularis propria between these two groups. CONCLUSIONS: These data clearly demonstrated the effectiveness of preoperative HCR therapy for improving long-term results of patients with carcinoma of the rectum, especially those demonstrating an advanced stage of disease.