Shinichi Tsutsui

Prognostic value of epidermal growth factor receptor (EGFR) and its relationship to the estrogen receptor status in 1029 patients with breast cancer

An epidermal growth factor receptor (EGFR) has been reported to be associated with a poor clinical outcome in breast cancer, while its prognostic value remains controversial. Immunohistochemical staining for EGFR was performed on frozen sections of primary breast cancer from 1029 patients with a mean follow-up duration of 46 months. EGFR was positive in 277 (26.9%) of 1029 cases, which inversely correlated with the estrogen receptor (ER) status. A univariated analysis indicated that EGFR had a significant prognostic value in both the disease free survival (DFS) and the overall survival (OS), while the same effect was also found in node negative as well as node positive breast cancer. A multivariate analysis indicated that EGFR was an independently significant prognostic factor for DFS (p = 0.0174) and OS (p = 0.0105) in all patients, but that EGFR demonstrated a prognostic significance only for DFS (p =0.0241) in node negative and only for OS (p = 0.0333) in node positive breast cancer. When all patients were stratified for EGFR and ER, a multivariate analysis indicated that the combination of EGFR(+)/ER(−) was an independently significant factor for both DFS and OS in node negative as well as node positive breast cancer. In conclusion, the prognostic value of EGFR was demonstrated by a multivariate analysis in a large series of breast cancer patients, but the value of EGFR was somewhat insufficient to achieve statistical significance for both DFS and OS in the subgroups divided by nodal status. On the other hand, the prognostic value of combination of EGFR and ER was sufficient to achieve statistical significance based on a multivariate analysis for both DFS and OS in the subgroups of node negative as well as node positive breast cancer patients.

Reduced Expression of PTEN Protein and Its Prognostic Implications in Invasive Ductal Carcinoma of the Breast

Objective: The PTEN tumor suppressor gene has been demonstrated to be inactivated in a variety of human tumors. In breast cancer, the PTEN gene mutation is not commonly found whereas loss of heterozygosity affecting the PTEN locus is frequently found. The aim of this study was to analyze PTEN protein expression in breast cancer and to evaluate the prognostic significance of PTEN protein expression. Methods: Paraffin-embedded sections ofinvasive ductal carcinoma of the breast were immunohistochemically stained for PTEN protein expression in 236 breast cancers. The immunohistochemical expression of breast cancer cells was judged to be either normal or reduced compared with the PTEN protein expression of the normal mammary gland. Results: The expression of PTEN protein was found to have decreased in 67 (28%) of 236 breast cancers. The reduced expression correlated with lymph node metastasis (p = 0.0371), but not with tumor size, nuclear grade, MIB-1 counts or p53 protein expression. Univariate analysis indicated that patients with a reduced PTEN expression had a shorter disease-free survival (DFS) than those with a normal PTEN expression (p = 0.0174). Univariate analyses also determined tumor size, lymph node metastases, nuclear grade, MIB-1 counts, p53 protein as well as PTEN protein expression to be significant factors for DFS, while multivariate analysis determined lymph node metastases and the MIB-1 counts to be independent significant factors for DFS. Conclusions: The inactivation of PTEN, demonstrated by a reduced expression of PTEN protein by immunohistochemistry, was found in about one third of all breast cancers. The reduced expression of PTEN protein correlated with lymph node metastases and a worse prognosis in the patients with breast cancer.

Multivariate analysis of postoperative complications after esophageal resection

To determine the contributing factors for eight postoperative complications after esophagectomy through a right thoracoabdominal approach, a multivariate analysis was carried out on preoperative and intraoperative variables in 141 patients with thoracic esophageal cancer. Although postoperative complications occurred in 125 patients, only 7 died of such complications. The multivariate analysis indicated that the retrosternal route was a significant factor predisposing to postoperative atelectasis. Age, preoperative arterial oxygen tension, and volume transfused were significant factors predisposing to postoperative hypoxemia, whereas age, routes other than the intrathoracic route, and volume transfused were significant factors predisposing to prolonged respiratory support. In addition, preoperative total serum bilirubin level and volume transfused were significant factors predisposing to postoperative hyperbilirubinemia; preoperative serum creatinine level was a significant contributing factor for postoperative renal insufficiency; and sex, antesternal route, and substituted colon were significant contributing factors for anastomotic leakage. There were no significant factors predisposing to postoperative pneumonia and liver dysfunction. These significant factors should be taken into consideration not only during perioperative management but also when choosing the operative procedures and extending the surgical indication for esophagectomy through a right thoracoabdominal approach.

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.

Resection margin for squamous cell carcinoma of the esophagus.

ObjectiveThe safe resection margin in esophagectomy for esophageal squamous cell carcinoma (SCC) was determined based on the extent of epithelial and subepithelial accessory lesions from the main lesions of esophageal SCC. BackgroundThere have been many reports on the high incidence of a positive resection margin for esophageal cancer. Although there were some studies on the relationships of the proximal clearance to postoperative local recurrence, no pathologic study on the resection margin has been reported. MethodsFour hundred twenty specimens of a whole resected esophagus were examined histopathologically and the longitudinal length from the main lesion to the five types of accessory lesions was measured on microscopic slides. ResultsContiguous intraepithelial carcinoma existed in 69 (46%) of 150 sites of main lesions restricted to the mucosa or submucosa and subepithelial lesions existed in 131 (54%) of 245 sites and 82 (55%) of 150 sites of main lesions invading an adventitia and into neighboring structures, respectively. The risk of a positive resection margin due to subepithelial lesions was below 5% at 10 mm in the main lesion, restricted to the submucosa or the muscularis propria, and at 30 mm in the main lesion, invading the adventitia in the potentially curative operation cases. ConclusionThese clearances of the resection margin, in which the risk of a positive resection margin is below 5%, are acceptable, although these clearances should only be accepted after the extent of epithelial accessory lesions is accurately determined by the Lugols stain method.

