ERT Treatment Research Articles

Multiparametric magnetic resonance imaging of the liver and spleen in Gaucher disease.

To assess liver and spleen characteristics of a population with Gaucher disease (GD) using multiparametric MRI and MR elastography (MRE) for evaluation of diffuse liver and spleen disease, which includes liver fat fraction, liver and spleen volume and iron deposition, and liver and spleen stiffness correlated with DS3 Severity Scoring System for Gaucher disease (GD-DS3). We prospectively evaluated 41 patients with type 1 Gaucher disease using a 3.0T MRI and MRE between January 2019 and February 2020. Clinical, laboratory, and imaging data was collected. Mann-Whitney, Kruskal-Wallis, and Spearman's correlation were applied to evaluate liver and spleen MRI and MRE, clinical and laboratory variables, and GD-DS3. ERT and SRT treatment groups were compared. Hepatomegaly was seen in 15% and splenomegaly in 42% of the population. Moderate and strong and correlations were found between liver and spleen iron overload (rho = 0.537; p = 0.002); between liver and spleen volume (rho = 0.692, p < 0.001) and between liver and spleen stiffness (rho = 0.453, p = 0.006). Moderate correlations were found between liver stiffness and GD-DS3 (rho = 0.559; p < 0.001) and between splenic volume and GD-DS3 (rho = 0.524; p = 0.001). The prevalence of hepatosplenomegaly, liver fibrosis, and liver iron overload in treated patients with GD is low, which may be related to the beneficial effect of treatment. Liver MRE and splenic volume correlate with severity score and may be biomarkers of disease severity.

Dosimetric validation of intensity-modulated bolus electron conformal therapy planning and delivery using an anthropomorphic cylindrical head phantom.

This work investigated the dosimetric accuracy of the intensity-modulated bolus electron conformal therapy (IM-BECT) planning and delivery process using the decimal ElectronRT (eRT) treatment planning system. An IM-BECT treatment plan was designed using eRT for a cylindrical, anthropomorphic retromolar trigone phantom. Treatment planning involved specification of beam parameters and design of a variable thickness wax bolus and Passive Radiotherapy Intensity Modulator for Electrons (PRIME) device, which was comprised of 33 tungsten island blocks of discrete diameters from 0.158 to 0.223cm (Intensity Reduction Factors from 0.937 to 0.875, respectively) inside a 10.1×6.7 cm2 copper cutout. For comparison of calculation accuracy, a BECT plan was generated by copying the IM-BECT plan and removing the intensity modulation. For both plans, a 16 MeV electron beam was used with 104.7cm source-to-surface distance to bolus. In-phantom TLD-100 measurements (N=47) were compared with both eRT planned dose distributions, which used the pencil beam redefinition algorithm with modifications for passive electron intensity modulation (IM-PBRA). Dose difference and distance to agreement (DTA) metrics were computed for each measurement point. Comparison of measured dose distributions with planned dose distributions yielded dose differences (calculated minus measured) characterized by a mean and standard deviation of -0.36%±1.64% for the IM-BECT plan, which was similar to -0.36%±1.90% for the BECT plan. All dose measurements were within 5% of the planned dose distribution, with both the BECT and IM-BECT measurement sets having 46/47 (97.8%) points within 3% or within 3mm of the respective treatment plans. It was found that the IM-BECT treatment plan generated using eRT was sufficiently accurate for clinical use when compared to TLD measurements in a cylindrical, anthropomorphic phantom, and was similarly accurate to the BECT treatment plan in the same phantom.

