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Introduction In advanced basal cell carcinoma (BCC), the issue of whether Hedgehog inhibitors (HHIs) should be stopped or not after clinical complete response (cCR) achievement remains an unmet clinical need. Materials and Methods We conducted a retrospective, multicenter study across 7 Italian dermato-oncology units including patients with BCC who continued vismodegib after cCR between 2012 and 2019. We assessed the relationship between the duration of vismodegib intake (days to cCR [DTCR], days to stop after cCR [DTS], total treatment days [TTD]), and disease-free survival (DFS). Reasons to stop vismodegib were (R1) toxicity and (R2) disease recurrence. The relationship between DTCR, DTS, TTD, and DFS in the whole population and in R1 subgroup was assessed by Pearson's correlation coefficient (P  < .05) and Bayesian statistics (BF10). Results Sixty-eight BCC patients with a median (m) age of 75.5 years (39-100) were included. Most patients were male (N  = 43, 63%), without Gorlin syndrome (N  = 56, 82%) and with head and neck area as primary site (N  = 51, 75%). After cCR, out of 68 patients, 90% (N = 61/68) discontinued vismodegib: 82% (N  = 50/61) due to toxicity (R1), and 18% (N  = 11/61) due to recurrence (R2). Conversely, 10% (N  = 7/68) continued vismodegib until last follow-up. In the whole population (N  = 68), cCR was achieved with a mDTCR of 180.50 days. DFS showed a significant correlation with DTS (P  < .01, BF10 = 39.2) and TTD (P  < .01, BF10 = 35566), while it was not correlated to DTCR (BF10 < 0.1). The analysis of R1 subgroup (N  = 50) confirmed these results. DFS correlated with DTS in all recurrent patients (N  = 38, r  = 0.44, P  < .01) and in the recurrent patients who stopped vismodegib for toxicity (N  = 26, r  = 0.665, P  < .01). DFS was longer when vismodegib was maintained for >2 months after cCR (mDFS > 2 months, N  = 54 vs. ≤ 2 months, N  = 14: 470 vs. 175 d, P  < .01). Conclusions Our retrospective results suggest that HHIs should be continued after cCR to improve DFS in BCC. [ABSTRACT FROM AUTHOR]

Objectives: To investigate resistance-associated substitutions (RASs) as well as retreatment efficacies in a large cohort of European patients with failure of glecaprevir/pibrentasvir.Methods: Patients were identified from three European Resistance Reference centres in Spain, Italy and Germany. Sequencing of NS3, NS5A and NS5B was conducted and substitutions associated with resistance to direct antiviral agents were analysed. Clinical and virological parameters were documented retrospectively and retreatment efficacies were evaluated.Results: We evaluated 90 glecaprevir/pibrentasvir failures [3a (n = 36), 1a (n = 23), 2a/2c (n = 20), 1b (n = 10) and 4d (n = 1)]. Ten patients were cirrhotic, two had previous exposure to PEG-interferon and seven were coinfected with HIV; 80 had been treated for 8 weeks. Overall, 31 patients (34.4%) failed glecaprevir/pibrentasvir without any NS3 or NS5A RASs, 62.4% (53/85) showed RASs in NS5A, 15.6% (13/83) in NS3 and 10% (9/90) in both NS5A and NS3. Infection with HCV genotypes 1a and 3a was associated with a higher prevalence of NS5A RASs. Patients harbouring two (n = 34) or more (n = 8) RASs in NS5A were frequent. Retreatment was initiated in 56 patients, almost all (n = 52) with sofosbuvir/velpatasvir/voxilaprevir. The overall sustained virological response rate was 97.8% in patients with end-of-follow-up data available.Conclusions: One-third of patients failed glecaprevir/pibrentasvir without resistance. RASs in NS5A were more prevalent than in NS3 and were frequently observed as dual and triple combination patterns, with a high impact on NS5A inhibitor activity, particularly in genotypes 1a and 3a. Retreatment of glecaprevir/pibrentasvir failures with sofosbuvir/velpatasvir/voxilaprevir achieved viral suppression across all genotypes. [ABSTRACT FROM AUTHOR]

The WHO estimates that more than 185 million people are infected with hepatitis C virus (HCV) worldwide. The aim of the study is to assess the incremental cost-effectiveness ratio (ICER) of the use of daclatasvir (DCV) + sofosbuvir (SOF) + ribavirin (RBV) for 12 and 16 weeks vs SOF + RBV for 16 and 24 weeks for the treatment of genotype 3 HCV infected cirrhotic patients from the Italian National Health Service (NHS) perspective. A published cohort-based Markov model was used to perform the analysis estimating the lifetime direct medical costs associated with the management of the pathology and the quality adjusted life years gained by patients. Deterministic and probabilistic sensitivity analyses were performed to test the robustness of the results. SOF + RBV for 16 weeks was excluded from the analysis due to the significant lower effectiveness, compared with SOF + RBV for 24 weeks (51% vs 79%). DCV + SOF + RBV would increase QALYs and costs in all the comparisons: the ICERs obtained comparing DCV + SOF + RBV for 12 and 16 weeks with SOF + RBV for 24 weeks (reference scenario) are 38,572 €/QALY and 16,436 €/QALY, respectively, both below the 40,000 €/QALY threshold identified by the Italian Health Economics Association. Sensitivity analyses confirmed the robustness of the results. The use of DCV + SOF + RBV is likely to be cost-effective compared with SOF + RBV (for 24 weeks) for the treatment of cirrhotic patients infected with genotype 3 HCV considering a threshold value of 40,000 €/QALY. [ABSTRACT FROM AUTHOR]

