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Competing Interests: The authors declare that they have no conflict of interest.

Introduction: Studies have reported the feasibility of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) in elderly people with respect to both short- and long-term outcomes. As the elderly population in society increases, the requirement for managing super-elderly patients aged ≥85 years with EGC will also increase. This study aims to identify the long-term clinical outcomes of ESD for clinical T1N0 EGC in patients aged ≥85 years., Methods: A total of 370 consecutive patients aged ≥85 years with clinical T1N0 EGC who were managed in 11 institutions were reviewed retrospectively. On the basis of treatment strategy, we compared the overall survival (OS) and disease-specific survival (DSS) after performing propensity score-matched analysis between patients undergoing ESD (ESD group) and those not undergoing treatment (conservative treatment group). The potential prognostic factors were also investigated in the propensity score-matched patients., Results: After propensity score matching, we found that the 3-year OS and DSS rates were significantly higher in the ESD group than in the conservative treatment group (OS, 82.2% vs. 50.5%; p < 0.001; DSS, 100% vs. 80.1%; p = 0.008). Furthermore, ESD was identified as a significant factor for prolonged OS, whereas Charlson comorbidity index (CCI) ≥3 and prognostic nutritional index (PNI) <36.2 were associated with reduced OS., Conclusion: ESD was associated with improved OS in patients with clinical T1N0 EGC aged ≥85 years compared with the absence of treatment. Furthermore, CCI and PNI were helpful for patient selection., (© 2022 S. Karger AG, Basel.)

Background and Aim: Post-endoscopic submucosal dissection electrocoagulation syndrome (PECS) has become a common adverse event after colorectal endoscopic submucosal dissection (ESD) and esophageal ESD. However, little is known about PECS after gastric ESD. Therefore, this study aimed to investigate the clinical features of PECS after gastric ESD., Methods: Patients who underwent ESD for gastric cancer or adenoma between January 2016 and December 2017 were retrospectively investigated. PECS was clinically diagnosed based on the presence of upper abdominal pain and localized abdominal tenderness with a temperature of >37.5°C, without perforation. We analyzed the clinical features of PECS., Results: A total of 637 ESD cases were enrolled; PECS occurred in 32 patients (5.0%), all of whom were diagnosed on postoperative Day 1. Among PECS cases, unplanned prolongation of hospitalization or fasting period was observed in 15 patients (47%). As a result, the median durations of hospitalization and fasting period were significantly longer in PECS cases (P = 0.008 and P < 0.001, respectively); however, the mean differences were less than a day. Additionally, all PECS cases recovered with conservative treatment., Conclusions: PECS is considered a common adverse event after gastric ESD. More than half of patients with PECS could start diets and be discharged as well as those without PECS., (© 2021 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

A 59-year-old man was treated for early gastric cancer with endoscopic submucosal dissection (ESD) 10 years prior to the study. Two months after the first ESD, he was diagnosed with recurrence on the ESD scar and treated via ESD again. The horizontal margin could not be evaluated because of cauterization, and the patient was carefully observed. He was admitted to our hospital complaining of low backache and diagnosed with disseminated carcinomatosis of the bone marrow associated with gastric cancer after examination. Although he started chemotherapy, he died after 6 months. In this study, we report a rare case of disseminated carcinomatosis of the bone marrow associated with gastric cancer, which developed 10 years after ESD.

Epstein-Barr virus (EBV) latently infects malignant epithelial cells in approximately 10% of all gastric cancers. Latent membrane protein 1 (LMP1), an oncogenic protein, plays an important role in malignant transformation in EBV-associated nasopharyngeal carcinoma and B-cell lymphoma; however, its expression has not been detected in EBV-associated gastric cancer. To address why LMP1 has not been detected in EBV-positive gastric tumors, we focused on the interactions between LMP1-positive and -negative cells and stably expressed LMP1 in the gastric cancer cell line AGS. We showed that the number of LMP1-positive cells decreased gradually with each cell passage when the cells were co-cultured with LMP1-negative cells. Time-lapse imaging showed that LMP1-positive cells were eliminated from a monolayer of LMP1-negative cells. Furthermore, LMP1-positive cells stimulated the proliferation of surrounding LMP1-negative cells, but not LMP1-positive cells, via exosome-mediated EGFR activation. Our data indicate that LMP1 expression drives cell competition between LMP1-positive and -negative cells, affecting the behavior of the cells within gastric tissue.

Background/objective: Laparoscopic gastrectomy (LG) is increasingly used to treat gastric cancer. Simultaneously, internal hernia (IH) has been reported after LG with Roux-en-Y reconstruction (RY). The aim of this study was to investigate IH after LG with RY for gastric cancer., Methods: This study included 15 patients with IH from a database of 355 consecutive patients who underwent LG with RY for gastric cancers. We retrospectively analyzed IH incidence and clinical characteristics by operative procedures., Results: The total incidence of IH was 4.2%. The incidence of IH at Petersen's defect tended to decrease with modifications to the reconstruction methods, but not significantly so. The incidence of IH at jejunojejunostomy mesenteric defect significantly decreased with closure of this defect (p = 0.01). The incidence of IH at transverse mesocolic defect was 1.3% in patients who underwent retrocolic RY; emergent small-bowel resection was only required in two cases of herniation through this defect after laparoscopic total gastrectomy., Conclusion: Retrocolic RY with appropriate closure of defects can reduce IH incidence at Petersen's defect and at jejunojejunostomy mesenteric defect. Although the IH incidence at the transverse mesocolic defect is not particularly high, the possibility of herniation through this defect should be kept in mind., (Copyright © 2017. Published by Elsevier Taiwan.)

Testing of drug effects and cytotoxicity by using cultured cells has been widely performed as an alternative to animal testing. However, the estimation of pharmacokinetics by conventional cell-based assay methods is difficult because of the inability to evaluate multiorgan effects. An important challenge in the field is to mimic the organ-to-organ network in the human body by using a microfluidic network connecting small-scale tissues based on recently emerging MicroTAS (Micro Total Analysis Systems) technology for prediction of pharmacokinetics. Here, we describe an on-chip small intestine-liver coupled model for pharmacokinetic studies. To construct an in vitro pharmacokinetic model that appropriately models in vivo conditions, physiological parameters such as the structure of internal circulation, volume ratios of each organ, and blood flow ratio of the portal vein to the hepatic artery were mimicked using microfluidic networks. To demonstrate interactions between organs in vitro in pharmacokinetic studies, Caco-2, HepG2, and A549 cell cultures were used as organ models of the small intestine, liver, and lung, respectively, and connected to each other through a microporous membrane and microchannels to prepare a simple model of a physiological organ-to-organ network. The on-chip organ model assay using three types of substrate-epirubicine (EPI), irinotecan (CPT-11), and cyclophosphamide (CPA)-were conducted to model the effects of orally administered or biologically active anticancer drugs. The result suggested that the device can replicate physiological phenomena such as activity of the anticancer drugs on the target cells. This microfluidic device can thus be used as an in vitro organ model to predict the pharmacokinetics of drugs in the human body and may thus provide not only an alternative to animal testing but also a method of obtaining parameters for in silico models of physiologically based pharmacokinetics., (© 2014 Society for Laboratory Automation and Screening.)

