Historically, treatment of TSC-associated hamartomas has focused on a combination of active and watchful waiting, palliative treatments with drug therapy, and surgical procedures to reduce tumor burden (Table 1)

Historically, treatment of TSC-associated hamartomas has focused on a combination of active and watchful waiting, palliative treatments with drug therapy, and surgical procedures to reduce tumor burden (Table 1). Table 1 Common treatment modalities for SEGA, angiomyolipoma, skin lesions, and pulmonary LAM 0.001).56 No new lesions, evidence of increased intracranial pressure, worsened hydrocephalus, or need for surgical resection or any other therapy was reported. growth. By targeting mammalian target of rapamycin with everolimus, an orally active rapamycin derivative, clinically meaningful and statistically significant reductions in tumor burden have been achieved for the main brain (subependymal giant cell astrocytoma) and renal manifestations (angiomyolipoma) associated with TSC. This review provides an overview of TSC, everolimus, and the clinical trials that led to its approval for the treatment of TSC-associated subependymal giant cell astrocytoma and renal angiomyolipoma. (encoding hamartin) or (encoding tuberin) genes, both of which are integral to the normal functioning of the mammalian target of rapamycin (mTOR) pathway.18C20 The mTOR pathway integrates many cellular inputs to affect a variety of downstream signaling cascades that get excited about cellular processes such as for example cellular metabolism, growth, proliferation, angiogenesis, and survival.1,6,8,21 tuberin and Hamartin interact to create a dimer that activates a GTPase, preventing phosphorylation from the Difference proteinRas homolog enriched in human brain (Rheb)and inhibiting activation of mTOR organic 1 (mTORC1), a serine threonine kinase.22,23 In sufferers with TSC, the hamartin/tuberin dimer struggles to form due to mutations in and 28(5):602C607, Copyright ? 2013 by Sage. Reprinted by Authorization of SAGE Magazines.22 Abbreviations: 4E-BP1, 4E binding proteins 1; Abl, Abelson kinase; Akt, proteins kinase B; eIF-4E, eukaryotic initiation aspect 4E; IGF-1R, insulin-like development aspect-1 receptor; PI3K, phosphoinositide 3-kinase; Pten, tensin and phosphatase homolog; RAS, rat sarcoma; S6K1, 40 S ribosomal S6 kinase; TSC1, tuberous sclerosis complicated 1; TSC2, tuberous sclerosis complicated 2. TSC is normally considered to develop from comprehensive loss of useful or and comes after Knudsons two-hit hypothesis whereby the initial hit, leading to a mutation in a single allele from the or gene, is normally followed by another strike, somatic mutation, in the matching TSC wildtype allele.8 Disease severity could be variable, within families even, and could reflect differential appearance of mutant and normal TSC alleles.25 mutations, which occur in 70%C80% of cases, are more prevalent than mutations, which occur in 20%C30% of cases.26 Research of TSC sufferers have discovered that the clinical manifestations of TSC are more frequent and frequently more serious in sufferers with mutations.18,19 Data from genotype/phenotype research suggest that different kinds and locations of TSC germline mutations could be connected with distinct neurocognitive phenotypes.19,27,28 Management and current therapeutic strategies Recently, a subcommittee on the Tuberous Sclerosis Complex Clinical Consensus Conference (sponsored with the Tuberous Sclerosis Alliance) analyzed and updated the tips for security and administration of sufferers with TSC.29 Particular guidance on screening process and follow-up evaluations, aswell as defined time intervals for clinical evaluations clearly, is expected in the TSC guidelines and can help standardize and enhance the clinical caution of TSC patients. These guidelines will be posted and open to clinicians soon. Historically, treatment of TSC-associated hamartomas provides focused on a combined mix of energetic and watchful waiting around, palliative remedies with medication therapy, and surgical treatments to lessen tumor burden (Desk 1). Desk 1 Common treatment modalities for SEGA, angiomyolipoma, skin damage, and pulmonary LAM 0.001).56 No new lesions, proof increased intracranial pressure, worsened hydrocephalus, or dependence on surgical resection or any other therapy was reported. Everolimus was connected with SYM2206 a significant decrease in the overall regularity of scientific and subclinical seizures (median transformation ?1 seizure; 0.02).56 Standard of living in Youth Epilepsy results improved as time passes (58.74 14 at baseline; 63.4 12.4 at three months; 62.1 14.2 in six months).53 This trial continues in the extension stage, and outcomes for sufferers treated up to three years had been reported by Krueger et al recently.57 Of the initial 28 sufferers enrolled 25 were continuing treatment at the info cutoff for the 3-year expansion research57 After a median publicity of 34.2 months, the principal SEGA volume was reduced from 1.74 cm3 at baseline to 0.97 cm3 at thirty six months.57 Reductions 30% from baseline at two years, 30 months, and thirty six months had been observed in 79.2%, 64.7%, and 77.8% of sufferers, respectively, and reductions 50% were.Historically, treatment of TSC-associated hamartomas provides focused on a combined mix of active and watchful waiting, palliative remedies with drug therapy, and surgical treatments to lessen tumor burden (Table 1). Table 1 Common treatment modalities for SEGA, angiomyolipoma, skin damage, and pulmonary LAM 0.001).56 No new lesions, proof increased intracranial pressure, worsened hydrocephalus, or dependence on surgical resection or any other therapy was reported. tuberin) genes, both which are essential to the standard functioning from the mammalian focus on of rapamycin (mTOR) pathway.18C20 The mTOR pathway integrates many cellular inputs to affect a variety of downstream signaling cascades that get excited about cellular processes such as for example cellular metabolism, growth, proliferation, angiogenesis, and survival.1,6,8,21 Hamartin and tuberin interact to create a dimer that activates a GTPase, stopping phosphorylation from the Difference proteinRas homolog enriched in human brain (Rheb)and inhibiting activation of mTOR organic 1 (mTORC1), a serine threonine kinase.22,23 In sufferers with TSC, the hamartin/tuberin dimer struggles to form due to mutations in and 28(5):602C607, Copyright ? 2013 by Sage. Reprinted by Authorization of SAGE Magazines.22 Abbreviations: 4E-BP1, 4E binding proteins 1; Abl, Abelson kinase; Akt, proteins kinase B; eIF-4E, eukaryotic initiation aspect 4E; IGF-1R, insulin-like development aspect-1 receptor; PI3K, phosphoinositide 3-kinase; Pten, phosphatase and tensin homolog; RAS, rat sarcoma; S6K1, 40 S ribosomal S6 kinase; TSC1, tuberous sclerosis complex 1; TSC2, tuberous sclerosis complex 2. TSC is usually thought to develop from total loss of functional or and follows Knudsons two-hit hypothesis whereby the first hit, causing a mutation in one allele of the or gene, is usually followed by a second hit, somatic mutation, in the corresponding TSC wildtype allele.8 Disease severity can be variable, even within families, and may reflect differential expression of normal and mutant TSC alleles.25 mutations, which occur in 70%C80% of cases, are more common than mutations, which occur in 20%C30% of cases.26 Studies of TSC patients have found that the clinical manifestations of TSC are more frequent and often more severe in patients with mutations.18,19 Data from genotype/phenotype studies suggest that different types and locations of TSC germline mutations may be associated with distinct neurocognitive phenotypes.19,27,28 Management and current therapeutic strategies Recently, a subcommittee at the Tuberous Sclerosis Complex Clinical Consensus Conference (sponsored by the Tuberous Sclerosis Alliance) examined and updated the recommendations for surveillance and management of patients with TSC.29 Specific guidance on screening and follow-up evaluations, as well as clearly defined time intervals for clinical evaluations, is expected in the TSC guidelines and will help to standardize and improve the clinical care of TSC patients. These guidelines will soon be published and available to clinicians. Historically, treatment of TSC-associated hamartomas has focused on a combination of active and watchful waiting, palliative treatments with drug therapy, and surgical procedures to reduce tumor burden (Table 1). Table 1 Common treatment modalities for SEGA, angiomyolipoma, skin lesions, and pulmonary LAM 0.001).56 No new lesions, evidence of increased intracranial pressure, worsened hydrocephalus, or need for surgical resection or any other therapy was reported. Everolimus was associated with a significant reduction in the overall frequency of clinical and subclinical seizures (median switch ?1 seizure; 0.02).56 Quality of Life in Child years Epilepsy scores improved over time (58.74 14 at baseline; 63.4 12.4 at 3 months; 62.1 14.2 at 6 months).53 This trial continues in the extension phase, and results for patients treated up to 3 years were recently reported by Krueger et al.57 Of the original 28 patients enrolled 25 were continuing treatment at the data cutoff for the 3-year extension study57 After a median exposure of 34.2 months, the primary SEGA volume was reduced from 1.74 cm3 at baseline to 0.97 cm3 at 36 months.57 Reductions 30% from baseline at 24 months, 30 months, and 36 months were seen in 79.2%, 64.7%, and 77.8% of patients, respectively, and reductions 50% were seen in 50.0%, 41.2%, and 55.6% of patients, respectively57 At 24 months, improvements in facial angiofibromas compared with the previous visit were observed in eight of nine patients (88.9%).57 A subgroup analysis of patients enrolled in this trial reported a significant change in white matter diffusion in patients treated with everolimus, suggesting that treatment alters the genetic defects in normal-appearing white matter in the brain of TSC patients.58 Significant changes in fractional anisotropy and radial diffusivity were observed in the corpus callosum, internal capsule, and geniculocalcarine regions of.Historically, treatment of TSC-associated hamartomas has focused on a combination of active and watchful waiting, palliative treatments with drug therapy, and surgical procedures to reduce tumor burden (Table 1). Table 1 Common treatment modalities for SEGA, angiomyolipoma, skin lesions, and pulmonary LAM 0.001).56 No new lesions, evidence of increased intracranial pressure, worsened hydrocephalus, or need for surgical resection or any other therapy was reported. pathway, which affects many cellular processes involved in tumor growth. By targeting mammalian target of rapamycin with everolimus, an orally active rapamycin derivative, clinically meaningful and statistically significant reductions in tumor burden have been achieved for the main brain (subependymal giant cell astrocytoma) and renal manifestations (angiomyolipoma) associated with TSC. This review provides an overview of TSC, everolimus, and the clinical trials that led to its approval for the treatment of TSC-associated subependymal giant cell astrocytoma and renal angiomyolipoma. (encoding hamartin) or (encoding tuberin) genes, both of which are integral to the normal functioning of the mammalian target of rapamycin (mTOR) pathway.18C20 The mTOR pathway integrates numerous cellular inputs to affect a variety of downstream signaling cascades that get excited about cellular processes such as for example cellular metabolism, growth, proliferation, angiogenesis, and survival.1,6,8,21 Hamartin and tuberin interact to create a dimer that activates a GTPase, avoiding phosphorylation from the Distance proteinRas homolog enriched in mind (Rheb)and inhibiting activation of mTOR organic 1 (mTORC1), a serine threonine kinase.22,23 In individuals with TSC, the hamartin/tuberin dimer struggles to form due to mutations in and 28(5):602C607, Copyright ? 2013 by Sage. Reprinted by Authorization of SAGE Magazines.22 Abbreviations: 4E-BP1, 4E binding proteins 1; Abl, Abelson kinase; Akt, proteins kinase B; eIF-4E, eukaryotic initiation element 4E; IGF-1R, insulin-like development element-1 receptor; PI3K, phosphoinositide 3-kinase; Pten, phosphatase and tensin homolog; RAS, rat sarcoma; S6K1, 40 S ribosomal S6 kinase; TSC1, tuberous sclerosis complicated 1; TSC2, tuberous sclerosis complicated 2. TSC can be considered to develop from full loss of practical or and comes after Knudsons two-hit hypothesis whereby the 1st hit, leading to a mutation in a single allele from the or gene, can be followed by another strike, somatic mutation, in the related TSC wildtype allele.8 Disease severity could be variable, even within family members, and may reveal differential expression of normal and mutant TSC alleles.25 mutations, which occur in 70%C80% of cases, are more prevalent than mutations, which occur in 20%C30% of cases.26 Research of TSC individuals have discovered that the clinical manifestations of TSC are more frequent and frequently more serious in individuals with mutations.18,19 Data from genotype/phenotype research suggest that different kinds and locations of TSC germline mutations could be connected with distinct neurocognitive phenotypes.19,27,28 Management and current therapeutic strategies Recently, a subcommittee in the Tuberous Sclerosis Complex Clinical SYM2206 Consensus Conference (sponsored from the Tuberous Sclerosis Alliance) evaluated and updated the tips for monitoring and administration of individuals with TSC.29 Particular guidance on testing and follow-up evaluations, aswell as clearly defined time intervals for clinical evaluations, is expected in the TSC guidelines and can help standardize and enhance the clinical care and attention of TSC patients. These recommendations will be released and open to clinicians. Historically, treatment of TSC-associated hamartomas offers focused on a combined mix of energetic and watchful waiting around, palliative remedies with medication therapy, and surgical treatments to lessen tumor burden (Desk 1). Desk 1 Common treatment modalities for SEGA, angiomyolipoma, skin damage, and pulmonary LAM 0.001).56 No new lesions, proof increased intracranial pressure, worsened hydrocephalus, or dependence on surgical resection or any other therapy was reported. Everolimus was connected with a significant decrease in the overall rate of recurrence of medical and subclinical seizures (median modification ?1 seizure; 0.02).56 Standard of living in Years as a child Epilepsy results improved as time passes (58.74 14 at baseline; 63.4 12.4 at three months; 62.1 14.2 in six months).53 This trial continues in the extension stage, and effects for individuals treated up to three years were recently reported by Krueger et al.57 Of the initial 28 individuals enrolled 25 were continuing treatment at the info cutoff for the 3-year expansion research57 After a median publicity of 34.2 months, the principal SEGA volume was reduced from 1.74 cm3 at baseline to 0.97 cm3 at thirty six months.57 Reductions 30% from baseline at two years, 30 months, and thirty six months were observed in 79.2%, 64.7%, and 77.8% of individuals, respectively, and reductions 50% were observed in 50.0%, 41.2%, and 55.6% of individuals, respectively57 At two years, improvements in facial angiofibromas weighed against the prior visit were seen in eight of nine individuals (88.9%).57 A subgroup analysis of individuals signed up for this trial reported a substantial change in white matter diffusion in individuals treated with everolimus, recommending that treatment alters the genetic problems in normal-appearing white matter in the mind of TSC individuals.58 Significant shifts in fractional anisotropy and radial diffusivity had been seen in the corpus callosum, internal capsule, and geniculocalcarine parts of individuals treated with everolimus, no shifts were seen in the age- and gender-matched control band of individuals with TSC.58 SYM2206 Mean (95% CI) fractional anisotropy significantly increased by 0.04 (0.019C0.062) in every three brain areas after 12C18 weeks.Everolimus was associated with a significant reduction in the overall rate of recurrence of clinical and subclinical seizures (median switch ?1 seizure; 0.02).56 Quality of Life in Child years Epilepsy scores improved over time (58.74 14 at baseline; 63.4 12.4 at 3 months; 62.1 14.2 at 6 months).53 This trial continues in the extension phase, and effects for individuals treated up to 3 years were recently reported by Krueger et al.57 Of the original 28 individuals enrolled 25 were continuing treatment at the data cutoff for the 3-year extension study57 After a median exposure of 34.2 months, the primary SEGA volume was reduced from 1.74 cm3 at baseline to 0.97 cm3 at 36 months.57 Reductions 30% from baseline at 24 months, 30 months, and 36 months were seen in 79.2%, 64.7%, and 77.8% of individuals, respectively, and reductions 50% were seen in 50.0%, 41.2%, and 55.6% of individuals, respectively57 At 24 months, improvements in facial angiofibromas compared with the previous visit were observed in eight of nine individuals (88.9%).57 A subgroup analysis of individuals enrolled in this trial reported a significant change in white matter diffusion in individuals treated with everolimus, suggesting that treatment alters the genetic problems in normal-appearing white matter in the brain of TSC individuals.58 Significant changes in fractional anisotropy and radial diffusivity were observed in the corpus callosum, internal capsule, and geniculocalcarine regions of individuals treated with everolimus, and no changes were observed in the age- and gender-matched control group of individuals with TSC.58 Mean (95% CI) fractional anisotropy significantly increased by 0.04 (0.019C0.062) in all three brain areas after 12C18 weeks of everolimus treatment ( 0.05), and this was