Hiroshi Yoshimura

Prognostic Impact of Hypoxia-Inducible Factors 1α and 2α in Colorectal Cancer Patients: Correlation with Tumor Angiogenesis and Cyclooxygenase-2 Expression

Purpose: Angiogenesis plays an important role in a multitude of biological processes including those of tumorigenesis and cancer progression. Hypoxia is the prime driving factor for tumor angiogenesis and the family of hypoxia-inducible factors (HIFs) plays a pivotal role in this process. The role of HIF in tumor angiogenesis has been underscored in different carcinomas but yet to be reported for colorectal carcinomas. Experimental Design: In this study, we examined HIF [HIF-1α (HIF1) and HIF-2α (HIF2)] expression in 87 curatively resected colorectal carcinoma samples, and the results were correlated with clinicopathological factors, microvessel density, cyclooxygenase 2 expression, and patient prognosis. Results: HIF1 (44.8%) was more frequently expressed than HIF2 (29.9%). Most of the clinicopathological factors representing the tumor aggressiveness were significantly correlated with overexpression of HIF2 but not with HIF1 expression. HIF2 expression had direct correlation with microvessel density and cyclooxygenase 2 expression. and, in contrast, HIF1 expression had a weak but significant inverse correlation in T1 and T2 tumors only. HIF2 expression alone and the combined expression of HIF1 and HIF2 had significant impact on patient survival. In the multivariate analysis, however, only the combined expression of HIF1 and HIF2 remained independently significant. Conclusions: Taken together, our results suggest that HIF2 expression may play an important role in angiogenesis and that the combined expression of HIF1 and HIF2 may play an important role in tumor progression and prognosis of colorectal carcinomas. Therefore, HIF expression could be a useful target for therapeutic intervention.

Downregulation of KiSS‐1 expression is responsible for tumor invasion and worse prognosis in gastric carcinoma

KiSS‐1 is a promising candidate tumor‐suppressor gene and may play a key role in the metastatic cascade. The expression profile and the role of KiSS‐1 in cancer progression are largely unknown in most of the cancers, including gastric cancer. In this study, KiSS‐1 expression was evaluated by RNase protection assay and localization was done by in situ hybridization in 40 gastric cancers and their adjacent normal gastric mucosa. For comparison with clinicopathologic characteristics and patient prognosis, all patients were divided into 2 groups having high and low KiSS‐1 expression by using the median as the cutoff value of KiSS‐1 expression as determined by the RNase protection assay. Gastric cancers with low KiSS‐1 had frequent venous invasion, distant metastasis and tumor recurrence. Accordingly, patients with low KiSS‐1‐expressing tumors had a significantly worse overall and disease‐free survival. In multivariate analysis, KiSS‐1 became the strongest independent prognostic factor among the conventional prognosticators for gastric cancer patients. Collectively, these findings suggest that KiSS‐1 may play a crucial role in gastric cancer invasion and could be a useful target for therapeutic intervention.

Expression and prognostic significance of PTEN product protein in patients with esophageal squamous cell carcinoma

PTEN is a candidate tumor‐suppressor gene in a variety of malignant tumors. The prognostic importance of PTEN product protein (PTEN) and its correlation with clinicopathologic characteristics have yet to be delineated in patients with esophageal carcinoma.

Esophageal Resection in Elderly Esophageal Carcinoma Patients: Improvement in Postoperative Complications

BACKGROUND Advanced age is considered to be a relative contraindication for radical esophagectomy with a three-field lymph node dissection. METHODS Preoperative risks, postoperative morbidity and mortality, and long-term survival in 55 elderly patients (> or =70 years) who had undergone extensive esophagectomy for esophageal carcinoma were compared with those of 149 younger patients (<70 years). RESULTS Elderly patients had worse preoperative cardiopulmonary function and had more frequent postoperative cardiopulmonary complications compared with younger patients (p < 0.05). The postoperative death rate was not statistically different between the elderly (10.9%) and younger groups (5.4%). When the study period was divided into an early and a late phase, the postoperative death rate dropped significantly (p < 0.05) in recent years (1.4%) when compared with the previous era (10.0%). The overall survival rates were not different between elderly and younger patients. CONCLUSIONS Preoperative cardiopulmonary risk factors and postoperative complications after esophagectomy were more frequently noticed in elderly patients than in younger patients. A dramatic improvement in postoperative death was noticed in recent years. The long-term survival of elderly patients after extended esophagectomy was almost similar to that in younger patients.

