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.

Higher baseline TSH levels predict early hypothyroidism during cancer immunotherapy.

BACKGROUND AND PURPOSE: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that enhance the immune response against cancer cells. ICIs are generally well tolerated, although endocrine immune-related adverse events (irAEs) are common. We investigated the risk factors for thyroid irAEs in patients treated with ICIs. Moreover, we evaluated the clinical outcome of subjects who became hypothyroid compared to euthyroid patients. PATIENTS AND METHODS: We retrospectively analyzed a series of 195 consecutively subjects treated with ICIs for metastatic tumors at the University of Naples "Federico II" between January 2014 and March 2020. Only subjects tested for thyroid function before and during the treatment with ICIs were included. RESULTS: In the 96 patients treated with ICIs who were included [66 males, median age: 62 years (27-87)], thyroid irAEs occurred in 36 (37.5%), 16 (16.7%) a transient thyrotoxicosis, and 20 (20.8%) an hypothyroidism (in nine subjects hypothyroidism was preceded by a transient thyrotoxicosis). Only baseline TSH levels above 1.67 mIU/L and positive anti-thyroid antibodies (Ab-T) were associated with a higher risk of hypothyroidism. Patients with hypothyroidism during ICI treatment showed an improved 2-year PFS (HR = 0.82 CI 0.47-1.43; p = 0.0132) and OS (HR = 0.38 CI 95% 0.17-0.80; p = 0.011) compared to euthyroid patients. CONCLUSIONS: Baseline TSH levels above 1.67 mIU/L and presence of Ab-T are risk factors for the development of thyroid irAEs. Patients affected by thyroid irAEs showed a longer survival than patients who remained euthyroid.

BROX haploinsufficiency in familial nonmedullary thyroid cancer.

BACKGROUND: The familial nonmedullary thyroid cancer (FNMTC) is suspected to be a Mendelian condition in up to 3-8% of thyroid cancers. The susceptibility chromosomal loci and genes of 95% of FNMTC cases remain to be characterized. The inheritance of FNMTC appears to be autosomal dominant with incomplete penetrance and variable expressivity. The finding of the causative gene of FNMTC and the identification of patients at risk that need genetic testing were our aim. METHODS: We analyzed by whole-exome sequencing patients and non-affected relatives of five families with at least two family members affected by papillary thyroid cancer, selecting for new or extremely rare variants with predicted pathogenic value. RESULTS: A family showed, in all three affected members, a new loss-of-function variant (frameshift deletion) in BROX gene at 1q41 that was absent from all internal and external databases. In a second family with three affected relatives, we found an additional new BROX variant. The smaller families presented no variants in BROX or in the other causative genes studied. CONCLUSIONS: BROX could be a new causative gene for FNMTC. Variants in BROX may result in the haploinsufficiency of a key gene involved in the morphogenesis of MVBs, in the endosomal sorting of cargo proteins, and in EGFR. Functional studies are needed to support this result. The thorough genomic analysis by NGS in all families with three or more affected members should become a routine approach to obtain a comprehensive genetic view and find confirmative second cases.

Consequences of atmospheric contamination by radioiodine: the Chernobyl and Fukushima accidents.

PURPOSE: After the accidents of nuclear power plants at Chernobyl and at Fukushima, huge amounts of radioactive iodine were released into the atmosphere. METHODS: We reviewed data on the health consequences of these accidents with a focus on thyroid consequences. RESULTS: Among the 2 million children who were living in highly contaminated regions in Belarus, Ukraine and Russia, 7000 cases of thyroid cancer had occurred in 2005. This is the most significant radiation-induced consequence of the Chernobyl accident. The increased incidence of thyroid cancer observed in adult population who lived in these highly contaminated regions is at least in major part related to screening and it is not possible to individualize among these thyroid cancers those that are potentially caused by radiation exposure. For populations who lived outside these regions at the time of the accident, there is no detectable consequence of the radiation exposure on the thyroid gland. Among children who lived nearby the Fukushima power plant in 2011, there is currently no evidence of an increased incidence of thyroid cancer. Ultrasonography screening in these individuals detected a number of thyroid cancers that are probably not related to the accident. Because thyroid cancer is frequent, studies have been carried out to distinguish radiation-induced from their sporadic counterparts, and genomic signatures might be helpful. CONCLUSIONS: The consequences of the Chernobyl accident clearly demonstrate that populations living nearby a nuclear power plant should be protected in case of accident by sheltering, food restrictions and prophylaxis of thyroid irradiation by potassium iodine administration, if the predicted estimated dose to the thyroid gland of children might be >50 mGy. These countermeasures should be applied in priority to children, adolescents and pregnant women; they are safe and effective.

