Histological characterisation and prognostic evaluation of 62 gastric neuroendocrine carcinomas.

AIM OF THE STUDY: To determine the significance of expression of synaptophysin, chromogranin A, and Ki-67 and their association with clinicopathological parameters, and to find out the possible prognostic factors in gastric neuroendocrine carcinoma (G-NEC). MATERIAL AND METHODS: We investigated the immunohistochemical features and prognosis of 62 G-NECs, and evaluated the association among expressions of synaptophysin, chromogranin A, and Ki-67, clinicopathological variables, and outcome. RESULTS: Chromogranin A expression was found more commonly in small-cell NECs (9/9, 100%) than in large-cell NECs (27/53, 51%) (p = 0.008). No statistical significance was found in Ki-67 (p = 0.494) or synaptophysin (p > 0.1) expression between NEC cell types. Correlation analyses revealed that Ki-67 expression was significantly associated with mid-third disease of stomach (p = 0.005) and vascular involvement (p = 0.006), and had a trend of significant correlation with tumour relapse (p = 0.078). High expression of chromogranin A was significantly associated with histology of small-cell NECs (p = 0.008) and lesser tumour greatest dimension (p = 0.038). The prognostic significance was determined by means of Kaplan-Meier survival estimates and log-rank tests, and as a result, early TNM staging and postoperative chemotherapy were found to be correlated with longer overall survival (p < 0.05). Univariate analysis revealed associations between poor prognosis in NECs and several factors, including high TNM staging (p = 0.048), vascular involvement (p = 0.023), relapse (p = 0.004), and microscopic/macroscopic residual tumour (R1/2, p < 0.001). In a multivariate analysis, relapse was identified as the sole independent prognostic factor. CONCLUSIONS: No significant correlation between survival and expression of synaptophysin, chromogranin A, or Ki-67 has been determined in G-NECs. Our study indicated that early diagnosis, no-residual-tumour resection, and postoperative chemotherapy were possible prognostic factors.

Effect of invariant chain on major histocompatibility complex class I molecule expression and stability on human breast tumor cell lines.

Invariant chain (Ii) binds to the human leukocyte antigen (HLA) class II molecule and assists it in the process of peptide acquisition. In addition, Ii binds to the HLA class I molecule, although there has been little study of its effects on the HLA class I molecule. In addition to its normal expression on antigen-presenting cells, Ii expression is up regulated in a variety of tumors. By flow cytometric analysis, we found that expression of Ii resulted in an increase in the number of cell surface HLA class I molecules and in the proportion of unstable HLA class I molecules at the surface of breast tumor cell lines. These data suggest that the expression of Ii by tumor cells may quantitatively and qualitatively alter the presentation of antigens on those cells.

CCL21 induces extensive intratumoral immune cell infiltration and specific anti-tumor cellular immunity.

Chemokines are vital messengers that regulate immune cell activity. The chemokine CCL21 is normally expressed in secondary lymphoid organs and acts as a chemoattractant for several populations of immune cells. Herein, we report that intratumoral CCL21 administration recruited significant numbers of immune cells into murine pancreatic tumors and inhibited tumor growth. Detailed flow cytometric and confocal analysis of CCL21-treated tumor cell isolates revealed increased lymphoid-related dendritic cells (lDC) and myeloid DC (mDC), naïve and mature T cells, natural killer (NK) cells, and NKT cells infiltrating the tumor mass. Furthermore, CCL21 intratumoral treatments resulted in significant tumor growth inhibition in wild-type (WT) C57BL/6 mice, but no therapeutic benefit was observed in C57BL/6 RAG2-/-Pfp-/- mice, suggesting that the growth inhibition observed was immunologically mediated. CCL21 intratumoral injections generated immune responses that were tumor-specific and that could be transferred to naïve animals via splenocytes. In addition, intratumoral injection of CCL21 into pancreatic tumors reduced the growth of distant tumors as well as treated tumors. Thus, these data demonstrate in a pancreatic tumor model that intratumoral administration of CCL21 can cause significant immune cell infiltration of the tumor mass, delay growth of treated tumors, and generate a tumor-specific cellular immune response.

Flt3 ligand delivered in a pluronic formulation prolongs the survival of mice with orthotopic pancreatic adenocarcinoma.

