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Human epidermal growth factor receptor 2 (HER2) is overexpressed in breast and gastric cancers and this causes poor clinical outcomes. Although both T-DM1 and Enhertu are approved as an HER2-targeting antibody-drug conjugate (ADC), the effects of these drugs are still not satisfactory to eradicate diverse tumors expressing HER2. To address this shortfall in HER2-targeted therapeutics, an elaborate cleavable linker is created and a novel HER2-targeting ADC composed with trastuzumab and monomethyl auristatin F, which is being investigated in a phase 1 clinical trial and is referred to as LegoChem Bisciences-ADC (LCB-ADC). LCB-ADC displays a higher cytotoxic potency than T-DM1 and it also has a higher G2/M arrest ratio. In animal studies, LCB-ADC produces noticeable tumor growth inhibition compared with trastuzumab or T-DM1 in an HER2 high-expressing N87 xenograft tumor. Especially, LCB-ADC shows good efficacy in terms of suppressing tumor growth in a patient-derived xenograft (PDX) model of HER2-positive gastric cancer as well as in T-DM1-resistant models such as HER2 low-expressing HER2 low expressing JIMT-1 xenograft tumor and PDX. Collectively, the results demonstrate that LCB-ADC with the elaborate linker has a higher efficacy and greater biostability than its ADC counterparts and may successfully treat cancers that are nonresponsive to previous therapeutics., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Aim: To compare the patency and safety of covered metallic stents (CMS) and the double-J stent (DJS) for treating malignant ureteral obstruction (MUO) in advanced gastric cancer (AGC)., Materials and Methods: Between 2016 and 2018, the medical records of 61 patients (84 ureters; CMS, 39 patients, 54 ureters; DJS, 22 patients, 30 ureters) with MUO caused by AGC were reviewed retrospectively. The Kaplan-Meier method and log-rank test were used to evaluate differences of primary or assisted primary patency between groups. Cox regression was conducted separately for early (within 7 days) and late (after 7 days) primary patency., Results: Technical success of CMS placement was 100% (54/54) and 96.8% (29/30) for DJS (p=0.357). The cumulative stent patency rates at 1, 3, 6, and 12 months were 77%, 74%, 70%, and 70%, in the CMS group and 72%, 60%, 53%, and 26%, in the DJS group. Apart from the period within 7 days (p=0.784), primary patency was consistently higher in the CMS group when compared to the DJS group over the entire follow-up period (p=0.034). Assisted primary patency was consistently higher in the CMS group than in the DJS group over the entire follow-up period (p=0.001). The CMS group was more likely to have complications than the DJS group (48.1% versus 16.7%, p=0.004). Complications were minor, self-limiting events such as haematuria/haematoma., Conclusion: CMS had better late patency and assisted primary patency than DJS. Procedure-related minor complications more frequently occurred with CMS., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

The expression of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 2 (LINGO2) has been reported in Parkinson's disease; however, its role in other diseases is unknown. Gastric cancer is the second leading cause of cancer death. Cancer stem cells (CSC) are a subpopulation of cancer cells that contribute to the initiation and invasion of cancer. We identified LINGO2 as a CSC-associated protein in gastric cancers both in vitro and in patient-derived tissues. We studied the effect of LINGO2 on cell motility, stemness, tumorigenicity, and angiogenic capacity using cells sorted based on LINGO2 expression and LINGO2-silenced cells. Tissue microarray analysis showed that LINGO2 expression was significantly elevated in advanced gastric cancers. The overall survival of patients expressing high LINGO2 was significantly shorter than that of patients with low LINGO2. Cells expressing high LINGO2 showed elevated cell motility, angiogenic capacity, and tumorigenicity, while LINGO2 silencing reversed these properties. Silencing LINGO2 reduced kinase B (AKT)/extracellular signal-regulated kinase (ERK)/ERK kinase (MEK) phosphorylation and decreased epithelial-mesenchymal transition (EMT)-associated markers-N-Cadherin and Vimentin and stemness-associated markers- POU class 5 homeobox 1 (OCT4) and Indian hedgehog (IHH), and markedly decreased the CD44⁺ population. These indicate the involvement of LINGO2 in gastric cancer initiation and progression by altering cell motility, stemness, and tumorigenicity, suggesting LINGO2 as a putative target for gastric cancer treatment.

Background: Both QKI and TMEFF2 genes are considered putative tumor suppressor genes (TSGs). In gastric (GC) and colorectal (CRC) cancers, downregulation of their expressions is known to be frequent. However, QKI and TMEFF2 mutations that could potentially inactivate their functions are not reported in cancers., Methods: In a genome database, we observed that both QKI and TMEFF2 harbor mononucleotide repeats, which could be mutated in cancers with high microsatellite instability (MSI-H). For this, we studied 79 GCs and 124 CRCs for the mutations and their intratumoral heterogeneity (ITH)., Results: Six of 34 GCs (17.6%) and 10 of 79 CRCs (12.7%) with MSI-H exhibited QKI frameshift mutations while five of 79 CRCs (6.3%) with high MSI (MSI-H) exhibited TMEFF2 frameshift mutations. However, we found no such mutation in microsatellite stable/low MSI (MSS/MSI-L) cancers within the mononucleotide repeats. We also studied ITH for the detected frameshift mutations in 16 cases of CRCs and detected that QKI and TMEFF2 frameshift mutations showed regional ITH in 2 (12.5%) and 1 (6.3%) cases, respectively., Conclusions: Our data show that candidate TSG genes QKI and TMEFF2 harbor mutational ITH as well as the frameshift mutations in GC and CRC with MSI-H. From this observation, frameshift mutations of QKI and TMEFF2 may play a role in tumorigenesis through their TSG inactivation in GC and CRC.

The use of four groups of tumor immune microenvironments (TME) based on PD-L1 and tumor-infiltrating T lymphocytes (TIL) is a reliable biomarker for anti-PD-1/PD-L1 inhibitor therapy. We classified the TME in 241 gastric cancers which were subdivided according to 40 EBV+, 76 microsatellite instability-high (MSI-H), and 125 EBV-/microsatellite-stable (MSS) subtypes by quantitative image analysis (QIA) and correlated the results with mRNA expression levels. The mean PD-L1 ratio and CD8 ratio in EBV+, MSI-H, and EBV-/MSS GCs were significantly different (P < 0.006). The PD-L1 ratio and CD8 ratio obtained by QIA correlated well with the RNA levels of PD-L1 (r = 0.63) and CD8 (r = 0.67), respectively. The TME were type I (PD-L1 H /CD8 H ) in 45, type II (PD-L1 L /CD8 L ) in 106, type III (PD-L1 H /CD8 L ) in 8, and type IV (PD-L1 L /CD8 H ) in 82 cases. The type I TME was significantly associated with high TIL (P = 3.0E-11) and EBV+ status (P = 8.55E-08). In conclusion, QIA results correlated well with the mRNA expression levels and classified TME of gastric cancers.

GLI1 is a transcription factor for hedgehog signaling that plays a crucial role in signaling pathways for controlling cell proliferation, alterations of which are known to contribute to tumorigenesis. Aim of this study was to explore whether GLI1 gene is mutated in gastric (GC) and colorectal cancers (CRC). In a public database, we found that GLI1 had a G7 mononucleotide repeat in the coding sequences that could be a mutation target in the cancers with microsatellite instability (MSI). In this study, we analyzed frameshift mutation of GLI1 in 79 GCs and 129 CRCs (high MSI (MSI-H) or microsatellite stable (MSS)) by single-strand conformation polymorphism analysis and DNA sequencing. We found 10 frameshift mutations in the repeat, nine for CRCs and one for GC. All of the mutations were detected in cancers with MSI-H and there was a statistical difference in the frameshift mutation frequencies between the cancers with MSI-H (10/113) and MSS (0/90). We also analyzed intratumoral heterogeneity (ITH) of the frameshift mutation in 16 CRCs and found that the mutations exhibited regional ITH in three of the CRCs (18.8%). Our data indicate GLI1 harbored not only frameshift mutation but also its mutational ITH, which together could be a feature of GC and CRC with MSI-H.

