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Abstract Background Bronchial thermoplasty (BT) is a non-pharmacological intervention for severe asthma whose mechanism of action is not completely explained by a reduction of airway smooth muscle (ASM). In this study we analyzed the effect of BT on nerve fibers and inflammatory components in the bronchial mucosa at 1 year. Methods Endobronchial biopsies were obtained from 12 subjects (mean age 47 ± 11.3 years, 50% male) with severe asthma. Biopsies were performed at baseline (T0) and after 1 (T1), 2 (T2) and 12 (T12) months post-BT, and studied with immunocytochemistry and microscopy methods. Clinical data including Asthma Quality of Life Questionnaire (AQLQ) and Asthma Control Questionnaire (ACQ) scores, exacerbations, hospitalizations, oral corticosteroids use were also collected at the same time points. Results A statistically significant reduction at T1, T2 and T12 of nerve fibers was observed in the submucosa and in ASM compared to T0. Among inflammatory cells, only CD68 showed significant changes at all time points. Improvement of all clinical outcomes was documented and persisted at the end of follow up. Conclusions A reduction of nerve fibers in epithelium and in ASM occurs earlier and persists at one year after BT. We propose that nerve ablation may contribute to mediate the beneficial effects of BT in severe asthma. Trial registration Registered on April 2, 2013 at ClinicalTrials.gov Identifier: NCT01839591.

Background: We studied the relationship between dietary intake of vegetables and fruit and lung cancer risk in Harbin, Heilongjiang province, northeast China, an area with a very high baseline risk of lung cancer in both sexes.Patients and methods: We used data from a case–control study, conducted from 1987 to 1990, among 218 cases with incident, histologically confirmed lung cancer and 436 controls admitted to the same hospitals as cases with non-neoplastic, non-lung diseases unrelated to smoking and other potential risk factors for lung cancer.Results: Compared with the lowest tertile of intake of vegetables, fruit or both, the multivariate odds ratios (ORs) for the highest tertile of intake were 0.39 [95% confidence interval (CI) 0.25–0.62], 0.73 (95% CI 0.48–1.11) and 0.40 (95% CI 0.25–0.63), respectively. In particular, high intake of Chinese cabbage (OR = 0.53), chives (OR = 0 .54), carrots (OR = 0.51) and celery (OR = 0.40) was inversely associated with lung cancer. The OR was more than six-fold elevated for smokers reporting low intake of vegetables, and more than four-fold elevated for smokers reporting low intake of fruit, as compared with never smokers reporting high intake of these items.Conclusion: In agreement with previous studies, we found an inverse relation between vegetable and fruit intake and lung cancer risk in both strata of current and never smokers. [ABSTRACT FROM AUTHOR]

Background: The epidemiologic evidence for an etiologic role of fried foods and heterocyclic amines in colorectal carcinogenesis is inconsistent.Patients and methods: We have investigated the relation between fried foods and colorectal cancer risk using data from a large, multicentric case–control study conducted in Italy and Switzerland between 1992 and 2000, with 1394 cases of colon cancer, 886 cases of rectal cancer and 4765 controls.Results: After allowing for major relevant covariates, the multivariate odds ratios (ORs) for an increment of one portion per week of fried foods were 0.97 [95% confidence interval (CI) = 0.93–1.01] for colon cancer and 1.04 (95% CI = 1.00–1.09) for rectal cancer. When we analyzed the type of fats mainly used for frying, we found that olive oil, but not other types of oils, appeared to protect from colon cancer risk (OR = 0.89, 95% CI = 0.82–0.98).Conclusions: Our results do not indicate a relevant role of fried foods on colorectal cancer risk. We found a possible favorable effect of (fried) olive oil on colon cancer risk but not on rectal cancer risk. [ABSTRACT FROM AUTHOR]

