Targeting the NLRP3 inflammasome as new therapeutic avenue for inflammatory bowel disease.

The incidence and prevalence of inflammatory bowel disease (IBD) are increasing worldwide. Current approved medication for IBD treatment in the clinic mainly includes corticosteroids and neutralization antibodies to pro-inflammatory cytokines. However, drug resistance and severe side effect hinder long-term efficacy of these agents. The NOD-like receptor family pyrin domain containing protein 3 (NLRP3) is exclusively expressed in several inflammatory and autoimmune diseases. Excessive expression, aberrant activation, polymorphism, and gain-of-function mutation of the NLRP3 inflammasome contribute to IBD pathogenesis. In this article, we summarize the regulatory factors to NLRP3, and review recently developed NLRP3 inhibitors and their preclinical and clinical applications in treating inflammatory and autoimmune diseases. We present our views on the therapeutic potential of NLRP3 inhibitors as emerging therapeutic avenue for IBD.

Surgical resection with hyperthermic intraperitoneal chemotherapy for gastric cancer patients with peritoneal dissemination.

BACKGROUND: The prognosis for gastric cancer patients with peritoneal dissemination is very poor. The purpose of this study was to evaluate the survival benefit from gastrectomy with hyperthermic intraperitoneal chemotherapy (HIPEC) for gastric cancer patients with peritoneal dissemination. METHODS: From 1992 to 2002, 128 gastric cancer patients with peritoneal dissemination underwent surgery at the Department of Surgery, Ruijin Hospital, Shanghai, China. The clinicopathological characteristics and survival were compared between the resection and the non-resection groups, and between the resection alone and the resection with HIPEC groups. RESULTS: The 5-year survival rates were 5.5% for patients in the resection group and 0% for patients in the non-resection group (P < 0.001). Multivariate analysis showed surgical resection was significantly associated with better prognosis in gastric cancer patients with peritoneal dissemination. In the patients who underwent resection, the survival difference between the resection alone and the resection with HIPEC groups was significant (P = 0.025), and HIPEC was an independent prognostic factor by multivariate analysis. CONCLUSIONS: The HIPEC procedure was an independent prognostic factor after resection for patients with peritoneal dissemination. Therefore, gastrectomy with HIPEC may be an option for those patients. The survival benefit of this strategy should be validated by large cohort prospective clinical trials.

Value of multidetector-row computed tomography in the preoperative T and N staging of gastric carcinoma: a large-scale Chinese study.

OBJECTIVES: To investigate the value of multidetector-row computed tomography (MDCT) in the preoperative T and N staging of gastric carcinoma and to further investigate the clinicopathological factors affecting the diagnostic accuracy. METHODS: Seven hundred ninety gastric carcinoma patients underwent preoperative MDCT examination. The results of MDCT were compared with surgical and pathological findings. RESULTS: Early gastric carcinoma patients whose primary tumor was detected by MDCT had higher incidence of lymph node metastasis, larger tumor size, and deeper invasion. The overall accuracy of MDCT in determining T stage of gastric carcinoma was 73.80% (T1 45.93%, T2 53.03%, T3 86.49%, and T4 85.79%). The overall accuracy of MDCT in preoperative N staging was 75.22% (N0 76.17%, N1 68.81%, and N2 80.63%). The overall diagnostic sensitivity, specificity, and accuracy of MDCT for determining lymph node metastasis was 86.26%, 76.17%, and 82.09%, respectively. Multivariate analysis showed that the diagnostic sensitivity of MDCT in determining lymph node metastasis related with tumor size, N stage, and number of metastatic lymph nodes. CONCLUSIONS: The clinical value of MDCT in the preoperative T and N staging of gastric carcinoma is relatively high. MDCT can be the first choice for the preoperative evaluation of patients with gastric carcinoma.

Gastric cancer surgery and its hazards: post operative infection is the most important complication.