Clinicopathological features of superficial squamous cell carcinoma of the esophagus

BACKGROUND The depth of penetration is the crucial factor determining the prognosis of esophageal carcinoma patients. Patients with superficial esophageal carcinoma have a significantly favorable clinical course compared with those with advanced cancers. The outcome for patients with mucosal cancer is excellent with a 5-year survival rate exceeding 80%. On the other hand, submucosal cancer often metastasizes to lymph nodes or other organs, and the prognosis of these patients is far from satisfactory. METHODS Among 165 patients with squamous cell carcinoma of the esophagus, surgically resected between December 1979 and April 1995, 30 patients (18.2%) had superficial esophageal carcinoma (SEC) confined to the epithelium, lamina propria mucosa, or submucosa. Disease profile and clinicopathological characteristics of these 30 patients were studied. RESULTS The incidence of SEC has increased from 6.3% (2 of 32) in the first 5-year period (1979 to 1984) to 27.4% (20 of 73) in the recent 5-year period (1991 to 1995). Subjective symptoms were present in 2 (13.3%) with 15 mucosal cancers and in 4 (26.7%) with 15 submucosal cancers. The remaining 24 patients (80%) had no subjective symptoms. Twenty-two patients (73.3%) were diagnosed to have the lesions by endoscopic examination at the time of screening for gastric problems, and only 3 were detected by gastrointestinal series. None of the 15 patients with mucosal cancer had lymphatic invasion, venous invasion, or lymph node metastasis. On the other hand, in those with submucosal cancers, 9 (60%) had lymphatic invasion, 5 (33.3%) venous invasion, and 8 (53.3%) lymph node metastases. Twenty-two patients are alive without recurrence. The 3- and 5-year survival rates are 86.7% and 86.7% for patients with mucosal cancer and 72.2% and 65.0% for those with submucosal cancer, respectively. CONCLUSION Esophagectomy with wide lymphadenectomy should be carried out for submucosal cancer, whereas esophagectomy with moderate lymphadenectomy can be preferred for mucosal cancer.

Clinicopathologic Features of Superficial Esophageal Cancer: Results of Consecutive 100 Patients

BackgroundThe depth of tumor penetration is a crucial factor in determining the prognosis of patients with esophageal carcinoma. Patients with superficial esophageal carcinoma (SEC) have a far more favorable clinical course compared with those with advanced cancers. The outcome for patients with mucosal cancer is excellent with a 5-year survival rate exceeding 80%. On the other hand, submucosal cancer often metastasizes to regional and/or distant lymph nodes or other organs, and the prognosis of these patients are far from satisfactory.MethodsAmong 334 patients with esophageal cancer who underwent surgery between December 1980 and December 2006, 100 patients (30%) had SEC confined to the epithelium, lamina propria mucosa, or submucosa. Patient and tumor characteristics of those 100 patients were studied.ResultsThe prevalence of SEC has increased from 13% (8 of 61) in the initial 5-year period (1985–1989) to 44% (41 of 93) in the recent 7-year period (2000–2006). Subjective symptoms were present in 7 (14%) of 51 mucosal cancers and in 13 (27%) of 49 submucosal cancers. The remaining 80 patients (80%) had no subjective symptoms. Ninety-one patients (91%) were diagnosed to have the lesions by endoscopy at the time of screening for gastric problems, and only nine were detected by gastrointestinal series. Four of 51 patients with mucosal cancer had venous or lymph vessel invasion, and among those, only one (2%) had a solitary perigastric lymph node metastasis. In 49 patients with submucosal cancer, 35 (71%) had lymph vessel invasion, 28 (57%) had venous invasion, and 16 (33%) had lymph node metastases. In particular, 15 of 35 patients with positive lymph vessel invasion had lymph node metastasis, whereas only 1 of 14 with negative lymph vessel invasion had lymph node metastasis (P < .05). Among 17 patients with nodal involvement, 4 patients with upper thoracic SEC had upper mediastinum and/or cervical nodal metastases, 11 patients with middle thoracic SEC had widespread upper and lower mediastinal and abdominal metastases, and 2 patients with lower thoracic SEC had lower and abdominal lymph node metastases. Seventy-nine patients were alive without recurrence at last follow-up. Five of 49 patients with submucosal cancer died of recurrent disease, and 4 of these developed regional nodal recurrence around the bilateral laryngeal recurrent nerves. Forty-two patients (42%) developed double cancers during the follow-up period, and 5 died of a second cancer. The 3- and 5-year survival rates of all 100 patients were 85% and 73%, and those disease-specific survival rates were 96% and 93%, respectively. The 3- and 5-year survival rates for patients with mucosal cancer were 89% and 83%, and those for submucosal cancer were 80%, and 64%, respectively.ConclusionsEsophagectomy with extensive lymphadenectomy should be carried out particularly for upper thoracic submucosal cancer, whereas esophagectomy with moderate lymphadenectomy may be preferred for mucosal cancer. Patients with SEC should be examined for another primary cancer preoperatively and periodically during follow-up.

Lymph node classification of esophageal squamous cell carcinoma and adenocarcinoma

The lymphatic channels of the esophagus run vertically along the axis of the esophagus and some of them drain into the cervical lymph glands upwards and into the abdominal glands downwards, and the pattern of lymph node metastasis of esophageal carcinoma is widespread. In various classifications of pattern of lymphatic spread, four classifications were proposed; location, number, ratio, and size. No definite survival advantage of aggressive lymph node dissection during esophagectomy has been proved compared with less dissection. Stage migration, micrometastasis, and sentinel lymph node concept all make it possible to individualize surgical management of esophageal carcinoma as a part of various multimodal treatments. Early diagnosis, standardization of surgery including routine lymph node dissection, and perioperative management of patients have all led to better survival rates of esophageal carcinoma.

