Impact of Alcian blue and periodic acid Schiff expression on the prognosis of gastric signet ring cell carcinoma

BACKGROUND The Alcian blue(AB)and periodic acid Schiff(PAS)stains are representative mucus markers in gastric signet ring cell carcinoma(SRCC).They are low-cost special staining methods used to detect acidic mucus and neutral mucus,respectively.However,the clinical importance of the special combined AB and PAS stain is unclear.AIM To investigate AB expression,PAS expression and the AB-to-PAS(A/P)ratio in gastric SRCC patients and to assess patient prognosis.METHODS Paraffin-embedded sections from 83 patients with gastric SRCC were stained with AB and PAS,and signet ring cell positivity was assessed quantitatively.Immuno-histochemical staining for Ki67,protein 53(P53)and human epidermal growth factor receptor 2(HER2)was performed simultaneously.The cancer-specific survival(CSS)rate was estimated via Kaplan-Meier analysis.Cox proportional hazards models were used for univariate and multivariate survival analyses.RESULTS Kaplan-Meier survival analysis revealed that the 3-year CSS rate was significantly greater in the high-PAS-expression subgroup than in the low-PAS-expression subgroup(P<0.001).The 3-year CSS rate in the A/P≤0.5 group was significantly greater than that in the A/P>0.5 group(P=0.042).Univariate Cox regression analysis revealed that the factors affecting prognosis included tumor diameter,lymph node metastasis,vessel carcinoma embolus,tumor stage,the A/P ratio and the expression of Ki67,P53 and the PAS.Cox multivariate regression analysis confirmed that low PAS expression[hazard ratio(HR)=3.809,95%confidence interval(CI):1.563-9.283,P=0.003]and large tumor diameter(HR=2.761,95%CI:1.086-7.020,P=0.033)were independent risk factors for poor prognosis.CONCLUSION A/P>0.5 is potentially a risk factor for prognosis,and low PAS expression is an independent risk factor in the prognosis of gastric SRCC.PAS expression and the A/P ratio could help in predicting the clinical prognosis of patients with SRCC.

The Relationship between the Expression of p27^(Kip1),p53 and the Infiltration,Metastasis and Prognosis in Gastric Carcinoma

Objective: To study the relationship between the expression of p27Kip1 and p53, and the infiltration, metastasis and prognosis in gastric carcinoma. Methods: The expression of p27Kip1 and p53 at protein level was determined by immunohistochemical assay (two-step method) in 100 cases of gastric carcinoma. Results: Of the 100 cases, the positive rate of p27Kip1 and p53 expressions were 44% and 49%, respectively. In the group of gastric carcinomas with deep infiltration (infiltration group), lymph nodes metastasis group (metastasis group) and death-within-5-years group (death group), the expression of p27Kip1 was statistically lower (_P<0.05). In the metastasis group and death group, the expression of p53 was significantly higher (P<0.05). The results of the monovariate analysis revealed that the 5-year survival rate of the high p27Kip1 expression group was 70.59%, which is higher than those of the low p27Kip1 expression group (54.55%) and the negative experession group (26%). The 5-year survival rate of the high p53 expression group was 19.23%, which was lower than those of the p53 low expression group (43.75%) and the negative group (53.19%). Cox multivariate analysis showed that p27Kip1, like p53, was an independent prognostic index. But p27Klpl protein expression was a stronger independent survival predictor (RR=3.06) than p53 expression (RR=2.33). Conclusion: The low expression of p27Kip1 and the high expression of p53 reflected the more frequent invasion and metastasis, which resulted in the reduced survival of patients. As an independent markers of the gastric carcinoma, the expression of p27Kip1 is more useful than that of p53 in the prognosis prediction of gastric carcinoma.

Immunosuppressive tumor microenvironment in gastric signet-ring cell carcinoma

Gastric signet-ring cell carcinoma(GSRCC)is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis.Studies have shown that early GSRCC has a good prognosis,while advanced GSRCC is insensitive to radiotherapy,chemotherapy or immune checkpoint blockade therapy.With technological advancement of single-cell RNA sequencing analysis and cytometry by time of flight mass cytometry,more detailed atlas of tumor microenvironment(TME)in GSRCC and its association with prognosis could be investigated extensively.Recently,two single-cell RNA sequencing studies revealed that GSRCC harbored a unique TME,manifested as highly immunosuppressive,leading to high immune escape.The TME of advanced GSRCC was enriched for immunosuppressive factors,including the loss of CXCL13+-cluster of differentiation 8+-Tex cells and declined clonal crosstalk among populations of T and B cells.In addition,GSRCC was mainly infiltrated by follicular B cells.The increased proportion of SRCC was accompanied by a decrease in mucosaassociated lymphoid tissue-derived B cells and a significant increase in follicular B cells,which may be one of the reasons for the poor prognosis of GSRCC.By understanding the relationship between immunosuppressive TME and poor prognosis in GSRCC and the underlying mechanism,more effective immunotherapy strategies and improved treatment outcomes of GSRCC can be anticipated.

