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Peritoneal lavage with distilled water has been performed during colorectal cancer surgery. This study investigated the cytocidal effects of hypotonic shock in vitro and in vivo in colorectal cancer cells.Three human colorectal cancer cell lines, DLD1, HT29, and CACO2, were exposed to distilled water, and morphological changes were observed under a differential interference contrast microscope connected to a high-speed digital video camera. Cell volume changes were assessed using a high-resolution flow cytometer. Re-incubation experiments were performed to investigate the cytocidal effects of distilled water. In the in vivo experiment, cancer cells after hypotonic shock were injected intraperitoneally into mice and the degree of established peritoneal metastasis was subsequently evaluated. The effects of the blockade of Cl(-) channels on these cells during hypotonic shock were also analyzed.Morphological observations revealed a rapid cell swelling followed by cell rupture. Measurements of cell volume changes showed that mild hypotonic shock induced regulatory volume decrease (RVD) while severe hypotonic shock broke cells into fragments. Re-incubation experiments demonstrated the cytocidal effects of hypotonicity. In vivo experiments revealed the absence of peritoneal dissemination in mice in the distilled water group, and its presence in all mice in the control group. The blockade of Cl(-) channels increased cell volume by inhibiting RVD and enhanced cytocidal effects during mild hypotonic shock.These results clearly support the efficacy of peritoneal lavage with distilled water during colorectal cancer surgery and suggest that regulating of Cl(-) transport may enhance the cytocidal effects of hypotonic shock.

This study aimed to clarify the efficacy of anatomical resection (AR) for the treatment of hepatocellular carcinoma (HCC) compared with that of nonanatomical resection (NAR) based on the stratification of liver function (LF).The clinical records of 174 patients with a single HCC, 2-5 cm in diameter and without macroscopic vascular invasion, were analyzed. AR was performed in 132 patients and NAR was performed in 42 patients. The indocyanine green retention rate at 15 min (ICGR15) of the 78 patients classified as the good-LF group was 10-20 % and the ICGR15 of the 54 patients classified as the poor-LF group was 20-40 %.The 5-year overall survival (OS) and disease-free survival rates of the 174 patients were 67.6 and 33.4 %, respectively. Cox proportional hazard analysis identified ICGR15 ≥ 20 %, liver cirrhosis, α-fetoprotein ≥ 100 mg/dL, and infiltrating growth as independent prognostic factors. Liver cirrhosis was significantly less frequent in patients who underwent AR than in patients who underwent NAR (52 vs. 79 %, p = 0.002). In the subgroup analysis of the good-LF group, there were no significant differences in 5-year OS after AR and NAR (73.3 vs. 65.2 %, p = 0.857). By contrast, in the subgroup analysis of the poor-LF group, the 5-year OS after AR was significantly worse than after NAR (45.3 vs. 77.4 %, p = 0.044).In patients with an ICGR15 ≥ 20 %, we recommend NAR rather than AR for the treatment of a solitary 2-5-cm-diameter HCC and without macroscopic vascular invasion.

The purpose of this nonrandomized retrospective study was to report our new procedures using polyethylene glycolic acid (PGA) felt with fibrin sealant to prevent severe pancreatic fistula in patients undergoing pancreatic surgery.From 2000 to 2008, 54 and 63 patients underwent pancreaticoduodenectomy (PD) and distal pancreatectomy (DP), respectively. Of those patients, we applied PGA felt with fibrin sealant to 18 PD patients and 26 DP patients. In PD patients, the PGA felt was wrapped around the pancreatic suture site, while in DP patients, the PGA felt was wrapped around the predictive division site. The pancreaticojejunostomy site in PD patients and the cut stump in DP patients were coated with fibrin sealant. We compared the occurrence rates for severe postoperative pancreatic fistula (POPF) that occurred after PD or DP both with and without our new procedures.Before introduction of our procedures, severe POPF developed in 14 of 36 PD patients (39%) and 10 of 37 DP patients (27%). In contrast, after introduction of our procedures, the incidence of POPF was only one in both of 18 PD (6%; P = 0.016) and 26 DP (4%; P = 0.017) patients.In summary, our procedure using PGA felt with fibrin sealant may reduce the risk of severe POPF.

Aberrant methylation of promoter CpG islands is associated with transcriptional inactivation of tumor-suppressor genes in cancer. TFPI2, a Kunitz-type serine proteinase inhibitor, has been identified as a putative tumor-suppressor gene from genome-wide screening for aberrant methylation, using a microarray combined with the methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-aza-dCyd) in various types of tumors. We assessed the methylation status of TFPI2 and investigated its expression pattern in human primary gastric cancer (GC) tissues and in GC cell lines. Hypermethylation of the promoter CpG island, which was observed in more or less all of GC cell lines, was prevalent in a high proportion of primary GC tissues (15/18, or 83%), compared with noncancerous (4/18, or 22%) or normal (0/3, or 0%) stomach tissues, and expression of TFPI2 mRNA was reduced in 7 of the 17 primary GC tissues (41%). Moreover, immunohistochemical analyses showed decreased levels of TFPI-2 protein, compared with adjacent noncancerous tissues in 8 of the 20 primary GC tissues examined (40%). TFPI2 mRNA expression was restored in gene-silenced GC cells after treatment with 5-aza-dCyd. Aberrant methylation of TFPI2 promoter CpG island occurred not only in GC cells but also in primary GC tissues at a high frequency, suggesting that epigenetic silencing of TFPI2 may contribute to gastric carcinogenesis.

Hepatocyte growth factor (HGF) plays a definitive role in invasive, angiogenic, and metastatic activities of tumor cells by binding to the c-Met receptor. NK4, a competitive antagonist for HGF and the c-Met receptor, prevents tumor cell growth and metastasis via its bifunctional properties to act as an HGF antagonist and angiogenesis inhibitor. In the present study, we investigated the inhibitory effectiveness of NK4 on hematogenous pulmonary metastasis of the CT26 murine colon cancer cell line, focusing on tumor cell adhesion to endothelial cells. In an in vitro adhesion assay, HGF facilitated adhesion of CT26 cells to a murine endothelial cell line (F-2) in a dose-dependent manner. Furthermore, the enhancing effect of HGF on CT26-F-2 cell interaction was blocked by NK4 as well as by anti-HGF antibody. Similarly, HGF-induced phosphorylation of focal adhesion kinase (FAK), downstream of integrin signaling, was reduced by NK4 and by anti-HGF antibody. However, distinct integrin expression on the surface of CT26 cells was not altered by HGF. In an in vivo experimental pulmonary metastasis assay, stable NK4 expression potently decreased the number of pulmonary metastatic foci. The NK4-induced suppression of pulmonary metastasis was partially reversed when HGF was intraperitoneally administered in an adhesive phase. These results suggest that NK4 could act on tumor cells to inhibit CT26 adhesion to endothelial cells by reducing FAK phosphorylation, which is regulated by inside-out HGF/c-Met signaling, and thereby suppress hematogenous pulmonary metastasis.

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 (P0.003); 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.