Aim: To investigate the relationship between histological mixed-type of early gastric cancer (EGC) in the mucosa and submucosa and lymph node metastasis (LNM)., Methods: This study included 298 patients who underwent gastrectomy for EGC between 2005 and 2012. Enrolled lesions were divided into groups of pure differentiated (pure D), pure undifferentiated (pure U), and mixed-type according to the proportion of the differentiated and undifferentiated components observed under a microscope. We reviewed the clinicopathological features, including age, sex, location, size, gross type, lymphovascular invasion, ulceration, and LNM, among the three groups. Furthermore, we evaluated the predictors of LNM in the mucosa-confined EGC., Results: Of the 298 patients, 165 (55.4%) had mucosa-confined EGC and 133 (44.6%) had submucosa-invasive EGC. Only 13 (7.9%) cases of mucosa-confined EGC and 30 (22.6%) cases of submucosa-invasive EGC were observed to have LNM. The submucosal invasion (OR = 4.58, 95%CI: 1.23-16.97, P = 0.023), pure U type (OR = 4.97, 95%CI: 1.21-20.39, P = 0.026), and mixed-type (OR = 5.84, 95%CI: 1.05-32.61, P = 0.044) were independent risk factors for LNM in EGC. The rate of LNM in mucosa-confined EGC was higher in the mixed-type group ( P = 0.012) and pure U group ( P = 0.010) than in the pure D group, but no significant difference was found between the mixed-type group and pure U group ( P = 0.739). Similarly, the rate of LNM in the submucosa-invasive EGC was higher in the mixed-type ( P = 0.012) and pure U group ( P = 0.009) than in the pure D group but was not significantly different between the mixed-type and pure U group ( P = 0.375). Multivariate logistic analysis showed that only female sex (OR = 5.83, 95%CI: 1.64-20.70, P = 0.028) and presence of lymphovascular invasion (OR = 13.18, 95%CI: 1.39-125.30, P = 0.020) were independent risk factors for LNM in mucosa-confined EGC, while histological type was not an independent risk factor for LNM in mucosa-confined EGC ( P = 0.106)., Conclusion: For mucosal EGC, histological mixed-type is not an independent risk factor for LNM and could be managed in the same way as the undifferentiated type., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to disclose.

Background/aim: To maximize success rate for development of HER2-targeted therapeutics, patient-derived xenograft (PDX) models reflecting HER2-positive gastric cancer (HER2 + GC) patients were established., Materials and Methods: GC tissues obtained from surgery of GC patients were implanted into immune-deficient mice, and tumor tissue of HER2 + PDXs were verified of the patient-mimic HER2 expression by immunohistochemistry and explored for the feasibility by testing with Herceptin, the approved therapeutics and novel HER2 antibody therapeutics being developed., Results: We obtained 5 cases of HER2 + GC PDX models reflecting patient's GC tumor, consisting of 2 cases of HER2 3+ and 2 cases of HER2 2+. Novel HER2 antibody displayed significantly improved anti-cancer efficacy in combination with Herceptin., Conclusion: The HER2 + GC PDX models were successfully established to be utilized for preclinical evaluation of HER2-targeting drugs and combined therapies for GC treatment, as an ideal platform of personalized tools for precision therapy., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Designing nanocarriers with active targeting has been increasingly emphasized as for an ideal delivery mechanism of anti-cancer therapeutic agents, but the actualization has been constrained by lack of reliable strategy ultimately applicable. Here, we designed and verified a strategy to achieve active targeting nanomedicine that works in a living body, utilizing animal models bearing a patient's tumor tissue and subjected to the same treatments that would be used in the clinic. The concept for this strategy was that a novel peptide probe and its counterpart protein, which responded to a therapy, were identified, and then the inherent ability of the peptide to target the designated tumor protein was used for active targeting in vivo. An initial dose of ionizing radiation was locally delivered to the gastric cancer (GC) tumor of a patient-derived xenograft mouse model, and phage-displayed peptide library was intravenously injected. The peptides tightly bound to the tumor were recovered, and the counterpart protein was subsequently identified. Peptide-conjugated liposomal drug showed dramatically improved therapeutic efficacy and possibility of diagnostic imaging with radiation. These results strongly suggested the potential of our strategy to achieve in vivo functional active targeting and to be applied clinically for human cancer treatment., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Sorafenib is a multi-kinase inhibitor used in the treatment of various cancers. This study investigated the inhibitory effect of sorafenib on xenograft models of gastric cancer cells and 5-fluorouracil (5-FU)-resistant cells., Methods: The half-maximal inhibitory concentration (IC 50 ) of sorafenib in NCI-N87 cells was determined. Xenograft models were established using BALB/c nude mice and were divided into four groups treated with vehicle, sorafenib (20 mg kg -1  day -1 ), 5-FU (50 mg kg -1  week -1 ), or a combination of sorafenib (20 mg kg -1  day -1 ) plus 5-FU (50 mg kg -1  week -1 ). 5-FU-resistant NCI-N87 cells were established by repeated exposure to 5-FU., Results: Sorafenib inhibited NCI-N87 cell growth in a concentration-dependent manner with a mean IC 50 of 16.345 ± 5.391 μM. Phosphorylation levels of mitogen-activated protein kinase kinase and extracellular signal-regulated kinase in these cells decreased in a dose-dependent manner after exposure to sorafenib. Sorafenib induced the activation of caspase-3, and its combination with 5-FU more effectively inhibited the growth of xenograft tumors than either sorafenib or 5-FU alone (p < 0.05). Sorafenib markedly inhibited 5-FU-resistant NCI-N87 cell growth as well as sphere formation in both parental and 5-FU-resistant NCI-N87 cells., Conclusions: The sorafenib and 5-FU combination exhibited enhanced antitumor effects in a gastric cancer xenograft model and inhibited 5-FU-resistant cell proliferation and sphere formation. These findings suggest that sorafenib is useful in overcoming gastric cancer resistance to conventional chemotherapy.

Objective: The aim of this study was to assess the feasibility of a modified FOLFOX regimen as first-line treatment in elderly patients with metastatic gastric cancer (GC) or colorectal cancer (CRC)., Methods: We included chemotherapy-naïve patients over 80 years old with metastatic GC or CRC in our study. From September 2008 to November 2014, 28 consecutive patients were enrolled and treated with modified FOLFOX., Results: The study population consisted of an equal number of GC and CRC patients. The median age was 82.2 years in the GC group and 81.1 years in the CRC group. The total number of administered cycles was 89 (with a median of 6 per patient) in the GC group and 112 (with a median of 8 per patient) in the CRC group. Median progression-free survival (PFS) and overall survival (OS) were 5.4 and 6.6 months in the GC group and 7.3 and 8.1 months in the CRC group, respectively. There was no significant difference in PFS (p = 0.941) and OS (p = 0.238) between the GC and the CRC group. The 1-year survival rates were 35.7% with GC and 42.9% with CRC. Common grade 3/4 hematology toxicities were neutropenia (10.7%) and anemia (14.3%). Salvage chemotherapy was administered to 1 patient with GC and 7 patients with CRC., Conclusions: The modified FOLFOX regimen can be cautiously considered as a first-line treatment option in extremely elderly patients with metastatic GC or CRC., (© 2017 S. Karger AG, Basel.)

