Therapeutic Monitoring of Palbociclib, Ribociclib, Abemaciclib, M2, M20, and Letrozole in Human Plasma: A Novel LC-MS/MS Method.

BACKGROUND: Therapeutic drug monitoring (TDM) using cyclin-dependent kinase inhibitors (CDK4/6is) is a novel approach for optimizing treatment outcomes. Currently, palbociclib, ribociclib, and abemaciclib are the available CDK4/6is and are primarily coadministered with letrozole. This study aimed to develop and validate an LC-MS/MS method for the simultaneous analysis of CDK4/6is, 2 active metabolites of abemaciclib (M2 and M20), and letrozole in human plasma for use in TDM studies. METHODS: Sample pretreatment comprised protein precipitation with methanol and dilution of the supernatant with an aqueous mobile phase. Chromatographic separation was achieved using a reversed-phase XBridge BEH C18 column (2.5 µm, 3.0 × 75 mm XP), with methanol serving as the organic mobile phase and pyrrolidine-pyrrolidinium formate (0.005:0.005 mol/L) buffer (pH 11.3) as the aqueous mobile phase. A triple quadrupole mass spectrometer was used for the detection, with the ESI source switched from negative to positive ionization mode and the acquisition performed in multiple reaction monitoring mode. RESULTS: The complete validation procedure was successfully performed in accordance with the latest regulatory guidelines. The following analytical ranges (ng/mL) were established for the tested compounds: 6-300, palbociclib and letrozole; 120-6000, ribociclib; 40-800, abemaciclib; and 20-400, M2 and M20. All results met the acceptance criteria for linearity, accuracy, precision, selectivity, sensitivity, matrix effects, and carryover. A total of 85 patient samples were analyzed, and all measured concentrations were within the validated ranges. The percent difference for the reanalyzed samples ranged from -11.2% to 7.0%. CONCLUSIONS: A simple and robust LC-MS/MS method was successfully validated for the simultaneous quantification of CDK4/6is, M2, M20, and letrozole in human plasma. The assay was found to be suitable for measuring steady-state trough concentrations of the analytes in patient samples.

Pharmacoutilization and adherence to sacubitril/valsartan in real world: the REAL.IT study in HFrEF.

AIMS: The current European Society of Cardiology (ESC) guidelines provide clear indications for the treatment of acute and chronic heart failure (HF). Nevertheless, there is a constant need for real-world evidence regarding the effectiveness, adherence, and persistence of drug therapy. We investigated the use of sacubitril/valsartan for the treatment of HF with reduced ejection fraction in real-world clinical practice in Italy. METHODS AND RESULTS: An observational, retrospective, non-interventional cohort study based on electronic medical records from nine specialized hospital HF centres in Italy was carried out on patients with prescription of sacubitril/valsartan. Overall, 948 patients had a prescription of sacubitril/valsartan, with 924 characterized over 6 months and followed up for 12 months. Pharmacoutilization data at 1 year of follow-up were available for 225 patients {mean age 69.7 years [standard deviation (SD) = 10.8], 81.8% male}. Of those, 398 (45.2%) reached the target dose of sacubitril/valsartan of 97/103 mg in a mean time of 6.9 (SD = 6.2) weeks. Blood pressure and hypotension in 61 patients (65%) and worsening of chronic kidney disease in 10 patients (10.6%) were the main reasons for not reaching the target dose. Approximatively 50% of patients had a change in sacubitril/valsartan dose during follow-up, and 158 (70.2%) were persistent with the treatment during the last 3 months of follow-up. A sensitivity analysis (persistence during the last 4 months of follow-up) showed persistence for 162 patients (72.0%). Adherence data, available for 387 patients, showed full adherence for 205 (53%). Discontinuation (102/717 patients, 14.2%) was mainly due to hypotension and occurred after a mean time of 34.3 (SD = 28.7) weeks. During follow-up, out of 606 patients with available data, 434 patients (71.6%) had an HF add-on drug or drugs concomitant with sacubitril/valsartan. HF-related hospitalization during follow-up was numerically higher in non-persistent (16/67 patients, 23.9%) vs. patients persistent to sacubitril/valsartan (30/158, 19%) (P = 0.405). CONCLUSIONS: Real-world data on the use of sacubitril/valsartan in clinical practice in Italy show a rapid titration to the target dose, high therapeutic adherence enabling a good level of therapeutic management in line with ESC guidelines for patients with reduced ejection fraction.

