Background: The CFTR modulator elexacaftor/tezacaftor/ivacaftor (ETI) has transformed cystic fibrosis (CF) care, but national-level real-world data on long-term effectiveness, durability of response, and treatment de-escalation remain limited. Methods: We conducted a nationwide longitudinal study using the Italian Cystic Fibrosis Registry. People with CF aged ≥6 years who initiated ETI between October 2019 and December 2022 and received ≥3 months of continuous therapy were included. Lung function (percent predicted FEV1, ppFEV1), nutritional status (BMI or BMI z-score), hospital days, complications, microbiology, and chronic treatments were assessed during the two years before and up to two years after ETI initiation. Longitudinal changes were analyzed using generalized estimating equations with multiple imputation for missing data. Results: The cohort included 2276 individuals (mean age 27.9 ± 13.3 years; 49% female). Mean ppFEV1 declined during the pre-ETI period but increased by 9.9 percentage points at 12 months after ETI initiation (p < 0.001) and remained 6.8 percentage points above baseline at 24 months. A decline between 12 and 24 months was observed overall, except in individuals with severe baseline lung disease (ppFEV1 < 40%), who maintained stable improvements. Mean annual hospital days decreased by approximately 65% and remained low throughout follow-up. Nutritional status improved, with a mean BMI increase of approximately 1.05 kg/m2 compared with immediate pre-treatment in adults and a BMI z-score increase of 0.2 SD compared with pre-treatment timepoints in children. Use of most standard CF therapies declined substantially, particularly among individuals with ppFEV1 ≥ 40%. The prevalence of allergic bronchopulmonary aspergillosis decreased, while liver disease prevalence increased modestly, largely reflecting transient elevations in liver enzymes. Conclusions: In this nationwide real-world cohort, ETI was associated with sustained improvements in lung function, nutritional status, and hospitalization burden. The attenuation of lung function gains after the first year, particularly in less severe disease, supports the need for individualized monitoring and cautious treatment de-escalation in the ETI era.

BACKGROUND:Lumacaftor-ivacaftor (LUM-IVA) is a CFTR modulator approved for children aged >1 year who are homozygous for the F508del variant, targeting the underlying molecular defect. Despite evidence from clinical trials, real-world data in preschool-aged children remain limited. This study evaluated the effectiveness, safety, and tolerability of LUM-IVA in this population over 12 months of follow-up. METHODS:We conducted a multicenter, prospective study in Italy including 69 children with CF aged 1-6 years treated with LUM-IVA. Anthropometric, laboratory, microbiological, and functional parameters were collected at baseline, and after 3, 6 and 12 months. RESULTS:The median age was 3.82 years. LUM-IVA treatment was associated with significant reductions in sweat chloride concentration and pulmonary exacerbation frequency between baseline and 3/6 months. Weight improved significantly between T0 and T3 and between T1 and T2. Lung Clearance Index (LCI) also showed significant improvement between baseline and 6-12 months. Adverse events were mild and manageable; temporary treatment interruptions occurred, with no permanent discontinuations. CONCLUSION:In conclusion, in this real-world cohort of preschool children with CF homozygous for F508del, LUM-IVA therapy was associated with improvements in sweat chloride, pulmonary exacerbation frequency, and weight over 12 months, with an acceptable safety profile. These observational findings support the feasibility of early CFTR modulator therapy. IMPACT:LUM-IVA therapy in preschool children with CF shows significant real-world improvements in sweat chloride, exacerbations, weight, and LCI over 12 months, with an acceptable safety profile. It provides crucial real-world, observational data on LUM-IVA effectiveness and safety. The findings support the early use of LUM-IVA in young children with CF and potentially mitigate early progressive CF damage.

BackgroundNotwithstanding guidance from the European Cystic Fibrosis (CF) Society (ECFS) neonatal screening (NBS) working group, significant variation persists in the evaluation and management of Cystic Fibrosis Screen Positive, Inconclusive Diagnosis (CFSPID) subjects, leaving many aspects of care under debate. This study reports the results of a national survey investigating management and treatment approaches of pre-school CFSPIDs in Italy.MethodsIn February 2024, a comprehensive questionnaire was distributed to all Italian CF centers. The survey explored various aspects of CFSPID management in the year 2023, including patient visit schedules, sweat tests (ST) timing, screening procedures, therapeutic interventions, and discharge criteria. Data on regional NBS protocols, number of CFSPID cases, and CF:CFSPID ratio were also collected.ResultsBy December 31, 2023, CF Italian centers were following 522 CFSPIDs. In 2023, CF NBS identified 85 CF and 68 CFSPID cases, resulting in a CF:CFSPID ratio of 1.25:1. Seven centers diagnosed more CFSPID than CF, with the lowest CF:CFSPID ratio being 0.20:1. A quarter of all centers reported management plans that deviated widely from ECFS guidelines. Respiratory cultures were performed in 16 (69.6%) centers in the absence of symptoms. Nine (38.9%) prescribed antibiotics in any case of positive Pseudomonas aeruginosa cultures, including first detections and asymptomatic subjects. Spirometries were performed by 14/23 centers (60.9%) in procedure-competent children at each visit. Follow up care continued after age 6 for all CFSPIDs in 15 (65.2%) centers regardless of age, genotype or ST results. A diagnosis of CF was established based on repeated pathological STs and/or multiorgan involvement. Children with STs in intermediate range and mono-organ involvement were classified as CFTR-related disorders (CFTR-RD).ConclusionsDespite available data on clinical course and recommendations on management of CFSPIDs, different approaches persist in clinical practice. Further efforts should be considered to disseminate and encourage adherence to international guidelines.

