Search

Figure S2 shows OS in strata of MSC risk level in patients with PD-L1>=50% and with PD-L1

Purpose:Immune-checkpoint inhibitors (ICI) have improved the survival of patients with non–small cell lung cancer (NSCLC). However, only a subset of patients benefit from ICIs, and the role of PD-L1 as predictive biomarker is still debated. A plasma immune-related miRNA-signature classifier (MSC) was established in lung cancer screening settings to identify the lethal form of the disease in early stages. In this exploratory study, we tested the efficacy of the MSC as prognostic marker in patients with advanced NSCLC treated with ICIs.Experimental Design:The MSC risk level was prospectively assessed in a consecutive series of 140 patients with NSCLC before starting treatment with ICIs. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in strata of PD-L1 and MSC alone or combined were considered as endpoints. Multiple plasma samples to monitor MSC risk level during treatment were also profiled.Results:Adequate tissue and plasma samples were available from 111 (79%) and 104 (75%) patients with NSCLC, respectively. MSC risk level was associated with ORR (P = 0.0009), PFS [multivariate HR = 0.31; 95% confidence interval (CI), 0.17–0.56; P = 0.0001], and OS (multivariate HR = 0.33; 95% CI, 0.18–0.59; P = 0.0002). The combination of MSC and PD-L1 stratified patients into three risk groups having 39%–18%–0% 1-year PFS (P < 0.0001) and 88%–44%–0% 1-year OS (P < 0.0001), according to the presence of 2–1–0 favorable markers. During treatment, MSC risk level decreased or remained low until tumor progression in patients with responsive or stable disease.Conclusions:The plasma MSC test could supplement PD-L1 tumor expression to identify a subgroup of patients with advanced lung cancer with worse ORR, PFS, and OS in immunotherapy regimens.

Supplementary Table S1, Table S2 and Table S3

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.

Treatment of metastatic melanoma has rapidly changed during the last years, and patients often require a multidisciplinary approach to achieve effective results. We aimed to assess the survival benefit achieved through surgical approach to patients with small bowel (SB) metastases from cutaneous melanoma, to emphasize the potential role of surgery in association with novel therapies.Ninety consecutive patients with cutaneous melanoma diagnosed as having resectable SB metastases from 1995 to 2015 were retrospectively investigated.Median age at surgery of melanoma metastases was 53.4 years. Among 30 patients who had a curative-intent resection, the 5- and 10-year survival rates were 61% and 54%, respectively, while among 60 patients treated with a palliative surgery the corresponding rates were both 4%. Among 29 patients, for whom the interval time between the occurrence of SB metastases and the previous surgical event on GI tract was ≥36 months, the 5-year overall survival rate was 42%; for 56 patients who had an interval time36 months the corresponding survival rate was 14%. Within the whole series, an absence of any residual disease after surgery (R0) was a factor affecting better survival, regardless of the evidence of metastases in other organs.Our observational data showed that surgical treatment for patients with SB metastases from melanoma might increase survival, but further studies are needed to confirm this finding. In the age of novel available therapies, the increase in survival time given by surgery may offer important chances for patients to benefit from systemic therapies.

To compare real-world persistence, effectiveness and tolerability of ustekinumab versus TNF inhibitors (TNFi) in psoriatic arthritis (PsA).One-year data from Italian subjects enrolled in the PsABio study (PsA patients receiving 1st- to 3rd-line treatment with ustekinumab or TNFi) were evaluated. Treatment persistence was analysed using Kaplan-Meier curves; hazard ratios (HR) of stopping treatment, and the corresponding 95% confidence intervals (CI), were computed through Cox regression models. Proportions of patients reaching clinical effectiveness endpoints were analysed using logistic regression, including propensity score (PS) adjustment for imbalanced baseline covariates, and non-response imputation if treatment was stopped/switched.Among 222 participants with follow-up data (effectiveness set), 101 received ustekinumab and 121 TNFi. In the ustekinumab group, 74.3% continued treatment up to 12±3 months compared to 63.6% in the TNFi group. Ustekinumab showed better persistence than TNFi, overall and in specific subgroups (females, monotherapy without methotrexate, BMI25 or30 kg/m2, patients receiving ustekinumab as 2nd-line treatment instead of a second TNFi). Overall, the PS-adjusted HR of treatment discontinuation was 0.46 (95% CI: 0.26-0.82) for ustekinumab vs. TNFi. cDAPSA LDA/remission was achieved in 43.5% of ustekinumab and 43.6% of TNFi-treated patients, while MDA was achieved in 24.2% and 28.0% of patients, respectively. After PS adjustment, odds ratios of clinical effectiveness did not differ significantly. Both treatments showed an acceptable safety profile.This prospective, real-life study found a better persistence of ustekinumab than TNFi in PsA patients. At 1 year, both treatments showed similar effectiveness.