A randomized controlled trial comparing two doses of emotion regulation therapy: Preliminary evidence that gains in attentional and metacognitive regulation reduce worry, rumination, and distress

BackgroundEmotion regulation therapy (ERT) promotes resilience in distress disorders by strengthening attentional and metacognitive capacities. Regulation skills are presented with the goal of ameliorating the perseverative negative thinking (PNT) that characterizes these disorders. This study tested ERT in a randomized controlled trial comparing the effectiveness of 16-session (ERT16) versus 8-session (ERT8) doses. MethodPatients (N = 72) endorsing elevated worry and/or rumination and meeting diagnostic criteria for a distress disorder were randomized to ERT8 or ERT16. PNT, anxiety/depressive symptoms, functioning/quality of life, and treatment mechanisms (attention shifting, attention focusing, decentering, reappraisal) were measured at pre, mid, and post treatment. Clinical symptom severity was also assigned via diagnostic interview at each timepoint. ResultsERT produced significant improvements across outcomes. ERT16 showed an advantage over ERT8 for distress disorder severity, worry, rumination, and attention shifting from pre-post treatment. Changes in ERT treatment mechanisms mediated changes in clinical improvement. ConclusionThese findings provide evidence of the effectiveness of two doses of ERT in reducing PNT and distress through improvements in regulation skills. Clinicaltrials.gov identifierNCT04060940.

The Role of Lipid Profile Assessment in Monitoring the effect of Imiglucerase in Children with Gaucher Disease

Background: Gaucher disease (GD) is an autosomal recessive hereditary illness. Many biomarkers may have a role in the etiology, pathophysiology, diagnosis, and prognosis of GD in children, which is linked to difficulties owing to the involvement of multiple organs, including the liver, spleen, and bones. Objectives to: evaluate the impact of lipid profile levels in monitoring the response to the treatment for GD patients who are on enzyme replacement therapy. Methods: A case control study was done on sixty-seven children suffered from GD recruited from Children Welfare Hospital Consultation Clinic, Gastroenterology and Hepatology Teaching Hospital and Central Child’s Teaching Hospital. The levels of total cholesterol, triglyceride, LDL-C and HDL-C were determined in GD patients’ samples who were classified according to the duration of receiving treatment into four groups, first group include 9 newly diagnosed un treated patients, second group include 18 patients receiving treatment for 3-6 months, third group comprise 20 patients received treatment for 6-12 months (n=20) and fourth group include 20 patients received ERT for more than one year and compared with a control group comprise twenty age and sex-matched control subjects. The practical part of the study was conducted at research laboratories in the Department of Pharmacy, Al-Kunooze University College, Basra-Iraq during the period from November 2021 to February 2022. Results: The results showed that triglyceride (TG) levels in whole Gaucher patients were significantly greater than in age-matched controls, whereas total cholesterol and HDL-C levels in patients were significantly lower than in controls. Non-significant variations in LDL-C levels, on the other hand, were observed. The negative significant correlations between the levels of TG and the period of receiving treatment and the positive significant correlations between the levels of total cholesterol and the period of receiving treatment revealed that these parameters were remarkably associated with the period of receiving ERT treatment. The effect of ERT was also demonstrated by the results of the ANOVA test, which revealed significant variations in the levels of TG and HDL-C across the patient subgroups. Conclusions: TG and HDL-C have been shown to have diagnostic significance in newly diagnosed untreated individuals with a wide range of treatment responses, limiting their utility in treatment monitoring whereas LDL-C showed to be neither affected by the disease nor by the treatment.

Understanding and modifying Fabry disease: Rationale and design of a pivotal Phase 3 study and results from a patient-reported outcome validation study

The use of available treatments for Fabry disease (FD) (including enzyme replacement therapy [ERT]) may be restricted by their limited symptom improvement and mode of administration. Lucerastat is currently being investigated in the MODIFY study as oral substrate reduction therapy for the treatment of FD. By reducing the net globotriaosylceramide (Gb3) load in tissues, lucerastat has disease-modifying potential to improve symptoms and delay disease progression.MODIFY is a multicenter, double-blind, randomized, placebo-controlled, parallel-group Phase 3 study (ClinicalTrial.gov: NCT03425539); here we present the rationale and design of this study. Eligible adults with a genetically confirmed diagnosis of FD and FD-specific neuropathic pain entered screening. Patients were randomized (2:1) to receive either oral lucerastat twice daily or placebo for 6 months; treatment allocation was stratified according to sex and ERT treatment status. The main objectives of MODIFY are to assess the effects of lucerastat on neuropathic pain, gastrointestinal (GI) symptoms, FD biomarkers, and determine its safety and tolerability.Neuropathic pain and GI symptoms are key features of FD that have a significant impact on quality of life. Despite various tools available to assess pain and GI symptoms, there are currently limited tools available to assess neuropathic and GI symptoms in FD, validated according to health authority guidelines. Based on FDA recommendations, we undertook a patient-reported outcome (PRO) validation study, using a novel eDiary-based PRO tool to assess the validity of evaluating neuropathic pain as a primary efficacy endpoint in MODIFY. Results from the PRO validation study are included.To date, MODIFY is the largest Phase 3 clinical study conducted in patients with FD. Enrollment to MODIFY is now complete, with 118 patients randomized. Results will be presented in a separate publication. Long-term effects of lucerastat are being assessed in the ongoing open-label extension study (NCT03737214).