Background: There is some evidence that alcohol consumption is inversely associated with renal cell cancer (RCC), but the issue is still unclear. Patients and methods: We investigated the relation using data from two Italian multicentric case–control studies conducted from 1985 to 2004, including a total of 1115 incident, histologically confirmed cases and 2582 controls hospitalised with acute, non-neoplastic conditions. Results: Compared with non-drinkers, the multivariate odds ratios (ORs) of RCC were 0.87 [95% confidence interval (CI) 0.73–1.04] for ≤4 drinks per day, 0.76 (95% CI 0.59–0.99) for >4 to ≤8 drinks per day and 0.70 (95% CI 0.50–0.97) for >8 drinks per day of alcoholic beverages, with a significant inverse trend in risk (P value = 0.01). The ORs were 0.85 (95% CI 0.71–1.02) for wine, 0.84 (95% CI 0.68–1.03) for beer and 0.86 (95% CI 0.70–1.05) for spirits consumption, as compared with abstainers. No trend in risk of RCC emerged with duration (P value = 0.94) and age at starting alcohol consumption (P value = 0.81). Results were consistent in men and women, as well as in strata of age, smoking and body mass index. Conclusions: This pooled analysis found an inverse association between alcohol drinking and RCC. Risks continued to decrease even above eight drinks per day (i.e. >100 g/day) of alcohol intake, with no apparent levelling in risk. [ABSTRACT FROM AUTHOR]

Objectives: To assess through an indirect treatment comparison (ITC) the potential benefit of faricimab over the anti-vascular endothelial growth factor (VEGF) real-life scenario, hereby defined standard of care (SoC), in Italy, that is, aflibercept, bevacizumab, and ranibizumab, in patients with neovascular age-related macular degeneration (nAMD) naïve to any anti-VEGF treatment., Methods: Individual patient-level data from the phase III clinical trials TENAYA and LUCERNE (faricimab cohort) and the real-world study RADIANCE (RADIANCE cohort) were used. Efficacy was evaluated with changes in best corrected visual acuity (BCVA) and central subfield thickness (CST) from baseline to 1 year (week 52 in the RADIANCE and week 48 in the faricimab cohorts, respectively). Propensity score-based inverse probability of treatment weighting was utilized to balance cohorts and mitigate bias due to potential confounding. Sensitivity analyses were performed to evaluate treatment differences adjusted for the number of injections., Results: The ITC included 513 patients treated with faricimab and 263 patients treated with SoC. At 1 year, faricimab showed a greater mean BCVA gain (treatment difference +5.4 letters, p<0.001) and CST reduction (treatment difference -71.8 μm, p<0.001) compared to SoC. Sensitivity analyses confirmed the robustness of results, showing a BCVA improvement of +4.0 letters and a CST reduction of -71.5 μm in favor of faricimab., Conclusions: Despite the limitations due to the use of ITC and the comparison between clinical trials and real-world cohorts, the present analysis suggests potential benefits in terms of vision gain and CST reduction in naïve nAMD patients treated with faricimab compared with SoC in a real-world setting., Competing Interests: Conflict of interest: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CG Roche; FT None; MP Abbvie, Novartis, Bayer, Roche, Zeiss; FV Bayer, Novartis, Abbvie, Roche; MN Roche; SV Abbvie, Alimera, Apellis, Bayer. B&I, Novartis, Roche, Zeiss; LB is an employee at Roche; ES is an employee at Roche; GV is an employee at Roche; PL Aerie, Allergan, Annexon, Apellis, Bausch & Lomb, Bayer, Biogen, Boehringer Ingelheim, Eyepoint Pharmaceuticals, I-Care, Genentech, Novartis, Ocular Therapeutix, Outlook Therapeutics, and Roche, (© 2024 The Authors.)