Introduction Hypothermia is a well-known risk of the perioperative period and considered a preventable effect of anesthesia care. Nevertheless, it is not fully controlled, causing a number of adverse outcomes following surgical operations and thus increasing length of stay in hospital and treatment costs. The aim of this study was to assess the budget impact (BI) of the implementation of proactive strategies to prevent inadvertent perioperative hypothermia (IPH) in surgical patients in Italy, as recommended by international guidelines and by a good clinical practice (GCP) guideline of the Italian Society of Anesthesia, Analgesia, Reanimation, and Intensive Care. Methods BI was calculated over a 3-year period from the perspective of the Italian National Health Service (NHS). Model inputs were extracted from national literature when available and otherwise from international sources. The reference analytic model was based on the cost-effectiveness analysis of the National Institute for Health and Care Excellence clinical guidance 65. Estimates were based on assessments made about current malpractice in Italy and on a hypothesis of how future practice might change by implementing the GCP. Model output included overall BI results, variations in the number of warmed patients, medical-device average costs and use of mix. Results The base-case estimate quantified a decrease of 35% in extra days of hospital stay due to IPH and a net BI of -€60.92 million. Conclusion Increasing protocol adoption for preventing IPH would lead to both clinical advantages and significant savings for the NHS. Its large diffusion in Italian hospitals is thus desirable.

Annalisa Natalicchio,1 Camilla Sculco,2 Gianni Belletti,2 Martina Fontanelli,2 Carlotta Galeone,3 Antonio Carlo Bossi4 1Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy; 2Healthcare Network Partners Italy, Bologna, Italy; 3Biostatistics & Outcome Research, Statinfo, Briosco (MB), Italy; 4Humanitas Gavazzeni Diabetes Centre, Bergamo, ItalyCorrespondence: Camilla Sculco Email c.sculco@hnpgroup.euPurpose: Telephone coaching and health apps are effective means to support subjects with diabetes. Patient support programs (PSP) on type 2 diabetes are scanty, and none has been conducted in Italy. In a pilot phase, conducted during the COVID-19 pandemic, we aimed to examine the feasibility and acceptance of such program.Methods: The “BE THere for diabetes CARE” (BETHCARE) project is a real-world PSP conducted through telephone and digital coaching system to provide educational and emotional support to Italian adults with diabetes receiving long-acting basal insulin degludec. This pilot phase was conducted in 11 centres that enrolled a total of 63 patients (89% with type-2 diabetes). Counselors contacted patients to define a set of emotional, physical and nutritional targets, and monitoring calls were performed on a monthly basis. Data were collected on socio-demographic and anthropometric characteristics, selected clinical information, quality of life, achievement of targets and patient satisfaction.Results: Fifty-eight subjects (92%) chose to participate by telephone and 5 (8%) by mobile app. Most participants (ie, ≥ 80%) evaluated counselors’ calls “useful/very useful”, duration of calls “adequate/adequately long”, were satisfied with the educational pathway and declared to be more confident in diabetes management after the program. About half of participants were confident to maintain their targets after the PSP. Achievement of nutritional targets improved during counseling, from a mean score of 1.56 at week 1 to 1.88 at week 16 (p-value = 0.03). No significant variations in the achievement of emotional and physical targets emerged. Mean patients weight decreased from 84.9 kg (week 1) to 84.3 kg (week 4) and then levelled off (84.2 kg, week 16).Conclusion: This project demonstrated the feasibility and patient appreciation of a PSP in diabetes care, which is particularly important for a chronic disease of the elderly and during a pandemic period when face-to-face counseling is problematic.Keywords: diabetes, patient support programs, real-world

Introduction The epidemiology of atopic dermatitis (AD) is largely different in preschool and schoolchildren. We summarized the available epidemiological data on schoolchildren (6-11 years) and adolescents (12-17 years) in Italy and reviewed information on systemic treatments for moderate-to-severe AD in adolescents. Evidence acquisition In January 2019, we searched for data on prevalence and/or incidence of AD and on the efficacy, effectiveness and safety of systemic AD therapies. Papers were evaluated and selected, and relevant information was extracted. Twenty papers from 17 studies reported original epidemiological information on AD in Italy. Evidence synthesis Most studies were conducted before 2005. Though variations emerged between studies, the lifetime prevalence of AD was estimated between 15%-17% in schoolchildren and between 8%-13% in adolescents. The (12-months) period prevalence of AD was estimated between 8%-10% in children and between 8%-11% in adolescents. Up-to-date information on the prevalence of severe AD is not available. Cyclosporine A may be used in pediatric age patients (children and adolescents) with persistent or severe AD refractory to topical treatments, but its use has several limitations, and is not recommended in patients younger than 16 years. The treatment paradigm of AD is still far from being satisfactory. Conclusions We provided a quantitative synthesis of AD epidemiology in Italian schoolchildren and adolescents. Recent data are needed, as most information dates back to the 1990s or early 2000s, and data on the incidence of AD, the proportion of severe cases, and treatment of severe cases in the Real-World are scanty.