Relationship between co-stimulatory molecule B7-H3 expression and gastric carcinoma histology and prognosis

AIM:To investigate the expression of co-stimulatorymolecule B7-H3 in gastric carcinoma and adenomatissue as well as normal gastric tissue and to explore therelationship between B7-H3 expression and pathologicalfeatures and prognosis of gastric carcinoma.METHODS:B7-H3 expression was detected in 102samples of human gastric carcinoma and 10 samples ofgastric adenoma and 10 samples of normal gastric tissueby immunohistochemical assay.Correlation betweenthe expression of B7-H3 and the patients'age,sex,gastric carcinoma locus,tumor size,tissue type,tumorinfiltration depth,differentiation degree,lymph nodemetastasis,and survival time was analyzed.RESULTS:B7-H3 was expressed in all gastric adenomasamples and in 58.8% samples of gastric carcinoma.B7-H3 expression in gastric carcinoma samples wasnot related with the patients'age,sex,lymph nodemetastasis,and tumor size(P>0.05),but with thesurvival time,infiltration depth of tumor and tissue type.CONCLUSION:Detection of B7-H3 expression in gastriccarcinoma tissue is beneficial to the judgment of theprognosis of gastric carcinoma patients and the choice oftreatment.

Clinicopathological,treatment,and prognosis study of 43 gastric neuroendocrine carcinomas

AIM To provide more information and therapeutic methods about gastric neuroendocrine carcinomas(G-NECs) which occur rarely but are highly malignant and clinically challenging.METHODS We retrospectively analyzed the clinicopathological characteristics, treatments, and prognosis of 43 G-NEC patients at our hospital between January 2007 and December 2014. The diagnosis was based on the 2010 World Health Organization criteria.RESULTS Forty-three G-NECs containing 39 small cell carcinomas and 4 large cell NECs with Ki67 > 60% were included in this study, accounting for only 0.95% of all gastric carcinomas. The median patient age was 62 years (range, 33-82) and the male-to-female ratio was 4.4:1. All patients underwent surgery, including 38 curative resections and 5 palliative resections. Among these 43 patients, nearly half(48.84%) of these tumors were located in the cardiac region of the stomach, regional lymph node metastasis was found in 31 cases(72.09%), and liver metastasis was found in 6 cases(13.95%). Follow-up information was got for 40 patients. Twentythree die of this disease with a median survival of 31 mo(range 1-90). The 1-year, 2-year, 3-year, and 5-year survival rate was 77.50%, 57.04%, 44.51%, and 35.05%, respectively. Survival was better in patients with tumor located in the cardiac region of the stomach, less than 7 lymph nodes metastasis and no liver metastasis. Five patients did not undergo postoperative chemotherapy, and the median survival time for these patients was 15 mo. For the remaining 34 patients who received postoperative chemotherapy, the median survival time was 44 mo and those received etoposide, cisplatin, and Paclitaxel survived the best. One patient with resected liver metastasis who received postoperative Capecitabine plus Oxaliplatin and Paclitaxel systemic chemotherapy plus octreotide LAR(30 mg intramuscularly, every 4 wk, for 2 years) has survived for 74 mo with no recurrence.CONCLUSION G-NECs are mostly nonfunctioning, which lead to a delay in detection. Local and/or distant metastases were noticed in most patients when diagnosed, and they required postoperative medical treatment. Adjuvant etoposide, cisplatin plus Paclitaxel systemic chemotherapy is recommended for these patients.