BACKGROUND:Cystic fibrosis (CF) is a genetic disease caused by CFTR protein dysfunction. Elexacaftor/tezacaftor/ivacaftor (ETI) shows promise in improving outcomes for people with CF (pwCF) with Phe508del combined with gating (F/G) or residual function (F/RF) mutations, though real-world evidence remains scarce. OBJECTIVES:This study evaluated the effectiveness and safety of ETI therapy in pwCF with F/G and F/RF genotypes in real-world settings. METHODS:A multicentre, retrospective study enrolled 78 pwCF (24 F/G and 54 F/RF) receiving ETI after prior CFTR modulator treatments (ivacaftor and tezacaftor/ivacaftor). Endpoints included changes in ppFEV1, sweat chloride concentration (SCC), CFQ-R respiratory domain scores, body mass index (BMI), pulmonary exacerbations (PEx), and antibiotic use over 24 weeks. Safety was assessed via self-reported adverse events. RESULTS:ETI improved ppFEV1 (mean increase: 3.8; 95 % CI, 1.8-5.8), SCC (mean decrease: -23.7 mmol/L; 95 % CI, -28.6 to -18.9), and CFQ-R scores (median improvement: 9.4 points; p < 0.05). BMI increased (mean change: 0.41 kg/m2; 95 % CI, 0.05-0.76), while PEx and antibiotic use decreased by 65.2 % and >50 %, respectively (p < 0.001). Subgroup analysis revealed greater ppFEV1 improvement in F/G patients (6.0 points; 95 % CI, 2.6-9.4) compared to F/RF patients (2.8 points; 95 % CI, 0.4-5.2). No serious adverse events were reported. CONCLUSIONS:ETI therapy provides significant clinical benefits in pwCF with F/G and F/RF genotypes, including improved lung function, SCC normalization, and reduced PEx, compared with previous modulator treatments. Further research is needed to confirm long-term outcomes.

Fibrosis transmembrane conductance regulator (CFTR) modulators (CFTRms) have significantly improved outcomes in people with cystic fibrosis (CF). Real-world evidence, particularly from national and international CF registries, is essential to assess their long-term effectiveness and safety. We reviewed published studies using registry data to evaluate the impact of CFTRms on clinical outcomes in individuals with CF. A narrative review of studies published between 2015 and 2025 was conducted, focusing on registry-based evaluations of ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, and elexacaftor/tezacaftor/ivacaftor. Primary outcomes included lung function, pulmonary exacerbations, nutritional status, and survival. Fifty-seven registry-based studies confirmed the benefits of CFTRms across diverse CF populations. Ivacaftor has demonstrated sustained improvements in forced expiratory volume in one second (FEV1), reduced exacerbations, and improved nutritional outcomes. Lumacaftor/ivacaftor and tezacaftor/ivacaftor have shown modest benefits, especially in homozygous F508del patients. The introduction of elexacaftor/tezacaftor/ivacaftor has led to unprecedented improvements in lung function and quality of life, along with a reduced need for lung transplantation. Methodological heterogeneity and incomplete data remain challenges. Registry data provide essential, complementary evidence to clinical trials and support the effectiveness of CFTRms in routine care. Continued efforts are needed to harmonize registry methodologies and outcome measures.

