Regional Formularies in Italy: current state and future perspectives

Regional Formularies in Italy: current state and future perspectives Regional Formularies (RF) are considered part of pharmaceutical policies implemented by regions to govern access of medicines to regional market. However, they have been actually challenged, because of their presumed impact on differences of patient's access across the regions. The paper aimed at investigating the current status of RF and Regional Therapeutic Committees (CTR) and at suggesting/recommending possible reforms. The current status was investigated through a questionnaire administered to the regional pharmaceutical departments. Recommendations were retrieved from a multi -stakeholder work group carried out on 30-31 March 2023, embedded into a Forum focused on the regional pharmaceutical policies. Nineteen out of twenty-one regions responded to the survey: 12 use RF, mainly managed by the CTR; the RF frequency of update and the time needed for drugs listing greatly vary across regions; pharmacists, specialists and general practitioners are always represented in CTR, whereas other healthcare professionals and experts are more rarely involved; in 3 regions the CTR does not publish any RF update; the CTR mainly rely, to take decisions, on the dimension of the target population, the cost of therapy compared to alternative treatments and the impact on pharmaceutical expenditure. The working group recommended to overcome the RFs, if they are merely considered a list of available drugs at regional level, focusing CTR activities to ensure market access and to govern the prescribing behaviour, and strengthening/anticipating the flow of information from the Italian Medicines Agency (AIFA) to the regions, to enable a more efficient approach to local access to drugs

Accelerated partial breast irradiation using 3D conformal radiotherapy: Toxicity and cosmetic outcome

Purpose: The aim of this paper is to analyze the incidence of acute and late toxicity and cosmetic outcome in breast cancer patients submitted to breast conserving surgery and three-dimensional conformal radiotherapy (3D-CRT) to deliver accelerated partial breast irradiation (APBI). Methods and materials: 84 patients were treated with 3D-CRT for APBI. This technique was assessed in patients with low risk stage I breast cancer enrolled from September 2005 to July 2011. The prescribed dose was 34/38.5 Gy delivered in 10 fractions twice daily over 5 consecutive days. Four to five nocoplanar 6 MV beams were used. In all CT scans Gross Tumor Volume (GTV) was defined around the surgical clips. A 1.5 cm margin was added by defining a Clinical Target Volume (CTV). A margin of 1 cm was added to CTV to define the planning target volume (PTV). The doseevolume constraints were followed in accordance with the NSABP/RTOG protocol. Late toxicity was evaluated according to the RTOG grading schema. The cosmetic assessment was performed using the Harvard scale. Results: Median patient age was 66 years (range 51e87). Median follow-up was 36.5 months (range 13 e83). The overall incidence of acute skin toxicities was 46.4% for grade 1 and 1% for grade 2. The incidence of late toxicity was 16.7% for grade 1, 2.4% for grade 2 and 3.6% for grade 3. No grade 4 toxicity was observed. The most pronounced grade 2 late toxicity was telangiectasia, developed in three patients. Cosmetics results were excellent for 52%, good for 42%, fair for 5% and poor for 1% of the patients. There was no statistical correlation between toxicity rates and prescribed doses (p ¼ 0.33) or irradiated volume (p ¼ 0.45). Conclusions: APBI using 3D-CRT is technically feasible with very low acute and late toxicity. Long-term results are needed to assess its efficacy in reducing the incidence of breast relapse

Adrenal rest tumour of the liver

A 58 year old man with chronic hepatitis B and HIV infection underwent a scheduled abdominal ultrasound for liver cancer screening. A focal hypoechoic lesion of 25mm. was discovered in the segment VII of the liver. Liver function tests and tumor markers levels (α-fetoprotein, Carcinoembryonic antigen (CEA), Ca 19.9) were within normal limits. On contrast abdominal computed tomography (CT) the mass was enhanced heterogeneously in the arterial phase with minimal washout in the portal and delayed phases. On superparamagnetic iron oxide-enhanced magnetic resonance imaging (MRI) the lesion appeared to be slightly hypointense on T1 (Fig. 1A), hyperintense on T2 fat suppression and clearly hypervascular in the arterial phase (Fig 1B). Based on the above radiological findings and the clinical history a diagnosis of hepatocellular carcinoma (HCC) was suspected. The patient underwent a subsegmental liver resection and the postoperative recovery was uneventful. At histology the lesion was diagnosed as an adrenal rest tumor based on morphology and immunostaining (staining was positive for cytokeratin, vimentin, alpha-inhibin; negative for polyclonal CEA and Hepatocyte specific antigen 1). The lesion was adjacent to an area of mature adrenal cortex, surrounded by hepatic tissue. (Fig 1C). Adrenal rest tumor is very rare in the liver and it is supposed to originate from ectopic adrenocortical tissue. Radiologically, adrenal rest tumor shares many features with HCC.(1) Presence of fat components and hypervascularity are suggestive for the diagnosis especially for lesions located beneath the posterior capsule of the right lobe

