Hand-assisted laparoscopic transhiatal esophagectomy with a systematic procedure for en bloc infracarinal lymph node dissection.

Laparoscopic transhiatal esophagectomy is a minimally invasive approach for esophageal cancer. However, a transhiatal procedure has not yet been established for en bloc mediastinal dissection. The purpose of this study was to present our novel procedure, hand-assisted laparoscopic transhiatal esophagectomy, with a systematic procedure for en bloc mediastinal dissection. The perioperative outcomes of patients who underwent this procedure were retrospectively analyzed. Transhiatal subtotal mobilization of the thoracic esophagus with en bloc lymph node dissection distally from the carina was performed according to a standardized procedure using a hand-assisted laparoscopic technique, in which the operator used a long sealing device under appropriate expansion of the operative field by hand assistance and long retractors. The thoracoscopic procedure was performed for upper mediastinal dissection following esophageal resection and retrosternal stomach roll reconstruction, and was avoided based on the nodal status and operative risk. A total of 57 patients underwent surgery between January 2012 and June 2013, and the transthoracic procedure was performed on 34 of these patients. In groups with and without the transthoracic procedure, total operation times were 370 and 216 minutes, blood losses were 238 and 139 mL, and the numbers of retrieved nodes were 39 and 24, respectively. R0 resection rates were similar between the groups. The incidence of recurrent laryngeal nerve palsy was significantly higher in the group with the transthoracic procedure, whereas no significant differences were observed in that of pneumonia between these groups. The hand-assisted laparoscopic transhiatal method, which is characterized by a systematic procedure for en bloc mediastinal dissection supported by hand and long device use, was safe and feasible for minimally invasive esophagectomy.

Frequent silencing of RUNX3 in esophageal squamous cell carcinomas is associated with radioresistance and poor prognosis.

Radiotherapy is an effective treatment for some esophageal cancers, but the molecular mechanisms of radiosensitivity remain unknown. RUNX3, a novel tumor suppressor of gastric cancer, functions in transforming growth factor (TGF)-beta-dependent apoptosis. We obtained paired samples from 62 patients with advanced esophageal cancers diagnosed initially as T3 or T4 with image diagnosis; one sample was obtained from a biopsy before presurgical radiotherapy, and the other was resected in surgical specimens after radiotherapy. RUNX3 was repressed in 67.7% cases of the pretreatment biopsy samples and 96.7% cases of the irradiated, resected samples. The nuclear expression of RUNX3 was associated with radiosensitivity and a better prognosis than cytoplasmic or no RUNX3 expression (P<0.003); cytoplasmic RUNX3 expression was strictly associated with radioresistance. RUNX3 was downregulated and its promoter was hypermethylated in all radioresistant esophageal cancer cell lines examined. Stable transfection of esophageal cancer cells with RUNX3 slightly inhibited cell proliferation in vitro, enhanced the antiproliferative and apoptotic effects of TGF-beta and increased radiosensitivity in conjunction with Bim induction. In contrast, transfection of RUNX3-expressing cells with a RUNX3 antisense construct or a Bim-specific small interfering RNA induced radioresistance. Treatment with 5-aza-2'-deoxycytidine restored RUNX3 expression, increased radiosensitivity and induced Bim in both control and radioresistant cells. These results suggest that RUNX3 silencing promotes radioresistance in esophageal cancers. Examination of RUNX3 expression in pretreatment specimens may predict radiosensitivity, and induction of RUNX3 expression may increase tumor radiosensitivity.

Overexpression of RegIV in peritoneal dissemination of gastric cancer and its potential as A novel marker for the detection of peritoneal micrometastasis.

