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We present a case of acute esophageal necrosis (AEN) and two acquired esophageal stenosis cases which showed a similar clinical course after an episode of septic shock. Extensive stenosis of the distal esophagus developed in all cases, which were refractory to dilation therapy and required surgical intervention. The etiology of the latter two cases was deduced from the stenosis after septic shock-induced AEN. Since the diagnosis of AEN is based on its characteristic endoscopic findings which can only be confirmed at the onset of the disease, we therefore called these cases "septic shock-related esophageal stenosis" or abbreviated to "septic esophageal stenosis". Further study of similar cases is required for understanding the etiology and management of AEN and the relevant disorder which may cause esophageal stenosis.

Epigenetic gene inactivation plays a key role in the development of various types of cancer. Using methylated CpG island amplification coupled with representational difference analysis to identify genes inactivated by DNA methylation in gastric cancer, we identified seven DNA fragments corresponding to the 5' CpG islands of the affected genes. One of the clones recovered was identical to the 5' flanking region of DFNA5, a gene previously shown to be associated with deafness and induced by DNA damage. Further analysis revealed that DFNA5 is expressed in normal tissues but is down-regulated in gastric cancer cell lines due to methylation of the region around its transcription start site. Treating gastric cancer cells that lacked DFNA5 expression with a methyltransferase inhibitor, 5-aza-2'-deoxycytidine, restored the gene's expression. Methylation of DFNA5 was detected in 50% of primary gastric tumors, and was correlated with positivity for Epstein-Barr virus and the absence of metastasis. Moreover, introduction of exogenous DFNA5 into silenced cells suppressed colony formation. Taken together, these data suggest that the silencing of DFNA5 occurs frequently in gastric cancer and may play a key role in development and progression of the disease.

症例は76歳, 男性. 黄疸で発症し入院したがその約1年前より心窩部痛を自覚していた. 腹部CTにて, 胆嚢内結石と肝内胆管および総肝管の拡張を認め, 結石が胆嚢頸部に嵌頓し総肝管の右壁を圧排していた. 内視鏡的逆行性胆道ドレナージにより減黄したものの, その後胆管炎を併発したため, 内視鏡的経鼻胆道ドレナージに変更した. 手術では, 胆嚢を切開した上で頸部に嵌頓した結石を除去し, 胆嚢総肝管瘻合併Mirizzi症候群であることを確認した上で, 胆嚢摘出を行い, 総肝管の欠損部周囲を肝円索の一部を用いて被覆し, 肝円索内を通して総肝管ドレナージチューブを留置した. 術後50日目にドレナージチューブを抜去し, その後も肝障害はなく, 術後69日目に退院した. 胆嚢総肝管瘻を合併したMirizzi症候群の手術では, 術中所見に応じて総肝管ドレナージの方法を選択する必要がある.

BACKGROUND The CpG island methylator phenotype (CIMP), which is characterized by simultaneous methylation of the CpG islands of multiple genes, has been recognized as one of the important mechanisms in gastrointestinal carcinogenesis. METHODS Methylation of the 5 methylated-in-tumors (MINT) loci and 12 tumor-related genes in 78 primary gastric carcinomas was examined using combined bisulfite-restriction analysis. Epstein–Barr virus (EBV)-associated gastric tumors were detected using real-time polymerase chain reaction analysis followed by an evaluation of the correlations between CIMP status, EBV-association, and genetic alteration of p53 and K-ras. The authors compared the clinicopathologic features of gastric carcinomas that had high CIMP methylation (CIMP-H) with tumors that had low CIMP methylation (CIMP-L) or negative CIMP methylation (CIMP-N). RESULTS The methylation profiles of 12 genes showed nonrandom methylation, supporting the presence of CIMP in gastric carcinoma. No p53 mutations were detected among CIMP-H tumors, and no EBV association was detected in tumors that showed mutation of p53 and K-ras. In a multiple logistic regression model with CIMP-H as the dependent variable, proximal location (P = .011), diffuse type (P = .019), and less advanced pathologic TNM status (P = .043) contributed significantly to CIMP-H. Patients who had CIMP-N gastric tumors had a significantly worse survival than patients who had CIMP-H tumors (P = .004) or CIMP-L tumors (P = .012). EBV-associated tumors were associated strongly with CIMP-H, hypermethylation of tumor-related genes, and no p53 or K-ras mutation. CONCLUSIONS CIMP status appeared to be associated with distinct genetic, epigenetic, and clinicopathologic features in gastric carcinomas. The finding that gastric carcinomas arose through different molecular pathways may affect not only tumor characteristics but also patient prognosis. Cancer 2006. © 2006 American Cancer Society.