Elexacaftor/tezacaftor/ivacaftor (ETI) is a cystic fibrosis (CF) transmembrane conductance regulator modulator, which has shown efficacy in people with CF (pwCF) carrying the F508del (F) variant, both in homozygosity and heterozygosity with a minimal function (MF) variant. Limited data exist on the effects of ETI in pwCF with advanced lung disease. Our aim was to investigate ETI safety and effectiveness in this patient group in a real-life setting over 2 years. A multicenter observational cohort study was designed to gather real-world information on the effect of ETI treatment on CF patients (aged >12 years, genotype: F/MF mutation) with advanced lung disease as defined by a FEV1 < 40% predicted. Retrospective demographic and clinical data were recorded for the two years preceding and the two years following ETI initiation. The following outcomes were investigated: treatment-associated adverse events (AEs), drug interruptions (temporary or permanent), variations in percent predicted FEV1 (ppFEV1), sweat chloride concentration (SwCl), antibiotic use, body mass index (BMI), and quality of life. A total of 124 (51.6% males) pwCF were treated with ETI over 2 years. The median (IQR) age and ppFEV1 were 34 (26, 43) years and 34 (29, 41) percentage points, respectively. ETI was discontinued in two pwCF due to lung transplantation, and temporarily interrupted in two because of skin rash, and in three following elevated levels of aminotransferase. Most AEs were mild and short-lasting. In 12.1% pwCF, we registered an increase greater than twice the upper limit of the normal range in alanine aminotransferase, and in 16% we registered an increase in conjugated bilirubin with no increase in aminotransferase. Both increases were recurrent in about half of the subjects. The mean differences (95% CI) for ppFEV1 and SwCl, assessed as mean values in the pre-ETI and ETI treatment periods, were +11.8 (11.1 to 12.6) and -43.7 (-47.6 to -39.9) mmol/L. A modest increase in ppFEV1 persisted during the second year of treatment. Number of oral and IV antibiotic cycles/year, as well as hospitalizations/year, decreased significantly from 3.6 to 1.2, from 2.4 to 0.6, and from 2.1 to 0.5 during ETI treatment. A total of 8 of 16 (50%) pwCF were taken off the waiting list for lung transplantation, and significant reductions in the percentages of pwCF using long-term oxygen therapy and non-invasive ventilation were observed. A poor concordance between ppFEV1 and SwCl was found. In only 3/82 (3.7%), subjects with chronic airway infection by Pseudomonas aeruginosa cultures were always negative during ETI treatment. In CF patients with advanced lung disease on ETI treatment, we observed an improvement in a number of clinically significant outcomes over a 2-year study period. However, several additional observations, such as liver dysfunction, variable degrees of lung function improvement, and limited impact on chronic airway infection, underscore the fact that the benefit-risk profile of ETI treatment in cystic fibrosis patients with advanced lung disease has not been fully elucidated and warrants prolonged-term monitoring.

Background: Cystic fibrosis (CF) is characterized by chronic neutrophilic inflammation in the airways. Elexacaftor/tezacaftor/ivacaftor (ETI) therapy has demonstrably improved clinical outcomes and quality of life in people with CF (pwCF), but its effects on systemic inflammatory parameters remain unclear. Objective: To evaluate the impact of ETI on systemic inflammation in children and adolescents with CF. Design: Retrospective, dual-center observational, propensity score-matching study of pediatric pwCF on ETI. Methods: PwCF aged ⩽ 18 years treated with ETI at two Italian reference centers were included in this study. Data on immunoglobulins (Ig) (A, G, and M), γ-globulin, leukocyte levels, percent predicted forced expiratory volume in the first second (ppFEV1), sweat chloride (SC) concentration, and sputum cultures were collected at baseline, 12, and 24 months of treatment. Laboratory data of a control group (pwCF, not in ETI therapy, same demographic characteristics as the study group) were also collected. Results: Sixty-six patients (30 males, median age: 12 years, F508del homozygous: 23) were included. Mean IgG levels (SD) significantly decreased ( p = 0.001) from 1168.20 mg/dl (344.41) at baseline to 1093.05 mg/dl (258.73; 12 months) and 1092.87 mg/dl (232.42; 24 months). Similar reductions were observed for IgA and γ-globulin; IgM reduction was not statistically significant. Leukocyte levels also decreased significantly from 8.04 × 10 3 /µl (3.23 × 10 3 ) at baseline to 6.61 × 10 3 /µl (1.74 × 10 3 ) (12 months) and 6.45 × 10 3 /µl (1.70 × 10 3 ; 24 months). As for the control group, no significant changes in the levels of Ig, leukocytes, and γ-globulin were detected throughout the study period ( p > 0.05). The mean (SD) ppFEV1 and the overall mean (SD) SC concentration significantly decreased during the follow-up. Regarding cultures, 18 (27%) of the 27 patients positive (41%) for Staphylococcus aureus at baseline became negative during treatment. Three patients (4%) with persistently positive cultures for Pseudomonas aeruginosa during the first 12 months, became negative after 24 months. One patient (1.5%), with a baseline positive culture for Pseudomonas Aeruginosa , showed negative cultures after 12 months. Conclusion: ETI treatment improved respiratory outcomes and significantly reduced values of IgG, IgA, γ-globulin, and leukocytes, suggesting an effect on the systemic inflammatory response. Further research is warranted to elucidate the role of inflammatory parameters in monitoring response to therapy.

Background: Over the past decades, efforts have been made to improve the nutritional well-being of people with cystic fibrosis (pwCF). Due to the correlation observed between nutritional indices and lung function, prevailing recommendations consistently advocate for BMI percentile goals at or above the 50th percentile in pwCF. Recent global trends show a notable increase in overweight and obese statuses among pwCF. This study aims to explore the nutritional status of Italian pwCF. Methods: Data from the Italian CF Patient’s Registry were analysed to assess the proportion of individuals categorized as underweight, target weight, overweight, and obese from 2010 to 2021. Patient-level comparison data from 2021 were also examined to identify the potential determinants of overweight and obesity. Results: Analysis spanning 2010 to 2021 reveals a decrease of approximately 40% in underweight status among adults, while the proportion of malnourished patients younger than 18 years remained stable. Conversely, there was a substantial increase of over 70% in overweight status and over 85% in obesity among adults, with minor fluctuations observed among children and adolescents. Patient factors associated with increased obesity incidence included age older than 45 years, male gender, pancreatic sufficiency, possession of at least one CFTR variant conferring residual function, ppFEV1 > 90, and lower prevalence of Pseudomonas aeruginosa colonization. Conclusions: Our study confirms the evolving nutritional status landscape among Italian adult pwCF, with a significant shift towards overweight and obesity over the past decade. These trends highlight the need for proactive measures within CF standards of care to adapt and address the changing needs of patients.

