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Recurrent gastric cancer(GC)with splenic metastasis showed poor prognosis, and its treatment strategy remains unclear. Recently, studies identified the considerable prognostic effect of metastasectomy in GC following intensive chemotherapy. Here, we successfully treated a patient with Epstein-Barr virus-positive esophagogastric junctional cancer with splenic metastasis who underwent metastasectomy and obtained pathological complete response following immune checkpoint therapy and had long-term survival. We reviewed the literature to discuss the clinical significance of our treatment strategy.

Enteral nutrition has been reported to be safe and effective in malnourished patients undergoing upper gastrointestinal surgery. In this study, we devised night home enteral nutrition (N-HEN) as a novel nutritional strategy and evaluated the efficacy in gastric cancer patients following total gastrectomy. Between January 2017 and March 2021, 24 patients were prospectively included in the protocol and supported by N-HEN for three postoperative months through a jejunostomy during the night (Elental:1200 kcal/day), and 22 patients without N-HEN were followed as a control group (CG). Body weight loss, nutritional indicators and tolerance to chemotherapy were evaluated. After 3 and 6 months, patients with N-HEN had significantly less body weight loss than CG (3 months P P P P = 0.0037). Albumin, total protein and hemoglobin, tended to be higher after 3 and 6 months in patients with N-HEN than CG, and total cholesterol after 6 months. Concerning the tolerance to adjuvant chemotherapy in Stage II–III patients, patients with N-HEN significantly had a higher completion rate (P = 0.0420: N-HEN 70% vs. CG 29%) and longer duration (P = 0.0313: N-HEN 458 days vs. CG 261 days) as planned. Continuous monitoring of blood glucose concentration in patients with N-HEN did not show nocturnal hypoglycemia or hyperglycemia. N-HEN could be a novel enforced and physiologically effective nutritional strategy to support potentially malnourished patients following total gastrectomy.

Stage Ⅳ gastric cancer(GC)with ovarian metastasis showed poor prognosis and its treatment strategy remains unclear. Recent studies identified the favorable prognostic effect of conversion surgery in Stage Ⅳ GC following intensive chemotherapy. We report here a case with advanced GC and ovarian metastasis, who underwent conversion surgery for them followed by chemotherapy and had a long-term survival. We reviewed the literatures in order to discuss clinical significance of our treatment strategy.

KEYNOTE-158 and 061 trials revealed the efficacy and safety of pembrolizumab(KEYTRUDA®)treatment in patients with recurrent high microsatellite instability(MSI-high)gastric cancer following gastrectomy. Here, we successfully treated an elderly case with recurrences following radical gastrectomy for advanced gastric cancer using pembrolizumab as a second- line chemotherapy. Even in elderly patients, pembrolizumab might contribute to effective and safe treatment in late-line chemotherapy for recurrent MSI-high gastric cancer.

Postoperative low nutrition, body weight loss and poor QOL are pivotal clinical issues for elderly patients following total gastrectomy for advanced gastric cancer. Here, we report a successfully treated high-risk elderly case using home night enteral nutrition and adjuvant chemotherapy following laparoscopic total gastrectomy for advanced gastric cancer. Home night enteral nutrition might not impair oral intake and daily QOL, and could be a useful treatment strategy for elderly patients following total gastrectomy.

TAGS trial revealed the efficacy and safety of trifluridine/tipiracil(Lonsurf®)treatment in patients with metastatic gastric cancer following gastrectomy. Here, we successfully treated 38 months survival case after recurrences following radical gastrectomy for advanced adenocarcinoma of esophago-gastric junction using historical recommended chemotherapy regimens and trifluridine/tipiracil as a fifth-line chemotherapy. Trifluridine/tipiracil therapy contributed to effective and safety treatment even in late-line chemotherapy for recurrent gastric cancer.

A 74-year-old woman presented with abdominal discomfort and was diagnosed with an unresectable advanced gastric cancer(T4aN3aM1, stage Ⅳ)based on a thorough examination. S-1/cisplatin therapy was administered as first-line treatment and paclitaxel/ramucirumab therapy as the second-line treatment. However, because the patient developed a peritoneal dissemination and her lymph node metastasis increased despite these regimens, nivolumab was introduced as a third- line treatment. The CT scan revealed that after the 5 courses of nivolumab, both the peritoneal dissemination and metastatic lymph nodes shrunk; after 12 courses of nivolumab, the peritoneal dissemination almost disappeared. Although nivolumab, an anti-programmed cell death-1(PD-1)antibody, has the possibility to cause immune-related adverse events not seen with conventional chemotherapy, in the present case, these events did not occur and the antitumor effects were maintained for a relatively long period without a decrease in the performance status(PS). We experienced a case of peritoneal metastasis from gastric cancer with a good response to nivolumab. Herein, this case is reported with some literature review.

Nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1(PD-1), was approved for use in the treatment of patients with advanced gastric or gastroesophageal junction cancer who had been previously treated with B2 chemotherapy regimens in Japan.We investigated the efficacy of nivolumab therapy in 15 consecutive patients with advanced gastric cancer between October 2017 and December 2018 in our facility.In our study, the 6-month overall survival rate was 67.7%, and the median survival time(MST)was 6.3 months. Immune-related adverse events(irAEs)occurred in the following patients: 2 patients, interstitial pneumonia(13%); 1 patient, myocarditis (6.7%); 1 patient, hypothyroidism(6.7%); and 1 patient, liver dysfunction(6.7%). Of the patients with an absolute lym- phocyte count(ALC)of C2,000/mL at baseline, 33%(4/12)experienced irAEs, while of those with an ALC of2,000/mL, 67% had irAEs. The 6-month overall survival rate was better in patients with an ALC1,600/mL(100%, 4/4)than in those with an ALC of C1,600/mL(35%, 4/11). The 6-month overall survival rate of the patients with a neutrophil-to-lymphocyte ratio(NLR)of4 was 63%, which was better than the 33% rate in those with an NLR of B4.Nivolumab therapy was a safe and feasible treatment option. The cutoff values of ALC of 2,000/mL for irAEs and of ALC of 1,600/mL and NLR of 4 for prognosis might be effective surrogate markers in nivolumab treatment.

Laparoscopy and endoscopy cooperative surgery(LECS)is an excellent surgical procedure that prevents excessive resection of the gastrointestinal wall and maintains gastrointestinal functions. However, LECS is not recommended for large gastrointestinal stromal tumor(GIST)sized more than 5 cm and/or ulcerative GIST because of the oncological risk of peritoneal dissemination. Here, we report the case of an elderly patient who was successfully treated with LECS-assisted open partial gastrectomy for an ulcerative GIST near the esophagogastric junction.

The stomach is an organ considered resistant to ischemia because of the microvascular networks in the stomach wall, and gastric remnant necrosis following gastrectomy is rare. Herein, we report a case of gastric remnant necrosis following gastrectomy successfully treated using a conservative approach.An 83-year-old woman underwent laparoscopic distal gastrectomy, D1 plus lymphadenectomy, Billroth Ⅰreconstruction, and suture closure of the esophageal hiatus for early gastric cancer and giant esophageal hiatal hernia. The amylase level of the drainage fluid was abnormally high on postoperative day(POD)3, and contrast-enhanced CT confirmed gastric remnant necrosis. The patient was treated using a conservative approach, as her general condition was stable. Postoperative fluoroscopy on POD 21 revealed contrast media leakage from the gastric remnant; however, adequate drainage was observed. Upper gastrointestinal(GI)endoscopy on POD 23 demonstrated circumferential gastric remnant necrosis, whereas GI endoscopy on POD 52 revealed a decrease in the size of the gastric remnant, proliferation of the granulation tissue, and regeneration of mucosa in the gastric remnant.Gastric remnant necrosis following gastrectomy is a rare complication and is associated with poor prognosis. In most cases, total resection of the remnant stomach is warranted. However, for high surgical risk cases, conservative treatment options should be considered based on an assessment of patients' general condition.

The 8th edition of the UICC TNM Classification was released in 2017 and introduced N3a/N3b groupings for gastric cancer. The purpose of this study was to evaluate the validity of the new classification for Stage Ⅲ gastric cancer.Clinical and pathological data on 388 patients who underwent R0 resection from January 1992 to December 2016 in our institution were retrospectively analyzed. The survival in the 7th and 8th edition stage groupings were compared. Differences in survival according to N classification were also examined in the groups with T4a tumor depth.1. The 5-year overall survival(OS)probabilities for Stage ⅢA, ⅢB, and ⅢC of 7th edition were 47.6%, 55.0%, and 28.5%(p=0.0003)and the recurrence-free survival(RFS)rates were 81.1%, 79.4%, and 58.7%(p=0.0013), respectively. In contrast, the OS probabilities of the 8th edition were 50.2%, 41.3% and 30.1%(p=0.0009)and the RFS were 81.6%, 70.9% and 50.0%(p=0.0003), respectively. 2. For T4a tumor depth, the OS probabilities of N1, N2, N3a, and N3b were 48.8%, 54.0%, 27.5%, and 25.1%(p=0.0012)and the RFS were 82.7%, 81.2%, 57.0% and 48.7%(p=0.0013), respectively.The 8th edition of the UICC TNM classification may provide better accuracy than that of the 7th edition in predicting the prognosis of Stage Ⅲ gastric cancer.

