Yoichi Hamai

A Single Nucleotide Polymorphism in the 5′ Untranslated Region of the EGF Gene Is Associated with Occurrence and Malignant Progression of Gastric Cancer

Objective: Epidermal growth factor (EGF) has many biological functions and plays an important role in the progression of various tumors including gastric cancer. An A-G single nucleotide polymorphism (SNP) at position 61 in the 5′-untranslated region (UTR) of the EGF gene has recently been reported to be associated with different levels of EGF production. We examined whether this polymorphism is correlated with the development and malignant phenotypes of gastric cancer. Methods: The study population included 200 gastric cancer patients and 230 healthy control subjects. The SNP in the 5′-UTR of the EGF gene was analyzed by polymerase chain reaction-restriction fragment length polymorphism. Results: The A allele was significantly less frequent in patients than in controls (p = 0.01). Individuals with the A/A or A/G genotype showed a significantly lower risk of gastric cancer than those with the G/G genotype [adjusted odds ratio (OR) = 0.56], whereas the same genotypes were associated with malignant progression of this cancer, e.g. deeper tumor invasion, increased lymph node metastasis and advanced clinical stage, and histological classification in gastric cancer patients (adjusted OR = 1.80, 1.98, 2.26 and 1.89, respectively). Conclusions: Our findings suggest that the A-G polymorphism of EGF is involved not only in the occurrence but also in the malignant progression of gastric cancer.

Histone H3 acetylation is associated with reduced p21WAF1/CIP1 expression by gastric carcinoma

Histone acetylation appears to play an important role in transcriptional regulation. Inactivation of chromatin by histone deacetylation is involved in the transcriptional repression of several tumour suppressor genes, including p21WAF1/CIP1. However, the in vivo status of histone acetylation in human cancers, including gastric carcinoma, is not well understood. This study shows that histone H3 in the p21WAF1/CIP1 promoter region is hypoacetylated and that this hypoacetylation is associated with reduced p21WAF1/CIP1 expression in gastric carcinoma specimens. Chromatin immunoprecipitation assays revealed that histone H3 was hypoacetylated in the p21WAF1/CIP1 promoter and coding regions in 10 (34.5%) and 10 (34.5%) of 29 gastric carcinoma specimens, respectively. Hypoacetylation of histone H4 in the p21WAF1/CIP1 promoter and coding regions was observed in 6 (20.7%) and 16 (55.2%) of 29 gastric carcinoma specimens, respectively. p21WAF1/CIP1 mRNA levels were associated with histone H3 acetylation status in the p21WAF1/CIP1 promoter region (p = 0.047) but not p53 mutation status (p = 0.460). In gastric carcinoma cell lines, expression of p21WAF1/CIP1 protein was induced by trichostatin A, a histone deacetylase inhibitor. This induction was associated with hyperacetylation of histone H3 in the p21WAF1/CIP1 promoter region. Hyperacetylation of histone H4 in the p21WAF1/CIP1 promoter region did not appear to be associated with increased expression. Induction of p21WAF1/CIP1 protein expression was associated with hyperacetylation of histones H3 and H4 in the p21WAF1/CIP1 coding region. Expression of a dominant‐negative mutant of p53 reduced expression of p21WAF1/CIP1 protein. Histone H4 acetylation in both the promoter and coding regions of the p21WAF1/CIP1 gene in cells expressing dominant‐negative p53 was less than half of that in cells expressing wild‐type p53, whereas histone H3 acetylation in both the promoter and coding regions was slightly reduced (by approximately 20%) in cells expressing the dominant‐negative p53. These findings provide evidence that alteration of histone acetylation occurs in human cancer tissue specimens such as those from gastric carcinoma. Copyright

DNA hypermethylation and histone hypoacetylation of the HLTF gene are associated with reduced expression in gastric carcinoma

The SWI/SNF proteins are ATP‐dependent chromatin remodeling enzymes that have been implicated in the regulation of gene expression. Recent studies have shown that members of the SWI/ SNF superfamily can function as tumor suppressor genes. DNA methylation and transcriptional inactivation of the HLTF gene, which is a homologue to the SWI/SNF genes, have been observed in colon cancer. In the present study, we studied the DNA methylation status of the HLTF gene by methylation‐specific PCR in 50 gastric carcinoma tissues, and seven gastric carcinoma cell lines and compared the methylation status with the levels of HLTF mRNA expression. DNA methylation of the HLTF gene was found in 25 (50%) of 50 gastric carcinomas, and levels of HLTF mRNA were associated with methylation status of HLTF (P=0.027; Mann‐Whitney U test). No correlations were found between HLTF mRNA levels and DNA methylation and T grade, N grade, tumor stage, or histological type. In corresponding non‐neoplastic mucosae, DNA methylation of the HLTF gene was found in 1 (7%) of 15 samples. The methylated allele was not detected in any of 10 normal gastric mucosae from 10 healthy volunteers. Among seven gastric carcinoma cell lines, the KATO‐III cell line showed loss of HLTF mRNA expression associated with DNA methylation. This loss was rectified by treatment with both Aza‐2′‐deoxycytidine, a demethylating agent, and trichostatin A, a histone deacetylase inhibitor. Chromatin immunoprecipitation assay revealed that the acetylation levels of histones H3 and H4 in the 5’CpG island of the HLTF gene were inversely associated with DNA methylation status. These results suggest that transcriptional inactivation of HLTF by aberrant DNA methylation and histone deacetylation may be involved in stomach carcinogenesis through down‐regulation of HLTF expression.