Background: The aim of the study was to investigate trends in cancer prognosis by examining the relationship between period of diagnosis and probability of death from cancer in a population-based cohort., Methods: Within a cohort of Japanese men and women aged 40-69 years and free of prior diagnosis of cancer and cardiovascular disease at baseline, data from 4403 patients diagnosed with cancer between 1990 and 2006 and followed up until 2012 were analyzed using survival regression models to assess the presence of an effect of the period of diagnosis (before 1998 versus after 1998) on the risk of dying from cancer., Results: We noted a significant decrease in risk of dying from cancer among individuals diagnosed after 1998 with lung cancer (hazard ratio [HR]=0.676 [0.571-0.800]) or colorectal cancer (HR=0.801 [0.661-0.970]). A decrease in the estimated five-year probability of death from cancer was also noted between the first (before 1998) and the second (after 1998) period of diagnosis for lung and colorectal cancers (e.g., 85.4% vs. 73.3% for lung cancer and 44.6% vs. 37.7% for colorectal cancer, respectively, for stage III in men aged 60 at diagnosis)., Conclusions: This study presented the first scientific evidence of improvement in prognosis for lung and colorectal cancer patients in a population-based cohort in Japan. Our results suggest that recent advances in cancer treatment could have influenced cancer survival differently among lung, colorectal and gastric cancers., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

POU5F1B (POU domain class 5 transcription factor 1B), a processed pseudogene that is highly homologous to OCT4, was recently shown to be transcribed in cancer cells, but its clinical relevance and biological function have remained unclear. We now show that POU5F1B, which is located adjacent to MYC on human chromosome 8q24, is frequently amplified in gastric cancer (GC) cell lines. POU5F1B, but not OCT4, was also found to be expressed at a high level in GC cell lines and clinical specimens. In addition, the DNA copy number and mRNA abundance for POU5F1B showed a positive correlation in both cancer cell lines and GC specimens. Overexpression of POU5F1B in GC cells promoted colony formation in vitro as well as both tumorigenicity and tumor growth in vivo, and these effects were enhanced in the additional presence of MYC overexpression. Furthermore, knockdown of POU5F1B expression with a short hairpin RNA confirmed a role for the endogenous pseudogene in the promotion of cancer cell growth in vitro and tumor growth in vivo. POU5F1B overexpression induced upregulation of various growth factors in GC cells as well as exhibited mitogenic, angiogenic and antiapoptotic effects in GC xenografts. Finally, amplification of POU5F1B was detected in 17 (12%) of 145 cases of GC and was a significant predictor of poor prognosis in patients with stage IV disease. In conclusion, we found that the POU5F1B pseudogene is amplified and expressed at a high level in, as well as confers an aggressive phenotype on, GC, and that POU5F1B amplification is associated with a poor prognosis in GC patients.

Background: We aimed to evaluate the efficacy of a new combination antiemetic therapy comprising aprepitant, granisetron, and dexamethasone in gastric cancer patients undergoing chemotherapy with cisplatin and S-1., Methods: Gastric cancer patients scheduled to receive their first course of chemotherapy with cisplatin (60 mg/m(2)) and S-1 (80 mg/m(2)) were treated with a new combination antiemetic therapy aprepitant, granisetron, and dexamethasone on day 1; aprepitant and dexamethasone on days 2 and 3; and dexamethasone on day 4. The patients reported vomiting, nausea, use of rescue therapy, and change in the amount of diet intake, and completed the Functional Living Index-Emesis (FLIE) questionnaire. The primary endpoint was complete response (CR; no emesis and use of no rescue antiemetics) during the overall study phase (0-120 h after cisplatin administration). The secondary endpoints included complete protection (CP; CR plus no significant nausea); change in the amount of diet intake; and the impact of chemotherapy-induced nausea and vomiting (CINV) on daily life during the overall, acute (0-24 h), and delayed (24-120 h) phases., Results: Fifty-three patients were included. CR was achieved in 88.7, 98.1, and 88.7% of patients in the overall, acute, and delayed phases, respectively. The corresponding rates of CP were 67.9, 96.2, and 67.9%. Approximately half of the patients had some degree of anorexia. FLIE results indicated that 79.5% of patients reported "minimal or no impact of CINV on daily life"., Conclusions: Addition of aprepitant to standard antiemetic therapy was effective in gastric cancer patients undergoing treatment with cisplatin and S-1.

Objective: Malignancy-related thromboembolism, also referred to as Trousseau's syndrome, can present as acute cerebral infarction, nonbacterial thrombotic endocarditis (NBTE), and migratory thrombophlebitis. Therefore, many physical, neurological, and psychological symptoms associated with Trousseau's syndrome may occur in the clinical course., Method: To illustrate this, we report a case of a male patient in his 50s with carcinomatous peritonitis caused by gastric cancer, with multiple cerebral infractions that developed during disease progression. The patient was admitted to our hospital for the treatment of side effects of chemotherapy, although he strongly hoped to go home as soon as possible. In addition to making social supports plans, we were required to perform intensive total palliative care, because of his physical pain, general fatigue, anorexia, abdominal and neck pain, and psychological issues (insomnia, delirium, depression, suicidal thoughts, self-mutilation, panic attacks, agoraphobia, fear of death, and feelings of hopelessness)., Results: To the best of our knowledge, based on the literature search, this is the first reported case of Trousseau's syndrome described in the context of total palliative care, especially psychological care., Significance of Results: We propose that neurological symptoms of Trousseau's syndrome cause these extensive mental disorders. Furthermore, because of the prognosis of Trousseau's syndrome, we should utilize our expertise fulfill the patient's wishes.

A 69-year-old man was admitted with right flank pain. The patient was diagnosed with advanced gastric cancer with multiple metastases in the liver and abdominal lymph nodes and underwent chemotherapy. Three days following the initial administration of S-1 plus cisplatin, the patient developed tumor lysis syndrome (TLS) with increased LDH, hyperuricemia, hyperkalemia, and elevated creatinine. Although rare, TLS following chemotherapy for solid tumors is a potentially fatal complication, and high physician awareness is required, especially in patients with risk factors, such as bulky disease.

