Safety and efficacy of non-ablative CO2 laser treatment of vulvo-vaginal atrophy in women with history of breast cancer.

PURPOSE: Breast cancer survivors (BCS) suffer severe vulvo-vaginal atrophy (VVA) and some of the most effective therapies are contraindicated. In literature we have no data about the non-ablative CO2 laser on these women. The aim of this study was to examine its efficacy, safety and acceptability in BCS. MATERIALS AND METHODS: The enrolled women underwent 3 sessions of laser therapy (t0, t1, t2) and a one-month follow up examination (t3). At each time point we measured objective signs of VVA via VHI (Vaginal Health Index) and VuHI (Vulvar Health Index) and subjective parameters (Dryness, Burning, Itching, Dysuria) via visual analog scales (VAS). In sexually active women we evaluated the sexual function with FSFI (Female Sexual Function Index), FSDS (Female Sexual Distress Score) scores and MENQOL (menopause quality of life questionnaire). RESULTS: We enrolled 26 BCS. The mean VHI, VuVHI, dryness and burning VAS scores improved significantly and this improvement was not influenced by the initial VVA grade. MENQOL sexual domain, Lubrication, Orgasm and Pain domains and FSFI total score improved significantly, while Desire, Arousal and Satisfaction domains of FSFI and FSDS did not. At t0 women using Aromatase Inhibitors suffered more severe vaginal dryness than women using Tamoxifen or no therapy, but the three subgroups improved without differences. No adverse event and minimum discomfort were reported. CONCLUSIONS: The non-ablative CO2 laser is a safe and effective treatment of VVA and has positive effects on sexual function in BCS regardless the use of adjuvant therapies and the initial grade of VVA.

Inducing cancer indolence by targeting mitochondrial Complex I is potentiated by blocking macrophage-mediated adaptive responses.

Converting carcinomas in benign oncocytomas has been suggested as a potential anti-cancer strategy. One of the oncocytoma hallmarks is the lack of respiratory complex I (CI). Here we use genetic ablation of this enzyme to induce indolence in two cancer types, and show this is reversed by allowing the stabilization of Hypoxia Inducible Factor-1 alpha (HIF-1α). We further show that on the long run CI-deficient tumors re-adapt to their inability to respond to hypoxia, concordantly with the persistence of human oncocytomas. We demonstrate that CI-deficient tumors survive and carry out angiogenesis, despite their inability to stabilize HIF-1α. Such adaptive response is mediated by tumor associated macrophages, whose blockage improves the effect of CI ablation. Additionally, the simultaneous pharmacological inhibition of CI function through metformin and macrophage infiltration through PLX-3397 impairs tumor growth in vivo in a synergistic manner, setting the basis for an efficient combinatorial adjuvant therapy in clinical trials.

Reversal of liver fibrosis by the antagonism of endocannabinoid CB1 receptor in a rat model of CCl(4)-induced advanced cirrhosis.

The endocannabinoid system is involved in the pathogenesis of liver fibrosis. Although many substances have been proved to reduce fibrosis in experimental models of chronic liver injury, most of them appear to be effective only if given as a prophylactic or early treatment. This study aimed to explore the effect of pharmacological antagonism of the endocannabinoid cannabinoid type 1 (CB1) receptor started after the stage of full-blown cirrhosis had been reached. Wistar-Han rats with carbon tetrachloride (CCl(4))-induced cirrhosis were randomized to receive the CB1 receptor antagonist Rimonabant (10 mg/kg/day) or the vehicle for 2 weeks. Age-matched healthy rats served as controls. Liver fibrosis was assessed using Sirius red staining, hydroxyproline concentration and α-smooth muscle actin expression. Hepatic gene expression of mediators of fibrogenesis and inflammation were evaluated by real-time PCR. We also assessed the hepatic expression of CB1 and CB2 receptors and that of the enzymes implicated in the endocannabinoid metabolism. Fibrosis was significantly reduced in rats treated with Rimonabant compared with rats receiving the vehicle. CB1 receptor antagonism limited the gene upregulation of fibrogenic and inflammatory mediators occurring in untreated cirrhotic rats. CB1 and CB2 receptor expression was increased in cirrhotic animals. Interestingly, pharmacological CB1 receptor antagonism was associated with a further induction of the CB2 receptor expression. Regression of fibrosis can be achieved by pharmacological blockade of the CB1 receptor even when started in an advanced stage of the disease. This effect is associated with the suppression of pro-fibrogenic and inflammatory mediators and may have been indirectly favoured by the induction of CB2 receptor expression.