Italian Health Ministry Research Articles

Alterations of the intestinal mucus layer correlate with dysbiosis and immune dysregulation in human Type 1 Diabetes

In preclinical models of Type 1 Diabetes (T1D) the integrity of the gut barrier (GB) is instrumental to avoid dysregulated crosstalk between the commensal microbiota and immune cells and to prevent autoimmunity. The GB is composed of the intestinal epithelial barrier (IEB) and of the mucus layer containing mucins and antimicrobial peptides (AMPs) that are crucial to maintain immune tolerance. In preclinical models of T1D the alterations of the GB primarily affect the mucus layer. In human T1D increased gut permeability and IEB damage have been demonstrated but the integrity of the mucus layer was never assessed. We evaluated GB integrity by measuring serological markers of IEB damage (serological levels of zonulin) and bacterial translocation such as lipopolysaccharide binding protein (LBP) and myeloid differentiation protein 2 (MD2), and mRNA expression of tight junction proteins, mucins and AMPs in intestinal tissue of T1D patients and healthy controls (HC). Simultaneously, we performed immunological profiling on intestinal tissue and 16S rRNA analysis on the mucus-associated gut microbiota (MAGM). Our data show a GB damage with mucus layer alterations and reduced mRNA expression of several mucins (MUC2, MUC12, MUC13, MUC15, MUC20, MUC21) and AMPs (HD4 and HD5) in T1D patients. Mucus layer alterations correlated with reduced relative abundance of short chain fatty acids (SCFA)-producing bacteria such as Bifidobacterium dentium, Clostridium butyricum and Roseburia intestinalis that regulate mucin expression and intestinal immune homeostasis. In T1D patients we also found intestinal immune dysregulation with higher percentages of effector T cells such as T helper (Th) 1, Th17 and TNF-α+ T cells. Our data show that mucus layer alterations are present in T1D subjects and associated with dysbiosis and immune dysregulation. Research Grants from the Juvenile Diabetes Foundation (Grant 1-INO-2018-640-A-N to MF and 2-SRA-2019-680-S-B to JD) and from the Italian Ministry of Health (Grant RF19-12370721 to MF).

A Decision-tree Approach to Stratify DLBCL Risk Based on Stromal and Immune Microenvironment Determinants.

A Decision-tree Approach to Stratify DLBCL Risk Based on Stromal and Immune Microenvironment Determinants.

Danazol Treatment for Thrombocytopenia in Myelodysplastic Syndromes: Can an "Old-fashioned" Drug be Effective?

Danazol Treatment for Thrombocytopenia in Myelodysplastic Syndromes: Can an "Old-fashioned" Drug be Effective?

The EASY-NET research programme: background, structure, and methodology

This is the first contribution of a series of interventions describing the EASY-NET research program (Bando Ricerca Finalizzata 2016, funds 2014-2015; NET-2016-02364191). Here, the objective is to illustrate the background and the research question, the structure and organization, the methodologies and the expected results of the programme. The main theme is audit&feedback (A&F), a proven and widespread technique for improving the quality of health care. EASY-NET, funded by the Italian Ministry of Health and by the governments of the participating Italian Regions, starts its research activities in 2019 with the aim of evaluating the effectiveness of A&F in improving care for different clinical conditions in various organizational and legislative contexts. The research network involves seven Italian Regions, each conducting specific research activities described by as many work packages (WP): Lazio (the leading Region, coordinator of the research activities), Friuli Venezia Giulia, Piedmont, Lombardy, Emilia-Romagna, Calabria, and Sicily. The involved clinical areas include the management of chronic diseases, emergency care for acute conditions, surgery in the oncological area, the treatment of heart disease, obstetrics, and the use of caesarean section and post-acute rehabilitation. The involved settings concern the community, the hospital, the emergency room, and the rehabilitation facilities. Different experimental or quasi-experimental study designs are applied in each WP to achieve specific objectives of the specific clinical and organizational context. In all WPs, the process and outcome indicators are calculated on the basis of the Health Information Systems (HIS) and, in some cases, they are integrated with measures obtained from ad hoc data collections. The programme aims to contribute to the scientific evidence on A&F also exploring the obstacles and favourable factors for its effectiveness and to promote its implementation in the health service, with the ultimate aim of improving the access to healthcare and the health outcomes for citizens.

