Purpose : It has been found that expression of vascular endothelial growth factor-C (VEGF-C) in several carcinomas is significantly associated with angiogenesis, lymphangiogenesis and regional lymph node metastasis. However, VEGF-C expression in bladder transitional cell carcinoma (TCC) has not yet been reported. To elucidate the role of VEGF-C in bladder TCC, we examined VEGF-C expression in bladder TCC and pelvic lymph node metastasis specimens obtained from patients who underwent radical cystectomy. Methods : Eighty-seven patients who underwent radical cystectomy for clinically organ-confined TCC of the bladder were enrolled in the present study. No neoadjuvant treatments, except transurethral resection of the tumor, were given to these patients. The VEGF-C expressions of 87 bladder tumors and 20 pelvic lymph node metastasis specimens were examined immunohistochemically and the association between VEGF-C expression and clinicopathological factors, including angiogenesis as evaluated by microvessel density (MVD), was also examined. Results : Vascular endothelial growth factor-C expression was found in the cytoplasm of tumor cells, but not in the normal transitional epithelium. Vascular endothelial growth factor-C expression was significantly associated with the pathological T stage ( P = 0.0289), pelvic lymph node metastasis ( P < 0.0001), lymphatic involvement ( P = 0.0008), venous involvement ( P = 0.0002) and high MVD ( P = 0.0043). The multivariate analysis demonstrated that VEGF-C expression and high MVD in bladder TCC were independent risk factors influencing the pelvic lymph node metastasis. Moreover, the patients with VEGF-C-positive tumors had significantly poorer prognoses than those with the VEGF-C-negative tumors ( P = 0.0087) in the univariate analysis. The multivariate analysis based on Cox proportional hazard model showed that the independent prognostic factors were patient age ( P = 0.0132) and pelvic lymph node metastasis ( P = 0.0333).Conclusion : The present study suggests that VEGF-C expression is an important predictive factor of pelvic lymph node metastasis in bladder cancer patients.
Recently, novel molecular targeted agents markedly changed the treatment of renal cell carcinoma (RCC), with promising results. However, there is little understanding of how these agents affect immune cell populations in RCC, an immunogenic tumor. Therefore, we investigated the changes in the peripheral blood immune cells in 58 RCC patients during the first 4 weeks of treatment with sorafenib, sunitinib, everolimus, or temsirolimus and evaluated whether these changes were associated with clinical outcomes. The immunological parameters were the proportion of type-1 (Th1) and type-2 (Th2) T cells, regulatory T cells (Treg), mature dendritic cells, and the neutrophil-to-lymphocyte ratio (NLR). The changes in these immune cells varied with the agents and the clinical response, dichotomized by the median progression-free survival (PFS) time (PFS-short or PFS-long). A significant decrease in the Th1/Th2 ratio was seen after sunitinib treatment only in the PFS-short group, suggesting a shift toward Th2 that down-regulates host immunity. The NLRs indicative of the balance between host immunity and cancer-related inflammation were consistently lower in the PFS-long group than in the PFS-short group, suggesting that lower NLR is associated with better clinical response. Only sunitinib decreased NLR remarkably regardless of PFS status, which may favor anti-tumor immunity. When patients were dichotomized by the cutoff values, Th1/Th2 ratio was not associated with PFS in any targeted therapy, while lower pre-treatment NLR was associated with longer PFS in each targeted therapy. In addition, in RCC patients given sequential targeted therapy, those with a lower baseline NLR survived significantly longer compared with the counterparts. Moreover, those whose baseline NLR was sustained low during the initial therapy survived the longest. Our results suggest the diverse changes in host immune cells in RCC patients during targeted therapy. The changes in NLR during the early phase of targeted therapy may be a powerful discriminator of who will benefit from the subsequent treatment.
Background: To elucidate whether Hand -Foot skin reaction could become a biomarker of clinical outcome in patients with metastatic renal cell carcinoma treated with sorafenib, we retrospectively examined the association between the Hand -Foot skin reaction and the clinical outcome in metastatic renal cell carcinoma patients treated with sorafenib. Methods: Thirty-six Japanese metastatic renal cell carcinoma patients treated with sorafenib were enrolled and divided into the groups with or without Hand -Foot skin reaction. Patient characteristics, best tumor response, progression-free survival and adverse events were investigated and compared between these two groups. Results: A sorafenib-induced Hand -Foot skin reaction in metastatic renal cell carcinoma patients was observed at a significantly higher rate in patients in the favorable-risk group in the Memorial Sloan-Kettering Cancer Center risk classification, and with Eastern Cooperative Oncology Group Performance Status of one or less, prior nephrectomy, higher hemoglobin, lower lactate dehydrogenase and lower C-reactive protein. The mean best tumor response was significantly better in the group with Hand -Foot skin reaction (216.7%) than that in the group without it (17.9%; P , 0.001). The median progression-free survival was significantly longer in the group with Hand -Foot skin reaction (4.6 months) than that in the group without it (1.5 months; P ¼ 0.002). In multivariate analysis, only Hand -Foot skin reaction was shown to be a predictive factor of progression-free survival (hazard ratio 0.312, P ¼ 0.010). Conclusions: A sorafenib-induced Hand -Foot skin reaction in metastatic renal cell carcinoma patients emerged at a significantly higher rate in patients in the favorable-risk group in the Memorial Sloan-Kettering Cancer Center risk classification and was significantly associated with best tumor response and progression-free survival, suggesting that Hand -Foot skin reaction might be an independent predictive factor for clinical outcome in metastatic renal cell carcinoma patients treated with sorafenib.
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