Reported Adverse Events in a Multicenter Cohort of Patients Ages 6-18 Years with Cystic Fibrosis and at Least one F508del Allele Receiving Elexacaftor/Tezacaftor/Ivacaftor.

OBJECTIVE: 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 one 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 0·026). 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.

Humanisation and health needs in children: present or future?

AIM: For a few years, teledentistry has been an emerging innovative strategy with potential in the field of paediatric dentistry. There are still few studies in this regard, so further research is needed to verify and ensure that teledentistry is not only an accessible mode of communication, but above all effective and evidence-based. This study aimed to use a preliminary telematic approach to promote the compliance of patients in the developmental age during the first dental visit. MATERIALS: Two hundred patients were selected according to the eligibility criteria, and distributed in two groups: a study group with the preliminary telematic approach (ATP) before the first visit and a control group with traditional first visit without ATP. Through an ordinal semi-proportional regression model, the degrees of collaboration between the study and control groups were compared, correcting the estimate for age groups, the presence of systemic pathologies, disorders of cognition, attention and learning, degree of anxiety and previous medical-dental experiences. CONCLUSION: The preliminary telematic approach could be useful as a support to the traditional paediatric dental visit, to promote better management and fidelity of the patient, reducing anxiety and increasing collaboration during the first visit.

Long-term effects of bronchopulmonary dysplasia on lung function: a pilot study in preschool children's cohort.

INTRODUCTION: Although the long term negative effects of bronchopulmonary dysplasia (BPD) are well known, follow-up studies of preterm infants with BPD into childhood are lacking. METHODS: Forty-two preschool children (age range 3-6 years) who were born before 32 weeks of gestational age and affected by BPD were enrolled. Pre-, peri-, and post-natal data were collected. During the follow up appointment complete physical examination and lung function (impulse oscillometry (IOS)) were recorded. The European Community Respiratory Health Survey (ECRHS) questionnaire was administered to all enrolled subjects. RESULTS: Thirty patients were included in the final analysis. The BPD group did not differ in comparison to the non-BPD group in terms of lung function (p > 0.05). By comparing all subjects enrolled, We detected extremely low-birth-weight (ELBW) infants with height-, weight-, and gender-related reference values and a significant trend of increasing resistance values (R5Hz, R5-20 Hz) and respiratory impedance (Z5Hz) (p < 0.05). No significant difference in bronchial reversibility test was observed among BPD non-BPD groups (p < 0.05). The frequency of gastroesophageal reflux disease was significantly higher in patients with BPD when compared to non-BPD group (p < 0.05). Significant differences in gestational age, oxygen supplementation (days), mechanical ventilation therapy (days), and sepsis between BPD and non-BPD groups were also observed (p < 0.05). There were no significant differences in the prevalence of family and personal history of atopy and/or allergic diseases, tobacco exposure, respiratory symptoms, respiratory syncytial virus bronchiolitis, exercise induced dyspnea, treatment with ß-2 bronchodilators and inhaled corticosteroids among the groups (p > 0.05). CONCLUSIONS: The respiratory function in preschool children born with ELBW is characterized by an increase in impedance and resistance of small airways. No statistically significant differences were found between ELBW children with BPD and without BPD. With regards to the smallest gestational age, the longer duration of O2 therapy during hospitalization, and sepsis significantly resulted in a worse respiratory function.

Lung clearance index evaluation in detecting nocturnal hypoxemia in cystic fibrosis patients: Toward a new diagnostic tool.

BACKGROUND: Nocturnal hypoxemia adversely affects outcomes in patients with cystic fibrosis (CF). Although an early detection of this abnormality may be desirable, still its predictability remains uncertain. The Lung Clearance Index (LCI) is a measure of lung ventilation distribution obtained from a multiple-breath washout technique (MBW), recently implemented in patients with CF. This study aimed to establish whether the LCI predicts nocturnal hypoxemia in patients with stable CF, with mild to moderate disease, and normal diurnal gas exchange. METHODS: 31 stable patients (15 males, mean age 17.4 ± 5.2 years) with mild to moderate CF, normoxic when awake, were enrolled. In all patients we performed nocturnal cardio-respiratory polygraphy, lung function measurement, and MBW test to derive LCI values. RESULTS: LCI was abnormal in most of the patients and inversely correlated with mean nocturnal SpO2 (r = -0.880 p < 0.01). A receiver operating characteristic (ROC) analysis, performed to assess whether LCI predicted nocturnal hypoxemia, revealed a high predictive accuracy of LCI for nocturnal desaturation (AUC = 0.96; Youden index = 0.79). Forced expiratory volume in 1 s (FEV1) was predictive only in patients with more severe airway obstruction, with a moderate degree of accuracy (AUC 0.71). CONCLUSIONS: The LCI showed a high effectiveness in predicting nocturnal hypoxemia in stable patients with CF, particularly when compared with a traditional parameter of lung function such as FEV1.

