Primary Gastric Tumors Research Articles

Clinical and therapeutic relevance of PIM1 kinase in gastric cancer

Gastric cancer is a leading cause of cancer-related mortality, and chemotherapeutic options are currently limited. PIM1 kinase, an oncogene that promotes tumorigenesis in several cancer types, might represent a novel therapeutic target in gastric cancer. We studied the expression and genomic status of PIM1 in human primary gastric normal and tumor tissue samples by immunohistochemistry and array-based comparative genomic hybridization (aCGH). To ascertain whether PIM1 expression predicted susceptibility to PIM1 kinase-specific inhibition, the cytotoxic effect of a previously reported PIM1-specific small molecular inhibitor (K00135) was investigated in two gastric cancer cell lines with high (IM95) and undetectable (NUGC-4) PIM1 expression levels. PIM1 expression was exclusively nuclear in normal gastric epithelial cells, while aberrant expression/localization (decreased nuclear and/or increased cytoplasmic expression) was observed in 75.6% (68/90) of the human gastric cancer tissue samples, with a significant inverse correlation between nuclear and cytoplasmic expression levels. Clinicopathological analyses revealed that decreased nuclear PIM1 expression correlated with poorer survival and greater depth of tumor invasion, while increased cytoplasmic PIM1 expression correlated inversely with the presence of lymphovascular invasion. High-level PIM1 amplification was identified in 10.5% of gastric cancers by aCGH. K00135 impaired the survival of IM95, while it had no significant effect on NUGC-4 survival. Our findings demonstrate the clinical and therapeutic relevance of PIM1 in gastric cancers, and suggest that PIM1 represents a potential therapeutic target.

Response to imatinib rechallenge in a patient with a recurrent gastrointestinal stromal tumor after adjuvant therapy: a case report

IntroductionAdjuvant imatinib improves recurrence-free survival of patients following resection of primary KIT-positive gastrointestinal stromal tumors. However, it is unknown whether patients who previously received adjuvant imatinib therapy will respond to imatinib rechallenge as treatment for recurrent disease. Here we present the first report documenting the benefits of imatinib rechallenge in a patient previously exposed to imatinib during adjuvant treatment.Case presentationA 51-year-old Asian woman with a wedge-resected primary gastric gastrointestinal stromal tumor at high risk of relapse underwent two years of adjuvant treatment with imatinib. Only 10 months after the completion of adjuvant imatinib treatment, a computed tomography scan revealed gastrointestinal stromal tumor recurrence in this patient, with multiple peritoneal nodules in the upper abdomen being detected. Our patient was rechallenged with imatinib 400 mg/day and had a partial response after one month of treatment. Imatinib rechallenge was well tolerated by our patient; the only adverse events she experienced were grade 1 edema, anemia and fatigue. Our patient maintained a partial response two years and six months after the imatinib rechallenge. However, computed tomography scans three months later showed that our patient had disease progression.ConclusionsThis case report demonstrates that a patient with a gastrointestinal stromal tumor who had previously received adjuvant imatinib therapy responded to imatinib rechallenge as treatment for her recurrent disease. These results indicate that imatinib sensitivity can be maintained in a patient with previous exposure to adjuvant imatinib therapy.

Clinical Implications of the Histologically and Immunohistochemically Detected Solitary Lymph Node Metastases in Gastric Cancer