Myeloma with extramedullary plasmacytomas not adjacent to bone (EMP) is associated with an extremely poor outcome compared with paraosseous plasmacytomas (PP) as current therapeutic approaches are unsatisfactory. The role of new molecules and in particular of monoclonal antibodies is under investigation. To determine whether daratumumab-based regimens are effective for myeloma with EMP, we report herein an initial multicenter observational analysis of 102 myeloma patients with EMP (n = 10) and PP (n = 25) at diagnosis and EMP (n = 28) and PP (n = 39) at relapse, treated with daratumumab-based regimens at 11 Haematological Centers in Italy.EMP and PP at diagnosis were associated with higher biochemical (90% vs. 96%, respectively) and instrumental ORR (86% vs. 83.3%, respectively), while at relapse, biochemical (74% vs. 73%) and instrumental (53% vs. 59%) ORR were lower. Median OS was inferior in EMP patients compared with patients with PP both at diagnosis (21.0 months vs. NR) (p = 0.005) and at relapse (32.0 vs. 40.0 months) (p = 0.428), although, during relapse, there was no statistically significant difference between the two groups. Surprisingly, at diagnosis, median TTP and median TTNT were not reached either in EMP patients or PP patients and during relapse there were no statistically significant differences in terms of median TTP (20 months for two groups), and median TTNT (24 months for PP patients vs. 22 months for EMP patients) between the two groups. Median TTR was 1 month in all populations.These promising results were documented even in the absence of local radiotherapy and in transplant-ineligible patients., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Conflict of interest: No potential conflict of interest was reported by the author(s)., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Stress hormones like catecholamine and cortisol are thought to reflect the magnitude of physical stress in adults and were studied in relationship to the cause of death and agony time. Intrauterine distress, intrapartum events, and modes of delivery can affect the fetal endocrine stress response, as reflected by biochemical analyses. The aim of the present study was to evaluate the role of catecholamines and cortisol as markers of ante-mortem fetal distress. The role of cortisol as a marker of circadian timing of delivery was also assessed., Methods: A 2-year prospective cohort-comparison inclusion of stillbirths and newborns took place with collection of antemortem data, labor parameters, neonatal outcome, post-mortem data and blood samples. Stillbirths were classified as acute or chronic on the basis of a multidisciplinary evaluation. Heart blood of stillbirths and cord blood of newborns were analyzed by high pressure liquid chromatography (HPLC) for adrenaline and noradrenaline and by immunoassay for cortisol determination., Results: Fifteen stillbirths and 46 newborns, as a comparison group, delivered by spontaneous vaginal birth, elective, and emergency cesarean sections were included. Stillbirths' main cause of death was cord thrombosis. Levels of adrenaline and noradrenaline (median: 14,188 pg/ml and 230.5 pg/ml, respectively) were significantly higher (p < 0.001) in stillbirths than in newborns and were also higher in acute compared to chronic distress. Cortisol levels were significantly higher (p < 0.05) in spontaneous vaginal delivery (median: 18.2 μg/dl) compared to elective cesarean sections (median: 3.8 μg/dl). No difference in cortisol concentrations was detected between newborns delivered at morning and at afternoon/evening., Conclusion: Our results suggest that the biochemical measurement of adrenaline and noradrenaline levels might reflect a marked physical stress response during the process of death in stillbirths. On the contrary, the elevation of cortisol levels could mirror the elevation in maternal cortisol level during vaginal delivery. For the post-mortem evaluation of stillbirths, the analysis of CA levels could provide additional data on the duration of distress, useful to integrate the forensic diagnosis., (© 2024. The Author(s).)

Objective . Real-time adaptive particle therapy is being investigated as a means to maximize the treatment delivery accuracy. To react to dosimetric errors, a system for fast and reliable verification of the agreement between planned and delivered doses is essential. This study presents a clinically feasible, real-time 4D-dose reconstruction system, synchronized with the treatment delivery and motion of the patient, which can provide the necessary feedback on the quality of the delivery. Approach . A GPU-based analytical dose engine capable of millisecond dose calculation for carbon ion therapy has been developed and interfaced with the next generation of the dose delivery system (DDS) in use at Centro Nazionale di Adroterapia Oncologica (CNAO). The system receives the spot parameters and the motion information of the patient during the treatment and performs the reconstruction of the planned and delivered 4D-doses. After each iso-energy layer, the results are displayed on a graphical user interface by the end of the spill pause of the synchrotron, permitting verification against the reference dose. The framework has been verified experimentally at CNAO for a lung cancer case based on a virtual phantom 4DCT. The patient's motion was mimicked by a moving Ionization Chamber (IC) 2D-array. Main results . For the investigated static and 4D-optimized treatment delivery cases, real-time dose reconstruction was achieved with an average pencil beam dose calculation speed up to more than one order of magnitude smaller than the spot delivery. The reconstructed doses have been benchmarked against offline log-file based dose reconstruction with the TRiP98 treatment planning system, as well as QA measurements with the IC 2D-array, where an average gamma-index passing rate (3%/3 mm) of 99.8% and 98.3%, respectively, were achieved. Significance . This work provides the first real-time 4D-dose reconstruction engine for carbon ion therapy. The framework integration with the CNAO DDS paves the way for a swift transition to the clinics., (Creative Commons Attribution license.)