Cutaneous complications of immunosuppression in 812 transplant recipients: a 40-year single center experience.

BACKGROUND: As a consequence of the improvement in survival after solid organ transplantation, to visit transplant recipients with neoplastic and non-neoplastic skin disorders due to immunosuppressive treatment has become common for dermatologists. METHODS: Our endpoints were: 1) to investigate the most common skin diseases in a population of transplant recipients; 2) their associations with the type of immunosuppressant or transplant received; and 3) to compare our single center 40-year experience with the literature data. We retrospectively analyzed the clinical details of the adult patients transplanted in the years 1974-2014, visited for consultation at the Unit of Dermatology of our hospital. RESULTS: Pathologic conditions were observed in more than 3/4 of 812 adults during the follow-up (mean 12.1 years): nonmelanoma skin cancers or actinic keratoses were seen in 44.0% (N.=357) of patients, non-neoplastic events in 55.2% (N.=448). Heart transplant had the statistically significant highest rate of NMSC and AK (52.6%, P=0.0352). Patients receiving cyclosporine A developed at least one non-melanoma skin cancer or actinic keratosis in 57.7% of cases (P=0.0001), while tacrolimus showed a lower risk (33%, P=0.0001). CONCLUSIONS: As transplant recipients are susceptible to skin changes, especially after immunosuppressant treatments, a dermatological follow-up should be scheduled for each patient.

The variegated histopathological features of atypical lentiginous melanocytic nevi: a single institution experience.

BACKGROUND: Atypical lentiginous melanocytic nevi (ALMNs) are atypical pigmented lesions with histopathological features similar to those of dysplastic nevi, with a lentiginous pattern. Variable histopathological features of ALMNs were observed in our practice. METHODS: We described the histopathological features of ALMNs diagnosed in the period 2009-2015. Our cases were divided into 2 groups: Group 1: ALMNs showing the same histopathological features as previously described in the literature; Group 2: ALMNs with different features. RESULTS: Twenty-nine ALMNs were diagnosed; 2 groups of ALMNs were identified. Group 1 ALMNs showed a constant, mild epidermal acanthosis; frequently, an inflammatory infiltrate and dermal fibrosis, cytological atypia and mild architectural atypia. Group 2 ALMNs showed a constant psoriasis-like acanthosis with a hypercellularity of the rete ridges; cytological atypia was rare, whereas architectural atypia was constantly observed. Immunohistochemistry (MART-1 staining) revealed that the melanocytes were localized at the dermo-epidermal junction in both groups. ALMNs showed a broad spectrum of histopathological features. CONCLUSIONS: Our main finding was a constant architectural atypia in all lesions of Group 2. The identification of a unique type of ALMN seems no longer possible. The correct recognition of such benign, though atypical, melanocytic lesions is important in order to avoid an overdiagnosis of cutaneous melanoma and to prevent their potential evolution to the latter.

Local ablative therapy of oligoprogressive TKI-treated thyroid cancer.

Metastatic cancer patients generally respond well to treatment with tyrosine kinase inhibitors (TKIs). However, TKI resistance occurs in almost all cases and often leads to a change in treatment. Recent guidelines, including thyroid cancer, raised the possibility of locally treating TKI-resistant oligoprogressive disease, i.e., one or a few progressing lesions in an otherwise treatment-responsive metastatic cancer, thereby obviating the need to change the ongoing TKI. To determine the benefits of this intervention, we reviewed studies on the use of LAT for TKI-treated oligoprogressive cancers. We found that in non-small cell lung cancer at least, LAT prolongs disease control and the duration of exposure to a TKI irrespective of the LAT used. Moreover, we reviewed the local ablative therapies (LATs) that are feasible for the local control of oligoprogressive thyroid cancer. Lastly, we report two illustrative cases of patients with oligoprogressive thyroid cancer treated with two different LATs while on therapy with TKIs. Both LATs extended the duration of disease control and the time of exposure to the ongoing TKI, thereby indicating that LAT is a favorable option for TKI-treated oligoprogressive thyroid cancer. Prospective randomized studies are needed to verify the benefit of LATs in terms of progression-free and overall survival in this increasingly frequent clinical setting.