BACKGROUND: Regenerating gene type IV (RegIV) is a candidate marker for cancer and inflammatory bowel disease. In this study, its potential as a novel marker for the detection of gastric cancer peritoneal micrometastases was examined. PATIENTS AND METHODS: RegIV mRNA levels in the peritoneal washes of 95 gastric cancer patients and 22 with benign disease were quantified by real-time RT-PCR. To examine whether expression of RegIV enhance tumorigenicity or not, thirty two mice were injected intraperitoneally or subcutaneously with RegIV transfectants of TMK-1 cells, parental TMK-1 cells, or neomycin control transfectants. RESULTS: RegIV expression was markedly higher in patients with peritoneal metastases compared to those without. The level of RegIV mRNA in gastric cancer patients was related to the extent of wall penetration. A cut-off value for RegIV-positive expression was based on an analysis of negative control patients with benign disease, and gastric cancer patients above the cut-off value constituted the micrometastasis (MM+) group. Based on this criteria, 3 out of 43 T1 or T2 cases were MM+ (93% specificity). Among 15 patients with peritoneal dissemination (7 out of 15 cases were positive by cytology), 14 cases were positive for RegIV expression (93% sensitivity), while analysis of carcinoembryonic antigen (CEA) mRNA failed to detect micrometastases in 4 cases (73% sensitivity). Combined analysis of CEA and RegIV improved the accuracy of diagnosis to 100%. The prognosis of RegIV-positive cases was significantly worse than that of RegIV-negative cases. Multivariate analysis using the Cox proportional hazards model suggested that RegIV may be an independent prognostic factor. Stable expression of RegIV significantly enhanced peritoneal metastasis in an animal model of gastric cancer. CONCLUSION: These findings suggest that RegIV mRNA expression has the potential to serve as a novel marker for detecting peritoneal dissemination in gastric cancer.

Genomic loss and epigenetic silencing of very-low-density lipoprotein receptor involved in gastric carcinogenesis.

Homozygous loss in the genomic sequence, a mechanism for inactivating tumor-suppressor genes (TSGs) in cancer, has been used as a tag for the identification of novel TSGs, and array-based comparative genomic hybridization (array-CGH) has a great potential for high-throughput identification of this change. We identified a homozygous loss of the very-low-density lipoprotein receptor (VLDLR) gene (9p24.2) from genome-wide screening for copy-number alterations in 32 gastric cancer (GC) cell lines using array-CGH. Although previous reports demonstrated mRNA or protein expression of VLDLR in various cancers including GC, the association between genomic losses or epigenetic silencing of this gene and carcinogenesis has never been reported before. Homozygous deletion of VLDLR was also seen in primary GCs, albeit infrequently, and about half of GC cell lines showed lost or reduced VLDLR expression. The VLDLR expression was restored in gene-silenced GC cells after treatment with 5-aza 2'-deoxycytidine. According to methylation analyses, hypermethylation of the VLDLR promoter region, which all of GC lines without its expression showed, occurred in some primary GCs. Restoration of VLDLR type I expression in GC cells reduced colony formation. These results suggest that not only the expression of VLDLR but also genetic or epigenetic silencing of this gene may contribute to tumor formation and be involved in gastric carcinogenesis.

Cytoplasmic sequestration of the polyomavirus enhancer binding protein 2 (PEBP2)/core binding factor alpha (CBFalpha) subunit by the leukemia-related PEBP2/CBFbeta-SMMHC fusion protein inhibits PEBP2/CBF-mediated transactivation.