Background: New indications for existing medicines are increasing over time. In most countries, drug pricing and reimbursement conditions are renegotiated every time a new indication is approved. There is a growing interest in the price negotiation model for new indications, specifically comparing an indication-based versus blended approach. However, little evidence currently exists regarding the complexity of these negotiations and their impact on actual prices. Italy has recently transitioned from an indication-based approach to a blended price model. This study aims to measure the impact of price and reimbursement negotiation of new indications on discounts (i.e. actual prices) and on the negotiation duration, used as a proxy of its complexity., Methods: We considered new indications approved through a European centralized procedure from January 2013 to March 2022 for which the price and reimbursement status was approved in Italy between January 2015 and March 2022, amounting to 52 new indications. Data on the timeframe of the Italian price and reimbursement process and its phases were obtained from publicly available sources. Discounts for the first indication and their subsequent increases for new indications were estimated by comparing ex-factory prices and tendered prices. To calculate p-values, we employed the Mann-Whitney test, and multiple regression models were utilized to examine correlations between negotiation time and the characteristics of the medicines., Results: The mean time to reimbursement was 603 days, in contrast to 583 days for the first launch. Price negotiation took longer for rare diseases, cancer drugs, and in case of therapies with minor added therapeutic value. On average, the additional discount (on top of discounts for prior indications) was 13%, significantly lower than the mean discount for the first indications approved (24.9%). The discounts increment was lower, but negotiation took longer if a Managed Entry Agreement accompanied the final agreement. Additionally, discounts have increased over the years., Conclusion: The negotiation for new indications takes longer than the first one, and provides, on average, an additional discount of 13%. While our findings bear the potential for significant policy implications, they necessitate prudent interpretation due to a limited number of observations. The increasing trend in additional discounts over time applied to all indications in recent negotiations, may suggest a descending trend of value for new indications and a shift from an indication-based pricing approach to a blended model. Otherwise, budget impact considerations might have outweighed a value-based approach in the recent negotiations. If so, two potential options for restoring a value-based approach are returning to an indication-based pricing or giving explicit and higher weight to value within a blended model., (© 2023. The Author(s).)

Introduction: Generalized pustular psoriasis (GPP) is a rare and chronic, debilitating skin condition characterized, in its acute flare phase, by clinically severe and potentially life-threatening systemic manifestations. Data on GPP are still scanty, particularly in Europe and at a national level. The aim of this study was to provide expert indications on several disease-related and patient-related aspects of GPP, with specific focus to the Italian context., Methods: We conducted an iterative eDelphi study following the recommended criteria for reporting methods and results. After a thorough bibliographic review aimed to identify unknown or controversial issues in GPP, the following areas were investigated through a few specific questions/statements for each area: (1) disease epidemiology; (2) disease characteristics, with specific interest toward GPP flares; (3) diagnosis and diagnostic delay; (4) GPP treatment; (5) GPP patient journey and use of healthcare resources in Italy; (6) unmet needs and quality of life. An Executive Board of 9 principal investigators revised and approved the topics to be examined and overviewed the whole project. A total of 35 experts from different Italian areas, including 34 board-certified Italian dermatologists and 1 representative of patients' associations, took part in the study., Results: A high agreement in responses from Italian experts emerged during two eDelphi iterations on - among several other aspects - GPP prevalence and incidence in Italy, use of European Rare and Severe Psoriasis Expert Network diagnostic criteria, flare frequency and duration, best diagnostic and care pathway, and main unmet needs of Italian patients. On the other hand, a broad spectrum of treatments (of different drug classes) was reported both in the acute and chronic phases of GPP, and no consensus on the issue was thus achieved., Conclusions: Consensus findings from this Delphi study of GPP experts may be useful to fill gaps of knowledge and improve awareness of this rare disease, as well as to help clinical and public health management of GPP in Italy., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Despite the increasing importance of innovative medications and bariatric surgery for the treatment of obesity, lifestyle interventions (diet and physical activity) remain the first-line therapy for this disease. The use of digital devices in healthcare aims to respond to the patient's needs, in order to make obesity treatment more accessible, so our study aims to assess the safety and efficacy of a Digital Therapy for Obesity App (DTxO) for achieving weight loss and its maintenance in patients affected with obesity undergoing an experimental non-pharmacological treatment. Here we present the study protocol of a prospective, multicenter, pragmatic, randomized, double-arm, placebo-controlled, parallel, single-blind study on obese patients who will be treated with a new digital therapy to obtain an improvement in their disease condition through the application of different simultaneous strategies (a dietary regimen and personalized advice program, a tailored physical exercise program, a cognitive-behavioural assessment and program, alerts and reminders, dedicated section on prescribed drugs intake, and chat and online visits with clinical professionals). We believe that DTxO will offer a promising intervention channel and self-regulation tool holding the potentiality to decrease treatment burden and treat more patients thanks to the partial replacement of traditional medical consultation with digital or telephone management, improving self- engagement and reducing the high demands the "obesity pandemic" for both patients and national health services in terms of time, cost, and effort. Clinical trial registration : clinicaltrials.gov, identifier, NCT05394779., Competing Interests: GG was employed by the company Advice Pharma Group. CG was employed by Statinfo. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Castelnuovo, Capodaglio, De Amicis, Gilardini, Mambrini, Pietrabissa, Cavaggioni, Piazzolla, Galeone, Garavaglia, Bertoli and the DEMETRA Study Group.)