Deiodinases and stem cells: an intimate relationship.

Thyroid hormone is a major determinant of tissue functions in vivo. The deiodinase family controls the tissue-specific activation or inactivation of intracellular thyroid hormones. Precise control of the T3-dependent transcriptional program is required by multiple cell systems, including the stem cell. In this context, the identification of a close connection between thyroid hormones and different signal pathways involved in the control of stem cell functions suggested that the deiodinases may play a role in the definition of stem cell biology and physiology. Stem cells have an unlimited self-renewal capacity and the potential to differentiate into different types of mature cells. Deciphering how all these events are achieved, how the T3 signal is controlled and integrated in stem cells and their niches, and how it can impact on them is essentially unknown and represents a challenge for coming years. In this review, I will explore the role played by the deiodinases in the modulation of the TH signal in stem cells of adult tissues, namely muscle and intestine, and how their actions control the delicate balance among self-renewal, proliferation and differentiation. Elucidation of the molecular mechanisms presiding thyroid hormone action in stem cells may reveal therapeutic potential, for example in the fields of regenerative diseases and cancer.

Crown Ether Nucleophilic Catalysts (CENCs): Agents for Enhanced Silicon Radiofluorination.

New bifunctional phase transfer agents were synthesized and investigated for their abilities to promote rapid fluorination at silicon. These agents, dubbed crown ether nucleophilic catalysts (CENCs), are 18-crown-6 derivatives containing a side-arm and a potentially nucleophilic hydroxyl group. These CENCs proved efficacious in the fluorination of hindered silicon substrates, with fluorination yields dependent on the length of linker connecting the metal chelating unit to the hydroxyl group. The efficacy of these CENCs was also demonstrated for rapid radiofluorination under mild conditions for eventual application in molecular imaging with positron emission tomography (PET). The hydrolysis-resistant aryl silicon fragment is promising as a convenient synthon for labeling potential PET radiotracers.

Management strategies in patients affected by chronic total occlusions: results from the Italian Registry of Chronic Total Occlusions.

BACKGROUND: Through contemporary literature, the optimal strategy to manage coronary chronic total occlusions (CTOs) remains under debate. OBJECTIVES: The aim of the Italian Registry of Chronic Total Occlusions (IRCTO) was to provide data on prevalence, characteristics, and outcome of CTO patients according to the management strategy. METHODS: The IRCTO is a prospective real world multicentre registry enrolling patients showing at least one CTO. Clinical and angiographic data were collected independently from the therapeutic strategy [optimal medical therapy (MT), percutaneous coronary intervention (PCI), or coronary artery bypass grafting (CABG)]; a comparative 1-year clinical follow-up was performed. RESULTS: A total of 1777 patients were enrolled for an overall CTO prevalence of 13.3%. The adopted therapeutic strategies were as follows: MT in 826 patients (46.5%), PCI in 776 patients (43.7%), and CABG in the remaining 175 patients (9.8%). At 1-year follow-up, patients undergoing PCI showed lower rate of major adverse cardiac and cerebrovascular events (MACCE) (2.6% vs. 8.2% and vs. 6.9%; P < 0.001 and P < 0.01) and cardiac death (1.4% vs. 4.7% and vs. 6.3%; P < 0.001 and P < 0.001) in comparison with those treated with MT and CABG, respectively. After propensity score-matching analysis, patients treated with PCI showed lower incidence of cardiac death (1.5 vs. 4.4%; P < 0.001), acute myocardial infarction (1.1 vs. 2.9%; P = 0.03), and re-hospitalization (2.3 vs. 4.4% P = 0.04) in comparison with those managed by MT. CONCLUSIONS: Our data showed how CTO PCI might significantly improve the survival and decrease MACCE occurrence at 1 year follow-up in comparison with MT and/or CABG.

Acid-sensing ion channels are involved in epithelial Na+ uptake in the rainbow trout Oncorhynchus mykiss.