The polyomavirus enhancer binding protein 2 (PEBP2)/core binding factor (CBF) is a transcription factor composed of two subunits, alpha and beta. The gene encoding the beta subunit is disrupted by inv(16), resulting in the formation of a chimeric protein, beta-SMMHC, which is associated with acute myelogenous leukemia. To understand the effect of beta-SMMHC on PEBP2-mediated transactivation, we used a luciferase assay system in which contribution of both the alpha and beta subunits was absolutely required to activate transcription. Using this system, we found that the minimal region of the beta subunit required for transactivation resides between amino acid 1 and 135, which is known to dimerize with the alpha subunit. In contrast, beta-SMMHC, despite having this minimal region for dimerization and transactivation, failed to support transcription with the alpha subunit. Furthermore beta-SMMHC blocked the synergistic transcription achieved by PEBP2 and CCAAT/enhancer binding protein alpha. By using a construct in which the PEBP2 alpha subunit was fused to the glucocorticoid receptor ligand binding domain, we demonstrated that coexpressed beta-SMMHC tightly sequestered the alpha subunit in the cytoplasm and blocked dexamethasone-dependent nuclear translocation of the alpha subunit. Thus, the result suggess that beta-SMMHC inhibits PEBP2-mediated transcription via cytoplasmic sequestration of the alpha subunit. Lastly proliferation of ME-1 cells that harbor inv(16) was blocked by an antisense oligonucleotide complementary to the junction of the chimeric mRNA, suggesting that beta-SMMHC contributes to leukemogenesis by blocking the differentiation of myeloid cells.

In situ tissue engineering of the bile duct using polypropylene mesh-collagen tubes.

Multiple attempts have been made to replace biliary defects with a variety of materials. Recently, successful biliary reconstruction using the Gore-Tex vascular graft has been reported experimentally and clinically. We designed a new artificial bile duct consisting of collagen sponge and polypropylene mesh. We presently evaluated the feasibility of using this prosthesis as a scaffold for bile duct tissue regeneration in a canine model. Our prosthesis, a sponge made from porcine dermal collagen, is reinforced with a polypropylene mesh cylinder. We used the prosthesis to reconstruct the middle portion of the common bile duct in seven beagle dogs to evaluate its efficacy. While one dog died of biliary stricture 8 months after operation, six survived without problems to scheduled time points for tissue evaluation at 1 to 12 months. All prostheses had become completely incorporated into the host. A confluent epithelial lining was observed within 3 months. In cholangiograms the prosthesis displayed long-term patency in the six dogs and provided satisfactory bile drainage for up to 12 months. Our graft thus shows promise for repair of biliary defects and should lead to development of a new treatment for biliary reconstruction.

Milky spots as the implantation site for malignant cells in peritoneal dissemination in mice.

We examined the site-specific implantation of cancer cells in peritoneal tissues after an i.p. inoculation of 10(5) P388 leukemia cells. Twenty-four h after the inoculation, the number of viable cancer cells infiltrating into specific tissue sites of the peritoneum was estimated by an i.p. transfer method. A descending order of tissue implantation with cancer cells was established as omentum > gonadal fat > mesenterium > posterior abdominal wall > stomach, liver, intestine, anterior abdominal wall, and lung. A significant correlation was established between the logarithm of the number of infiltrating cancer cells and the logarithm of the number of milky spots. Next, the omentum was examined microscopically after i.p. inoculation with P388 leukemia cells labeled with bromodeoxyuridine or B-16 PC melanoma, which were differentiated from the other cells by an immunocytological method using anti-bromodeoxyuridine antibody or by the melanin of the B-16 PC melanoma cells. These cancer cells were found microscopically to be infiltrating only the milky spots, whereas none were seen at the other sites. These results suggest that cancer cells seeded i.p. specifically infiltrate the milky spots in the early stage of peritoneal metastases.

Overexpression of cyclooxygenase-2 in squamous cell carcinoma of the urinary bladder.

Epidemiological studies indicate that the development of squamous cell carcinoma of the urinary bladder is closely associated with chronic inflammation of the urinary tract, but the underlying mechanism is unknown. Cyclooxygenase (COX)-2 is involved in tumorigenesis in many tumors. The purpose of this study was to investigate the role of COX-2 in squamous cell carcinoma of the urinary bladder by immunoblot and immunohistochemical analyses. COX-2 protein was undetectable in normal bladder samples, but was expressed in 29 of 29 (100%) squamous cell carcinomas and in 8 of 8 (100%) squamous metaplasias. The expression of COX-2 showed intense, homogenous cytoplasmic immunostaining in squamous cell carcinomas. In contrast, COX-2 was heterogeneously expressed in 6 of 12 (50%) cases of transitional cell carcinoma of the bladder combined with squamous cell carcinoma, consistent with previous findings. We provide the first evidence that COX-2 is expressed in squamous cell carcinomas of the urinary bladder and in the precursor lesions, indicating its involvement in the development of this type of malignancy.