Frameshift mutation of genes containing mononucleotide repeats is a feature of gastric (GC) and colorectal cancers (CRC) with microsatellite instability (MSI). In the public genome database, we found that human HSPA4 gene encoding a heats hock protein 70 protein (HSP70-4) and MED13 gene had mononucleotide repeats in the coding sequences that could be targets for frameshift mutation in cancers with MSI. HSP70-4 is a member of HSP70 that is known to play a role in cell survival. MED13 is a member of MED genome-wide transcription regulators that function as a regulator for diverse biological processes. In this study, we analyzed the mutations in 79 GCs and 124 CRCs including high MSI (MSI-H) and microsatellite stable/low MSI (MSS/MSI-L) cases by single-strand conformation polymorphism analysis and DNA sequencing. We found frameshift mutations of HSPA4 gene in two cancers (one GC and one CRC) and MED13 gene in the other two cancers (one GC and one CRC). The frameshift mutations were deletions of one base (c.2396delA (p.Asn799MetfsX50)) in HSPA4 and (c.2175delA (p.Lys725AsnfsX4)) in MED13. Each of HSPA4 and MED13 mutations were detected in GC with MSI-H (1/34: 2.9 %) and CRC with MSI-H (1/79: 1.3 %), but not in those with MSS. Our data show that unconventional HSPA4 and MED13 genes harbored frameshift mutations in GC and CRC with MSI. These mutations might possibly inactivate their functions and could be a feature of GC and CRC with MSI-H.

A transcription factor-encoding gene ZNF292 is considered a candidate tumor suppressor gene (TSG). Its mutations have been identified in cancers from liver, colon, and bone marrow. However, ZNF292 inactivating mutations that might suppress the TSG functions have not been reported in gastric (GC) and colorectal cancers (CRC) with microsatellite instability (MSI). In a public database, we found that ZNF292 gene had mononucleotide repeats in the coding sequences that might be mutation targets in the cancers with MSI. In this study, we analyzed 79 GCs and 124 CRCs including high MSI (MSI-H) and microsatellite stable/low MSI (MSS/MSI-L) cases for the detection of somatic mutations in the repeats. Overall, we identified frameshift mutations of ZNF292 in 3 (8.8%) GCs and 11 (13.9%) CRCs with MSI-H (14/113), but not in MSS/MSI-L cancers (0/90) (p < 0.001). Also, we studied intratumoral heterogeneity (ITH) of the ZNF292 frameshift mutations in 16 CRCs and found that two (12.5%) had regional ITH of the mutations. Our data show that ZNF292 gene harbors not only frameshift mutations but also mutational ITH, which together may be features of GC and CRC with MSI-H. Based on this, the ZNF292 frameshift mutations may possibly contribute to tumorigenesis by altering its TSG functions in GC and CRC., (© 2016 APMIS. Published by John Wiley & Sons Ltd.)

Krukenberg tumor, a rare metastatic ovarian tumor arising from gastrointestinal adenocarcinoma mainly, tends to occur in premenopausal females. Finding the origin of a Krukenberg tumor is crucial for determining prognosis. In Eastern countries, the most common origin of Krukenberg tumor is stomach cancer, which is generally diagnosed via endoscopic biopsy to investigate an abnormal mucosal lesion. Here, we describe a case of huge adnexal mass in a 33-year-old woman who presented with abdominal distension. Two independent endoscopic examinations performed by experts in two tertiary university hospitals revealed no abnormal mucosal lesion. The patient was diagnosed with a Krukenberg tumor according to findings from random endoscopic biopsies taken from normal-looking gastric mucosa in our hospital. It is very rare to be diagnosed via a random biopsy in cases where three well-trained endoscopists had not found any mucosal lesion previously. Thus, in this case, random biopsy was helpful in finding the origin of a Krukenberg tumor.

Background/aims: This study aims to determine the feasibility and effectiveness of concurrent chemoradiotherapy with the combination of S-1 and cisplatin in locally advanced gastric cancer., Methodology: Treatment-naive patients with locally advanced gastric cancer were enrolled. The patients received concurrent radiation (a total dose of 45 Gy: 25 fractions of 1.8 Gy) and chemotherapy. S-1 was given orally at 60 mg/mg² bid for 21 consecutive days with a resting period of 7 days. Cisplatin was given intravenously at 70 mg/m² for 2 hours on day 1. The tumor response was evaluated 4-5 weeks after the completion of radiotherapy, and surgical resection was tried with curative intent if possible., Results: Nine patients were enrolled, and all patients completed the initially planned concurrent chemoradiotherapy. Clinical response rate was 88.9% (8/9). Seven (77.8%) out of 9 patients underwent surgery, and an R0 resection was achieved in all of them. Pathological assessment of tumor regression after preoperative chemoradiotherapy showed total regression in 1 patient (14.3%), near total regression in 2 (28.6%), moderate regression in 3 (42.9%), and minimal regression in 1 (14.3%). Grade III/IV toxicity included anemia (44.4%), neutropenia (33.3%), and thrombocytopenia (22.2%)., Conclusions: Preoperative concurrent chemoradiotherapy with S-1 and cisplatin is feasible and safe, and could offer an improved chance of tumor regression and curative resection in patients with locally advanced gastric cancer. Further trials with larger numbers of patients are warranted.

Background: The multifocality rate of EGC ranges from 4 to 20%, but there are few data regarding both lymph node metastasis and feasibility of the endoscopic treatment. We investigated the risk of lymph node metastasis with the purpose to evaluate the potential for endoscopic treatment in patients with multifocal EGC., Methods: We retrospectively reviewed the medical records of patients who underwent radical gastrectomy to treat EGC between January 2001 and December 2007 at Severance Hospital, Seoul, Korea. Synchronous multifocal EGC was defined as EGC having two or more malignant foci, whereas solitary EGC was defined as EGC having single focus., Results: Of 1,693 patients, 55 (3.2%) were diagnosed with synchronous multifocal EGC. The rates of lymph node metastasis were 12.7% in synchronous multifocal EGC and 10% in solitary EGC. In the multivariate analysis, synchronous multifocal EGC was not associated with lymph node metastasis (odds ratio, 1.1; 95% confidence interval, 0.4-2.7) compared with solitary EGC. In a subgroup analysis of 55 patients with synchronous multifocal EGC, older age (≥65 years) and lymphovascular invasion were associated with lymph node metastasis. In synchronous multifocal EGC, none of the cases had lymph node metastasis in major and minor lesions representing mucosal cancer without lymphovascular invasion., Conclusions: Synchronous multifocality of EGC does not increase the risk of lymph node metastasis compared with solitary EGC. Therefore, endoscopic treatment can be planned when major and minor lesions are predicted to represent mucosal cancer without lymphovascular invasion.