A role for acid-sensing ion channels (ASICs) to serve as epithelial channels for Na(+) uptake by the gill of freshwater rainbow trout was investigated. We found that the ASIC inhibitors 4',6-diamidino-2-phenylindole and diminazene decreased Na(+) uptake in adult rainbow trout in a dose-dependent manner, with IC50 values of 0.12 and 0.96 µM, respectively. Furthermore, we cloned the trout ASIC1 and ASIC4 homologs and demonstrated that they are expressed differentially in the tissues of the rainbow trout, including gills and isolated mitochondrion-rich cells. Immunohistochemical analysis using custom-made anti-zASIC4.2 antibody and the Na(+)-K(+)-ATPase (α5-subunit) antibody demonstrated that the trout ASIC localizes to Na(+)/K(+)-ATPase-rich cells in the gill. Moreover, three-dimensional rendering of confocal micrographs demonstrated that ASIC is found in the apical region of mitochondrion-rich cells. We present a revised model whereby ASIC4 is proposed as one mechanism for Na(+) uptake from dilute freshwater in the gill of rainbow trout.

First self-adjuvant multicomponent potential vaccine candidates by tethering of four or eight MUC1 antigenic immunodominant PDTRP units on a calixarene platform: synthesis and biological evaluation.

MUC1 protein overexpressed in human epithelial carcinoma is a target in development of novel anticancer vaccines. Multiple units of immunodominant B-cell epitope PDTRP MUC1 core sequence were conjugated to calix[4,8]arene platforms containing TLR2 ligand, to produce two novel anticancer self-adjuvant vaccine candidates. The immunogenicity of the synthetic constructs was investigated by immunization of mice in vivo. ELISA assay evidenced that the vaccine candidates stimulate anti MUC1 IgG antibody production (major for the octavalent construct) and no additive effect but a multivalency effect was observed when compared to an analogous monovalent. Octa- and tetravalent constructs lacking in PDTRP peptide moieties did not show anti MUC1 IgG antibody production in mice. The antibodies induced by the synthesized constructs are able to recognize the MUC1 structures present on MCF7 tumor cells. The results display that calixarenes are convenient platforms for building multicomponent self-adjuvant vaccine constructs promising as immunotherapeutic anticancer agents.

Impact of renal function on clopidogrel-induced antiplatelet effects in coronary artery disease patients without diabetes mellitus.

Diabetes mellitus (DM) is the most important predictor of chronic kidney disease (CKD), and pharmacodynamic (PD) studies have shown that DM patients with impaired renal function are characterized by reduced clopidogrel response. However, post-hoc PD studies conducted in unselected cohorts, composed of both DM and non-DM patients, have reached controversial findings on the effects of CKD on clopidogrel response, likely attributed to patient heterogeneity. The impact of renal function on clopidogrel response in non-DM patients remains unexplored and represented the aim of this prospective investigation. We conducted a prospective PD investigation in non-DM patients with and without CKD defined as an estimated glomerular filtration rate (eGFR) below or above 60 mL/min, respectively. All patients had known coronary artery disease and were on maintenance aspirin therapy. PD assessments were assessed at baseline and 2 and 24 h after a 600 mg loading dose of clopidogrel. PD assays included light transmission aggregometry (LTA) using 5 and 20 µmol ADP with and without PGE1 and flow cytometric assessment of the phosphorylation status of the vasodilator-stimulated phosphoprotein (VASP) to determine the platelet reactivity index. A total of 60 patients were studied (n = 30 eGFR ≥60 mL/min; n = 30 eGFR <60 mL/min). At baseline there were no differences between groups. Following clopidogrel loading dose administration, levels of on-treatment platelet reactivity were similar between groups at 2 and 24 h as measured with LTA and VASP. Accordingly, there were no differences in rates of high on-treatment platelet reactivity between groups. In non-DM patients with CAD, the presence of impaired renal function is not associated with differences in clopidogrel-induced antiplatelet effects compared with patients with preserved renal function.

Effects of cangrelor in coronary artery disease patients with and without diabetes mellitus: an in vitro pharmacodynamic investigation.