Impact of black soldier fly larvae meal on the chemical and nutritional characteristics of rainbow trout fillets.

The present research studied the effect of a dietary inclusion with Hermetia illucens larvae meal (Hi) on rainbow trout's fillets chemical composition. The effect of Hi inclusion in diets on rainbow trout chemical characteristics was evaluated. Trout were fed three different diets: control (C, no Hi inclusion), 25% and 50% of substitution of fish meal with Hi (Hi25 and Hi50, respectively). Fillets were analysed to quantify proximate composition, carbohydrates percentage, colour parameters, nucleotides concentration, fatty acids profile, volatile organic compounds (VOCs) and myofibrillar and sarcoplasmic concentrations. Diets did not affect proximate composition. Contrariwise, Hi50 diet decreased fillet yellowness and both substitution percentages affected negatively adenosine monophosphate concentration. Saturated fatty acids, mostly C12 : 0, increased their contents in relation with Hi inclusion at the expense of monounsaturated and polyunsaturated (both n-3 and n-6) fatty acids. Less modifications were reported in VOCs as only heptanal and octanal concentrations were affected, no new compounds appeared in relation with Hi inclusion. No modifications in proteins patterns were shown even if myofibrillar content decreased in trout fed Hi50. The results highlighted that chemical modifications occurred in fillets were related to the chemical composition of the H. illucens meal and to the percentage of inclusion in the diet. Substitution of fish meal with a precisely percentage of H. illucens meal could be a potential future solution in order to decrease the quantity of fish meal used in aquafeeds.

Use of robotic colonoscopy in patients with previous incomplete colonoscopy.

OBJECTIVE: Conventional colonoscopy (CC) is the gold standard to diagnostic and therapeutic approach to colon. However, in few cases, cecal intubation could fail due to colon anatomy, patient compliance and physician expertise. Endotics robotic colonoscopy is a novel, safe, mini-invasive modality to explore the entire colon. Our aim was to assess, in a retrospective study, Endotics ability of cecal intubation in all cases in which CC failed. PATIENTS AND METHODS: Between January 2008 and December 2012, 276 Endotics robotic colonscopy examinations were performed at the Gastroenterology and Metabolic Diseases Unit of Pisa University Hospital, Pisa, Italy, in a series of consecutive patients who had undergone CC and failed cecal intubation. RESULTS: We assessed the cecal intubation rate in 102 patients addressed to Endotics after previous incomplete CC. Overall, endotics system was successful in 93.1% of the incomplete conventional colonoscopy cases (95% performance). CONCLUSIONS: Whenever the intended exploration of the entire colon with CC failed, the endotics robotic endoscopy represented a useful tool as it helped examine the entire colon in almost all cases.

EXHALED BREATH TEMPERATURE IN ASTHMATIC CHILDREN.

Asthma is characterized by chronic inflammation of airways. Currently, no traditional method allows an easy daily evaluation of the degree of airway inflammation. Measuring inflammatory biomarkers in the breath is a very attractive approach to monitor asthma inflammation. In recent years, the measurement of exhaled breath temperature (EBT) has been proposed as a method capable of detecting the inflammatory status of the airways. The objective of this study is to strengthen the role of EBT in the diagnosis and monitoring of asthma. The study sample was represented by a group of 40 patients, of both sexes, aged 6-15 years. The elective criteria for submitting patients to EBT determination were abstaining from drugs in the preceding 24 h, fasting for at least 2 h, physical resting for at least 30 minutes, a body temperature between 35-37°C. The temperature in the room of the surveys ranged from 18 to 25°C. The EBT values of asthmatic patients were higher [(median (IQR): 29.77°C (30.67°C to 29.38°C) range 28.46°C min-max 34.78°C] than those of non-asthmatic ones (median (IQR): 28.22°C (29.09°C-27.7°C), range 27.09°C min-max 30.07°C] and this difference was highly significant (p less than 0.001). Furthermore, no significant difference was found between the EBT values of the following groups of patients: those exposed and not exposed to passive smoking, those receiving and not receiving leukotriene drugs, those receiving and not receiving specific immunotherapy, monoallergic patients and poliallergic ones, those sensitized and not sensitized to house dust, perennial allergic patients and seasonal allergic ones. In addition, the evaluation of the correlation of EBT values with body temperature (r=0.119, p=0.464) and ambient temperature (r=-304, p = 0.057) did not show any significant correlation. Finally, no statistically significant correlation was demonstrated between EBT values and FEV1 (r=-0055, p=0.81, Fig. 4). In conclusion, the data of the present study further support the hypothesis that EBT can be considered a good method for monitoring asthma.

