Reduced expression of thrombospondin-1 correlates with a poor prognosis in patients with non-small cell lung cancer

Thorombospondin-1 (TSP-1) is a 450 kDa extracellular matrix glycoprotein, with anti-angiogenic activity. We analyzed the relationship in TSP-1 expression and Microvessel count (MVC), and also clinical factors, using immunohistochemical methods for non-small cell cancer (NSCLC). Histopathologically, there was inverse correlation between TSP-1 expression and MVC for squamous cell carcinoma, but not for adenocarcinoma cases. Among 199 completely resected cases of NSCLC, the 5-year survival was 77.0% when the expression of TSP-1 was maintained and 55.1% when the expression were reduced, respectively (P=0.0046). When compared with TSP-1 expression in the high MVC subgroup, there was significantly shorter survival time when TSP-1 expression was reduced (P=0.0091), and no significant difference was seen for the low MVC subgroup. Multivariate analysis revealed that expression of TSP-1 is as a prognostic factor of NSCLC. Our present data suggest that TSP-1 might not be a direct anti-angiogenic factor and the TSP-1 expression is a prognostic indicator of NSCLC.     

Adjuvant therapy for colorectal carcinoma

Adjuvant therapy for colorectal carcinoma has been developed over the last two decades. We have reviewed the history of adjuvant chemotherapy for colorectal carcinoma in the United States, Europe and Japan with regard to the rationale of the chemotherapy regimen and the survival benefit for the establishment of a standard regimen. Treatment with 5-fluorouracil (5-FU) and leucovorin (LV) for postoperative adjuvant chemotherapy had an overall survival benefit, compared with surgery alone, in randomized controlled trials in the United States and Europe for Dukes' C colon carcinoma. In contrast, the survival benefit of adjuvant chemotherapy for Dukes' B colon carcinoma and for rectal carcinoma has not yet been established. In Japan, randomized controlled trials have examined combination treatment with mitomycin (MMC) and oral fluoropyrimidines for colorectal carcinoma compared with surgery alone. A meta-analysis indicated that combination treatment with MMC and oral fluoropyrimidines had a survival benefit for colorectal carcinoma. The survival benefit of combination treatment with irinotecan (CPT-11) + 5-FU + LV or uracil + tegaful (UFT) + LV (Orzel) for adjuvant chemotherapy are currently being compared with 5-FU + LV. Meta-analysis revealed a survival benefit at 2-years in the prevention of liver metastasis following intraportal or intraarterial infusion of 5-FU. The survival benefit of preoperative radiotherapy was superior to postoperative radiotherapy for advanced rectal carcinoma in association with the prevention of local recurrence. Clinical trial data suggest that the current standard regimen of adjuvant chemotherapy is a combination of 5-FU and LV for Dukes' C colon carcinoma and that radiotherapy for local control of rectal carcinoma has a survival benefit.     

Radiotherapy after transcatheter arterial chemoembolization for patients with hepatocellular carcinoma and portal vein tumor thrombus

Transcatheter arterial chemoembolization (TACE) is used in the treatment of hepatocellular carcinoma; however, it has limited effect on portal vein tumor thrombus (PVTT). The purpose of this study was to assess the feasibility and efficacy of radiotherapy targeting the PVTT after TACE for the tumor in the hepatic parenchyma. TACE was performed using epirubicin hydrochloride, iodized poppy seed oil, and gelatin sponge particles. Radiotherapy was performed targeting the PVTT to a total dose of 50 Gy in 25 fractions during 5 weeks. Twenty consecutive patients were treated with this combined treatment. Sixteen of 20 patients could complete the planned radiotherapy. Partial response was observed in 10, no change in 4, and progression in 6. The response rate was 50% (95% CI 28-72%). The 1-year overall survival rate was 25% (95% CI 6-44%), and the median survival time was 5.3 months. It was difficult to determine the late toxicities because of disease progression and additional TACE, and only one patient died without disease progression. Radiotherapy after TACE is feasible for patients with hepatocellular carcinoma and PVTT. The survival figure, however, is still dismal, and further investigation is needed to establish the best combination of treatment modalities.     