Accuracy, acceptability, and feasibility of diagnostic tests for the screening of Strongyloides stercoralis in the field (ESTRELLA): a cross-sectional study in Ecuador

WHO recommends the implementation of control programmes for strongyloidiasis, a neglected tropical disease caused by Strongyloides stercoralis. Specific recommendations on the diagnostic test or tests to be used for such programmes have yet to be defined. The primary objective of this study was to estimate the accuracy of five tests for strongyloidiasis. Secondary objectives were to evaluate acceptability and feasibility of use in an endemic area. The ESTRELLA study was a cross-sectional study for which we enrolled school-age children living in remote villages of Ecuador. Recruitment took place in two periods (Sept 9-19, 2021, and April 18-June 11, 2022). Children supplied one fresh stool sample and underwent blood collection via finger prick. Faecal tests were a modified Baermann method and an in-house real-time PCR test. Antibody assays were a recombinant antigen rapid diagnostic test; a crude antigen-based ELISA (Bordier ELISA); and an ELISA based on two recombinant antigens (Strongy Detect ELISA). A Bayesian latent class model was used to analyse the data. 778 children were enrolled in the study and provided the required samples. Strongy Detect ELISA had the highest sensitivity at 83·5% (95% credible interval 73·8-91·8), while Bordier ELISA had the highest specificity (100%, 99·8-100). Bordier ELISA plus either PCR or Baermann had the best performance in terms of positive and negative predictive values. The procedures were well accepted by the target population. However, study staff found the Baermann method cumbersome and time-consuming and were concerned about the amount of plastic waste produced. The combination of Bordier ELISA with either faecal test performed best in this study. Practical aspects (including costs, logistics, and local expertise) should, however, also be taken into consideration when selecting tests in different contexts. Acceptability might differ in other settings. Italian Ministry of Health. For the Spanish translation of the abstract see Supplementary Materials section.

Two Cases of TMEM151A-Associated Paroxysmal Dyskinesia in a Single-Center Series of PRRT2-Negative Patients.

Two Cases of TMEM151A-Associated Paroxysmal Dyskinesia in a Single-Center Series of PRRT2-Negative Patients.

Early Multi-Target Treatment of Mild-to-Moderate COVID-19, Particularly in Terms of Non-Steroidal Anti-Inflammatory Drugs and Indomethacin

Recently, in Italy, a flowchart to be used by General Practitioners for the at-home treatment of patients with COVID-19, has been released. It states that early at-home treatment for SARS-CoV-2 infection is possible due to the availability of specific antiviral drugs to be used in at-risk patients, and that non-steroidal anti-inflammatory drugs (NSAIDs) have an important function in combating the virus. Therefore, the use of NSAIDs is not only rational but also effective in cases that cannot be treated using antivirals. These seemingly simple concepts have been applied in Italy since the beginning of the pandemic by doctors that belong to Italian groups created in order to help COVID-19 patients early at home, at a time of organizational difficulties within Italian health institutions and government. However, this approach was largely boycotted by both the Italian Ministry of Health and medical institutions, which mainly suggested the use of paracetamol as symptomatic, and a wait-and-watch approach for the first three days from the onset of symptoms. In this article, we analyze the rationale for the use of NSAIDs and, in particular, the multi-targeted approach including indomethacin in synergism with flavonoids and low-dose aspirin, as early at-home treatment of patients with COVID-19. Applying these simple concepts from the beginning could have reduced the high lethality of the disease during the first two years of the pandemic and prevented hospital overload. In perspective, it is still necessary to systematically address the comparison between different therapeutic approaches to this viral disease on an experimental basis.

Mitigating the economic burden of GnRH agonist therapy for progestogen-resistant endometriosis: why not?