Pancreatic adenocarcinoma is a devastating disease, characterized by asymptomatic development and extremely poor prognosis. Given the resistance of pancreatic cancer to standard chemo- and radiotherapy, we have focused on the development of immunotherapies for this disease. The number of dendritic cells (DCs), natural killer (NK) cells, and T-cells in the blood and secondary lymphoid organs is regulated by a group of hematopoietic growth factors, which includes fms-like tyrosine kinase-3 ligand (Flt3L). We have demonstrated previously that the bioavailability and in vivo half-life of Flt3L are increased by Flt3L formulation in the pluronic ProGelzx. In this study, we first examined the effectiveness of Flt3L delivered in ProGelz against subcutaneous (s.c.) pancreatic adenocarcinomas in mice. We found that an intramuscular (i.m.) injection of Flt3L in ProGelz significantly increased the survival of mice bearing s.c. pancreatic tumors, compared to the administration of phosphate-buffered saline (PBS) in ProGelz. We then tested Flt3L in ProGelz in an orthotopic pancreatic tumor model, and demonstrated that it significantly enhanced the survival of tumor-bearing mice, compared to PBS in ProGelz. Overall, these observations suggest that Flt3L formulated in ProGelz may have potential clinical utility as a treatment for pancreatic cancer.

Salvage therapy with mitoxantrone, etoposide, bleomycin and dexamethasone for refractory or relapsed aggressive non-Hodgkin's lymphoma patients with a poor performance status or comorbidity.

The treatment of refractory or relapsed aggressive non-Hodgkin's lymphoma (NHL) in patients in a state of poor health is difficult due to their ineligibility to receive intensive salvage chemotherapy. In the present study, 16 refractory or relapsed aggressive NHL patients with a poor performance status or comorbidities were treated with mitoxantrone, etoposide, bleomycin and dexamethasone (MEBD) therapy. The treatment consisted of 10 mg/m2 intravenous (IV) mitoxantrone on day 1, 75 mg/m2 IV etoposide on days 1-3, 20 mg IV dexamethasone on days 1-4 and 15 mg intramuscular bleomycin on days 1, 4, 8 and 12, every 21 days. The efficacy and toxicity of the regimen were evaluated. The overall response rate was 68.8%, with a complete response rate of 18.8% and a partial response rate of 50.0%. The efficacy of the treatment for B-cell lymphoma was greater than that for T-cell lymphoma. The median progression-free survival time for the patients was 16.7 months and the median overall survival time was 22.4 months. The one-year overall survival rate was 62.5% and the two-year overall survival rate was 43.8%. The most common toxicity symptom was myelosuppression. In conclusion, refractory or relapsed aggressive NHL patients with a poor performance status or comorbidity are eligible for chemotherapy. MEBD therapy is an effective and feasible salvage regimen for NHL patients in a state of poor health.

Association between ERCC2 polymorphisms and glioma risk: a meta-analysis.

ERCC2 is an essential component of the nucleotide excision repair pathway which is involved in the effective maintenance of genome integrity. Association studies on ERCC2 polymorphisms and glioma risk have yielded inconclusive results. This meta-analysis was performed to gain a better insight into the relationship between ERCC2 polymorphisms and glioma risk. A systematic literature search updated to December 2, 2013 was performed in the Pubmed and EMBASE databases. Crude pooled odds ratios (ORs) with their corresponding 95% confidence intervals (95% CIs) were used to estimate the association between ERCC2 polymorphisms and glioma risk under a suitable effect model according to heterogeneity. All analyses were performed using Review Manager 5 (version 5.2) and STATA (version 12.0). The combined results demonstrated rs13181 to be significantly associated with glioma risk (G allele versus T allele: OR=1.15, 95% CI=1.05-1.26, P=0.002; dominant model: OR=1.22, 95% CI=1.07-1.39, P=0.002; recessive model: OR=1.18, 95% CI=0.98-1.41, P=0.070). We also found that rs13181 acts in an allele dose-dependent manner (GG versus TT: OR=1.30, 95% CI=1.07-1.57, P=0.009; TG versus TT: OR=1.20, 95%=CI 1.05-1.37, P=0.009; trend test, P=0.004). However, no evidence was found in analyses for the association between other 3 ERCC2 polymorphisms (rs238406, rs1799793, and rs1052555) and susceptibility to glioma development. Our meta-analysis suggests that rs13181 is significantly associated with glioma risk in an allele dose-dependent manner, whereas, 3 other ERCC2 polymorphisms (rs238406, rs1799793, and rs1052555) may have no influence.