Involvement of IL-2/IL-2R system activation by parasite antigen in polyclonal expansion of CD4(+)25(+) HTLV-1-infected T-cells in human carriers of both HTLV-1 and S. stercoralis

The intermediate state of HTLV-1 infection, often found in individuals dually infected with Strongyloides stercoralis (S. stercoralis) and HTLV-1, is assumed to be a preleukemic state of adult T-cell leukemia (ATL). To investigate the effects of S. stercoralis superinfection on the natural history of HTLV-1 infection, we characterized peripheral blood samples of these individuals in Okinawa, Japan, an endemic area for both HTLV-1 and S. stercoralis and we studied effects of the parasite antigen on T-cells. The dually infected individuals showed a significantly higher provirus load and an increase in CD4(+)25(+) T cell population, with a significant, positive correlation. This increase was attributable to polyclonal expansion of HTLV-1-infected cells, as demonstrated by inverse-long PCR analysis of the integration sites. S. stercoralis antigen activated the IL-2 promoter in reporter gene assays, induced production of IL-2 by PBMC in vitro, and supported growth of IL-2 dependent cell lines immortalized by HTLV-1 infection or the transduction of Tax. Taken collectively, these results indicate that S. stercoralis infection induces polyclonal expansion of HTLV-1-infected cells by activating the IL-2/IL-2R system in dually infected carriers, an event which may be a precipitating factor for ATL and inflammatory diseases.     

Combination therapy of percutaneous ethanol injection and radiofrequency ablation against hepatocellular carcinomas difficult to treat

High-grade B-cell non-Hodgkin's lymphoma (NHL), a diagnostic disease for the acquired immunodeficiency syndrome (AIDS), is a late manifestation of HIV infection and is generally related to severe lymphopenia. We reviewed the main clinico-pathological features of this disease and analysed its pathogenetic mechanisms with potential therapeutic implications.     

Retroviral-mediated IL-12 gene transduction into human CD34+ cell-derived dendritic cells

Genetically modified dendritic cells (DCs) with Th1 type cytokine genes are useful for activating anti-tumor immune response. We made human interleukin (IL)-12 p70 gene-transduced DCs generated from CD34+ progenitor cells using a retrovirus system and investigated the function of IL-12-producing DCs. We used the pMX retroviral vector and made cytokine gene-containing viral vectors referred to as GFP pMX and hIL-12 pMX. Supernatants from BOSC23 cells transfected with GFP pMX and hIL-12 pMX were harvested and used for transfection of DC. Cord blood CD34+ cells were incubated with supernatants containing retrovirus for 48 h with cytokines such as IL-3, IL-6, SCF, Flt3 ligand (FL), bFGF and IGF-I. The cells were cultured for 12 days in the presence of GM-CSF, SCF, FL, IL-4 and TNF-alpha to get mature DC-enriched population. Analysis of surface marker on DCs and allogeneic MLR assay were also performed. After a 14-day culture, 60-70% of cultured CD34+ cells were DC marker (CD1a, DEC205) positive. The IL-12 p70 protein levels in supernatant of DC-GFP and DC-hIL-12 were 0.2 ng/ml and 53 ng/ml/5 x 10(5) DCs for 72 h, respectively. The addition of CH296 fibronectin fragment (FN) increased 3-fold IL-12 gene transduction efficiency into DCs. MLR assay showed that IL-12-producing DC exhibited more potent T cell growth-stimulating activity compared with GFP-DC. These results suggested that genetically modified CD34+ cell-derived DCs with human IL-12 gene are fully efficient in T cell priming, and could be a good tool for effective cancer immunotherapy.     