Upregulation of hypoxia inducible factor 1α mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma

AIM： To investigate the implication of the hypoxia inducible factor HIF-1α mRNA in gastric carcinoma and its relation to the expression of vascular endothelial growth factor （VEGF） protein, tumor angiogenesis invasion/metastasis and the patient＇s survival. METHODS： In situ hybridization was used to examine expression of HIF-1α mRNA, and immunohistochemical staining was used to examine expression of VEGF protein and CD34 in 118 specimens from patients with gastric carcinoma. RESULTS： The positive rates of HIF-1α mRNA and VEGF protein were 49.15% and 55.92%, respectively. Positive expressions of HIF-1α and VEGF in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis were dramatically stronger than stage T1-T2 cases and those without vessel invasion, lymph node metastasis and distant metastasis. The mean microvascular density （MVD） in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis was significantly higher than stage T1-T2 tumors and those without vessel invasion, lymph node metastasis and distant metastasis. The mean MVD in tumors with positive HIF-1α and VEGF expression was significantly higher than that in tumors with negative HIF-1α and VEGF expression. The expression of HIF- 1α was positively correlated with VEGF protein. There were positive correlations between MVD and expression of HIF-1α and VEGF. The mean survival time and the S-year survival rate in cases with positive expression HIF-1α and VEGF and MVD value ≥ 41.5/0.72 mm^2 were significantly lower than those with negative expression of HIF-1α and VEGF and MVD value 〈 41.5/0.72 mm^2. CONCLUSION： Overexpression of HIF-1α is found in gastric carcinoma. HIF-1α may induce the angiogenesis in gastric carcinoma by upregulating the transcription of VEGF gene, and take part in tumor invasion and metastasis. They can be used as prognostic markers of gastric cancer in clinical practice.

Co-expression of CDX2 and MUC2 in gastric carcinomas: Correlations with clinico-pathological parameters and prognosis

AIM: To evaluate the role of CDX2 homeobox protein as a predictor for cancer progression and prognosis as well as its correlation with MUC2 expression. CDX2 represents a transcription factor for various intestinal genes (including MUC2) and thus an important regulator of intestinal differentiation, which could previously be identified in gastric carcinomas and intestinal metaplasia. METHODS: Formalin-fixed and paraffin-embedded tissues from 190 gastric carcinoma patients were stained with monodonal antibodies recognizing CDX2 and MUC2, respectively. Immunoreactivity was evaluated semiquantitatively and statistical analyses including x2 tests, uni- and multi-variate survival analyses were performed. RESULTS: CDX2 was mostly expressed in a nuclear or supranuclear pattern,whereas MUC2 showed an almost exclusive supranuclear reactivity.Both antigens were present in >80% of areas exhibiting intestinal metaplasia. An immunoreactivity in >5% of the tumor area was observed in 57% (CDX2) or in 21% (MUC2) of the carcinomas.The presence of both molecules did not correlate with WHO, Lauren and Goseki classification (with the exception of a significantly stronger MUC2 expression in mucinous tumors). CDX2 correlated with a lower pT and pN stage in the subgroups of intestinal and stage I cancers and was associated with MUC2 positivity.A prognostic impact of CDX2 or MUC2 was not observed. CONCLUSION: CDX2 and MUC2 play an important role in the differentiation of normal, inflamed, and neoplastic gastric tissues. According to our results, loss of CDX2 may represent a marker of tumor progression in early gastric cancer and carcinomas with an intestinal phenotype.

Effect of lymph node micrometastases on prognosis of gastric carcinoma

AIM： To evaluate the relationship between lymph node micrometastases and prognosis of patients with gastric carcinoma and to evaluate the significance of the new assessment of nodal status in determining the pN categories in the 5th edition of the UICC TNM classification.METHODS： A total of 850 lymph nodes from 30 patients with gastric carcinoma who underwent gastrectomy with lymphadenectomy were assessed by reverse transcription polymerase chain reaction assay in addition to histologic examination. Cytokeratin-20 gene marker was used in this assay.RESULTS： Routine examination by HE staining confirmed metastasis in 233 lymph nodes from 20 patients. All these 233 lymph nodes were oltokeratin-20 positive. Moreover, lymph node micrometastases were detected in an additional 67 lymph nodes in 12 of these 20 patients. Lymph node micrometastases were also detected in t0 lymph nodes from 2 of 10 patients who had no obvious metastases identified by HE staining. Totally, lymph node micrometastases were identified by the reverse transcription polymerase chain reaction assay in 77 （12.5%） lymph nodes from 14 （46.7%） patients with gastric carcinoma. Of 27 patients who underwent curative resection, 7 （25.9%） were up-staged （from Ⅰ B stage to Ⅱ stage in 1 patient, from IB stage to ⅢA stage in 1 patient, from Ⅱ stage to ⅢA stage in 1 patient, from ⅢA stage to ⅢB stage in 1 patient, from ⅢA stage to Ⅳ stage in 1 patient, from ⅢB stage to Ⅳ stage in 2 patients）. In a median follow-up of 32 （range 8-36） too, Kaplan-Meier survival analysis showed significant improvements in median survival （22.86 ± 3.17 mo, 95% CI： 16.64-29.08 mo vs 18.00 ± 7.4 mo, 95% CI： 3.33-32.67 mo） of patients with negative lymph node micrometastases over patients with positive lymph node micrometastases （log-rank, P 〈 0.05）.CONCLUSION： Lymph node micrometastases have a significant impact on the current staging system of gastric carcinoma, and are significant risk factors for prognosis of patients with gastric carcinoma.