BACKGROUND: The role of allium vegetables on gastric cancer (GC) risk remains unclear. METHODS: We evaluated whether higher intakes of allium vegetables reduce GC risk using individual participant data from 17 studies participating in the "Stomach cancer Pooling (StoP) Project", including 6097 GC cases and 13,017 controls. Study-specific odds ratios (ORs) were pooled using a two-stage modelling approach. RESULTS: Total allium vegetables intake was inversely associated with GC risk. The pooled OR for the highest versus the lowest study-specific tertile of consumption was 0.71 (95% confidence interval, CI, 0.56-0.90), with substantial heterogeneity across studies (I(2) > 50%). Pooled ORs for high versus low consumption were 0.69 (95% CI, 0.55-0.86) for onions and 0.83 (95% CI, 0.75-0.93) for garlic. The inverse association with allium vegetables was evident in Asian (OR 0.50, 95% CI, 0.29-0.86) but not European (OR 0.96, 95% CI, 0.81-1.13) and American (OR 0.66, 95% CI, 0.39-1.11) studies. Results were consistent across all other strata. CONCLUSIONS: In a worldwide consortium of epidemiological studies, we found an inverse association between allium vegetables and GC, with a stronger association seen in Asian studies. The heterogeneity of results across geographic regions and possible residual confounding suggest caution in results interpretation.

BACKGROUND AND OBJECTIVES Infantile hemangiomas (IHs) are the most common benign tumors in infanthood. Although they are often self-limiting, management of IHs is still controversial because residual lesions may persist in some cases. The aim of this study is to report our experience with patients affected with IH and investigate the frequency of residual lesions in treated versus untreated patients. STUDY DESIGN/MATERIALS AND METHODS This retrospective observational study enrolled patients with IHs evaluated over the past 10 years. Patients were managed with systemic or local pharmacotherapy, laser therapy, a combination of them, or with observation only. RESULTS A total of 432 patients were included: 71% received one or more therapies for IHs; 75.2% of untreated patients had at least one residual lesion compared with 41.4% of treated patients (P

Despite widespread use of decitabine to treat acute myeloid leukaemia (AML), data on its effectiveness and safety in the real-world setting are scanty. Thus, to analyze the performance of decitabine in clinical practice, we pooled together patient-level data of three multicentric observational studies conducted since 2013 throughout Italy, including 306 elderly AML patients (median age 75 years), unfit for intensive chemotherapy, treated with first-line decitabine therapy at the registered schedule of 20 mg/m2 /iv daily for 5 days every 4 weeks. Overall response rate (ORR), overall survival (OS) curves, and multivariate hazard ratios (HRs) of all-cause mortality were computed. Overall, 1940 cycles of therapy were administered (median, 5 cycles/patient). A total of 148 subjects were responders and, therefore, ORR was 48.4%. Seventy-one patients (23.2%) had complete remission, 32 (10.5%) had partial remission, and 45 (14.7%) had haematologic improvement. Median OS was 11.6 months for patients with favourable-intermediate cytogenetic risk and 7.9 months for those with adverse cytogenetic risk. Median relapse-free survival after CR was 10.9 months (95% confidence interval [CI]: 8.7-16.0). In multivariate analysis, mortality was higher in patients with adverse cytogenetic risk (HR=1.58; 95% CI: 1.13-2.21) and increased continuously with white blood cell (WBC) count (HR=1.12; 95% CI: 1.06-1.18). A total of 183 infectious adverse events occurred in 136 patients mainly (>90%) within the first five cycles of therapy. This pooled analysis of clinical care studies confirmed, outside of clinical trials, the effectiveness of decitabine as first-line therapy for AML in elderly patients unfit for intensive chemotherapy. An adverse cytogenetic profile and a higher WBC count at diagnosis were, in this real life setting, unfavourable predictors of survival.

Sulphurous thermal water inhalations have been traditionally used in the treatment of airway diseases. In vivo and in vitro studies reported that they ameliorate mucus rheology, mucociliary clearance and reduce inflammation. Cigarette smoking induces an inflammatory damage, with consequent remodeling of respiratory airways, which in turn affect pulmonary functions. Despite the anti-inflammatory effects of H2S are clinically documented in several airway inflammatory diseases, data on the effects of sulphurous thermal water treatment on pulmonary function and biomarkers of airways inflammation in smokers are still scant. Therefore, we investigated whether a conventional cycle of sulphurous thermal water inhalation produced changes in markers of respiratory inflammation and function. A cohort of 504 heavy current and former smokers underwent 10-day cycles of sulphurous thermal water inhalation. Pulmonary function and metabolic analyses on exhaled breath condensate were then performed at day 0 and after the 10-day treatment. Spirometric data did not change after spa therapy, while exhaled breath condensate analysis revealed that a single 10-day cycle of sulphurous water inhalation was sufficient to induce a statistically significant increase of citrulline levels along with a decrease in ornithine levels, thus shifting arginine metabolism towards a reduced nitric oxide production, i.e. an anti-inflammatory profile. Overall, sulphurous thermal water inhalation impacts on arginine catatabolic intermediates of airways cells, shifting their metabolic balance towards a reduction of the inflammatory activity, with potential benefits for smokers.