Topographic correlation between the primary gastric tumor and the first peri- and extragastric lymphatic drain basin (solitary lymph node metastasis) on gastrectomy specimens, represents a reliable method to investigate and understand the exact pattern of lymphatic drainage from a gastric tumor. Analyzing that correlation, useful information regarding the extent of the appropriate oncological perigastric lymphadenectomy will be provided. We retrospectively evaluate the usefulness of a modified D2 lymphadenectomy in gastric cancer patients, based on the topographic correlation between the primary tumor and the location of the solitary lymph node metastases, as they were detected by histology and immunohistochemistry. Between April 2003 and March 2010, 134 gastric cancer patients were submitted to a modified D2 lymphadenectomy. Postoperatively, the standard histological ex-amination by hematoxylin and eosin (HE) staining, disclosed metastatic infiltration of at least two lymph nodes in 90 patients, solitary lymph node metastases were histologically detected in 10 patients, while the remaining 34 patients were classified as pN0. All lymph nodes of the ten patients with histological solitary lymph node metastases, as well as the 34 patients who had been classified as pN0 by histology, were further submitted to immunohistochemistry for micrometastases detection. More than one micrometastases were detected in none of them, while in seven patients solitary micrometastases were detected either in the level I perigastric or in the level II extragastric lymph nodes stations (skip micrometastases). Solitary lymph node metastases were detected by histology in ten patients and by immunohistochemistry in additional seven (nine females and eight males). Solitary metastases were detected in the level I LN stations in seven patients (four by histology and three by immunohistochemistry) and in the level II LN stations in ten patients (six by histology and four by immunohistochemistry). In order of frequency, the solitary lymph node metastases were located in the no 7 (n = 6), no 6 (n = 4), no 9 (n = 2), no 5 (n = 2), no 4 (n = 1), no 8 (n = 1) and no 12 (n = 1) LN stations. Skip metastases encountered the 60% of the histologically detected, 57% of the immunohistochemically detected and 59% of all solitary lymph node metastases. 80% of solitary metastases in the level II LN stations, were mainly located in the nos 7-9 lymph node stations complex. Tumors of the lower and middle-third of the stomach were equally drained both to the level I and level II lymph node stations, while 67% of the tumors towards the lesser curvature, were mainly drained in the level II lymph node stations. D2 lymphadenectomy increases the number of true R0 resections. Thus, a modified D2 lymphadenectomy should be routinely performed in gastric cancer patients.

Predictive values of 5-fluorouracil pathway genes for S-1 treatment in patients with advanced gastric cancer

Determination of significant associations between gene expression and predefined endpoints might improve treatment tailoring for advanced gastric cancer. We investigated the mRNA expression of 5-fluorouracil (5-FU) pathway genes in prechemotherapeutic tumor samples of primary gastric cancer to try to predict the treatment outcome of S-1 monotherapy. 5-FU pathway genes, dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidylate synthase (TS), and thymidine phosphorylase (TP), were analyzed using quantitative real-time PCR of RNA extracted from archived formalin-fixed paraffin-embedded tissues. We selected the median value for each gene as a cutoff to separate patients into high and low gene expression groups. High OPRT gene expression was significantly associated with tumor response (P = 0.014). In a combined analysis including OPRT, patients with high OPRT and TP showed a higher overall response rate than did the remaining patients (40 vs. 10%, respectively; P = 0.002). For survival, patients with high OPRT and low TS levels showed prolonged survival in both progression-free survival (3.4 vs. 2.4 months, P = 0.024) and overall survival (11.0 vs. 8.2 months, P = 0.007). In a multivariate analysis, the combinations of OPRT and TP for response and OPRT and TS for both progression-free survival and overall survival were independent variables. To conclude, mRNA expression levels of molecular markers in formalin-fixed paraffin-embedded specimens of primary gastric tumors can be useful for identifying patients with advanced gastric cancer who would most likely benefit from S-1 treatment.

Down‐regulated SPARCL1 is associated with clinical significance in human gastric cancer

SPARC-like protein 1 (SPARCL1), a member of extracelluar matrix glycoprotein, is involved in many physiological functions. Tissue microarray (TMA) blocks were constructed based on 1,072 Chinese patients, containing both gastric cancer (GC) tissues and adjacent normal mucosa tissues. We analyzed the expression of SPARCL1 from both mRNA and protein level, using Real-time quantitative polymerase chain reaction (qRT-PCR), semi-quantitative PCR, immunohistochemistry (IHC), and Western blotting. Loss of heterozygosity analysis at the SPARCL1 gene locus was carried out using ten paired tumor and matched normal tissues. SPARCL1 mRNA was significantly reduced in tumor specimens compared with normal tissues. Down-regulation of SPARCL1 protein was detected in 413 cases (38.7%) of 1,072 primary gastric tumor tissues. Kaplan-Meier survival curves demonstrated that SPARCL1-positive patients had better median survival time than SPARCL1-negative patients (59 months vs. 28 months, P = 0.001). Multivariate survival analysis revealed that SPARCL1 was an independent prognostic factor in gastric adenocarcinoma patients with no metastasis and well/moderately differentiated. The incidence of LOH for each individual marker was 12.5% (1/8) for D4S2462, 20% (2/10) for D4S2929, and 33.3% (3/9) for SPARCL1. Our study revealed the clinical significance of SPARCL1 expression, providing a basis that the loss of SPARCL1 is a negative event in GC progression and prognosis. Furthermore, SPARCL1 protein might be considered to be a potential differentiation marker.