A single nucleotide polymorphism in the transmembrane domain coding region of HER-2 is associated with development and malignant phenotype of gastric cancer

Alterations of the HER‐2 (erbB‐2/neu) proto‐oncogene have been associated with carcinogenesis and poor prognosis of certain cancers. A single nucleotide polymorphism (Ile/Val, A/G) in the transmembrane domain was reported to be associated with a risk of breast cancer. In our study, we examined the association between the HER‐2 polymorphism and gastric carcinoma. The Ile/Ile, Ile/Val and Val/Val genotypes were found in 146 (68.9%), 56 (26.4%) and 10 (4.7%) of 212 gastric cancer patients and in 234 (81.5%), 48 (16.7%) and 5 (1.8%) of 287 control subjects, respectively. The Ile/Val or Val/Val genotype was significantly more frequent in patients than in controls (p = 0.005 and 0.033, respectively). The OR of Val/Val genotype then revealed a significantly enhanced risk of 3.25 (95% CI 1.09–9.70) compared to Ile/Ile genotype; heterozygous Ile/Val genotype showed an intermediate risk of 1.97 (1.27–3.06). In patients, carcinomas of advanced stage were significantly more frequent in patients with Ile/Val or Val/Val genotype than those with Ile/Ile genotype (p < 0.001). The logistic regression analysis for tumor invasion, lymph node metastasis and distant metastasis revealed that lymph node metastasis was most closely associated with the HER‐2 genotype. These results suggest that this nucleotide polymorphism in the transmembrane domain‐coding region of HER‐2 could be associated with development of gastric carcinoma and may serve as a predictor of risk for a malignant phenotype of gastric cancer. The association of HER‐2 genotype with clinicopathologic characteristics of gastric cancer was also suggested, which has to be confirmed with a larger sample size.

Effects of neoadjuvant chemoradiotherapy on postoperative morbidity and mortality associated with esophageal cancer

We compared the surgical outcomes between 114 patients who did not receive neoadjuvant therapy (group 1) and 92 others who received neoadjuvant chemoradiotherapy (nCRT) (group 2), and assessed the preoperative and surgical factors that influence postoperative morbidity to determine the impact of nCRT on morbidity and mortality after esophagectomy via cervical, right transthoracic, and abdominal approaches. The overall postoperative morbidity rates were 44.7% and 55.4% in groups 1 and 2, respectively (P = 0.13). Rates of anastomotic leak (8.8% vs. 16.3%; P = 0.10), pneumonia (9.6% vs. 13.0%; P = 0.44), recurrent nerve palsy (15.8% vs. 10.9%; P = 0.31), and all other complications did not significantly differ between the groups. Multivariable analysis revealed cervical lymph node dissection (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.01-3.84; P = 0.047) as the sole independent covariate for overall morbidity. Furthermore, a history of cardiovascular disease (OR, 2.90; 95% CI, 1.03-8.24; P = 0.045), the retrosternal reconstruction route (OR, 15.15; 95% CI, 3.56-62.50; P = 0.0002), and a longer surgical duration (OR, 1.01; 95% CI, 1.002-1.02; P = 0.01) were independent covariates for anastomotic leakage, and advanced age (OR, 1.08; 95% CI, 1.01-1.15; P = 0.02) and lower body mass index (OR, 1.16; 95% CI, 1.01-1.33; P = 0.04) were independent covariates for pneumonia. However, whether or not patients received nCRT was irrelevant. We found that nCRT is safe for three-incision esophagectomy and it does not increase the incidence of postoperative morbidity and mortality relative to esophagectomy alone.