Low socioeconomic position (SEP) is a strong risk factor for incidence and premature mortality from several cancers. Our study aimed at quantifying the association between SEP and gastric cancer (GC) risk through an individual participant data meta-analysis within the “Stomach cancer Pooling (StoP) Project”. Educational level and household income were used as proxies for the SEP. We estimated pooled odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) across levels of education and household income by pooling study-specific ORs through random-effects meta-analytic models. The relative index of inequality (RII) was also computed. A total of 9,773 GC cases and 24,373 controls from 25 studies from Europe, Asia and America were included. The pooled OR for the highest compared to the lowest level of education was 0.60 (95% CI, 0.44–0.84), while the pooled RII was 0.45 (95% CI, 0.29–0.69). A strong inverse association was observed both for noncardia (OR 0.39, 95% CI, 0.22–0.70) and cardia GC (OR 0.47, 95% CI, 0.22–0.99). The relation was stronger among H. pylori negative subjects (RII 0.14, 95% CI, 0.04–0.48) as compared to H. pylori positive ones (RII 0.29, 95% CI, 0.10–0.84), in the absence of a significant interaction (p = 0.28). The highest household income category showed a pooled OR of 0.65 (95% CI, 0.48–0.89), while the corresponding RII was 0.40 (95% CI, 0.22–0.72). Our collaborative pooled-analysis showed a strong inverse relationship between SEP indicators and GC risk. Our data call for public health interventions to reduce GC risk among the more vulnerable groups of the population. This project was supported by the “Associazione Italiana per la Ricerca sul Cancro” (AIRC), Projects no. 16715 and 21378 (Investigator Grant), by the “Fondazione Italiana per la Ricerca sul Cancro” (FIRC) and by the Italian Ministry of Health (Young Researchers, GR-2011-02347943 to SB). MR is grateful to the FIRC who supported his work from 2015 to 2017. Our study was also funded by FEDER through the Operational Programme Competitiveness and Internationalization and national funding from the Foundation for Science and Technology – FCT (Portuguese Ministry of Science, Technology and Higher Education) under the Unidade de Investigação em Epidemiologia – Instituto de Saúde Pública da Universidade do Porto (EPIUnit; POCI-01-0145-FEDER-006862; Ref. UID/DTP/04750/2013). AF (PD/BD/105823/2014) was awarded an individual scholarship through national funding from FCT/MCTES.

Purpose: Immune-checkpoint inhibitors (ICI) have improved the survival of patients with non–small cell lung cancer (NSCLC). However, only a subset of patients benefit from ICIs, and the role of PD-L1 as predictive biomarker is still debated. A plasma immune-related miRNA-signature classifier (MSC) was established in lung cancer screening settings to identify the lethal form of the disease in early stages. In this exploratory study, we tested the efficacy of the MSC as prognostic marker in patients with advanced NSCLC treated with ICIs. Experimental Design: The MSC risk level was prospectively assessed in a consecutive series of 140 patients with NSCLC before starting treatment with ICIs. Overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in strata of PD-L1 and MSC alone or combined were considered as endpoints. Multiple plasma samples to monitor MSC risk level during treatment were also profiled. Results: Adequate tissue and plasma samples were available from 111 (79%) and 104 (75%) patients with NSCLC, respectively. MSC risk level was associated with ORR (P = 0.0009), PFS [multivariate HR = 0.31; 95% confidence interval (CI), 0.17–0.56; P = 0.0001], and OS (multivariate HR = 0.33; 95% CI, 0.18–0.59; P = 0.0002). The combination of MSC and PD-L1 stratified patients into three risk groups having 39%–18%–0% 1-year PFS (P < 0.0001) and 88%–44%–0% 1-year OS (P < 0.0001), according to the presence of 2–1–0 favorable markers. During treatment, MSC risk level decreased or remained low until tumor progression in patients with responsive or stable disease. Conclusions: The plasma MSC test could supplement PD-L1 tumor expression to identify a subgroup of patients with advanced lung cancer with worse ORR, PFS, and OS in immunotherapy regimens.

Purpose: The effects of growth hormone (GH) replacement on bone mass and body composition in adult with GH deficiency (AGHD) are still debated with regard to their persistence in the long term. Moreover, the impact of gender on the response to GH is controversial. Aim of this study was to evaluate the long-term effects of rhGH replacement on bone mass and body composition in a monocentric cohort of patients with AGHD.Methods: Data from 138 patients with AGHD (34.3 ± 14.3 years, 48 women and 90 men) treated with rhGH for a period of at least 3 years up to a maximum of 10 were retrospectively collected. Bone mineral density (BMD) at the lumbar spine, femur, and radius, and total and truncular body composition were evaluated by dual energy X-ray absorption (DXA) before and during treatment. Clinical and laboratory evaluations were performed before and during the treatment period on an annual basis.Results: Lumbar spine BMD consistently increased in males, while in females decreased after a transient improvement observed during the first 4 years of therapy. There were no significant changes in femoral BMD in either sexes, while a progressive increase at radius was observed only in males. Lean mass significantly increased in both sexes, while fat mass decreased only in males.Conclusions: In AGHD patients long-term rhGH replacement therapy induces a positive effect with regard to bone mass and body composition. A sexual dimorphism in the response to treatment is evident, with males displaying more favorable outcome.