Distinct Nongenomic Signal Transduction Pathways Controlled by 17b-Estradiol Regulate DNA Synthesis and Cyclin D1 Gene Transcription in HepG2 Cells

Estrogens induce cell proliferation in target tissues by stimulating progression through the G1 phase of the cell cycle. Activation of cyclin D1 gene expression is a critical feature of this hormonal action. The existence of rapid/nongenomic estradiol-regulated protein kinase C (PKC-a) and extracellular signal-regulated kinase (ERK) signal transduction pathways, their cross talk, and role played in DNA synthesis and cyclin D1 gene transcription have been studied herein in human hepatoma HepG2 cells. 17b-Estradiol was found to rapidly activate PKC-a translocation and ERK-2/mitogen-activated protein kinase phosphorylation in this cell line. These actions were independent of each other, preceding the increase of thymidine incorporation into DNA and cyclin D1 expression, and did not involve DNA binding by estrogen receptor. The results obtained with specific inhibitors indicated that PKC-a pathway is necessary to mediate the estradiol-induced Gl-S progression of HepG2 cells, but it does not exert any effect(s) on cyclin D1 gene expression. On the contrary, ERK-2 cascade was strongly involved in both Gl-S progression and cyclin D1, gene transcription. Deletion of its activating protein-1 responsive element motif resulted in attenuation of cyclin D1 promoter responsiveness to estrogen. These results indicate that estrogen-induced cyclin D1 transcription can occuir in HepG2 cells independently of the transcriptional activity of estrogen receptor, sustaining the pivotal role played by nongenomic pathways of estrogen action in hormone-induced proliferation

MRI and correlation between TNM and CEA, CA19.9, AFP in rectal cancer Experience of a single academic surgical center

In our study we examined 75 patients treated for rectal cancer in the period between 01/01/2011 and 31/12/2014. Out of these 75 patients, we considered those 36 staged through MRI. We then compared the TNM stage obtained through MRI with the one emerged from histological examination. The correlation between the two TNM stages was assessed considering all patients staged through MRI and dividing the cases according to the submission or not to a neoadjuvant treatment. Finally, we analyzed serum levels of tumor markers CEA, CA 19.9 and AFP, relating them with the final disease stage. Data analysis showed a statistically significant correlation in the T stages, especially in the population not subjected to neoadjuvant treatment. Instead, for N, we found no statistically significant correlation. Similarly, none of the tumor markers presented a statistically significant correlation with disease stage. However, according to the positivity of tumor markers, we associated the following score: 0, (no positive marker)1 (only one marker positive) 2 (two markers positive) 3 (three markers positive). In presence of three markers positive, meaning the highest score, we found a statistically significant correlation with N + staging of the disease, obtained by postoperative pathologic examination. The conclusion is that MRI is certainly effective in T stage evaluation. Probably, for limph node involvement evaluation, more reliable parameters for establishing possible lymph node malignancy need to be found. The role of the tumor markers CEA, CA 19.9, AFP during preoperative evaluation of rectal tumors remains undefined. KEY WORDS: MRI, Rectal cancer, Tumor markes, Tumor regression, T stage

A Model-Aware Comprehensive Tool for Battery Energy Storage System Sizing

This paper presents a parametric procedure to size a hybrid system consisting of renewable generation (wind turbines and photovoltaic panels) and Battery Energy Storage Systems (BESS). To cope with the increasing installation of grid-scale BESS, an innovative, fast and flexible procedure for evaluating an efficient size for this asset has been developed. The tool exploits a high-fidelity empirical model to assess stand-alone BESS or hybrid power plants under different service stacking configurations. The economic performance has been evaluated considering the revenue stacking that occurs when participating in up to four distinct energy markets and the degradation of the BESS performances due to both cycle- and calendar-aging. The parametric nature of the tool enables the investigation of a wide range of system parameters, including novel BESS control logic, market prices, and energy production. The presented outcomes detail the techno-economic performances of a hybrid system over a 20-year scenario, proposing a sensitivity analysis of both technical and economic parameters. The case study results highlight the necessity of steering BESS investment towards the coupling of RES and accurate planning of the service stacking. Indeed, the implementation of a storage system in an energy district improves the internal rate of return of the project by up to 10% in the best-case scenario. Moreover, accurate service stacking has shown a boost in revenues by up to 44% with the same degradation