Textbook Outcome as a measure of surgical quality assessment and prognosis in gastric neuroendocrine carcinoma:A large multicenter sample analysis

Objective:Quality assurance is crucial for oncological surgical treatment assessment.For rare diseases,singlequality indicators are not enough.We aim to develop a comprehensive and reproducible measurement,called the"Textbook Outcome"(TO),to assess the quality of surgical treatment and prognosis of gastric neuroendocrine carcinoma(G-NEC)patients.Methods:Data from patients with primary diagnosed G-NEC included in 24 high-volume Chinese hospitals from October 2005 to September 2018 were analyzed.TO included receiving a curative resection,≥15 lymph nodes examined,no severe postoperative complications,hospital stay≤21 d,and no hospital readmission≤30 d after discharge.Hospital variation in TO was analyzed using a case mix-adjusted funnel plot.Prognostic factors of survival and risk factors for non-Textbook Outcome(non-TO)were analyzed using Cox and logistic models,respectively.Results:TO was achieved in 56.6%of 860 G-NEC patients.TO patients had better overall survival(OS),disease-free survival(DFS),and recurrence-free survival(RFS)than non-TO patients(P<0.05).Moreover,TO patients accounted for 60.3%of patients without recurrence.Multivariate Cox analysis revealed non-TO as an independent risk factor for OS,DFS,and RFS of G-NEC patients(P<0.05).Increasing TO rates were associated with improved OS for G-NEC patients,but not hospital volume.Multivariate logistic regression revealed that nonlower tumors,open surgery,and>200 mL blood loss were independent risk factors for non-TO patients(P<0.05).Conclusions:TO is strongly associated with multicenter surgical quality and prognosis for G-NEC patients.Factors predicting non-TO are identified,which may help guide strategies to optimize G-NEC outcomes.

Clinicopathological characteristics and prognosis of gastric signet ring cell carcinoma

BACKGROUND The clinicopathological features and prognosis of gastric signet ring cell carcinoma(GSRC)remain controversial,particularly with regard to sensitivity to postoperative adjuvant therapy.AIM To compare the pathological features of GSRC with those of gastric adenocarcinoma of different degrees of differentiation and the differences in survival prognosis between the different disease processes.METHODS By screening gastric cancer patients from 2010 to 2015 in the database of Surveillance,Epidemiology and End Results,and collecting the clinicopathological and prognostic data of gastric cancer patients who underwent surgery from January 2014 to December 2016 in the Second Affiliated Hospital of Nanchang University,we analyzed the general pathological characteristics of GSRC by the chi-square test.Univariate and multivariate analyses were conducted to compare the factors affecting the survival and prognosis of early and advanced gastric adenocarcinoma.The Kaplan-Meier curves were plotted to reveal the survival difference between early and advanced GSRC and different differentiated types of gastric adenocarcinoma.The prognosis model of advanced GSRC was established with R software,and the area under curve(AUC)and C-index were used to assess the accuracy of the model.RESULTS Analysis of pathological features revealed that signet ring-cell carcinoma(SRC)was more frequently seen in younger(<60 years),female,and White patients compared to non-SRC patients.SRC was less commonly associated with early gastric cancer(EGC)(23.60%vs 39.10%),lower N0(38.61%vs 61.03%),and larger tumour sizes>5 cm(31.15%vs 27.10%)compared to the differentiated type,while the opposite was true compared to the undifferentiated type.Survival prognostic analysis found no significant difference in the prognosis of SRC patients among EGC patients.In contrast,among advanced gastric cancer(AGC)patients,the prognosis of SRC patients was correlated with age,race,tumour size,AJCC stage,T-stage,and postoperative adjuvant therapy.The predictive model showed that the 3-year AUC was 0.787,5-year AUC was 0.806,and C-index was 0.766.Compared to non-SRC patients,patients with SRC had a better prognosis in EGC[hazard ratio(HR):0.626,95%confidence interval(CI):0.427-0.919,P<0.05]and a worse prognosis in AGC(HR:1.139,95%CI:1.030-1.258,P<0.05).When non-SRC was divided into differentiated and undifferentiated types for comparison,it was found that in EGC,SRC had a better prognosis than differentiated and undifferentiated types,while there was no significant difference between differentiated and undifferentiated types.In AGC,there was no significant difference in prognosis between SRC and undifferentiated types,both of which were worse than differentiated types.A prognostic analysis of postoperative adjuvant therapy for SRC in patients with AGC revealed that adjuvant postoperative radiotherapy or chemotherapy significantly improved patient survival(34.6%and 36.2%vs 18.6%,P<0.05).CONCLUSION The prognosis of SRC is better than that of undifferentiated type,especially in EGC,and its prognosis is even better than that of differentiated type.SRC patients can benefit from early detection,surgical resection,and aggressive adjuvant therapy.