ObjectiveIn 2017, the Italian Medicines Agency (Agenzia Italiana del Farmaco, AIFA) introduced a standardised process to appraise innovativeness of medicines. Innovative medicines are provided speeder market access and dedicated funds. Innovativeness criteria are: unmet therapeutic need, added therapeutic value and quality of the evidence (Grading of Recommendations Assessment, Development and Evaluation method). We investigated the role played by these three criteria on the final decision aimed to understand how the new Italian innovativeness appraisal framework was implemented.DesignA desk research gathered AIFA’s appraisal reports on innovativeness and data analyses were conducted. No patients were directly involved in this study.Setting and participantsWe scrutinised all 77 appraisal reports available on AIFA’s website (2017–2020).Primary and secondary outcome measuresThe impact of the three domains on final decision was investigated through a series of univariate analyses.ResultsAmong 77 appraisal reports on innovativeness available, 49 (64%) and 28 (36%) were for oncology and non-oncology medicines, respectively. The appraisals were equally distributed among ‘fully innovative’ (36%), ‘conditionally innovative’ (30%) and ‘not innovative’ (34%). Added therapeutic value was the most important driver on innovativeness decision, followed by quality of the evidence. Drugs for rare diseases and with paediatric/mixed indications were appraised ‘innovative’ by a larger proportion, but no statistical significance was found.ConclusionsDespite some limitations, including the moderate number of appraisals, this paper provides an insight into the determinants of innovativeness appraisals for medicines in Italy and the accuracy of the appraisal process. This has important implications in terms of transparency and accountability in the prioritisation process applied to innovative medicines.

Over the last few decades, social epidemiology has developed as a solid epidemiology branch, focusing on understanding how social experiences influence population health. At the same time, growing of collaborative and interdisciplinary research led to the proliferation of multi-institutional consortia, able to assess and quantify risk-disease associations of interest with a higher degree of accuracy, to explore subgroups of the population, and to investigate interactions between environmental, genetic, and socioeconomic factors. Increasing evidence shows that low Socioeconomic Position (SEP) is a strong determinant of morbidity and premature mortality from selected non-communicable diseases, including several cancers. Thus, an accurate quantification of the impact of SEP on cancer risk is of major importance to plan public health interventions for cancer incidence and socioeconomic disparities reduction. Large data consortia as the Stomach Cancer Pooling (StoP) Project and the International Head and Neck Cancer Epidemiology (INHANCE), in which the University of Milan is proactively involved, allowed investigators to address the effects of education and household income, the main SEP determinants, on gastric and head and neck cancer, respectively, confirming the existence of a strong association between low SEP and those major neoplasms.

Patient quality of life (QoL) is a pivotal parameter, which is often used by clinicians to evaluate how treatments and therapies influence patients’ functionality and emotional state, aiming to ameliorate interventions and their outcomes. Currently, the majority of questionnaires assessing the QoL are designed with the main contribution of clinicians and, therefore, include items that are cantered on the disease rather than on its multifaceted impact on people’s life. The failure to truly grasp the patients’ perspective, their needs, aspirations, perceptions and emotional state, is a major drawback that sets medical care on clinical parameters alone. We aimed to bridge this gap by establishing an innovative patient-designed QoL index to provide a new, unbiased tool considering the patients’ perception of their own well-being. Based predominantly on patients’ contribution, we defined specific areas (physical, emotional, social, functional, economical) and the respective characterizing features, and applied a pseudo-Delphi methodology combined with customer-satisfaction techniques. For each feature, the degree of agreement and the importance were assessed on a Likert scale. A synthetic QoL index was created by weighting the importance of each item. The methodology tested led to the development of a valid patient-designed QoL index, providing a way forward that could potentially be applied to many different conditions. The areas and the features included are indeed common to all patients, irrespective of their disease. We found that the process of methodology development enhanced the patients’ awareness of their subjective experience with the disease, and enabled them to better present their situation to the clinicians. The patient-designed QoL index provides a descriptive model that can be helpful to patients, clinicians and third parties and that can be further integrated with clinical details to obtain an overall view of the course of treatment for each patient.

Epidermolysis Bullosa (EB) is a group of genetic conditions that cause fragile and blistering skin. Although there are different types of EB, which differ in severity, their signs and symptoms overlap. As a result of this disorder, patients face an unbearable burden in their lives, and their Quality of Life (QoL) is negatively affected at every life cycle stage. Nevertheless, the assessment of the quality of life of these patients is scanty. This project aims to develop a patient-centered questionnaire to assess the QoL of EB patients. This tool will be a valid aid for clinicians to understand patients better and identify the areas that need more attention; moreover, it will allow them to follow the patients over time and evaluate the impact of any treatments. The methodological process to develop the questionnaire consisted of two phases: firstly, a critical review of scientific literature was performed; secondly, a pseudo-Delphi study was carried out. A multidisciplinary panel (including patients, caregivers, and clinicians) actively participated in round tables to discuss the main areas of interest. Starting from this initial set of areas and through the repetition of Delphi (up to three rounds), a gradual refinement of the statements was carried out to define a list of items to be included in an easy-to-use but meaningful questionnaire. The final patient-centered questionnaire is thus able to measure the QoL beyond the physical symptoms and the clinical evolution of the disease, encompassing functional autonomy, psycho-emotional state, social relations and the working field.