A case of two primary gastric malignancies: adenocarcinoma and squamous cell carcinoma of the stomach

D Gastric cancer is the second leading cause of death from cancer worldwide. Despite this fact, there has been an overall decrease in the incidence of gastric cancer over the past few decades.1 Therefore, it is important to understand the different histological manifestations of the disease. The most common form of gastric cancer is adenocarcinoma. In contrast, squamous cell carcinoma of the stomach is rare and has been described in numerous case reports.2,3 In addition, cases of rimary gastric adenosquamous carcinoma also have been eported.4,5 We present a case of a woman with two gastric tumors in separate locations with different histological characteristics; one an adenocarcinoma, the other squamous cell carcinoma. To our knowledge there are no reported cases of two separate gastric primary tumors consisting of these two pathologic diagnoses.

REGIV as a potential biomarker for peritoneal dissemination in gastric adenocarcinoma

This study examined the clinical significance of regenerating islet-derived family member 4 (REGIV) in surgically resected gastric tumors. The potential of REGIV as a biomarker in gastric cancer was also assessed including its predictive value for prognosis and recurrence after surgery. Immunohistochemistry was performed to assess the clinical significance of REGIV expression status in surgically resected specimens. The quantitative genetic diagnostic method, transcription-reverse transcription concerted reaction (TRC) that targeted REGIV mRNA was applied for prediction of peritoneal recurrence in gastric cancer. Positive immunostaining for REGIV was observed in 85 cases (52.5%), and correlated significantly with diffuse type histopathology (P = 0.001), advanced T stage (P = 0.022), and frequent peritoneal recurrence (P = 0.009). Multivariate analysis identified advanced T stage (P < 0.001) and REGIV expression (P = 0.034) as independent prognostic factors for peritoneal recurrence-free survival. Overexpression of REGIV protein was evident in the majority of peritoneal tumors (93.8%). REGIV mRNA assessed by TRC could be a predictive marker for peritoneal recurrence after curative operation. REGIV overexpression is common in primary gastric tumors and a potentially suitable marker of diffuse type histopathology and peritoneal dissemination. Overexpression of REGIV mRNA, assessed by the TRC method, is a potentially suitable marker of peritoneal recurrence after curative resection.

Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype

Identification and characterization of cancer stem cells (CSCs) in gastric cancer are difficult owing to the lack of specific markers and consensus methods. In this study, we show that cells with the CD90 surface marker in gastric tumors could be enriched under non-adherent, serum-free and sphere-forming conditions. These CD90(+) cells possess a higher ability to initiate tumor in vivo and could re-establish the cellular hierarchy of tumors from single-cell implantation, demonstrating their self-renewal properties. Interestingly, higher proportion of CD90(+) cells correlates with higher in vivo tumorigenicity of gastric primary tumor models. In addition, it was found that ERBB2 was overexpressed in about 25% of the gastric primary tumor models, which correlates with the higher level of CD90 expression in these tumors. Trastuzumab (humanized anti-ERBB2 antibody) treatment of high-tumorigenic gastric primary tumor models could reduce the CD90(+) population in tumor mass and suppress tumor growth when combined with traditional chemotherapy. Moreover, tumorigenicity of tumor cells could also be suppressed when trastuzumab treatment starts at the same time as cell implantation. Therefore, we have identified a CSC population in gastric primary tumors characterized by their CD90 phenotype. The finding that trastuzumab targets the CSC population in gastric tumors suggests that ERBB2 signaling has a role in maintaining CSC populations, thus contributing to carcinogenesis and tumor invasion. In conclusion, the results from this study provide new insights into the gastric tumorigenic process and offer potential implications for the development of anticancer drugs as well as therapeutic treatment of gastric cancers.

