Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis.

BACKGROUND: Ivacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF. METHODS: In this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements. RESULTS: Seven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (-40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed. CONCLUSIONS: In this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age.

Long-term tezacaftor/ivacaftor safety and efficacy in people with cystic fibrosis and an F508del-CFTR mutation: 96-week, open-label extension of the EXTEND trial.

BACKGROUND: Study 661-110 (EXTEND) is a phase 3, open-label, three-part rollover study designed to assess the long-term safety and efficacy of tezacaftor/ivacaftor (TEZ/IVA) in participants aged ≥12 years homozygous for F508del (F/F) or heterozygous for F508del and a residual function mutation (F/RF). TEZ/IVA was shown to be safe and efficacious for up to 120 weeks in Part A. Here we report results from Part B, which evaluated safety and efficacy for an additional 96 weeks. METHODS: Part B enrolled participants aged ≥12 years with CF and F/F or F/RF genotypes who completed TEZ/IVA treatment in either Study 661-110 Part A, Study 661-112 (F/F), or Study 661-114 (F/F). Participants received TEZ 100 mg/IVA 150 mg fixed-dose combination once daily (morning) and IVA 150 mg once daily (evening) for 96 weeks. Safety endpoints included adverse events (AEs) and serum liver function tests. Efficacy endpoints included absolute change from baseline in percent predicted forced expiratory volume in 1 second (ppFEV1) and pulmonary exacerbation (PEx) rate. RESULTS: 464 participants were enrolled from Part A (n=377) and other eligible studies (n=87); 463 received ≥1 dose of TEZ/IVA. Overall, 92.2% had ≥1 AE, 0.9% had AEs leading to treatment discontinuation, and 29.4% reported serious AEs. The most common AEs, which were generally consistent with common manifestations of CF, included infective PEx of CF, cough, nasopharyngitis, hemoptysis, and headache. Lung function was maintained over 96 weeks in both genotype groups. PEx rates per year were comparable with Part A. CONCLUSIONS: TEZ/IVA was generally safe and well tolerated over a further 96 weeks; safety data were consistent with Part A. Improvements in ppFEV1 and PEx rates were maintained for an additional 96 weeks in Part B.

A Phase 3, open-label, 96-week trial to study the safety, tolerability, and efficacy of tezacaftor/ivacaftor in children ≥ 6 years of age homozygous for F508del or heterozygous for F508del and a residual function CFTR variant.

BACKGROUND: Two previous Phase 3 studies ("parent studies") showed that tezacaftor/ivacaftor was generally safe and efficacious for up to 24 weeks in children 6 through 11 years of age with cystic fibrosis (CF) and F508del/F508del (F/F) or F508del/residual function (F/RF) genotypes. We assessed the safety and efficacy of tezacaftor/ivacaftor in an open-label, 96-week extension study. METHODS: This was a Phase 3, 2-part, multicenter, open-label, extension study in children 6 through 11 years of age at treatment initiation (Study VX17-661-116; NCT03537651). The primary endpoint was safety and tolerability. Secondary endpoints were absolute change from baseline in lung clearance index2.5 (LCI2.5), sweat chloride (SwCl) concentration, Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score, and body mass index (BMI). RESULTS: One-hundred thirty children enrolled and received ≥ 1 dose of tezacaftor/ivacaftor; 109 completed treatment. Most (n = 129) had ≥ 1 treatment-emergent adverse event (TEAE), the majority of which were mild or moderate in severity and generally consistent with common manifestations of CF. Exposure-adjusted TEAE rates were similar to or lower than those in the parent studies. Five (3.8%) had TEAEs leading to treatment discontinuation. Efficacy results from the parent studies were maintained, with improvements in lung function, SwCl concentration, CFQ­R respiratory domain score, and BMI observed from parent study baseline to Week 96. CONCLUSIONS: Tezacaftor/ivacaftor is generally safe and well tolerated, and treatment effects are maintained for up to 120 weeks. These results support long-term use of tezacaftor/ivacaftor in children ≥ 6 years of age with CF and F/F or F/RF genotypes.

Synchronous parathyroid carcinoma, parathyroid adenoma, and papillary thyroid carcinoma in a patient with severe and long-standing hyperparathyroidism.