Four long-chain, linear fatty acid dopamides (N-acyldopamines) have been identified in nervous bovine and rat tissues. Two unsaturated members of this family of lipids, N-arachidonoyl-dopamine (NADA) and N-oleoyl-dopamine, were shown to potently activate the transient receptor potential channel type V1 (TRPV1), also known as the vanilloid receptor type 1 for capsaicin. However, the other two congeners, N-palmitoyl- and N-stearoyl-dopamine (PALDA and STEARDA), are inactive on TRPV1. We have investigated here the possibility that the two compounds act by enhancing the effect of NADA on TRPV1 ('entourage' effect). When pre-incubated for 5 min with cells, both compounds dose-dependently enhanced NADA's TRPV1-mediated effect on intracellular Ca(2+) in human embryonic kidney cells overexpressing the human TRPV1. In the presence of either PALDA or STEARDA (0.1-10 microm), the EC(50) of NADA was lowered from approximately 90 to approximately 30 nm. The effect on intracellular Ca(2+) by another endovanilloid, N-arachidonoyl-ethanolamine (anandamide, 50 nm), was also enhanced dose-dependently by both PALDA and STEARDA. PALDA and STEARDA also acted in synergy with low pH (6.0-6.7) to enhance intracellular Ca(2+) via TRPV1. When co-injected with NADA (0.5 micrograms) in rat hind paws, STEARDA (5 micrograms) potentiated NADA's TRPV1-mediated nociceptive effect by significantly shortening the withdrawal latencies from a radiant heat source. STEARDA (1 and 10 micrograms) also enhanced the nocifensive behavior induced by carrageenan in a typical test of inflammatory pain. These data indicate that, despite their inactivity per se on TRPV1, PALDA and STEARDA may play a role as 'entourage' compounds on chemicophysical agents that interact with these receptors, with possible implications in inflammatory and neuropathic pain. [ABSTRACT FROM AUTHOR]

Background: Fibromyalgia syndrome is a chronic multifaceted disease characterized by widespread pain, muscle stiffness, fatigue, unrefreshing sleep and cognitive disorders. To date, no medication has been shown to significantly improve pain, associated symptoms and Quality of Life in fibromyalgic patients., Methods: In this retrospective observational study, we analyzed data regarding 407 patients with diagnosis of fibromyalgia syndrome who between 2013 and 2016 have been prescribed orally ultramicronized palmitoylethanolamide tablets (Normast® Epitech Group SpA, Saccolongo, Italy) regardless of the concomitant pharmacological therapy (add-on treatment)., Results: Regarding efficacy, in the 359 analyzed patients, the change over time in Visual Analogue Scale pain score was statistically significant, ranging from 75.84 (±15.15) to 52.49 (±16.73) (p<0.001). Regarding quality of life, the change over time in Fibromyalgia Impact Questionnaire score was statistically significant, ranging from 68.4 (±14.1) to 49.1 (±19.6) (p<0.001). In the treated population, only 36 patients (13,7%) reported Adverse Events predominantly of gastrointestinal type (diarrhea, dyspepsia, bloating, constipation, vomiting). Globally, 151 patients (57,63%) left the treatment due to inefficacy., Conclusion: The results of ultramicronized palmitoylethanolamide treatment in this retrospective analysis represent an important step for the development of a new and well-tolerated therapy for fibromyalgia syndrome, mostly suitable for these patients who need long-term treatments. Further methodologically stronger studies will be necessary to validate our observation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Study Objective: To evaluate the effectiveness and safety of the combination of N-palmitoylethanolamine (PEA) and transpolydatin vs placebo in the treatment of primary dysmenorrhea in adolescents and young women., Design, Setting, and Participants: Randomized treatment and follow-up of 220 cases of primary dysmenorrhea in the Department of Medicine and Health Sciences, Institute of Gynecology and Obstetrics, University of Molise, Italy., Methods: Between February 2013 and February 2014, we treated 220 young women aged 16 to 24 years who had primary dysmenorrhea: 110 patients were treated with the oral combination of PEA-transpolydatin: 400 mg + 40 mg (1 tablet a day for 10 days from the 24th day of cycle) and 110 patients with placebo (1 tablet a day for 10 days from the 24th day of cycle). A follow-up was performed after treatment, and all girls were seen at this time. A 10-point visual analog scale was used to measure the improvement of pelvic pain. For categorical variables, the χ(2) test and analysis of variance were performed to value the significance of differences between groups. A value of P < .05 was considered statistically significant., Results: An improvement of pelvic pain was seen in 98.18% (95% confidence interval 97.64% to 98.60%) of cases in group 1 vs 56.36% (95% confidence interval 48.62% to 63.81%) in group 2 (P < .001). The combination of PEA and transpolydatin was more effective than placebo (P < .001)., Conclusion: The combination of PEA and transpolydatin shows promise as a valid adjuvant therapy in the medical treatment of primary dysmenorrhea in adolescents and young women., (Copyright © 2015 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Animal data suggest that dietary fat composition may influence endocannabinoid (EC) response and dietary behavior. This study tested the hypothesis that fatty acid composition of a meal can influence the short-term response of ECs and subsequent energy intake in humans. Fifteen volunteers on three occasions were randomly offered a meal containing 30 g of bread and 30 mL of one of three selected oils: sunflower oil (SO), high oleic sunflower oil (HOSO) and virgin olive oil (VOO). Plasma EC concentrations and appetite ratings over 2 h and energy intake over 24 h following the experimental meal were measured. Results showed that after HOSO and VOO consumption the circulating oleoylethanolamide (OEA) was significantly higher than after SO consumption; a concomitantly significant reduction of energy intake was found. For the first time the oleic acid content of a meal was demonstrated to increase the post-prandial response of circulating OEA and to reduce energy intake at subsequent meals in humans.