Leiomyosarcoma of the sigmoid colon with multiple liver metastases and gastric cancer: a case report

BackgroundLeiomyosarcoma (LMS) of the gastrointestinal tract is an extremely rare high-grade neoplasm with poor prognosis. For advanced LMS with distant metastasis, the decision as to the choice of the most appropriate therapeutic strategy, including chemotherapy and surgery, is difficult. Here, we present an unusual case of LMS of the sigmoid colon with liver metastases and gastric cancer. The survival of this patient was prolonged by a combined modality therapy involving chemotherapy and surgery.Case presentationA 66-year-old woman who had been diagnosed with advanced gastric cancer and multiple liver metastases was referred to our hospital. The initial treatment with docetaxel and S-1 considerably reduced both the gastric cancer and liver tumors; consequently we performed surgical resection. Pathological examination revealed that no viable tumor cells remained in the stomach and chemotherapy resulted in complete remission of the gastric cancer. The liver tumors were immunohistochemically diagnosed as LMS. A tumor of the sigmoid colon was subsequently discovered and the liver tumors were found to have recurred. The surgically resected sigmoid colon and liver tumors were all immunohistochemically diagnosed as LMS. These findings indicated that the multiple liver metastases arose from the LMS in the sigmoid colon, and that they were accompanied by advanced gastric cancer. We performed another surgical resection and administered chemotherapy to treat the recurring liver metastases. The patient survived for 4 years and 10 months after initial presentation at our hospital.ConclusionColonic LMS is rare and its joint occurrence with gastric cancer is extremely unusual. Although LMS is a high-grade neoplasm, a multimodal therapeutic approach can increase patient survival time even when multiple liver metastases are present.

Laparoscopic Thoracic Duct Clipping for Persistent Chylothorax After Extrapleural Pneumonectomy

We describe a 68-year-old man who was treated by laparoscopic thoracic duct clipping for persistent chylothorax after an extrapleural pneumonectomy for malignant pleural mesothelioma. Initial conservative treatment did not resolve the postoperative chylothorax. A second surgery through the thoracic approach was considered invasive and difficult after extrapleural pneumonectomy. A laparoscopic approach proved effective and resolved the chylothorax. Thus, laparoscopic thoracic duct clipping is considered very useful for treating chylothorax.

Esophageal bypass operation prior to definitive chemoradiotherapy in advanced esophageal cancer with tracheobronchial invasion.

BACKGROUND In T4 esophageal cancer with tracheobronchial invasion, an esophagorespiratory fistula (ERF) often occurs during or after chemoradiotherapy. We have performed esophageal bypass operations prior to definitive chemoradiotherapy for these patients to increase the chemoradiotherapy completion rate by minimizing the potential effect of an ERF. The aim of this study was to examine the clinical outcome of esophageal bypass surgery prior to chemoradiotherapy. METHODS Between 1997 and 2010, 17 patients underwent esophageal bypass surgery followed by definitive chemoradiotherapy for esophageal cancer with tracheobronchial invasion (bypass group). Ten patients in the same circumstances were treated with chemoradiotherapy alone (control group). Overall survival, the clinical effect of chemoradiotherapy, the ERF incidence rate, and the safety of esophageal bypass surgery were assessed. RESULTS The overall response rate to chemoradiotherapy was 64.7% in the bypass group and 90.0% in the control group. Except for 2 patients with ERF at initial diagnosis, 4 (26.7%) of the 15 patients developed ERF in the bypass group, and 3 (30.0%) of the 10 patients developed ERF in the control group during or after chemoradiotherapy. The 2-year and 3-year overall survival rates were 17.6% and 17.6% in the bypass group and 20.0% and 0% in the control group, respectively (p = 0.924); long-term survival of more than 3 years was seen only in the bypass group. CONCLUSIONS Esophageal bypass surgery prior to definitive chemoradiotherapy could be performed safely, and this strategy contributed to long-term survival in the patients who achieved a good response to chemoradiotherapy but developed an ERF.

Successful management of multiple esophagorespiratory fistulas using two types of stent: report of a case.

We herein describe a 41-year-old man with esophageal cancer who developed three esophagorespiratory fistulas (ERFs) that were successfully treated using one esophageal and three airway stents. A self-expandable metallic stent (SEMS) was initially inserted into the esophagus to close an ERF in the right bronchus. However, two new ERFs developed in the trachea and the left main bronchus 3 months later because of pressure necrosis and penetration of the esophageal SEMS. These secondary ERFs were subsequently closed using two silicone stents, together with one SEMS in the airway. This experience suggests that appropriate stenting can control multiple and large ERFs.

Skin Tube Reconstruction for Esophageal Defect Due to Postoperative Complication

The occurrence of esophageal conduit necrosis after esophagectomy in patients with esophageal cancer is rare, but it is associated with severe and fatal complications, and the subsequent surgical reconstruction required by such patients is challenging. We reconstructed the esophagus using a skin tube prepared from a myocutaneous flap of the anterior chest wall in a patient whose entire thoracic esophagus was missing due to reconstructed conduit necrosis after surgery for esophageal cancer. Four years after skin tube reconstruction, the patient remains free of cancer recurrence with good oral intake and has resumed routine activities. Thus, the skin tube is considered very useful for salvage esophageal reconstruction.