BACKGROUND/AIMS: To evaluate early surgical outcome and analyze postoperative complications of gastric cancer surgery, on the basis of standard auditing system. METHODOLOGY: 357 patients who underwent operations for gastric cancer were included in this study. We applied POSSUM (Physiological and Operative Severity Score for the enumeration of Morbidity and mortality) system to predict morbidity. The observed to estimated morbidity ratio (O: E) was calculated to give risk adjusted morbidity. All the complications were stratified according to its severity and analyzed separately. RESULTS: Observed morbidity was not significantly different from predicted value, the O: E ratio was 1.01. Overall, 137 patients were observed to have postop complications (including 5 death); infection was the main complication which complicated about 17 per cent patients and occupying 44 per cent of all complications. Pulmonary infection rate was on the top. CONCLUSIONS: Post operative complication is higher in gastric cancer surgery. POSSUM system along with stratification of complications is a reliable algorithm in surgical audit to analyze various complications. Postoperative infection is the culprit of various complications. Postoperative infection especially the pulmo-nary infection stands on the top of all complications. More prospective study including basic researches is necessary to explore the etiology of different compilations.

[Capecitabine combined with cisplatin as first-line therapy in Chinese patients with advanced gastric carcinoma-a phase II clinical study].

OBJECTIVE: To evaluate the effectiveness and safety of the combination chemotherapy of capecitabine (X) with fractionated administration of cisplatin (C) in Chinese patients with advanced gastric cancer (AGC). METHODS: 141 patients with AGC were enrolled between July 2002 and August 2004. All patients had measurable tumor according to the criteria of RECIST, Karnofsky performance status > or = 60, adequate bone marrow, renal and hepatic functions. Prior radiotherapy or adjuvant chemotherapy was not permitted. Patients received oral administration of capecitabine at a dose of 1000 mg/m(2) twice a day on D1-D14, and intravenous infusion of fractionated cisplatin at a dose of 20 mg/m(2)/day on D1-D5. The regimen was repeated every 3 weeks, totally for 6 cycles. RESULTS: Of the 141 evaluable patients, there were 104 men and 37 women, with a median age of 54 years (range, 23 - 80 years). Metastases before chemotherapy were detected in lymph nodes (46.8%), liver (40.4%), lung (5.7%) and other area (10.6%). The median treatment duration was 6 cycles (range, 3 - 6 cycles). The objective response rate (RR) was 36.2% (51/141). The median follow-up period was 17.5 months. The median time to progress (TTP) was 9.0 months, and the median overall survival (OS) was 12.0 months. The most common treatment-related adverse events (grade 3/4) were: hand-foot syndrome (HFS) (2.1%), leucopenia (0.7%), abnormal alanine transaminase elevation (2.8%). There was no treatment-related death. CONCLUSION: Capecitabine combined with fractionated cisplatin is highly effective and well tolerated as a first-line treatment for advanced gastric cancer, with comparable results to 5-Fu plus cisplatin combination therapy.

The impact of hyperthermic chemotherapy on human gastric cancer cell lines: preliminary results.

In this preliminary study, we evaluated the impact of hyperthermia (HT) and hyperthermic chemotherapy (HTCT) on six human gastric cancer cell lines and explored the mechanisms of cell-killing effect under HTCT. Treatment conditions were categorized into 4 modes: i) normothermic control (NT), ii) HT, iii) normothermic chemotherapy (NTCT) and iv) HTCT. According to the data of MTT and LM observations, isolated HT only temporarily inhibited cell proliferation and had no cell-killing effect on gastric cancer cell lines employed in our study except for SNU-1. Combining with HT enhanced the cytotoxicity of CDDP in all gastric cell lines and the concentration inhibiting cell proliferation and inducing cell death of HTCT was much lower than that of NTCT. There was a synergistic effect of HT and chemotherapy on inhibiting proliferation in each cell line in a certain range of CDDP concentration. The data of TEM and FCM proved that HTCT induced cell death with two modes - apoptosis and necrosis, and apoptosis was the major type. Microarray illustrated that, under HTCT, a total of 58 gene expressions were regulated according to the filtering criteria, including 10 extra genes with an expression change below the threshold or even unchanged when treated with either HT or CDDP alone. Five of these 10 genes were verified by QRT-PCR. These genes may include the target genes for the enhancing effect of HT on chemotherapy and their effects should be further validated by functional analysis.

[The relationship between frameshift mutations of transforming growth factor-beta type II receptor, insulin growth factor II receptor, bcl-2 associated X protein, E2F4 and microsatellite instability in gastric carcinoma].