Prospective randomized controlled studies have indicated that endoscopic placement of self-expandable metal stents (SEMSs)is an effective treatment option for patients with malignant gastric outlet obstruction (GOO). We report a case of effective palliation of gastric cancer-related jejunum stricture with a SEMS. A7 7-year-old woman, who had previously undergone partial remnant gastrectomy and Roux-en-Y reconstruction, was diagnosed with abdominal recurrence of gastric cancer. After a 4 month observation period, which the patient opted for with informed consent, recurrent vomiting and loss of appetite ensued. Computed tomography (CT) and upper gastrointestinal series (UGI) examinations revealed a single intestinal stenosis caused by a recurrent tumor. Endoscopic placement of a SEMS palliated this intestinal obstruction, and her oral intake improved (GOOSS score improved from 0 to 3). Upper gastrointestinal series verified that the SEMS maintained its lumen 3 months after the procedure. Endoscopic treatment with a SEMS can be more effective for malignant intestinal stenosis caused by abdominal recurrence of gastric cancer, especially when it is difficult to laparotomy adhesion derived previous operation or peritonitis carcinomatosa. Further studies may be needed to clarify the clinical benefits of stent placement for patients with abdominal recurrence of gastric cancer.

Recent advances in anti-cancer drug treatments enable us to improve prognosis in Stage IV gastric cancer. In particular, in recent reports patients with only cytology positive (CY1) non-curative factors have comparatively better prognosis than others. This study was designed to evaluate our outcomes, to allow identification of CY1 gastric cancer patients and to investigate new treatment strategies.Between 2000 and 2008, 336 patients underwent peritoneal washing cytology for gastric cancer intra-operatively. Of these, 35 patients (10.4%) were diagnosed with CY1 gastric cancer.1 ) In all CY1 gastric cancers, 1-year, 3-year, and 5-year survival rates were 49%, 11%, and 5.7%, respectively. Clinical factors such as number of non-curative factors (p=0.008) and gastrectomy (p=0.001)were significantly related to poor prognosis. 2 ) The number of CY1 patients with only CY1 non-curative factors (Group C) and multiple non-curative factors (Group CM)were 14 and 21, respectively. The number of CY1 patients with gastrectomy and without gastrectomy were 30 (MST 366 days, Group C: 14 Group CM: 16) and 5 (MST: 88 days, Group CM: 5), respectively. 3 ) In CY1 patients with gastrectomy, patients treated with S-1 based chemotherapy had better prognosis in both Group C and Group CM. 4 ) 8 CY1 patients with neoadjuvant chemotherapy (NAC) followed by gastrectomy (MST 501 days, 1-year survival rate 62.5%) tended to have better prognosis than those without NAC (MST 132 days, 1-year survival rate 25.0% (p= 0.055).Gastrectomy, number of non-curative factor, S-1 based chemotherapy and NAC were keys to improving prognosis by subgroup analyses in CY1 gastric cancer.

The present study investigated generational changes in the clinicopathological characteristics of younger patients with gastric carcinoma (GC). The medical records of 1,420 patients who had undergone gastrectomy for GC between 1997 and 2012 were reviewed retrospectively. The patients were divided into 2 groups based on age, with 49 patients below the age of 40 and 1,371 patients above the age of 40. Moreover, the clincopathological features of the 49 patients below the age of 40 were compared with age-matched GC patients who had undergone gastrectomy from 1985 to 1996. Younger GC patients group had a higher number of women and a higher incidence of undifferentiated GC, although there was no prognostic significance between the 2 groups. Comparison of three-generational younger GC patient groups (1985-1996, 1997-2002, and 2003-2012) demonstrated no difference in survival curve between the 3 groups, although a higher incidence of undifferentiated GC was observed with time. Furthermore, in younger patients with undifferentiated GC, the last generational group (2003-2012) had a tendency towards an improved prognosis in the early postoperative period. This study demonstrated that there was no prognostic significance between GC patients below the age of 40 and over the age of 40. Chemotherapy might contribute to improved prognosis in younger GC patients.

The aim of this study was to clarify the influence of a high body mass index (BMI) on short- and long-term outcomes of patients after esophagectomy for cancer.A total of 164 patients with a BM ≥ 18.5 who underwent esophagectomy for cancer from July 2008 through March 2013 were enrolled. Patients were divided into 2 groups according to BMI: BMI5 (normal BMI group) and BM ≥ 25 (high BMI group). Further, the short- and long-term outcomes after esophagectomy were retrospectively analyzed.The median BMI was 21.6. The high BMI group (n=26) had significantly more histological adenocarcinomas than the normal BMI group (p=0.003). Other clinicopathological factors such as the type of surgery performed, R0 resections, and perioperative complications, were not influenced by the BMI. There were no significant differences between the 2 groups in the 3-year disease-free rates and 3-year overall survival rates.Esophagectomy for patients with a high BMI is acceptable based on the similar short- and long-term outcomes when compared with normal BMI patients.

In advanced gastric cancer patients, preoperative multi detector row computed tomography (MDCT) often reveals abnormal ascites, which can indicate the possibility of peritoneal metastasis. The aim of this study was to clarify the clinical significance of preoperative ascites revealed by MDCT in gastric cancer patients. The study included a total of 183 advanced gastric cancer patients who underwent consecutive surgical procedures from February 2008 to November 2011. The results indicate that the presence of ascites on MDCT is significantly correlated with peritoneal metastasis (p.005), pathological T4 (p0.005), R1-R2 (p.01), and a positive diagnosis of peritoneal washing cytology(p.05). Multivariate analysis indicated that the presence of ascites on MDCT was an independent prognostic factor (hazard ratio[HR]2.6). In conclusion, the presence of ascites on preoperative MDCT is strongly associated with peritoneal metastasis, and might indicate the need for diagnostic laparoscopy to evaluate Stage IV factors and select the best treatment strategy.

The patient was a 48-year-old woman who was diagnosed with early gastric cancer during a long-term follow-up period for Gardner syndrome. Subtotal colectomy for colon leiomyoma was performed when the patient was 22 years old. Partial resection of the ileum was performed for ileum leiomyoma at the age of 27. Total resection of the remaining colon with ileostomy was performed for a pelvic desmoid tumor at the age of 40. In addition, resection of a desmoid tumor of the abdominal wall was performed 8 times in the 25 years since the first operation. During the follow-up for gastric polyps associated with Gardner syndrome, gastric cancer was detected from biopsy specimens of a wide range of the fundus polyps. Endoscopic resection was considered not to be applicable because of the extensive nature of the lesion. Total gastrectomy was also considered not to be applicable because of concerns about short bowel syndrome due to intestinal reconstruction. Therefore, proximal gastrectomy with esophagogastric anastomosis was performed. The pathological diagnosis was 0-IIa, 70 × 44 mm, tub1, m, ly0, v0, n0, PM (-), DM (-), stageIA. The postoperative course was uneventful, and the patient was discharged on postoperative day (POD) 16. We speculate that long-term survival of patients with Gardner syndrome without severe short bowel syndrome might result in carcinogenesis of gastric polyps.