Alpha-Galactosidase A p.A143T, a non-Fabry disease-causing variant.

BackgroundFabry disease (FD) is an X-linked multisystemic disorder with a heterogeneous phenotype. Especially atypical or late-onset type 2 phenotypes present a therapeutical dilemma.MethodsTo determine the clinical impact of the alpha-Galactosidase A (GLA) p.A143T/ c.427G > A variation, we retrospectively analyzed 25 p.A143T patients in comparison to 58 FD patients with other missense mutations.Resultsp.A143T patients suffering from stroke/ transient ischemic attacks had slightly decreased residual GLA activities, and/or increased lyso-Gb3 levels, suspecting FD. However, most male p.A143T patients presented with significant residual GLA activity (~50 % of reference), which was associated with normal lyso-Gb3 levels. Additionally, p.A143T patients showed less severe FD-typical symptoms and absent FD-typical renal and cardiac involvement in comparison to FD patients with other missense mutations. Two tested female p.A143T patients with stroke/TIA did not show skewed X chromosome inactivation. No accumulation of neurologic events in family members of p.A143T patients with stroke/transient ischemic attacks was observed.ConclusionsWe conclude that GLA p.A143T seems to be most likely a neutral variant or a possible modifier instead of a disease-causing mutation. Therefore, we suggest that p.A143T patients with stroke/transient ischemic attacks of unknown etiology should be further evaluated, since the diagnosis of FD is not probable and subsequent ERT or chaperone treatment should not be an unreflected option.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-016-0441-z) contains supplementary material, which is available to authorized users.

Biochemical response to substrate reduction therapy versus enzyme replacement therapy in Gaucher disease type 1 patients.

BackgroundWe retrospectively compared biochemical responses in type 1 Gaucher disease patients to treatment with glycosphingolipid synthesis inhibitors miglustat and eliglustat and ERT.MethodsSeventeen GD1 patients were included (n = 6 eliglustat, (two switched from ERT), n = 9 miglustat (seven switchers), n = 4 ERT (median dose 60U/kg/m). Plasma protein markers reflecting disease burden (chitotriosidase, CCL18) and lipids reflecting substrate accumulation (glucosylsphingosine, glucosylceramide) were determined. Also, liver and spleen volumes, hemoglobin, platelets, and fat fraction were measured.ResultsIn patients naïve to treatment, chitotriosidase, CCL18 and glucosylsphingosine decreased comparably upon eliglustat and ERT treatment, while the response to miglustat was less. After 2 years, median decrease of chitotriosidase was 89 % (range 77–98), 88 % (78–92) and 37 % (29–46) for eliglustat, ERT and miglustat naïve patients respectively; decrease of CCL18 was 73 % (63–78), 54 % (43–86), and 10 % (3–18); decrease of glucosylsphingosine was 86 % (78–93), 78 % (65–91), 48 % (46–50). Plasma glucosylceramide in eliglustat treated patients (n = 4) reached values below the normal range (n = 20 healthy controls). Biochemical markers decreased or stabilized in switchers from ERT to eliglustat (n = 2), but less in miglustat switchers (n = 7). Clinical parameters responded comparably upon eliglustat and ERT treatment.ConclusionsOur explorative study provides evidence that biochemical markers respond comparably in patients receiving eliglustat treatment and ERT, while the corresponding response to miglustat treatment is less.