Whole genome-scale integrated analyses of exon array and array-comparative genomic hybridization are expected to enable the identification of unknown genetic features of cancer cells. Here, we evaluated this approach in 22 gastric and colorectal cancer cell lines, focusing on protein kinase genes and genes belonging to the cadherin-catenin family. Regarding alternative splicing patterns, several cancer cell lines predominantly expressed isoform 1 of protein kinase A catalytic subunit beta (PRKACB). Paired gastric cancer specimens demonstrated that isoform 1 of PRKACB was a novel cancer-related variant transcript in gastric cancers. In addition, the exon array analysis clearly identified exon 3 or exon 3-4 skipping in catenin beta 1, a short intron insertion with exon 9 skipping in CDH1, and a deletional transcript of CDH13. These abnormal transcripts were shown to have arisen from small genomic deletions. Meanwhile, an integrated analysis of 11 gastric cancer cell lines revealed that four cell lines amplified fibroblast growth factor receptor 2, with truncated forms observed in two of the cell lines. Gene amplification, and not the truncated form, was found to determine the sensitivity to a fibroblast growth factor receptor inhibitor, indicating that our cell line panel might be useful for cell-based evaluations of specific inhibitors. Using an integrated analysis, we identified several abnormal transcripts and genomic alterations in gastric and colorectal cancer cells. Our approach might enable genetic changes to be identified more efficiently, and the present results warrant further investigation using clinical samples and integrated analyses., (© 2011 Japanese Cancer Association.)

There is no standard treatment for peritoneal carcinomatosis (PC) from gastric cancer. New bidirectional chemotherapy (neoadjuvant intraperitoneal-systemic chemotherapy protocol (NIPS)) was developed. The aim of the present study was to assess the safety and efficacy of NIPS and to show the selection for cytoreductive surgery on PC from gastric cancer. Seventy-nine patients with PC from gastric cancer were treated with NIPS. A peritoneal port system was introduced into the abdominal cavity. The peritoneal wash cytological examination through a port was done before and after NIPS. The patients were treated with oral TS-1 twice a daily for 21 days, followed by a 1-week rest. On day 1, 8, and 15 from the start of oral TS-1 administration, 30 mg/m(2) of Docetaxel and 30 mg/m(2) of cisplatinum with 500 ml of saline were introduced into the peritoneal cavity through the port. A median course of oral TS-1 was 2.1 course and a median time of IP chemoterapy was 5.8. Peritoneal free cancer cells (PFCCs) had been detected in 65 (82.2%) patients before NIPS, and the positive cytology changed to be negative in 41 (63.0%) patients after NIPS. After NIPS, 41 patients underwent laparotomy, and complete cytoreduction was done in 32 (78%) patients. Complete cytoreduction was done in 27 (51.9%) of 52 patients with negative cytology but in only 4 (14.8%) of 27 patients with positive cytology (P < 0.001). Patients with negative cytology after NIPS survived significantly longer than those with positive cytology. The adverse effects after NIPS were mild and there was no treatment-related deaths. The grade 3/4 hematological adverse effects were found in 2 (2.6%) patients. Grade 3 renal toxicity and port site infection was found in three patients, respectively. NIPS using a port system is a safe and effective treatment for PC. Peritoneal wash cytology through a port system is a good indicator to select the patients to perform cytoreductive surgery., ((c) 2009 Wiley-Liss, Inc.)

Surgical treatments for early gastric cancer, such as endoscopic procedures, are currently performed as standard therapy. However, when surgery is not possible due to physical or mental conditions, effective chemotherapy with minimum side effects is a second choice, although a suitable regimen has yet to be recommended. We thus retrospectively evaluated the Int FP regimen for 10 early gastric cancer patients. The results show an efficacy ratio of 100% (CR 8 cases, PR 2 cases). The two PR cases subsequently underwent surgical treatment. The 1-, 3-, and 5-year survival rates of all cases were 100%, 90% and 60%, respectively. The 1-, 3-, and 5-year survival rates of patients with chemotherapy alone were 100%, 87.5% and 50%, respectively, although none of the patients died of cancer (5-year survival rate of 100%). One out of the 8 CR cases relapsed 7 months after achieving CR. This patient then received chemotherapy with the same regimen, achieving a second CR and survived for 66 months without disease. All cases developed hematological toxicities, although they were all under grade 2 except for 2 cases which were grade 3 (decrease of WBC or Hb). Non-hematological toxicities were seen in 7 cases, all under grade 2. These results, although from a limited number of subjects, indicated that the IntFP regimen is safe and may contribute to achieving pathological CR and long-term survival of patients with early gastric cancer.

Recently, it became possible to reduce the size of tumors in patients with advanced or relapsed gastric cancer by chemotherapy with the combination of several kinds of anti-cancer drugs which are all effective and allowed for use with gastric cancer patients. However, chemotherapy alone can not cure patients with advanced gastric cancer that was shown to improve median survival time (MST), compared with patients provided with the best supportive care (BSC). According to reports from Europe, US and Japan,the MST of patients with advanced gastric cancer and those with peritoneal expansion treated by chemotherapy is almost 7-12 months and 5-6 months,respectively, both of which are short and unsatisfactory. From March 2002, we started to treat patients with advanced gastric cancer (stage IV) with a new regimen; intermittent dosage of 5-FU (-->S-1), CDDP and paclitaxel utilizing the difference of cell cycle between normal and cancer cells (intermittent FP . weekly PTX). In the present study, therefore, we analyzed advanced gastric cancer patients with peritoneal expansion (9 cases, 4 with cancerous peritonitis) treated with this regimen. The results were as follows. The one-and 2-year survival rate was 55.6% and 27.8%, respectively, and the MST was 14 months. Four patients (44.4%) had hematological toxicities over grade 3. All of them had anemia (3 cases) and neutropenia (3 cases). Toxicities of thrombocytopenia were all under grade 1 and nonhematological toxicities were all under grade 2, which were clinically manageable. These results, although the sample was small, suggested that this may contribute to the extension of survival time of patients with stage IV advanced gastric cancer with peritoneal expansion.