Implementation of pre-emptive testing of a pharmacogenomic panel in clinical practice: Where do we stand?

Adverse drug reactions (ADRs) account for a large proportion of hospitalizations among adults and are more common in multimorbid patients, worsening clinical outcomes and burdening healthcare resources. Over the past decade, pharmacogenomics has been developed as a practical tool for optimizing treatment outcomes by mitigating the risk of ADRs. Some single-gene reactive tests are already used in clinical practice, including the DPYD test for fluoropyrimidines, which demonstrates how integrating pharmacogenomic data into routine care can improve patient safety in a cost-effective manner. The evolution from reactive single-gene testing to comprehensive pre-emptive genotyping panels holds great potential for refining drug prescribing practices. Several implementation projects have been conducted to test the feasibility of applying different genetic panels in clinical practice. Recently, the results of a large prospective randomized trial in Europe (the PREPARE study by Ubiquitous Pharmacogenomics consortium) have provided the first evidence that prospective application of a pre-emptive pharmacogenomic test panel in clinical practice, in seven European healthcare systems, is feasible and yielded a 30% reduction in the risk of developing clinically relevant toxicities. Nevertheless, some important questions remain unanswered and will hopefully be addressed by future dedicated studies. These issues include the cost-effectiveness of applying a pre-emptive genotyping panel, the role of multiple co-medications, the transferability of currently tested pharmacogenetic guidelines among patients of non-European origin and the impact of rare pharmacogenetic variants that are not detected by currently used genotyping approaches.

Association of ADME gene polymorphisms on toxicity to CDK4/6 inhibitors in patients with HR+ HER2- metastatic breast cancer.

A wide interindividual variability in therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) palbociclib, ribociclib and abemaciclib, among patients with HR+/HER2- metastatic breast cancer has been reported. This study explored the impact of genetic polymorphisms in ADME genes (responsible for drug absorption, distribution, metabolism, and elimination) on CDKis safety profiles in 230 patients. Selected endpoints include grade 3/4 neutropenia at day 14 of the first treatment cycle, early dose-limiting toxicities (DLTs), and dose reductions within the initial three cycles. Our analysis revealed associations between these endpoints and polymorphisms in CYP3A4, CYP3A5, ABCB1, and ABCG2 genes. Their impact on CDKis plasma concentrations (Ctrough) was also examined. Specifically, ABCB1 c.1236C>T and c.2677C>T polymorphisms correlated significantly with grade 3/4 neutropenia at day 14 (OR 3.94, 95% CI 1.32-11.75; p = 0.014 and OR 3.32, 95% CI 1.12-9.85; p = 0.030). Additionally, ABCB1 c.3435C>T was associated with an elevated risk of early DLTs and dose reductions (OR 3.28, 95% CI 1.22-8.84, p = 0.019; OR 2.60, 95% CI 1.20-5.60, p = 0.015). Carriers of the CYP3A4*22 allele also demonstrated in univariate a higher risk of early DLTs (OR 3.10, 95% CI 1.01-9.56, p = 0.049). Furthermore, individuals with the ABCB1 1236T-3435T-2677T(A) variant haplotype exhibited significant associations with grade 3/4 neutropenia at day 14 (OR 3.36, 95% CI 1.20-9.41; p = 0.021) and early DLTs in univariate (OR 3.08, 95% CI 1.19-7.95; p = 0.020). Homozygous carriers of the ABCB1 T-T-T(A) haplotype tended to have a higher mean ribociclib Ctrough (934.0 ng/mL vs. 752.0 ng/mL and 668.0 ng/mL). Regardless preliminary, these findings offer promising insights into the role of pharmacogenetic markers in CDKis safety profiles, potentially contributing to address the interindividual variability in CDKis responses.

Clinical impact of body mass index on palbociclib treatment outcomes and effect on exposure.