driven by a decrease in radial diffusivity in the corpus callosum and the geniculocalcarine tract ( 0.01 for each).58 A Phase III, randomized double-blind placebo-controlled trial, A Randomised Double-blind Placebo-controlled Study of Everolimus in the Treatment of Individuals With Subependymal Gaint Cell Astrocytomas (SEGA) Associated With Tuberous Sclerosis Complex (TSC) (EXIST-1)(“type”:”clinical-trial”,”attrs”:”text”:”NCT 00789828″,”term_id”:”NCT00789828″NCT 0078982859), investigated the effectiveness of everolimus versus placebo in 117 TSC individuals with SEGA (Table 3).36 Individuals were randomized to everolimus 4.5 mg/m2 per day (n = 78) or placebo (n = 39), and baseline demographics and disease characteristics were generally well balanced with the exception of a higher proportion of males and the presence of hydrocephalus in the everolimus group.36 The median age of individuals was 9.5 years (range 0.8C26.6 years), and 51% and 64% of patients in the everolimus and placebo arms, respectively, had one target SEGA lesion; 44% and 36% of individuals in the everolimus and placebo arms, respectively, experienced two SEGA lesions.36 One or more skin lesions were present in 110 individuals (92% [n = 72] of individuals in the everolimus arm and 97% of individuals in the placebo arm [n = 38]), and 38% Rabbit polyclonal to AGAP (n = 30) of individuals in the everolimus arm and 36% (n = 14) of individuals in the placebo arm experienced one or more angiomyolipomas.36 After a median follow-up of 9.7 months, the SEGA response ratethe proportion of individuals with a reduction in sum of volumes of target SEGA lesions 50% relative to baseline in the absence of nontarget lesion worsening, new lesions 1 cm in diameter, or new/worsening hydrocephaluswas 35% (95% CI: 24%C46%) in the everolimus group and 0% (95% CI: 0%C9%) in the placebo group (difference in response rate 35%, 95% CI: 15%C52%; 0.0001).36 Table 3 Effectiveness and security analyses from EXIST-1 and EXIST-2 0.0001)Key secondary end points? Most common AEs were mouth ulceration (32% vs 5% EVE vs PBO), stomatitis (31% vs 21% EVE vs PBO), convulsions (23% vs 26% EVE vs PBO), and pyrexia (22% vs 15% EVE vs PBO)? Change from baseline to week 24 in the total quantity of seizures per 24 hours? Dental 4.5 mg/m2/day everolimus titrated to target whole blood trough level of 5C15 ng/mL? C No significant difference in seizure rate of recurrence was found in the everolimus arm relative to placebo (= 0.20)? Time to progression of SEGA? C No EVE individuals progressed vs six PBO individuals (15.4%) (= 0.0002)? Pores and skin lesion response rate (among individuals with 1 pores and skin lesion at baseline; n = 110)? C 42% vs 11% (EVE vs PBO; = 0.0004)Exploratory end points? Angiomyolipoma response rate (among individuals with 1 angiomyolipoma 1 cm in longest diameter at baseline; n = 44) 53% vs 0% (EVE vs PBO)EXIST-260Primary end point? AEs were mostly grade 1/2 in severity? TSC or sporadic lymphangioleiomyomatosis sufferers (n = 118) with 1 angiomyolipoma 3 cm in longest size, no requirement of angiomyolipoma-related surgery, or zero angiomyolipoma-related embolization or bleeding in former six months? Angiomyolipoma response price? C 42% vs 0% (EVE vs SYM2206 PBO; 0.0001) Essential secondary end factors? Many common AEs had been stomatitis (48% vs 8% EVE vs PBO), nasopharyngitis (24% vs 31% EVE vs PBO), and acne-like skin damage (22% vs 5% EVE vs PBO)Essential secondary end factors? Time for you to development of angiomyolipoma? C EVE was more advanced than PBO (threat proportion: 0.08; 95% CI: 0.02C0.37; 0.0001)? Mouth 10 mg/time EVE? Epidermis lesion response price (among sufferers with 1 epidermis lesion at baseline; n = 114): 26% vs 0% (EVE vs PBO; = 0.0002) Open in another window Abbreviations: AE, adverse event; CI, self-confidence period; EVE, everolimus; EXIST, Evaluating everolimus Within a scholarly research of TSC; PBO, placebo; SEGA, subependymal large cell astrocytoma; TSC, tuberous sclerosis complicated; vs, versus. The median time for you to SEGA progression had not been reached in either treatment arm, and estimated progression-free rates at six months were 100% for everolimus and 86% for placebo.36 Analysis of change in seizure frequency was inconclusivea fact that was related to the technique of assessment, an individual 24-hour video electroencephalography, which limited the amount of evaluable patients likely. burden have already been attained for the primary brain (subependymal