Purpose: AZD2171 is an oral, highly potent, and selective vascular endothelial growth factor signaling inhibitor that inhibits all vascular endothelial growth factor receptor tyrosine kinases. The purpose of this study was to investigate the activity of AZD2171 in gastric cancer., Experimental Design: We examined the antitumor effect of AZD2171 on the eight gastric cancer cell lines in vitro and in vivo., Results: AZD2171 directly inhibited the growth of two gastric cancer cell lines (KATO-III and OCUM2M), with an IC(50) of 0.15 and 0.37 micromol/L, respectively, more potently than the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. Reverse transcription-PCR experiments and immunoblotting revealed that sensitive cell lines dominantly expressed COOH terminus-truncated fibroblast growth factor receptor 2 (FGFR2) splicing variants that were constitutively phosphorylated and spontaneously dimerized. AZD2171 completely inhibited the phosphorylation of FGFR2 and downstream signaling proteins (FRS2, AKT, and mitogen-activated protein kinase) in sensitive cell lines at a 10-fold lower concentration (0.1 micromol/L) than in the other cell lines. An in vitro kinase assay showed that AZD2171 inhibited kinase activity of immunoprecipitated FGFR2 with submicromolar K(i) values ( approximately 0.05 micromol/L). Finally, we assessed the antitumor activity of AZD2171 in human gastric tumor xenograft models in mice. Oral administration of AZD2171 (1.5 or 6 mg/kg/d) significantly and dose-dependently inhibited tumor growth in mice bearing KATO-III and OCUM2M tumor xenografts., Conclusions: AZD2171 exerted potent antitumor activity against gastric cancer xenografts overexpressing FGFR2. The results of these preclinical studies indicate that AZD2171 may provide clinical benefit in patients with certain types of gastric cancer.

We report a case of TS-1-resistant recurrent gastric cancer with lung metastasis responding to TS-1 and irinotecan (CPT-11) combination therapy. A 72-year-old man underwent total gastrectomy with pancreaticosplenectomy for advanced gastric cancer on October 18, 2001, and partial hepatectomy for postoperative liver metastasis on August 22, 2002. In March 2004, a chest computed tomography scan revealed metastatic lesions in the bilateral lungs, and he received a single administration of TS-1, resulting in partial response. After 13 courses, this therapy was discontinued due to progressive disease. Then,TS-1 and CPT-11 combination therapy was chosen as the second-line chemotherapy. After 4 courses, a partial response was obtained in lung metastasis, and thereafter has been maintained. He has been treated on an outpatient basis because of no grade 3 or severer adverse reactions. TS-1 and CPT-11 combination therapy could be a promising regimen as the second-line chemotherapy for gastric cancer resistant to TS-1.

Uridine phosphorylase (UP) is one of the enzymes involved in 5-fluorouracil (5-FU) activation. The expression was compared in paired specimens from cancerous and non-cancerous regions of gastric, colon and lung cancer patients. Among 28 paired gastric samples, 20 cases showed greater expression in tumors than in normal surrounding tissues and 8 cases showed equal or lower expression levels in tumors. All the gastric patients received 5-FU before and/or after the surgical resection and the prognosis of the patients, whose UP tumor expression increased, was relatively better than that of the patients with equal or less UP gene tumor expression. In contrast, most of the colon (22 cases in total) and all the lung cancer patients (14 in total) did not receive 5-FU and the majority of the colon (12 cases) and lung (10 cases) specimens showed lower expression in the cancerous region. The differential expression between cancerous and non-cancerous regions in colon and lung cancers was not linked with the prognosis. These data suggest that the paired expression level of the UP gene in gastric cancer is a possible prognostic marker for the patients who received 5-FU.

A 64-year-old woman was admitted to the hospital for abdominal fullness and constipation. In the pelvic cavity, an abdominal CT scan revealed massive ascites showing malignancy on histological examination. Upper GI endoscopy revealed type 3 gastric cancer from the anglus to the cardia. A barium-enema showed a stenotic lesion at the sigmoid colon due to peritoneal dissemination. An abnormally high CA125(1,400 mg/ml) level was detected in serum. We performed systemic chemotherapy of TS-1, CDDP and peritoneal infusion of docetaxel on the nonresected gastric cancer with peritoneal dissemination. After 2 cycles, cytology of ascites revealed no malignancy, and the serum CA125 value regained its normal level. After 3 cycles, the killer cell effect was recognized by laparoscopic examination and the stenotic change of sigmoid colon had almost disappeared. The patient clinically achieved good QOL by this method, which was very effective for nonresected gastric cancer with peritoneal dissemination.

Since the advent of imatinib mesylate (IM), its clinical efficacy against gastrointestinal stromal tumor (GIST) has been widely acknowledged, and therapeutic strategies for this disease have undergone great changes. We recently experienced a case of giant GIST of the stomach that was successfully treated with IM neoadjuvant therapy prior to surgical resection, but liver metastasis recurred 1 year and 7 months after the operation. The patient was a 65-year-old male who presented at our department with the chief complaints of dizziness, malaise, and fever in April 2002. An abdominal CT revealed a mass with a maximum diameter of 17 cm, as well as a cystic septate mass, 12 cm in diameter, with a thick capsule in the left lobe of the liver. The patient was diagnosed with GIST of the stomach and liver metastasis. Since radical operation was considered difficult at that point, IM (400 mg/day) was started on May 9. The result of treatment was determined to be PR, and radical operation was considered feasible. On March 18, 2003, total gastrectomy and left hepatic lobectomy/S 6 partial lobectomy were performed in the surgery department of our hospital. The postoperative course was favorable and oral administration of IM was resumed soon after the operation. However, the drug was discontinued for financial reasons and a decreased white blood cell count (grade 3) 2 months after the operation. Recurrence in the liver and abdominal wall was found in October 2004, and oral administration of IM was resumed again. Currently, treatment with IM is ongoing. Case reports on the efficacy of IM neoadjuvant therapy are occasionally found in the literature, but there are few reports on its long-term prognosis. We report this case with a discussion of future therapeutic options.

We report herein a case of a 65-year-old woman who had a gastrointestinal stromal tumor (GIST) of the stomach. Preoperative endoscopic and X-ray examinations showed a spherical submucosal tumor in the gastric fornix. We resected the tumor by laparoscopic surgery, because it was detected by computed tomography (CT) and positron emission tomography (PET), and they did not detect distant metastasis. Postoperative histologic examination revealed that the tumor was composed of spindle-shaped cells with elongated nuclei and showed little mitosis. Almost all of the cells showed immunoreactivity for c-kit, CD34, vimentin and but did not show alpha-smooth muscle actin (SMA), S-100, or desmin. The Ki-67 labeling index was 0.8%. The tumor did not show differentiation toward smooth muscle or neural cells. Pathological findings showed this tumor was probably benign. In such cases, careful follow-up is needed to detect liver metastasis and local recurrence.