OBJECTIVE: To determine the microsatellite instability in gastric carcinomas, examine the frameshift mutations of transforming growth factor-beta type II receptor (TGFbetaRII), insulin growth factor II receptor (IGFIIR), bcl-2 associated X protein (BAX) and E2F4, and investigate whether or how alterations of the TGFbetaRII, IGFIIR, BAX and E2F4 gene are associated with MSI in gastric cancer. METHODS: Formalin-fixed, paraffin-embedded gastrectomy specimens and matching normal tissues of 65 cases of gastric carcinomas were retrieved from shanghai Ruijin Hospital and Shanghai East Hospital. DNA was extracted from tissue sections using phenol chloral isoamyl alcohol. Sections with no more than 50% of tumor cell areas were isolated by microdissection. DNA was amplified by PCR-based single strand conformation polymorphism (SSCP) for microsatellite analysis and was sequenced directly. Frameshift mutations in the coding regions, repetitive mononucleotide tracts of (A)10 for TGFbetaRII, (G)8 for IGFIIR, (G)8 for BAX, and trinucleotide repeats of (AGC)13 for transcription factors E2F4 were detected using PCR. Tumors were classified as being microsatellite stable (MSS) or having a low frequency of MSI (MSI-L, one of markers different in the tumor) or a high frequency of MSI (MSI-H, two or more of markers different). RESULTS: Eleven cases (18.0%) showed MSI-L, 12 (19.7%) showed MSI-H and 38 (62.3%) cases showed MSS. The mutation rates of TGFbetaRII, IGFIIR, BAX and E2F4 gene were 19.7%, 4.9%, 6.6% and 16.4% respectively. Among the 12 MSI-H gastric cancers, there were 10 TGFbetaRII mutations, 3 IGFIIR mutations, 4 BAX mutations and 10 E2F4 gene mutations. The alterations in the repeats of the related genes presented polymorphisms. Associations of MSI-H status and mutations of the 4 genes were highly significant (P < 0.01, respectively). No repeat tracts mutations in TGFbetaRII, IGFIIR, BAX and E2F4 gene were found in MSS tumors. CONCLUSIONS: The repeat coding regions within TGFbetaRII, IGFIIR, BAX and E2F4 gene are the targets of microsatellite instability. Frameshift mutations of the 4 genes play an important role in the development and progression of gastric cancers with microsatellite instability.

Hepatic preconditioning of doxorubicin in stop-flow chemotherapy: NF-kappaB/IkappaB-alpha pathway and expression of HSP72.

AIM: To provide hepatic protection through administration of doxorubicin before stop-flow chemotherapy (SFC) and to investigate the expression of heat shock protein 72 (HSP72) and role of nuclear factor kappa B (NF-kappaB) in this effect. METHODS: The hepatic preconditioning of doxorubicin was established in a porcine model by injection of doxorubicin (1 mg/kg) before SFC. The experimental animals were randomized into two groups: groups receiving doxorubicin (DOX) and normal saline (NS). Serial serum and tissue samples were taken from both groups to evaluate the protection of doxorubicin. Western blot and immuno-precipitation were applied to detect the expression of HSP72, NF-kappaB p65 protein, inhibitor kappaB-alpha (IkappaB-alpha) and phosphorylated IkappaB-alpha as well. The expression of tumor necrosis factor alpha (TNF-alpha) was estimated by semiquantitative RT-PCR. And the extent of the hepatic injury was estimated with the level of serum aminotransferases. RESULTS: An abundance production of HSP72 in porcine liver was observed after 24 h of intravenous administration of doxorubicin, but without any change in the expression of NF-kappaB p65 subunit in cytoplasm. NF-kappaB p65 subunit accumulated in nuclei at the end of SFC and reached its highest level at 30 min after the restoration of the abdominal circulation and decreased gradually during the 6 h after SFC in NS group, while there was little change in DOX group. There was also a slight decrease of IkappaB-alpha at 30 min after the restoration of the abdominal circulation in NS group accompanying with the appearance of phosphorylated IkappaB-alpha. The expression of TNF-alpha was significantly higher in NS group than that in DOX group (average 1.40+/-0.17 vs 0.62+/-0.22, P<0.01) at serial time points after SFC. Serum ALT and AST levels of NS group were higher after 24 h than those of DOX group (93.2+/-7.8 IU/L vs 53.3+/-13.9 IU/L, 217.0+/-29.4 IU/L vs 155.0+/-15.6 IU/L for ALT and AST respectively, P<0.05) and after 48 h than those of DOX group (66.6+/-18.1 IU/L vs 43.3+/-16.7 IU/L, 174.4+/-21.3 IU/L vs 125.7+/-10.5 IU/L for ALT and AST respectively, P<0.05). CONCLUSION: Doxorubicin renders the liver to be tolerant to the hepatic influence in SFC in a porcine model through the NF-kappaB/IkappaB-alpha pathway with the expression of HSP72.