Objective The objective of this study was to describe reported adverse events (AEs) associated with elexacaftor/tezacaftor/ivacaftor (ETI) in a pediatric sample with cystic fibrosis (CF) aged 6-18 years, with at least one F508del variant, followed at multiple Italian CF centers. Study design This was a retrospective, multicenter, observational study. All children receiving ETI therapy from October 2019 to December 2023 were included. We assessed the prevalence and type of any reported potential drug-related AEs, regardless of discontinuation necessity. Persistent AEs were defined as those continuing at the end of the observation period. Results Among 608 patients on ETI, 109 (17.9%) reported at least 1 AE. The majority (n = 85, 77.9%) were temporary, with a median duration of 11 days (range 1-441 days). Only 7 (1.1%) patients permanently discontinued treatment, suggesting good overall safety of ETI. The most common AEs leading to discontinuation were transaminase elevations (temporary 14.1%, persistent 25.9%) and urticaria (temporary 41.2%, persistent 7.4%). Creatinine phosphokinase elevation was uncommon. No significant differences in AEs were observed based on sex, age groups (6-11 vs 12-18 years), or genotype. Pre-existing CF-related liver disease was associated with an increased risk of transaminase elevations. We identified significant variability in the percentage of reported AEs (ANOVA P value .026). Conclusions This real-world study highlights significant variability in reported AEs. Our findings suggest that ETI is a safe and well-tolerated therapy in children and adolescents with CF. However, further long-term safety and effectiveness investigations are warranted.

INTRODUCTION:Italian Cystic Fibrosis Registry (ICFR) collects data of patients with cystic fibrosis (CF) through the collaboration with Italian CF referral and support Centres (Italian law 548/93). It aims at analysing medium and long-term clinical and epidemiological trends, identifying healthcare needs at regional and national levels, contributing to healthcare programmes, and resource allocation. Italian data are also compared at international level through the collaboration with the European CF Registry for sharing epidemiological data on general aspects like CF epidemiology and specific topics such as the use of CFTR modulators.OBJECTIVES:The purpose of this Report is to provide updated demographic and clinical data of the Italian FC population for the years 2021 and 2022, to contribute essential information for the implementation of projects aimed at improving the management of patients affected by this disease.DESIGN:Analyses and results presented in this Report pertain to patients currently under care at Italian National Referral and Support Centres for Cystic Fibrosis and Paediatric Hospital 'Bambino Gesù' in the 2021-2022 period. Data were submitted by clinical Centres through a dedicated web-based software and underwent dual quality control (QC) measures: automated quantitative QC within the software and secondary QC at the European level before the integration into the European Cystic Fibrosis Registry. These measures ensure data completeness, accuracy, and longitudinal consistency with European core data.SETTING AND PARTICIPANTS:A total of 27 CF Centres, including referral and support centres, as well as 'Bambino Gesù' Children's Hospital CF centre, submitted their data to ICFR for the years 2021-2022. Althourgh CF Centres in Verona and Messina do not use the ICFR software, their data are centrally collected and subsequently forwarded to the European Registry. Data from service centres in Treviso and Rovereto are transmitted via the Verona CF Centre. Data from Sardinia Centre are currently unavailable.RESULTS:The results section provides a comprehensive overview of various aspects of CF epidemiology and patient characteristics. 1.Demography: in 2021 and 2022, 5,977 and 6,077 CF patients were respectively included in the ICFR, with median ages of 23.3 and 23.7 years. The prevalence rates were 10.1 and 10.3 per 100,000 residents in Italy for the respective years, with males comprising 51.6% on average. The distribution by age showed a higher frequency among patients aged 7 to 35 years; adult patients constituted 63.5% on average in both years. 2. Diagnosis: most CF patients were diagnosed before the age of two (mean value 57.9%), with a significant percentage diagnosed in adult age (35.4% in 2021 and 25.6% in 2022). 3.New diagnoses: there were 113 new diagnoses in 2021 and 121 in 2022, with estimated incidences of 1 in 9,097 living births in 2021 and 1 in 6,232 in 2022. 4. Genetics: genetic analyses were conducted on 99.9% of patients, revealing CFTR gene mutations in over 98% of cases. The F508del mutation was the most common (44% of alleles in 2021), with 18% of patients having at least one "residual function" mutation. Gating mutations were present in 3.4% of Italian patients, while 20% had at least one-stop codon mutation. 5.Lung function: lung function, measured by percent predicted (pp)FEV1 (Forced Expiratory Volume in the first second) progressively declined before adulthood, with the majority of paediatric patients (92.8% in 2021 and 93.8% in 2022) maintaining a ppFEV1≥70%. 6.Nutrition: critical periods for nutrition were identified as the first 6 months of life and adolescence, with higher prevalence of malnourished male adolescents compared to females. Suboptimal BMI values were more common in adult females (28.7% in 2021 and 26.9% in 2022) compared to males (14.2% in 2021 and 12.6% in 2022). 7. Complications: CF-related liver disease without cirrhosis was prevalent in patients under 18 years (21.9% in 2021 and 21.2 in 2022), while CF-related diabetes was most frequent in adults (24.2%). 8.Transplantation: over the two-year period, 28 patients underwent double-lung transplantation, with median ages of 29.1 in 2021 and 35.3 in 2022, respectively. Median waiting times ranged from 9.4 to 11.6 months. 9.Microbiology: chronic Pseudomonas aeruginosa infection affected 37.2% of adult patients in 2021 and 36.0% in 2022, compared to 7.4% and 6.5% in paediatric patients. Staphylococcus aureus infection rates were 34.6% and 42.2% in 2021 among adults and 34.4% and 36.7% in 2022 among paediatric patients. 10. Mortality: a total of 34 patients died during the 2021-22 period (19 females, 15 males), with median ages at death of 43.7 years in 2021 and 46 years in 2022 (excluding transplanted patients).CONCLUSIONS:The present Report is an update of the data published in the past years and summarizes the main epidemiological and clinical data regarding Italian CF subjects in the years 2021 and 2022. The number of patients registered in 2021 was 5,977, while in 2022 was 6,077. The population coverage estimates for 2022 to be around 97%. In 2020, 60.5% of patients were older than 18 years, in 2022 adult patients account for 63.5% of the Italian CF population. Over the years, therefore, an increase in the median age of Italian CF patients has been observed, reaching 23.7 years in 2022. The absolute number of new diagnoses per year remains substantially unchanged over the years (a total of 234 in the period under review). The median age at diagnosis in 2022 was 2.5 months, 62.6% of subjects are really diagnosed within the first year of life and almost 90% of them are diagnosed through neonatal screening. In 2022, almost all patients underwent genetic analysis (99.9%). Data collected confirm the great variability among Italian CF patients. As regards respiratory function, what is reported in previous reports is here confirmed, with an ever-increasing percentage of subjects under the age of 18 having normal respiratory function, moreover, less than 1% of paediatric patients has a severe lung function (ppFEV1<40). The marked improvement in this indicator in the adult population seems to be mainly due to the introduction from 2021 in Italy of therapy with highly effective CFTR modulators. At the same time, the close positive correlation between nutritional status and respiratory function is confirmed for the adult population. As regards chronic infection by Pseudomonas aeruginosa, in 2022, a reduction in the percentage of chronic infection is observed both among adults (36% vs 38.8% in 2020) and in paediatric patients (6.5% vs 7.6% in 2020). The most frequent complication in both paediatric and adult populations is liver disease (respectively, in 24.2% and 41.3% of subjects). In the two-year period, 34 patients died; their median age at death was between 43 and 46 years (transplant patients excluded); only two patients under the age of 18 died in the period 2021 and 2022, confirming once again that mortality in paediatric age is a rare event. The data presented in this Report shows how the register can be a national and international point of reference for CF patients and the scientific community, a tool for describing the Italian CF population over the years, and a starting point for planning epidemiological studies and clinical studies.