We report an unusual case of a pedunculated gastrointestinal stromal tumor (GIST) of the stomach with extragastric growth. An 84-year-old woman was referred to our hospital for investigation of anemia. Barium meal examination showed a defect occupying the lesser curvature of the stomach from the middle of the corpus to the fornix and an abdominal computed tomography scan, showed a lesion, 20 cm in diameter, touching the surface of the spleen. Laparotomy revealed a tumor located between the liver and spleen. As the tumor appeared to be connected with the posterior wall of the gastric corpus by a pedicle, it was resected with a pedunculated lesion of the stomach. Based on the pathological findings, the tumor was diagnosed as a GIST of uncommitted type, with low-grade malignancy.

Objective: To investigate the relation of liver-type fatty-acid-binding protein (L-FABP) expression to the clinicopathological characteristics or the fatty acid synthase status of gastric cancers., Methods: L-FABP expression was examined immunohistochemically in 667 gastric cancers, 60 gastric adenomas, and non-neoplastic epithelium contiguous with cancer tissue including normal foveolae, intestinal metaplasia, regenerative epithelium, and gastric glands., Results: L-FABP was positive in 38% (high in 9% and low in 29%) of gastric cancers. It occurred preferentially in papillary carcinomas, female cases, and in patients under 50 years. In gastric cancers, L-FABP expression had no intimate correlation with the FAS status, and it showed no relationship with prognosis and cancer progression as indicated by venous and lymphatic permeation, and nodal or hepatic metastasis. Gastric tubular adenomas mainly revealed low (22%) expression of L-FABP while intestinal metaplasia showed the most frequent (>95%) and intense L-FABP expression. Normal foveolae and gastric glands showed no or less L-FABP expression., Conclusions: L-FABP is highly and intensely expressed in metaplasia and in a subset of gastric adenocarcinomas, without association with progression, prognosis and fatty acid synthase status of the carcinoma., (Copyright 2004 S. Karger AG, Basel)

Background: We conducted a feasibility study using S-1, a novel oral derivative of 5-fluorouracil, as postoperative adjuvant chemotherapy for curatively resected gastric cancer patients., Methods: Adjuvant chemotherapy consisted of eight courses (4-week administration and 2-week withdrawal) of S-1, at 80-120 mg/body per day. Forty-one patients from 11 institutions were enrolled in this pilot study, from November 1999 to October 2000., Results: Thirty-five patients were eligible. In 7 patients, S-1 administration was discontinued due to recurrence. Among the 28 patients without recurrence, the planned eight courses of S-1 were administered to 17 patients (60.7%). In 4 patients, S-1 administration was discontinued due to subjective symptoms, such as anorexia, in the first course. Adverse reactions such as neutropenia, leukopenia, elevated total bilirubin, anorexia, general fatigue, diarrhea, nausea, and stomatitis were seen in more than half of the patients. Although grade 3 neutropenia (29.3%), leukopenia (9.8%), and diarrhea (9.8%) were observed, no grade 4 adverse effects appeared. Compared with the treatment of unresectable or recurrent gastric cancer with S-1, the incidence of adverse reactions in the adjuvant setting was slightly higher, probably due to the influence of gastrectomy., Conclusion: Except for the early development of anorexia, most likely due to adverse effects of surgery, postoperative administration of S-1 for 1 year seems feasible as adjuvant chemotherapy for gastric cancer.

Objective: Fatty acid-binding proteins (FABPs) are involved in lipid metabolism by intracellular transport of long-chain fatty acids. Heart-type (H-) FABP has been reported to inhibit cell growth and induce cell differentiation, but to our knowledge the significance of H-FABP expression in human gastric carcinoma has not been elucidated. The aim of the current study was to examine the expression of H-FABP and its relation to clinicopathologic parameters and fatty acid synthase (FAS) status of gastric carcinoma, since gastric cancer shows increased expression of FAS., Methods: Immunohistochemistry with anti-H-FABP antibody was performed in 669 gastric carcinomas and 60 tubular adenomas of the stomach. H-FABP-positive and H-FABP-negative carcinomas were analyzed for their clinicopathologic characteristics and FAS status., Results: None of the adenomas expressed H-FABP, whereas 127 of 669 carcinomas (19.0%) were positive for the protein. H-FABP positivity was associated with the depth of invasion (p <0.0001), vascular invasion (p <0.0001), lymph node metastasis (p <0.0001), hepatic metastasis (p=0.0011), stage of the carcinoma (p <0.0001) and FAS status of the carcinoma (p=0.0476). A higher survival rate was noted in H-FABP-negative cases compared with H-FABP-positive cases (p=0.0004)., Conclusions: A subset of human gastric carcinoma expresses H-FABP and its expression is associated with FAS status, disease progression, tumor aggressiveness and poor patient survival.

Background/aims: dThdPase (thymidine phosphorylase) is an enzyme that is involved in pyrimidine nucleoside metabolism. It has been recently reported that dThdPase is identical to platelet-derived endothelial cell growth factor. Previous studies demonstrated that the immunohistochemical expression of dThdPase was related with disease progression. The purpose of this study was to examine the expression levels of dThdPase and their prognostic significance in gastric carcinoma, prospectively., Methodology: We obtained fresh samples (tumors and adjacent normal mucosa) from 263 patients with gastric cancer who underwent gastrectomy between April 1998 and March 2000. dThdPase was analyzed by the enzyme-linked immunosorbent assay method., Results: The expression levels of dThdPase in tumors (98.4 +/- 62.5 U/mg protein) was significantly higher than that in normal mucosa (46.5 +/- 27.8 U/mg protein) (P < 0.0001). Intratumoral dThdPase levels were significantly higher in Borrmann types II and III macroscopically (P < 0.01), in poorly differentiated type histologically (P < 0.05), and in the tumor-invading serosa (P < 0.001). The expression levels of dThdPase were also significantly higher in tumor tissue from patients with lymph node metastasis (P < 0.01) and in that from patients with lymphatic invasion (P < 0.05). The survival rate of patients with tumor of high dThdPase (> or = 100 U/mg protein) was significantly poorer than that of patients with tumor of low dThdPase (< 100 U/mg protein) (P < 0.05)., Conclusions: These findings indicate that the measurement of dThdPase may provide useful information for predicting prognosis in gastric carcinomas.

To clarify the mechanism of tumor metastasis, lymph nodes micrometastasis and expression of MMP-7, which is related to lymph node metastases, were investigated in 45 submucosal, invasive gastric carcinomas. Metastases to lymph nodes were detected in 12 of 45 cases(26.7%) by HE stain. In 13 of 45 cases (28.9%), only micrometastases were detected by immunostaining with anti-cytokeratin antibody. The incidence of micrometastases was higher in poorly-differentiated carcinoma than well-differentiated carcinoma. Expression of MMP-7 was higher in metastasis positive cases than in negative cases. In poorly-differentiated cases, expression of MMP-7 was associated with micrometastasis. In conclusion, expression of MMP-7 may play an important role not only in tumor metastasis but in micrometastasis to lymph node especially in poorly-differentiated cases.