The impact of body mass index (BMI) on treatment outcomes in patients with cancer is gaining increasing attention given the limited data available. The aim of this study was to investigate the contribution of BMI on the safety and efficacy profile of palbociclib in 134 patients with metastatic luminal-like breast cancer treated with palbociclib and endocrine therapy (ET). Normal-weight and underweight patients (BMI<25) were compared with overweight and obese (BMI≥25). Detailed clinical and demographic data were collected. Patients with a BMI<25 had a higher incidence of relevant-hematologic toxicities (p = 0.001), dose reduction events (p = 0.003), and tolerated lower dose intensities (p = 0.023) compared to patients with a BMI≥25. In addition, patients with a BMI<25 had significantly shorter progression-free survival (log-rank p = 0.0332). A significant difference was observed in the subgroup of patients for whom systemic palbociclib concentrations were available: patients with a BMI<25 had a 25% higher median minimum plasma concentrations (Cmin) compared to BMI≥25. This study provides compelling evidence for a clinically relevant contribution of BMI in discriminating a group of patients who experienced multiple toxicities that appeared to affect treatment adherence and lead to poorer survival. BMI could become a valuable tool for personalizing the starting dose of palbociclib to improve its safety and efficacy.

Sacubitril/Valsartan in Heart Failure with Reduced Ejection Fraction: Real-World Experience from Italy (the REAL.IT Study).

Sacubitril/valsartan reduces heart failure (HF)-related hospitalizations and cardiovascular mortality in PARADIGM-HF and has become a foundational treatment for HF with reduced ejection fraction (HFrEF). However, data of its routine real-world use are limited, and evidence from Italian settings is lacking. The REAL.IT study aimed to characterize the demographics, pharmacotherapy, clinical characteristics and outcomes of sacubitril/valsartan-treated Italian patients with HFrEF. Electronic medical records of patients initiating sacubitril/valsartan from October 2016 to June 2019 at nine specialized hospital outpatient HF centers across Italy were reviewed. Overall, 924 adults (mean age 64.5 years, 84.6% male) were included. At baseline, 38.7% had an ischemic HF etiology, 45.9% hypertension, 23.2% atrial fibrillation, 25.4% diabetes mellitus, 26.1% an implantable cardioverter-defibrillator and 31.9% coronary artery bypass grafting. There were no clear patterns of patient selection over time. During follow-up, NYHA class improved in 37.5% of patients after a mean of 5.3 ± 3.8 months; 36.1% and 16.7% of patients were in NYHA class III during characterization and after one year of follow-up, respectively. Left ventricular ejection fraction (LVEF) improved ≥5% in 56.3% of patients at one year; 39.7% had ≥30% reduction of N-terminal pro-B-type natriuretic peptide; 2.2% had hyperkalemia during characterization and 2.6% during follow-up; and 3.8% had hypotension during characterization and 12% during follow-up. A total of 50 (5.8%) of patients had device implantation (ICD/CRT) during follow-up. HF-related hospitalization was recorded in 19.6% of patients during follow-up; 3.8% of patients died, approximately 1.3% from cardiovascular causes. Our real-world data confirm the favorable effectiveness and tolerability of sacubitril/valsartan observed in pivotal randomized controlled trials.

An Integrated Pharmacological Counselling Approach to Guide Decision-Making in the Treatment with CDK4/6 Inhibitors for Metastatic Breast Cancer.

A wide inter-individual variability in the therapeutic response to cyclin-dependent kinases 4 and 6 inhibitors (CDKis) has been reported. We herein present a case series of five patients treated with either palbociclib or ribociclib referred to our clinical pharmacological counselling, including therapeutic drug monitoring (TDM), pharmacogenetics, and drug-drug interaction analysis to support clinicians in the management of CDKis treatment for metastatic breast cancer. Patients' plasma samples for TDM analysis were collected at steady state and analyzed by an LC-MS/MS method for minimum plasma concentration (Cmin) evaluation. Under and overexposure to the drug were defined based on the mean Cmin values observed in population pharmacokinetic studies. Polymorphisms in selected genes encoding for proteins involved in drug absorption, distribution, metabolism, and elimination were analyzed (CYP3A4, CYP3A5, ABCB1, SLCO1B1, and ABCG2). Three of the five reported cases presented a CDKi plasma level above the population mean value and were referred for toxicity. One of them presented a low function ABCB1 haplotype (ABCB1-rs1128503, rs1045642, and rs2032582), possibly causative of both increased drug oral absorption and plasmatic concentration. Two patients showed underexposure to CDKis, and one of them was referred for early progression. In one patient, a CYP3A5*1/*3 genotype was found to be potentially responsible for more efficient drug metabolism and lower drug plasma concentration. This intensified pharmacological approach in clinical practice has been shown to be potentially effective in supporting prescribing oncologists with dose and drug selection and could be ultimately useful for increasing both the safety and efficacy profiles of CDKi treatment.