Covering the Cover

Covering the Cover

The EGFR Ligands Amphiregulin and Heparin-Binding EGF-like Growth Factor Promote Peritoneal Carcinomatosis in CXCR4-Expressing Gastric Cancer

Peritoneal carcinomatosis, often associated with malignant ascites, is the most frequent cause of death in patients with advanced gastric cancer. We previously showed that the CXCR4/CXCL12 axis is involved in the development of peritoneal carcinomatosis from gastric cancer. Here, we investigated whether epidermal growth factor receptor (EGFR) ligands are also involved in the development of peritoneal carcinomatosis from gastric cancer. The functional involvement of expression of the ErbB family of receptors and/or EGFR ligands was examined in CXCR4-expressing human gastric cancer cells and fibroblasts, clinical samples (primary tumors and ascites), and an animal model. High concentration of the EGFR ligands amphiregulin and heparin-binding EGF-like growth factor (HB-EGF), as well as of CXCL12, were present in malignant ascites. Human gastric cancer cell lines and primary gastric tumors, with high potential to generate peritoneal carcinomatosis, expressed high levels of EGFR and CXCR4 mRNA and protein. Both amphiregulin and HB-EGF enhanced the proliferation, migration, and functional CXCR4 expression in highly CXCR4-expressing gastric cancer NUGC4 cells. Amphiregulin strongly enhanced the proliferation of NUGC4 cells, whereas HB-EGF markedly induced the migration of fibroblasts. Moreover, HB-EGF and CXCL12 together enhanced TNFα-converting enzyme (TACE)-dependent amphiregulin shedding from NUGC4 cells. In an experimental peritoneal carcinomatosis model in mice, cetuximab effectively reduced tumor growth and ascites formation. Our results strongly suggest that the EGFR ligands amphiregulin and HB-EGF play an important role, interacting with the CXCL12/CXCR4 axis, in the development of peritoneal carcinomatosis from gastric cancer, indicating that these two axes may be potential therapeutic targets for peritoneal carcinomatosis of gastric carcinoma.

The expression of CXCL12 and CXCR4 in gastric cancer and their correlation to lymph node metastasis

The purpose of this study was to investigate the expression of CXCL12 and its receptor CXCR4 in gastric cancer and to determine their relationship with lymph node metastasis. Fifty patients with pathologically confirmed gastric cancer were analyzed from September 2004 to December 2004. The expression levels of CXCL12 and CXCR4 were examined by immunohistochemical staining in the primary gastric tumor tissues, adjacent normal mucosa tissues, and metastatic lymph nodes and were analyzed along with clinicopathological risk factors, to determine their correlation with the prognosis. Positive staining for CXCL12 and CXCR4 was identified in 90.0 and 80.0% of the primary gastric tumor tissues, respectively, with significantly higher expression intensities observed in the primary gastric tumor tissues than in the adjacent normal mucosa tissues (P < 0.01 and P = 0.01, respectively). Positive staining for CXCL12 and CXCR4 was identified in 94.4 and 91.7% of metastatic lymph nodes, respectively, with significantly higher expression intensities in the metastatic lymph nodes than in the adjacent normal mucosa tissues (P < 0.01 and P = 0.01, respectively). Expression of CXCL12 in the primary gastric tumor tissues was not significantly associated with the clinicopathological characteristics of the tumor or the disease prognosis. However, the intensity of CXCR4 staining in primary tumor tissues was positively related with lymph node metastasis, TNM staging, and disease prognosis (P = 0.04, 0.03, 0.03, respectively). CXCL12 and CXCR4 are related to formation of gastric tumors and lymph node metastasis. Furthermore, the expression of CXCR4 could be used as a biomarker to predict malignant features of gastric cancer.

Genomic Loss ofmiR-486Regulates Tumor Progression and theOLFM4Antiapoptotic Factor in Gastric Cancer

MicroRNAs (miRNA) play pivotal oncogenic and tumor-suppressor roles in several human cancers. We sought to discover novel tumor-suppressor miRNAs in gastric cancer (GC). Using Agilent miRNA microarrays, we compared miRNA expression profiles of 40 primary gastric tumors and 40 gastric normal tissues, identifying miRNAs significantly downregulated in gastric tumors. Among the top 80 miRNAs differentially expressed between gastric tumors and normals (false discovery rate < 0.01), we identified hsa-miR-486 (miR-486) as a significantly downregulated miRNA in primary GCs and GC cell lines. Restoration of miR-486 expression in GC cell lines (YCC3, SCH and AGS) caused suppression of several pro-oncogenic traits, whereas conversely inhibiting miR-486 expression in YCC6 GC cells enhanced cellular proliferation. Array-CGH analysis of 106 primary GCs revealed genomic loss of the miR-486 locus in approximately 25% to 30% of GCs, including two tumors with focal genomic losses specifically deleting miR-486, consistent with miR-486 playing a tumor-suppressive role. Bioinformatic analysis identified the secreted antiapoptotic glycoprotein OLFM4 as a potential miR-486 target. Restoring miR-486 expression in GC cells decreased endogenous OLFM4 transcript and protein levels, and also inhibited expression of luciferase reporters containing an OLFM4 3' untranslated region with predicted miR-486 binding sites. Supporting the biological relevance of OLFM4 as a miR-486 target, proliferation in GC cells was also significantly reduced by OLFM4 silencing. miR-486 may function as a novel tumor-suppressor miRNA in GC. Its antioncogenic activity may involve the direct targeting and inhibition of OLFM4.