Phase II, open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification.

PURPOSE: Melanomas harbor aberrations in the c-Kit gene. We tested the efficiency of the tyrosine kinase inhibitor imatinib in selected patients with metastatic melanoma harboring c-Kit mutations or amplifications. PATIENTS AND METHODS: Forty-three patients with metastatic melanoma harboring c-Kit aberrations were enrolled on this phase II trial. Each patient received a continuous dose of imatinib 400 mg/d unless intolerable toxicities or disease progression occurred. Fifteen patients who experienced progression of disease were allowed to escalate the dose to 800 mg/d. RESULTS: Forty-three patients were eligible for evaluation, and the median follow-up time was 12.0 months. The median progression-free survival (PFS) was 3.5 months, and the 6-month PFS rate was 36.6%. Rate of total disease control was 53.5%: 10 patients (23.3%; 95% CI, 10.2% to 36.4%) and 13 patients (30.2%; 95% CI, 16.0% to 44.4%) achieved partial response (PR) and stable disease (SD), respectively. Eighteen patients (41.9%) demonstrated regression of tumor mass. Notably, nine of the 10 PRs were observed in patients with mutations in exons 11 or 13. The 1-year overall survival (OS) rate was 51.0%. The median PFS and OS times for patients who had PR or SD versus disease progression were 9.0 months versus 1.5 months (P < .001) and 15.0 months versus 9.0 months (P = .036), respectively. Imatinib 400 mg/d was well tolerated, and only one of the 15 patients who received dose escalation to 800 mg/d achieved SD. CONCLUSION: Imatinib demonstrated significant activity in patients with metastatic melanoma harboring genetic c-Kit aberrations, with an overall response rate of 23.3%. Escalation to 800 mg/d could not restore disease control.

[Inhibitory effect of photodynamic therapy combined with paclitaxel on the proliferation of esophageal carcinoma Eca-109 cells].

OBJECTIVE: To investigate the inhibitory effect of photodynamic therapy (PDT) in combination with paclitaxel (PCT) on proliferation in esophageal carcinoma Eca-109 cells line. METHODS: Eca-109 cells were treated with PCT alone, HPD alone at different doses, or their combinations. For the combined treatments, the cells were exposed to PCT for 12 h followed by incubation with HPD at high, middle or low concentrations for 4 h. PDT was then performed on these treated cells and fluorescence microscopic observation was made before and after PDT. The cell survival was measured by MTT assay, and the cell apoptosis rate analyzed by flow cytometry after a 24-h cell incubation following PDT. RESULTS: The fluorescence excitation of the cells was weakened after PDT. Combined treatments resulted in significantly lowered cell survival rate and increased cell apoptosis rates as compared to those of the control cells and the cells treated with PCT alone and low-dose HPD (P<0.01). Significant differences were also noted among the cells exposed to HPD at different concentrations (P<0.05). CONCLUSION: PDT combined with PCT have significant synergetic effects in inhibiting the proliferation of human esophageal carcinoma cells and inducing their apoptosis in vitro.

CCL21 is an effective surgical neoadjuvant for treatment of mammary tumors.

In previous studies, the chemokine CCL21 has shown biological activities that include T cell, natural killer (NK) cell, and dendritic cell (DC) chemoattraction. The goal of this study was to determine the effects of administering CCL21 to orthotopic mammary tumors in terms of impact on tumor growth rate, immune cell infiltration of the primary tumor and survival. We found that a single intratumoral administration of CCL21 slowed the growth of orthotopic mammary tumors and increased intratumoral infiltration by T cells, NK cells and DCs. CCL21 intratumoral administration also prolonged the survival of tumor-earing mice. Furthermore, mice that received intratumoral neoadjuvant CCL21 ior to surgical resection of tumors survived significantly longer than control mice. The urviving neoadjuvant CCL21-reated mice, when challenged again with cl-6, had significantly slower rate of tumor growth than challenged control mice. Thus, our ata indicate that CCL21 treatment prior to mammary tumor resection can significantly rolong survival and increase resistance to subsequent tumor challenge. Overall, our indings suggest that intratumoral administration of CCL21 has potential as a neoadjuvant mmunotherapy for breast cancer.