Background: Recently, endoscopic submucosal dissection has been carefully applied in early gastric cancer (EGC) with undifferentiated type. However, there are no individual guidelines for endoscopic treatment of EGCs with poorly differentiated tubular adenocarcinoma or signet ring cell carcinoma. The aim of this study was to investigate and compare the clinicopathologic features of these two types of EGC to guide the application of endoscopic treatment., Methods: Patients to undergo radical gastrectomy for the treatment of EGC were selected for inclusion in this study. Histology was classified according to the Japanese Gastric Cancer Association. Between January 2005 and December 2008, 288 patients with poorly differentiated EGC and 419 patients with signet ring cell EGC were enrolled. Their medical records were reviewed retrospectively., Results: Compared with signet ring cell EGC, poorly differentiated EGC had higher rates of male gender, old age (≥45 years), large tumor length (>20 mm), ulcer, submucosal invasion, lymphovascular invasion, and lymph node metastasis. In the multivariate analyses, poorly differentiated EGC was significantly associated with ulcer (odds ratio [OR]: 2.4, 95% confidence interval [CI]: 1.5-3.8), submucosal invasion (OR: 3.6, 95% CI: 2.6-5.1) and lymphovascular invasion (OR: 2.0, 95% CI: 1.1-3.6) with a reference of signet ring cell EGC. The independent risk factors for lymph node metastasis were large tumor length, submucosal invasion, and lymphovascular invasion in both types of EGC. Young age was an independent risk factor of lymph node metastasis only in poorly differentiated EGC., Conclusions: Poorly differentiated EGC has clinicopathologic features that are less favorable to endoscopic treatment than are those of signet ring cell EGC. Therefore, these two types of EGC should be approached separately, not as a united type of undifferentiated histology, during the planning of endoscopic treatment.

Parts of gastric (GC) and colorectal cancers (CRC) exhibit microsatellite instability (MSI) that causes frameshift mutations and contributes to cancer development. DNA replication and repair play crucial roles in maintenance of genome stability, and their alterations contribute to cancer development. In this study, we analyzed mutation of RFC1 and RFC3, clamp loaders in DNA replication, in GC and CRC with MSI. We analyzed mononucleotide repeats in RFC1 and RFC3 in 29 GC with high MSI (MSI-H), 20 GC with low MSI (MSI-L), 45 GC with stable MSI (MSS), 35 CRC with MSI-H, 20 CRC with MSI-L, and 45 CRC with MSS by single-strand conformation polymorphism. We also analyzed RFC3 expression in the GC and CRC. We found RFC3 frameshift mutations in 7 GC (24.1%) and 9 CRC with MSI-H (25.7%) but not in cancers with MSI-L or MSS. The mutations consisted of 14 c.244delA, one 243&#95;244delAA, and one c.244dupA, which would result in premature stops of RFC3 amino acid synthesis. Loss of RFC3 expression was observed in 51% of the GC and 65% of the CRC, but all of the cancers with RFC3 frameshift mutations were weak or negative. Our data indicate RFC3 mutation and loss of RFC3 expression occur in large fractions of GC and CRC and suggest that these alterations may contribute to the cancer pathogenesis by deregulating DNA repair and replication., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Coordinated protein phosphorylation and dephosphorylation are crucial in the regulation of cell signaling, and disruption of the coordination is known to play important roles in cancer development. Recent reports revealed that classical protein tyrosine phosphatase (PTP)-encoded genes are somatically mutated in human colorectal cancer. However, data on dual specificity phosphatase (DPTP) gene mutations in human cancers are lacking. By analyzing a public genomic database, we found that five DPTP genes, CDC14A, MTM1, MTMR3, SSH1, and SSH2, have mononucleotide repeats in their coding DNA sequences. To see whether these genes are mutated in cancers with microsatellite instability (MSI), we analyzed the mononucleotide repeats in 26 gastric cancers (GC) with MSI (MSI-H), 12 GC with low MSI (MSI-L), 45 GC with stable MSI (MSS), 33 colorectal cancers (CRC) with MSI-H, 14 CRC with MSI-L, and 45 CRC with MSS by single-strand conformation polymorphism (SSCP). We found CDC14A and MTMR3 mutations in five and one cancer (s), respectively. These mutations were detected in MSI-H cancers, but not in MSI-L or MSS cancers. The GC and CRC with MSI-H harbored the mutations in 15% and 6%, respectively. The CDC14A and MTMR3 mutations detected in the GC and CRC were deletion or duplication mutations of one base in the nucleotide repeats that would result in premature stops of the amino acid syntheses. Our data show that frameshift mutations of DPTP genes in MSI-H cancers occur at moderate frequencies. The data suggested that alterations in the CDC14A and MTMR3 genes may play a role in the development of GC and CRC with MSI-H by deregulating phosphatase functions possibly together with mutations of classical PTP genes.

Background/aims: It is well known that endoscopic insertion of self-expandable metallic stents (SEMS) is safe and effective for the palliative treatment of malignant strictures involving the upper gastrointestinal tract. But, most previous studies focused on stent insertion for esophageal or gastroduodenal obstructions. Only a few cases of stent insertion for recurrent malignant obstruction after gastric cancer surgery have been reported in studies in fewer than 40 patients. The aim of this study was to evaluate the clinical effectiveness of the placement of SEMS in patients with anastomotic recurrence after gastric cancer surgery and compare the clinical outcome according to stent and operation type., Methodology: The data were collected from 47 patients in whom SEMS were placed by endoscopic approach for recurrent malignant obstruction after gastric cancer surgery. Technical and clinical success and complications according to operation and stent type were evaluated. Also, Overall survival and stent patency rates were calculated., Results: Stent placement was technically successful in 45 of the 47 patients (95.7%). After stent placement, 91.5% of the patients showed improvement in their dietary intake level. A statistically significant improvement in overall Gastric Outlet Obstruction Scoring System between pre- and postprocedure was noted (p<0.001). Stent failure occurred in 13 patients (stent migration: 4; tumor overgrowth: 1; tumor ingrowth: 8). The median survival and stent patency period were 101 days and 63 days, respectively., Conclusions: SEMS insertion in patients with anastomotic recurrence of gastric cancer after gastric cancer surgery is technically feasible and clinically effective.

Mounting evidence indicates that alterations of autophagy processes are directly involved in the development of many human diseases, including cancers. Autophagy-related gene (ATG) products are main players in the autophagy process. In humans there are 16 known ATG genes, of which four (ATG2B, ATG5, ATG9B and ATG12) have mononucleotide repeats with seven or more nucleotides. Frameshift mutations of genes with mononucleotide repeats are features of cancers with microsatellite instability (MSI). It is not known whether ATG genes with mononucleotide repeats are altered by frameshift mutations in gastric and colorectal carcinomas with MSI. For this, we analysed the mononecleotide repeats in ATG2B, ATG5, ATG9B and ATG12 in 32 gastric carcinomas with high MSI (MSI-H), 13 gastric carcinomas with low MSI (MSI-L), 43 colorectal carcinomas with MSI-H and 15 colorectal carcinomas with MSI-L by a single-strand conformation polymorphism (SSCP) analysis. We found ATG2B, ATG5, ATG9B and ATG12 mutations in 10, 2, 13 and 0 cancers, respectively. The mutations were detected in MSI-H cancers but not in MSI-L cancers. Gastric and colorectal cancers with MSI-H harboured one or more ATG mutations in 28.1% and 27.9%, respectively. Our data indicate that frameshift mutations in ATG genes with mononucleotide repeats are common in gastric and colorectal carcinomas with MSI-H, and suggest that these mutations may contribute to cancer development by deregulating the autophagy process.

Purpose: To identify a desirable serum marker for screening tools for gastric cancer, we evaluated the validity of 3 biomarkers, namely, carcinoembryonic antigen (CEA), pepsinogens (PGs), and high sensitive C-reactive protein (hsCRP)., Methods: We estimated the mean serum levels of CEA, PGs, and hsCRP and compared the sensitivity and specificity of these 3 biomarkers in 378 subjects who were classified into 7 groups: normal, chronic atrophic gastritis, intestinal metaplasia, adenoma, early gastric cancer (EGC), advanced gastric cancer (AGC) without metastasis, and AGC with metastasis (M1)., Results: There were no significant differences among the normal, high-risk (chronic atrophic gastritis, intestinal metaplasia, and adenoma), and EGC groups for CEA and hsCRP. However, the levels of CEA were relatively higher in the AGC group with intestinal-type cancer (P<0.01). Likewise, hsCRP was relatively higher in the AGC group with diffuse-type cancer (P<0.01). For the PG I/II ratio, there was no significant difference among the normal, high-risk, and cancer groups, including EGC (P<0.01). In addition, there was a negative correlation with grades (gammas=-0.480, P<0.01). However, the PG I/II ratio was relatively less effective in diffuse-type cancer compared with intestinal-type cancer. The combination of serum hsCRP and the PG I/II ratio had a higher sensitivity (77%) than did the PG I/II ratio alone (61%) in diffuse-type cancers., Conclusions: The combination of serum hsCRP and PG I/II ratio would be helpful as a screening tool for gastric cancer in high incidence populations and may help to select high-risk subjects in need of further specific invasive screening tools such as endoscopy.