EXPRESSION OF CDX2 IS ASSOCIATED WITH CLINICOPATHOLOGIC FEATURES AND PROGNOSIS OF GASTRIC CARCINOMA.

Objective： To explore the correlation between the Cdx2 expression and clinicopathologic features of patients with gastric carcinoma, and to evaluate the role of Cdx2 as a prognostic indicator of gastric carcinoma. Methods： The expression of Cdx2 was studied using immunohistochemistry of paraffin-embedded tumor specimens from 154 patients who underwent D2 resection for gastric adenocarcinoma from 1994 to 1998. Results： Cdx2 expression was detected in 35.1% （54 of 154） of gastric carcinoma cases. Expression of Cdx2 was significantly higher in intestinal-type carcinomas than in diffuse-type carcinomas, and in cases with TNM stage Ⅰ and Ⅱ than those with TNM stage Ⅲ and Ⅳ （P〈0.001 and P=-0.012, respectively）. There was a clear negative correlation between Cdx2 expression and lymph node metastasis （P=-0.049）. The patients with Cdx2-positive expression showed higher survival rate than those with Cdx2-negative expression （P〈0.0001）. Multivariate analysis revealed that the expression of Cdx2 was the independent prognostic indicator in this series （P〈0.001）. Conclusion： These data suggest that Cdx2 has significant value in predicting prognosis of gastric carcinoma.

The Number of Ezrin-Expressing Lymphocytes Correlating with Tumor Cell Apoptosis and Prognosis of Human Gastric Carcinoma

Background: Ezrin is a linker protein between actin filaments and cell adhesion molecules, which plays an important role in cancer progression. There are only a few studies available that have investigated ezrin expression in different types of tumors. However, the prognostic importance of ezrin and its correlation with clinicopathological characteristics are yet to be delineated in gastric carcinoma. Methods: Specimens from 124 gastric carcinoma patients of T2 and T3 diseases treated in a defined period with curative operation were evaluated for ezrin, CD8 and cleaved caspase-3 expression by immunohistochemical methods. Results: Ezrin expression was detected in both cancer cells and interstitial cells (ISCs) infiltrated into the tumor. According to our criterion, 37 patients (29.8%) were positive for ezrin expression and 87 (70.2%) were negative. A significant correlation between ezrin expression and any of the clinicopathological characteristics could not be found. In Spearman-rank correlation test, a significant correlation was found between the number of ezrin-stained ISCs and apoptotic index (AI) of cancer cells. Also the AI of cancer cells was significantly higher in ezrin-positive group when compared with ezrin-negative group. Patients with ezrin-expressing tumors had a significantly better disease-free survival, and in multivariable analysis ezrin expression status remained significant as an independent prognostic factor. Conclusion: Taken together, our results suggest that ezrin expression may play a vital role in tumor apoptosis and that it can be a useful tool for therapeutic intervention.