•Gilbert's syndrome testing is needed for post-ETI hyperbilirubinemia.•ETI therapy is safe for Gilbert's syndrome-related hyperbilirubinemia.•More research is needed to understand causality and mechanisms.

There is limited information available on the clinical data, sweat test trends, and outcomes of individuals with cystic fibrosis (CF) who present with an isolated episode of hypoelectrolytemia with metabolic alkalosis (HMA). This study describes a cohort of Italian individuals with HMA as presenting symptom. The study is a retrospective multicenter analysis of individuals who presented with HMA as an initial symptom and was followed at 8 Italian CF Centers, from March 1988 to March 2022. Demographic, clinical, microbiological, biochemical, and genetic data were extracted from local health records. Ninety-three individuals were enrolled in the study. At first evaluation, 82 (88.2

BACKGROUND:Elexacaftor/tezacaftor/ivacaftor (ETI) is the newest cystic fibrosis transmembrane conductance regulator (CFTR) modulator drug approved for the treatment of patients with cystic fibrosis (pwCF) aged ≥6 years with at least one copy of the F508del mutation (F) in the CFTR gene or another mutation that is responsive to treatment with ETI. This study determined the effectiveness and safety of ETI in a cohort of severely affected pwCF with an F/F genotype. METHODS:Retrospective observational study in F/F pwCF treated for 48 weeks, enrolled in an ETI managed access program available to subjects with advanced lung disease (ppFEV1 < 40). Twenty-six patients from three centres were included. The main outcomes included lung function, sweat chloride concentration (SCC), nutrition, frequency of pulmonary exacerbations (PEx), CFQ-R, and safety. RESULTS:ppFEV1 improved by 12.06 (95%CI 8.54, 15.57) from baseline after 4 weeks of treatment with ETI, 15.32 (11.3, 19.34) after 24 weeks, and 14.48 (10.64, 18.32) after 48 weeks. The increase in FEV1 was accompanied by a decrease in SCC, improvement of BMI, and noticeable reduction in PEx. An overall good safety profile was observed. CONCLUSIONS:In F/F pwCF with advanced lung disease with an F/F genotype, ETI was safe and associated with clinical improvement.