This study was designed to establish a new diagnostic criteria of preoperative nodal status with high specificity on multidetector row computed tomography (MDCT) to extract advanced gastric cancer (GC) patients with an unfavorable prognosis. From total of 480 GC patients who underwent surgical resection, 58 consecutive patients with a preoperative diagnosis of nodal metastasis on MDCT were included in this retrospective study. Nodal status on MDCT was reassessed and a prognostic analysis was performed in the present study. Among several clinical nodal diagnostic criteria on MDCT, a cut-off value of the short-axis diameter measuring ≥15 mm showed the highest specificity (100 %). The prognostic analysis revealed that patients with nodal counts on MDCT of ≥3 (p = 0.035) as well as those with a nodal diameter ≥15 mm (p

Our previous studies suggest that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer. This study was conducted to determine whether alteration of RUNX3 gene expression could be detected in the normal-looking gastric remnant mucosa, and to ascertain any difference in the potential of gastric carcinogenesis between the anastomotic site and other areas in the remnant stomach after distal gastrectomy for peptic ulcer (RB group) or gastric cancer (RM group), by analysing RUNX3 expression with special reference to topography. A total of 89 patients underwent distal gastrectomy for gastric cancer from the intact stomach (GCI group) and 58 patients underwent resection of the remnant stomach for gastric cancer (RB group: 34 cases, RM group: 24 cases). We detected RUNX3 and gene promoter methylation by in situ hybridisation, quantitative reverse transcriptase–polymerase chain reaction (RT–PCR), and methylation-specific PCR. The interval between the initial surgery and surgery for remnant gastric cancer (interval time) was 10.4 years in the RM group, and 27.5 years in the RB group. Cancers in the RB group were significantly more predominant in the anastomosis area (P

Regenerating islet-derived family, member 4 (Reg IV) is a candidate marker for cancer and inflammatory bowel disease. In the present study, immunohistochemical analysis of Reg IV was performed in various human neoplastic (n = 289) and non-neoplastic tissues. In the stomach, foveolar epithelium was negative for Reg IV, whereas goblet cells of intestinal metaplasia and neuroendocrine cells at the base of intestinal metaplasia expressed Reg IV. Neuroendocrine cells of the small intestine and colon showed strong expression of Reg IV, whereas goblet cells of the small intestine and colon showed weak or no expression of Reg IV. Insulin-producing beta cells of the endocrine pancreas were positive for Reg IV. Among 143 gastric adenocarcinomas, Reg IV expression was detected in 42 (29.4%) and was associated with both the intestinal mucin phenotype and neuroendocrine differentiation. No association was found between Reg IV expression and clinical characteristics such as tumour stage and patient prognosis. Of 36 colorectal adenocarcinomas, 13 (36.1%) were positive for Reg IV, which was associated with tumour stage (p = 0.0379, Fisher's exact test). Expression of Reg IV was detected in 14 (93.3%) of 15 colorectal carcinoid tumours. Reg IV expression was also detected in 5 (21.7%) of 23 ductal adenocarcinomas of the pancreas. In contrast, lung cancers (n = 30) and breast cancers (n = 30) did not express Reg IV. This is the first immunohistochemical analysis of the expression and distribution of Reg IV protein in human tumours. These data suggest that Reg IV is expressed by gastrointestinal and pancreatic tumours, including adenocarcinomas and carcinoid tumours, and that Reg IV is associated with intestinal and neuroendocrine differentiation of the stomach and gastric carcinoma.

Advanced gastric cancer is often accompanied by metastasis to the peritoneum, resulting in a high mortality rate. Mechanisms involved in gastric cancer metastasis have not been fully clarified because metastasis involves multiple steps and requires a combination of altered expressions of many different genes. Thus, independent analysis of any single gene would be insufficient to understand all of the aspects of gastric cancer peritoneal dissemination. In this study, we performed a global analysis of the differential gene expression of a gastric cancer cell line established from a primary main tumour (SNU-1) and of other cell lines established from the metastasis to the peritoneal cavity (SNU-5, SNU-16, SNU-620, KATO-III and GT3TKB). The application of a high-density cDNA microarray method made it possible to analyse the expression of approximately 21 168 genes. Our examinations of SNU-5, SNU-16, SNU-620, KATO-III and GT3TKB showed that 24 genes were up-regulated and 17 genes down-regulated besides expression sequence tags. The analysis revealed the following altered expression such as: (a) up-regulation of CD44 (cell adhesion), keratins 7, 8, and 14 (epitherial marker), aldehyde dehydrogenase (drug metabolism), CD9 and IP3 receptor type3 (signal transduction); (b) down-regulation of IL2 receptor γ, IL4-Stat (immune response), p27 (cell cycle) and integrin β4 (adhesion) in gastric cancer cells from malignant ascites. We then analysed eight gastric cancer cell lines with Northern blot and observed preferential up-regulation and down-regulation of these selected genes in cells prone to peritoneal dissemination. Reverse transcriptase–polymerase chain reaction confirmed that several genes selected by DNA microarray were also overexpressed in clinical samples of malignant ascites. It is therefore considered that these genes may be related to the peritoneal dissemination of gastric cancers. The results of this global gene expression analysis of gastric cancer cells with peritoneal dissemination, promise to provide a new insight into the study of human gastric cancer peritoneal dissemination. British Journal of Cancer (2002) 87, 1153–1161. doi:10.1038/sj.bjc.6600580 www.bjcancer.com © 2002 Cancer Research UK

This report describes the case of a 34-year-old premenopausal woman in whom bilateral huge ovarian metastases were found immediately after initial surgery for sigmoid colon cancer. Both ovaries had been intact at the time of sigmoidectomy, but 2 months later, she complained of persistent vaginal bleeding, and large bilateral metastases were detected in both ovaries. Oophorectomy with intraperitoneal chemotherapy proved ineffective and the patient died 3 months later, after a second operation, from peritoneal dissemination. This case report serves to demonstrate the importance of searching for synchronous or nonsynchronous metastases to the ovaries after surgery for colon cancer in young women. Consideration should also be given to the feasibility of performing prophylactic oophorectomy or administering intensive chemotherapy in association with colon resections for carcinoma for premenopausal women because of the ineffectiveness of these modalities as treatment for metastatic disease.

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.

Background The term "early recurrence" of pancreatic cancer has not been well-defined in most previous studies. Methods The clinical records of 86 patients who underwent macroscopic curative pancreatectomy for pancreatic cancer between 2000 and 2009 were retrospectively examined. We divided 55 patients who experienced disease recurrence into two groups, the early and late recurrence groups, using the minimum p value approach. The relationships between the interval prior to recurrence and clinical outcomes were investigated. Results The cumulative 5-year overall survival rates for all 86 patients were 30.2%. For 55 patients who experienced disease recurrence, the optimal cut-off value for differentiating early ( n = 37) and late ( n = 18) recurrence based on the overall survival was 12 months ( p = 0.0000045). The Cox proportional hazard analysis identified carbohydrate antigen 19-9 > 100 U/ml ( p = 0.017) and surgical margin ( p = 0.007) as the independent prognostic factors associated with overall survival. Positive surgical margin ( p = 0.037) and severe venous invasion ( p = 0.005) were identified as independent factors associated with early recurrence. Conclusion Twelve months after pancreatectomy is the optimal cut-off value for defining early versus late recurrence based on the overall survival. Early recurrence was related to the status of the surgical margin and venous invasion.