In vitro and in vivo induction of apoptosis by sphingosine and N, N-dimethylsphingosine in human epidermoid carcinoma KB-3-1 and its multidrug-resistant cells.

Sphingolipid breakdown products, including ceramide and sphingosine, regulate cell growth, cell differentiation, and apoptosis. We examined the effect of various agents, including sphingolipids, on apoptosis induction in human epidermoid carcinoma KB-3-1 and its multidrug-resistant (MDR) subclone KB-C2 cells which express P-glycoprotein. Adriamycin (ADM) induced apoptosis in KB-3-1 cells but not in KB-C2 MDR cells at the concentration of 50 microg/ml. On the other hand, 15 microM sphingosine or its methylated derivative N, N-dimethylsphingosine (DMS) induced apoptosis in both cell types in vitro. These results suggested that KB-C2 MDR cells were resistant to apoptosis induction by ADM but sensitive to that by sphingosine and DMS. Ceramide and sphingosine-1-phosphate, the initial metabolites of sphingosine, failed to induce apoptosis under the same experimental condition as sphingosine/DMS. The protein kinase C (PKC) inhibitors H7 and staurosporine did not induce apoptosis in either cell line, suggesting that PKC-independent signaling is involved in apoptosis induced by sphingosine and DMS, although both sphingosine and DMS have been shown to down-regulate PKC. Furthermore, DMS significantly inhibited the growth of KB-3-1 as well as KB-C2 MDR tumors in vivo, with evidence of increased apoptosis. The intracellular level of exogenously added [3H]sphingosine or [14C]DMS did not differ between the KB-3-1 parent cell line and its MDR subclone KB-C2, whereas that of [14C]ADM was reduced in KB-C2 MDR cells compared to KB-3-1 cells. These results suggest that P-glycoprotein acts as a transporter for ADM but not for sphingosine or DMS. Furthermore, DMS at the concentrations which induce apoptosis in KB-C2 cells did not affect the level of [14C]ADM. Because sphingosine and DMS induce apoptosis regardless of P-glycoprotein expression, they may provide a new strategy and a promising approach to the treatment of anticancer drug-resistant cancer.

Suppression of bcl-2 gene expression by sphingosine in the apoptosis of human leukemic HL-60 cells during phorbol ester-induced terminal differentiation.

Our recent studies have shown that intracellular levels of sphingosine, an endogenous PKC inhibitor, increase during apoptosis resulting from phorbol ester (PMA)-induced terminal differentiation of human myeloid leukemic HL-60 cells, and have suggested that sphingosine may function as an endogenous mediator of apoptosis in these cells [Ohta, et al. (1995) Cancer Res. 55, 691-697]. We report here that apoptosis induced by PMA, sphingosine, and N,N-dimethylsphingosine (DMS) was accompanied by a concomitant decrease of bcl-2 expression in both RNA and protein levels in HL-60 cells, while expression of bcl-XL and bax mRNA did not change, and neither sphingosine nor DMS induced differentiation of HL-60 cells. In contrast, in apoptotic cells induced by pharmaceutical PKC inhibitors H7 or staurosporine, expression of bcl-2 did not change nor did the intracellular sphingosine concentration. These results suggest that sphingosine may function as an endogenous mediator of apoptotic signaling in PMA-induced terminal differentiation of HL-60 cells through bcl-2 down-regulation, probably independent from PKC inhibition.

Sphingosine induces apoptosis in androgen-independent human prostatic carcinoma DU-145 cells by suppression of bcl-X(L) gene expression.