Apoptosis and apoptosis-associated gene products related to the response to neoadjuvant chemotherapy for gastric cancer

To evaluate the effect of neoadjuvant chemotherapy on gastric cancer, we examined the correlation between induction of apoptosis and expression of p53, Bcl-2, and Bax. Eighty-five patients with advanced gastric cancer were retrospectively divided into the following two groups: 54 patients received 5-fluorouracil (5-FU) at 300 mg/body/day for 14 days and cisplatin (CDDP) at 15 mg/body/day for 2 days as group A; 31 patients without any preoperative chemotherapy as group B. According to histological changes in tumors due to neoadjuvant chemotherapy, the therapeutic effects on tumors were evaluated. The apoptotic index (AI) of group A was significantly higher than that of group B (1.12+/-0.40 vs. 0.67+/-0.24; p<0.01). In group A, the AI of p53-positive cases was significantly lower than that of negative cases (0.92+/-0.32 vs. 1.39+/-0.32; p<0.01). The AI of histological responders was significantly higher than that of non-responders (1.34+/-0.35 vs. 1.02+/-0.38; p<0.01). There was no significant correlation between AI and expression of Bcl-2 or Bax. In group A, histological responders, Bcl-2 positive, and high AI patients had better prognosis, respectively. In conclusion, neoadjuvant chemotherapy for gastric cancer enhanced induction of apoptosis, and AI might be useful to evaluate the effect of neoadjuvant chemotherapy.     

Postoperative adjuvant chemotherapy is effective in gastric cancer with serosal invasion: significance in patients chosen for multivariate analysis

There are few reports on overall usefulness of adjuvant chemotherapy in gastric cancer patients. We tried to clarify, using multivariate analysis, usefulness of postoperative adjuvant oral chemotherapy in advanced gastric cancer patients after curative resection. Four hundred and eighty-two gastric cancer patients enrolled in a randomized controlled trial were classified into 2 groups based on postoperative chemotherapeutic regimen: oral doxifluridine (5'-DFUR, an intermediate metabolite of capecitabine) (n=245) or oral 5-fluorouracil (5-FU) (n=237). The significant prognostic factors in patients with serosal invasion were chemotherapeutics (5'-DFUR vs. 5-FU) (risk ratio 1.649; 95% CI, 1.112-2.437), lymph node metastasis (no vs. yes) (2.823; 1.422-5.604), and tumor differentiation (differentiated vs. undifferentiated) (1.727; 1.068-2.791). Significant factors influencing peritoneal recurrence time were chemotherapeutics (1.756; 1.063-2.902), serosal invasion (no vs. yes) (2.237; 1.264-3.961), lymph node metastasis (2.541; 1.267-5.095), tumor differentiation (2.656; 1.374-5.136), and tumor location (others vs. total) (3.595; 2.006-6.443). There were no differences in the overall survival between chemotherapy. However, 5'-DFUR produced a better survival time of patients with serosal invasion than 5-FU, that might be attributed to the prevention of peritoneal recurrence in this subset.     

Clinical significance of nm23 expression and chromosome 17 numerical aberrations in primary gastric cancer

The metastasis suppressor gene nm23 located on chromosome 17 might be one of the targets in deletions of chromosome 17. In this study, we analyzed the expression of nm23 and chromosome 17 aberrations in gastric cancer and assessed their clinicopathological and prognostic significance. In 103 gastric cancer patients, we examined nm23 expression by immunohistochemistry and detected chromosome 17 aberrations by fluorescence in situ hybridization. There was a significant difference in the expression of nm23 among differentiated histologic types (well > moderately > poorly) (p < 0.01). Negative expression of nm23 correlated with depth of invasion (p < 0.01), lymph node metastasis (p < 0.05), lymphatic invasion (p < 0.05), venous invasion (p < 0.05), poor prognosis (p < 0.05), and chromosome 17 loss (p < 0.05). Chromosome 17 aberrations broadly correlated with clinicopathological variables and were associated with poor prognosis (p < 0.05). Univariate analyses identified nm23 (p < 0.05), chromosome 17 aberrations (p < 0.05), tumor size (p < 0.01), depth of invasion (p < 0.0001), lymph node metastasis (P < 0.001), hepatic metastasis (p < 0.01), peritoneal dissemination (p < 0.01), and lymphatic invasion (p < 0.01) as significant prognostic factors. Multivariate analysis showed that expression of nm23 and chromosome 17 aberrations were not independent prognostic indicators. Our results indicate that negative expression of nm23 and chromosome 17 numerical aberrations correlate with tumor progression and poor prognosis but are not independent prognostic indicators.