Background and Objectives: Both thymidine phosphorylase (dThdPase) and vascular endothelial growth factor (VEGF) are well-characterized inducers of angiogenesis. The purpose of this study was to examine the expression of these antigens and their prognostic significance in gastric carcinoma., Methods: Medical records of 102 patients with stage II tumor were retrospectively reviewed. Primary tumors were studied by immunohistochemical staining for dThdPase and VEGF., Results: Positive dThdPase expression was observed in 52 (51%) tumors and positive VEGF expression in 53 (52%) tumors. There was a significant correlation between the positive expression of VEGF and lymphatic invasion. The patients with dThdPase-positive carcinoma showed a significantly worse prognosis than those with dThdPase-negative carcinoma in stage II. Moreover, the frequency of hepatic recurrence was significantly higher in the patients with dThdPase-positive and VEGF-positive tumors than in those with dThdPase-negative and VEGF-negative tumors., Conclusions: Combination analysis of dThdPase and VEGF expression in gastric carcinoma appears to be well-characterized inductors of prognosis and metastasis.

The purpose of this study was to examine the correlations among enhancement of apoptosis, cell proliferation and expression of oncogenes in gastric carcinomas induced by preoperative oral administration of 5-fluorouracil (5-FU). The occurrence of spontaneous apoptotic cell death in 42 patients with gastric carcinoma was analyzed in the biopsy specimens preoperatively. p53 status was examined by polymerase chain reaction-single strand confirmation polymorphism and sequencing. Fourteen patients received oral administration of 5-FU at 300 mg/body/day for 7 days preoperatively. For detection of apoptotic cells, apoptotic incidences (AIs) were examined by the terminal deoxynucleotidyl transferase-mediated deoxy-uridine triphosphate biotin nick end labeling method, on gastric carcinoma lesions based on the endoscopic findings before administration in the biopsy and resected tissues. Expressions of p53, Bcl-2, Bax gene and proliferating cell nuclear antigen (PCNA) were also examined by immunohistochemical staining. On preoperative biopsy, p53 point mutation was observed in 14 of the 42 tumors. The immunohistochemical staining status and point mutation of p53 gene (positive or negative) were identical in 32 of the 42 tumors (76.2%). The average AIs of the biopsy specimens were 1.58+/-1.26% on p53-negative staining (n=19) and 1.14+/-1.02% on p53-positive staining (n=23), a significant association was not recognized between p53 expression and AI. In the preoperative administration group, the PCNA labeling index was significantly higher in the biopsy specimens than in the resected tissues (43. 6+/-12.8% vs. 35.3+/-8.8%, p<0.01). In addition, postoperatively, the rate of AI was significantly more accelerated in p53-negative staining (n=6) than in p53-positive staining (n=8) (0.89+/-0. 65%right curved arrow 4.18+/-3.26%, p<0.05 vs. 1.20+/-0.60%right curved arrow 2.60+/-2.60%, NS). There was no significant correlation between AI and Bcl-2 or Bax staining. Immunohistochemical analysis of p53 and PCNA stainings in biopsy specimens appears to be a well-characterized indicator of sensitivity of chemotherapy in gastric carcinomas.

Small cell carcinoma of the stomach has an aggressive feature, and the survival rate of the patients is poor. The purpose of this study was to determine the clinical course, and effects of histopathologic characteristics of specific tumors including DNA contents and immunohistochemical aspects in patients with small cell carcinoma of the stomach. Medical records of 8 patients who presented with small cell carcinoma of the stomach were retrospectively reviewed. Primary tumors were studied by flow cytometric analysis and immunohistochemical staining for the p53 protein, PCNA (proliferating cell nuclear antigen), factor VIII related antigen (specific for endothelial cells), VEGF (vascular endothelial growth factor) and PD-ECGF (platelet-derived endothelial cell growth factor). DNA aneuploid was observed in 4 cases. Staining for the p53 product was positive in 50% of all the cases. The average PCNA labeling rate (LR) was 71.3+/-9.9%. Positive VEGF expression was found in 7 tumors and positive PD-ECGF expression was found in all tumors. The estimated median survival was 252 days for all the patients. Liver metastases were observed in 4 of the 8 patients, however, surgery and chemotherapy have given us one long-term survivor (43 months). Higher PCNA LR of small cell carcinoma may be an unfavorable characteristic of biological behavior. Moreover, both VEGF and PD-ECGF positivity are well-characterized inducers of hepatic metastasis.

A pilot study of continuous or intermittent low dose 5-FU and cisplatin chemotherapy (low-dose FP therapy) was conducted at the Department of Surgery of Sapporo Medical University School of Medicine (Group A) and Sapporo Tsukisamu Hospital, and at the Department of Internal Medicine of the Kochi Prefectural Center Hospital (Group B). The cases with esophageal cancer, stomach cancer, pancreatic cancer, hepatocellular carcinoma or colonic cancer co-existing with their inoperable lesion(s) were considered in this chemotherapy. The rates of complete and partial response and of side effects were studied. Also, the effects of low-dose FP on the prognosis of the patients with pancreatic or colonic cancers were investigated. The procedure consisted of continuous 5-FU 320 mg/m2 i.v. with daily CDDP 2.5 mg/m2 i.v. for five days/week rescue was performed for at least four weeks as a rule. The rates of complete response and partial response were 64% (Group A) and 56% (Group B) in esophageal cancer, 62% (Group A and B) in stomach cancer, 48% (Group A) and 57% (Group B) in colonic cancer, and 8% (Group A) and 21% (Group B). The overall response rate was 57.8%. The frequencies of severe side effect(s) (grades 3 and 4) were within three to eight percent, and no death from side effect(s) was experienced. The effects of low-dose FP therapy on the prognosis of stage IV colonic cancer and stage IV b pancreatic cancer were studied retrospectively. It is suggested that this chemotherapy might contribute to the survival of patients with these two cancers. Otherwise, the chemotherapy of intermittent administration (day by day) of 5-FU 750 mg/m2 i.v. and CDDP 2.5 mg/m2 i.v. was selected in order to decrease the rate of side effects and their severity. The pilot study encountered no severe side effects, no cases with grade 4 side effect were experienced but the remission rates were mostly similar to that of sequential low-dose FP therapy. However, the side effect of low grade ones as symptoms in gastrointestinal tract were observed in more patients. We concluded that sequential or intermittent 5-FU/CDDP therapy might be fairly effective, and since the adjuvant chemotherapy of choice for advanced or recurrent gastrointestinal cancer, their FP therapy might be one of the adjuvant treatments.