Effectiveness of anti-vascular endothelial growth factors in neovascular age-related macular degeneration and variables associated with visual acuity outcomes: Results from the EAGLE study.

OBJECTIVE: To assess the overall effectiveness of anti-vascular endothelial growth factor (VEGF) therapy in treatment-naïve patients with neovascular age-related macular degeneration (nAMD) in a clinical practice setting. STUDY DESIGN: EAGLE was a retrospective, 2-year, cohort observational, multicenter study conducted in Italy that analyzed secondary data of treatment-naïve patients with nAMD. The primary endpoint evaluated the mean annualized number of anti-VEGF injections at Years 1 and 2. The main secondary endpoints analyzed the mean change in visual acuity (VA) from baseline and variables associated with visual outcomes at Years 1 and 2. RESULTS: Of the 752 patients enrolled, 745 (99.07%) received the first dose of anti-VEGF in 2016. Overall, 429 (57.05%) and 335 (44.5%) patients completed the 1- and 2-year follow-ups, respectively. At baseline, mean (standard deviation, SD) age was 75.6 (8.8) years and the mean (SD) VA was 53.43 (22.8) letters. The mean (SD) number of injections performed over the 2 years was 8.2 (4.1) resulting in a mean (SD) change in VA of 2.45 (19.36) (P = 0.0005) letters at Year 1 and -1.34 (20.85) (P = 0.3984) letters at Year 2. Linear regression models showed that age, baseline VA, number of injections, and early fluid resolution were the variables independently associated with visual outcomes at Years 1 and 2. CONCLUSIONS: The EAGLE study analyzed the routine clinical practice management of patients with nAMD in Italy. The study suggested that visual outcomes in clinical practice may be improved with earlier diagnosis, higher number of injections, and accurate fluid resolution targeting during treatment induction.

Safety and tolerability of ranibizumab in uni/bilateral neovascular age-related macular degeneration: 12-month TWEYEs study.

BACKGROUND: To evaluate the safety and tolerability of ranibizumab 0.5 mg in patients with uni/bilateral neovascular age-related macular degeneration (nAMD) and best-corrected visual acuity (BCVA)<2/10 and/or second eye affected, regardless of BCVA. METHODS: In this 12-month, prospective, multicentre, open-label, single arm, pragmatic interventional study, patients (N=941) aged ≥ 50 years were to receive ranibizumab as per approved label, monthly until maximum stable visual acuity (VA) was achieved (initially, three or more injections may be required). Thereafter, patients were to be monitored monthly for VA and treatment was to be resumed if VA was reduced due to disease activity. RESULTS: Of the 936 patients treated with ranibizumab at least once during the study, 823/113 were unilaterally/bilaterally (not simultaneously) treated . The mean (SD) number of ranibizumab injections during the study was 5.4 (2.9)/10.6 (5.0) injections in uni/bilaterally treated patients. Three systemic drug-related adverse events (AEs) (all serious, all in unilaterally treated patients) and 18 systemic AE of special interest (AESIs) (11 serious, 16/2 in unilaterally/bilaterally treated patients) occurred during the study. The annual incidence rate (AIR) (events/1000 person-years) for systemic drug-related AEs, considering a 15-day/30-day risk period, 11.0/8.5 for unilaterally treated patients. Considering the same risk period, the AIR (events/1000 person-years) for systemic AESIs for unilaterally treated patients was 22.1/19.9. Considering a 30-day risk period, the AIR (events/1000 treated eye-years) of ocular drug-related AEs was 23 and AESIs was 11.5. CONCLUSIONS: The low incidence of AEs and AESIs demonstrated the good safety and tolerability of ranibizumab in unilaterally/bilaterally treated patients with nAMD in this real-world setting.