To analyze hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) using the tumor-node-metastasis (TNM) staging system.We retrospectively analyzed 372 patients with HCC who underwent hepatectomy between 1980 and 2009. We studied the outcomes of HCC patients with PVTT to evaluate the American Joint Committee on Cancer TNM staging system (7(th) edition) for stratifying and predicting the prognosis of a large cohort of HCC patients after hepatectomy in a single-center. Portal vein invasion (vp) 1 was defined as an invasion or tumor thrombus distal to the second branch of the portal vein, vp2 as an invasion or tumor thrombus in the second branch of the portal vein, vp3 as an invasion or tumor thrombus in the first branch of the portal vein, and vp4 as an invasion or tumor thrombus in the portal trunk or extending to a branch on the contralateral side.The cumulative 5-year overall survival (5yrOS) and 5-year disease-free survival (5yrDFS) rates of the 372 patients were 58.3% and 31.3%, respectively. The 5yrDFS and 5yrOS of vp3-4 patients (n = 10) were 20.0%, and 30.0%, respectively, which was comparable with the corresponding survival rates of vp1-2 patients (P = 0.466 and 0.586, respectively). In the subgroup analysis of patients with macroscopic PVTT (vp2-4), the OS of the patients who underwent preoperative transarterial chemoembolization was comparable to that of patients who did not (P = 0.747). There was a significant difference in the DFS between patients with stage I HCC and those with stage II HCC (5yrDFS 39.2% vs 23.1%, P0.001); however, the DFS for stage II was similar to that for stage III (5yrDFS 23.1% vs 13.8%, P = 0.330). In the subgroup analysis of stage II-III HCC (n = 148), only alpha-fetoprotein (AFP)100 mg/dL was independently associated with DFS.Hepatectomy for vp3-4 HCC results in a survival rate similar to hepatectomy for vp1-2. AFP stratified the stage II-III HCC patients according to prognosis.

It is of great clinical concern to preoperatively predict the need for blood transfusions during hepatectomy for hepatocellular carcinoma (HCC).A total of 168 consecutive patients undergoing elective hepatectomy for HCC were retrospectively reviewed. We investigated preoperative factors potentially influencing intraoperative blood transfusion and established a predictive scoring system for intraoperative blood transfusion.Thirty-eight patients (22.6%) received red cell blood transfusion during surgery. A preoperative predicting scoring system for blood transfusion was constructed using the following four factors: platelet count10×10(4)/mm(3) (2 points), α-fetoprotein ≥80 ng/ml (1 point), tumor size ≥4.0 cm (1 point), and major hepatectomy (1 point). The nomogram showed an area under the curve (AUC) of 0.760. This scoring system was highly predictive for blood transfusion (AUC=0.758). When the score was 0 points, the incidence of intraoperative blood transfusion was 3%. The rate increased to 10% and 38% when the score was 1 and 2 points, respectively, and reached 45% when the score was 3 points or more.This predictive scoring system would be useful for preoperatively assessing the need for intraoperative blood transfusions during hepatectomy for HCC.

We perform preoperative chemoradiotherapy for patients with advanced lower rectal cancer in our department. In April 2012, we started laparoscopic lateral lymph node dissection for preventive dissection in patients without lateral lymph node enlargement on preoperative diagnosis. We compared the short-term results of laparoscopic lateral dissection with those of laparotomy.The subjects comprised 43 patients undergoing lateral dissection by laparotomy( open group) and 5 patients undergoing laparoscopic lateral dissection (lap group).There were no significant differences in the baseline characteristics of patients between the lap group and the open group. However, operative time (min) was significantly longer( 536.2 vs 324.8) and the volume of blood loss( g) was significantly lower( 139.0 vs 697.8) in the lap group. No significant differences were observed in the number of dissected lymph nodes, postoperative complications, or the duration of hospital stay.Although the operative time was longer with laparoscopy-assisted lateral lymph node dissection, this procedure was safely performed with minimal blood loss. Our findings confirmed that there were no problems with standardization of this technique or oncological outcomes, and hence, we are examining the indications for therapeutic dissection.

We encountered a case of esophageal squamous cell carcinoma (ESCC) with submucosal tumor (SMT)-like tumor in the cardia of the stomach, formed by direct invasion of the gastric wall. The patient was a 72-year-old woman with dysphagia. Upper endoscopy showed a giant SMT-like tumor in the cardia of the stomach, and imaging studies revealed metastasis to the nearby and distant lymph nodes. Although squamous cell carcinoma was diagnosed by biopsy of the SMT-like tumor in the gastric cardia, gastric involvement was suspected via metastasis to the perigastric lymph nodes or direct invasion of the gastric wall by the ESCC, because the primary lesion of ESCC could not be identified during the examinations. FP chemotherapy (days 1-5, 800 mg/m2 5-fluorouracil[5-FU]; day 1, 80 mg/m2 cisplatin[CDDP]) was initiated for the treatment of ESCC. Considering the risk of invasion, we discontinued the chemotherapy and performed lower esophagectomy and cardiectomy. Pathologically, the primary lesion of the ESCC was detected in the abdominal esophagus, and the SMT-like tumor in the gastric cardia was determined to result from direct invasion of the gastric wall by the ESCC. We herein report a rare case of ESCC with an SMT-like tumor in the gastric cardia formed by direct invasion of the gastric wall.

Chylothorax following resection for esophageal carcinoma is a relatively rare complication. There is no proven therapy for chylothorax. We report 5 cases of chylothorax following resection for esophageal carcinoma that were cured by Lipiodol lymphangiography. The tumor was located in the middle thoracic esophagus and cervical esophagus in 4 and 1 cases, respectively. The depth of tumor invasion before preoperative therapy was T4 and T1b in 3 and 2 cases, respectively. The thoracic duct was ligated and resected in 2 cases and preserved in 3 cases. Chylothorax was diagnosed on the basis of the identification of chyle-like hydrothorax, and conservative therapy was initiated in all cases. However, it was not effective. Therefore, continuous subcutaneous octreotide was instituted in 3 cases. The discharge from the thoracic tube persisted. Eventually, Lipiodol lymphangiography was performed in all cases. The pleural effusion drainage decreased immediately, and the thoracic drain was withdrawn 5-9 days after lymphangiography in 4 cases. However, the volume of discharge did not change, and therefore, thoracic duct ligation was performed in 1 case. Lipiodol lymphangiography was performed for chylothorax following esophageal carcinoma resection in 5 cases. It was effective in 4 cases. Lipiodol lymphangiography may be an effective therapeutic method for treating conventionally untreatable chylothorax.

Our recent studies indicate that omental milky spots are frequently involved in the early stage of peritoneal cancer dissemination. We have used carcinoembryonic antigen (CEA)-specific RT-PCR for omental milky spots to predict peritoneal recurrence in gastric cancer patients. CEA mRNA was found to be positive in both 10 peritoneal washes and 16 greater omenta of 30 gastric cancer patients, including all 6 patients who showed positive results for both cytology and RT-PCR of peritoneal wash and omentum. Three of the 6 cases with positive RT-PCR in the greater omentum but not in the peritoneal wash showed recurrence of peritoneal carcinomatosa within 2 years after operation. Micrometastasis on omental milky spots was histologically confirmed in 6 of 30 gastric cancer cases. Non-specific band was detected only in the omentum of 1 case of 15 benign disease (7%), but not in peritoneal washes (0%), probably due to weak expression of CEA in mesothelial cells. Our results show that CEA-specific RT-PCR targeting micro-metastases on omental milky spots is more sensitive than targeting the peritoneal wash or conventional cytology, and suggest that this method is useful for the prediction of peritoneal recurrence in gastric cancer patients. © 2001 Wiley-Liss, Inc.