[Transcription factor Sp1 expression in gastric cancer and its prognostic value].

OBJECTIVE: To investigate the expression of transcription factor Sp1 in human gastric cancer tissues and normal gastric mucosa, and its prognostic significance. METHODS: By using immunohistochemistry, we studied the Sp1 expression patterns in 65 cases of gastric cancer with various clinico-pathologic characteristics, and 40 normal gastric mucosa specimens obtained from patients who underwent partial gastrectomy for benign gastric diseases. The significance of Sp1 expression on the survival of patients was evaluated. RESULTS: The expression rate of Sp1 in normal gastric mucosa was 12.5% (5/40). The positively stained glandular cells were mainly limited to those in the neck region. Cells at the basal portion of the gland were essentially negative. In sharp contrast, Sp1 expression rate in gastric cancer lesions was 53.8% (35/65). The medium survival time in patients who had a tumor with negative, weak and strong Sp1 expression was 1700, 1560 and 1026 days, respectively (P = 0.036). Sp1 protein expression was closely related to the depth of tumor invasion and TNM stage (P = 0.001, P = 0.026), but not related to the number of metastatic lymph nodes and Lauren's classification (P = 0.306, P = 0.667). CONCLUSION: Normal and malignant gastric tissues have unique Sp1 expression patterns. Sp1 might be served as an independent prognostic factor.

[Inhibitory effect of dendritic cells pulsed with MAGE-3 peptide on transplanted murine gastric cancer in mice].

OBJECTIVE: To observe the inhibitory effect of MAGE-3 peptide pulsed DC on transplanted murine gastric cancer in 615 mice. METHODS: The CTL clones directed against MAGE-3 peptide were tested for the ability to lyse the gastric cancer cell line MFC which can express MAGE-3 antigen. In immunoprotection experiment, mice of the study group were immunized with MAGE-3 peptide pulsed DC (DC/MAGE-3) at the dosage of 1 x 10(6) on d0 and d7 by sc inoculation, mice of control groups were immunized with influenza virus peptide pulsed DC (DC/Nup) or unpulsed DC at the same dosage on days as the DC/MAGE-3 group. On d14, all the mice were challenged with sc injections of 5 x 10(5) MFC gastric cancer cells. In immunotherapy experiment, all the mice were sc injected 5 x 10(5) MFC gastric cancer cells on d0, and on d3, d10 mice of each groups were sc inoculated with DC/MAGE-3, DC/Nup or unpulsed DC at the dosage of 1 x 10(6) respectively. All mice were monitored closely with respect to tumor growth and survival times. RESULTS: The CTL clone induce by MAGE-3 peptide could lyse the MFC cells efficiently. Immunization of mice with DC pulsed with MAGE-3 generated partial protective immunity against MFC tumor, as well as significant inhibition of tumor growth in a 3-day tumor model. CONCLUSION: The tumor vaccine with DCs pulsed with MAGE-3 peptide possesses the ability to stimulate tumor specific CTL activity and to establish antitumor immunity when administered in vivo.

Correlation of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase with sensitivity of gastrointestinal cancer cells to 5-fluorouracil and 5-fluoro-2'-deoxyuridine.