Platelets from patients with diabetes mellitus (DM) are hyper-reactive and whether cangrelor, a potent intravenous P2Y(12) receptor blocker, has differential pharmacodynamic (PD) effects according DM status is unknown. The aim of this investigation was to evaluate the in vitro PD effects of cangrelor in coronary artery disease (CAD) patients with and without DM. This prospective study enrolled 120 clopidogrel-naïve patients with CAD on aspirin therapy. PD assessments using cangrelor (500 nmol/l) in vitro included vasodilator-stimulated phosphoprotein assay to obtain the P2Y(12) reactivity index (PRI), and multiple electrode aggregometry (MEA). In a 20 patients subgroup, dose-dependent response was assessed following exposure to escalating concentrations (baseline, 5, 50, 500 and 5,000 nmol/l); thrombin generation processes were evaluated by thromboelastography (TEG). PD data were evaluable in 103 patients. No differences in baseline PD parameters were observed in DM (n = 48) and non-DM (n = 45) subjects. Cangrelor reduced PRI values irrespective of DM status (p < 0.0001), yielding no difference in patients with and without DM (16.1 ± 12.3 vs. 16.8 ± 11.3; p = 0.346). All MEA values were significantly reduced, although this was of greater magnitude with purinergic compared to non-purinergic agonists. A trend analysis showed a dose-dependent effect on platelet inhibition, with no interaction due to DM status, whereas no significant dose-dependent effect was observed for TEG-derived parameters. Therefore, in vitro cangrelor provides potent and dose-dependent blockade of the platelet P2Y(12) receptor, with no differential effect in DM and non-DM patients. In addition, in vitro cangrelor exerts moderate inhibitory effects on non-purinergic platelet signaling pathways, without modulating platelet-derived thrombin generation processes.

Deiodination in cancer growth: the role of type III deiodinase.

Thyroid hormone (TH) is a pleiotropic agent that has widespread biological functions, i.e., it controls cellular growth, tissue development and homeostasis and neoplastic transformation. Suitable TH levels are critical for the development of various types of tissues and are essential for the regulation of metabolic processes throughout life. The serum concentrations of TH affect its biological activity. Moreover, at tissue level, TH action is regulated by the expression and activity of deiodinases, i.e., the enzymes that mediate the metabolic pathways by activating and/or inactivating TH. The type I and II deiodinases (D1 and D2) initiate TH action by converting thyroxine (T4) into the active TH form (T3), whereas type III deiodinase (D3) mediates the local attenuation of TH by converting T4 and T3 into the inactive metabolites rT3 and T2, respectively. The deiodinase system is a potent mechanism of pre-receptoral control of TH action; it is often altered in such pathological conditions as cancer. D3 is widely expressed in embryonic tissues and in placenta, where it blocks excessive maternal-to-fetal transfer of TH. In contrast, during late neonatal and adult life, D3 is expressed mainly in the central nervous system and skin. Interestingly, D3 expression is re-activated in various types of human cancers. Here we review recent evidence that D3 expression plays a crucial role in human carcinogenesis, and speculate as to its complex role in the regulation of cell proliferation in several neoplastic contexts. It is conceivable that the local modulation of TH action via deiodinases is a powerful molecular tool to manipulate the intracellular TH status, thus influencing the growth and maintenance of selected hormone-dependent cancers.

Prasugrel.

Prasugrel is a third-generation thienopyridine which selectively inhibits the platelet P2Y(12) receptor more rapidly, more potently, and with less interindividual response variability compared with the second-generation thienopyridine clopidogrel. Large-scale phase III clinical testing showed that in high-to moderate-risk acute coronary syndrome patients undergoing percutaneous coronary intervention, prasugrel translates into a greater reduction in ischemic events, including stent thrombosis, in the short and long term compared to clopidogrel. Prasugrel, however, is associated with an increased risk of major bleeding, which is more pronounced in certain patient subgroups. The ideal patient population for prasugrel use are those patients without prior transient ischemic attack/stroke, <75 years of age and >60 kg in whom the greatest ischemic benefit is achieved without a significant increase in major bleeding risk. Dose modifications in specific populations or at given time-points may represent an avenue to minimize bleeding risk and therefore maximize the clinical benefit of prasugrel. Ongoing clinical studies with prasugrel will better define the safety and efficacy profiles of this agent and potentially set the basis for new indications for use.