Unlabelled: The subjects were 39 patients with gastric cancer and 44 patients with colorectal cancer divided into a group administered 400 mg/day of UFT orally for 2 weeks preoperatively (UFT group) and a group administered 400 mg/day of UFT as well as 40 mg/m2 (i.v.) of cisplatin (CDDP) by drip infusion once concomitantly (UFT + CDDP group). The thymidylate synthase (TS) inhibitory rate was measured in resected specimens and lymph nodes, and the concomitant effects of UFT and CDDP were investigated., Results: 1) The TS inhibitory rate in tumor tissue showed no significant difference between the two groups. 2) The TS inhibitory rate of metastasized lymph nodes was higher in UFT + CDDP group than in the UFT group in gastric cancer patients (p < 0.05). The TS inhibitory rate by lymph node metastasis in patients with gastric cancer or colorectal cancer was significantly higher in metastasized lymph nodes than in non-metastasized lymph nodes in the UFT + CDDP group (p < 0.05 for gastric cancer, p < 0.05 for colorectal cancer). These results indicated that concomitant use of UFT and CDDP appeared to be more effective against metastasized lymph nodes, especially in cases of gastric cancer, than against the primary tumor focus.

We report a case of remitting seronegative symmetrical synovitis with pitting edema (RS3PE syndrome) associated with gastric carcinoma in an 80-year-old woman who developed polyarthritis with marked pitting edema of the dorsa of both hands and feet 7 days after fiberscopic examination of the stomach. A mass lesion was identified and histology of the biopsy specimen revealed gastric carcinoma. Polyarthritis and edema were partially relieved by an intraarticular injection of corticosteroid. Shortly after resection of the gastric carcinoma, her symptoms and signs disappeared. She has been free of symptoms for 3 yrs without medication.

The authors describe an extremely rare case of extrahepatic hepatocellular carcinoma. The patient was a 70-year-old man who was examined by a local doctor because of abdominal discomfort. Barium meal examination demonstrated a defect occupying the lesser curvature of the stomach from the middle of the corpus to the fornix. On an abdominal computed tomography (CT) scan, the lesion, 10 cm in diameter, touched the lower surface of the caudate lobe of the liver. Under laparotomy, the tumor was found between the caudate lobe of the liver and posterior wall of the gastric corpus. As the tumor appeared to be connected with the caudate lobe by a pedicle, only the tumor was resected. Histological examination showed the tumor to be hepatocellular carcinoma of Edmondson's grade III-IV, pedunculated type.

This paper describes an unusual case of an 80-year-old man followed up for multifocal gastric cancers. There were three separate polypoid carcinomas and one adenomatous polyp with no sign of malignancy. We measured the DNA content of the gastric cancer and adenomatous cells obtained from endoscopically biopsied specimens. The adenomatous polyp and one of the cancerous lesions showed DNA diploidy. The other two cancerous lesions showed DNA aneuploidy, with different DNA index (DI) values (1.12 and 1.64, respectively). It is considered that the three cancers arose from different stem lines. However, an operation was not performed because the patient refused gastrectomy, and therefore only conservative follow up has been continued. Presentation of this case is followed by a detailed discussion focusing on the possible development of carcinoma in gastric adenomatous polyps in view of the data from the literature.

Flow cytometric (FCM) DNA studies were performed on cell suspensions obtained by endoscopic biopsy in 73 patients with gastric cancer and in 61 patients with gastric remnant. In cancer, DNA aneuploidies were detected in 49 tumors (67.1%), including 51.7% (15/29) of early gastric cancers and 77.3% (34/44) of advanced gastric cancers. Nuclear DNA content of biopsy materials had a significant correlation with that of surgically obtained ones, providing the estimation of the original ploidy pattern and DNA index (p < 0.01). The serosal invasion, lymph node metastasis, lymphatic invasion, and vascular invasion of the DNA aneuploidy were significantly higher than those of the DNA diploidy (p < 0.05). In patients with gastric remnant, 9 biopsy specimens in the anastomotic site showed DNA aneuploidy (13.9%). The DNA measurement of the endoscopically obtained specimens may provide additional preoperative information and help to identify biologic variables.

Cell proliferation of 174 specimens obtained from the primary gastric cancers using endoscopic biopsy was investigated by immunohistochemical analysis with the monoclonal antibody PC10, which recognizes a proliferating cell nuclear antigen (PCNA) in formalin-fixed and paraffin-embedded material. All the examined samples showed nuclear staining for PCNA in cancer cells. The investigation was to test the correlation between PCNA labeling and lymph node metastasis. DNA aneuploidy was often encountered in tumors with nodal involvement and lymphatic invasion. The logistic regression analysis identified PCNA labeling rates (LRs), tumor size, and macroscopic type as independent significant factors for lymph node metastasis. When the PCNA LRs and clinicopathologic parameters were entered into the Cox regression analysis, PCNA LRs and DNA ploidy emerged as independent significant prognostic factors. In addition, combination assay of PCNA LRs and DNA ploidy yielded a powerful prognostic indication for patients with gastric cancer.

Background: Proliferative activities of tumors are thought to be prognostic features of malignant tumors, but their value as measured by proliferating cell nuclear antigen (PCNA) labeling remains unclear in gastric cancer., Methods: PCNA labeling rates (LR) were quantified in 121 paraffin-embedded biopsy specimens from primary tumors by immunocytochemistry., Results: Immunohistochemical analyses have demonstrated that PCNA presents an intense staining in the nuclei of tumor cells and mucous neck cells of gastric glands. The PCNA LR ranged from 12% to 79% (mean +/- standard deviation), and a significant correlation was found between bromodeoxyuridine labeling indices and PCNA LR: PCNA LR were closely associated with tumor size, serosal invasion, and nodal involvement. The patients with tumors with high PCNA LR (greater than 40%) were dead significantly earlier than were those with tumors with low PCNA LR: When the PCNA LR and all the clinicopathologic parameters were entered into a Cox regression model, PCNA LR emerged as an independent prognostic factor., Conclusion: These results indicate that PCNA LR may be a potentially useful prognostic factor for gastric cancer.