Aberrant methylation of a sodium co-transporter, solute carrier family 5 member 8 gene (SLC5A8) , has been detected in a subset of colorectal cancers, suggesting SLC5A8 may also serv

To clarify the role of DNA methylation in the silencing of the expression of cyclin-dependent kinase inhibitor p57KIP2 seen in certain tumors, we investigated the methylation status of its 5′ CpG island in various tumor cell lines and primary cancers. Dense methylation of the region around the transcription start site was detected in 1 out of 10 colorectal, 2 out of 8 gastric, and 6 out of 14 hematopoietic tumor cell lines and in 5 out of 35 (14%) gastric, 6 out of 20 (30%) hepatocellular, and 2 out of 18 (11%) pancreatic cancers; 7 out of 25 (28%) acute myeloid leukemia cases also showed methylation of the p57KIP2 gene, which strongly correlated with the CpG island methylator phenotype (P

We inserted Dumon stent to 13 patients with tracheobronchial stenosis due to advanced or recurrent esophageal carcinoma. Severe dyspnea was improved in 11 patients except for 2 patients with bilateral recurrent nerve palsy. 3 cases who had radiation therapy or chemotherapy lived over 150 days. We inserted esophageal stent in 4 cases. 2 patients died due to hemoptysis after 156 days and 35 days. We conclude that Dumon stent is one of the useful treatments in order to improve quality of life and prognosis of advanced or recurrent esophageal carcinoma.

Colorectal cancers with and without the replication error (RER) exhibit fundamental differences in genotype and phenotype. While alterations in APC, p53 , and K-ras genes have been characterized between RER+ and RER− colorectal cancers, the status of deleted in colorectal carcinomas (DCC) gene has not been yet. Alterations of DCC gene were analyzed in stage-matched two panels of 30 RER+ and 30 RER− colorectal cancers using semiquantitative reverse transcription-PCR and PCR-LOH analyses. Loss or reduction of DCC mRNA expression and allelic loss at the DCC locus were significantly less frequent in RER+ cancers than in RER− cancers. Interestingly, reduced DCC mRNA expression was observed in all 5 RER− cancers with liver metastasis. Our results support the concept that RER+ and RER− colorectal cancers represent different pathways of carcinogenesis and may give a hint for clarifying the specific mechanism of DCC inactivation in RER− colorectal cancers.

p16 (MTS-1, multiple tumor suppressor gene 1), a putative tumor suppressor gene, is one of the cyclin-dependent kinase inhibitors (CDI) and it regulates the G1/S transition of the cell cycle. To clarify the role of p16 in primary gastric cancer, we have investigated somatic mutations of this gene by using the polymerase chain reaction/single strand conformation polymorphism (PCR-SSCP) method. In 23 surgical specimens of primary gastric cancer, none were detected in exon1 and exon 2. Among the 6 human gastric cancer cell lines examined, PCR products were not found in 2, MKN28 and MKN45, suggesting the presence of homozygous deletions. No mutation was found in the other 4 cell lines. Furthermore, decreased expression levels were not observed in 13 gastric cancer tissues by reverse transcription PCR (RT-PCR). Considering the above results of PCR-SSCP and RT-PCR, genetic alterations of the p16 gene are rarely implicated in human gastric cancer tumorigenesis.

We experienced a case of intrabronchial leiomyoma which was successfully resected by laser therapy. A 71-year-old woman was admitted to the hospital because of severe coughing and dyspnea. Bronchoscopy showed a pedunculated polyp in the entrance of the left basal bronchus. The polyp was resected by laser therapy throught a bronchoscope under general anesthesia. The day after the operation, the wheezing of the left lung ceased. Bronchoscopy showed that the left basal bronchus opened completely. There was a remarkable improvement in the %VC and FEV1% after the operation. (from 69.51 and 73.11 to 80.2 and 91.67 respectively) Histopathologically the polyp was leiomyoma and a special stain was confirmatory. Intrabronchial leiomyoma is a comparatively rare desease, so we reported this case, together with a review of the literature.