OBJECTIVE: To describe a patient presenting with the rare constellation of synchronous parathyroid carcinoma, parathyroid adenoma, and papillary thyroid carcinoma. METHODS: We summarize the clinical presentation, diagnostic work-up, surgical management, and pathologic features of our patient and review the pertinent literature. RESULTS: The patient was a 59-year-old man who presented with severe clinical manifestations of long-standing primary hyperparathyroidism, a serum calcium concentration of 14.4 mg/dL, and a parathyroid hormone level of 2,023 pg/mL. He was found to have a 3.4-cm parathyroid carcinoma on the left side and a 3.2-cm papillary carcinoma in the right thyroid lobe. In addition, a 917-mg parathyroid adenoma was found on the right side. CONCLUSION: Synchronous parathyroid and thyroid carcinomas are extremely rare. To our knowledge, our patient is the first documented case with a parathyroid adenoma in addition to synchronous parathyroid and thyroid carcinomas. The presence of concurrent parathyroid carcinoma and parathyroid adenoma can cause diagnostic confusion and should be considered in patients presenting with severe hyperparathyroidism. Any concomitant thyroid nodules must be investigated to rule out thyroid carcinoma.

Thyroid function in the critically ill newborn and child.

PURPOSE OF REVIEW: Here we review typical thyroid function alterations observed in the critically ill pediatric patient. RECENT FINDINGS: Abnormalities in the hypothalamic-pituitary-thyroid axis have recently been confirmed to be prevalent in similar proportions in pediatric and adult patients. Significant benefits of therapy have yet to be demonstrated. SUMMARY: At present, there is no evidence of benefit in giving thyroid hormone to patients with nonthyroidal illness who have low serum T3 or T4 concentrations, including preterm infants and postcardiac surgery patients.

Insulin signaling in alpha cells modulates glucagon secretion in vivo.

Glucagon plays an important role in glucose homeostasis by regulating hepatic glucose output in both normo- and hypoglycemic conditions. In this study, we created and characterized alpha cell-specific insulin receptor knockout (alphaIRKO) mice to directly explore the role of insulin signaling in the regulation of glucagon secretion in vivo. Adult male alphaIRKO mice exhibited mild glucose intolerance, hyperglycemia, and hyperglucagonemia in the fed state and enhanced glucagon secretion in response to L-arginine stimulation. Hyperinsulinemic-hypoglycemic clamp studies revealed an enhanced glucagon secretory response and an abnormal norepinephrine response to hypoglycemia in alphaIRKO mice. The mutants also exhibited an age-dependent increase in beta cell mass. Furthermore, siRNA-mediated knockdown of insulin receptor in glucagon-secreting InR1G cells promoted enhanced glucagon secretion and complemented our in vivo findings. Together, these data indicate a significant role for intraislet insulin signaling in the regulation of alpha cell function in both normo- and hypoglycemic conditions.

Cell polarity protein Spa2P associates with proteins involved in actin function in Saccharomyces cerevisiae.

Spa2p is a nonessential protein that regulates yeast cell polarity. It localizes early to the presumptive bud site and remains at sites of growth throughout the cell cycle. To understand how Spa2p localization is regulated and to gain insight into its molecular function in cell polarity, we used a coimmunoprecipitation strategy followed by tandem mass spectrometry analysis to identify proteins that associate with Spa2p in vivo. We identified Myo1p, Myo2p, Pan1p, and the protein encoded by YFR016c as proteins that interact with Spa2p. Strikingly, all of these proteins are involved in cell polarity and/or actin function. Here we focus on the functional significance of the interactions of Spa2p with Myo2p and Myo1p. We find that localization of Spa2GFP to sites of polarized growth depends on functional Myo2p but not on Myo1p. We also find that Spa2p, like Myo2p, cosediments with F-actin in an ATP-sensitive manner. We hypothesize that Spa2p associates with actin via a direct or indirect interaction with Myo2p and that Spa2p may be involved in mediating polarized localization of polarity proteins via Myo2p. In addition, we observe an enhanced cell-separation defect in a myo1spa2 strain at 37 degrees C. This provides further evidence that Spa2p is involved in cytokinesis and cell wall morphogenesis.

Peripheral keratitis associated with erythema elevatum diutinum.

PURPOSE: To describe a case of peripheral keratitis associated with erythema elevatum diutinum (EED), an unusual immune-complex-mediated cutaneous vasculitis. DESIGN: Observational case report. METHODS: A 25-year-old man who was diagnosed 15 months previously with erythema elevatum diutinum presented with an inflammatory peripheral keratitis of the left eye. RESULTS: Serologic investigations for systemic disorders associated with vasculitic peripheral ulcerative keratitis were unremarkable. As the sclerokeratitis was thought to represent an ocular extension of the patient's cutaneous vasculitis, dapsone therapy was initiated and resulted in a rapid response of both the cutaneous and the ocular inflammation. CONCLUSIONS: Erythema elevatum diutinum should be included in the differential diagnosis of vasculitic peripheral keratitis.