Thirty-five hepatocellular carcinomas (HCCs) associated with hepatitis C virus (HCV) were analysed by comparative genomic hybridization (CGH), to screen for changes in copy-number of DNA sequences. Chromosomal losses were noted in 1p34–36 (37%), 4q12–21 (48%), 5q13–21 (35%), 6q13–16 (23%), 8p21–23 (28%), 13q (20%), 16q (33%) and 17p13 (37%). Gains were noted in 1q (46%), 6p (20%), 8q21–24 (31%) and 17q (43%). High level gains indicative of gene amplifications were found in 7q31 (3%), 11q13 (3%), 14q12 (6%) and 17q12 (3%); amplification at 14q12 may be characteristic for HCCs. No significant difference in chromosomal aberrations was noted between carcinomas associated with HCV-infection in our study and those reported earlier in HCCs infected with hepatitis B virus (HBV), indicating that both HBV- and HCV-related carcinomas may progress through a similar cascade of molecular events. © 1999 Cancer Research Campaign

ACR-CH, which consists of aclarubicin (ACR) adsorbed onto activated carbon particles, was developed for locoregional chemotherapy for breast cancer. Thirty patients with breast cancer received an ACR (10 mg) injection intra- and peri-tumorally, either as ACR-CH or as ACR aqueous solution (ACR-AQ) 5 min before the operation for breast cancer. The ACR concentrations were significantly higher in the peritumoral regions and regional lymph nodes, and were also significantly lower in the blood plasma in patients given ACR-CH versus patients given ACR-AQ.

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.

The aim of this study was to characterize changes in outcome following hepatectomy for hepatocellular carcinoma (HCC) over a 30-year period.The clinical records of 372 patients who underwent a macroscopic curative hepatectomy for treatment of HCC between 1980 and 2009 were retrospectively examined. Patients were divided into two groups: an early group (1980-2000) and a late group (2001-2009). The relationship between the chronological treatment period and the surgical outcomes was investigated.The disease-free survival (DFS) was comparable between the early and late groups (at 5 years: 30.3% vs. 31.2%, p=0.526), however, the overall survival (OS) of the late group was significantly better than the one of the early group (at 5 years: 80.1% vs. 50.4%, p0.001), with this being an independent prognostic factor. Among the 148 patients who underwent transarterial chemoembolization (TACE) for initial hepatic recurrence, the OS after initial recurrence of the late group was significantly better than that of the early group (p=0.002). The OS after initial recurrence was significantly better in patients who underwent repeat hepatectomy than in those who underwent TACE (p=0.044).The results of hepatectomy for HCC have improved over time by use of various combination therapies after initial HCC recurrence. A repeat hepatectomy may be an acceptable treatment option for HCC recurrence in selected patients.

Although metastasis to subcarinal or main bronchial lymph nodes (LNs) is common in patients with esophageal cancer, the procedure for their dissection using a laparoscopic transhiatal approach (LTHA) has not been established because of the difficulties associated with this surgery. We developed a novel and simple technique for their dissection using LTHA.An abdominal wall sealing device was placed in the upper abdomen, and four ports were inserted. After division of the gastrosplenic ligament by hand-assisted laparoscopic surgery, the esophageal hiatus was opened and carbon dioxide was introduced into the mediastinum. The pericardial adipose tissue was divided, and the pericardium was exposed. The posterior plane of the pericardium was separated and extended, and the anterior side of the subcarinal LNs and bilateral main bronchial LNs were separated. The posterior side of these LNs was then separated. Finally, while lifting these LNs like a membrane, they were resected from the bilateral main bronchi and tracheal bifurcation. The treatment outcomes of 18 patients with esophageal cancer who underwent subcarinal and main bronchial LN dissection by LTHA were compared with those of 19 patients who underwent the procedure by video-assisted thoracic surgery.The number of resected subcarinal and main bronchial LNs in the two groups was not significantly different. The total operative time and total operative bleeding in the two groups was also not significantly different. Postoperative factors, such as the extubation time after surgery, frequency of postoperative complications, and the length of the postoperative hospital stay in the two groups was not significantly different.Our surgical procedure resulted in a good surgical view of the mediastinum, and en-bloc dissection of the subcarinal and main bronchial LNs was performed safely.

This is a case report of cholangiectasis with cholangiocarcinoma in a 37-year-old female. Both computed tomography (CT) and endoscopic retrograde cholangio-pancreatography (ERCP) demonstrated gallstone, and intrahepatic bile duct dilatation with the stone. The diagnosis was intrahepatic cholangiectasis without common bile duct-dilatation. Hepatectomy of segment 3 with resection of the extrahepatic bile duct and reconstruction of the biliary tract was performed. Upon pathological examination, an early stage of cholangiocarcinoma was pointed out within the small range of common bile duct without dilatation or stone. Cholangiocarcinoma with cholangiectasis has been reported to be induced by counter flow of pancreas and intestinal juice because of the pancreaticobiliary maljunction. So we usually choose a diversion operation as our tactics to get rid of the counter flow of those digestive juices. Despite the above-mentioned tendency, this is a very rare case of carcinogenesis in common bile duct without dilatation.

Lymph node (LN) metastasis in colorectal cancer (CRC) is a critical factor in making accurate prognoses and therapeutic decisions. This study evaluated the clinical performance of the one-step nucleic acid amplification (OSNA) assay in accurately diagnosing LN metastases in CRC patients through the specific detection of cytokeratin 19 mRNA levels in LNs.The OSNA assay was performed on 121 LNs dissected from early-stage CRC patients (pStage 0 or I) or from patients with benign colorectal disease (study 1). Separately, 385 LNs were dissected from 85 CRC patients (any stage); the OSNA assay was performed on half of each LN, and the results were compared with histopathological examination in 2-mm intervals of the other LN half (study 2).In study 1, all 121 histopathologically negative LNs were also negative by the OSNA assay (concordance rate for metastasis negative: 1.0, 95% confidence interval [95% CI]: 0.976-1.0). In study 2, the concordance rate between the OSNA assay and the 2-mm-interval histopathological examination was 0.971 (95% CI: 0.950-0.984), with a sensitivity of 0.952 (95% CI: 0.881-0.987) and a specificity of 0.977 (95% CI: 0.953-0.991).The OSNA assay provided a judgment performance equivalent to a 2-mm-interval histopathological examination, a more detailed assay than the common pathological examination. Therefore, the OSNA assay is considered a new molecular examination method for the diagnosis of LN metastases in CRC patients in clinical settings.