Abstract Background Positron emission tomography (PET) using anti-1-amino-3-18fluorine-fluorocyclobutane-1-carboxylic acid (18F-fluciclovine) shows preferential glioma cell uptake with low activity in normal brain. Dynamic contrast-enhanced (DCE) MRI may also be used to investigate regions of glioma that do not show gadolinium-enhancement on post-contrast T1-weighted MR sequences (Gd-T1) and may reflect tumour infiltration beyond the Gd-T1 enhancing margin. There is a paucity of data on how 18F-fluciclovine uptake correlates with Gd-T1 and DCE-MRI activity, how it correlates with tumour biology and whether significant changes in uptake occur during treatment. The aims of this pilot study were: 1 To compare 18F-fluciclovine PET, DCE-MRI and Gd-T1 in patients undergoing chemoradiotherapy for glioblastoma (GBM) 2 To investigate correlation between 18F-fluciclovine uptake, MRI findings, and tumour biology in a pre-clinical glioma model. Material and Methods 18F-fluciclovine-PET-CT and MRI including DCE-MRI were acquired before, during and after adjuvant chemoradiotherapy (60 Gy in 30 fractions with temozolomide) in GBM patients. DCE-MRI and Gd-T1 volumes were manually contoured, and PET volumes defined using semi-automatic thresholding. Gd-T1 was subtracted from PET and DCE-MRI volumes to identify areas beyond the Gd-T1 volume boundary and similarity of the PET and DCE-MRI volumes outside the Gd-T1 volume boundary were measured using the Dice similarity coefficient (DSC). CT-2A tumour cells were stereotactically injected into the right striatum of 8 to 10-week-old C57BL6J mice and they underwent MRI and 18F-fluciclovine PET-CT. Post-mortem mice brains underwent immunohistochemistry staining for ASCT2 (amino acid transporter), nestin (stemness) and Ki-67 (proliferation) to assess for biologically active tumour. Results 6 patients were recruited (GBM 1-6). For GBM 1-3: PET volumes were greater than DCE-MRI, in turn greater than Gd-T1. For GBM 4-6, Gd-T1 volumes were similar to DCE-MRI and both were greater than PET volumes. GBM 1-3 had lower overall survival than GBM 4-6: median 249 vs. 903 days. 18F-fluciclovine uptake and Gd uptake (on DCE-MRI) was seen beyond the margins of the standard Gd-T1 volume. Comparing these regions beyond the Gd-T1 margins, the PET and DCE-MRI had low DSC, suggesting distinct areas of fluciclovine and DCE-MRI uptake. Pre-clinical PET-CT demonstrated tumour-specific 18F-fluciclovine uptake which corresponded to biologically active tumour based on immunostaining for Ki-67, nestin and ASCT2. Conclusion Results from this joint pre-clinical and clinical pilot study suggest volumes of 18F-fluciclovine-PET activity beyond that depicted by MRI-DCE and Gd-T1 are associated with a poorer prognosis in patients undergoing chemoradiotherapy for GBM. The pre-clinical model confirmed 18F-fluciclovine uptake reflected biologically active tumour.

BACKGROUND:In recent years, patients with cystic fibrosis (CF) conductance regulator (CFTR) variant poly(T) sequences have been increasingly reported with a wide spectrum of clinical severity. We describe the long-term clinical outcomes and progression to a CF diagnosis over time in a large Italian cohort of patients carrying the CFTR F508del/5T;TG12 genotype. METHODS:A retrospective analysis of subjects from 10 CF centres in Italy with the F508del/5T;TG12 genotype was performed. Demographic, clinical, microbiological, and biochemical data, as well as information about the follow-ups and complications of the enroled patients, were collected. RESULTS:A total of 129 subjects (54 females; median age: 15.0 years, range: 0-58 years; 59 older than 18 years) were included. In terms of initial diagnoses, 30 were CF (23.3%), 41 were CFTR-related disorder (CFTR-RD) (31.7%), and 58 were CF transmembrane conductance regulator-related metabolic syndrome/cystic fibrosis screen positive, inconclusive diagnosis (CRMS/CFSPID) (45.0%). After a median follow-up of 6.7 years (range 0.2-25 years), 15 patients progressed to CF, bringing the total number of CF diagnoses to 45/129 (34.9%). Most of these patients had mild lung diseases with pancreatic sufficiency and a low prevalence of CF-related complications. CONCLUSIONS:At the end of the study, 34.9% of subjects with the CFTR F508del/5T;TG12 genotype were diagnosed with CF. We suggest including patients with the F508del/5T;TG12 genotype in long-term follow-ups.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe multiorgan hypersensitivity reaction mostly caused by several eliciting drugs in patients with a genetic predisposition. Anti-convulsants are the main drugs involved both in adults and in children. Incidence of DRESS in children is very variable, from 1:1,000 to 1:10,000, and the mortality rate seems to be lower than 10%. The treatment of choice is the prompt withdrawn of the offending drug and using intravenous immunoglobulins and corticosteroids used in synergy. In recent years, emerging studies have outlined the disease more clearly. We present a paediatric case in which the patient developed DRESS syndrome as a result of exposure to lamotrigine before and carbamazepine after and a relapse after exposure to omeprazole. Starting from this case report we provide an overview on DRESS syndrome.