Lesser curvature lymph node dissection is often performed at the end of the procedure in laparoscopic distal gastrectomy. In obese patients, it can be difficult to secure a visual field, and bleeding or injury of the remnant stomach may occur.After separating the duodenum using an automated suturing instrument, the stomach is rolled under the left diaphragm. An assistant holds the gastric angle near the lesser curvature with forceps in the right hand, and pulls the stomach cephalad toward the left side of the patient. As a result, the region from the esophagogastric junction to the gastric angle is aligned, enabling use of an ultrasonically activated scalpel from the right side of the operator. Dissection is performed from around the posterior wall of the esophagogastric junction to the gastric angle. After dissecting the posterior wall as much as possible, dissection of the anterior wall is performed to complete the lesser curvature procedure.This technique enables safe and reliable dissection of the lesser curvature while avoiding bleeding and damage to the stomach wall.

Laparoscopy and endoscopy cooperative surgery(LECS)is an excellent surgical procedure that utilizes the advantages of both methods. Furthermore, non-exposed endoscopic wall-inversion surgery(NEWS)is a more promising procedure that enables avoidance of tumor exposure of and dissemination to the abdominal cavity. However, NEWS has the potential risk of postoperative ulceration, leading to delayed perforation because of mucosal defect. We invented a modified NEWS, which was a safe procedure, by including the all-layer suture to close the mucosal defect. We present a case of gastrointestinal stromal tumor(GIST)near the esophagogastric junction, which was treated with modified NEWS.

The REGATTA trial revealed that chemotherapy is the standard strategy for gastric cancer patients with Stage Ⅳ factors. However, some recent studies have identified the prognostic effect of conversion surgery after complete response to Stage Ⅳ factors during chemotherapy. Here, we report a case with Stage Ⅳ factors successfully treated via intensive chemotherapy and conversion surgery without any adverse events and complications, using preoperative parenteral hyper-nutrition and postoperative enteral nutrition. Nutrition might be the key strategy during the treatment of gastric cancer patients with Stage Ⅳ factors.

The prognosis of patients with gastric cancer and stage IV factors is poor. However, several recent studies have identified that curative surgery followed by S-1 chemotherapy for cytology positive (CY1) only patients contributed to a better prognosis. This study was designed to compare the prognosis between curative and palliative gastrectomy followed by chemotherapy in CY1 only stage IV gastric cancer. Between 2001 and 2016, 1507 patients underwent gastrectomy for gastric cancer. Of these, 51 consecutive patients with only CY1 factor who underwent gastrectomy followed by chemotherapy were enrolled in this study. (1) Twenty three (45%) patients underwent curative D2 or D2+ gastrectomy, and the remaining 28 (55%) patients underwent palliative gastrectomy, followed by S-1 based or another historical recommended chemotherapy postoperatively. (2) Compared with patients undergoing palliative gastrectomy, patients undergoing curative gastrectomy had a significantly better prognosis (P = 0.042; median survival time: curative vs. palliative, 22.6 months vs. 11.8 months) and a lower incidence of recurrences (P = 0.091). Two- and five-year overall survival rates of patients following curative gastrectomy were 48.2% and 18.2%, respectively. A multivariate analysis showed that venous invasion [P = 0.006; hazard ratio (HR), 3.70 (95% CI: 1.27–9.43)] and curative gastrectomy [P

Re-laparotomy with resection of the mesh after abdominal incisional hernia repair may cause recurrence of the hernia and infection of the mesh. In the present study, we performed laparoscopic distal gastrectomy(LDG)for early gastric cancer without the resection of the mesh in such a case. A 82-year-old man who had undergone abdominal vascular replacement, cholecystectomy, abdominal incisional hernia repair with the mesh, sigmoidectomy had local recurrence of gastric cancer after endoscopic submucosal resection. We diagnosed as cStage IA and performed LDG without resection of the mesh. He had no recurrence of hernia nor infection of the mesh. Minimizing damage to the abdominal wall by laparoscopic surgery can prevent them.