Characteristics and prognosis of gastric cancer in patients aged ≥ 70 years

AIM:To elucidate the prognostic value of age for gastric cancer and identify the optimal treatment for elderly gastric cancer patients.METHODS:We enrolled 920 patients with gastric cancer who underwent gastrectomy between January 2003and December 2007 in our center.Patients were categorized into three groups:younger group(age<50years),middle-aged group(50-69 years),and elderly group(≥70 years).Clinicopathological features were compared among the three groups and potential prognostic factors were analyzed.The log-rank test was used to assess statistical differences between curves.Independent prognostic factors were identified by the Cox proportional hazards regression model.Stratified analysis was used to investigate the impact of age on survival at each stage.Cancer-specific survival was also compared among the three groups by excluding deaths due to reasons other than gastric cancer.We analyzed the potential prognostic factors for patients aged≥70years.Finally,the impact of extent of lymphadenectomy and postoperative chemotherapy on survival for each age group was evaluated.RESULTS:In the elderly group,there was a male predominance.At the same time,cancers of the upper third of the stomach,differentiated type,and less-invasive surgery were more common than in the younger or middle-aged groups.Elderly patients were more likely to have advanced tumor-node-metastasis(TNM)stage and larger tumors,but less likely to have distant metastasis.Although 5-year overall survival(OS)rate specific to gastric cancer was not significantly different among the three groups,elderly patients demonstrated a significantly lower 5-year OS rate than the younger and middle-aged patients(elderly vs middle-aged vs younger patients=22.0%vs 36.6%vs 38.0%,respectively).In the TNM-stratified analysis,the differences in OS were only observed in patients withⅡandⅢtumors.In multivariate analysis,only surgical margin status,pT4,lymph node metastasis,M1 and sex were independent prognostic factors for elderly patients.The5-year OS rate did not differ between elderly patients undergoing D1 and D2 lymph node resection,and these patients benefited little from chemotherapy.CONCLUSION:Age≥70 years was an independent prognostic factor for gastric cancer after gastrectomy.D1 resection is appropriate and postoperative chemotherapy is possibly unnecessary for elderly patients with gastric cancer.

Clinicopathologic characteristics of gastric carcinoma in elderly patients: A comparison with young patients

AIM:To examine the clinicopathologic features of elderly patients with gastric carcinoma and to investigate the relationship between prognosis and age.METHODS: We reviewed the hospital records of 2 014patients with gastric carcinoma retrospectively to compare the clinicopathologic findings in elderly (age ＞70 years) and young (age ＜36 years) patients during the period from 1986 to 2000 in a tertiary referral center in Gwangju, Korea. Overall survival was the main outcome measure.RESULTS: Of the 2 014 patients, 194 (9.6%) were in the elderly group and 137 (6.8%) were in the young group.The elderly and young patients had similar distributions with respect to depth of invasion, nodal involvement, hepatic metastasis, peritoneal dissemination, tumor stage at the initial diagnosis, and type of surgery. Synchronous multiple carcinomas were found in 14/194 (7.2%) of the elderly group and 4/137 (2.9%) of the young group (P＜0.05). Using the Borrmann classification, type Ⅳ was more frequent in the young patients than in the elderly patients (P＜0.05).Significantly more elderly patients had a well or moderately differentiated histology, and more young patients had a poorly differentiated histology and signet ring cell carcinoma (P＜0.001). The 5-year survival rates of elderly and young patients did not differ statistically (52.8% vs 46.5%,P = 0.5290). Multivariate analysis showed that the histologic type, nodal involvement and operative curability were significant prognostic factors, and age itself was not an independent prognostic factor of survival for elderly gastric carcinoma patients.CONCLUSION: Elderly patients with gastric carcinoma do not have a worse prognosis than young patients. The important prognostic factor is whether the patients undergo a curative resection.

Expression and clinical significance of CD73 and hypoxia-inducible factor-1α in gastric carcinoma

AIM: To investigate the expression of CD73 and hypoxia-inducible factor-1α (HIF-1α) in human gastric carcinoma, and explore their clinical significance and prognostic value. METHODS: CD73 and HIF-1α expressions were detected by immunohistochemistry in consecutive sections of tissue samples from 68 gastric carcinoma patients. The peritumor tissues 2 cm away from the tumor were obtained and served as controls. The presence of CD73 and HIF-1α was analyzed by immunohis-tochemistry using the Envision technique. RESULTS: CD73 and HIF-1α expressions in gastric carcinoma were significantly higher than those in gastric mucosal tissues as control (P < 0.001) and showed a close correlation (Spearman r = 0.390, P = 0.001). Overexpression of CD73 was positively correlated with differentiation of tumor (P = 0.000), histopathology (P = 0.041), depth of invasion (P < 0.001), nodal status (P = 0.003), metastasis (P = 0.013), and the American Joint Committee on Cancer (AJCC) stage (P < 0.001). High expression of HIF-1α was positively correlated with tumor diameter (P = 0.031), depth of invasion (P = 0.022), and AJCC stage (P = 0.035). The overall survival rate was low in the patients with high expression of CD73 (P < 0.001). Moreover, CD73+/HIF-1α+ patients had the worst prognosis (P < 0.001). CD73 expression was proven to be an independent predictor for patients with gastric carcinoma by both multivariate Cox regression analysis (P = 0.021) and receiver operating characteristic curves (P = 0.001).CONCLUSION: CD73 expression correlates closely with HIF-1α expression in gastric carcinoma. CD73 could be an independent prognostic indicator for gastric carcinoma.