Abstract 2190: ADAMTS8 at 11q25 is a tumor suppressor antagonizing Ras-signaling and methylated in multiple carcinomas

Abstract As opposed to most matrix metalloproteinases which facilitate tumor progression, a growing list of ADAMTS secreted protease members was reported to display tumor suppressive properties with their expressions frequently altered in diverse types of tumors. Here, ADAMTS8 was shown to be located at an LOH locus at 11q25 by array CGH. We further showed that ADAMTS8 was frequently downregulated or silenced in multiple cancer cell lines while broadly expressed in normal tissues. Analysis on the methylation status of the ADAMTS8 promoter CpG island showed that methylation was cancer-specific and ADAMTS8 methylation was correlated with the silencing of ADAMTS8. In addition, expression of ADAMTS8 could be restored with pharmacological or genetic demethylation and hence indicating that CpG methylation directly contributes to the downregulation of ADAMTS8. Aberrant methylation was also frequently detected in primary NPC, gastric and colorectal tumors, but seldom in normal tissues. Ectopic expression of ADAMTS8 led to marked inhibition of cell growth in colony formation assays and cell migration in wound healing assay along with the reduction of phosphorylated ERK protein. The inhibitory effect on tumor cell growth and Ras-ERK pathway by ADAMTS8 indicates its role as a functional tumor suppressor. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2190. doi:10.1158/1538-7445.AM2011-2190

Therapeutic potential of PRL-3 targeting and clinical significance of PRL-3 genomic amplification in gastric cancer

BackgroundPhosphatase of regenerating liver-3 (PRL-3) has deserved attention as a crucial molecule in the multiple steps of metastasis. In the present study, we examined the mechanisms regulating PRL-3 expression, and assessed the clinical potential of PRL-3-targeted therapy in gastric cancer.MethodsPRL-3 genomic amplification was analyzed using quantitative-polymerase chain reaction and/or fluorescence in situ hybridization in 77 primary gastric tumors. The anticancer activity of PRL-3 inhibitor (1-4-bromo-2-benzylidene rhodanine) treatment was evaluated against cancer cells with different genetic and expression status.ResultsPRL-3 genomic amplification was closely concordant with high level of its protein expression in cell lines, and was found in 20% (8/40) among human primary tumors with its expression, which were all stage III/IV disease (40%, 8/20), but in none (0/37) among those without expression. Additionally, PRL-3 genomic amplification was associated with metastatic lymph node status, leading to advanced stage and thereby poor outcomes in patients with lymph node metastasis (P = 0.021). PRL-3 small interfering RNA robustly repressed metastatic properties, including cell proliferation, invasion, and anchorage-independent colony formation. Although neither PRL-3 genomic amplification nor expression level was responsible for the sensitivity to PRL-3 inhibitor treatment, the inhibitor showed dose-dependent anticancer efficacy, and remarkably induced apoptosis on all the tested cell lines with PRL-3 expression.ConclusionsWe have for the first time, demonstrated that PRL-3 genomic amplification is one of the predominant mechanisms inducing its expression, especially in more advanced stage, and that PRL-3-targeted therapy may have a great potential against gastric cancer with its expression.