Nearly 70% of gastric cancer recurrences occur as peritoneal dissemination. Most of the treatment for recurrence of gastric cancer dissemination is chemotherapy; depending on the symptoms and the site of recurrence, palliative bypass surgery may be performed. Intensive treatment is often difficult for elderly patients over 85-years-old. This case was a 91-year-old female who underwent total gastrectomy for gastric cancer(signet-ring cell carcinoma)7years prior. Two years ago, a stenosis due to recurrence was revealed in the small intestine and bypass surgery was performed. At that time, she was 89-years-old, and chemotherapy was continued for 1 year. Six months ago, recurrence was revealed in the esophago-jejuno anastomosis. Since the stenosis was severe, it was possible to resume oral reconstitution by inserting a metallic stent. Chemotherapy(S-1)is currently ongoing. There are few reports of long-term treatment for recurrence of gastric cancer peritoneal dissemination in elderly people over 80 years of age. This report is a case of long-term survival involving multidisciplinary treatments, which improved the quality of life(QOL)over the age of 90 years.

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

We previously performed a global analysis of the gene expression of gastric cancer cell lines established from metastases to the peritoneal cavity with the cDNA microarray method, which made it possible to analyse the expression of approximately 21168 genes for the identification of novel markers for the detection of micrometastases in the peritoneal cavity. One of the upregulated genes is dopa decarboxylase (DDC), which is responsible for the synthesis of the key neurotransmitters dopamine and serotonine. We have examined its potential as a novel marker for the detection of peritoneal micrometastases of gastric cancer.DDC mRNA in the peritoneal wash from 112 gastric cancer patients was quantified for comparison of carcinoembryonic antigen (CEA) mRNA by means of real-time reverse transcriptase-polymerase chain reaction (RT-PCR) with a fluorescently labelled probe to predict peritoneal recurrence. The quantity of DDC and CEA correlated with wall penetration. Real-time RT-PCR could quantitate 10-10(6) DDC-expressing gastric cancer cells per 10(7) mesothelial cells. The cutoff value was set at the upper limit of the quantitative value for noncancer patients, and those above this cutoff value constituted the micrometastasis (MM+) group. Of 15 cases with peritoneal dissemination, 13 were MM+DDC (87% sensitivity), and one of 48 t1 cases was MM+ (98% specificity). DDC levels in peritoneal washes from patients with synchronous peritoneal metastases were more than 50 times higher than in those from patients without metastasis (P

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

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.

Our recent analysis of gastric cancers using comparative genomic hybridization (CGH) revealed a novel high frequent copy number increase in the long arm of chromosome 20. Tumour-amplified kinase BTAK was recently cloned from breast cancers and mapped on 20q13 as a target gene for this amplification in human breast cancers. In the study presented here, we analysed BTAK copy-number and expression, and their relation to the ploidy pattern in 72 primary gastric cancers. Furthermore, wild-type BTAK and its deletion mutants were transfected to gastric cancers to examine changes in cell proliferation and DNA ploidy pattern. Evaluation of 72 unselected primary gastric cancers found BTAK amplification in 5% and overexpression in more than 50%. All four clinical samples with BTAK amplification showed aneuploidy and poor prognosis. Transfection of BTAK in near-diploid gastric cancers induced another aneuploid cell population. In contrast, the c-terminal-deleted mutant of BTAK induced no effect in DNA ploidy pattern and inhibited gastric cancer cell proliferation. These results suggest that BTAK may be involved in gastric cancer cell aneuploid formation, and is a candidate gene for the increase in the number of copies of the 20q, and thus may contribute to an increase in the malignant phenotype of gastric cancer. © 2001 Cancer Research Campaign http://www.bjcancer.com

A 70-year-old woman with unresectable advanced gastric cancer accompanied by peritoneal dissemination underwent jejunostomy, and was treated with S-1 and low-dose CDDP. One course consisted of S-1 (80 mg/day) via an intestinal fistula tube from days 1 to 14. This was followed by 7 days rest, and CDDP (20 mg/day) was administered by 1-hour continuous intravenous infusion on day 1 and 8. She continued to receive this chemotherapy for a total of 14 courses, followed by 3 courses of a weekly paclitaxel regimen. She died 14 months after surgery. All chemotherapy had been conducted in an outpatient setting. We concluded that the administration of S-1, combined with low-dose CDDP (div) through a jejunostomy, can improve the quality of life (QOL) of a patient who has unresectable advanced gastric and is incapable of oral intake. We report this rare case with a review of the literature.