Background/aims: Endocannabinoids include anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Endocannabinoid-related molecules like oleoyl-ethanolamine (OEA) and palmitoyl-ethanolamine (PEA) have also been identified. AEA contributes to the pathogenesis of cardiovascular alterations in experimental cirrhosis, but data on the endocannabinoid system in human cirrhosis are lacking. Thus, we aimed to assess whether circulating and hepatic endocannabinoids are upregulated in cirrhotic patients and whether their levels correlate with systemic haemodynamics and liver function., Methods: The endocannabinoid levels were measured in peripheral and hepatic veins and liver tissue by isotope-dilution liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry. Systemic haemodynamics were assessed by the transthoracic electrical bioimpedance technique. Portal pressure was evaluated by hepatic venous pressure gradient., Results: Circulating AEA and, to a greater extent, PEA and OEA were significantly higher in cirrhotic patients than in controls. PEA and OEA were also increased in the cirrhotic liver tissue. AEA, OEA and PEA levels were significantly higher in peripheral than in the hepatic veins of cirrhotic patients, while the opposite occurred for 2-AG. Finally, circulating AEA, OEA and PEA correlated with parameters of liver function, such as serum bilirubin and international normalized ratio. No correlations were found with systemic haemodynamics., Conclusions: The endocannabinoid system is upregulated in human cirrhosis. Peripheral AEA is increased in patients with a high model of end-stage liver disease score and may reflect the extent of liver dysfunction. In contrast, the 2-AG levels, the other major endocannabinoid, are not affected by cirrhosis. The upregulation of the endocannabinoid-related molecules, OEA and PEA, is even greater than that of AEA, prompting pharmacological studies on these compounds.

Objective: Glaucoma is generally managed by decreasing the intraocular pressure (IOP) to a level believed to prevent further damage to the optic disc and loss of visual field. This may be achieved medically or surgically. The objective of this pharmacoeconomic analysis was to investigate the 4-year costs of bimatoprost 0.03% (Lumigan) eye drops as an alternative to filtration surgery (FS) for glaucoma patients on maximum tolerable medical therapy (MTMT)., Research Design and Method: A Markov model was designed using effectiveness and resource use data from a randomized clinical trial and expert statements (Delphi panel). The RCT covered 83 patients on MTMT. The Model compared bimatoprost with FS. In the bimatoprost model arm patients began treatment with bimatoprost. If target IOP (-20%) was not reached using medical therapy the patient proceeded with FS. In the FS model arm, FS was performed after the first ophthalmologist visit. Unit costs were obtained from an Italian chart and tariffs review (healthcare sector perspective)., Results: The RCT showed that 74.7% of the patients delayed the need for FS by 3 months. The Markov model forecasted that 64.2% of the patients could delay the need for FS by 1 year, and forecasted 34.0% could avoid FS after 4 years. The 4-year cost per patient in the bimatoprost and FS arms was E3438 and E4194, respectively (incremental costs of E755). The major cost drivers for the bimatoprost arm were patients who needed combination therapy or FS if the target IOP was not reached. In the FS arm, the major cost drives were the initial surgery costs and pressure-lowering medications used as add-on therapy after FS., Conclusions: The analysis shows that in a 4-year perspective bimatoprost is cheaper compared to FS. In addition, the postponement of FS associated with bimatoprost may have important implications for waiting list planning.