large cell astrocytoma) and renal manifestations (angiomyolipoma) connected with TSC. This review has an summary of TSC, everolimus, as well as the scientific trials that resulted in its acceptance for the treating TSC-associated subependymal large cell astrocytoma and renal angiomyolipoma. (encoding hamartin) or (encoding tuberin) genes, both which are essential to the standard functioning from SYM2206 the mammalian focus on of rapamycin (mTOR) pathway.18C20 The mTOR pathway integrates many cellular inputs to affect a variety of downstream signaling cascades that get excited about cellular processes such as for example cellular metabolism, growth, proliferation, angiogenesis, and survival.1,6,8,21 Hamartin and tuberin interact to create a dimer that activates a GTPase, stopping phosphorylation from the Difference proteinRas homolog enriched in human brain (Rheb)and inhibiting activation of mTOR organic 1 (mTORC1), a serine threonine kinase.22,23 In sufferers with TSC, the hamartin/tuberin dimer struggles to form due to mutations in and 28(5):602C607, Copyright ? 2013 by Sage. Reprinted by Authorization of SAGE Magazines.22 Abbreviations: 4E-BP1, 4E binding proteins 1; Abl, Abelson kinase; Akt, proteins kinase B; eIF-4E, eukaryotic initiation aspect 4E; IGF-1R, insulin-like development aspect-1 receptor; PI3K, phosphoinositide 3-kinase; Pten, phosphatase and tensin homolog; RAS, rat sarcoma; S6K1, 40 S ribosomal S6 kinase; TSC1, tuberous sclerosis complicated 1; TSC2, tuberous sclerosis complicated 2. TSC is certainly considered to develop from comprehensive loss of useful or and comes after Knudsons two-hit hypothesis whereby the initial hit, leading to a mutation in a single allele from the or gene, is certainly followed by another strike, somatic mutation, in the matching TSC wildtype allele.8 Disease severity could be variable, even within households, and may reveal differential expression of normal and mutant TSC alleles.25 mutations, which occur in 70%C80% of cases, are more prevalent than mutations, which occur in 20%C30% of cases.26 Research of TSC sufferers have discovered that the clinical manifestations of TSC are more frequent and frequently more serious in sufferers with mutations.18,19 Data from genotype/phenotype research suggest that different kinds and locations of TSC germline mutations could be connected with distinct neurocognitive phenotypes.19,27,28 Management and current therapeutic strategies Recently, a subcommittee on the Tuberous Sclerosis Complex Clinical Consensus Conference (sponsored with the Tuberous Sclerosis Alliance) analyzed and updated the tips for security and administration of sufferers with TSC.29 Particular guidance on screening process and follow-up evaluations, aswell as clearly defined time intervals for clinical evaluations, is expected in the TSC guidelines and can help standardize and enhance the clinical caution of TSC patients. These suggestions will be released and open to clinicians. Historically, treatment of TSC-associated hamartomas provides focused on a combined mix of energetic and watchful waiting around, palliative remedies with medication therapy, and surgical treatments to lessen tumor burden (Desk 1). Desk 1 Common treatment modalities for SEGA, angiomyolipoma, skin damage, and pulmonary LAM 0.001).56 No new lesions, proof increased intracranial pressure, worsened hydrocephalus, or dependence on surgical resection or any other therapy was reported. Everolimus was connected with a significant decrease in the overall rate of recurrence of medical and subclinical seizures (median modification ?1 seizure; 0.02).56 Standard of living in Years as a child Epilepsy results improved as time passes (58.74 14 at baseline; 63.4 12.4 at three months; 62.1 14.2 in six months).53 This trial continues in the extension stage, and effects for individuals treated up to three years were recently reported by Krueger et al.57 Of the initial 28 individuals enrolled 25 were continuing treatment at the info cutoff for the 3-year expansion research57 After a median publicity of 34.2 months, the principal SEGA volume was reduced from 1.74 cm3 at baseline to 0.97 cm3 at thirty six months.57 Reductions 30% from baseline at two years, 30 months, and thirty six months were observed in 79.2%, 64.7%, and 77.8% of individuals, respectively, and reductions 50% were observed in 50.0%, 41.2%, and 55.6% of individuals, respectively57 At two years, improvements in.

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