The generation and storage of data have dramatically increased worldwide in the last two decades. Computing and networking capabilities combined with openness enhance the potential impact of the accumulated data, offering society an opportunity to drive massive social, political, and economic change. Open data is a recent approach. In summary, open data can be freely used, shared, and built-on by anyone, anywhere, for any purpose. Though health open data are not regularly available, it is estimated that the value of a more effective use of data resources in the US health care sector alone could be worth USD 300 billion annually. To date, Open Government data count more than 10,000 datasets in Italy but only a few concern healthcare. In this chapter, we will try to clarify what open data are and, after having recalled the principles of Open Government, the attention will draw on open data in the health and pharmaceutical context, focusing on the state of the art in Italy and worldwide.

Background Over the past number of years, N-methyl-D-aspartate (NMDA) inhibitory drugs, like ketamine, have been introduced as adjuvant treatments for postoperative acute pain, within a multimodal approach. A further extension of this strategy could be the use of opioids with NMDA receptor (NMDAr) antagonism activity for control of postoperative pain. Methadone has a unique pharmacodynamic profile: it is both a μ-agonist and an NMDAr-blocker. Objective We designed this study to investigate the precise contribution of NMDAr antagonism in methadone-induced analgesia. Design Single-centre, prospective, randomised, double-blind study. Setting National Cancer Center - Fondazione IRCCS Istituto Nazionale Tumori Milano; patients were recruited between March 2010 and June 2012. Patients Ninety-six patients scheduled for an open laparotomy for anterior resection of the rectum. Interventions We randomly assigned patients to four groups: 0-Mo (placebo and morphine), K-Mo [S(+)-ketamine and morphine], 0-Me (placebo and methadone), K-Me [S(+)-ketamine and methadone]. Main outcome measures The primary end-point was the extent of mechanical static (punctuate) hyperalgesia to von Frey hair stimulation lateral to the surgical incision. Results Peri-incisional hyperalgesia was 8.4 cm (95% confidence interval, 1.5 to 15.41) lower in the treatment group (K-Me) compared with the control group (0-Mo) at 24 h after surgery (P = 0.02). No significant differences were observed between the groups at 48 h after surgery (P = 0.88). Both groups treated with methadone had significantly lower pain during rest and movement, as measured with a Numerical Rating Scale at 24 h. At 48 h, only the movement Numerical Rating Scale was significantly lower. No difference occurred in opioid consumption. Conclusion Methadone provides effective control of acute postoperative pain, independently, by modulation of the hyperalgesia mechanism. Clinical trial registration ClinicalTrials.gov, no.: NCT01594047.

IntroductionSitagliptin is a dipeptidyl peptidase 4 inhibitor for the treatment of type 2 diabetes (T2D). Limited real-world data on its effectiveness and safety are available from an Italian population.Research design and methodsWe evaluated long-term clinical data from the single-arm PERsistent Sitagliptin Treatment & Outcomes (PERS&O) study, which collected information on 440 patients with TD2 (275 men, 165 women; mean age 64.1 years; disease median duration: 12 years) treated with sitagliptin ‘add-on’. For each patient, we estimated the 10-year cardiovascular (CV) risk using the UK Prospective Diabetes Study (UKPDS) Risk Engine (RE). Drug survival was evaluated using Kaplan-Meier survival curves; repeated measures mixed effects models were used to evaluate the evolution of glycated hemoglobin (HbA1c) and CV risk during sitagliptin treatment.ResultsAt baseline, most patients were overweight or obese (median body mass index (BMI) (kg/m2) 30.2); median HbA1c was 8.4%; median fasting plasma glucose: 172 mg/dL; median UKPDS RE score: 24.8%, being higher in men (median 30.2%) than in women (median 17.0%) as expected. Median follow-up from starting sitagliptin treatment was 5.6 years. From Kaplan-Meier curves, the estimated median drug survival was 32.8 months when considering discontinuation for any cause and 58.4 months when considering discontinuation for loss of efficacy. A significant improvement in HbA1c was evident during treatment with sitagliptin (pConclusionPatients with T2D treated with sitagliptin achieved an improvement in metabolic control and a reduction in CV risk and did not experience relevant adverse events.

Background Sentinel Node Biopsy (SNB) is routinely performed for primary melanoma, but its role in the treatment of Local Recurrence (LR) and In-Transit metastasis (IT) is controversial. This study aims to assess the role of SNB in melanoma patients who developed first loco-regional recurrence. Methods A series of consecutive melanoma patients who received SNB for a first IT or LR at the National Cancer Institute of Milan, Italy, from 2000 to 2015 were selected from a prospective database. Clinicopathological characteristics were analyzed. Results Seventy-two patients met selection criteria. Forty-three patients (59.7%) received SNB for LR and 29 (40.3%) for IT. The average interval between treatment of primitive melanoma and first recurrence diagnosis was 19 months (interquartile range: 6.9–49.0). SN identification rate was 97.2%. SN positivity was detected in 26 (37.1%) patients. The SN-positive ratein melanoma patients who had LR or IT was significantly higher than reported for primary tumours. Of patients with nodal involvement 17 had LR and 9 IT lesions. Disease Free Survival (DFS) was slightly higher in SN negative patients, in the absence of statistically significant differences. Overall Survival (OS) analysis showed similar values in the two groups. Conclusion Since DFS and OS do not show significant differences between SN negative and positive patients, our data do not give clear indications about performing SNB in case of first LR or IT. However, we suggest submitting patients with LR to this procedure to obtain a more accurate staging and eventually candidate these patients to adjuvant treatment.