RUNX3 is a novel gastric cancer tumor suppressor. RUNX3 promoter hypermethylation is associated with many types of cancer, including colorectal cancer. Furthermore, the RUNX3 promotor is one of the CpG island methylator phenotype (CIMP)-specific promotors. CIMP is a distinct phenotype associated with microsatellite instability (MSI) in colorectal cancer. In this study, the suitability of the quantitative analysis of RUNX3 promoter hypermethylation as a novel serum tumor marker was investigated. Moreover, we investigated the relationship between RUNX3 promoter methylation and MSI in colorectal cancer.A RUNX3 real-time quantitative methylation-specific PCR (RTQ-MSP) technique we developed was used to analyze the CpG sites in the RUNX3 promoter of 119 colorectal tumors and 344 sera from colorectal cancer patients. MSI analysis of 119 colorectal tumors was performed with five microsatellite markers (BAT25, BAT26, D5S346, D2S123, and D17S250).Proximal colon tumors exhibited significantly higher RUNX3 methylation than their paired normal tissues (p=0.0438). Analysis of the clinicopathological parameters revealed that a proximal location (p=0.0054), lymphatic invasion (p0.0001), and an advanced pathological stage (p=0.0018) were associated with significantly higher RUNX3 methylation. Assessment of the relationship between RUNX3 methylation and tumor MSI revealed 11 out of 13 tumors with high-frequency MSI (85%) were positive for RUNX3 hypermethylation, significantly more than the tumors with low-frequency MSI or which were microsatellite stable (34%, p=0.0070). In preoperative sera from 344 colorectal cancer patients, significantly higher RUNX3 methylation was associated with lymphatic invasion (p=0.0487) and an advanced pathological stage (p=0.0466). Post-operative follow-up data revealed that recurrence cases exhibited significantly higher preoperative serum RUNX3 methylation than non-recurrence cases (p=0.0003). Concomitant analysis of carcinoembryonic antigen (CEA) levels in the preoperative sera showed that 17.7% (61/344) were CEA-negative but RUNX3 methylation-positive, which means assessing both serum RUNX3 methylation and CEA should improve diagnosis of colorectal carcinoma.RTQ-MSP-based quantification of serum RUNX3 methylation is useful for the detection and monitoring of colorectal cancer.

RELN (Reelin) is an extracellular glycoprotein that plays a critical role in neuronal migration. Here we show that the RELN gene is frequently silenced in gastric cancers (GCs) by aberrant promoter hypermethylation. Although RELN was strongly expressed in non-tumor gastric epithelia, its expression was weak, or absent, in GC cell lines and primary GC tumors. Absence of RELN expression significantly correlated with a more advanced stage of GC. Methylation of the RELN promoter was frequently found in GC cell lines and in primary GC tumors. These findings suggest that disruption of the RELN pathway may be involved in gastric carcinogenesis.

Hepatocyte growth factor (HGF) has been shown to be involved in malignant behaviors, such as invasion and metastasis, in different tumors. Hence, HGF could be a target molecule for control of the malignant potential of cancer. NK4 is a competitive antagonist for HGF and exerts an antitumor activity, not only by HGF antagonism but also by antiangiogenesis. Here, we studied the participation of cellular immunity in CT26 tumor regression by NK4 gene transfer. In vivo experiments showed that NK4-induced inhibition of subcutaneous tumor growth (as demonstrated in immunocompetent BALB/c mice) was weakened in T lymphocyte-deficient nude mice. In addition, the immunocompetent BALB/c mice that had shown complete regression of CT26-NK4 tumors generated an immune memory against repeated challenge with the same tumor antigen. Immunohistochemistry of tumor-infiltrating lymphocytes showed that the ratio of CD8/CD4 in CT26-NK4 tumors was significantly higher than that in control tumors. Also, the presence of tumor-specific cytotoxic T lymphocytes (CTL) was demonstrated by cytotoxicity assays. Depletion of CD8+ T lymphocytes markedly abrogated the antitumor activity of NK4. However, NK4 had no direct effect on the in vitro cellular immune system. Taken together, these data indicate that NK4 expression by gene transfer, at the tumor site, triggers tumor-specific CTL activation, resulting in complete CT26 tumor regression in vivo. This action was considered to be due to apoptosis induced by NK4's potent antiangiogenic and HGF antagonistic effects.

The anti-cancer drug aclarubicin (2.0 mg/kg body weight) was injected into the left popliteal lymph node (the primary draining node of the foot-pad region) or into the tail vein, 8 days after a subcutaneous inoculation of 5 x 10(5) P388 leukemia cells/mouse in the left hind paw foot-pad of mouse (donor). During this time, metastases were established in the lower para-aortic nodes (the secondary draining nodes of this region). On day 10, the lower para-aortic nodes taken from each donor were transferred intraperitoneally to a normal mouse (recipient). From the recipients' survival time, the viable P388 leukemia cell number in the para-aortic nodes per donor mouse was estimated with a calibration line. The recipients' survival curve in the intralymphatic chemotherapy group was statistically significantly better than that in the intravenous chemotherapy group.

Objective: Regenerating islet-derived family, member 4 (regenerating gene type IV, Reg IV) is overexpressed in colorectal cancer (CRC). The aim of this study was to investigate the diagnostic utility of Reg IV determination in sera from patients with CRC. Methods: We examined the expression and distribution of Reg IV in CRC by immunohistochemistry and determined Reg IV levels in sera from patients with CRC by enzyme-linked immunosorbent assay. Results: Immunostaining revealed that 23 of 80 (29%) CRC cases were positive for Reg IV. CRC cases with metastatic recurrence in the liver showed more frequently Reg IV staining than those without (p = 0.0102). Patients with CRC showing Reg IV staining had a significantly worse survival than those without Reg IV staining (p = 0.0117). Preoperatively, serum Reg IV concentrations were not elevated in CRC patients at stage 0–III, being in contrast to the significantly increased preoperative levels in stage IV CRC patients with liver metastasis. Conclusion: These results suggest that Reg IV is a prognosticator for poor survival. Serum Reg IV concentration may predict CRC recurrence in the liver.

Primary peritoneal adenocarcinoma is rare, originating in the paramesonephric duct (müllerian duct). We report two cases of primary peritoneal adenocarcinoma. Both patients received a surgical resection. The pathological diagnosis of the resected specimen was papillary adenocarcinoma with clear cell carcinoma. The response after the combination chemotherapy using CDDP and TS-1 was "PR", and these treatments were effective to improve the patients' quality of life in each case.

AIM: To determine the best cut-off value between the early and late recurrence periods after the initial recurrence of hepatocellular carcinoma (HCC). METHODS: The clinical records of 404 patients who underwent macroscopic curative hepatectomy for HCC between 1980 and 2010 were retrospectively examined. We divided the 252 patients experienced a recurrence of HCC into two groups, the early and late recurrence groups using the “minimum P-value” approach. Factors for early recurrence were investigated using all 404 patients, and factors related to late recurrence were investigated in the patients who were confirmed to be recurrence free at the end of the early recurrence period. RESULTS: For the 252 patients who experienced a recurrence, the optimal cut-off value for differentiating early and late recurrence based on the overall survival after initial recurrence was 17 mo (5-year overall survival after initial recurrence: 15.4% vs 36.3%, P = 0.000018). Cox proportional hazard analysis identified early recurrence (P = 0.003) as one of the independent prognostic factors associated with overall survival after initial recurrence. A logistic regression model showed that an alpha-fetoprotein level > 100 ng/mL (P < 0.001), multiple HCC (P < 0.001), serosal invasion (P = 0.031), and microvascular invasion (P = 0.012) were independent factors associated with early recurrence, whereas the only independent factor related to late recurrence was liver cirrhosis (P = 0.002). CONCLUSION: Seventeen months after hepatectomy is a useful cut-off value between early and late recurrence of HCC based on the prognosis and different etiologies.