Background/aims: Ghrelin is a peptide hormone produced mainly in the stomach, and obestatin is derived by proteolytic cleavage of the ghrelin prepro-hormone. The aim of this study was to determine the postoperative serial changes in these hormones and whether hyperplasia of ghrelin-expressing cells occurs in the remnant stomach., Methods: We prospectively analyzed serial serum samples of 45 early gastric cancer patients and remnant stomach samples of 24 patients., Result: The serum obestatin level on day 2 was lower than that on day 0, and it subsequently returned to the level observed on day 0. In contrast, the serum ghrelin level was lower on days 120 and 210 than on day 0. Eventually, the obestatin/ghrelin ratio was significantly high on day 210 (p = 0.0003). Moreover, we did not observe an increase in the number of ghrelin-expressing cells. The number of ghrelin-expressing cells correlated with the serum ghrelin level., Conclusion: The serum level of obestatin and ghrelin exhibits a different time course in patients who have undergone gastrectomy, and there was no ghrelin-expressing cell hyperplasia in the remnant stomach despite the decrease in serum ghrelin., (Copyright 2009 S. Karger AG, Basel.)

Purpose: The expression of nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), one of TGF-beta superfamily gene, is reported to be responsible for NSAID-induced apoptosis. We analyzed NAG-1 expression in gastric cancer and adenoma to find out its clinical implication., Methods: Immunostaining was performed using standard procedures with antibody to NAG-1 on gastric tissue microarrays of tissue specimens obtained by gastrectomy. The immunoreactivity of normal and tumor tissues was graded as no, weak, moderate, and strong expression., Results: The NAG-1 expression was stronger in intestinal metaplasia and adenoma than normal gastric epithelium. 47 (74.6%) of 63 normal gastric epithelium showed no or weak expression, but 33 (56.9%) of 58 and 13 (86.7%) of 15 intestinal metaplsia and adenoma showed moderate or strong expression. Only NAG-1 expression in diffuse type gastric cancer was weaker than in normal gastric tissue. Compared to intestinal metaplasia, both intestinal and diffuse type gastric cancer showed weaker expression. The intensity of NAG-1 expression inversely correlated with tumor differentiation and T and N stage status. While only 1 (2.2%) of 45 T1 stage cases lacked NAG-1 expression, 27 (45.8%) of 59 T3 stage cases lacked NAG-1 expression. Likewise, in N0 stage tumors only 10 (15.4%) of 65 cases lacked NAG-1 expression, but 17 (63.0%) of 27 N3 cases lacked NAG-1 expression., Conclusions: The NAG-1 was expressed strongly in intestinal metaplasia and adenoma, and inversely correlated to tumor stages. This interesting finding may provide new targets for chemoprevention and future development of drugs.

Photodynamic therapy (PDT) shows a limited antitumor effect in treating gastrointestinal tumors because of improper light penetration or insufficient photosensitizer uptake. The aim of this study was to evaluate the cytotoxic effect of PDT combined with paclitaxel on in vitro cancer cells. In vitro photodynamic therapy was performed in gastric cancer cells (NCI-N87) and bile duct cancer cells (YGIC-6B) using verteporfin (2 ug mL(-1)) and a PTH light source (1 000 W, Oriel Co.) with 665-675 nm narrow band pass filter. Cytotoxicity was compared using the MTT assay between cancer cells treated with PDT alone or pretreated with paclitaxel (IC(25)). Apoptotic changes were evaluated using DAPI staining, DNA fragmentation analysis, Annexin V-FITC apoptosis assay, cell cycle analysis, and western blots for cytochrome c, Bax, and Bid. The PDT-induced cytotoxicity was potentiated by pretreating with low dose paclitaxel (P < 0.001). The enhanced cytotoxicity was due to an augmented apoptotic response mediated by exaggerated cytochrome c released from mitochondria, without Bax or Bid activation. These results show that paclitaxel pretreatment enhances PDT-mediated cancer therapy.

Purpose: The purpose of this study was to extend the application of self-expandable metallic stents by investigating their usefulness in treating colorectal obstructions caused by unresectable extrinsic tumors., Methods: From January 2000 to November 2005, a total of 60 colorectal stenting procedures were performed, and 57 stents were deployed in 39 patients with extrinsic tumors. The success rate and complications were analyzed retrospectively., Results: The most common etiology and location of obstruction were advanced gastric cancer and transverse colon. Technical success was 34 of 39 patients (87.2 percent). The causes of technical failure were immediate stent migration (n = 1), technical problems (n = 1), and access failure because of bowel immobilization (n = 3). Clinical success was 32 of 34 technical successes (82.1 percent). The two patients without clinical success had multifocal strictures of the bowel. Complications occurred in 22 of 57 stents (38.6 percent), including stent reobstruction (n = 14) and stent migration (n = 5). All of stent migrations except one developed with covered stents., Conclusions: In patients with colonic obstruction caused by extrinsic tumors, stent insertion provided effective symptom relief and can be a reasonable alternative choice to a colostomy. An uncovered stent might be more preferable, considering less migration and remaining short life expectancy, compared with a covered stent.

Background and Objective: EUS has become a valuable tool for the selection of patients who are suitable for EMR of early gastric cancer (EGC). The aim of this study was to evaluate the various clinicopathologic factors affecting the diagnostic accuracy of EUS in EGC., Design and Setting: A retrospective, single-center study., Patients: A total of 206 patients suspected of EGC endoscopically who underwent EUS examination and curative treatment for EGC at Severance Hospital, Seoul, Korea, from October 2001 to May 2005 were included., Interventions: We reviewed the medical records of 206 patients and compared preoperative EUS staging with final histopathologic staging of the resected specimen according to the clinicopathologic parameters., Main Outcome Measurements and Results: The diagnostic accuracy of EUS for predicting tumor invasion depth was significantly affected by the histopathologic differentiation and the size of tumor. The differentiated cell types were associated with higher diagnostic accuracy in predicting the tumor invasion. Lesions located in the mid one third of the stomach larger than 3 cm had significantly higher probability of overstaging. Poorly differentiated histologic diagnosis had a significantly higher probability of understaging. There was no significant factor associated with the endosonographic prediction of lymph node metastasis., Conclusions: EGC with undifferentiated histopathologic features or large tumor size is more frequently associated with an incorrect diagnosis in tumor invasion depth by EUS. EGC with a size larger than 3 cm and poorly differentiated histologic diagnosis should be cautiously considered in the decision on treatment modality by pretreatment EUS staging.