Our recent studies have suggested that sphingosine, an endogenous protein kinase C (PKC) inhibitor, may mediate apoptosis induced by a phorbol ester (PMA) in human promyelocytic leukemia HL-60 cells [Ohta et al. Cancer Res. 1995;55:691-697], and that the apoptotic induction by both PMA and sphingosine is accompanied by down-regulation of bcl-2, a gene which acts to prevent apoptotic cell death [Sakakura et al. FEBS Lett. 1996;397:177-180]. In this study, we examined the sphingosine-induced apoptosis of the androgen-independent human prostatic carcinoma cell line DU-145, which expresses bcl-X(L) and Bax but not bcl-2, and found that treatment of DU-145 cells with sphingosine suppressed bcl-X(L) in both mRNA and protein levels but did not change bax expression at all. In contrast, in apoptotic cells treated with a PKC inhibitor, staurosporine, no effect on bcl-X(L) or bax expression was observed. The initial metabolites of sphingosine in the cells, ceramide and sphingosine 1-phosphate, failed to induce apoptosis. These results indicate that, in DU-145 cells, sphingosine, but not its metabolites, induces apoptosis through down-regulation of bcl-X(L), independently of PKC inhibition. Our present results, together with previous observations, strongly suggest that apoptosis regulatory genes differ according to cell type and apoptosis induction through sphingosine is accompanied by inhibition of either bcl-2 or bcl-X(L) activity in these cells.

An improved rapid procedure for fluorescence in situ hybridization that is applicable to intraoperative cancer cytodiagnosis.

Fluorescence in situ hybridization (FISH) is among the most simple and useful methods for detecting numerical and structural aberration of chromosomes but it requires 12-24 h to complete. We devised a rapid FISH method that can be performed within 2 h. Here we describe the technique, which we have found to be extreme simple and as sensitive and specific as standard FISH, making it highly suitable for clinical use.

Inhibition of MAP kinase by sphingosine and its methylated derivative, N,N-dimethylsphingosine.

Endogenous sphingolipid metabolites such as ceramides and sphingosines have been increasingly recognized as lipid mediators of cell growth, differentiation and apoptosis. We have previously studied the ability of sphingosine (Sph) and N,N-dimethylsphingosine (DMS) to induce apoptosis in a variety of solid tumor cell lines. Here we report that in tumor cell lines displaying high mitogen-activated protein kinase activity (MAPK), treatment with 5 mu M of these sphingolipids significantly inhibited MAPK activity within 2-5 min (p < 0.005-0.01 as compared to controls) and induced apoptosis within hours. In contrast, untransformed cells and those tumor cell lines with low MAPK activity showed no significant change in activity and no apoptosis. High concentrations of C2-ceramide (50-100 mM), which induced apoptosis in the solid tumor cells, did not show significant effect on MAPK activity. MAPK activity was not directly inhibited in vitro, but tyrosine phosphatase activity was increased 2-4 fold in solid tumor cells by Sph or DMS (p < 0.01-0.05), suggesting that a phosphatase may play an important role in sphingolipid-directed MAPK regulation. Sph/DMS-induced apoptosis, but not MAPK inhibition, was blocked by protease inhibitors, indicating that MAPK inhibition is an earlier step of Sph/DMS-induced apoptosis than proteolysis. Furthermore, in human breast carcinoma MDA468 cells and human epidermal carcinoma A431 cells, both of which overexpress the epidermal growth factor (EGF) receptor, 20-200 nM EGF inhibited MAPK (p < 0.005-0.01) and induced apoptosis. These observations suggest that inhibition of the MAPK cascade may be involved in apoptotic signaling by Sph/DMS in some solid tumor cells, or by EGF in some cancer cells which overexpress the EGF receptor. Finally, the PKC-specific inhibitor, calphostin C, under conditions in which PKC is completely suppressed, inhibited MAPK activity and induced apoptosis only weakly in these solid tumor cells, whereas the non-specific PKC inhibitor staurosporine induced both apoptosis and MAPK inhibition significantly, suggesting that MAPK inhibition and apoptosis by Sph/DMS occurs independently of PKC in these cell lines, although these pathways may act cooperatively in other cell types. This study provides insight into possible mechanisms involved in sphingolipid-induced apoptosis in solid cancer tumor cell lines.