HF progression among outpatients with HF in a community setting.

BACKGROUND: Incidence and prognostic impact of heart failure (HF) progression has been not well addressed. METHODS: From 2009 until 2015, consecutive ambulatory HF patients were recruited. HF progression was defined by the presence of at least two of the following criteria: step up of ≥1 New York Heart Association (NYHA) class; decrease LVEF ≥ 10 points; association of diuretics or increase ≥ 50% of furosemide dosage, or HF hospitalization. RESULTS: 2528 met study criteria (mean age 76; 42% women). Of these, 48% had ischemic heart disease, 18% patients with LVEF ≤ 35%. During a median follow-up of 2.4 years, overall mortality was 31% (95% CI: 29%-33%), whereas rate of HF progression or death was 57% (95% CI: 55%-59%). The 4-year incidence of HF progression was 39% (95% CI: 37%-41%) whereas the competing mortality rate was 18% (95% CI: 16%-19%). Rates of HF progression and death were higher in HF patients with LVEF ≤ 35% vs >35% (HF progression: 42% vs 38%, p = 0.012; death as a competing risk: 22% vs 17%, p = 0.002). HF progression identified HF patients with a worse survival (HR = 3.16, 95% CI: 2.75-3.72). In cause-specific Cox models, age, previous HF hospitalization, chronic obstructive pulmonary disease, chronic kidney disease, anemia, sex, LVEF ≤ 35% emerged as prognostic factors of HF progression. CONCLUSIONS: Among outpatients with HF, at 4 years 39% presented a HF progression, while 18% died before any sign of HF progression. This trend was higher in patients with LVEF ≤ 35%. These findings may have implications for healthcare planning and resource allocation.

Characteristics of newly diagnosed COPD patients treated with triple inhaled therapy by general practitioners: a real world Italian study.

Factors predicting prescriptions of triple therapy were investigated in a large group of general practitioners in Italy. In the population treated by identified general practitioners, a cohort of newly diagnosed chronic obstructive pulmonary disease patients was extracted from IMS Health Longitudinal Database during the period 2010-2013. From the diagnosis, 1-year follow-up was evaluated. Thirty-two thousand forty-six newly diagnosed chronic obstructive pulmonary disease patients were evaluated (57.7% male, mean age 67 years). During 2 years prior to diagnosis less than 13% of patients were requested with a pulmonology evaluation and less than 5% with a spirometry; 65.1% cases were prescribed with a respiratory drug, which in 9.6% of cases was inhaled corticosteroid/long-acting ß2-agonist fixed-dose combination. Two thousand and twenty eight patients (6.3% of the newly diagnosed chronic obstructive pulmonary disease patients) were treated with triple therapy during the first year of follow-up, whose 858 (42.3%) starting immediately, and 762 (37.6%) following an initial treatment with inhaled corticosteroid/long-acting ß2-agonist fixed-dose combination. Being older, being requested with pulmonologist evaluation or spirometry, being prescribed with a inhaled corticosteroid/long-acting ß2-agonist fixed-dose combination at diagnosis resulted independent predictors of triple therapy use. CHRONIC LUNG DISEASE: ENSURING CORRECT PRESCRIPTIONS FOR EARLY-STAGE DISEASE: An improved education program for doctors promoting correct use of medication for chronic lung disease is needed in Italy. Current guidelines state that inhaled corticosteroids (ICSs) should be reserved for patients with severe chronic obstructive pulmonary disease (COPD), but it appears that doctors do not always follow this advice. Fabiano Di Marco, at San Paolo Hospital-Università degli Studi di Milano, and co-workers analyzed data from 32,046 COPD patients newly-diagnosed by family doctors in Italy between 2010 and 2013. When the researchers followed up on patients after 1 year, 2028 (6.3%) of newly-diagnosed patients were being treated with triple inhaled therapy incorporating ICSs-42% of these patients had started triple therapy immediately upon diagnosis. Being an older male and having been prescribed with a ICS/LABA FDC at diagnosis were strong predictors of triple therapy use within 1 year from the diagnosis.