AIM: To determine the expression levels of three metabolic enzymes of fluoropyrimidines: thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) in seven human gastrointestinal cancer cell lines, and to compare the enzyme levels with the sensitivity to 5-fluorouracil (5-FU) and 5-fluoro-2'-deoxyuridine (FdUrd). METHODS: TS, TP and DPD mRNA levels were assessed by semi-quantitative RT-PCR, TP and DPD protein contents were measured by ELISA. Fifty percent inhibitory concentrations of growth (IC50), representing the sensitivity to drugs, were determined by MTT assay. RESULTS: IC50 values ranged from 1.28 to 12.26 microM for 5-FU, and from 5.02 to 24.21 microM for FdUrd, respectively. Cell lines with lower DPD mRNA and protein levels tended to be more sensitive to 5-FU (P<0.05), but neither TS nor TP correlated with 5-FU IC50 (P>0.05). Only TS mRNA level was sharply related with FdUrd sensitivity (P<0.05), but TP and DPD were not (P>0.05). A correlation was found between mRNA and protein levels of DPD (P<0.05), but not TP (P<0.05). CONCLUSION: DPD and TS enzyme levels may be useful indicators in predicting the antitumor activity of 5-FU or FdUrd, respectively.

Antitumor effects of vaccine consisting of dendritic cells pulsed with tumor RNA from gastric cancer.

AIM: To investigate the immunotherapeutic potential of vaccine consisting of dendritic cells (DCs) pulsed with total RNA from MFC gastric cancer cells. METHODS: DCs were prepared from the spleens of strain 615 mice by magnetic cell sorting (MACS). After culture for 24 h, DCs were pulsed with total RNA from MFC gastric cancer cells. Mice of one group were immunized with tumor RNA pulsed DC (RNA/DC) at the dosage of 1X10(6) on d 14 and 7 by s c inoculation before tumor implantation. Mice of another group were immunized with unpulsed DC (UDC) at the same dosage on days as the RNA/DC group. The third group of control mice was untreated. On d 0, all the mice were challenged with s c injections of 5X10(5) MFC gastric cancer cells. After inoculation, the mice were monitored closely with respect to tumor growth. Activities of NK cells in PBL and splenocytes and CTL were tested. RESULTS: On d 21 after tumor cell inoculation, the mice of control group manifested the largest tumors with volume at a mean of 2.6323+/-1.1435 cm(3), followed by the UDC and RNA/DC groups with mean volumes at 0.7536+/-0.3659 cm(3) and 0.3688+/-0.6571 cm(3), respectively. The activities of NK cells in PBL and splenocytes in RNA/DC group were 66.2% and 65.4%, respectively, higher than that in the control group. The tumor specific CTL activity in RNA/DC group was 49.5%, higher than that in the control group. CONCLUSION: The tumor vaccine with DCs pulsed with total RNA from gastric cancer cells possesses the ability to stimulate tumor specific CTL activity and to establish anti-tumor immunity when administered in vivo.

Inhibition of human telomerase in MKN-45 cell line by antisense hTR expression vector induces cell apoptosis and growth arrest.

AIM: To investigate the effects of antisense human telomerase RNA (hTR)on the biologic behavior of human gastric cancer cell line: MKN-45 by gene transfection and its potential role in the gene therapy of gastric cancer. METHODS: The hTR cDNA fragment was cloned from MKN-45 through RT-PCR and subcloned into eukaryotic expression vector (pEF6/V5-His-TOPO) in cis-direction or trans-direction by DNA recombinant methods. The constructed sense, antisense and empty vectors were transfected into MKN-45 cell lines separately by lipofectin-mediated DNA transfection technology. After drug selection, the expression of antisense hTR gene in stable transfectants and normal MKN-45 cells was detected by RT-PCR, the telomerase activity by TRAP, the apoptotic features by PI and Hoechst 33258 staining, the cell cycle distribution by flow cytometry and the population doubling time by cell counting. Comparison among the stable transfectants and normal MKN-45 cells was made. RESULTS: The sense, antisense hTR eukaryotic expression vectors and empty vector were successfully constructed and proved to be the same as original design by restriction endonuclease analysis and sequencing. Then, they were successfully transfected into MKN-45 cell lines separately with lipofectin. The expression of antisense hTR gene was only detected in MKN-45 cells stably transfected with antisense hTR vector (named as MKN-45-ahTR) but not in the control cells. In MKN-45-ahTR, the telomerase activity was inhibited by 75%, the apoptotic rate was increased to 25.3%, the percentage of cells in the G0/G1 phase was increased to 65%, the proliferation index was decreased to 35% and the population doubling time was prolonged to 35.3 hours. However, the telomerase activity, the apoptotic rate, the distribution of cell cycle, the proliferation index and the population doubling time were not different among the control cells. CONCLUSION: Antisense hTR can significantly inhibit telomerase activity and proliferation of MKN-45 cells and induce cell apoptosis. Antisense gene therapy based on telomerase inhibition can be a potential therapeutic approach to the treatment of gastric cancer.