G.P.5 - Blood film examination for vacuolated and PAS-positive lymphocytes as diagnostic screening test for patients with late onset Pompe disease (LOPD)

Pompe disease is an inherited metabolic multisystemic disorder resulting in glycogen storage in different tissues, caused by a deficiency of the lysosomal enzyme acid alfa-glucosidase. Glycogen storage is often a morphological marker in muscle biopsy of Pompe patients but it could be also present in other tissues. Abnormal cytoplasmic vacuolation of lymphocytes, detectable on routine blood film examination, has been recently proposed as possible screening in these patients. We examined blood smear of 16 LOPD patients, aged 14-71 years. The cohort phenotype encompasses 3 patients with presymptomatic hyperckemia, 2 with myalgia and faticability, and 11 with proximal muscle weakness. Among those, 6 patients are on ERT treatment. We collected also peripheral blood films from 20 healthy controls and from 12 patients affected by other muscle glycogenoses. Blood sample was followed by preparation of four blood films: two of them were stained by May-Grunwald/ Giemsa (MGG) end the other two by PAS. . To investigate the diagnostic value of the test, we quantified the percentage of vacuolated lymphocytes and the percentage of PAS-positive lymphocytes. The mean values of PAS-positive lymphocytes in LOPD patients (25.6%) were significantly higher than those of healthy controls (4.6%) and of patients with other muscle glycogenoses (4.8%). In this group of patients, we have shown that PAS-positive cytoplasmic vacuolation of lymphocytes in peripheral blood films could be considered as a reliable screening tool to support an early diagnosis of Pompe disease.

Blood film examination for vacuolated and PASpositive lymphocytes as diagnostic screening test for patients with late onset Pompe disease (LOPD)

Pompe disease is an inherited metabolic multisystemic disorder resulting in glycogen storage in different tissues, caused by a deficiency of the lysosomal enzyme acid alfa-glucosidase. Glycogen storage is often a morphological marker in muscle biopsy of Pompe patients but it could be also present in other tissues. Abnormal cytoplasmic vacuolation of lymphocytes, detectable on routine blood film examination, has been recently proposed as possible screening in these patients. We examined blood smear of 16 LOPD patients, aged 14-71 years. The cohort phenotype encompasses 3 patients with presymptomatic hyperckemia, 2 with myalgia and faticability, and 11 with proximal muscle weakness. Among those, 6 patients are on ERT treatment. We collected also peripheral blood films from 20 healthy controls and from 12 patients affected by other muscle glycogenoses. Blood sample was followed by preparation of four blood films: two of them were stained by May-Grunwald/ Giemsa (MGG) end the other two by PAS. . To investigate the diagnostic value of the test, we quantified the percentage of vacuolated lymphocytes and the percentage of PAS-positive lymphocytes. The mean values of PAS-positive lymphocytes in LOPD patients (25.6%) were significantly higher than those of healthy controls (4.6%) and of patients with other muscle glycogenoses (4.8%). In this group of patients, we have shown that PAS-positive cytoplasmic vacuolation of lymphocytes in peripheral blood films could be considered as a reliable screening tool to support an early diagnosis of Pompe disease.

Survival and associated factors in 268 adults with Pompe disease prior to treatment with enzyme replacement therapy