Antitumor activity of epigenetic immunomodulation combined with CTLA-4 blockade in syngeneic mouse models.

The multifaceted immunomodulatory activity of DNA hypomethylating agents improves immunogenicity and immune recognition of neoplastic cells; thus, we predicted they could be utilized to design new immunotherapeutic combinations in cancer. Testing this hypothesis, the antitumor efficacy of the DNA hypomethylating agent 5-aza-2'-deoxycytidine (5-AZA-CdR) combined with the anti-CTLA-4 monoclonal antibody (mAb) 9H10 in syngeneic transplantable murine models was investigated. Murine mammary carcinoma TS/A or mesothelioma AB1 cells were injected in BALB/c, athymic nude, and SCID/Beige mice that were treated with 5-AZA-CdR, mAb 9H10, or their combination. Tumor volumes were captured at different time-points; molecular and immunohistochemical assays investigated changes in neoplastic and normal tissues. A significant antitumor effect of 5-AZA-CdR combined with mAb 9H10 was found: compared to controls, a 77% (p < 0.01), 54% (p < 0.01) and 33% (p = 0.2) decrease in TS/A tumor growth was induced by 5-AZA-CdR combined with mAb 9H10, 5-AZA-CdR or mAb 9H10, respectively. These antitumor activities were confirmed utilizing the AB1 model. 5-AZA-CdR-based regimens induced a promoter-demethylation-sustained tumor expression of cancer testis antigens. MHC class I expression was up-regulated by 5-AZA-CdR. Antitumor efficacy of 5-AZA-CdR in athymic nude and SCID/Beige mice was not increased by mAb 9H10. In BALB/c mice, combined treatment induced the highest tumor infiltration by CD3+ lymphocytes, which included both CD8+ and CD4+ T cells; no such infiltrates were observed in normal tissues. This significant immune-related antitumor activity of 5-AZA-CdR combined with CTLA-4 blockade, demonstrated in highly aggressive mouse tumor models, provides a strong scientific rationale to implement epigenetically-based immunotherapies in cancer patients.

DC current pulses for OTSC clip fragmentation: technology and experimental study.

BACKGROUND: The OTSC clip is used in endoscopic management of gastrointestinal lesions. In rare cases, the removal of the OTSC clip might be desirable. The objective of the study is to investigate feasibility, efficacy, and safety of a novel endoscopic instrument system for removal of the OTSC clip. METHODS: The study series has been conducted in a porcine model. Clip removal is performed with a prototype instrumentation that is designed to locally melt the clip by applying an electrical current pulse onto the clip structure. This system has been evaluated in an animal study (n = 10) in a pig model. A cap prototype with an elongated sleeve has been used for extraction of the OTSC clip fragments. RESULTS: 23 of 24 implanted OTSC clips were successfully opened by applying in a total of 74 current pulses. Superficial mucosal coagulation marks were observed in 14 of the 24 application sites. No other findings such as hemorrhage, deep thermal wall lesions, or perforation were observed. CONCLUSIONS: The study confirms the effectiveness and safety of the proposed endoscopic removal technique. Safe extraction of the clip fragments was feasible with an elongated sleeve at the distal cap. Limitations of the methods are the animal model and the experimental nature of the prototype instrumentation.

Isolation of NDM-1-producing Pseudomonas aeruginosa sequence type ST235 from a stem cell transplant patient in Italy, May 2013.

We describe the first isolation of an NDM-1-producing Pseudomonas aeruginosa in Italy. In May 2013, a patient with acute lymphoblastic leukaemia and history of prior hospitalisation in Belgrad, Serbia, underwent stem cell transplantation at a tertiary care hospital in Rome, Italy. After transplantion, sepsis by NDM-1-producing P. aeruginosa occurred, leading to septic shock and fatal outcome.