Relationship between cell adhesion molecules expression and the biological behavior of gastric carcinoma

AIM: To evaluate the relationship between the expression of cell adhesion molecules (CAMs) and the biological behavior of gastric carcinoma. METHODS: Expression of syndecan-1, E-cadherin and integrin β3 were evaluated by immunohistochemical study in a total of 118 gastric carcinomas and 20 non- tumor gastric mucosas. RESULTS: The expressions of syndecan-1 and E-cadherin were significantly lower in gastric carcinoma compared to non-tumor gastric mucosa, and the low expression rates were positively correlated to the tumor invasion depth, vessel invasion, lymph node metastasis and distant metastasis (P < 0.01 in all cases). However, the expression of integrin β3 was significantly higher in gastric carcinoma compared to non-tumor gastric mucosa, and the high expression rates were positively correlated to the tumor invasion depth, vessel invasion, lymph node metastasis and distant metastasis (P < 0.01 in all cases). In addition, the three protein expressions were correlated to the tumor growth pattern (P < 0.01, P < 0.01, and P < 0.05 respectively), but not correlated to tumor differentiation (P > 0.05, P > 0.05 and P > 0.05 respectively). Positive correlation was observed between the expressions of syndecan-1 and E-cadherin, but they which were negatively correlated to the expression of integrin β3 (P < 0.01 in all cases). Univariate analysis demonstrated that the mean survival time and 5-year survival rate were lower in the cases with low expressions of syndecan-1 and E-cadherin and high expression of integrin β3 (P < 0.01, in all cases). COX multivariate analysis showed that the expression level of syndecan-1 could be an independent prognostic index of gastric carcinoma (P < 0.01), whereas E-cadherin and integrin β3 could not be independent indexes (P > 0.05, P > 0.05 respectively). CONCLUSION: The low expression of syndecan-1 and E-cadherin and the high expression of integrin β3 are significantly correlated with the invasion and metastasis of gastric carcinoma, and they are highly correlated with each other. Therefore they may serve as important prognostic markers of gastric carcinoma.

Epstein-Barr virus-associated lymphoepithelioma-like early gastric carcinomas and endoscopic submucosal dissection: Case series

Epstein-Barr virus (EBV)-associated lymphoepithelioma-like gastric carcinoma (LELC) is characterized by a lower lymph node (LN) metastasis rate and a higher survival rate than other forms of gastric cancer. Although current prognosis for LELC is favorable, the most common approach is radical gastrectomy involving an extensive D2 lymph node dissection. Here, we report four cases of EBV-associated early LELC that were treated by an alternative approach, endoscopic submucosal dissection (ESD). The long-term outcome of this procedure is discussed. All patients were treated by ESD en bloc, and all ESD specimens showed tumor-free lateral resection margins. None of the lesions showed lymphovascular invasion. A pathological examination of ESD specimens revealed submucosal invasion of more than 500 &#x003bc;m in all four cases. One patient underwent additional radical surgery post-ESD; no residual tumor or LN metastasis was noted in the surgical specimen. The other three patients did not undergo additional surgery, either because of severe comorbidity or their refusal to undergo operation, but were subjected to medical follow-up. None of the ESD-treated patients reported local recurrence or distant metastases during the 27-32 mo of follow-up after ESD.

E-cadherin and beta-catenin expression in Epstein-Barr virus-associated gastric carcinoma and their prognostic significance

AIM： To examine the role of E-cadherin and betacatenin in carcinogenesis and to assess their prognostic implication in Epstein-Barr virus-associated gastric carcinomas （EBV-GCs）. METHODS： We compared the frequency of E-cadherin and beta-catenin expression in 59 EBV-GCs and 120 non-EBV-GCs, and examined the association between patients＇ prognosis and the expressions of these proteins. RESULTS： Neither the cellular-membranous nor the cytoplasmic E-cadherin expression showed any difference between EBV-GCs and non-EBV-GCs. On the other hand, loss of membranous expression of beta- catenin occurred more frequently in non-EBV-GCs than EBV-GCs [odds ratio = 0.41; 950 confidence interval （CI）, 0.19-0.90]. Furthermore, the nuclear and/or cytoplosmic expression of beta-catenin was seen more frequently in EBV-GCs than non-EBV-GCs （odds ratio = 2.23; 95% CI, 0.97-5.09）, and was observed in a larger proportion of carcinoma cells of EBV-GCs than non-EBV-GCs （P = 0.024）. Survival analysis for non-EBV-GC revealed that lymph node metastasis was significantly associated with poor prognosis （P 〈 0.001）. Among EBV- GCs, the depth of invasion （P = 0.005）, lymph node metastasis （P = 0.004） and an intestinal type by Lauren classification （hazard ratio = 9.47; 95% CI, 2.67-33.6） were significantly associated with poor prognosis. On the other hand, nuclear and/or cytoplasmic expression of beta-catenin was associated with a better prognosis in patients with EBV-GC （hazard ratio = 0.32; 95% CI, 0.11-0.93）. CONCLUSION： We observed more frequent preservation of beta-catenin in cell membrane and accumulation in nuclei and/or cytoplasm in EBV-GCs than in non-EBV- GCs. Factors involved in the prognosis of EBV-GCs and non-EBV-GCs are different in the two conditions.