Is it possible to reduce the cost of GnRH agonist treatment for endometriosis by using non-standard dosing regimens? An extended-interval dosing regimen of a 3.75 mg depot formulation of triptorelin injected every 6 weeks instead of every 4 weeks reduces the cost by one-third without compromising the effect on pain relief. Cost constitutes a limit to prolonged GnRH agonists use. Alternative modalities to reduce the economic burden of GnRH agonist treatment have been anecdotally attempted. A systematic review was conducted to evaluate and compare the effect of three alternative modalities for GnRH use in women with endometriosis, i.e. intermittent oestrogen deprivation therapy, reduced drug dosage, and extended-interval dosing regimens of depot formulations. A PubMed and Embase search was initially conducted in October 2022 and updated in January 2023 using the following search strings: (endometriosis OR adenomyosis) AND (GnRH-agonists OR gonadotropin-releasing hormone agonists OR triptorelin OR leuprorelin OR goserelin OR buserelin OR nafarelin). Full-length articles published in English in peer-reviewed journals since 1 January 1980, and reporting original data on GnRH agonist treatment of pain symptoms associated with endometriosis were selected. Information was extracted on study design, GnRH-agonist used, dosage, total duration of therapy, side effects, treatment adherence, and pelvic pain relief. Reviews, commentaries, conference proceedings, case reports, and letters to the editor were excluded. Of the 1664 records screened, 14 studies regarding clinical outcomes associated with the 3 considered alternative modalities for GnRH agonist use were eventually included (intermittent oestrogen deprivation therapy, n = 2; low-dose or 'draw-back' therapy, n = 8; extended-interval dosing regimen, n = 4). Six studies were randomized controlled trials (RCTs) (double blind, n = 2) and eight adopted a prospective cohort design (non-comparative, n = 6; comparative, n = 2). A total of 776 women with endometriosis were recruited in the above studies (intermittent oestrogen deprivation therapy, n = 77; low-dose or 'draw-back' therapy, n = 528; extended-interval dosing regimen, n = 171). Robust data demonstrating cost saving without detrimental clinical consequences were available for the extended-interval dosing regimen only. In particular, the 3.75 mg triptorelin depot preparation inhibits ovarian function for a longer period compared with the 3.75 mg leuprorelin depot preparation, allowing injections every 6 instead of 4 weeks. Based on the cost indicated by the Italian Medicine Agency for the 3.75 mg triptorelin depot preparation, this would translate in a yearly saving of €744.60 (€2230.15-€1485.55; -33.4%). The quality of the evidence reported in the selected articles was not formally evaluated and a quantitative synthesis could not be performed. Some studies were old and the tested therapeutic approaches were apparently obsolete. Only cost containment associated with GnRH analogue use, and not cost-effectiveness, has been addressed. Consuming less resources without negatively impacting on health outcomes carries ethical and practical implications for individuals and the community, as this approach may result in overall increased healthcare access. This study was supported by the Italian Ministry of Health (Ricerca Corrente 2023, IRCCS Ca' Granda Ospedale Maggiore Policlinico Milano). E.S. discloses payments from Ferring for research grants and honoraria from Merck-Serono for lectures. All other authors declare they have no conflict of interest. N/A.

Sarilumab plus standard of care vs standard of care for the treatment of severe COVID-19: a phase 3, randomized, open-labeled, multi-center study (ESCAPE study).

Among interleukin-6 inhibitors suggested for use in COVID-19, there are few robust evidences for the efficacy of sarilumab. Herein, we evaluated the efficacy and safety of sarilumab in severe COVID-19. In this phase 3, open-labeled, randomized clinical trial, conducted at 5 Italian hospitals, adults with severe COVID-19 pneumonia (excluding mechanically ventilated) were randomized 2:1 to receive intravenous sarilumab (400mg, repeatable after 12h) plus standard of care (SOC) (arm A) or to continue SOC (arm B). Randomization was web-based. As post-hoc analyses, the participants were stratified according to baseline inflammatory parameters. The primary endpoint was analysed on the modified Intention-To-Treat population, including all the randomized patients who received any study treatment (sarilumab or SOC). It was time to clinical improvement of 2 points on a 7-points ordinal scale, from baseline to day 30. We used Kaplan Meier method and log-rank test to compare the primary outcome between two arms, and Cox regression stratified by clinical center and adjusted for severity of illness, to estimate the hazard ratio (HR). The trial was registered with EudraCT (2020-001390-76). Between May 2020 and May 2021, 191 patients were assessed for eligibility, of whom, excluding nine dropouts, 176 were assigned to arm A (121) and B (55). At day 30, no significant differences in the primary endpoint were found (88% [95% CI 81-94] in arm A vs 85% [74-93], HR 1.07 [0.8-1.5] in arm B; log-rank p=0.50). After stratifying for inflammatory parameters, arm A showed higher probability of improvement than B without statistical significance in the strata with C reactive protein (CRP)<7mg/dL (88% [77-96] vs 79% [63-91], HR 1.55 [0.9-2.6]; log-rank p=0.049) and in the strata with lymphocytes <870/mmc (90% [79-96]) vs (73% [55-89], HR 1.53 [0.9-2.7]; log-rank p=0.058). Overall, 39/121 (32%) AEs were reported in arm A and 14/55 (23%) in B (p=0.195), while serious AEs were 22/121 (18%) and 7/55 (11%), respectively (p=0.244). There were no treatment-related deaths. The efficacy of sarilumab in severe COVID-19 was not demonstrated both in the overall and in the stratified for severity analysis population. Exploratory analyses suggested that subsets of patients with lower CRP values or lower lymphocyte counts might have had benefit with sarilumab treatment, but this finding would require replication in other studies. The relatively low rate of concomitant corticosteroid use, could partially explain our results. This study was supported by INMI "Lazzaro Spallanzani" Ricerca Corrente Linea 1 on emerging and reemerging infections, funded by Italian Ministry of Health.