Methionine-dependence and combination chemotherapy on human gastric cancer cells in vitro.

AIM: To elucidate whether human primary gastric cancer and gastric mucosa epithelial cells in vitro can grow normally in a methionine (Met) depleted environment, i.e. Met-dependence, and whether Met-depleting status can enhance the killing effect of chemotherapy on gastric cancer cells. METHODS: Fresh human gastric cancer and mucosal tissues were managed to form monocellular suspensions, which were then cultured in the Met-free but homocysteine-containing (Met(-)Hcy(+)) medium, with different chemotherapeutic drugs. The proliferation of the cells was examined by cell counter, flow cytometry (FCM) and microcytotoxicity assay (MTT). RESULTS: The growth of human primary gastric cancer cells in Met(-)Hcy(+) was suppressed, manifested by the decrease of total cell counts [1.46 +/- 0.42 (x 10(9).L(-1)) in Met(-)Hcy(+) vs 1.64 +/-0.44(x 10(9).L(-1)) in Met(+)Hcy(-), P<0.01], the decline in the percentage of G(0)G(1) phase cells (0.69 +/- 0.24 in Met(-)Hcy(+) vs 0.80 +/- 0.18 in Met(+)Hcy(-), P<0.01) and the increase of S cells (0.24 +/- 0.20 in Met(-)Hcy(+) vs 0.17 +/- 0.16 in Met(+)Hcy(-), P<0.01); however, gastric mucosal cells grew normally. If Met(-)Hcy(+) medium was used in combination with chemotherapeutic drugs, the number of surviving gastric cancer cells dropped significantly. CONCLUSION: Human primary gastric cancer cells in vitro are Met-dependent; however, gastric mucosal cells have not shown the same characteristics. Met(-)Hcy(+) environment may strengthen the killing effect of chemotherapy on human primary gastric cancer cells.

Expression of vascular endothelial growth factor C and chemokine receptor CCR7 in gastric carcinoma and their values in predicting lymph node metastasis.

AIM: To study the expression of vascular endothelial growth factor C (VEGF-C) and chemokine receptor CCR7 in gastric carcinoma and to investigate their associations with lymph node metastasis of gastric carcinoma and their values in predicting lymph node metastasis. METHODS: The expression of VEGF-C and CCR7 in gastric carcinoma tissues obtained from 118 patients who underwent curative gastrectomy was examined by immunohistochemistry. Among these patients, 39 patients underwent multi-slice spiral CT (MSCT) examination. RESULTS: VEGF-C and CCR7 were positively expressed in 52.5 and 53.4% of patients. VEGF-C expression was more frequently found in tumors with lymph node metastasis than those without it (P<0.001). VEGF-C expression was also closely related to lymphatic invasion (P<0.001), vascular invasion (P<0.01), and TNM stage (P<0.001). However, there was no significant correlation between VEGF-C expression and age at surgery, gender, tumor size, tumor location, Lauren classification, and depth of invasion. CCR7 expression was significantly higher in patients with lymph node metastasis compared with those without lymph node metastasis (P<0.001) and was also associated with tumor size (P<0.01), depth of invasion (P<0.001), lymphatic invasion (P<0.001), and TNM stage (P<0.001). However, the presence of CCR7 had no correlation to age at surgery, gender, tumor location, Lauren classification, and vascular invasion. Among the 39 patients who underwent MSCT examination, only CCR7 expression was related to lymph node metastasis determined by MSCT (P<0.05). In the current retrospective study, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of VEGF-C and CCR7 expression in the diagnosis of lymph node metastasis for patients with gastric carcinoma were 73.8%, 70.2%, 72.6%, 71.4% and 72.0%, and 82.0%, 77.2%, 79.4%, 80.0% and 79.7%, respectively. After subdivision according to the combination of VEGF-C and CCR7 expression, receiver operating characteristic (ROC) analysis showed that the accuracy of the combined examination of VEGF-C and CCR7 expression in predicting lymph node metastasis was relatively high (area under ROC curve [Az]=0.83). CONCLUSION: The expression of VEGF-C and CCR7 is related to lymph node metastasis of gastric carcinoma and both of them may become new targets for the treatment of gastric carcinoma. Furthermore, the combined examination of VEGF-C and CCR7 expression in endoscopic biopsy specimens may be useful in predicting lymph node metastasis of gastric carcinoma and deciding the extent of surgical lymph node resection.