To test HRCT with either visual or quantitative analysis in both short-term and long-term follow-up of stable IPF against long-term (transplant-free) survival, beyond 2 years of disease stability. Fifty-eight IPF patients had FVC measurements and HRCTs at baseline (HRCT0), 10–14 months (HRCT1) and 22–26 months (HRCT2). Visual scoring, CALIPER quantitative analysis of HRCT measures, and their deltas were evaluated against combined all-cause mortality and lung transplantation by adjusted Cox proportional hazard models at each time interval. At HRCT1, a ≥ 20% relative increase in CALIPER-total lung fibrosis yielded the highest radiological association with outcome (C-statistic 0.62). Moreover, the model combining FVC% drop ≥ 10% and ≥ 20% relative increase of CALIPER-total lung fibrosis improved the stratification of outcome (C-statistic 0.69, high-risk category HR 12.1; landmark analysis at HRCT1 C-statistic 0.66, HR 14.9 and at HRCT2 C-statistic 0.61, HR 21.8). Likewise, at HRCT2, the model combining FVC% decrease trend and ≥ 20% relative increase of CALIPER-pulmonary vessel–related volume (VRS) improved the stratification of outcome (C-statistic 0.65, HR 11.0; landmark analysis at HRCT1 C-statistic 0.62, HR 13.8 and at HRCT2 C-statistic 0.58, HR 12.6). A less robust stratification of outcome distinction was also demonstrated with the categorical visual scoring of disease change. Annual combined CALIPER -FVC changes showed the greatest stratification of long-term outcome in stable IPF patients, beyond 2 years. • Longitudinal high-resolution computed tomography (HRCT) data is more helpful than baseline HRCT alone for stratification of long-term outcome in IPF. • HRCT changes by visual or quantitative analysis can be added with benefit to the current spirometric reference standard to improve stratification of long-term outcome in IPF. • HRCT follow-up at 12–14 months is more helpful than HRCT follow-up at 23–26 months in clinically stable subjects with IPF.

An association between heavy alcohol drinking and gastric cancer risk has been recently reported, but the issue is still open to discussion and quantification. We investigated the role of alcohol d ...

Introduction Debate remains about prognostic factors in primary Merkel cell carcinoma (MCC). We investigated clinicopathological factors as determinants of survival in patients with MCC submitted to sentinel node biopsy. Methods Sixty-four consecutive patients treated for a primary MCC were identified from a prospectively maintained database at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. Time to events outcome were described by product limit estimators and proportional hazards model was used to investigate the association between outcome and potential predictors. Results The most common site of primary tumor was lower limbs (56.3%). The size of primary lesion was ≤2 cm in 67.2% of cases. Presence of residual disease after the diagnostic surgical excision was observed in 28% of cases. All patients received sentinel node biopsy (SNB) and a SN positivity was detected in 26.6%. The median follow up was 78 months. Disease recurrence occurred in 17 patients (26.6%). In the SN negative group 10 recurrences occurred (21.3%), whereas 7 (41.2%) were found in SN positive one. Nine patients SN negative (19.1%) died of disease and 3 (17.6%) among SN positive. SN status was not associated with survival (p = 0.78). Neither age, gender, size and site of primary tumor resulted predictors of patients' outcome. The presence of residual tumor in the specimen of the wide local excision, after the diagnostic surgical excision, was the only variable associated with survival (p = 0.03). Conclusions Presence of residual tumor in the specimen of the wide local excision is the main prognostic factor in MCC patients.

Background Incidence and prevalence of Crohn’s disease (CD) have increased during the last decades in several world areas. Italian data on CD are scattered between various administrative, educational and scientific sources, and findings are poorly summarized. Aims We conducted a review focusing not only on prevalence and incidence of CD in Italy, but also on mortality, treatments, delayed diagnosis and hospitalization. Methods In October 2015, we searched for quantitative epidemiological data of CD using PubMed/Medline, EMBASE, and the Cochrane Database of Systematic Reviews. We also conducted searches on selected web resources for databases and educational publications. Results Sixteen studies reporting data on incidence of CD from Italy were found. Incidence rates of CD in the early 2010’s in Italy were 3.5–4 cases per 100,000 inhabitants per year. Ten investigations provided data on CD prevalence, with large variability between Italian areas. Most studies considering data at two or more time points or across consecutive time periods reported increasing incidence or prevalence of CD. Conclusion This review of Italian epidemiological data indicates that CD incidence and prevalence are continuing to (moderately) increase. Diagnostic delay, treatments, hospitalization and surgery for CD in Italy were also reviewed and quantified, though information is somewhat limited.