Multidisciplinary approach for HCC patients: hepatology for the oncologists.

Hepatocellular carcinoma (HCC) is a complex and heterogeneous disease, often associated with underlying conditions, like cirrhosis or other relevant co-morbidities that worsen the prognosis and make the clinical management more challenging. Current recommendations emphasize the importance of a multidisciplinary approach for the management of HCC patients and stress the crucial role of careful prevention and the management of cirrhosis-associated complications. This article discusses the importance of a multidisciplinary approach in the treatment of HCC patients. Current recommendations for the treatment of cirrhotic patients with HCC are also reviewed.

Erectile dysfunction after prostate three-dimensional conformal radiation therapy. Correlation with the dose to the penile bulb.

PURPOSE: Erectile dysfunction is associated with all the common treatment options for prostate cancer. The aim of this research was to evaluate the relationship between erectile function and radiation dose to the penile bulb (PB) and other proximal penile structures in men receiving conformal radiotherapy (CRT) without hormonal therapy (HT) for prostate cancer, whose sexual function was known before treatment. PATIENTS AND METHODS: The study included 19 patients treated with 3D-CRT for localized prostate cancer at our department, who were self-reported to be potent before treatment, had not received HT, and had complete follow-up data available. Our evaluation was based on the International Index of Erectile Function (IIEF-5). Dose-volume histograms (DVHs) were used to evaluate the dose to the PB. Statistical analysis was performed with an unconditional logistic regression model. RESULTS: All patients reported change in potency after radiation. Eight patients (42%) remained potent but showed a decrease of 1 or 2 levels of potency, as defined by the IIEF-5 questionnaire (reduced potency group), while 11 patients (58%) reported a change of higher levels and revealed a severe erectile dysfunction after 2 years (impotence group). Multivariate analysis of morphological and dosimetric variables yielded significance for the mean dose (p = 0.05 with an odds ratio of 1.14 and 95% CI 1-1.30). Patients receiving a mean dose of less than 50 Gy to the PB appear to have a much greater likelihood of maintaining potency. CONCLUSION: Our data suggest a possible existence of a dose-volume correlation between the dose applied to the PB and radiation-induced impotence.

Epigenetic remodelling of gene expression profiles of neoplastic and normal tissues: immunotherapeutic implications.

BACKGROUND: Epigenetic remodelling of cancer cells is an attractive therapeutic strategy and distinct DNA hypomethylating agents (DHA) are being actively evaluated in patients with hemopoietic or solid tumours. However, no studies have investigated the modulation of gene expression profiles (GEP) induced by DHA in transformed and benign tissues. Such information is mandatory to clarify the fine molecular mechanism(s) underlying the clinical efficacy of DHA, to identify appropriate therapeutic combinations, and to address safety issues related to their demethylating potential in normal tissues. Thus, utilising a syngeneic mouse model, we investigated the remodelling of GEP of neoplastic and normal tissues induced by systemic administration of DHA. METHODS: The murine mammary carcinoma cells TS/A were injected s.c. into female BALB/c mice that were treated i.p. with four cycles of the DHA 5-aza-2'-deoxycytidine (5-AZA-CdR) at a fractioned daily dose of 0.75 mg kg(-1) (q8 h × 3 days, every week). Whole mouse transcriptomes were analysed by microarrays in neoplastic and normal tissues from control and treated mice. Results were processed by bioinformatic analyses. RESULTS: In all, 332 genes were significantly (P ≤ 0.05; FC ≥ 4) modulated (294 up and 38 downregulated) in neoplastic tissues from 5-AZA-CdR-treated mice compared with controls. In decreasing order of magnitude, changes in GEP significantly (P ≤ 0.05) affected immunologic, transport, signal transduction, spermatogenesis, and G-protein-coupled receptor protein signalling pathways. Epigenetic remodelling was essentially restricted to tumour tissues, leaving substantially unaltered normal ones. CONCLUSION: The ability of 5-AZA-CdR to selectively target tumour GEP and its major impact on immune-related genes, strongly support the clinical use of DHA alone or combined with immunotherapeutic agents.

Therapeutic options for breast cancer treatment in patients previously irradiated for Hodgkin's disease: radical mastectomy or conservative surgery followed by reirradiation?

