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INTRODUCTION: Diabetic foot represents one of the most serious and expensive complications of diabetes and is subject to a high percentage of amputations that are almost always preceded by ulcers ascribable to neuropathy and/or vasculopathy. Videocapillaroscopy (VCS) can be a valuable aid in order to uncover morpho-structural anomalies in the vascular bed, both at the level of the oral mucosa and at the level of the terminal vessels of the lower limb. MATERIALS AND METHODS: Sixty subjects divided into 4 groups were enrolled: 15 healthy subjects; 15 patients with diabetes for more than 10 years without ulcerative foot lesions; 15 patients with neuropathic diabetic foot (clinical diagnosis, MDNS); 15 patients with ischemic diabetic foot (clinical diagnosis, ABI, lower limb doppler). A complete videocapillaroscopic mapping of the oral mucosa was carried out on each patient. The areas investigated were: labial mucosa, the retro-commissural region of the buccal mucosa, and the vestibular masticatory mucosa (II and V sextant). RESULTS: The analysis of the morphological and densitometric characteristics of the capillaries revealed the following: a significant reduction in capillary density in neuropathic (mean ± SD 7.32 ± 2.1) and ischemic patients (mean ± SD 4.32 ± 3.2) compared to the control group of patients (both diabetic mean ± SD 12.98 ± 3.1 and healthy mean ± SD 19.04 ± 3.16) (ANOVA test and Bonferroni t test p < 0.05); a reduction in the average length of the capillaries and a significant increase in tortuosity (ANOVA test and Bonferroni t test p < 0.05). In the neuropathic patients, a recurrent capillaroscopic pattern that we defined as "sun" was found, with capillaries arranged radially around an avascular area. CONCLUSIONS: The data obtained from this preliminary study suggest a potential diagnostic role of oral capillaroscopy in the early and subclinical identification of microangiopathic damage in patients with diabetic foot.
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Purpose: Osteosarcoma, the most common primary bone tumor, is characterized by an aggressive behavior with high tendency to develop lung metastases as well as by multiple genetic aberrations that have hindered the development of targeted therapies. New therapeutic approaches are urgently needed; however, novel combinations with immunotherapies and checkpoint inhibitors require suitable preclinical models with intact immune systems to be properly tested.Experimental Design: We have developed immunocompetent osteosarcoma models that grow orthotopically in the bone and spontaneously metastasize to the lungs, mimicking human osteosarcoma. These models have been used to test the efficacy of trabectedin, a chemotherapeutic drug utilized clinically for sarcomas and ovarian cancer.Results: Trabectedin, as monotherapy, significantly inhibited osteosarcoma primary tumor growth and lung metastases by both targeting neoplastic cells and reprogramming the tumor immune microenvironment. Specifically, trabectedin induced a striking differentiation of tumor cells by favoring the recruitment of Runx2, the master genetic regulator of osteoblastogenesis, on the promoter of genes involved in the physiologic process of terminal osteoblast differentiation. Differentiated neoplastic cells, as expected, showed reduced proliferation rate. Concomitantly, trabectedin enhanced the number of tumor-infiltrating T lymphocytes, with local CD8 T cells, however, likely post-activated or exhausted, as suggested by their high expression of the inhibitory checkpoint molecule PD-1. Accordingly, the combination with a PD-1-blocking antibody significantly increased trabectedin efficacy in controlling osteosarcoma progression.Conclusions: These results demonstrate the therapeutic efficacy of trabectedin in osteosarcoma treatment, unveiling its multiple activities and providing a solid rationale for its combination with immune checkpoint inhibitors. Clin Cancer Res; 23(17); 5149-61. ©2017 AACR.