Acute decompensated heart failure in the emergency department: Identification of early predictors of outcome.

Identification of clinical factors that can predict mortality and hospital early readmission in acute decompensated heart failure (ADHF) patients can help emergency department (ED) physician optimize the care-path and resource utilization.We conducted a retrospective observational study of 530 ADHF patients evaluated in the ED of an Italian academic hospital in 2013.Median age was 82 years, females were 55%; 31.1% of patients were discharged directly from the ED (12.5% after short staying in the observation unit), while 68.9% were admitted to a hospital ward (58.3% directly from the ED and 10.6% after a short observation). At 30 days, readmission rate was 17.7% while crude mortality rate was 9.4%; this latter was higher in patients admitted to a hospital ward in comparison to those who were discharged directly from the ED (12.6% vs. 2.4%, P < .001). Thirty-day mortality was significantly related to older age, higher triage priority, lower mean blood pressure (MBP), and lower pulse oxygen saturation (POS). At 180 days, crude mortality rate was 23.2%, higher in admitted patients compared with discharged ones (29.6% vs. 9.1%, P < .001) and was significantly related to older age, higher serum creatinine, and lower MBP and POS. At 12 and 22 months, crude mortality rates resulted 30.4% and 45.1%, respectively.Simple and objective parameters, such as age ≤82 years, MBP > 104 mm Hg, POS > 94%, may guide the ED physician to identify low-risk patients who can be safely discharged directly from the emergency room or after observation unit stay.

An observation of prescription behaviors and adherence to guidelines in patients with COPD: real world data from October 2012 to September 2014.

INTRODUCTION: GOLD guideline recommendations are currently the "gold standard" for the treatment of COPD patients. OBJECTIVES: The objective of this analysis was to evaluate compliance with GOLD guidelines in managing COPD patients' treatment by general practitioners (GPs) and pulmonologists. Since inhaled corticosteroid (ICS) use is defined as inappropriate in mild and moderate COPD patients, special attention was paid to ICS therapy use in these classes. METHODS: The study was based on the Italian GP database IMS Health Longitudinal Patient Database (IMS Health LPD) and on the Patient Analyzer specialist IMS Health database. The observed cohort included all patients with a diagnosis of COPD, aged 40 years or more, with at least one ATC R03 class prescription, visited by GPs and pulmonologists during four timeframes: October 2012 - March 2013 (cohort 1), April 2013 - September 2013 (cohort 2), October 2013 - March 2014 (cohort 3); April 2014 - September 2014 (cohort 4). Patients were classified into disease severity groups following 2008 GOLD guidelines, based on FEV1 value. RESULTS: Cohorts were quite similar in size (about two thousand patients per cohort). Pulmonologists visited more severe patients than GPs. About 50% of GPs' mild and moderate patients received treatments containing inhaled corticosteroids. Pulmonologists were more adherent to guidelines, with smaller percentages of mild patients treated with therapies containing ICS (ranging from 19.0% to 30.1%). An improvement in adherence was observed during the four time periods, with a decrease in the use of therapies containing ICS in mild and moderate patients. In absolute terms, it emerged that GPs more often prescribe ICS improperly to patients in the mild and moderate severity classes than pulmonologists. CONCLUSION: Real world data indicate that adherence to GOLD guidelines is only partially met by GPs in their general practice and shows higher prescription appropriateness by pulmonologists.

Epidemiology of Frequently Occurring Skin Diseases in Italian Children from 2006 to 2012: A Retrospective, Population-Based Study.