Purpose: Our previous results suggested that a lack of RUNX3 function contributed to human gastric carcinogenesis, but the role of RUNX3 in progression and metastasis remains unclear. We examined RUNX3 expression in clinical samples of peritoneal metastases in gastric cancers. Changes in metastatic potential were assessed in animal experiments using stable RUNX3 transfectants of gastric cancer cells. Finally, global expression changes were analyzed using a cDNA microarray. Experimental Design and Results: Significant down-regulation of RUNX3 through methylation on the promoter region was observed in primary tumors (75%) as well as in all clinical peritoneal metastases of gastric cancers (100%) compared with normal gastric mucosa. Stable transfection of RUNX3 inhibited cell proliferation slightly, and modest transforming growth factor-β (TGF-β)–induced antiproliferative and apoptotic effects were observed. Interestingly, it strongly inhibited peritoneal metastases of gastric cancers in animal model (P < 0.01). Furthermore, we did globally analyzed expression profiles of ∼21,000 genes in parent cells and stable transfectant of RUNX3 using a cDNA microarray. Microarray analysis identified ∼28 candidate genes under the possible downstream control of RUNX3, some of these genes were considered to be possibly involved in peritoneal metastases, which were related to signal transduction (vav3, TOLL-like receptor, MAPKK, MET, S1 00A1 1, and cathepsin E), apoptosis (caspase 9), immune responses (CD55 and TLR1O), and cell adhesion (sialyltransferase 1 and galectin 4). Some of the genes are involved in the TGF-β signaling pathway. Conclusion: These results indicate that silencing of RUNX3 affects expression of important genes involved in aspects of metastasis including cell adhesion, proliferation, apoptosis, and promoting the peritoneal metastasis of gastric cancer. Identification of such genes could suggest new therapeutic modalities and therapeutic targets.

Correct preoperative diagnosis of jejunal cancer is difficult, and there are no clear guidelines for the postoperative follow-up to monitor the recurrence of jejunal cancer. This report describes asynchronous ovarian metastasis from jejunal cancer occurring after initial operation. The patient was a 68-year-old postmenopausal woman with a preoperatively correctly diagnosed jejunal cancer. Partial resection of the jejunum with regional lymph node dissection was performed, with both ovaries intact at the first operation. Three months later, vaginal bleeding and a large metastasis in the left ovary were detected, for which a left oophorectomy was performed. Peritoneal dissemination was also detected perioperatively, so that chemotherapy with 5-FU/leukovoline was started. The patient is still alive more than 12 months after the most recent operation. Our case demonstrates that it is necessary to pay careful attention to synchronous or non-synchronous metastases to the ovaries after operation for jejunal cancer in females. Consideration should also be given to the efficacy of oophorectomy for ovarian metastases and of intensive chemotherapy combined with jejunal resection for carcinoma because of the poor prognosis of these treatment modalities.

Peritoneal metastasis is the most frequent form of recurrence for advanced gastric cancer. We previously performed a global analysis of the gene expression of gastric cancer cell lines established from peritoneal metastasis with cDNA microarray. One of the up-regulated genes is L-3 phosphoserine phosphatase (L3-PP). We have examined its potential as a novel marker for the detection of peritoneal micrometastasis of gastric cancer. L3-PP mRNA in peritoneal wash in 93 gastric cancer patients was quantified for comparison of carcinoembryonic antigen (CEA) mRNA by means of real-time RT-PCR to predict peritoneal recurrence. The quantity of L3-PP and CEA correlated with wall penetration. Eleven out of 18 cases with peritoneal dissemination were L3-PP+ (61% sensitivity). For three out of 18 cases of peritoneal dissemination, only L3-PP could detect micrometastasis of gastric cancer. Consequently, free cancer cells that cannot be detected by CEA mRNA could be detected using L3-PP mRNA. Although CEA alone was not sufficient, L3-PP and CEA in combination can attain a higher accuracy of detection.

Our previous studies suggest that lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer, but potential roles of other members of the RUNX family genes have not yet been reported. We examined the expression of 3 Runt-related (RUNX) genes, RUNX1, RUNX2 and CBFB, in gastric cancer cell lines and primary gastric cancer specimens and compared them to those of RUNX3 reported earlier in conjunction with clinicopathologic factors. Expression of RUNX family genes in 9 gastric cancer cell lines, 56 primary gastric cancer specimens and surrounding normal gastric mucosa were estimated by Northern blot analysis, quantitative RT-PCR and in situ hybridization. Northern blot analysis in gastric cancer cell lines showed downregulation of RUNX1 and RUNX3 in 67% and 78% of the cell lines tested, respectively. The ratio of the average RUNX mRNA/beta-actin mRNA ratio (x10(3)) for RUNX1 was 48.0 +/- 21.1 vs. 21.4 +/- 8.1; RUNX2, 1.1 +/- 0.3 vs. 1.0 +/- 0.2; RUNX3, 9.2 +/- 6.3 vs. 3.1 +/- 1.3 and CBFB, 42.0 +/- 19.4 vs. 21.0 +/- 8.4 (normal vs. tumor, respectively, average +/-SD). The basal RUNX2 expression was very weak, and there was no significant change in gastric cancers. Both RUNX1 and RUNX3 showed remarkable downregulation in 62% and 69%, respectively, of surgically resected specimens compared to surrounding mucosa analyzed by quantitative RT-PCR (p < 0.01). Furthermore, CBFB, the gene encoding the cofactor of RUNX1, -2, -3, was also downregulated in significant fraction (32%, p < 0.05). The percentage of downregulation of RUNX1, RUNX3 and CBFB increased as the cancer stage progressed. Tricostatin A and 5'-azacitidin reactivate RUNX3 expression, but they could not reactivate expression of RUNX1 and CBFBeta in gastric cancer cells, suggesting that the downregulation was due to mechanisms other than methylation of the promoter region. These findings suggest that RUNX1 and CBFBeta in addition to RUNX3 play some roles in gastric cancers and that roles of RUNX gene family in gastric cancer are more widespread and complex than previously realized.

The purpose of this retrospective study was to evaluate the clinical presentation as well as surgical intervention for ovarian metastasis from colorectal cancers identified during postoperative follow-up.Nine cases of ovarian metastasis were observed among 452 female patients with colon cancers between 1990 and 2000. Initial symptoms were pain (67%), pelvic mass (50%), vaginal bleeding (33%), and uterine bleeding (17%). On pathological evaluation, six cases (67%) were found to be moderately differentiated, and three (33%) well differentiated adenocarcinomas.Early diagnosis is very difficult. The growth of metastatic ovarian tumors are slow in elder patients, its growth is rapid in younger patients, and frequently diagnosed as huge ovarian tumors. In some cases, as cystic ovarian lesions they were identified in their early stage but could not be diagnosed as ovarian metastases, later curative operation could not be performed. The consulting gynecologist could not reach the correct diagnosis. Regular postoperative pelvic CT or MRI should be helpful for diagnosis. Although serum CEA levels did not increase in most cases, tumor markers CA125 and SLX were elevated in several cases, and thus may be useful for the detection of ovarian metastases. Surgical treatment consisted of bilateral and unilateral salpingo-oophorectomy or pelvic exenteration and additional hysterectomy for one patient because of association with cervical cancer. The median survival time after the primary operation was 20.8 months, ranging from 3 to 96 months. Peritoneal dissemination and bone metastases were frequently observed as recurrence after these operations. Two cases (non-synchronous solitary metastasis or direct involvement, located in the pelvis) survived more than 5 years (85 and 96 months, respectively), and both patients were treated with pelvic exenteration.This suggests that in general most cases with ovarian metastasis have a poor prognosis and that radical operation such as pelvic exenteration can improve survival only in cases of recurrent solitary ovarian metastasis or local extended disease, i.e. when the lesion is located only in the pelvis.

