Active metronomic vinorelbine schedules decrease plasma interleukin-2 levels in mice with Lewis lung carcinoma

The aim of our study was to investigate the effects of metronomic vinorelbine (mVNR) in a tumor model of Lewis Lung (LL) cancer in immunocompetent C57BL/6 mice, looking at the plasma levels of interleukin-2 (IL-2) and interleukin-8 (IL-8). mVNR caused a concentration-dependent antiproliferative effect in vitro on LL/2 cells. The in vivo experiment showed the significant antitumor effects of mVNR at the dose of 4 mg/Kg and 5 mg/Kg, 3 times/week, and the significant dose-dependent decrease of IL-2 concentrations in plasma samples. Conversely, such an effect was not observed for IL-8. A significant decrease in microvessel density was also found at both the active mVNR doses. In conclusion, our study confirmed the activity of mVNR in an immunocompetent model of lung carcinoma and suggest multiple mechanisms of action, including the modulation of IL-2 levels

Synergistic activity of linifanib and irinotecan increases the survival of mice bearing orthotopically implanted human anaplastic thyroid cancer

Anaplastic thyroid cancer (ATC) is the most aggressive form of thyroid cancer, and novel combined therapies are urgently needed to prolong patient survival. No data are currently available on the preclinical activity of the combination of linifanib, a CSF-1R inhibitor, and irinotecan in ATC. The aim of the study was to evaluate the in vitro and in vivo activity of linifanib plus irinotecan. Proliferation and apoptosis assays were performed on 8305C and 8505C human ATC cell lines exposed to SN-38, the active metabolite of irinotecan, linifanib alone, and their concomitant combination. Synergism was evaluated by the combination index method. Quantification of pospho-CSF-1R levels was performed by ELISA. In vivo ATC orthotopic xenografts were treated with the single drugs, or their combination, to evaluate their impact on survival. Histology and immunohistochemistry were performed on ATC tissue samples. Both SN-38 and linifanib inhibited in vitro the proliferation of 8305C and 8505C cells in a concentration-dependent manner, whereas their concomitant treatment revealed a strong synergism in the ATC cells. A significant pro-apoptotic activity was found in both ATC cell lines treated with linifanib alone and in combination with SN-38. Moreover, linifanib significantly decreased the levels of phospho-CSF-1R after 24 h and 72 h in both 8505C and 8305C cells, and this was also observed with the concomitant administration of SN-38. In vivo, the combination of linifanib and irinotecan produced a greater survival result than either monotherapy, and resulted in a significant higher median survival. In some of the mice the combination produced a complete response with a macroscopic disappearance of the disease, as confirmed by histology. In conclusion, the synergistic ATC antitumor activity of linifanib/irinotecan combination significantly increased the survival of ATC affected mice and induced some complete responses, suggesting a potential role of this schedule in ATC patient's treatment

Coexistence of TERT promoter and BRAF mutations in cutaneous melanoma is associated with more clinicopathological features of aggressiveness

The recently described telomerase reverse transcriptase (TERT) promoter mutations are recurrent in cutaneous melanoma. Several authors have described an association between these molecular alterations, some histological parameters, and patient survival. BRAF mutations are very frequent in melanoma, but their actual role in the evolution of the disease is still unclear. Here, we investigated the relationship of TERT promoter mutations and BRAF mutations with the most relevant clinicopathological parameters, individually and coexisting, in order to evaluate their role as independent prognostic markers and to determine the effect of their coexistence. A TERT promoter alteration was found in 20 of 53 cases (38 %), significantly associated with histological type, increasing tumor thickness and mitotic rate, more advanced pathologic tumor (pT) stage, and absence of regression. A BRAF mutation was found in 21 of 53 cases (40 %), significantly associated with tumor thickness and presence of metastases in the sentinel lymph node. Coexistence of a TERT promoter and BRAF mutation was detected in 11 of 53 cases (21 %). This was associated with increasing thickness, high mitotic rate, lymph node metastasis, presence of ulceration, and absence of regression. Coexistence of a mutation in the TERT promoter and in the BRAF gene correlated with more prognostically relevant factors than either mutation alone. Our data lead us to hypothesize that TERT promoter and BRAF mutations cooperate in cutaneous melanoma. Further studies in larger cohorts of patients are needed to investigate how this synergistic effect is involved in the evolution of the disease

Vitamin D and the risk of acute allograft rejection following human liver transplantation.

BACKGROUND: Vitamin D may act as an immune modulator in experimental and human organ transplantation, but these data are yet to be confirmed in human liver transplantation (LT). AIM: This study aimed to assess the relationship between acute liver allograft cellular rejection (ACR) and pretransplant serum vitamin D concentration or post-transplant vitamin D supplementation. METHOD: We studied 133 LT recipients who underwent two per protocol allograft biopsies in the early post-operative period, plus on-demand biopsies as clinically indicated. ACR estimate was given according to the Banff scheme in biopsies obtained along two follow-up periods: (a) from the transplant operation to the end of the second month (0-2 months); (b) and from the third month to the end of the eighth month (3-8 months) post-LT. RESULTS: The median pretransplant serum 25-hydroxyvitamin D concentration was 12.5 ng/ml; 40 patients had concentrations < or =12.5 ng/ml, of whom six had < or =5.0 ng/ml. Seventy-nine recipients received oral vitamin D(3) supplementation to treat post-transplant osteoporosis. In the 0-2 months period, moderate-to-severe rejection episodes were independently associated with cytomegalovirus reactivation (P<0.005) and progressively lower pretransplant serum 25-hydroxyvitamin D concentrations (P<0.02). Early vitamin D(3) supplementation was independently associated with a lack of ACR (P<0.05). CONCLUSIONS: These results suggest that vitamin D may favour immune tolerance towards the liver allograft