Patients undergoing radiotherapy for the treatment of Hodgkin' disease (HD) occurred at young age present a higher risk to develop second cancer compared to general population. Among the possible second tumours, breast cancer is the most frequent and the age at presentation is younger than the "classic" form. Patients at risk for second cancer undergo a strict follow-up permitting often to diagnose breast cancer at early stages (I-II).The aim of this work is to review the various therapeutic options for the treatment of breast cancer in patients previously irradiated for HD, with particular attention to the possibility of reirradiation of mammary tissue thanks to the new radiotherapy techniques developed in the last years.

Homocysteine-induced toxicity increases TG2 expression in Neuro2a cells.

High levels of homocysteine promote cell damage mainly through induction of oxidative stress, endoplasmic reticulum (ER) stress, and activation of pro-inflammatory factors. The effects of homocysteine were here examined in the continuously dividing neuroblastoma cell line Neuro2a. Cell treatment with homocysteine (100-500 microM) for 4 h increased ROS production while reducing cell viability in a dose-dependent manner. Cell exposure to 250 microM homocysteine was able to induce transglutaminase 2 up-regulation and increased in situ transglutaminase activity. These effects were prevented by the incubation with the transglutaminase activity inhibitor cystamine. Homocysteine also induced NF-kappaB activation that seemed associated with transglutaminase 2 up-regulation since the specific NF-kappaB inhibition by SN50 was able to reduce transglutaminase expression and activity levels. In the light of these observations, it may be postulated that TG2 up-regulation is involved in cell response to homocysteine-induced stress, in which NF-kappaB activation plays also a pivotal role.

Duration of remission and long-term prognosis according to the extent of disease in patients with ulcerative colitis on continuous mesalamine treatment.

AIMS: To describe the long-term prognosis of ulcerative colitis (UC) and to establish whether a correlation exists between the different anatomic locations of the disease and the risk of relapse in a homogeneous cohort of patients with UC in clinical remission, all treated with fixed doses of oral mesalamine from the date of enrollment to the appearance of the first relapse. METHOD: We distinguished the patients with pancolitis and left-sided colitis from those with distal colitis. The follow-up lasted up to 5 and 6 years for the patients with pancolitis and left-sided colitis, respectively, and up to 9 years for the patients with distal colitis. RESULTS: One hundred and fifty patients satisfied the enrollment criteria. We registered 19 drop-outs. All the patients had relapsed within 9 years. In most cases relapses arose within 2-3 years. The patients with pancolitis had a shorter time to relapse (100% relapsed after 5 years) than the patients with left-sided colitis (100% after 6 years) or distal colitis (100% after 9 years). None of the enrolled patients developed a cancer. Extraintestinal complications were observed in 9% of cases and surgery was needed in five patients only. CONCLUSION: The first 2-3 years after the enrollment of patients with UC in remission was the period at higher risk of relapse. No relationship was found between the different anatomic locations of the disease and the risk of relapse, even if distal colitis showed a slightly better course.

Clinical relevance of colonic lesions in cirrhotic patients with portal hypertension.

BACKGROUND AND STUDY AIMS: This prospective study was conducted in order to evaluate whether the colonic lesions previously described in cirrhotic patients may be of clinical relevance. PATIENTS AND METHODS: Eighty-five patients with cirrhosis of the liver, but without colonic or systemic diseases unrelated to the liver disease, underwent colonoscopy and were followed up for at least 2 years. RESULTS: Colonic varices were observed in 31 % of the patients, portal hypertensive colopathy (PHC; defined as diffuse hyperemia, edema, spider angiomas, and spontaneous bleeding of the colonic mucosa) in 54 %, and normal colonic findings in 18 %. Colonic varices and PHC were present simultaneously in 27 % of the patients. Previous sclerotherapy or band ligation treatment for esophageal varices had been carried out in 27 % and 23 % of the patients, respectively. Portal hypertensive gastropathy was observed in 42 % of the patients. Polyps were found in 12 % of the cirrhotic patients and cancer in 3 %. All of the patients were followed up for at least 2 years; 34 % of them developed upper gastrointestinal hemorrhage (81 % from esophageal varices, 19 % from the stomach), while only 6 % developed lower gastrointestinal bleeding. CONCLUSIONS: Colonic lesions are frequent in cirrhotic patients, but statistical analysis showed that these lesions are not specific for the disease and do not correlate with the etiology and degree of cirrhosis, with the endoscopic treatment of esophageal varices, or with the risk of bleeding from the lower gastrointestinal tract.