Subjects who developed SARS-CoV-2 specific IgM after vaccination show a longer humoral immunity and a lower frequency of infection.

We have previously shown that eliciting SARS-CoV-2-specific IgM after vaccination is associated with higher levels of SARS-CoV-2 neutralizing IgG. This study aims to assess whether IgM development is also associated with longer-lasting immunity. We analysed anti-SARS-CoV-2 spike protein IgG and IgM (IgG-S, IgM-S), and anti-nucleocapsid IgG (IgG-N) in 1872 vaccinees at different time points: before the first dose (D1; w0), before the second dose (D2; w3) at three (w6) and 23 weeks (w29) after D2; moreover, 109 subjects were further tested at the booster dose (D3, w44), at 3 weeks (w47) and 6 months (w70) after D3. Two-level linear regression models were used to evaluate the differences in IgG-S levels. In subjects who had no evidence of a previous infection at D1 (non-infected, NI), IgM-S development after D1 and D2 was associated with higher IgG-S levels at short (w6, p<0.0001) and long (w29, p<0.001) follow-up. Similar IgG-S levels were observed after D3. The majority (28/33, 85%) of the NI subjects who had developed IgM-S in response to vaccination did not experience infection. The development of anti-SARS-CoV-2 IgM-S following D1 and D2 is associated with higher IgG-S levels. Most individuals who developed IgM-S never became infected, suggesting that IgM elicitation may be associated with a lower risk of infection. "Fondi Ricerca Corrente" and "Progetto Ricerca Finalizzata" COVID-2020 (Italian Ministry of Health); FUR 2020 Department of Excellence 2018-2022 (MIUR, Italy); the Brain Research Foundation Verona.

Abstract GS4-08: 10-year results of a phase 3 trial of low-dose tamoxifen in non-invasive breast cancer