Role of milky spots as selective implantation sites for malignant cells in peritoneal dissemination in mice.

We investigated the significance of milky spots for malignant cells in peritoneal dissemination using three mouse carcinomatous peritonitis models. P388 leukemia and Colon 26 cancer cells were labeled with bromodeoxyuridine (BrdU) and mice were inoculated intraperitoneally. After 24 h the greater omentum and the mesenterium were removed and stained immunohistochemically with anti-BrdU antibody. The labeled cells were found to have preferentially infiltrated into the milky spots in these specimens. Next, using B16 PC melanoma cells, which can be easily distinguished from the other cells by the intrinsic black melanin, the distribution of the melanoma cells was observed macro- and microscopically following intraperitoneal inoculation. The melanoma cells were similarly found to have selectively infiltrated into the milky spots in the omentum and mesenterium after 1 day. Moreover, the melanoma cells were growing and forming distinct metastic lesions within the milky spots 1 week later.

Endoscopic local injection of a new drug delivery formulation, anticancer drug bound to carbon particles, for digestive cancers: pilot study.

A new dosage formulation consisting of an anticancer drug bound to activated carbon particles was developed for the treatment of digestive cancer in patients in whom operation is contraindicated. The new formulation is designed to distribute higher levels of anticancer drug to the regional lymph nodes and at the injection site compared to distribution of the drug in aqueous solution. In 12 patients with histologically proven carcinoma (7 with superficial esophageal cancer and 5 with early or proper muscle layer-infiltrating gastric cancer), an anticancer drug bound to carbon particles (total dose, 40-100 mg peplomycin or 250-500 mg methotrexate per person) was injected endoscopically into the primary lesions. Eleven of the 12 patients are currently alive, 12-64 months after therapy, or they died without evidence of cancer 12-98 months after the treatment. One patient has remained cancer-free for 32 months after a second course of the new formulation therapy given to treat a recurrence detected 26 months after the first treatment. Endoscopic injection of this new dosage formulation seems to control these digestive cancers in patients in whom operation is contraindicated.

Complete omentectomy and extensive lymphadenectomy with gastrectomy improves the survival of gastric cancer patients with metastases in the adjacent peritoneum.

BACKGROUND/AIMS: The omentum is the site where peritoneal metastases occur most frequently. It has not been shown whether complete resection of the omenta during gastrectomy improves the survival of gastric cancer patients with macroscopic peritoneal metastases. METHODOLOGY: We retrospectively analyzed 126 patients who underwent gastrectomies for gastric cancer with peritoneal metastases but without hematogenous metastases. The 126 patients were stratified according to their grade of peritoneal metastases into three groups: the P1 patients (patients with peritoneal metastases in the adjacent peritoneum but not in the distant peritoneum); the P2 patients (patients with a few peritoneal metastases in the distant peritoneum); and the P3 patients (patients with many metastases in the distant peritoneum). In each group, the survival and clinicopathological characteristics were compared between patients treated by complete resection of the greater omentum and the lesser omentum plus extensive lymphadenectomy during gastrectomy, versus patients treated by incomplete resection of the omenta and non-extensive lymphadenectomy during gastrectomy. RESULTS: Complete omentectomy and extensive lymphadenectomy during gastrectomy improved survival significantly only in the P1 patients. Other clinicopathological characteristics did not differ between them. CONCLUSION: Complete omentectomy and extensive lymphadenectomy is recommended in patients with peritoneal metastases in the adjacent peritoneum but not in the distant peritoneum.

Endoscopic incision and balloon dilatation for cicatricial anastomotic strictures.