Angiopoietin 2 expression in invasive ductal carcinoma of the breast: its relationship to the VEGF expression and microvessel density

SummaryAngiopoietin (Ang) is a ligand for the endothelium-specific tyrosine kinase receptor Tie-2, while a shift in the Ang-1:Ang-2 expression ratio in favor of Ang-2 was found to be associated with tumor angiogenesis. In the present study, we analyzed the immunohistochemical expression of Ang-2 in a series of 198 breast cancers, in which VEGF expression and microvessel density (MVD) were previously determined. Ang-2 expression was negative in 24 (12%), positive in 50 (25%) and strongly positive in 124 (63%) of 198 cases. A significant correlation was found between Ang-2 and VEGF expressions (p=0.0004) and between Ang-2 expression and MVD (p=0.0006), while a high MVD was found in 10 (77%) of 13 tumors with a strongly positive VEGF and positive Ang-2 expression and in 40 (71%) of 56 tumors with a strongly positive VEGF and strongly positive Ang-2 expression. Although there was no difference in the disease free survival (DFS) stratified according to Ang-2 expression alone, the 69 patients with a strongly positive VEGF and a strongly positive or positive Ang-2 expression had a significantly (p=0.0316) worse DFS than those with other combinations of VEGF and Ang-2 expressions. A multivariate analysis indicated lymph node metastasis and MVD to be independently significant prognostic factors for DFS, while the combination of VEGF and Ang-2 expressions was not a significant factor for DFS. In conclusion, the Ang-2 expression was found to be closely correlated with VEGF expression and MVD in breast cancer, while a high MVD was frequently found in tumors with a high expression of both VEGF and Ang-2. The survival analysis demonstrated a high MVD, which was induced by a high expression of both VEGF and Ang-2, to therefore have a strong prognostic significance in breast cancer.

Prognostic value of microvessel density in invasive ductal carcinoma of the breast.

BackgroundAlthough the prognostic value of microvessel density (MVD) has been studied in breast cancer, the results still remain controversial.Patients and MethodsParaffin embedded sections of invasive ductal carcinoma of the breast were immunohistochemically stained for factor VIII-related antigen in 252 patients with a median follow-up duration of 7.0 years. MVD quantification of the three most vascular areas at a magnification of x 200 was performed.ResultsThe 252 patients were stratified into high and low MVD groups according to a cut-off value that was the upper one-third MVD value of all patients. The patients with a high MVD had a significantly worse outcome in terms of both disease free survival (DFS)(p < 0.0001) and overall survival (OS) (p = 0.0012) compared with those with a low MVD. The same effects were seen in patients with lymph node negative as well as positive breast cancer. Multivariate analyses indicated the nodal status, nuclear grade and MVD (p = 0.0001) to be independent prognostic factors for the DFS, while the nodal status, estrogen receptor status, tumor size and MVD (p = 0.0006) were independent prognostic factors for the OS.ConclusionMVD was found to be an independent prognostic indicator of recurrence and death for breast cancer, and is therefore considered to be a useful factor for selecting high risk patients to receive adjuvant therapies.

Carcinogenesis and histogenesis of esophageal carcinoma.

Dysplasia is one of the most important subjects regarding carcinogenesis of the esophagus, because there is continuing controversy as to whether esophageal dysplasia is a cancerous lesion or a noncancerous lesion.

What is the earliest malignant lesion in the esophagus

The incidence of early esophageal cancer is definitely increasing due to recent advances in diagnostics. When we discuss early carcinoma of the esophagus, however, there is still controversy as to whether dysplasia is either benign or the earliest malignant lesion.

Plasma D-dimer level as a mortality predictor in patients with advanced or recurrent colorectal cancer.

Objective: Plasma D-dimer levels are elevated in patients with a variety of solid tumors. Recently, it has been reported that the level before curative surgery is a prognostic factor for colorectal cancer (CRC). We investigated whether the plasma D-dimer level before systemic chemotherapies is a predictor for advanced or recurrent unresectable CRC. Methods: This study included 42 patients treated with systemic chemotherapies for advanced or recurrent unresectable CRC. Variables including clinicopathological factors, plasma D-dimer levels and the modified Glasgow Prognostic Factor Score (mGPS) were evaluated. Results: The plasma D-dimer level was closely related to the mGPS. Survival was shorter for patients with plasma D-dimer levels >5 µg/ml than for those with lower levels. Compared with an mGPS of 0 or 1, an mGPS of 2 was predictive of poor prognosis (p < 0.0001). Old age, advanced stage, plasma D-dimer level and mGPS were significantly associated with mortality, but plasma D-dimer level was the only independent risk factor in multivariate analysis, and was significant related to the clinical response to chemotherapy (p < 0.05). Conclusions: Survival was significantly shorter in patients with elevated plasma D-dimer levels having advanced or recurrent CRC. The plasma D-dimer level before systemic chemotherapies was an independent mortality predictor.