Abstract We have previously shown in a phase 3 trial that tamoxifen 5 mg/day for 3 years decreased by 52% the incidence of recurrence of invasive breast cancer or DCIS after a median follow-up of 5.1 years in women with excised non invasive breast disease, including atypical ductal hyperplasia, DCIS or LCIS (DeCensi et al. JCO 2019; 37:1629). Toxicity was negligible with only an extra hot flash per day in the tamoxifen arm compared with the placebo arm. These findings were incorporated into the ASCO clinical practice guidelines for breast cancer risk reduction as an alternative option to standard doses and duration of tamoxifen or aromatase inhibitors in women with non-invasive disease (Visvanathan et al. JCO 2019; 37:3152). In the present study we update the findings on breast cancer recurrence after a median of 9.14 years (interquartile range, IQR, 7.16-10.73) and a total of 10.57 person years of follow up to see if the treatment effect is retained with more events and after a median of approximately 6 years from treatment cessation. We conducted a national multicenter randomized trial of tamoxifen, 5 mg/d or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ. The primary end point was the incidence of invasive breast cancer or ductal carcinoma in situ. Between November 1, 2008, and March 31, 2015, 1,160 women were screened and 500 aged 75 years of age or younger were included in the study. Women with high-grade or comedo/necrotic DCIS received adjuvant radiotherapy of 50 Gy in 25 courses. The mean age was 54 years (standard deviation, 9 years), and 55% of participants were postmenopausal. The mean (SD) body mass index, kg/m2, was 25.7 (4.8) on tamoxifen and 25.3 (4.2) on placebo. Twenty percent had ADH, 11% had LCIS, and the remaining 69% had DCIS. After a median follow-up of 9.14 years, there were 22 neoplastic events (invasive breast cancer or DCIS) with tamoxifen and 37 with placebo (annual rate 11.09, 95% CI, 7-30-16.84 on T vs 19.71, 95% CI, 14.28-27.21 on P per 1,000 person-years; hazard ratio, 0.56; 95% CI, 0.33 to 0.95; P = .03), which resulted in a 5-year number needed to treat of 18. Overall, 71% of the recurrences were invasive breast cancer. The follow-up was updated with the most recent visit within 12 months in two thirds of the participants, so an update of all participants will be performed by Sept 30th with full analysis of neoplastic events, annual risk rate ratio, serious adverse events and deaths. Moreover, an updated analysis of potential effect modifiers will be conducted, including menopausal status, baseline estradiol levels, menopausal symptoms, BMI, smoking status and Ki-67 of the primary lesion. In conclusion, our findings indicate that low dose tamoxifen given for 3 years still significantly prevents recurrences from non-invasive breast cancer after a median of 6 years from treatment cessation, providing a valid prevention/interception option in this disease group. Supported by Ente Ospedaliero Ospedali Galliera, Genova, Italy, the Italian Ministry of Health (RFPS-2006-1-339898), the Italian Association for Cancer Research (IG 2008 Grant No. 5611), and the Italian League against Cancer (LILT 7-08). Citation Format: Andrea De Censi, Matteo Lazzeroni, Matteo Puntoni, Luca Boni, Aliana Guerrieri Gonzaga, Tania Buttiron Webber, Marianna Fava, Irene Maria Briata, Livia Giordano, Maria Digennaro, Laura Cortesi, Fabio Falcini, Franca Avino, Francesco Millo, Katia Cagossi, Elisa Gallerani, Alessia De Simone, Anna Cariello, Giuseppe Aprile, Maria Renne, Bernardo Bonanni. 10-year results of a phase 3 trial of low-dose tamoxifen in non-invasive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-08.

Colles' Fracture: An Epidemiological Nationwide Study in Italy from 2001 to 2016.

The present study aimed to evaluate the yearly number of Colles' fractures in Italy from 2001 to 2016, based on official information found in hospitalization records. A secondary aim was to estimate the average length of hospitalization for patients with a Colles' fracture. A tertiary aim was to investigate the distribution of the procedures generally performed for Colles' fractures' treatment in Italy. An analysis of the National Hospital Discharge records (SDO) maintained at the Italian Ministry of Health, concerning the 15 years of our study (from 2001 to 2016) was performed. Data are anonymous and include the patient's age, sex, domicile, length of hospital stays (days), primary diagnoses and primary procedures. From 2001 to 2016, 120,932 procedures for Colles' fracture were performed in Italy, which represented an incidence of 14.8 procedures for every 100,000 adult Italian inhabitants. The main number of surgeries was found in the 65-69- and 70-74-year age groups. In the present study, we review the epidemiology of Colles' fractures in the Italian population, the burden of the disease on the national health care system (in terms of length of hospitalization) and the distribution of the main surgical procedures performed for the treatment of the disease.

A platform for high-resolution immune liquid biopsy analysis to predict response in patients with renal cell carcinoma treated with nivolumab or cabozantinib: Preliminary data from I-RENE trial (Meet-URO 8 study).