Phase II study of a triplet regimen of S-1 combined with irinotecan and oxaliplatin in patients with metastatic gastric cancer: clinical and pharmacogenetic results

BackgroundThe aim of this study was to investigate the efficacy and safety of S-1/irinotecan/oxaliplatin (TIROX) in metastatic gastric cancer (MGC) and the association between treatment outcome and uridine diphosphate-glucuronosyltransferase (UGT) 1A polymorphisms. Patients and methodsPatients with previously untreated MGC received S-1 40 mg/m2 b.i.d. on days 1–14 and irinotecan 150 mg/m2 plus oxaliplatin 85 mg/m2 on day 1 every 3 weeks. ResultsForty-four patients were enrolled. In intent-to-treat analysis, the objective response rate was 75%, including the complete response (CR) rate of 14%. The median time to progression and overall survival was 10.2 and 17.6 months, respectively. Ten (26%) of the 39 patients with primary gastric tumor showed biopsy-confirmed gastric CR. Grade 3/4 neutropenia developed in 66% of patients and grade 3 febrile neutropenia in 16%. The most common grade 3 nonhematologic toxic effects were abdominal pain (18%), anorexia (16%), and diarrhea (14%). UGT1A polymorphisms were associated with significantly higher incidence of grade 4 leukopenia (UGT1A1*6), neutropenia (UGT1A1*6, UGT1A6*2, and UGT1A7*3), grade 3/4 febrile neutropenia (UGT1A1*6), and grade 3 abdominal pain (UGT1A1*6). ConclusionsThe TIROX regimen induced marked tumor reduction and promising survival with a manageable toxicity profile in MGC patients. UGT1A genotype may be predictive of TIROX toxicity.

Reduced expression of RAS protein activator like‐1 in gastric cancer

RAS signaling is frequently deregulated in human neoplasms. However, RAS mutations have been found in only a small proportion of human gastric cancers, implicating other mechanisms in the activation of RAS signaling in gastric tumorigenesis. We have previously reported that decreased expression of RAS protein activator like-1 (RASAL1), a member of the RAS-GTPase-activating proteins that switch off RAS activity, contributes to colon tumor progression. In our study, we explored the involvement of decreased RASAL1 expression in gastric tumorigenesis. RASAL1 expression was reduced in 6 of 10 gastric cancer cell lines examined by immunoblotting. Knockdown of RASAL1 increased mitogen-activated protein kinase signaling in response to growth factor stimulation, and the forced expression of RASAL1 reduced proliferation of gastric cancer cells. Immunohistochemical analyses in primary gastric tumors showed that RASAL1 expression was reduced in 23 of 48 (48%) of the gastric cancers but in none of the adenomas (0/10). Methylation of the RASAL1 promoter region and loss of heterozygosity (LOH) at the RASAL1 locus were examined to investigate the causes of RASAL1 silencing. All cell lines with reduced RASAL1 had RASAL1 methylation, and two had LOH. In primary gastric cancers, methylation or LOH was detected in 50% (6/12) of those with reduced RASAL1. Furthermore, RASAL1 expression was restored in some cell lines by histone deacetylase inhibitor treatment. Our findings demonstrate that reduced RASAL1 expression, partly due to genetic and epigenetic changes, contributes to gastric carcinogenesis, and also re-emphasize the importance of RAS signaling in gastric cancer development.

A Case of Synchronous Double Primary Cancer of Gastric Adenocarcinoma and Diffuse Large B Cell Lymphoma

The simultaneous occurrence of primary gastric lymphoma and adenocarcinoma is rarely reported. We here report a case of synchronous double primary tumor of advanced gastric cancer and diffuse large B cell lymphoma. A 65-year-old woman underwent an esophagogastroduodenoscopy for the evaluation of abdominal discomfort of two months' duration. The endoscopic examination showed an ulcerating tumor in the gastric antrum and thickened folds in the fundus and the microscopic examination revealed an adenocarcinoma in the antrum and a diffuse large B-cell lymphoma in the fundus. She has had total gastrectomy and CHOP chemotherapy with rituximab. Since the cases of synchronous double primary gastric tumors have been increased on the recent medical advances, when a gastric tumor is detected for the endoscopic examination, an endoscopist has to make every endeavor not to miss another tumor in the stomach.