Among 564 cases resected and reconstructed for an esophageal cancer at the department in a recent 12-year period, we experienced 4 cases (0.7%) of synchronous double cancer of esophageal and gastric early cancer. Of the 4 cases, 2 cases were referred to the hospital with the definite diagnosis which was made at elsewhere; one cases was detected having synchronous cancer at the outpatient clinic; and the remaining one cases was diagnosed by preoperative exploration for a rectal cancer. All 4 cases were diagnosed between 1991 and 1993 that might result from a remarkable improvement in endoscopic diagnostic technique. All 4 cases are alive and free from cancer. Operative procedure should be selected by the balance of surgical intervention and curability. The indication of more limited operation such as endoscopic mucosectomy or blunt dissection should be also considered for the esophageal cancer. The sufficient preoperative examination entertaining possible multiple gastric cancer, multiple esophageal cancer and synchronous triple cancer is important to gain a better prognosis.

Hepatoma-derived growth factor (HDGF) is a secreted heparin-binding growth factor that has been implicated in cancer development and progression. Here, we report that HDGF is a critical target for transcriptional repression by the tumor suppressor p53. Endogenous HDGF expression was decreased in cancer cells with introduction of wild-type p53, which also downregulated HDGF expression after DNA damage. In support of the likelihood that HDGF is a critical driver of cancer cell growth, addition of neutralizing HDGF antibodies to culture media was sufficient to block cell growth, migration, and invasion. Similarly, these effects were elicited by conditioned culture medium from p53-expressing cells, and they could be reversed by the addition of recombinant human HDGF. Interestingly, we found that HDGF was overexpressed also in primary gastric, breast, and lung cancer tissues harboring mutant p53 genes. Mechanistic investigations revealed that p53 repressed HDGF transcription by altering HDAC-dependent chromatin remodeling. Taken together, our results reveal a new pathway in which loss of p53 function contributes to the aggressive pathobiological potential of human cancers by elevating HDGF expression. Cancer Res; 71(22); 7038–47. ©2011 AACR.

BNIP3 protein is a proapoptotic member of the Bcl-2 family that is expressed in hypoxic regions of tumors. To examine its role in the progression of gastrointestinal cancer, we examined the expression and DNA methylation status of BNIP3 gene in a panel of colorectal and gastric cancer cell lines. BNIP3 was not expressed in 14 of the 24 cell lines tested, and its absence was not caused by gene mutation or by altered expression of hypoxia inducible factor-1, a key transcription factor that regulates BNIP3 expression. On the other hand, methylation of the 5′ CpG island of BNIP3 was closely correlated with silencing the gene. Moreover, treating methylated cells with the methyltransferase inhibitor 5-aza-2′-deoxycytidine restored hypoxia-induced expression of BNIP3 mRNA and protein, which in turn led to cell death. Aberrant methylation of BNIP3 was also detected in 66% of primary colorectal and 49% of primary gastric cancers, but not in normal tissue samples collected from areas adjacent to the tumors. Apparently, epigenetic alteration of BNIP3 is a frequent and cancer-specific event, which suggests that inactivation of BNIP3 likely plays a key role in the progression of some gastrointestinal cancers and that it may be a useful molecular target for therapy.

Ectopic (heterotopic) gastric mucosa (EGM) of the upper esophagus, referred as inlet patch, is an asymptomatic benign lesion that is often detected during endoscopic examination. Although it is considered a source of adenocarcinoma in the upper esophagus, only 17 cases of adenocarcinoma have been reported previously. We report a rare case of adenocarcinoma arising in EGM of the cervical esophagus.

Aberrant methylation of a sodium co-transporter, solute carrier family 5 member 8 gene (SLC5A8), has been detected in a subset of colorectal cancers, suggesting SLC5A8 may also serve as a tumor suppressor. To further investigate the role of epigenetic inactivation of SLC5A8 expression in gastric cancer, we determined the methylation status of the SLC5A8 5' CpG island (CGI) in a panel of gastric cancer cell lines and primary gastric cancers. We detected methylation of the 5'CGI in ten of twelve gastric cancer cell lines, and five of those showed dense methylation, which correlated with the absence of SLC5A8 transcription. Aberrant methylation of SLC5A8 was also detected in 23 of 71 (30%) primary gastric cancers, indicating that epigenetic inactivation of SLC5A8 is not a cell-line-specific phenomenon. SLC5A8 expression was restored in methylated cell lines by treatment with 5-aza-2'-deoxycytidine, a methyltransferase inhibitor. In addition, chromatin immunoprecipitation assays showed that acetylation of histone H3 in the 5' region of the gene correlated directly with SLC5A8 expression and inversely with DNA methylation. It thus appears that aberrant methylation of its 5'CGI and histone deacetylation play key roles in silencing SLC5A8 expression in gastric cancers.

