Project description:Preclinical studies indicate that the enzyme cyclooxygenase 2 plays an important role in ultraviolet-induced skin cancers. We evaluated the efficacy and safety of celecoxib, a cyclooxygenase 2 inhibitor, as a chemopreventive agent for actinic keratoses, the premalignant precursor of nonmelanoma skin cancers, and for nonmelanoma skin cancers, including cutaneous squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs).A double-blind placebo-controlled randomized trial involving 240 subjects aged 37-87 years with 10-40 actinic keratoses was conducted at eight US academic medical centers. Patients were randomly assigned to receive 200 mg of celecoxib or placebo administered orally twice daily for 9 months. Subjects were evaluated at 3, 6, 9 (ie, completion of treatment), and 11 months after randomization. The primary endpoint was the number of new actinic keratoses at the 9-month visit as a percentage of the number at the time of randomization. In an intent-to-treat analysis, the incidence of actinic keratoses was compared between the two groups using t tests. In exploratory analyses, we evaluated the number of nonmelanoma skin cancers combined and SCCs and BCCs separately per patient at 11 months after randomization using Poisson regression, after adjustment for patient characteristics and time on study. The numbers of adverse events in the two treatment arms were compared using ?(2) or Fisher exact tests. All statistical tests were two-sided.There was no difference in the incidence of actinic keratoses between the two groups at 9 months after randomization. However, at 11 months after randomization, there were fewer nonmelanoma skin cancers in the celecoxib arm than in the placebo arm (mean cumulative tumor number per patient 0.14 vs 0.35; rate ratio [RR] = .43, 95% confidence interval [CI] = 0.24 to 0.75; P = .003). After adjusting for age, sex, Fitzpatrick skin type, history of actinic keratosis at randomization, nonmelanoma skin cancer history, and patient time on study, the number of nonmelanoma skin cancers was lower in the celecoxib arm than in the placebo arm (RR = 0.41, 95% CI = 0.23 to 0.72, P = .002) as were the numbers of BCCs (RR = 0.40, 95% CI = 0.18 to 0.93, P = .032) and SCCs (RR = 0.42, 95% CI = 0.19 to 0.93, P = .032). Serious and cardiovascular adverse events were similar in the two groups.Celecoxib may be effective for prevention of SCCs and BCCs in individuals who have extensive actinic damage and are at high risk for development of nonmelanoma skin cancers.

Project description:Background and rationale: EGFR represents the main and more studied signal activation pathway in the development of colorectal carcinoma. KRAS, NRAS, BRAF and PI3KA mutations and ERBB2 and MET amplification are responsible for most of the cases of primary resistance to anti-EGFR antibody treatments. Despite the identification of these resistance mechanisms, a primary resistance to the therapy was detected in a certain percentage of cases, in which tumour bio-molecular characteristics would suggest a possible response to anti-EGFR antibody treatment. In these cases, pathway activation mechanisms should exist, which act in an alternative, complementary or parallel way than the EGFR one, allowing tumour progression despite of EGFR pharmacological deactivation. Skin toxicity is a characteristic of drugs having EGFR as a target and it shows itself mainly as a sterile acneiform folliculitis together with neutrophils perifollicular infiltrates but also as skin xerosis and paronychia starting from the earliest cycles of treatment. This skin toxicity seems to be closely related to EGFR activation of pro-inflammatory cytokines able to activate specific inflammatory activators, which induce neutrophils granulocytes chemotaxis. Lycopene is a compound belonging to carotenoid group, largely contained in tomatoes and their derivatives, which has an extreme antioxidant activity. In Dermatology, prolonged use of β-carotenoids in general and of lycopene in particular in the diet showed to be effective in skin protection from ageing, sunlight and radiotherapy damages because these compounds may accumulate in skin and thus contribute to reduce free radicals and inflammation effects. Moreover, lycopene ability to induce apoptosis and to inhibit cell cycle progression in some types of tumour cells, both in vitro and in vivo, has already been described. Lycopene seems to be able to suppress significantly PCNA (Proliferating cell nuclear antigen, cofactor of DNA polymerase-β) and β-catenin nuclear expression in neoplastic cells, essential substrate of WNT/β-catenin pathway, which is itself closely connected to activating pathways often involved in carcinogenesis of some kinds of tumours, in particular of colorectal carcinoma, like Akt/GSK3β/β-catenin and Hippo pathways. For its proved skin anti-inflammatory activity as powerful free radicals scavenger, lycopene, which accumulates itself specifically in skin, could be effective in reducing anti-EGFR drugs toxicity. Contemporary use of lycopene could have a positive effect on anti-EGFR drugs treatment effectiveness in patients with metastatic colorectal carcinoma due to its ability to interfere with pathways involved in neoplastic cells proliferation. Estimated population:100 patients (50 for each of the two groups of treatment) Study Framework: In this study, patients suffering from metastatic colorectal cancer and submitted to therapy with panitumumab would be enrolled. According to indications, panitumumab would be used: in first line combined with Folfox or Folfiri; in second line combined with Folfiri or treatments containing Irinotecan in monotherapy in any therapeutic line in patients resistant to Fluoropyrimidines, Oxaliplatin and Irinotecan or intolerant to these drugs. Standard schedules of these treatments would be used. This is a phase-II, randomized, double-blind study between experimental prophylactic treatment with Lycopene vs placebo: * Treatment A - lycopene tablets 20 mg * Treatment B - placebo tablets Patients should take orally Lycopene/placebo after dinner (to promote its absorption), starting the day before the beginning of treatment with panitumumab for the entire duration of the therapy, until progression of the disease or definitive drug suspension for toxicity. Objectives of the study Primary objective: to assess the effectiveness of lycopene versus placebo in reducing skin toxicity induced by panitumumab in patients treated for metastatic colorectal carcinoma. Secondary objective: to assess lycopene pharmacokinetics Exploratory objectives: to assess lycopene effectiveness versus placebo in increasing panitumumab effectiveness in terms of Disease Control (DC), Objective Response (OR) and Stabilisation of the Disease (SD). To assess lycopene effectiveness versus placebo in increasing panitumumab effectiveness in terms of Progression Free Survival (PFS). As far as randomization is concerned, the two groups will be balanced according to sex, therapeutic line and institution in which patients will be treated.

