Tatsuyuki Kawano

Ultra-high Magnification Endoscopic Observation of Carcinoma in situ of the Esophagus

Abstract: Super‐zooming observation of carcinoma in situ of the esophagus was achieved utilizing an ultra‐high magnification endoscope which has a 150X magnification capacity. Superficial flat and slightly depressed lesions (O‐llb and O‐llc according to the Japanese classification of esophageal cancer), usually observed as a well‐demarcated reddish patch, were revealed to be a composite of scattered red dots and a pinkish homogeneous background. Those red dots were disclosed to be intrapapillary capillary loop changes such as dilatation, meandering and caliber irregularities. These changes were never observed in normal mucosa or in the setting of esophagitis. These characteristic findings were confirmed histologically in the resected specimen.

A Comparison of Roux-en-Y and Billroth-I Reconstruction After Laparoscopy-assisted Distal Gastrectomy

Objective:The present study evaluated the efficacy of Roux-en-Y (R-Y) reconstruction and Billroth-I (B-I) reconstruction after laparoscopy-assisted distal gastrectomy (LADG). Patients and Methods:Between October 2000 and February 2006, a total of 133 consecutive patients who underwent LADG for gastric carcinoma were classified into 2 groups according to reconstruction (B-I, n = 65; R-Y, n = 68). Parameters analyzed included patients and tumor characteristics, operative details, postoperative outcomes, and nourishment state. Endoscopic findings of the gastric remnant and lower esophagus were evaluated at 12 months postoperatively. Results:Regarding postoperative complications, no significant differences were found between groups. In the B-I group, 3 patients developed anastomotic leakage and 4 patients suffered anastomotic stricture requiring endoscopic balloon dilation. So-called functional stasis after R-Y reconstruction was not found in this study. Incidence of heartburn at 12 months postoperatively was 37% in the B-I group and 8% in the R-Y group (P = 0.0002). Amount of meal consumed compared with preoperative value at 12 months postoperatively was significantly higher for the R-Y group than for the B-I group (83.6% ± 15.3% vs. 77.8% ± 16.0%; P = 0.047). Endoscopic findings showed that incidence of remnant gastritis was significantly lower in the R-Y group than in the B-I group (12% vs. 34%; P = 0.002). Bile reflux into the remnant stomach was not observed in the R-Y group. Conclusion:R-Y reconstruction seems superior to B-I reconstruction for preventing both bile reflux into the gastric remnant and postoperative complications. We consider R-Y reconstruction as a feasible and safe method for LADG.

YAP is a candidate oncogene for esophageal squamous-cell carcinoma

Yes-associated protein (YAP), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene located at chromosome 11q22. Since we previously reported amplification of 11q22 region in esophageal squamous cell carcinoma (ESCC), in this study we focused on the clinical significance and biological functions of YAP in this tumor. Frequent overexpression of YAP protein was observed in ESCC cells including those with a robust amplicon at position 11q22. Overexpression of the YAP protein was frequently detected in primary tumors of ESCC as well. Patients with YAP-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors, and YAP positivity was independently associated with a worse outcome in the multivariate analysis. Further analyses in cells in which YAP was either overexpressed or depleted confirmed that cell proliferation was promoted in a YAP isoform-independent but YAP expression level-dependent manner. YAP depletion inhibited cell proliferation mainly in the G(0)-G(1) phase and induced an increase in CDKN1A/p21 transcription but a decrease in BIRC5/survivin transcription. Our results indicate that YAP is a putative oncogene in ESCC and it represents a potential diagnostic and therapeutic target.

Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and human esophageal squamous cell carcinoma susceptibility

Many human cancers are caused by synthetic or natural chemical compounds in the environment. Esophageal squamous cell carcinoma has been reported to be epidemiologically associated with tobacco and alcohol consumption. We studied the association between genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and esophageal squamous cell carcinoma susceptibility. We examined genetic polymorphisms of the CYPIA1, GSTM1, CYPIIE1, ADH2, and ALDH2 genes in 94 Japanese patients with esophageal squamous cell carcinoma and 70 unrelated healthy Japanese persons. There were no significant differences between healthy controls and patients with esophageal cancer in the polymorphisms of the CYPIA1, GSTM1, and CYPIIE1 genes. On the other hand, there were significant differences in the ADH2 and ALDH2 polymorphisms between healthy controls and esophageal cancer patients. The ADH2(1)/ADH2(1) and ALDH2(1)/ALDH2(2) genotypes were independently and significantly higher in esophageal cancer patients than in healthy controls. Furthermore, persons with the combined genotypes ADH2(1)/ADH2(1) and ALDH2(1)/ALDH2(2) were at extraordinarily high risk for esophageal squamous cell carcinoma, with an odds ratio of 17.9 (p < 0.001). Thus polymorphisms of alcohol-metabolizing enzymes, that is, ADH2 and ALDH2, may be useful for screening patients at high risk for esophageal cancer, which might facilitate clarification of esophageal tumorigenesis and prevention of esophageal cancer.