Purpose: Chemokines play multiple roles in the development and progression of many different tumors. Our cDNA array data suggested that chemokine CXCL5 was upregulated in gastric cancer. Here, we analyzed CXCL5 protein expression in gastric cancer and investigated the clinical implications of CXCL5 upregulation., Methods: Immunostaining for CXCL5 was performed on gastric tissue microarrays of tissue specimens obtained by gastrectomy. The intensity of immunostaining in tumor tissue was considered strong when tumor tissue staining was more intense than in normal tissue; the intensity was null when staining was weaker in the tumor than in normal tissue; and the intensity was weak when staining was similar in both tissues. Serum CXCL5 levels and microvascular density in tumor tissue were measured by ELISA and monoclonal antibody to Factor VIII., Results: Strong CXCL5 expression correlated with tumor stage. CXCL5 expression did not correlate with T stage. However, N stage positively correlated with CXCL5 expression. Serum CXCL5 levels in late stage (IIIB, IV) gastric cancer patients were higher than in patients with benign conditions. Microvascular density was higher in tumors with strong CXCL5 expression, but the correlation with CXCL5 was not linear. Multiple logistic regression analyses showed that, compared to no or weak expression, strong expression of CXCL5 was a significant risk factor for high N stage (N2, N3)., Conclusions: CXCL5 overexpression was associated with late stage gastric cancer and high N stage. These results suggest a role for CXCL5 in the progression of gastric cancer, specifically in lymph node metastasis.

The disruption of tight junction protein expression in cancer might account for invasiveness, loss of cohesion, and lack of differentiation. Our cDNA array data indicated that claudin 7 was up-regulated in gastric carcinoma. We investigated the expression patterns and clinical implications of claudin 7 in gastric cancer. By immunohistochemical staining and Western blot, claudin 7 was significantly more often expressed in intestinal metaplasia, adenoma and cancer than in normal gastric epithelium. Twenty-seven (47.4%) of 57 normal gastric epithelium samples did not express claudin 7, but 50 (86.2%) of 58 intestinal metaplasia, 11 (91.7%) of 12 adenoma tissues, and 129 (82.7%) of 156 cancer samples did. Claudin 7 was more often unexpressed in diffuse type gastric cancer than in intestinal type. Only 13 (11.2%) of 116 intestinal type samples did not express claudin 7, but 14 (41.2%) of 34 diffuse type samples showed no expression. Compared to normal gastric epithelium, intestinal type gastric cancer significantly more often expressed claudin 7, but diffuse type did not. The expression pattern of claudin 7 did not change as cancer progressed. In this study we show that claudin 7 expression changed with the gastric carcinogenic process and that this is implicated in cancer characteristics.

Aims: Gastric carcinoma confined to the muscularis propria (MPGC) is considered an intermediate-stage carcinoma. A method of discriminating between more favourable and less favourable prognostic groups of this entity is critically needed in dealing with this heterogeneous disease. The aim of this study was to examine the correlation between survival of patients with MPGC and its various clinicopathological parameters., Methods and Results: Various clinicopathological parameters were studied in 171 tissue samples including: macroscopic appearance, size, age, sex, stage, invasion depth, Lauren and Ming classifications, extent, lymphatic emboli and nodal metastasis. Tumours macroscopically resembling early gastric cancers, younger patient age, absence of lymphatic tumour emboli and lower stage were significantly associated with better prognosis of MPGC by univariate analysis. Tumours macroscopically resembling early gastric cancers, younger patient age and Lauren's diffuse type were significantly associated with a better prognosis of MPGC by multivariate analysis., Conclusions: These indicators are practical parameters for predicting patient prognosis in clinical practice. The description of these parameters should be carefully noted in the final report and pathologists should evaluate the macroscopic appearance of MPGC.

Background/aims: Maspin is a member of the serpin family of protease inhibitors known to have tumor suppressor activity. However, molecular aspects in carcinogenesis and progression of gastric cancer remain largely unclear. Previously we reported for the first time that maspin is induced in the course of gastric carcinogenesis. In the present study we evaluated maspin induction in gastric adenocarcinoma in relation to a number of clinicopathologic feature., Methodology: Maspin expression was examined by Western blot analysis and immunohistochemical staining in 82 cases of gastric adenocarcinoma., Results: In Western blot analysis, gastric specimens of tumor showed increased maspin expression compared with corresponding normal tissues in 54 of 82 patients (66%). Tumor shows increased maspin expression compared with normal tissue in 81.1% of stage IV patients and 83.3% of N3 patients. The frequency of maspin induction was associated with the stage of gastric cancer (p = 0.01) and lymph node metastasis (p = 0.03). There was no significant association between maspin induction and Helicobacter pylori infection., Conclusions: Our data suggest that maspin may have an important role in the progression and metastasis of gastric adenocarcinoma.

Background/aims: Endoscopic mucosal resection (EMR) has been widely accepted as a treatment option for early gastric cancer (EGC) in selected cases. The purposes of this study were to evaluate the long-term outcomes and the factors affecting the clinical outcomes, of EMR performed in EGC., Methodology: Between April 1996 and March 2005, 147 patients have undergone EMR to treat EGC at Yonsei University Medical Center, Seoul, Korea. We assessed the clinical outcomes of the EMR for EGC in a long-term follow-up period. We also reviewed the medical records of the patients including demographic data, endoscopic characteristics of the lesion and histopathologic findings., Results: The histopathologic evaluations after the EMR treatment showed that overall complete resection rate was 84.6% (126/149) while complete resec tion rate of 93.5% was achieved in mucosal cancers (115/123). The success of complete resection was significantly affected by endoscopic gross type (depressed lesion), the degree of differentiation, and the depth of invasion, independently. There were only 5 cases of local recurrence during the follow-up periods, and the recurred or incompletely resected lesions were successfully treated by salvage operation or endoscopic retreatment. There was no disease-related or treatment-related mortality during the follow-up period., Conclusions: EMR is a good and safe curative treatment option with feasible clinical outcomes in patients with EGC. It must be emphasized that a proper selection of candidates is mandatory to improve the clinical outcome of EMR in EGC.

Background: To investigate the clinicopathological significance of promoter methylation of the helicase-like transcription factor (HLTF) in primary gastric cancer., Patients and Methods: Two-hundred fifty six patients participated in this study. Methylation status of HLTF gene was evaluated in fresh-frozen tissues by the methylation-specific polymerase chain reaction. All statistical analyses were two-sided, with a 5% type I error rate., Results: Aberrant methylation of HLTF was found in 98 (38%) of 256 gastric cancer patients. HLTF methylation was significantly associated with a family history in the early stages of gastric cancer, regardless of histologic types. In intestinal-type cases, HLTF methylation occurred in 15 (56%) of 27 patients with family histories, and in 26 (31%) of 85 patients without family histories (P = 0.02). In diffuse-type cases, patients with family histories were also found to exhibit a higher prevalence of HLTF methylation than those without family histories (61% vs. 34%; P = 0.009). HLTF methylation in both of the histologic types occurred in about 70-90% of the early stage cases in which the patient had a family history and in 15-30% of cases in which the patient did not have a family history. In our multivariate logistic regression analysis, the stage 1-2 cases with family histories were determined to carry a higher risk of HLTF methylation than did the stage 3-4 cases without family histories in both the intestinal-type (OR = 6.01, 95% CI = 1.20-30.01, P = 0.02) and the diffuse-type cancers (OR = 8.25, 95% CI = 1.67-40.86, P = 0.009)., Conclusions: These results suggest that HLTF methylation may play a crucial role in the early stages of gastric carcinogenesis in patients with family histories and may be a valuable susceptible marker for the risk of gastric cancer in individuals with family histories.