A randomized phase 2 study of docetaxel and S‐1 versus docetaxel and cisplatin in advanced gastric cancer with an evaluation of SPARC expression for personalized therapy

The purpose of this study was to compare 2 weekly docetaxel-based regimens as first-line treatments for advanced gastric cancer and to investigate the expression of secreted protein acidic and rich in cysteine (SPARC) and its abilities to predict treatment-related clinical outcomes. Patients were randomly selected to receive 3 weekly cycles of docetaxel (35 mg/m(2) on days 1 and 8) plus S-1 (35 mg/m(2) each twice daily on days 1-14) (DS), or docetaxel plus cisplatin (35 mg/m(2) each on days 1 and 8) (DC). Endpoints included overall response rate (primary), survival, toxicity, and quality of life (secondary). SPARC expression in prechemotherapy specimens of primary gastric tumors was evaluated via immunohistochemical analysis. Eighty patients were enrolled in the study. Confirmed overall response rates were 46% (95% confidence interval, 30%-62%) for DS and 24% (95% confidence interval, 11%-38%) for DC via intent-to-treat analysis. Median progression-free survival was 7.3 and 4.9 months and overall survival was 16.0 and 8.3 months for DS and DC, respectively. The most common grade ≥ 3 toxicity was neutropenia. Grade ≥ 3 mucositis (18%) and hand-foot syndrome (8%) were the toxicities most associated with DS, whereas anorexia (20%) and lethargy (20%) were more common with DC. High SPARC expression was related to early progression (hazard ratio, 3.67; P = .042) and poor overall survival (hazard ratio, 2.01; P = .010) in docetaxel chemotherapy on multivariate analysis. The outcomes in this study favored DS over DC for further phase 3 study. The findings suggest that split-dose weekly docetaxel alleviates hematological toxicity without compromising efficacy, and that SPARC expression may help individualize therapy in advanced gastric cancer.

Laparoscopic detection of sentinel node in gastric cancer surgery by indocyanine green fluorescence imaging

Indocyanine green (ICG) fluorescence imaging is a promising technique for detection of sentinel node (SN) as it avoids unnecessary resection. However, the ICG fluorescence imaging system cannot be used in laparoscopic surgery because of technological difficulties. A prototype laparoscopic detection system comprising an electron multiplier charge-coupled device (EM-CCD) as the detector and a xenon lamp as the light source was developed. The CCD camera head was attached to the end of a specially designed laparoscope that could transmit ICG fluorescence. The system allows visualization of both color and fluorescence images. Laparoscopic surgery in ten patients with gastric cancer included SN biopsy using ICG dye, ICG fluorescence images using our system, and laparoscopy-assisted gastrectomy (LAG) with lymphadenectomy. SNs were sliced into 2-mm sections for histological examination and imprint cytology. Immediately after intraoperative ICG injection by endoscopy, the laparoscopic ICG fluorescence imaging system allowed easy visualization of the lymphatic vessels draining from the primary gastric tumor toward the lymph nodes and traced the moving injected dye, whereas lymph vessels and nodes were hardly recognized by ICG green color through a standard laparoscope. Surgeons could confirm the removed lymph nodes stained with ICG by fluorescent imaging. SNs were successfully detected in all patients. Three patients had suspicious metastases in the SNs; two patients had lymph node metastases only in the SNs. Our newly developed laparoscopic ICG fluorescence imaging system is promising in the detection of SNs in laparoscopic gastric cancer surgery. The preliminary results suggest an easier and shorter learning curve of dye-guided SN biopsy in laparoscopic gastric surgery.

ß-catenin-independent noncanonical Wnt pathway might be induced in gastric cancers

Abnormal Wnt signaling is often observed in human cancers. Wnt5a is a representative Wnt ligand that can activate both β-catenin-dependent canonical and β-catenin-independent noncanonical Wnt pathways. However, the role of Wnt5a in carcinogenesis is controversial. This study was designed to understand whether Wnt5a in the Wnt pathway and its key downstream molecules such as MMP-7 and β-catenin are involved in gastric cancers. We analyzed the expressions of Wnt5a, MMP-7 and β-catenin genes in 40 primary gastric normal and tumor biopsies by RT-PCR and the subcellular localization of β-catenin by immunohistochemistry. Our results showed a specific combination of genes expressed significantly in the gastric tumor tissues: 65% of the tumor samples containing non-nuclear β-catenin were Wnt5a-positive, 42.5% were MMP-7-positive, and 35% of the samples involved both. Interestingly, normal samples did not show any relevant coexpression of Wnt5a and MMP-7 in the β-catenin-containing samples. These results suggest that the noncanonical Wnt pathway might be critically important in gastric carcinogenesis.