Project description:BACKGROUND:Si-Wu-Tang (SWT) is used to treat various gynecological disorders in Chinese medicine. This study investigated the antioxidant and physiological effects of SWT on the skin and liver in healthy adults. METHODS:This randomized, crossover, double-blind, placebo-controlled clinical trial was conducted at Chung Shan Medical University Hospital in December 2008. Participants with uncontrolled diabetes, heart disease, liver disease, kidney disease, cancer, and pregnancy were excluded. Sixty healthy volunteers taking no medications were recruited from the community based on the results of their medical history questionnaires and biochemical analyses to confirm their health status. The participants were assigned to two groups: one group drank 125 mL of placebo (n = 30) and the other drank SWT (n = 30) for six continuous days per month for 6 months. The placebo and SWT were then switched between the groups after a 1-month washout period. Anthropometric measurements (body weight, body fat, and body mass index) were performed and fasting blood samples were drawn for various biochemical assays at 1, 3, 6, 10 and 13 months. Abdominal ultrasound and skin examinations were performed at 1, 6 and 13 months. The skin examinations involved assessment of skin roughness, sebum content, hydration, surface water loss, erythema, melanin index, and elasticity on the face (sunlight-exposed sites: middle of ear and nose) and inner arm (sunlight-unexposed sites: center of wrist and elbow joint). RESULTS:Administration of SWT significantly increased the antioxidant index (P = 0.001) and antioxidant enzymes activities (P = 0.001) from baseline to month 6. SWT also suppressed the concentration of serum lipids (triglycerides, P = 0.01; high-density lipoprotein cholesterol, P = 0.23; low-density lipoprotein cholesterol, P = 0.48) and hepatic marker enzymes (glutamic pyruvic transaminase, P = 0.76; glutamic oxaloacetic transaminase, P = 0.65) when compared with the placebo group. Abdominal ultrasound in the SWT group revealed a positive impact of SWT on mild fatty liver, gallstones, and mild splenomegaly. Moreover, SWT intake concomitantly elevated erythema (P = 0.011) and markedly lowered skin surface water loss (P = 0.016), sebum content (P = 0.021), and wrinkles (P = 0.024). CONCLUSIONS:Oral administration of SWT for 6 months improved the antioxidant level and positively regulated the lipid profile, liver function, and skin integrity and texture.

Project description:BackgroundRuxolitinib, a selective inhibitor of Janus kinase (JAK) 1 and 2, has clinically significant activity in myelofibrosis.MethodsIn this double-blind trial, we randomly assigned patients with intermediate-2 or high-risk myelofibrosis to twice-daily oral ruxolitinib (155 patients) or placebo (154 patients). The primary end point was the proportion of patients with a reduction in spleen volume of 35% or more at 24 weeks, assessed by means of magnetic resonance imaging. Secondary end points included the durability of response, changes in symptom burden (assessed by the total symptom score), and overall survival.ResultsThe primary end point was reached in 41.9% of patients in the ruxolitinib group as compared with 0.7% in the placebo group (P<0.001). A reduction in spleen volume was maintained in patients who received ruxolitinib; 67.0% of the patients with a response had the response for 48 weeks or more. There was an improvement of 50% or more in the total symptom score at 24 weeks in 45.9% of patients who received ruxolitinib as compared with 5.3% of patients who received placebo (P<0.001). Thirteen deaths occurred in the ruxolitinib group as compared with 24 deaths in the placebo group (hazard ratio, 0.50; 95% confidence interval, 0.25 to 0.98; P=0.04). The rate of discontinuation of the study drug because of adverse events was 11.0% in the ruxolitinib group and 10.6% in the placebo group. Among patients who received ruxolitinib, anemia and thrombocytopenia were the most common adverse events, but they rarely led to discontinuation of the drug (in one patient for each event). Two patients had transformation to acute myeloid leukemia; both were in the ruxolitinib group.ConclusionsRuxolitinib, as compared with placebo, provided significant clinical benefits in patients with myelofibrosis by reducing spleen size, ameliorating debilitating myelofibrosis-related symptoms, and improving overall survival. These benefits came at the cost of more frequent anemia and thrombocytopenia in the early part of the treatment period. (Funded by Incyte; COMFORT-I ClinicalTrials.gov number, NCT00952289.).

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SKIP - A Double-blind Placebo-controlled Randomized Multicenter Trial of Skin Toxicity Treatment

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