Mitotic checkpoints prevent errors in chromosome segregation that can lead to neoplasia. Therefore, it is notable that gastric cancers often show impaired checkpoint function. In the present study, we examined the functional consequences of epigenetic inactivation of the mitotic checkpoint gene CHFR in gastric cancers. CHFR expression was silenced by DNA methylation of the 5' region of the gene in 20% of the gastric cancer cell lines tested and in 39% of primary gastric cancers; expression could be restored by treatment with 5-aza-2'-deoxycytidine, a methyltransferase inhibitor. In addition, histones H3 and H4 were found to be deacetylated in cell lines showing aberrant methylation, indicating a role for histone deacetylation in the methylation-dependent gene silencing. Cells not expressing CHFR showed impaired checkpoint function, which led to nuclear localization of cyclin B1 after treatment with docetaxel or paclitaxel, two microtubule inhibitors. Apparently, the absence of CHFR is associated with sensitivity of cells to mitotic stress caused by microtubule inhibition, and restoration of CHFR expression by 5-aza-2'-deoxycytidine or adenoviral gene transfer restored the checkpoint. By affecting mitotic checkpoint function, CHFR inactivation likely plays a key role in tumorigenesis in gastric cancer. Moreover, the aberrant methylation of CHFR appears to be a good molecular marker with which to predict the sensitivity of gastric cancers to microtubule inhibitors.

To evaluate the genetic factors of familial predisposition to gastric cancer, genetic alterations in the surgically resected stomach samples from gastric-cancer-prone families were investigated. Familial gastric cancer (FGC) was defined as gastric cancer occurring in a family with 3 or more gastric cancer patients over at least two successive generations. We examined replication error (RER) of six microsatellite markers and screened mutations of the 10-(A) repeat sequence in the transforming growth factor-beta receptor type II (TGF-betaRII) gene in individuals from seven unrelated FGC families. Three cases showed RER at one of the six (CA)n microsatellite markers but the other 4 cases showed no RER at any of these loci. No mutation was found in the 10-(A) repeat of the TGF-betaRII gene. Additionally, no germline mutation was found by polymerase chain reaction-single strand conformation polymorphism in exons 1-16 of E-cadherin, exons 5-8 of p53 and in the mutation cluster region of APC. These results indicate that disorders in the DNA mismatch repair system, E-cadherin, p53 and APC may be infrequently involved in the carcinogenesis of Japanese FGC.

The clinical features of familial gastric cancer are still unknown. To approach this question, we investigated the clinicopathological characteristics of 16 cases of familial gastric cancer. In this study the criteria used to define familial gastric cancer was the existence of three or more family members with gastric cancer in at least two successive generations. The clinicopathological characteristics of cases who fulfilled this criteria were studied. This study contained 16 familial gastric cancer probands. Seven cases (44%) of gastric cancer had developed at the cardiac region of the stomach. This frequency was significantly higher than for gastric cancer in the general population in Japan (15.4%, p < 0.01). Undifferentiated types were dominant in familial gastric cancer (69%, p < 0.05). Furthermore, the frequency of disseminated peritoneal (40%) and liver metastases (20%) in familial gastric cancer was also significantly higher than for gastric cancer in the general population in Japan (10.9%, p < 0.01, and 4.4%, p < 0.05, respectively). Familial gastric cancers were frequently located at the cardiac region and appeared to be more aggressive than sporadic gastric cancers. The unique characteristics of familial gastric cancer suggest a genetic background in their etiology.

Matrilysin is one of matrix metalloproteinases, which is supposed to have a specific role in tumor progression. Expression of matrilysin was investigated in gastric and esophageal cancers by an immunohistochemical examination. Matrilysin was expressed in all esophageal squamous cell carcinomas (13/13) and in the majority of gastric adenocarcinomas (31/35, 89%). The positive staining was observed in tumor cells of cancerous tissues. In gastric cancers, there were significant statistical correlations between matrilysin expression at the invasive front and nodal metastasis or advanced stage. These results suggest that overexpression of matrilysin has an important role in the progression of upper gastrointestinal cancers.