BACKGROUND/AIMS: Endoscopic incision or balloon dilatation is common therapy for cicatricial anastomotic strictures after gastrointestinal surgery. These therapies are not always effective. METHODOLOGY: There were 6 patients who failed either endoscopic incision or balloon dilatation alone and who underwent a combination of the two therapies. Two or three small radial incisions were made in the scar of the stricture with the endoscopic electrocautery under direct vision with fiberscopy. Then, the incisions were split bluntly and the stenosis was dilated over 15-20 minutes with balloon-dilator. This procedure was performed once or twice at a 2-week interval. RESULTS: In 5 of the 6 patients, the stenosis was improved in subjective criteria and objective symptoms. In the last patient, only objective improvement was noted. There were no complications. CONCLUSIONS: Endoscopic incision plus balloon dilatation is an effective and safe treatment for cicatricial anastomotic strictures which have failed either therapy alone.

A case of hyperosmolar nonketotic coma occurring during chemotherapy using cisplatin for gallbladder cancer.

A 61 year-old woman was admitted to our hospital because of an abdominal tumor. She was diagnosed with recurrent gallbladder cancer, and treated with cisplatin (CDDP). On day 6, after the 1st cycle of chemotherapy, she developed confusion and suddenly became comatose. She was diagnosed as having hyperosmolar nonketotic coma (HNC) on day 7. She had no history of diabetes mellitus. She recovered from HNC after 3 days of treatment with continuous infusion of 0.45% saline and moderate amounts of insulin. HNC may be a complication of CDDP chemotherapy in patients with malignancy. Early diagnosis and appropriate treatment is necessary for HNC occurring during chemotherapy for malignant disease.

Bowel perforation during chemotherapy for non-hodgkin's lymphoma.

Bowel perforation in patients with primary malignant lymphoma usually occurs at the site of tumor. A 78 year-old man underwent chemotherapy for malignant lymphoma. He presented with abdominal pain. An emergency operation was performed under a diagnosis of panperitonitis. At laparotomy, an anal-side perforation approximately 20 cm from the Treiz ligament was observed. Drainage and partial resection of the jejunum was performed. Histopathologic examination demonstrated that there was no characteristic finding of malignant lymphoma around the perforation site in the case. Perforation of the small intestine is one of the most critical complications during the chemotherapy for malignant lymphoma. In cases of chemotherapy for malignant lymphoma, especially systemic administration, we should keep in mind the possibility of perforation of the small intestine. Fortunately, emergency surgery saved the patient presented in this report. Early diagnosis and treatment are important to improve prognosis of bowel perforation in patients with primary malignant lymphoma.

Genomic alterations in primary gastric cancers analyzed by comparative genomic hybridization and clinicopathological factors.

BACKGROUND/AIMS: Genetic changes during the oncogenesis and progression of gastric cancer remain unclear. The aim of our study was to analyze chromosomal aberrations in primary gastric cancers. METHODOLOGY: Using comparative genomic hybridization, we screened 47 primary gastric cancers for changes in the number of copies of DNA sequences. RESULTS: Gains of chromosome arms 20q (55%), 20p (36%), 17q (32%), 19q (30%) and 16p (30%), and losses of chromosome arms 4q (40%), 17p (40%), 5q (38%), 18q (30%) and 4p (28%) were detected most frequently. In addition, a high level of amplification was observed at 3q21 (2%), 6p21 (4%), 7q31 (6%), 8q23-24 (2%), 19q12-13 (2%), and 20q13 (2%). Among these alterations, the gain of 20q was the most frequent change. We then compared these changes with clinicopathological factors and identified signet ring cell carcinomas in 6 cases. Our study demonstrated no amplification of chromosome 20q in signet ring cell carcinoma in contrast to that in the other histologic types of gastric cancer. CONCLUSIONS: Our findings may be related to the morphologic and clinical features of signet ring cell carcinoma, and several oncogenes mapped on 20q may play an important role as determinants of the clinical and histologic features of gastric cancer.