BACKGROUND: Recent estimates indicate an increase in the prevalence of skin diseases in children. Few large epidemiologic studies have examined prevalence trends in Europe. This study evaluated the incidence and prevalence of frequently occurring pediatric skin diseases (PSDs) in Italy as seen by family pediatricians (FPs). METHODS: Data were retrospectively extracted from the Pedianet database (2006-2012) in children ages 0 to 14 years presenting with a skin disease at their FP. The incidence and prevalence estimates were calculated per year and stratified according to sex, age, and geographic area. RESULTS: A mean of 145,233 children (52.1% male) across five Italian regions were registered with their participating FP for a total of 913,253 person-years of follow-up. The majority of patients were from the northeast (44.6%) and 37.7% were ages 5-9 years. Incidence estimates (new cases/1,000 person-years) for most PSDs increased from 2006 to 2012, the highest being for atopic dermatitis (AD) (14.1 vs 16.5), acute urticaria (10.1 vs 11.6), and contact dermatitis (9.3 vs 10.8), whereas psoriasis remained unchanged over the 7 years (0.61 vs 0.57). In contrast, prevalence estimates (cases/100 patients) increased two to three times for several PSDs, including AD (2.7% vs 8.5%), seborrheic dermatitis (0.5% vs 1.6%), chronic urticaria (0.4% vs 0.8%), and psoriasis (0.09% vs 0.22%). Differences in prevalence according to age range and geographic area were observed for psoriasis, AD, and urticaria. CONCLUSION: This study provides comprehensive evidence of the increasing prevalence and incidence of PSDs across Italy. Additional causality studies to address this important clinical and psychosocial problem are recommended.

Hepatotoxicity with low- and ultralow-dose flutamide: a surveillance study on 203 hyperandrogenic young females.

OBJECTIVE: To investigate the impact of low- and ultralow-dose regimens of flutamide on liver function of young hyperandrogenic females. DESIGN: A 10-year surveillance study. SETTING: University teaching hospital. PATIENT(S): Two hundred three hyperandrogenic young females (mean age: 20.9 ± 4.9 years). INTERVENTION(S): Inclusion criterion was receiving low- or ultralow-dose of flutamide as antiandrogenic treatment. Patients were categorized into Groups A and B, according to the administered dose (Group A = 62.5 mg/daily, Group B = 125 mg/daily). The two groups were further subdivided into subgroups (A1, A2, B1, B2) depending on the coadministration of estroprogestagen oral contraceptives (OCs) (A2, B2). MAIN OUTCOME MEASURE(S): Serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were periodically evaluated and used as markers of hepatotoxicity. RESULT(S): Mild-to-severe increase of circulating AST/ALT was detected in 19 (9.4%; 95% CI = 5.9%-14.4%) patients during the first year of treatment (mild = 16 [7.9%, 95% CI = 4.7%-12.7%], moderate = 2 [0.9%, 95% CI = 0.1%-3.9%], severe = 1 [0.5%, 95% CI = 0.0%-3.1%]). No statistical differences were observed in relation to flutamide dose regimens and coadministration of OC. The median time to hypertransaminasemia was 12 weeks (range: 2-48) with no difference between Group A and Group B. A significant correlation was observed between hepatotoxicity and pretreatment BMI, ALT basal level, and AST basal level. CONCLUSION(S): Hepatotoxicity is a rare but possible event using low- and ultralow-dose regimens of flutamide. We need larger study populations in order to identify risk patterns for hepatotoxicity development.

Davydov's procedure for the treatment of neovaginal prolapse in Rokitansky syndrome.

A 19-year-old woman with Rokitansky syndrome with neovaginal prolapse following self-dilation showed vaginal vault eversion of a 4- × 3-cm neovagina. A modified Davydov procedure was performed. No complications occurred. Vaginoscopy after 6 months showed an iodine-positive 8- × 3-cm neovagina. Functional results were assessed with the Female Sexual Function Index.

Levonorgestrel-releasing intrauterine system (LNG-IUS) as an effective treatment option for endometrial hyperplasia: a 15-year follow-up study.

The levonorgestrel-releasing intrauterine system may represent an effective treatment option in >85% of endometrial hyperplasia cases, but histologic regression during and/or at the end of treatment does not assure stable recovery. We recommend periodic endometrial samplings for at least the first 2 years of follow-up and long-term clinical surveillance thereafter.

The anorectic and obese adolescent.