712 Background: Nivolumab, an immune checkpoint inhibitor of PD-1, demonstrated a significant OS benefit in patients with metastatic renal cell carcinoma (mRCC), in progression after a previous line of therapy with anti-VEGFR agents. However, the features of effective immune response and predictive biomarkers of clinical benefit to PD-1 blockade have not yet been recognized. Methods: I-RENE is a prospective translational multicenter Italian study of a real-life mRCC patients treated with nivolumab or cabozantinib after failure of therapy with anti-VEGFR agents. 82 patients were enrolled from December 2018 to August 2022 (nivo 60, cabo 22), with blood samples obtained at baseline and at different time points in both treatment groups. An extended concept of "immune liquid biopsy" is being applied to the study, consisting in the phenotypic and transcriptional profile of lymphoid and myeloid subsets, immune-related miRNA quantification, cyto/chemo-kinome and RNAseq of extracellular vesicle. Results: Multiparametric flow cytometry, performed to monitor the blood frequency and different myeloid and lymphoid cells, show that monocyte subsets (classical, intermediate and non-classical CD14+ cells), monocytic myeloid derived suppressor cells (MDSC, such as CD14+HLA-DRneg and CD14+PD-L1+) and polymorphonucleate (PMN)-MDSC, remain either stable or increase during treatment; concomitantly, CD8+PD-1+ T cells (detected by anti-nivolumab IgG4) increment frequency, acquire the effector CD45RA-CCR7+ phenotype and express the proliferating marker Ki67. Patients receiving cabozantinib display instead a remarkable decrease of all myeloid cell subsets, paired by the boost of cytotoxic CD3-CD16+CD56dim NK cells and more marginally of CD8+PD1+ cells, Preliminary correlations indicate that clinical benefit of nivolumab seems to cluster with the lack of CD14+ cells and M-MDSC increase and blood frequency of total, and the boost in CD8+CD45RA-CCR7+Ki67+ effector T cells. In contrast, the cabozantinib-induced immune modulation occurring in patients treated with does not associate with clinical response Conclusions: This first set of data indicate blood as promising source of dynamic biomarkers for the development of algorithms predicting response to PD-1 blockade. Furthermore, the results so far collected suggest that the potent immunomodulation induced by cabozantinib on the immunosuppressive myeloid compartment may not lead to any tumor control in the absence of specific immune stimulation by checkpoint inhibitors. This study was supported by the Italian Ministry of health (RF-2016_02363001). Clinical trials.gov: NCT04891055 Clinical trial information: NCT04891055 .

Collecting ducts carcinoma: In depth exploration and biologically driven therapy (CICERONE).

TPS754 Background: Collecting duct carcinoma (CDC) is a rare type of non-clear cell renal cell carcinoma with an aggressive course and poor prognosis. The treatment of metastatic disease remains unsatisfactory as no standard-of-care has been established yet. The gap in the clinical management is certainly linked to the poor molecular characterization. To date, a comprehensive biological characterization of CDC and the identification of predictive biomarker is still lacking. Our previous studies proved that CDC is a molecularly heterogeneous disease composed of at least two subtypes distinguished by cell signalling, metabolic and immune-related alterations and featured by a prognostic signature associating T cell immunity and angiogenesis with good clinical outcome and sensitivity to cabozantinib (Gargiuli et al, Cancers 2021 Jun 10;13(12):2903; Todoerti et al, J Clin Oncol 40, no. 16_suppl (June 01, 2022) e16507-e16507; Verzoni et al, Ann Oncol 33:S1218-S121). The aim of CICERONE trial is to change the paradigm of CDC management providing therapies in a biologically informed manner starting from our previous findings. Methods: First, we will define a molecular taxonomy of CDC through comprehensive transcriptomic profiling of 100 CDC samples retrospectively collected within 12 months from the Italian Group of Uropathology Network and the European Union Hub Center. Pathologic review by genitourinary pathologist was required. RNA-Seq will be performed. Results will be merged to that already obtained by the same methodology from the BONSAI dataset (NCT03354884) and evaluated by unsupervised clustering analysis. We will identify differentially expressed genes and pathways. The immune and angiogenic signatures will be searched validating our preliminary results to identify predictive signatures for the subsequent prospective phase II trial. RNA-seq data will be also explored to detect fusion transcripts, as potential source of novel CDC oncogenic drivers, and study immune tumor content through Cybersort deconvolution. RT-qPCR on RNA derived from tumor and normal tissue will be performed to determine tumor specific origin of the fusion transcripts. Immune infiltrate will be also characterized by IHC, together with PDL-1 scoring. Subsequently we will conduct a prospective phase II trial in order to optimize treatment choice and validate prospectively the biological data. In this phase, previously untreated patients with metastatic CDC will be treated according to baseline tumor signature. Moreover, we will assess whether a new concept of immune liquid biopsy that includes the assessment of immunosuppressive vs antitumor immune cells may represent an accessible and compliant tool to test systemic immunity and its implications in response to treatment. This study was supported by the Italian Ministry of health (RF-2019-12369602). Clinical trial information: NCT05372302 .

Have Elbow Arthroscopy Hospitalizations Decreased over the Years? An Epidemiological Italian Study from 2001 to 2016.