Competing Interests: AM, CG e PC declare they have no conflict of interest related to this article. PR is an employee of PharmaLex Italy S.p.A.

Atopic dermatitis (AD) is one of the most common diseases worldwide. Severe AD has a major impact on the quality of life of patients. We performed a systematic literature review on the epidemiology of AD in Italian pre-school children (age 0-5 years) and we assessed the available data on the severity of AD. In August 2022, we performed a bibliographic search using PubMed/Medline and EMBASE. We identified 10 studies with Italian data on the prevalence and/or incidence of AD in pre-school children. The period (12 months) prevalence of AD varied widely across studies, ranging between 4.0% and 42.2%, with median estimates of 14.3% among all studies and 11.8% among studies from 2010 onwards. Applied to the Italian population, this leads to a prevalence of 309,000-375,000 pre-school AD cases. Only one study computed the incidence of AD, reporting rates of 9 cases per 100 person-years in children aged 0-1 year, and 2.5 cases per 100 person-years in children aged 1-4 years. Severity data from Italy were also reviewed, across three identified three studies. A point estimate found 8.4% of cases were considered severe in one study based on the Patient-Oriented Eczema Measure (POEM), with an overall range of 7.8-11% across different Italian studies and according to various severity score types.

Background: The beam energy is one of the most significant parameters in particle therapy since it is directly correlated to the particles' penetration depth inside the patient. Nowadays, the range accuracy is guaranteed by offline routine quality control checks mainly performed with water phantoms, 2D detectors with PMMA wedges, or multi-layer ionization chambers. The latter feature low sensitivity, slow collection time, and response dependent on external parameters, which represent limiting factors for the quality controls of beams delivered with fast energy switching modalities, as foreseen in future treatments. In this context, a device based on solid-state detectors technology, able to perform a direct and absolute beam energy measurement, is proposed as a viable alternative for quality assurance measurements and beam commissioning, paving the way for online range monitoring and treatment verification., Purpose: This work follows the proof of concept of an energy monitoring system for clinical proton beams, based on Ultra Fast Silicon Detectors (featuring tenths of ps time resolution in 50 μm active thickness, and single particle detection capability) and time-of-flight techniques. An upgrade of such a system is presented here, together with the description of a dedicated self-calibration method, proving that this second prototype is able to assess the mean particles energy of a monoenergetic beam without any constraint on the beam temporal structure, neither any a priori knowledge of the beam energy for the calibration of the system., Methods: A new detector geometry, consisting of sensors segmented in strips, has been designed and implemented in order to enhance the statistics of coincident protons, thus improving the accuracy of the measured time differences. The prototype was tested on the cyclotron proton beam of the Trento Protontherapy Center (TPC). In addition, a dedicated self-calibration method, exploiting the measurement of monoenergetic beams crossing the two telescope sensors for different flight distances, was introduced to remove the systematic uncertainties independently from any external reference., Results: The novel calibration strategy was applied to the experimental data collected at TPC (Trento) and CNAO (Pavia). Deviations between measured and reference beam energies in the order of a few hundreds of keV with a maximum uncertainty of 0.5 MeV were found, in compliance with the clinically required water range accuracy of 1 mm., Conclusions: The presented version of the telescope system, minimally perturbative of the beam, relies on a few seconds of acquisition time to achieve the required clinical accuracy and therefore represents a feasible solution for beam commission, quality assurance checks, and online beam energy monitoring., (© 2023 The Authors. Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Background: This study aimed to improve the understanding of the prognostic value of tumor mitotic rate (TMR) in cutaneous melanoma and assessed its significance as a predictor for overall, melanoma-specific, and recurrence-free survival., Patients and Methods: This is a retrospective multicenter Italian cohort study of 13,016 patients diagnosed with and treated for invasive primary melanoma between 2005 and 2020 with median follow-up of 5.5 years. The survival probability was assessed by Kaplan-Meier method, hazard ratios (HRs), and corresponding 95% confidence interval (CI) of all-cause mortality and recurrence/death by multivariable Cox proportional hazards models., Results: Higher dermal mitoses number was associated with decreased overall survival. Among patients with TMR 0/mm 2 , 1/mm 2 , 2/mm 2 -3/mm 2 , 4/mm 2 -10/mm 2 , and >10/mm 2 , 5-year overall survival (OS) was 97.3%, 93.6%, 88.3%, 73.0%, and 60.9%, respectively. In multivariate analyses, compared to TMR of 0/mm 2 , HRs for all-cause mortality were 1.35 (95% CI, 1.08-1.68), 1.70 (95% CI, 1.40-2.07), 2.04 (95% CI, 1.67-2.49), and 2.39 (95% CI, 1.90-3.00) for 1 mitoses/mm 2 , 2 mitoses/mm 2 -3 mitoses/mm 2 , 4 mitoses/mm 2 -10 mitoses/mm 2 , and >10 mitoses/mm 2 , respectively. A similar increase in risks was observed in melanoma-specific survival (MSS) and recurrence-free survival (RFS). The HRs for MSS and RFS for the highest compared to the lowest TMR category were 3.01 (95% CI, 2.20-4.11) and 2.26 (95% CI, 1.88-2.73), respectively. Sentinel lymph-node biopsy positivity was significantly associated with TMR increase even with adjustment for several potential confounders., Conclusions: A clear association was demonstrated between an increasing TMR and decreased OS, MSS, and RFS, suggesting a reconsideration of TMR prognostic role for future inclusion in the melanoma staging system., Plain Language Summary: The 8th American Joint Committee on Cancer for melanoma staging removed tumor mitotic rate (TMR) from the staging criteria for T1 melanomas, giving way to ulceration and tumor thickness as stronger prognostic predictors. However, it is still recommended that TMR should be assessed and recorded in all primary invasive melanomas. In a large retrospective multicenter study on primary invasive melanomas, we investigated the prognostic value of TMR to assess its significance as survival predictor. Our results showed a clear association between increasing TMR and decreased patients' survival, suggesting that TMR should be considered for inclusion in the melanoma staging system., (© 2023 American Cancer Society.)

Melanoma patients have a high risk of developing subsequent primary melanomas, a condition known as multiple primary melanoma (MPM). We aimed to compare risk factors of patients with MPM and single primary melanoma (SPM). Primary MPM and SPM consecutively treated at the National Cancer Institute in Milan, Italy, from 1978 to 2021 were retrospectively investigated. Demographic and clinicopathological characteristics were analyzed. Multivariate hazard ratios and mortality were estimated using Cox proportional hazards regression models. Overall, 9122 patients with SPM and 944 with MPM were included. A total of 1437 and 85 deaths occurred in SPM and MPM group, respectively. Of these, 1315 (14.4%) within SPM patients and 60 (6.4%) in MPM group were melanoma-specific deaths (MSDs). Males had a higher risk for MPM (hazard ratio = 1.29), while age was not associated with MPM (hazard ratio = 0.98). The risk of MPM decreased by about 50% for Breslow thickness >1 mm, and by about 45 and 75% in presence of mitoses and ulceration, respectively. The multivariate hazard ratio of death for MPM compared to SPM patients was 0.85 (95% confidence interval, CI: 0.67-1.06), while considering MSD the corresponding hazard ratio was 0.93 (95% CI: 0.71-1.22). Melanoma patients should receive regular follow-up with complete skin examination to detect early subsequent primary melanoma. Patients with more advanced primary have decreased risk of MPM, while males have higher risk. Our study reported no significant difference in mortality between SPM and MPM, but the issue is still open for discussion and further studies., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Innovative medicines are provided with dedicated funds and immediate market access in Italy. Innovativeness evaluation considers unmet need, added therapeutic value, and quality of the evidence., Objective: We aimed to evaluate the internal consistency and drivers of the innovativeness appraisal process., Methods: Appraisal reports on innovativeness refer to 1997-2021. We used both a descriptive approach and probabilistic multivariate analysis, using logistic regression models to compute odds ratios and 95% confidence intervals. The dependent variable is innovativeness status (innovative vs. non-innovative; full innovativeness vs. conditional innovativeness). Explanatory variables, besides the three above-mentioned domains, are the year of evaluation, drug type, target disease and population, and the number and type of available studies., Results: Among the 141 medicines scrutinized, 31.9%, 29.8%, and 38.3% were evaluated as fully innovative, conditionally innovative, and non-innovative, respectively. Added therapeutic value and the quality of the evidence were associated with the odds of receiving innovative status, and full compared with conditional innovativeness; unmet need was not a predictive variable. Other factors played a minor role: medicines for both solid tumours and rare diseases are more likely to be judged innovative; conditional innovativeness is more probable for medicines for rare diseases., Conclusions: Innovativeness status is driven by the added therapeutic value and quality of evidence. The appraisal process is internally consistent and predictable. This provides industry with a clear indication of what is needed to ensure that access to their medicines is prioritized., (© 2023. The Author(s).)