To The Editor, It has been shown that elexacaftor/tezacaftor/ivacaftor (ETI) cystic fibrosis transmembrane conductance regulator (CFTR) modulatory treatment is safe and efficacious in cystic fibrosis (CF) patients aged >12 years with at least one F508del CFTR allele.1, 2 However, the clinical consequences of CF often appear in early childhood and require aggressive symptomatic treatment with the aim of preserving lung function and maintaining adequate nutrition and growth.3 Unfortunately, some children still develop severe lung disease despite intensive care in specialized CF centers: the Italian CF Registry showed that about 1% of 674 children aged 6–11 years had <40% of predicted forced expiratory volume in the first second (FEV1) in 2020 (personal communication). Such cases are extremely difficult to manage and, when conventional treatment fails, the only alternative is lung transplantation. However, pediatric lung transplantations are often unavailable because of the scarcity of specialized centers, and the patients are at high risk of dying while they are still on the waiting list.4 It has been shown that ivacaftor, lumacaftor, and tezacaftor (used singly or in combination) are safe and efficacious in children aged 6–11 years.5 Furthermore, the results of a 24-week, Phase-III open-label trial of ETI have shown that the treatment was as safe and effective in CF patients aged 6–11 years with at least one F508del allele as in adults and adolescents.6 However, as is usual in clinical trials, this study excluded patients with severe pulmonary impairment (defined as an FEV1 of <40% of the predicted value). In 2021, Vertex Pharmaceuticals established an Italian managed access program (MAP) to allow severely affected CF patients aged 6–11 years with at least one F508del allele to receive ETI treatment before its reimbursed marketing authorization. The aim of this study was to evaluate the effectiveness and safety of a 24-week ETI treatment in a cohort of children with CF aged 6–11 years with severe lung disease. Our retrospective observational study involved nine patients enrolled in the MAP attending five CF centers between February and August 2021. The MAP inclusion criteria were homozygosity for F508del (F/F) or heterozygosity for F508del and one qualifying minimal function (MF) allele,6 an age of 6–11 years, and a highest predicted FEV1 of <40% in the preceding 60 days. The treatment was administered orally to all of the patients on the basis of their body weight.6 The primary objective was to measure the improvement in lung function in terms of the absolute change in the percentage of predicted (pp)FEV1 between the start of treatment and Week 24. The secondary endpoints were the absolute change in forced vital capacity (ppFVC), and in forced expiratory flow between 25% and 75% of FVC (ppFEF25–75), nutritional improvement, sweat chloride concentration (SCC), the quality of life, and the use of antibiotics. Detailed information concerning the study methods and a statistical plan is available in the Supporting Information. Nine patients (three males, 33.3%) had a median age of 9.75 years (range 6.42–11.33). Four (44.4%) were homozygous for F508del, and five (55.6%) were compound heterozygous for F508del and one MF mutation. All of the patients had pancreatic insufficiency. None had CF-related diabetes or underwent tube feeding; none were undergoing long-term oxygen treatment or noninvasive ventilation; none were on the lung transplantation waiting list; and none had previously received CFTR modulators. Details concerning their other characteristics are available in the Supporting Information: Table S1. Mean (SD) ppFEV1 was 31.30 (4.65) at baseline, 42.51 (6.98) after 4 weeks' treatment, 47.17 (6.46) after 12 weeks, and 53.67 (12.67) after 24 weeks. The mean absolute increase in ppFEV1 was 11.21 (95% confidence interval [CI] 7.39–15.03; p < 0.001) after 4 weeks' treatment, 15.87 (11.43–20.31; p < 0.001) after 12 weeks, and 22.4 (15.22–29.52; p < 0.001) after 24 weeks (Figure 1). The trends of ppFVC and ppFEF25–75 were similar (Table 1). The mean (SD) BMI for age z-score at baseline was −0.72 (1.00), but it progressively increased to −0.16 (0.74) over the 24-week treatment period (p < 0.05). The mean absolute change was 0.60 (95% CI 0.33–0.87; p < 0.001). The weight and height for age z-score also progressively increased (Table 1). The mean (SD) SCC significantly decreased from a baseline value of 102.72 (15.65) to 36.0 (11.12) mmol/L after 4 weeks' treatment (p < 0.00001), 29.0 (8.8) mmol/L after 12 weeks, and 23.8 (7.1) mmol/L after 24 weeks. The mean absolute change from baseline was −68.17 mmol/L (95% CI −81.54 to −54.79; p < 0.001) after 4 weeks, and −79.2 (−92.67 to −65.64; p < 0.001) after 24 weeks (Table 1). All of the patients had an SCC of <60 mmol/L after 24 weeks of treatment, and 67% had an SCC of <30 mmol/L. The cystic fibrosis questionnaire-revised (CFQ-R) respiratory domain score improved rapidly and in a sustained manner throughout the 24 weeks of treatment: the median baseline score of 25 (range 16.6–75) significantly increased to 83.3 (66.6–91.6) after 4 weeks (p < 0.001), and 100 (100–100) after 24 weeks (p < 0.001). During the 24 weeks before starting ETI, nine patients had required 17 hospitalizations. ETI treatment led to an 80% lower rate of antibiotic treatment over the 24 weeks of the study, and no hospitalization was reported. Eight patients (88.9%) remained free of antimicrobial use during the study period, and only one (11.1%) needed monthly 14-day oral antibiotic treatment. None of the children experienced any