In this study the expression levels of reversion-inducing-cysteine-rich protein with Kazal motifs (RECK) in gastric cancer cell lines and tissues have been analysed in order to assess their value as a prognostic indicator. The expressions of RECK, activated matrix metalloproteinase (MMP)-7, and vascular endothelial growth factor (VEGF) in gastric cancer tissues and cell lines were evaluated by Western blot analysis; and MMP-2 and MMP-9 were evaluated by gelatin zymography. RECK expression in the context of gastric cancer was also compared with various clinicopathologic parameters and compared to the expression of activated MMP-7, MMP-2, and MMP-9. Fifty-two percent of the 102 gastric cancer tissues and 81.8% of the 11 gastric cancer cell lines exhibited reduced RECK expression. We also detected a significant inverse correlation between RECK expression and macroscopic tumour growth (P=0.018), lymphatic invasion (P=0.018), lymph node metastasis (P=0.000), stage (P=0.000), and MMP-9 (P=0.039). No correlation between RECK expression and MMP-7 and MMP-2, VEGF were detected. Our data strongly supports the hypothesis that RECK is a suppressor of malignancy, and constitutes a good prognostic indicator in gastric cancer.

Since the underlying mechanism for the high incidence of aneuploidy in gastric cancer has not clarified, we screened 49 gastric cancers and five gastric cancer cell lines for mutations in the mitotic spindle checkpoint genes, Bub1 and Mad2, and we analyzed the functional consequences of these mutations. The presence of mutations in Bub1 and Mad2 coding sequences was primarily detected by RT-PCR-SSCP and subsequently confirmed by automatic sequencing of either the RT-PCR products and/or the PCR products from genomic DNA. Mad2 was mutated in 44.9% of gastric cancer tissues and one gastric cancer cell line, N87, but not Bub1. Of these, three mutational hotspots at codons 156, 165 and 182 were identified. Mutations at codons 165 and 182 led to amino acid substitutions, whereas the mutation at codon 156 was a silent one. Overexpression of mutant Mad2 in HeLa cells led to the appearance of aneuploid cells in the presence of nocodazole, and this indicated that these mutations caused a defect in MAD2 protein. Wild type and mutant MAD2 protein displayed distinct mobility on two-dimensional gel electrophoresis. Novel mutational hotspots in human Mad2 genes were discovered for the gastric cancers and these mutations caused the functional defects in the spindle checkpoint suggesting that these mutations might be involved in the development and progression of gastric cancer.

Background: During laparoscopic-assisted gastrectomy, it is impossible to identify early gastric cancer (EGC) lesions; therefore, a precise localization technique is needed. In this study, we used laparoscopic ultrasonography (LUS) after endoscopic clipping as a method of localizing EGC and evaluated the effectiveness of this method., Methods: A prospective study of 17 patients who had undergone laparoscopic-assisted gastrectomy was performed. Three endoscopic clips were applied just proximal to the tumor during the preoperative endoscopy. The applied clips were detected from the serosal side of the stomach using LUS. The serosal surface of the lesion was marked with dye., Results: In all patients, endoscopic clips were applied proximal to the lesion without complications, and the applied clips were confirmed by plain abdominal radiography. The clips were successfully detected by LUS in all patients. In the resected specimen, the serosal surface, marked with dye, was always just above the clips in the anterior wall or on the anterior wall opposite the clips applied in the posterior wall. The mean detection time was 4.7 min (range, 2-8). With this procedure, two patients underwent total gastrectomy and 15 patients underwent distal subtotal gastrectomy with gastroduodenostomy or gastrojejunostomy. Histological examination confirmed that the resection margins were tumor free in all patients. There was no operative morbidity related to the LUS procedure., Conclusions: Using LUS to detect endoscopic clips is an easy, safe, and accurate method to localize EGC lesions in laparoscopic-assisted gastrectomy.

Aim: To ascertain the adequacy of the microsatellite instability (MSI) as a prognostic indicator by assessing MSI status of patients with double primary gastric and colorectal cancer (DPGCC)., Methods: Sixteen patients were studied, all of whom exhibited sporadic DPGCC, and had no family history of hereditary non-polyposis colorectal cancer, according to the Amsterdam criteria. A total of 32 cancers from 16 DPGCC patients, and 216 single primary CRC, were assessed for MSI in 5 microsatellite loci, BAT25, BAT26, D2S123, D5S346, and D17S250., Results: MSI was observed in 6 (37.5%) of 16 GC and 4 (25.0%) of 16 CRC. Thirty tumors (13.9%) out of 216 single primary CRC and one tumor (16.7%) out of 6 double primary CRC were found to be microsatellite unstable. Of the 6 GC with MSI in DPGCC, 5 (31.3%) were MSI-high and one (6.3%) was MSI-low. In 5 of 16 DPGCC patients, the cancer recurred in or adjacent to the anastomosis or metastasized to the kidney or lung. The MSI-high DPGCC cases were associated with a younger age of onset (47.5 years vs 62.5 years), higher frequency of lymph node metastasis (100% vs 25%), and advanced Dukes stage (C, 100% vs 41.7%), as well as a higher frequency of recurrence or metastasis (100% vs 8.3%). Only recurrence or metastasis showed statistical significance by Fisher's exact test., Conclusion: Our data suggest that MSI may play an important role in the development of DPGCC, and that it may be used clinically as a molecular predictive marker for recurrence or late metastasis of DPGCC.

Background: Although there have been some reports on microsatellite alterations in gastric cancer, findings are inconsistent regarding the associations between histological classification and microsatellite instability (MSI). In the present study, we attempted to determine whether Lauren's histological subtypes are related with MSI status., Methods: Paraffin-embedded tissue samples from 14 diffuse-type and 14 intestinal-type gastric adenocarcinomas were matched up according to patient gender and age. Mononucleotide markers (BAT25 and BAT26) and dinucleotide markers (D2S123, D5S346, and D175S250) were used for MSI analyses. Microsatellite genotypes were categorized in terms of high MSI incidence (MSI-H, >30% positive marker) or low MSI incidence (MSI-L, <30% positive marker). Losses of hMLH1 and hMSH2 protein expression were immunohistochemically studied., Results: MSI-H was observed in 11 cases (78%) of the 14 intestinal-type cases as compared to 3 (21%) of the 14 diffuse-type cases (p=0.007). In MSI-H tumors, 10 cases (71%) showed losses of hMLH1 protein expression, while 2 cases (14%) in MSI-L tumors showed losses of hMLH1 protein expression (p=0.006)., Conclusion: MSI-H tumors are more frequently found in intestinal-type gastric cancer, which suggests the possibility that there are different pathogenic pathways in gastric carcinogenesis according to histologic type.

The expression of E-cadherin located in the adherens junction varies with disruption of glandular morphology and loss of differentiation. It has been suggested that the loss of tight junction function is related to tumor differentiation, but little is known about the roles of major proteins, such as claudin 4 and ZO-1, in gastric cancer. The aims of this study were to examine the differences in expression of E-cadherin, claudin 4, and ZO-1 proteins according to the pathological and clinical features of advanced gastric cancer. The expression of E-cadherin, claudin 4, and ZO-1 was analyzed immuno-histochemically using formalin-fixed, paraffin-embedded tissues obtained from 49 patients who underwent radical resection for advanced gastric cancer. Western blot analysis and RT-PCR were performed in representative tumors of the diffuse or intestinal type. Immunostaining for E-cadherin, claudin 4, and ZO-1 was reduced in 69, 69, and 37% of cancers, respectively. Similar patterns of expression were noted for E-cadherin and claudin 4, but ZO-1 expression differed. According to the Lauren classification, the reduced expression of E-cadherin and claudin 4 was more frequent in diffuse than intestinal type tumors (p<0.001). The reduced expression of E-cadherin and claudin 4 correlated with poor differentiation (p<0.05). Western blot analysis and RT-PCR also showed decreased claudin 4 expression in diffuse type tumors and poorly-differentiated adenocarcinoma. The reduced expression of claudin 4 and E-cadherin correlates with disruption of glandular structure and loss of differentiation, which suggests that the dysfunction of claudin 4 may play a role in the disruption of cell-to-cell adhesion in diffuse type gastric cancer and in a loss of differentiation.