High Expression of HER3 Is Associated with a Decreased Survival in Gastric Cancer

Background: The role of human epidermal growth factor receptor (HER) 3 and HER4 has been elucidated in gastric cancer. HER1 and HER2 overexpression are regarded as prognostic factors and targets of treatment. The dimerization of the HER family receptors activates downstream signal pathways and promotes tumor progression. This study investigated the positive correlation between HER1 and HER4 expression and the prognosis of patients with gastric cancers. Experimental Design: Tumor samples were obtained from gastric adenocarcinomas of 134 patients who underwent a gastrectomy from 1999 to 2002. The expression of each HER was analyzed in the tumor by immunohistochemical staining. Parametric correlations were done between HER expression and the clinicopathologic findings. A multivariate analysis was done with the overall survival. Results: HER3 expression was significantly associated with parameters involved with tumor progression, including the depth of tumor invasion (T1 versus T2-T4; P = 0.000), involved lymph nodes (P = 0.000), distant metastasis (P = 0.008), tumor stage (P = 0.000), and recurrent disease (P = 0.000). HER1 was also significantly associated with those factors excluding distant metastasis. A significant relationship was observed between the expression of HER1 and HER3 (P = 0.000). HER3 overexpression was associated with a significantly worse survival (P = 0.0000) and was an independent prognostic factor in the multivariate analysis (hazard ratio, 2.382; 95% confidence interval, 1.009-5.625; P = 0.048). Conclusions: HER3 overexpression is strongly associated with tumor progression and poor prognosis of patients with gastric cancer. It may become a new prognostic factor and a target of treatment.

Endoscopic Mucosal Resection Using a Cap: Techniques for Use and Preventing Perforation

Endoscopic mucosal resection (EMR) is one of several local treatments that provide a specimen for histopathological analysis. The authors developed a technique of EMR using a transparent plastic cap (EMRC) in 1992. By using the EMRC procedure, any part of the gastrointestinal tract mucosa can be easily accessed. The technical details of EMRC are described. The authors have performed EMR in 380 cases of gastrointestinal lesions. The most serious complication may be perforation. Two perforations (one in the esophagus and one in the colon) have occurred. By evaluating recorded videotapes, it was determined that the lack of submucosal saline injection was the major cause. Therefore, large volume injection, which creates a large bleb and potentially reduces the risk of perforation, is recommended. Furthermore, target mucosa should be strangulated at the middle part of the created bleb (never strangulated at the base). Particularly in the colon, injecting a sufficient volume of saline and controlling the power of suction are extremely important, because the cap on the colonoscope is relatively large in size.

DNA methylation status is inversely correlated with green tea intake and physical activity in gastric cancer patients

Epigenetic silencing of genes by aberrant DNA methylation is recognized as a crucial component of the mechanism underlying tumorigenesis. However, the relationship between DNA methylation and the past lifestyle in cancer patients remains largely unknown. We examined the methylation statuses of 6 tumor‐related genes, CDX2 (homeobox transcription factor), BMP‐2 (bone morphogenetic protein 2), p16 (INK4A), CACNA2D3 (calcium channel‐related), GATA‐5 (transcription factor) and ER (estrogen receptor), in 106 primary gastric carcinomas by methylation‐specific PCR and compared them with the past lifestyles of the patients. The methylation frequencies of the genes were 23.6, 21.7, 9.4, 32.4, 40.8 and 59.1%, respectively. Significant association was found between a decreased intake of green tea and methylation of CDX2 and BMP‐2. More physical activity was correlated with a lower methylation frequency of CACNA2D3. Of these 6 genes, the methylation statuses of CDX2, BMP‐2 and p16 revealed a significant interrelationship and those of CACNA2D3, GATA‐5 and ER did likewise. Thus, some epidemiological factors, such as green tea intake, could be important as to determination of the methylation statuses of selected genes and may influence the development of cancer, including that of the stomach.