We have examined the utility of DDC as a novel marker for the detection of peritoneal micrometastases of gastric cancer. DDC mRNA in the peritoneal wash from 114 gastric cancer patients was quantified for a comparison of carcinoembryonic antigen (CEA) mRNA by means of real-time RT-PCR with a fluorescently labeled probe to predict peritoneal recurrence. The cut-off value was set at the upper limit of the quantitative value for non-cancer patients, and those above this cut-off value constituted the micrometastasis (MM+) group. Thirteen of 15 cases with peritoneal dissemination were MM+DDC (87% sensitivity), and one of 48 t1 cases was MM+ (98% specificity). DDC levels in peritoneal washes from patients with synchronous peritoneal metastases were more than 50 times higher than in those from patients without metastasis (p0.01). For 15 cases of peritoneal dissemination (seven cases were cytologically positive), DDC was positive in 13 cases (87% sensitivity), but CEA failed to detect micrometastases in four cases (73% sensitivity), indicating that DDC is in some cases superior to CEA for the detection of peritoneal micrometastases of gastric cancer in terms of sensitivity as well as specificity, especially for poorly differentiated adenocarcinomas. Combination of CEA and DDC improved the accuracy of diagnosis up to 93%. These results suggest that DDC is potentially a novel marker for peritoneal dissemination of gastric cancer and that quantitative RT-PCR of DDC is reliable and efficient for the selection of patients for adjuvant intraperitoneal chemotherapy to prevent peritoneal recurrence.

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.

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 previous study using cDNA microarray showed that differentially expressed genes among gastric cancer cells involved in peritoneal dissemination could be positively identified. One of these genes, which is overexpressed, is inositol 1,4,5-trisphosphate receptor type 3 (IP3R3). IP3R3 is responsible for the intracellular Ca2+ release channel and for mobilizing stored Ca2+. Three different receptor types have been molecularly cloned and their genes have been classified into a family. However, the role of the IP3 signaling pathway in the peritoneal dissemination of gastric cancer is still unclear. In the study presented here, the IP3R3 is showed to be overexpressed in gastric cancer cell lines established from malignant ascites, but weakly expressed in a gastric cancer cell line established from primary tumor as well as normal gastric epithelial cells. IP3R1 and 2 are only weakly or not expressed in these cells. The antagonist of IP3R, 2APB, inhibited cell proliferation and induced apoptosis in gastric cancer cells from malignant ascites at concentrations of 100 nM to 100 microM in a dose-dependent manner. On the other hand, 2APB showed a weak effect on other gastric cancer cells established from primary tumors (SNU1), lymph node metastases or liver metastases (MKN1 or 74), methothelial cell lines Met5A and myeloid leukemia HL60 cells. This suggests that this inhibitory effect depends on the level of IP3R3 expression. As cells which express IP3R3 mRNA (i.e. pancreas ascinar cells) are known to have a secretory function in which IP3/Ca2+ signaling has been shown to be involved, IP3R3 may be a prerequisite for secretion of an enzyme, such as protease, in gastric cancer cells. These results indicate that IP3R3 may be specifically involved in gastric cancer peritoneal dissemination and that IP3R3 may be a molecular target of the peritoneal dissemination of gastric cancer. Its antagonist, 2APB, may thus be useful for the specific treatment of peritoneal dissemination of gastric cancer.

Our previous study using a cDNA microarray demonstrated that positive identification of differently expressed genes among gastric cancer cells involved in peritoneal dissemination could be accomplished. One of these genes with overexpression is inositol 1, 4, 5-trisphosphate receptor type 3 (IP3R3). IP3R3 is an intracellular Ca2+ release channel responsible for mobilizing stored Ca2+. Three different receptor types have been molecularly cloned, and their genes have been classified into a family. But the role of the IP3 signaling pathway in the peritoneal dissemination of gastric cancers is still unclear. In this study, IP3R3 is overexpressed in gastric cancer cell lines established from malignant ascites, but weakly expressed in gastric cancer cell lines established from primary tumor as well as in normal gastric epithelial cells. IP3R1 and 2 are expressed only weakly or not at all in these cells. The antagonist of IP3R, 2-APB, inhibited cell proliferation and induced apoptosis of gastric cancer cells from malignant ascites at concentrations of 100 nM to 100 microM in a dose dependent manner. Conversely, 2-APB showed a weak effect on other gastric cancer cells established from primary tumors (SNU1), lymph node metastases or liver metastases (MKN1 or 74), methothelial cell lines Met5A and myeloid leukemia cell HL60 cells. This suggests that this inhibitory effect depends on the level of IP3R3 expression. As cells that express IP3R3 mRNA (i.e., pancreatic aciner cells) are known to have a secretory function in which IP3/Ca2+ signaling has been shown to be involved, IP3R3 may be a prerequisite for secretion in gastric cancer cells. These results indicate that IP3R3 may be specifically involved in gastric cancer peritoneal dissemination and that IP3R3 may be a molecular target of the peritoneal dissemination of gastric cancer. Its antagonist, 2-APB, may thus be useful for the treatment of gastric cancer, especially for peritoneal dissemination.