[A preliminary study of endoscopic ultrasonography in the preoperative staging of early gastric carcinoma].

OBJECTIVE: To study the clinical value of endoscopic ultrasonography (EUS) in the preoperative staging of early gastric carcinoma. METHODS: EUS was performed in 149 gastric carcinoma patients proved by biopsy (including 33 patients with early gastric cancer), of which the results were compared with postoperative pathologic findings. RESULTS: The accuracy of EUS in determining the T stage of gastric carcinoma was 80.3% (T1 81.8%, T2 70.4%, T3 88.9%, T4 71.4%). The accuracy of EUS in differentiating early gastric carcinoma from advanced ones was 95.1%, and the accuracy of EUS in differentiating mucosal cancer from submucosal cancer was only 63.6%. The diagnostic accuracy of EUS for mucosal and submucosal cancer was 52.9% and 75%, with positive predictive value of 90% and 70.6%, respectively. The accuracy of invasion depth of EUS for the bulging and flat type of early gastric carcinoma was 100%, whereas the accuracy was only 58.6% for the depressed type. The accuracy of invasion depth of the differentiated and undifferentiated early cancer was 71.4%and 57.9%, without any significant difference (P > 0.05). The accuracy of invasion depth of EUS for early gastric carcinoma decreased as tumor size increased. The diagnostic accuracy of lymph node status of early gastric carcinoma by EUS was 90.9%, and the sensitivity and specificity of lymph node metastasis was 66.7% and 96.3%, respectively. CONCLUSION: The clinical value of endoscopic ultrasonography in the preoperative staging of early gastric carcinoma is relatively high.

Survival benefit of non-curative gastrectomy for gastric cancer patients with synchronous distant metastasis.

BACKGROUND: The prognosis for gastric cancer patients with distant metastasis is very poor. The purpose of this study was to evaluate the survival benefit of non-curative gastrectomy for gastric cancer patients with synchronous distant metastasis. METHODS: From 1992 to 2002, 253 gastric cancer patients with synchronous distant metastasis underwent surgery at the Department of Surgery, Ruijin Hospital, China. The clinicopathological characteristics and survival were compared between resection and non-resection groups. RESULTS: The 5-year survival rate was 6.5% for patients in resection group and 0% for patients in non-resection group (P < 0.001). Multivariate analysis showed that liver metastasis, peritoneal dissemination, and non-resection were significantly associated with poor prognosis in gastric cancer patients with distant metastasis. The survival difference between resection and non-resection groups was only observed in patients with single peritoneal dissemination (P < 0.001), but were not in patients with single liver metastasis (P = 0.428), distant nodes involvement (P = 0.490) and multiple metastatic sites (P = 0.192), respectively. CONCLUSIONS: Our results suggests that there were no survival benefit from non-curative gastrectomy for patients with single liver, distant nodes, or multiple sites metastasis. However, only patients with single peritoneal dissemination had survival benefit from non-curative resection. The value of non-curative resection should be evaluated by well-designed clinical trials.

[Value of multidetector-row CT in the preoperative prediction of peritoneal metastasis from gastric cancer: a single-center and large-scale study].