Fifty-five patients with high-grade advanced gastric cancer in whom the presence of stage IV was confirmed by preoperative diagnostic imaging were treated with PMUE therapy by a combined use of cisplatin (CDDP) 75 mg/m2, mitomycin C (MMC) 10 mg/body, etoposide 150 mg/body, and UFT (a combination of 1-(2-tetrahydrofuryl)-5-fluorouracil and uracil in a molar ratio of 1:4) 400 mg/day. CDDP and MMC was administered intravenously on the first day, followed by etoposide 50 mg/day on the 3rd, 4th, and 5th days. All the patients had measurable lesions that were evaluated by computed tomography scanning before and after the treatments. These patients were allocated randomly to two groups. Of these cases, 29 belonged to the neoadjuvant chemotherapy (NAC) group to whom PMUE therapy was given preoperatively; the remaining 26 patients underwent operation first and received PMUE thereafter (control group). Background factors did not differ significantly between the two groups. The response rate was higher in the NAC group than in the control group (62% in the former versus 35% in the latter). The resectability rates were 79% and 88% in the NAC and control groups, respectively. However, the rate of potentially curable cases was higher in the NAC group than in the control group (38% in the former versus 15% in the latter). Among the nonresection cases, the prognosis was highly unfavorable in both groups. In the resection cases, however, the survival rate was significantly better in the NAC group than in the control group. These results may indicate that in patients with high-grade, advanced gastric cancer initial chemotherapy (neoadjuvant chemotherapy) and then surgery should be considered.

A case of primary duodenal carcinoma simultaneously associated with an early gastric cancer is reported. A 72-year-old woman complaining of appetite loss and nausea was admitted in June 1988. Endoscopic examination showed an ulcerative lesion in the angle of the stomach and a Borrmann type 2 tumor in the bulb of the duodenum. Both lesions were revealed to be adenocarcinomas by histological examination of obtained biopsy specimens. Synchronous carcinoma was diagnosed and pancreatoduodenectomy and lymph node dissection were performed. The primary tumor of the duodenum was histologically a moderately differentiated adenocarcinoma, and the gastric cancer was a tumor limited to the mucosa. Metastasis was recognized in a regional lymph node (No. 14A). There has been no recurrence during the 4-year postoperative follow-up period. This result suggests that pancreatoduodenectomy with systematic regional lymph node dissection can greatly contribute to prolonging the survival of patients with advanced duodenal cancer. This case is very rare, in that curative operation was performed for a primary duodenal carcinoma simultaneously associated with an early gastric cancer.

The proliferative activity of gastric cancer cells was determined by DNA flow cytometric (FCM) analysis and labeling rates of Ki-67 and monoclonal antibodies and proliferation-associated nuclear antigen (p105) autoantibodies in 28 patients with fresh human gastric cancer cells. By setting the cutoff line at the level as used in a negative control study without primary antibody in the same sample, the Ki-67 and p105 labeling rates were calculated by the dual fluorescence analysis. A total of 43 experiments was performed on FCM analysis for each antigen: 28 with Ki-67 and 15 with p105. The mean Ki-67 labeling rate of gastric cancer cells was 45.1% (13.9-76.3%). The Ki-67 labeling rates were significantly higher for larger size tumor, peritoneal metastasis, and advanced clinical stage. A significant correlation was found between Ki-67 labeling rate and p105 labeling rate (P < 0.05). Bivariate FCM may be an easy method for obtaining useful information of cell kinetics.

Growth fractions in the cell cycle were demonstrated by flow cytometry with monoclonal antibody Ki-67 for gastric cancer. By setting the cut off line at the lowest channel number of S-phase, the Ki-67 labeling rate was calculated by Ki-DNA dual fluorescence analysis. In addition to 32 gastric cancers, we examined three cell lines (Colo 320, NUGC4 and MKN28) and compared the result with the BrdUrd labeling rate. The G0G1 ratio obtained with BrdUrd was generally correlated with the G0 + G1 ratio obtained with Ki-67. The S-phase fractions obtained with Ki-67, however were a little different from those obtained with BrdUrd because of the existence of S0. The mean Ki-67 labeling rate of gastric cancer was 45.1% (16.2-66.3%). Fifteen cases received Ki-67 immunohistochemical study in the same samples. The results of flow cytometric analysis were parallel to those of microscopic study, and a correlation line: y = 0.626x + 15.9145, r = 0.8031, (p less than 0.001) was obtained. Ki-67 antibodies may provide useful information on cell kinetics.

Heterogeneity of DNA content was analyzed in 389 samples from 65 resected gastric cancers. Analysis of the samples revealed that there were 14 homogeneously diploid tumours. Six tumours were uniformly DNA aneuploid, each tissue block containing the same DNA index. The other 45 tumours (69%) varied in DNA content heterogeneity. In 39 of 45 tumours, there was a mixture of diploid and aneuploid samples, and 25 of the 39 tumours had a single aneuploid stemline. In 14 out of 39 tumours, there was also a mixture of diploid and aneuploid samples having two or more DNA aneuploid stemlines. In the remaining six tumours, different DNA aneuploid stemlines were contained in different samples without evidence of diploidy. When four or fewer samples were analyzed, only 50% of the tumours were diagnosed as having DNA content heterogeneity. On the other hand, 78% of the tumours showed DNA heterogeneity when 5 or more samples were analyzed. If the tumours had not been widely sampled, about a quarter of the tumours would have been mislabeled as diploid. The patients with tumours showing homogeneous diploidy survived longer than those with tumours showing a mixture of diploid and aneuploid stemlines. The survival rate was lowest for the patients with tumours having a mixture of diploid and multiple aneuploid stemlines, compared with those showing homogeneous diploid or a mixture of diploid and single aneuploid stemlines. The data from the current study clearly demonstrate the importance of adequate sampling in assessing the ploidy status of gastric cancers to identify groups of patients running different clinical course and prognosis.

Paraffin-embedded tumor samples from 151 patients with stage I gastric cancer were analyzed by DNA flow cytometry, and 80 patients received an infusion of bromodeoxyuridine (BrdU) to determine S-phase fraction. S-phase fractions of tumors were measured by the immunohistochemical method using anti-BrdU monoclonal antibody. Of the 151 patients, 81 (54%), and 70 (46%) showed diploid and aneuploid patterns. There was no significant association between DNA ploidy and wall invasion, histologic type, or lymphatic invasion. Aneuploid tumors were associated with positive-vessel invasion. When the DNA ploidy and clinicopathological parameters were simultaneously entered into the Cox regression model, DNA ploidy and wall invasion emerged as independent prognostic parameters. Aneuploid tumors had significantly higher values of BrdU labeling indices than diploid ones. These results indicate that the determination of DNA ploidy patterns may be an important prognostic factor in patients with stage I gastric cancer, and may be useful in deciding the therapeutic schedule of patients with gastric cancer.