This study describes the trends of elbow arthroscopy in Italy and other countries in order to evaluate the yearly rates of EA. Its purpose is for future epidemiological studies to be able to compare their data between countries in order to understand the reasons for the increasing and decreasing trends. Data for this study were obtained from National Hospital Discharge records (SDO) at the Italian Ministry of Health (INHS). Data regarding sex, age, region of residence, region of surgery, length of hospitalization, and procedure codes were included. In total, 2414 elbow arthroscopies were performed in Italy from 2001 to 2016 in the adult population. The highest number of procedures was found in the 40-44 and 45-49 years age groups. Males represented the majority of patients undergoing EA both in total and over the years. An increase from 2001 to 2010 and a decrease from 2010 to 2016 were reported in the present analysis. According to other studies, males of 40-44 and 45-49 years age groups represent the most treated patients. Further epidemiological studies would provide data that could be compared between countries, reaching a general consensus on the best indications for this procedure.

The impact of the COVID-19 pandemic on Italian population-based cancer screening activities and test coverage: results from national cross-sectional repeated surveys in 2020.

In Italy, regions have the mandate to implement population-based screening programs for breast, cervical, and colorectal cancer. From March to May 2020, a severe lockdown was imposed due to the COVID-19 pandemic by the Italian Ministry of Health, with the suspension of screening programs. This paper describes the impact of the pandemic on Italian screening activities and test coverage in 2020 overall and by socioeconomic characteristics. The regional number of subjects invited and of screening tests performed in 2020 were compared with those in 2019. Invitation and examination coverage were also calculated. PASSI surveillance system, through telephone interviews, collects information about screening test uptake by test provider (public screening and private opportunistic). Test coverage and test uptake in the last year were computed by educational attainment, perceived economic difficulties, and citizenship. A reduction of subjects invited and tests performed, with differences between periods and geographical macro areas, was observed in 2020 vs. 2019. The reduction in examination coverage was larger than that in invitation coverage for all screening programs. From the second half of 2020, the trend for test coverage showed a decrease in all the macro areas for all the screening programs. Compared with the pre-pandemic period, there was a greater difference according to the level of education in the odds of having had a test last year vs. never having been screened or not being up to date with screening tests. The lockdown and the ongoing COVID-19 emergency caused an important delay in screening activities. This increased the preexisting individual and geographical inequalities in access. The opportunistic screening did not mitigate the impact of the pandemic. This study was partially supported by Italian Ministry of Health - Ricerca Corrente Annual Program 2023 and by the Emilian Region DGR 839/22.

What is the real price of SOP and OTC drugs? Pilot study on paracetamol

to investigate the actual selling prices of over-the-counter or self-medication (OTC) and non-prescription (SOP) packages of band C medicines, which are freely set by individual pharmacies, para-pharmacies, and corners of the large-scale retail trade. Specifically, the prices charged for paracetamol 500 mg 20 tablets (20 CPR) and 30 tablets (30 CPR) in the online sale, carried out by different retail outlets authorized by the Italian Ministry of Health, were surveyed. cross-sectional observational descriptive study. The availability for online purchase of one or more packages of paracetamol 500 mg 20 CPR and 30 CPR was checked for each outlet considered; for sites with at least one package available for sale, the lowest real price of each of the two packages (20 and 30 CPR) was recorded, differentiating among: 1. type of outlet (pharmacy or retail outlet); 2. originator (branded) or generic (unbranded) drug; 3. city of residence of the outlet (provincial capital city or not). the sample considered consists of 475 online retail sites (pharmacies, para-pharmacies, and large-scale retail stores) based in the 10 major Italian provincial capitals, including sites in the relevant provincial cities. the average real price, calculated as the average of all real prices recorded by packaging type; the minimum real price, i.e., or the lowest real price recorded by packaging type; the average discount, calculated as the difference between the average real price and the average value of the maximum recommended prices (set by the marketing authorization holder, AIC) for branded and unbranded packaging; the maximum discount, calculated as the difference between the minimum real price and the average value of the maximum recommended prices (set by the marketing authorization holder) for branded and unbranded packaging. a wide availability of paracetamol packages produced by multiple AIC holders (both branded and unbranded) was found in the country. The presence of several manufacturers of paracetamol 500 mg induces high price competition, as evident from the discounts given. However, discounts are very high on non-branded packs and lower on branded packs. However, analysis of consumption at the national level shows that price competitiveness does not reflect true market share competitiveness, as consumption is mainly concentrated on branded packs that have the highest prices. wide and homogeneous distribution of unbranded products from different holders is available throughout the country. These products have significantly lower prices than branded packages, and they also have heavy discounts applied (up to 70%, with minimum price per tablet going as low as 0.05 euros). However, contrary to what these premises might lead one to think, consumption is concentrated on the branded packages having the highest prices. For proper information to citizens and trade associations, it is important for the media to bring awareness of the real savings opportunities available nationwide for products of frequent and widespread use, such as the case of paracetamol 500 mg.