Ultra‐high Magnification Endoscopy of the Normal Esophageal Mucosa

Abstract: The normal esophageal mucosa was observed in detail using ultra‐high magnification endoscopy (UHM endoscopy). The UHM endoscope has a magnification capacity ranging from eight to 150x. High‐quality UHM endoscopic pictures can be continuously obtained by attaching a 2‐mm depth soft distal attachment to the tip of the UHM endoscope. The vascular architecture, which extends from the submucosal vessels through the proper mucosal layer, can be continuously visualized, thereby demonstrating the characteristic fine‐vascular network pattern, and the intrapapillary capillaries in the epithelium. With UHM endoscopy, intrapapillary capillaries can be clearly demonstrated as single loop vessels which we have termed “intrapapillary loops.” These structures cannot be observed with an ordinary magnifying endoscope which is capable of only 35x magnification. We conclude that a technique for obtaining high‐resolution endoscopic pictures has been established. The images obtained are useful for elucidating the microstructure of the esophageal mucosa, especially the fine‐vascular network and the newly recognized intrapapillary loop.

Prognostic Significance of VEGF Expression in Correlation With COX-2, Microvessel Density, and Clinicopathological Characteristics in Human Gastric Carcinoma

BackgroundMany studies have shown that angiogenesis plays an important role in the process of cancer development and progression. Vascular endothelial growth factor (VEGF) has a potent angiogenic activity, and cyclooxygenase-2 (COX-2) supports angiogenesis by regulated production of angiogenic factors, including VEGF. The purpose of this study was to examine the expression of VEGF in combination with COX-2 and CD34, their correlation with various clinicopathological factors, and their prognostic significance in human gastric carcinoma.MethodsSpecimens from 169 patients with different grade and stage gastric carcinoma were investigated by immunohistochemistry for COX-2 and VEGF expression. Tumor microvessel density was assessed with CD34 immunostaining. Correlations between the expression of VEGF, COX-2, CD34, and various clinicopathological factors were studied. The effect of these proteins on patient survival was determined.ResultsCOX-2 and VEGF were positively expressed in 36.7% and 50.3% of the patients, respectively. Positive correlation was found between VEGF and COX-2 and between VEGF and CD34. VEGF expression was correlated with depth of invasion; metastatic lymph nodes; lymphatic and venous invasion; and tumor, node, metastasis system stage. Patients with positive staining for VEGF showed far lower disease-free (64.9% vs. 81.3%) and overall (58.3% vs. 76.9%) survival rates than VEGF-negative patients. In multivariate analysis, only tumor location, depth of invasion, and lymph node metastasis were shown to be independent prognostic factors.ConclusionsVEGF expression correlates with angiogenesis and tumor progression and is a valuable prognostic factor in patients with gastric carcinoma.

Multiple Primary Cancers Associated with Esophageal Carcinoma

Abstract This study was conducted to examine the characteristics of esophageal cancers with primary synchronous or metachronous cancer in another organ. We retrospectively evaluated 744 patients who underwent esophagectomy for esophageal cancers between 1985 and 1998. The patients were divided into two groups according to whether they had multiple primary cancer (MPC) or nonmultiple primary cancer (NPC). Stage I cancer was significantly more frequent among patients with MPC than among those with NPC (P < 0.0001). Among patients with MPC, another primary cancer was found in the head and neck region in 70 (42.4%), in the stomach in 51 (30.9%), and in the colon, lung, breast, and other locations in the remaining patients. Of the 70 patients with another primary cancer in the head and neck region, 32 (45.7%) had pharyngeal cancer. Furthermore, the incidence of intraesophageal multiple cancer in the patients with primary cancer in the head and neck region was significantly higher than that in those whose other primary cancers were gastric cancer or in those with NPC (P = 0.0135, P < 0.0001). The 5-year survival rate of the patients with MPC was 51.28%, which was significantly higher than that of those with NPC (P = 0.019). In conclusion, a better knowledge of the relationships between esophageal carcinoma and cancers in other organs may lead to earlier detection of other primary cancers and improved therapeutic results.