Clinical significance of programmed death 1/programmed death ligand 1 pathway in gastric neuroendocrine carcinomas

BACKGROUND Recently, more and more studies have demonstrated the pivotal role of programmed death 1/programmed death ligand 1(PD-1/PD-L1) pathway in the immune evasion of tumors from the host immune system. However, the role of PD-1/PD-L1 pathway in gastric neuroendocrine carcinomas(G-NECs) remains unknown.AIM To investigate the expression of PD-1/PD-L1 and role of PD-1/PD-L1 pathway in G-NECs, which occur rarely but are highly malignant and clinically defiant.METHODS We investigated the expression of PD-L1 on tumor cells and PD-1^+, CD8^+, and FOXP3^+ T cell infiltration by immunohistochemistry in 43 resected G-NEC tissue specimens. The copy number alterations of PD-L1 were assessed by qRT-PCR.RESULTS Most of the G-NECs tumor cells exhibited a near-uniform expression pattern of PD-L1, while some showed a tumor-stromal interface enhanced pattern. Of the 43G-NECs, 21(48.8%) were classified as a high PD-L1 expression group, and the high expression of PD-L1 was associated with poor overall survival(OS). The high expression of PD-L1 was correlated with abundant PD-1^+ tumor infiltrating lymphocytes(TILs) instead of CD8^+ TILs and FOXP3^+ regulatory T cells(Tregs).Our analysis also suggested that the infiltration of CD8^+ TILs tended to be a favorable factor for OS, although the difference did not reach the statistical significance(P = 0.065). Meanwhile, PD-L1 was significantly overexpressed in cases with copy number gain as compared with those without.CONCLUSION Our data demonstrated for the first time that high expression of PD-L1 in GNECs is associated with a poor prognosis, while the high expression may be due to the copy number variation of PD-L1 gene or stimulation of TILs. These results provide a basis for the immunotherapy targeting PD-1/PD-L1 pathway in GNECs.

Clinicopathological and prognostic differences between mucinous gastric carcinoma and signet-ring cell carcinoma

Objective： To analyze the differences in clinicopathologic characteristics and prognosis between mucinous gastric carcinoma （MGC） and signet-ring cell carcinoma （SRCC）. Methods： Clinicopathologic and prognostic data of 1,637 patients with histologically confirmed MGC or SRCC who received surgical operations in the Department of Gastroenterological Surgery, Beijing Cancer Hospital between December 2004 and December 2009 were retrospectively collected and analyzed. The clinicopathological features were analyzed statistically using Z2 test. Survival was analyzed using the Kaplan- Meier method and multivariate analysis of Cox proportional hazards regression model （backward, stepwise）. Results： A total of 181 patients with gastric cancer （74 MGC, 107 SRCC） were included. MGC, when compared with SRCC, was featured by senile patients, stage III and I~, upper third stomach, large tumor size, positive lymph node metastasis, and positive lymphatic vascular invasion （P〈0.05）. The overall 5-year survival rate showed no difference between the two groups （48.8% vs. 44.8%, P〉0.05）. However, the survival rate for MGC patients was significant lower than that for SRCC patients when compared among the age 〈60 years, negative distant metastasis, and tumor localized at upper third stomach （P〈0.05）. Multivariate Cox proportional hazards models revealed that distant metastasis was a significant independent prognostic indicator in MGC group, and lymph node metastasis and distant metastasis was significant independent prognostic indicators in SRCC group. Conclusions： While compared with SRCC, MGC is associated with a more aggressive tumor biologic behavior. There is no statistically significant difference in distant metastasis, an independent prognostic indicator for both MGC and SRCC, which might be the reason for no significant difference of the overall survival rate between the patients with MGC and SRCC.