Overexpression of transforming growth factor-β1 in scirrhous carcinoma of the stomach correlates with decreased survival

A retrospective study of 50 patients with scirrhous carcinoma of the stomach who had undergone surgery was performed to elucidate whether immunohistochemical overexpression of transforming growth factor-β1 (TGF-β1) could predict the patients’ survival. To evaluate the proliferative activity of the tumor, the proliferating cell nuclear antigen (PCNA) index was used. Expression of TGF-β1 was low in 27 patients and high in 23. Clinicopathological characteristics were not significantly different between the two groups with high and low TGF-β1 expression. Tumors with higher TGF-β1 expression had higher PCNA indices (p = 0.0467, unpaired Student’s t test). The 5-year survival rate was 40.4% for the low TGF-β1 group and 28.7% for the high TGF-β1 group (p = 0.0388, log rank test). By multivariate analysis, pT, residual tumor, and TGF-β1 were the independent prognostic factors. These results suggest that immunohistochemical expression of TGF-β1 is one of the useful predictors for estimating the patients’ survival in scirrhous carcinoma of the stomach particularly of the T3 and T4 stages.

Prognostic significance of Fas and Fas ligand system-associated apoptosis in gastric cancer.

Background: Previous studies indicate that gastric carcinomas express Fas ligand and downregulate Fas to escape from the host immune attack; however, the prognostic importance of Fas/FasL expression in this tumor is yet to be evaluated.Methods: Specimens from 87 gastric carcinoma patients of different stages treated in a defined period with curative intent were evaluated for apoptosis, Fas, FasL, and CD8 expression using an immunohistochemical method.Results: The percentage of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive apoptotic cells expressed as apoptotic index (AI) was higher in 43 patients when the cut-off value was set at the median value. There were no significant correlations between AI and clinicopathologic parameters. Thirty-nine patients showed a high number of CD81 cells within cancer nests. Positive FasL and Fas expression was seen in 53 and 72 patients, respectively. CD8 and FasL expressions were related only to patients’ age. Fas expression had significant correlations with tumor invasion and Lauren classification. There were significant direct correlations between AI and number of nest CD81 cells and between AI and grade of Fas expression. Apoptotic index, pT stage, CD8 expression, and Fas expression were identified as independent prognostic factors.Conclusions: Spontaneous apoptosis in gastric carcinoma may be an independent prognosticator for survival and is significantly influenced by tumor Fas expression and number of nest CD81 cells.

Surgical treatment of superficial esophageal cancer

ObjectiveThe worldwide incidence of superficial esophageal cancer (SEC) is increasing. The aim of this study is to review the systematic surgical outcomes of esophagectomy for SEC.Data sourcesOnly manuscripts written in English and written between 1980 and 2003 were selected from MEDLINE. The keywords consisting of superficial esophageal cancer, early esophageal cancer, and early stage or superficial stage or stage I in esophageal cancer were searched.Study selectionThere were no exclusion criteria for published information relevant to the topics. The most representative articles were selected when there were several articles from the same institution. Case reports were excluded.Data extractionsThirty-two manuscripts were finally collected from MEDLINE and eight articles were also added from reference lists of the pertinent literatures. In evaluating the statistical analysis of the complications of the reported literature, collective method was used.Data synthesisThe collected information was organized.ConclusionsThe conclusions drawn from those articles showed that the overall prevalence of SEC accounted around 10% and increased to 25% in the 2000s. The overall incidence of lymph node metastasis of SEC was about 25% and its incidences in mucosal and submucosal cancer were 5 and 35%, respectively. The percentage of the cases of squamous cell carcinoma (SCC) vs adenocarcinoma (AC) widely varied depending on the geographic locations reported; most SCC cases were from the Asian countries and most AC cases were from the European countries. Clinical significance of multimodal treatment for SEC has dramatically developed in the recent era and could provide various potential therapeutic options for SEC. These concepts make it possible to individualize surgical management of SEC as part of various multimodal treatments. The operative approaches for SEC varied from minimally invasive thoracoscopic esophagectomy, limited transabdominal distal esophagectomy, conventional transthoracic esophagectomy, transhiatal esophagectomy without thoracotomy, en bloc esophagectomy, and to extended esophagectomy with a complete three-field lymph node dissection. A 5-year overall survival rate of SEC after esophagectomy was good (46 to 83%) to excellent (71 and 100%) for mucosal SEC, but far from satisfactory (33 and 78%) for submucosal SEC. Early diagnosis, development of multimodal treatment, standardization of the surgical procedure including routine lymph node dissection, and improved perioperative management of patients have led to a better survival for patients with SEC.