Antibiotic Susceptibility and Virulence Factors in Escherichia coli from Sympatric Wildlife of the Apuan Alps Regional Park (Tuscany, Italy)

Today a growing number of studies are focusing on antibiotic resistance in wildlife. This is due to the potential role of wild animals as reservoirs and spreaders of pathogenic and resistant bacteria. This study focused on isolating and identifying Escherichia coli from the feces of wild animals living in the Apuan Alps Regional Park (Tuscany, Italy) and evaluating some of their antibiotic resistance and pathogenicity traits. Eighty-five fecal samples from different species were studied. Seventy-one E. coli were identified by matrix assisted laser desorption ionization-time of flight mass spectrometry analysis, subjected to antibiograms and polymerase chain reaction for the detection of antibiotic resistance genes and pathogenicity factors. The highest resistance rates were found against cephalothin (39.4%) and ampicillin (33.8%), followed by amoxicillin/clavulanic acid (15.5%), streptomycin (12.7%), and tetracycline (5.6%). Regarding resistance genes, 39.4% of the isolates were negative for all tested genes. The remaining isolates were positive for blaCMY-2, sul2, strA-strB and aadA1, tet(B), and tet(A), encoding resistance to beta-lactams, trimethoprim/sulfamethoxazole, streptomycin, and tetracycline, respectively. With regard to virulence factors, 63.4% of the isolates were negative for all genes; 21.1% carried astA alone, which is associated with different pathotypes, 9.9% carried both escV and eaeA (aEPEC); single isolates (1.4%) harbored escV (aEPEC), escV associated with astA and eaeA (aEPEC), astA with stx2 and hlyA (EHEC) or astA and stx1, stx2, and hlyA (EHEC). These results show that wildlife from nonanthropized environments can be a reservoir for antibiotic-resistant microorganisms and suggest the need for a deeper knowledge on their origin and diffusion mechanisms through different ecological niches

Inhibitors of Protein Convertase Subtilisin/Kexin 9 (PCSK9) and Acute Coronary Syndrome (ACS): The State-of-the-Art

Acute Coronary Syndrome (ACS) remains one of the most frequent causes of morbidity and mortality in the world. Although the age- and gender-adjusted incidence of ACS is decreasing, the mortality associated with this condition remains high, especially 1-year after the acute event. Several studies demonstrated that PCSK9 inhibitors therapy determine a significant reduction of major adverse cardiovascular events (MACE) in post-ACS patients, through a process of plaque modification, by intervening in lipid metabolism and platelet aggregation and finally determining an improvement in endothelial function. In the EVACS (Evolocumab in Acute Coronary Syndrome) study, evolocumab allows >90% of patients to achieve LDL-C < 55 mg/dL according to ESC/EAS guidelines compared to 11% of patients who only receive statins. In the EVOPACS (EVOlocumab for Early Reduction of low-density lipoprotein (LDL)-cholesterol Levels in Patients With Acute Coronary Syndromes) study, evolocumab determined LDL levels reduction of 40.7% (95% CI: 45.2 to 36.2; p < 0.001) and allowed 95.7% of patients to achieve LDL levels <55 mg/dL. In ODYSSEY Outcome trial, alirocumab reduced the overall risk of MACE by 15% (HR = 0.85; CI: 0.78-0.93; p = 0.0003), with a reduced risk of all-cause mortality (HR = 0.85; CI: 0.73-0.98: nominal p = 0026), and fewer deaths for coronary heart disease (CHD) compared to the control group (HR = 0.92; CI: 0.76-1.11; p = 0.38). The present review aimed at describing the beneficial effect of PCSK9 inhibitors therapy early after ACS in reducing LDL circulating levels (LDL-C) and the risk of major adverse cardiovascular events, which was very high in the first year and persists higher later after the acute event

Predictive nomograms for oral tongue squamous cell carcinoma applying the American Joint Committee on Cancer/Union Internationale Contre le Cancer 8th edition staging system

Nomograms applying the 8th edition of the TNM staging system aimed at predicting overall (OS), disease-specific (DSS), locoregional recurrence-free (LRRFS) and distant recurrence-free survivals (DRFS) for oral tongue squamous cell carcinoma (OTSCC) are still lacking