Peritoneal metastasis is the most frequent form of recurrence for advanced gastric cancer. We previously performed a global analysis of the gene expression of gastric cancer cell lines established from peritoneal metastasis with cDNA microarray. One of the up-regulated genes is L-3-phosphoserine phosphatase (L3-PP). We have examined its potential as a novel marker for the detection of peritoneal micrometastasis of gastric cancer. L3-PP mRNA in peritoneal wash from 88 gastric cancer patients was quantified for comparison of carcinoembryonic antigen (CEA) mRNA by means of real-time RT-PCR with a fluorescently-labeled probe to predict peritoneal recurrence. The quantity of L3-PP and CEA correlated with wall penetration. The cut-off value was set at the upper limit of the quantitative value of T1 cases (tumor invades within submucosa) and those above the cut-off value constituted the micrometastasis (MM+) group; eight out of 14 cases with peritoneal dissemination were MM+ L3-PP (57.1% sensitivity) and two out of 57 T1 and T2 cases were MM+ (93% specificity). For two out of 14 cases of peritoneal dissemination only L3-PP could detect micrometastasis of gastric cancer, indicating that L3-PP is superior to CEA especially in poorly-differentiated adenocarcinoma. The combination of CEA and L3-PP improved the accuracy of diagnosis up to 85.7%. Consequently, free cancer cells that cannot be detected by CEA mRNA could be detected using L3-PP mRNA. CEA alone was not sufficient, but L3-PP and CEA in combination can attain a higher accuracy of detection.

Our recent analysis of gastric cancers and colorectal cancers using comparative genomic hybridization revealed a novel, high frequent copy number increases the long arm of chromosome 20 in association with possible involvement of liver metastases and poor prognosis. This led to further comparative genomic hybridization analysis of chromosomal aberrations in primary tumors of esophageal squamous cell carcinoma. The aim of the study presented here was to analyze the chromosomal aberrations and to determine the numbers of copies of AIB1, BTAK, DcR3 and E2F1 as putative target genes on chromosome 20q as well as their expression and relation to clinicopathological features in 41 primary tumors of esophageal squamous cell carcinoma.We used comparative genomic hybridization to screen 41 primary tumors of esophageal squamous cell carcinoma for changes in the number of copies of DNA sequences. To further characterize the gain of DNA sequences at 20q, we also performed fluorescence in situ hybridization analysis. We examined the relationship between these changes and clinicopathological factors.Gains in chromosome arm 20q were detected (34.1%) as well as a high level of gain in 20q12-13 (4.8%). AIB1 amplification was observed in 4.9% (2/41), BTAK amplification in 9.8% (4/41), DcR3 amplification was in 4.9% (2/41), and E2F1 amplification in 7.3% (3/41). The survival of patients with BTAK or E2F1 amplification was significantly lower than that of patients without these abnormalities.These findings provide evidence for a number of previously unknown genomic aberrations in esophageal squamous cell carcinoma, suggesting the existence of target regions relevant to its progression. Esophageal squamous cell carcinoma with 20q gain showed extensive lung metastases, pleural effusion and liver metastases and poorer prognosis compared to cases without 20q gain. Our results suggest that amplification of BTAK or E2F1 are likely to lead to an increase in the number of malignant phenotypes of esophageal squamous cell carcinoma and that these aberrations can be expected to be useful as markers of poor prognosis.

Generally, patients with advanced rectal cancer in whom surgical treatment is contraindicated receive radiation or chemotherapy. In such patients, we have administered local injection of methotrexate and mitomycin C bound to activated carbon particles. Four patients received intratumoral injection of the dosage formulation (total dose 100-400 mg of methotrexate or 8-32 mg of mitomycin C) under colonofiberscope. After the treatment, bleeding and pain were lessened in all 4 patients. In two patients, the tumor markedly decreased in size and there was no regrowth prior to death 12-14 months after the treatment. In another patient, bleeding and pain disappeared until the patient died of pulmonary and liver metastases. The fourth patient is alive without regrowth 5 months after treatment. Side effects were not severe.

For the regeneration of injured peripheral nerves, we have devised a PGA-tube that is composed of a tube of polyglycolic acid containing collagen sponge. This PGA-tube was applied clinically to reconstruct a peripheral nerve that had been resected during extended surgical resection of for intrapelvic recurrent rectal cancer. Four months after the surgical resection, the function of the left hip joint has improved remarkably, whereas the function had been lost just after the operation. It is suggested that the PGA-tube will be useful for regeneration of peripheral nerves that are resected during operation for intrapelvic malignancy.

Background: A novel distal subtotal gastrectomy was performed in 5 patients with macroscopically node-positive gastric cancer located in the greater curvature of the middle stomach. In these patients, total gastrectomy or standard distal subtotal gastrectomy has been typically performed. In these typical gastrectomies, the hepatic and the coeliac branches of the vagi are removed en bloc with the left gastric artery and the whole of the lesser omentum because the lymphatics along the left gastric artery are in the lower stream-regions of lymph flow from the cancer and metastases exist potentially. Methods: During novel distal subtotal gastrectomy the activated carbon method confirmed that the lymphatics along the ascending branch of the left gastric artery were not in the lower stream-region of lymph flow from the cancer. Then, we preserved the hepatic and coeliac branches of the vagi as well as the ascending branch of the left gastric artery and the upper part of the lesser omentum. The other arteries feeding the stomach were removed with the surrounding lymphatics. In novel distal subtotal gastrectomy the remnant stomach was fed only by the ascending branch of the left gastric artery, while in standard distal subtotal gastrectomy the remnant stomach was fed by the short gastric arteries. Conclusions: Although further examinations are necessary, novel distal subtotal gastrectomy may have superior merit such as good function of gallbladder because of the preservation of the vagal nerve system, compared with total gastrectomy or standard distal subtotal gastrectomy.

Comparative genomic hybridization (CGH) was used to screen for changes in the number of DNA sequence copies in 30 primary colorectal cancers and 16 liver metastases, to identify regions that contain genes important for the development and progression of colorectal cancer. In primary colorectal cancer, we found frequent gains at 7p21 (36.7%), 7q31-36 (30%), 8q23-24 (43.0%), 12p (30%), 14q24-32 (33.3%), 16p (40.0%), 20p (33.3%), 20q (63.3%) and 21q (36.3%), while loss was often noted at 18q12-23 (36.7%). In metastatic tumors, there were significantly more gains and losses of DNA sequences than in primary tumors, with gains at 8q23-24 (found in 62.5% of recurrences vs. 43.0% of primary tumors), 15q21-26 (37.5% vs. 20.0%), 19p (43.8% vs. 20.0%) and 20q (81.3% vs. 63.3%) and losses at 18q12-23 (50.0% vs. 36.7%). The pattern of genetic changes seen in metastatic tumors, with frequent gains at 8q23-24 and 20q and loss at 18q12-23, suggests the progression of colorectal cancer. We investigated a clinical follow-up study for all patients examined by CGH and directed our attention to the genetic changes consisting of gains at 8q and 20q. The incidence of liver metastases was higher in patients with primary colorectal cancer with these genetic changes. Gains at 8q and 20q might be useful to identify patients at high risk for developing liver metastases.