treatment-related adverse events, and there were no relevant abnormalities in the findings of clinical laboratory tests (serum chemistry, hematology, coagulation studies, liver function tests, and urinalysis), vital signs, or physical examinations (skin rash, arterial hypertension, and headache). No deaths occurred during the study period, and there were no study drug interruptions or discontinuations. ETI treatment improved lung function and nutrition, decreased SCC, greatly reduced the need for antibiotics, and improved the quality of life of CF patients aged 6–11 years with severe lung disease and at least one F508del CFTR allele. Although the children involved in this study had lower mean baseline ppFEV1 (38.96) and median CFQ-R respiratory domain scores (25 points) than those in the Phase III trial of their peers (respectively 88.8 and 80),6 the treatment was associated with an equally rapid and sustained improvement in lung function, and a greater mean absolute increase in ppFEV1 after 24 weeks of treatment (22.4, 95% CI 15.22–29.52 vs. 10.2, 95% CI 7.9–12.6). The improvement in ppFEV1 was accompanied by a rapid and sustained improvement in the CFQ-R respiratory domain score, which increased to the maximum of 100 in all cases. These findings underline the possibility of recovering some lung function and thus improving the well-being of children with CF. The study population also showed improvements in all of the growth and nutritional parameters during the 24 weeks of ETI treatment. The mean increase in the BMI z-score was higher than that observed in the Phase III trial (0.60 vs. 0.37) and, given the extraordinary decrease in the number of infections, catch-up growth could be expected. These findings confirm that CFTR modulatory treatment has beneficial effects on nutrition and overall growth in patients of all ages regardless of the severity of their pulmonary disease,1, 2, 6 and may therefore require a lifelong change in the approach to nutritional advice. The improvement in SCC was similar to that observed in the Phase III trial.6 Changes in SCC provide a direct indicator of systemic CFTR function, as has been shown by parallel measurements of CFTR function in the epithelia of CF patients with one or two F508del alleles.7 The marked decrease in the need for antibiotics presumably played a major role in the observed improvements. Our patients were characterized by a higher rate of hospitalizations and recurrent infections in the 24 weeks preceding the start of ETI treatment, but the striking results of the 24-week MAP included no reported hospitalization and the fact that 88.9% of the children did not require any antibiotic courses. The treatment was safe and well tolerated, and there was no need for any treatment interruptions or discontinuations. It is obviously necessary to collect safety data over a longer time and in larger groups of children, but the safety profile of ETI in CF patients aged 6–11 years has so far been consistent with its known profile in those aged >12 years.1, 2, 6 The most important limitations of this study are its retrospective design, the very small number of patients, and the lack of a control group. We have tried to limit the effects of these by adopting a descriptive rather than an analytical approach, and by making within-group comparisons. Further limitations are the lack of microbiological data and imaging findings. The findings of this study of a selected subgroup of children aged 6–11 years with at least one F508del CFTR allele and advanced CF-related lung disease further support early treatment with ETI. The recovery of lung function and improvement in growth dynamics raise the hope that such early treatment can avert serious long-term complications. However, longer observation times and more real-world and disease registry data are required to confirm the safety and effectiveness of the new and highly efficient CFTR modulators in children with CF. Donatello Salvatore: conceptualizaIon (lead); formal analysis (equal); methodology (equal); writing—original draft (lead); writing—review & editing (lead). Giuseppe Cimino: formal analysis (equal); writing—review & editing (equal). Patrizia Troiani: data curation (equal); investigation (equal); writing—review & editing (supporting). Elisabetta Bignamini: formal analysis (equal); writing—original draft (equal); writing—review & editing (equal). Irene Esposito: data curation (equal); investigation (equal); writing—review & editing (supporting). Giuseppina Leone: datacuration (equal); investigation (equal); writing—review & editing (supporting). Maurizio Zanda: writing—review & ediIng (supporting). Daniela Manunza: investigation (equal); writing—review & editing (supporting). Angela Pepe: data curation (equal); investigation (equal); writing—review & editing (supporting). The authors thank Professor Kevin Richard Smart for language help. Lega Italiana Fibrosi Cistica—Basilicata odv supported this study. This study did not receive any external funding. Donatello Salvatore has been the principal investigator in several clinical trials conducted by Vertex Pharmaceuticals and for which his institution has received funding; he has received fees for participation in advisory boards, satellite symposia, or specific projects. Elisabetta Bignamini has been the principal investigator in clinical trials conducted by Vertex Pharmaceuticals and for which her institution has received funding. Irene Esposito has received a fee for participation in a workshop conducted by Vertex Pharmaceuticals. The remaining authors declare no conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.