Acid sphingomyelinase deficiency (ASMD) is an ultra-rare disease, and several gaps of knowledge on various issues remain, particularly at a regional/national level. Expert opinions collected through well-defined consensus methodologies are increasingly used to make available reliable information in the context of rare/ultra-rare diseases. With the aim to provide indications on infantile neurovisceral ASMD (also formerly known as Niemann-Pick disease type A), chronic neurovisceral ASMD (formerly known as Niemann-Pick disease type A/B) and chronic visceral ASMD (formerly known as Niemann-Pick disease type B) in Italy, we conducted a Delphi consensus of experts focused on five main areas: (i) patients and disease characteristics; (ii) unmet needs and quality of life; (iii) diagnostic issues; (iv) treatment-related aspects; and (v) patient journey. Pre-specified, objective criteria were used to outline the multidisciplinary panel, based on 19 Italian experts in ASMD in paediatric and adult patients from different Italian Regions, including both clinicians (n = 16) and ASMD patients' advocacy or payors with expertise in rare diseases (n = 3). During two Delphi rounds, a high ratio of agreement was found on several topics related to ASMD characteristics, diagnosis, management and disease burden. Our findings may provide valuable indications for management of ASMD at a public health level in Italy., (© 2023. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Context: Urinary tract infections (UTIs) have a significant impact on patient's quality of life and society. Antibiotic therapy is the primary approach for the management of UTIs; however, it has major limits in the prevention of recurrent UTIs (rUTIs), also increasing the risk of development of multidrug-resistant micro-organisms., Objective: The aim of this paper is to discuss the European Association of Urology guidelines for the management of UTIs/rUTIs, the level of adherence to these recommendations, and the available evidence on the use of glycosaminoglycans (GAGs) as a possible alternative treatment to prevent rUTIs., Evidence Acquisition: This narrative review and expert meeting report is based on a literature search concerning the currently available UTI guidelines, the results of a survey administered to 227 urologists, and the opinion of an expert panel in the field of UTIs., Evidence Synthesis: Results obtained from the literature search showed that adherence to guidelines is not optimal. The survey demonstrated that antibiotics remain one of the treatments of UTIs. However, most of the urologists are aware of the problem caused by the resistance to antibiotics and prefer alternative methods for the prophylaxis of UTIs. Considering the alternative methods, the authors concluded that GAG therapy is highly effective in preventing rUTIs., Conclusions: Adherence to the international guidelines is important to align the clinical practice and avoid the spreading of antibiotic resistance. The survey outlines that the misuse and overuse of antibiotics are major problems; an analysis of clinical evidence confirms that GAG therapy is a valuable therapeutic approach to prevent the recurrence of episodes of UTIs and to limit the onset of antibiotic resistance., Patient Summary: Although antibiotic therapy is primarily used for the management of urinary tract infections (UTIs), misuse and overuse of antibiotics are of concern. Adherence to the international guidelines is important to prevent the spreading of antibiotic resistance. Clinical evidence confirms that the use of glycosaminoglycans is a valuable therapeutic approach to prevent UTI recurrence and limit the onset of antibiotic resistance., (© 2022 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology.)