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- Kingswood, JC, et al.
(författare)
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TuberOus SClerosis registry to increAse disease awareness (TOSCA) Post-Authorisation Safety Study of Everolimus in Patients With Tuberous Sclerosis Complex
- 2021
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Ingår i: Frontiers in neurology. - : Frontiers Media SA. - 1664-2295. ; 12, s. 630378-
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Tidskriftsartikel (refereegranskat)abstract
- This non-interventional post-authorisation safety study (PASS) assessed the long-term safety of everolimus in patients with tuberous sclerosis complex (TSC) who participated in the TuberOus SClerosis registry to increase disease Awareness (TOSCA) clinical study and received everolimus for the licensed indications in the European Union. The rate of adverse events (AEs), AEs that led to dose adjustments or treatment discontinuation, AEs of potential clinical interest, treatment-related AEs (TRAEs), serious AEs (SAEs), and deaths were documented. One hundred seventy-nine patients were included in the first 5 years of observation; 118 of 179 patients had an AE of any grade, with the most common AEs being stomatitis (7.8%) and headache (7.3%). AEs caused dose adjustments in 56 patients (31.3%) and treatment discontinuation in nine patients (5%). AEs appeared to be more frequent and severe in children. On Tanner staging, all patients displayed signs of age-appropriate sexual maturation. Twenty-two of 106 female (20.8%) patients had menstrual cycle disorders. The most frequent TRAEs were stomatitis (6.7%) and aphthous mouth ulcer (5.6%). SAEs were reported in 54 patients (30.2%); the most frequent SAE was pneumonia (>3% patients; grade 2, 1.1%, and grade 3, 2.8%). Three deaths were reported, all in patients who had discontinued everolimus for more than 28 days, and none were thought to be related to everolimus according to the treating physicians. The PASS sub-study reflects the safety and tolerability of everolimus in the management of TSC in real-world routine clinical practice.
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- Nabbout, R, et al.
(författare)
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Historical Patterns of Diagnosis, Treatments, and Outcome of Epilepsy Associated With Tuberous Sclerosis Complex: Results From TOSCA Registry
- 2021
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Ingår i: Frontiers in neurology. - : Frontiers Media SA. - 1664-2295. ; 12, s. 697467-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epilepsy is the most common neurological manifestation in individuals with tuberous sclerosis complex (TSC). However, real-world evidence on diagnosis and treatment patterns is limited. Here, we present data from TuberOus Sclerosis registry to increase disease Awareness (TOSCA) on changes in patterns of epilepsy diagnosis, treatments, and outcomes over time, and detailed epilepsy characteristics from the epilepsy substudy.Methods: TuberOus Sclerosis registry to increase disease Awareness (TOSCA) was a multicentre, international disease registry, consisting of a main study that collected data on overall diagnostic characteristics and associated clinical features, and six substudies focusing on specific TSC manifestations. The epilepsy substudy investigated detailed epilepsy characteristics and their correlation to genotype and intelligence quotient (IQ).Results: Epilepsy was reported in 85% of participants, more commonly in younger individuals (67.8% in 1970s to 91.8% in last decade), while rate of treatments was similar across ages (>93% for both infantile spasms and focal seizures, except prior to 1960). Vigabatrin (VGB) was the most commonly used antiepileptic drugs (AEDs). Individuals with infantile spasms showed a higher treatment response over time with lower usage of steroids. Individuals with focal seizures reported similar rates of drug resistance (32.5–43.3%). Use of vagus nerve stimulation (VNS), ketogenic diet, and surgery remained low.Discussion: The epilepsy substudy included 162 individuals from nine countries. At epilepsy onset, most individuals with infantile spasms (73.2%) and focal seizures (74.5%) received monotherapies. Vigabatrin was first-line treatment in 45% of individuals with infantile spasms. Changes in initial AEDs were commonly reported due to inadequate efficacy. TSC1 mutations were associated with less severe epilepsy phenotypes and more individuals with normal IQ. In individuals with TSC diagnosis before seizure onset, electroencephalogram (EEG) was performed prior to seizures in only 12.5 and 25% of subsequent infantile spasms and focal seizures, respectively.Conclusions: Our study confirms the high prevalence of epilepsy in TSC individuals and less severe phenotypes with TSC1 mutations. Vigabatrin improved the outcome of infantile spasms and should be used as first-line treatment. There is, however, still a need for improving therapies in focal seizures. Electroencephalogram follow-up prior to seizure-onset should be promoted for all infants with TSC in order to facilitate preventive or early treatment.
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- Radu, I.B., et al.