Aim: To study the correlation between lymph node metastatic disease and various pathological parameters. Lymph node metastasis is the most important factor in determining the prognosis of patients with early gastric cancer and is significantly associated with the submucosal invasion of neoplastic cells. However, the depth of submucosal layer as well as the depth of submucosal tumour invasion varies among different cases., Methods and Results: We studied various pathological parameters including the macroscopic appearance, location, size, area, differentiation, invasion depth, vascularity and fibrosis of submucosal gastric carcinomas (SMGC), using 248 age- and sex-matched tissue samples. The presence of lymphatic emboli, a larger area, greater size, a non-flat gross type and an increased vascularity of the tumour were significantly associated with node-positive SMGC. Among the three depth-related parameters, the ocular scale measurement, the sm3 method and the sm2 method, only the ocular scale measurement showed a significant correlation with node-positive SMGC. Using multivariate analysis, the incidence of lymph node metastasis increased in the lymphatic tumour emboli and in the tumours that invaded more than half of the submucosal layer., Conclusions: These histological indicators seem to be a feasible and easy way to predict lymph node metastatic disease from limited surgery specimens. Pathologists should carefully investigate the lymphatic invasion of tumour cells and measure the invasion depth of the tumour.

Gastric bronchogenic cyst is an extremely rare lesion. A 62-year-old Korean woman presented with an incidentally found perigastric nodule. An abdominal ultrasonogram and computed tomography showed a 1.5 cm solid, homogeneous, low-density nodule in the hepatogastric ligament near the gastric lesser curvature. At the time of surgery, a soft 1.7 cm nodule was found in the lesser curvature side just below the gastroesophageal junction, and a gelatinous mass was protruded from the nodule during the resection. Microscopically, the gastric subserosa showed cystic structures lined by pseudostratified ciliated columnar epithelium, seromucinous gland, connective tissue and complete layers of smooth muscle bundles. Neither cartilage nor gastrointestinal epithelium was identified. A mucocele was found near the cyst and foamy cells and faintly bluish mucinous substances were found near the cystic structures. All the mucinous substances were stained by alcian blue at pH 2.5 with varying degrees of staining intensity. The present case is the smallest reported cyst among the gastric bronchogenic cysts, and these lesions are unusually located at the lesser curvature side of the stomach. Although these lesions are very rare, gastric bronchogenic cyst should be included in the differential diagnosis of gastric wall mass.

Background: Capecitabine (Xeloda) is a novel, oral, selectively tumor-activated fluoropyrimidine with proven activity in the treatment of advanced colorectal cancer. This trial was conducted to evaluate the efficacy, safety and feasibility of capecitabine in previously untreated patients with advanced and/or metastatic gastric cancer, with a view to replacing 5-fluorouracil (5-FU) in such patients., Patients and Methods: Forty-four patients received capecitabine 1250 mg/m2 twice daily (2500 mg/m2/day) for 14 days followed by 7 days of rest, for up to six cycles., Results: Capecitabine produced an objective response rate of 34% (all partial responses) and stable disease in 14 patients (30%). The median time to disease progression (TTP) was 3.2 months [95% confidence interval (CI) 2.7-6.4 months] and median overall survival was 9.5 months (95% CI 6.9-13.2 months). Hand-foot syndrome (HFS), nausea, anorexia, diarrhea and vomiting were the most common adverse events. While HFS was the most frequent grade 3/4 toxicity (National Cancer Institute Common Toxicity Criteria), only 9% of patients experienced grade 3 HFS. Severe myelosuppression was not reported during the study., Conclusions: Capecitabine monotherapy is active and well tolerated as first-line therapy in patients with advanced/metastatic gastric cancer. Larger comparative trials investigating capecitabine-based combination regimens in patients with advanced gastric cancer are warranted.

In the current study, we compared the differential expression profiles of genes affected by endocrine disruptor in gastric carcinomas of the young and old using cDNA microarray. Five gastric carcinoma tissues of young patients (< or =35 years) were compared with 5 disease-free gastric tissues of age-matched healthy young people (experiment 1) and 5 gastric carcinoma tissues of old patients (> or =65 years) (experiment 2), respectively. We hybridized the tissues with IntelliGene Human DNA Chip for endocrine disruption study, and identified finally the results common to the two experiments. Of the 220 genes represented on the array, 6 genes were up-regulated and 3 genes were down-regulated in the gastric carcinomas of young patients compared with those of old patients and those of the young volunteers. In conclusion, the genes affected by endocrine disruptors were differently expressed in young-age gastric carcinoma versus the old-age gastric carcinoma. So, we suggest that the gastric carcinoma in the young is the result of a genetic background that differs from that of the old and endocrine disruptors may play an important role in the carcinogenesis of gastric carcinoma in the young.

Aim: Recent trends in treatment strategy for early gastric cancer (EGC) are towards minimal surgical procedures, such as endoscopic mucosal resection and laparoscopic partial resection. There is a possibility of incomplete removal of regional lymph nodes in minimal procedures, which may subsequently decrease the chance of a cure. Therefore, it is essential to be able to predict lymph node status and to make careful selection of candidates for mucosal resection., Methods and Results: We studied the relationship between lymph node status and various pathological parameters including macroscopic appearance, location, size, differentiation, presence of ulceration, vascularity, presence of gastritis cystica profunda-like glandular proliferation, disruption of the muscularis mucosae and invasion into the muscularis mucosae, using age- and sex-matched samples of 40 node-positive and 80 node-negative tumours to define the characteristics of intramucosal EGCs. Histological differentiation (P < 0.001), increased submucosal vascularity (P < 0.05), breakdown of the muscularis mucosae (P < 0.05), and invasion of tumour cells into the muscularis mucosae (P < 0.05) were correlated with the lymph node status of intramucosal gastric carcinoma. Furthermore, diffuse type histology (P < 0.001) and deep invasion into the muscularis mucosae (P < 0.05) were indicators of node-positive intramucosal EGCs., Conclusions: These histological indicators are easily accessible and seem to predict lymph node metastatic disease in limited surgical specimens. Patients should be carefully selected despite the recent trend toward less invasive resection of EGCs, especially for those apparently confined to the mucosa.

Background: Abnormal expression of E-cadherin plays an important role in the differentiation and progression of gastric carcinoma. There are a few identifiable clinical, histopathologic, and molecular changes that are related with the macroscopic growth patterns of gastric carcinoma. The aim of this study is to elucidate the relation between the macroscopic growth patterns of gastric carcinoma and the abnormal expression of E-cadherin, alpha- and beta-catenins., Study: A total of 97 cases of early gastric carcinoma were examined by immunohistochemistry using monoclonal antibodies against E-cadherin, alpha- and beta-catenins. Macroscopically, 52 cases were elevated types and 45 cases were depressed types., Results: Early gastric carcinomas with depressed growth showed diffuse histologic type, younger patients' age and smaller size more frequently than tumors with elevated growth. Abnormal expression rates of E-cadherin, alpha- and beta-catenins were 35.1, 36.1, and 46.4%, respectively. Abnormal expression of E-cadherin, alpha- and beta-catenins was significantly associated with depressed tumor growth and diffuse histologic type. By multiple logistic regression analysis. E-cadherin, age, Lauren classification, World Health Organization grade and size were identified as risk factors of macroscopic growth pattern of early gastric carcinomas. Positive associations between E-cadherin and beta-catenin and between alpha- and beta-catenins were found by log linear model analysis., Conclusion: We suggest that E-cadherin plays an important role in the macroscopic growth as well as microscopic differentiation of early gastric carcinomas.