OBJECTIVE: To investigate the value of multidetector-row computed tomography (MDCT) in preoperatively predicting peritoneal metastasis of gastric cancer and to evaluate the indication for laparoscopic staging of gastric cancer on the basis of MDCT features. METHODS: Six hundred and forty gastric cancer patients underwent preoperative MDCT examination, and the results of MDCT were compared with surgical and pathological findings. In addition, the relationship between MDCT features (depth of invasion, lymph node metastasis status, tumor size, and thickness of tumor) and peritoneal metastasis of gastric cancer was analyzed. RESULTS: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of MDCT in predicting peritoneal metastasis of gastric cancer were 51.0% (25/49), 99.3% (587/591), 86.2% (25/29), 96.1% (587/611), and 95.6% (612/640), respectively. Univariable analysis showed that all the four MDCT features (depth of invasion, lymph node metastasis status, tumor size, and tumor thickness) of gastric cancer were significantly correlated with the peritoneal metastasis of gastric cancer. None of the patients diagnosed with stage T(0~2)N(x)M(0) or T(x)N(0)M(0) gastric cancer by MDCT were found to have peritoneal metastasis. Receiver operating characteristic (ROC) analysis showed that the accuracy of the tumor size and thickness of gastric cancer in determining peritoneal metastasis was high(area under ROC curve was 0.83 and 0.75, respectively). Multivariable analysis showed that only tumor size was significantly correlated with the peritoneal metastasis from gastric cancer. CONCLUSIONS: The clinical value of MDCT in preoperative prediction of peritoneal metastasis from gastric cancer is favorable. Laparoscopy can be avoided in patients with small tumor size or stage T(0~2)N(x)M(0) or T(x)N(0)M(0) gastric cancer diagnosed by MDCT due to lower incidence of peritoneal metastasis.

[A comparative study on the efficacy of spleen-preserving modified D2 radical gastrectomy and D2 radical gastrectomy with splenectomy].

OBJECTIVE: To compare the efficacy of modified D(2) radical total gastrectomy with spleen-preserving and D(2) radical total gastrectomy with splenectomy in patients with gastric cancer located in the upper third, upper and middle third and entire stomach. METHODS: One hundred and twelve patients with gastric cancer in the upper third, upper and middle third, or entire stomach underwent radical total gastrectomy between January 1989 and December 1994. Modified D(2) total radical gastrectomy with spleen-preserving (spleen-preservation group) was performed in 61 patients, and 51 underwent D(2) total radical gastrectomy with splenectomy (splenectomy group). The differences in clinicopathological characteristics,5-year survival rate, incidence of postoperative complication and hospital stay between the two groups were analyzed retrospectively. RESULTS: There were no significant differences between the spleen-preservation group and the splenectomy group in gender, age, tumor size, T stage, N stage and TNM stage. The overall 5-year survival rate was 41.0% in the spleen-preservation group and 39.2% in the splenectomy group (P>0.05). The 5-year survival rates of patients with stage I, II, III and IIII were 100%, 66.7%, 27.8% and 17.4% in the spleen-preservation group, respectively, and were 100%, 70.0%, 26.7% and 5.6% in the splenectomy group, respectively (all P>0.05). The incidence of postoperative complication was lower in the spleen-preservation group (11.5% vs 27.5%, P<0.05). The mean hospital stay was longer in the splenectomy group (27.3 d vs 20.3 d, P=0.057). CONCLUSION: The efficacy of modified D(2) radical total gastrectomy with spleen-preserving for patients with gastric cancer in the upper third, upper and middle third or entire stomach is similar to that of D(2) radical total gastrectomy with splenectomy, and the spleen-preserving procedure is associated with decreased postoperative complication and improved survival.

[Chromosomal alterations analyzed by comparative genomic hybridization in primary gastric carcinoma].

OBJECTIVE: To identify genetic abnormalities in primary gastric carcinoma. METHODS: Comparative genomic hybridization (CGH) was used in screening DNA copy number changes along all chromosomes in 23 cases of primary gastric cancer. RESULTS: Twenty-one out of 23 cases showed chromosomal losses and gains for at least one of the chromosomal arms in primary gastric cancer. The mean number of chromosomal alterations was 7.52. Chromosomal gains predominated over chromosomal losses in a ratio of 5.38:2.14. The most often involved chromosomal gains were observed in 8q (9/21, 42.9%), 20q (9/21, 42.9%), 17q (8/21, 38.1%), 3q (7/21, 33.3%), 7q (7/21, 33.3%), 11q (6/21, 28.6%), 13q (6/21, 28.6%), 1q (5/21, 23.8%) and 20p (5/21, 23.8%). The chromosomal arms with frequent losses were 17p (7/21, 33.3%), 18q (6/21, 28.6%), 5q (5/21, 23.8%), 8p (5/21, 23.8%), and 9p (5/21, 23.8%). CONCLUSIONS: The phenomenon of gain and loss of chromosomal regions is observed in primary gastric cancer, which may induce the amplification of oncogenes and the loss of tumor suppressor genes to regulate the development and progression of gastric cancer.