(författare)
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Zoisite in cratonic eclogite xenoliths - Implications for water in the upper mantle
- 2022
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Ingår i: Lithos. - : Elsevier BV. - 0024-4937 .- 1872-6143. ; 418-419
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Tidskriftsartikel (refereegranskat)abstract
- A significant portion of the Earth's water is found at trace levels in nominally anhydrous rock forming minerals in the crust and mantle. Its distribution has far-reaching implications in melt-generating processes, mantle rheology and the stability of the lithosphere. We report petrographic, major and trace element, Fourier transform infrared spectroscopy and secondary ion mass spectrometry data on four eclogite xenoliths from the Obnazhennaya kimberlite, Siberia that contain hydrous minerals at upper mantle conditions. Al-rich (>9.9 wt% Al2O3) omphacitic clinopyroxene, a major mineral of eclogites, contains crystallographically controlled exsolutions of CaO-rich (up to 23.6 wt%) garnet (coronae, lenses), garnet-zoisite (lamellae) or amphiboles (needle/blade-like exsolutions). The omphacite hosting the exsolved lamellae shows enrichment or depletion in major (Al, Si, Mg) and trace (e.g., HREE) elements compatible with garnet and zoisite, proportional to the abundance of exsolutions.We argue that zoisite likely formed concomitantly with garnet exsolution from a water- and Al-rich precursory omphacite, without any fluid addition. The compositional gradients are consistent with diffusion-controlled partitioning in a closed system, and their preservation indicates the exsolution likely took place shortly prior to eclogite entrapment by the kimberlite. Large, non-exsolved, omphacite grains contain minimum ~870–1500 ppm wt. H2O (determined as OH). We infer that intertwined lamellae of hydrous garnet (600–960 ppm wt. H2O) and minor (<1%) zoisite (2 wt% H2O) formed at mantle conditions due to progressive exsolution, without external fluids. Recalculated whole rock water contents range from ~320 to 970 ppm wt. H2O. These estimates exceed by far those for the surrounding peridotitic mantle and suggest that, although a minor component, eclogites may locally be an important water reservoir in the cratonic mantle.
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- Sauter, M, et al.
(författare)
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Rare manifestations and malignancies in tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increAse disease awareness (TOSCA)
- 2021
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Ingår i: Orphanet journal of rare diseases. - : Springer Science and Business Media LLC. - 1750-1172. ; 16:1, s. 301-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundTuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant disorder caused by pathogenic variants in either theTSC1orTSC2gene. Common manifestations of TSC have been grouped into major and minor clinical diagnostic criteria and assessed in clinical routine workup. However, case studies point towards the existence of rare disease manifestations and to the potential association of TSC with malignant tumors. In this study we sought to characterize rare manifestations and malignancies using a large cohort of patients.MethodsTuberOus SClerosis registry to increAse disease awareness (TOSCA) is a multicenter, international disease registry collecting clinical manifestations and characteristics of patients with TSC, both retrospectively and prospectively. We report rates and characteristics of rare manifestations and malignancies in patients with TSC who had enrolled in the TOSCA registry. We also examined these manifestations by age, sex, and genotype (TSC1orTSC2).ResultsOverall, 2211 patients with TSC were enrolled in the study. Rare manifestations were reported in 382 (17.3%) study participants and malignancies in 65 (2.9%). Of these rare manifestations, the most frequent were bone sclerotic foci (39.5%), scoliosis (23%), thyroid adenoma (5.5%), adrenal angiomyolipoma (4.5%), hemihypertrophy and pancreatic neuroendocrine tumors (pNET; both 3.1%). These rare manifestations were more commonly observed in adults than children (66.2% vs. 22.7%), in females versus males (58.4% vs. 41.6%; except for scoliosis: 48.9% vs. 51.1%), and in those withTSC2versusTSC1(67.0% vs. 21.1%; except for thyroid adenoma: 42.9% vs. 57.1%). In the 65 individuals with reported malignancies, the most common were renal cell carcinoma (47.7%), followed by breast (10.8%) and thyroid cancer (9.2%). Although malignancies were more common in adult patients, 26.1% were reported in children and 63.1% in individuals < 40 years.TSC1mutations were over-represented in individuals with malignancies compared to the overall TOSCA cohort (32.1% vs. 18.5%).ConclusionRare manifestations were observed in a significant proportion of individuals with TSC. We recommend further examination of rare manifestations in TSC. Collectively, malignancies were infrequent findings in our cohort. However, compared to the general population, malignant tumors occurred earlier in age and some tumor types were more common.
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