In view of the menstrual disturbances involved, gynaecologists frequently come into contact with girls suffering from eating disorders that can rapidly evolve into anorexia nervosa. The ability to make a precocious diagnosis of the severity of both physical and psychopathological involvement, to offer clear explanations of the links between reproductive function and energy availability and to motivate psychotherapy can be of paramount importance for the prognosis. Similarly, obese adolescents might require counselling for menstrual disorders or alleged endocrine dysfunction. Knowledge of the markers of metabolic impairment and of the possible therapeutic approaches to essential obesity is a necessary complement to the management of the more usual conditions related to overweight, such as polycystic ovary syndrome. Presented here is an overview of recent evidence on the pathogenesis, endocrine profile, short- and long-term health repercussions, therapeutic strategies and clinical trials regarding these two opposing pathologies, both related to unhealthy eating behaviour and also to psycho-relational problems.

Levonorgestrel-releasing intrauterine system alone as primary treatment in young women with early endometrial cancer: case report.

Young women with polycystic ovary syndrome (PCOS) are at increased risk of endometrial adenocarcinoma (EAC) through chronic unopposed estrogen production. We describe the first case, to our knowledge, of grade 1 endometrioid EAC arising in the context of complex atypical endometrial hyperplasia in a 26-year-old woman with thrombophilia and PCOS who wished to retain fertility potential and was treated using a levonorgestrel-releasing intrauterine system alone. At first follow-up biopsy, a single focus of complex hyperplasia without atypia was documented. All specimens sampled during subsequent follow-up demonstrated inactive endometrium with pseudodecidual changes, and no ultrasonographic or magnetic resonance (MR) images exhibiting myometrial invasion or endoabdominal spread were observed. This successful outcome suggests that insertion of a levonorgestrel-releasing intrauterine system is a treatment option in selected young women with early-stage EAC who are not candidates for systemic therapy and who wish to maintain fertility potential. Close histologic follow-up is required, and immediate surgery is mandatory if endometrial cancer persists.

Global cardiovascular disease risk management in italian patients with metabolic syndrome in the clinical practice setting.

BACKGROUND: Metabolic syndrome is a highly prevalent condition in the Italian population. This study assesses the feasibility and efficacy of a multifactorial approach for primary prevention of cardiovascular disease risk assessment in patients with metabolic syndrome in the daily clinical practice setting. METHODS: 726 patients were enrolled (males : females = 7 : 3), their ages ranging from 26 to 70 years, with metabolic syndrome and cardiovascular death risk ≥5%, computed by means of the European Systematic COronary Risk Evaluation (SCORE) algorithm. The first phase (3 months) consisted of an improvement in lifestyle and, if necessary, the initial administration of an antihypertensive therapy (valsartan 160 mg/day for patients with blood pressure ≥140/90 mmHg and ≥130/80 mmHg for diabetic patients). During phase 2 (6 months), patients with systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg (≥130/80 mmHg for diabetic patients) were administered valsartan 160 mg/day + hydrochlorothiazide 12.5 mg/day combined; those with total cholesterol levels ≥190 mg/dL (≥175 mg/dL for diabetic patients) started treatment with fluvastatin 80 mg prolonged release (XL), as prescribed in the guidelines. A control group was approached with another conventional treatment. RESULTS: After 9 months of monitoring, the SBP dropped by 27 mmHg in the valsartan-treated patients and by 11 mmHg in the control group, while the DBP dropped by 12 mmHg in the former group and 2 mmHg in the latter. Total cholesterolaemia was reduced by 47 mg/dL in patients undergoing fluvastatin and valsartan therapy, by 19 mg/dL in those treated with valsartan only and by 33 mg/dL in those administered another conventional treatment. Relative risk reduction observed after 9 months, compared with the beginning of the study, was almost 48% in the valsartan/valsartan + fluvastatin group, versus 28% observed with the other conventional treatment. The reduction of risk at 60 years of age was an average of 39% at 3 months and 48% at 9 months, compared with the beginning of the study. Therapeutic success was accomplished with 78% of the patients treated with valsartan/valsartan + fluvastatin, compared with 47% of patients in the conventional therapy group. CONCLUSION: The present study demonstrated that the normalization of the main cardiovascular risk factors in patients with metabolic syndrome may be easily achieved in standard clinical practice settings, by leading an adequate lifestyle and, if necessary, the administration of antihypertensive and/or lipid-lowering monotherapy at the usual doses.