Increased Risk of Hospitalization for Pneumonia in Italian Adults from 2010 to 2019: Scientific Evidence for a Call to Action.

Background: Understanding trends in pneumonia-associated hospitalizations can help to quantify the burden of disease and identify risk conditions and at-risk populations. This study evaluated characteristics of hospitalizations due to pneumonia that occurred in Italy in a 10-year period from 2010 to 2019. Methods: All hospitalizations with a principal or secondary diagnosis of pneumonia over the 10-year period were included, which were identified by hospital discharges for all-cause pneumonia and pneumococcal pneumonia in the anonymized hospital discharge database of the Italian Health Ministry. Results: A total of 2,481,213 patients were hospitalized for pneumonia between 2010 and 2019; patients aged 75−86 years accounted for 30.1% of hospitalizations. Most hospitalizations (88.1%) had an unspecified pneumonia discharge code. In-hospital death was recorded in 13.0% of cases. The cumulative cost for pneumonia hospitalizations of the 10-year period were EUR 11,303,461,591. Over the observation period, the incidence rate for hospitalized all-cause pneumonia in any ages increased from 100 per 100,000 in 2010 to over 160 cases per 100,000 per year in 2019 (p < 0.001). Overall, there was a significant increase in annual percent changes in hospitalization rates (+3.47 per year), in-hospital death (+4.6% per year), and costs (+3.95% per year) over the 10-year period. Conclusions: Our analysis suggests that hospitalizations for pneumonia are increasing over time in almost all age groups, especially in the elderly. Given the substantial burden of pneumonia in terms of mortality, healthcare resources, and economic costs, greater public health efforts should thus be made to promote vaccinations against influenza and pneumococcus, particularly in high-risk groups.

Nilotinib: from animal-based studies to clinical investigation in Alzheimer's disease patients.

Nilotinib: from animal-based studies to clinical investigation in Alzheimer's disease patients.

Inherited rare variants in homologous recombination and neurodevelopmental genes are associated with increased risk of neuroblastoma.

Neuroblastoma (NB) is the most common solid extracranial paediatric tumour. Genome-wide association studies have driven the discovery of common risk variants, but no large study has investigated the contribution of rare variants to NB susceptibility. Here, we conducted a whole-exome sequencing (WES) of 664 NB cases and 822 controls and used independent validation datasets to identify genes with rare risk variants and involved pathways. WES was performed at 50×depth and variants were jointly called in cases and controls. We developed two models to identify mutations with high clinical impact (P/LP model) and to discover less penetrant risk mutations affecting non-canonical cancer pathways (RPV model). We performed a gene-level collapsing test using Firth's logistic regression in 242 selected cancer predisposition genes (CPGs) and a gene-sets burden analysis of biologically-informed pathways. Twelve percent of patients carried P/LP variants in CPGs and showed a significant enrichment (P=2.3×10-4) compared to controls (6%). We identified P/LP variants in 45 CPGs enriched in homologous recombination (HR) pathway. The most P/LP enriched genes in NB were BRCA1, ALK and RAD51C. Additionally, we found higher RPV burden in gene-sets of neuron differentiation, neural tube development and synapse assembly, and in gene-sets associated with neurodevelopmental disorders (NDD). The high fraction of NB patients with P/LP variants indicates the need of genetic counselling. Furthermore, inherited rare variants predispose to NB development by affecting mechanisms related to HR and neurodevelopmental processes, and demonstrate that NDD genes are altered in NB at the germline level. Associazione Italiana per la Ricerca sul Cancro, Fondazione Italiana per la Lotta al Neuroblastoma, Associazione Oncologia Pediatrica e Neuroblastoma, Regione Campania, Associazione Giulio Adelfio onlus, and Italian Health Ministry.