Background and purpose Adenoid cystic carcinoma (ACC) of salivary glands is characterized by long-term distant metastasis, most commonly in lungs. No agreement has been reached about the role of surgical treatment of pulmonary lesions. We evaluated the long-term results of lung metastasectomy for ACC in order to identify factors that should be taken into account in selecting patients eligible for surgery and treatment planning. Patients and methods A retrospective study was conducted on 109 patients selected from our institutional experience and from the International Registry of Lung Metastases. Survival was calculated by Kaplan-Meier estimate and prognostic factors endowed with a predictive power for most other metastatic cancers were investigated. Results The cumulative survival was 66.8% at 5 years and 40.5% at 10 years. In patients with a disease-free interval (DFI) greater than 36 months, the overall survival was 76.5% at 5 years. Survival in case of complete surgical resection was 69.5% at 5 years. Multivariate analysis confirmed DFI and completeness of resection resulted in the best prognostic variables. Discussion Lung metastasectomy should be considered as a therapeutic option to achieve local control of disease when 2 conditions are met: (1) complete surgical resection is feasible and (2) the time to pulmonary relapse after primary tumor treatment is greater than 36 months. Symptomatic benefits of an incomplete lung resection in slow-growing tumors such as ACC remain uncertain. The turning point in the management of disseminated cancers will be clarified with biological profiling of ACC and the development of targeted therapies.

Diets high in glycemic index (GI) and glycemic load (GL) have been related to an increased risk of selected cancers, but additional quantification is required. We updated a systematic review and meta-analysis published in 2015 to May 2019 to provide quantitative information on GI/GL and cancer risk. Relative risks (RR) and the corresponding 95 % confidence intervals (CI) for the highest versus the lowest categories of GI and GL were extracted from selected studies and pooled using random-effects models. Twenty reports (&gt, 22,000 cancer cases) have become available after January 2015, and 15 were added to the meta-analyses by cancer sites, which considered a total of 88 investigations. The five additional reports were reviewed, but not included in the meta-analyses, since data were inadequate to be pooled. For hormone-related cancers, summary RRs for the highest versus lowest GI and GL intakes were moderately increased. They ranged from 1.04 (breast) to 1.12 (endometrium) for GI and from 1.03 (prostate) to 1.22 (ovary) for GL, of borderline significance. High GI was associated with small increased risks of colorectal (summary RR for GI: 1.20, 95% CI, 1.07&ndash, 1.34&mdash, GL: 1.09, 95% CI, 0.97&ndash, 1.22, 19 studies), bladder (GI: 1.25, 95% CI, 1.11&ndash, 1.41&mdash, GL: 1.10, 95% CI, 0.85&ndash, 1.42, four studies) and kidney cancers (GI: 1.16, 95% CI, 1.02&ndash, 1.32&mdash, GL: 1.14, 95% CI, 0.81&ndash, 1.60, five studies). GL was not significantly related to those cancer sites. Stomach, prostate and lung cancers were not associated with GI and GL. The present analysis, based on an updated comprehensive evaluation of the epidemiological literature, indicates moderate unfavorable effects of high versus low GI on colorectal, and possibly bladder and kidney cancers, and a possible moderate positive association between GL and endometrial cancer.

Diets rich in vegetables and fruit have been associated with reduced risk of gastric cancer, and there is suggestive evidence that citrus fruits have a protective role. Our study aimed at evaluating and quantifying the association between citrus fruit intake and gastric cancer risk. We conducted a one-stage pooled analysis including 6,340 cases and 14,490 controls from 15 case–control studies from the stomach cancer pooling (StoP) project consortium. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) of gastric cancer across study-specific tertiles of citrus fruit intake (grams/week) were estimated by generalized linear mixed effect models, with logistic link function and random intercept for each study. The models were adjusted for sex, age, and the main recognized risk factors for gastric cancer. Compared to the first third of the distribution, the adjusted pooled OR (95% CI) for the highest third was 0.80 (0.73–0.87). The favourable effect of citrus fruits increased progressively until three servings/week and leveled off thereafter. The magnitude of the association was similar between cancer sub-sites and histotypes. The analysis by geographic area showed no association in studies from the Americas. Our data confirm an inverse association between citrus fruits and gastric cancer and provide precise estimates of the magnitude of the association. However, the null association found in studies from America and in some previous cohort studies prevent to draw definite conclusions on a protective effect of citrus fruit consumption. © 2018 UICC

Background: The hygiene hypothesis proposes that reduced exposure to infectious agents in early life would explain the increase of allergic and autoimmune diseases observed over the past decades in high-income countries. Methods: We conducted a matched case-control study on incident atopic dermatitis (AD). Cases were 426 outpatient children with a first diagnosis ofincident AD. Controls were 426 children attending a pediatric/dermatological visit for nonatopic disorders matched to cases (1:1). Particular attention was paid to the time elapsed between the markers of microbial exposure and disease onset, and we considered for controls the same time window of exposures from birth as his/her matched case. Odds ratios (ORs) were computed using multivariable conditional logistic regression models, according to center, sex, age, and period of enrollment, and including as potential confounders a family history of any allergy in parents, type of delivery, having siblings, keeping pets, age at weaning, and having had ≥4 infections. Results: The OR of AD first occurrence was 0.35 (P-value=.039) for children who had experienced ≥4 infections compared with those with no infections. A decreasing trend in risk was observed with increasing number of siblings (P-value=.023), the protective effect reaching about 40% for children with 2 or more siblings (OR=0.62; P-value=.048). Pet keeping, in particular daily contact with dogs, was inversely associated with AD risk (OR=0.40; P-value=.004). Conclusions: These results support the hygiene hypothesis in its broad sense. Early-life environmental exposures, including pathogens and commensals, act as “microbes contact carriers” influencing immune system balance early in life.