BackgroundPompe disease is a rare lysosomal storage disorder characterized by muscle weakness and wasting. The majority of adult patients have slowly progressive disease, which gradually impairs mobility and respiratory function and may lead to wheelchair and ventilator dependency. It is as yet unknown to what extent the disease reduces the life span of these patients. Our objective was to determine the survival of adults with Pompe disease not receiving ERT and to identify prognostic factors associated with survival.MethodsData of 268 patients were collected in a prospective international observational study conducted between 2002 and 2009. Survival analyses from time of diagnosis and from time of study entry were performed using Kaplan-Meier curves and Cox-proportional-hazards regression.ResultsMedian age at study entry was 48 years (range 19-79 years). Median survival after diagnosis was 27 years, while median age at diagnosis was 38 years. During follow-up, twenty-three patients died prior to ERT, with a median age at death of 55 (range 23-77 years). Use of wheelchair and/or respiratory support and patients' score on the Rotterdam Handicap Scale (RHS) were identified as prognostic factors for survival. Five-year survival for patients without a wheelchair or respiratory support was 95% compared to 74% in patients who were wheelchair-bound and used respiratory support. In a Dutch subgroup of 99 patients, we compared the observed number of deaths to the expected number of deaths in the age- and sex-matched general population. During a median follow-up of 2.3 years, the number of deaths among the Dutch Pompe patients was higher than the expected number of deaths in the general population.ConclusionOur study shows for the first time that untreated adults with Pompe disease have a higher mortality than the general population and that their levels of disability and handicap/participation are the most important factors associated with mortality. These results may be of relevance when addressing the effect of ERT or other potential treatment options on survival.

Constraints in the use of repair half times and mathematical modelling for the clinical application of HDR and PDR treatment schedules as an alternative for LDR brachytherapy

Abstract Using theoretical models based on radiobiological principles for the design of new treatment schedules for HDR and PDR brachytherapy, it is important to realise the impact of assumptions regarding the kinetics of repair. Extrapolations based on longer repair half times in a continuous LDR reference scheme may lead to the calculation of dangerously high doses for alternative HDR and PDR treatment schedules. We used the clinical experience obtained with conventional ERT and LDR brachytherapy in head and neck cancer as a clinical guideline to check the impact of the radiobiological parameters used. Biologically equivalent dose (BED) values for the in clinical practice of LDR brachytherapy recommended dose of 65–70 Gy (prescribed at a dose rate between 30–50 cGy/h) are calculated as a function of the repair half time. These BED values are compared with the biological effect of a clinical reference dose of conventional ERT with 2 Gy/day and complete repair between the fractions. From this comparison of LDR and ERT treatment schedules, a range of values for the repair half times of acute or late responding tissues is demarcated with a reasonable fit to the clinical data. For the acute effects (or tumor control) the best fits are obtained for repair half times of about 0.5 h, while for late effects the repair half times are at least 1 h and can be as high as 3 h. Within these ranges of repair half times for acute and late effects, the outcome of ‘alternative' HDR or PDR treatment schedules are discussed. It is predominantly the late reacting normal tissue with the longer repair half time for which problems will be encountered and no or only marginal gain is to be expected of decreasing the dose rate per pulse in PDR brachytherapy.

Constraints in the use of repair half times and mathematical modelling for the clinical application of HDR and PDR treatment schedules as an alternative for LDR brachytherapy

Using theoretical models based on radiobiological principles for the design of new treatment schedules for HDR and PDR brachytherapy, it is important to realise the impact of assumptions regarding the kinetics of repair. Extrapolations based on longer repair half times in a continuous LDR reference scheme may lead to the calculation of dangerously high doses for alternative HDR and PDR treatment schedules. We used the clinical experience obtained with conventional ERT and LDR brachytherapy in head and neck cancer as a clinical guideline to check the impact of the radiobiological parameters used. Biologically equivalent dose (BED) values for the in clinical practice of LDR brachytherapy recommended dose of 65–70 Gy (prescribed at a dose rate between 30–50 cGy/h) are calculated as a function of the repair half time. These BED values are compared with the biological effect of a clinical reference dose of conventional ERT with 2 Gy/day and complete repair between the fractions. From this comparison of LDR and ERT treatment schedules, a range of values for the repair half times of acute or late responding tissues is demarcated with a reasonable fit to the clinical data. For the acute effects (or tumor control) the best fits are obtained for repair half times of about 0.5 h, while for late effects the repair half times are at least 1 h and can be as high as 3 h. Within these ranges of repair half times for acute and late effects, the outcome of ‘alternative’ HDR or PDR treatment schedules are discussed. It is predominantly the late reacting normal tissue with the longer repair half time for which problems will be encountered and no or only marginal gain is to be expected of decreasing the dose rate per pulse in PDR brachytherapy.