Bone involvement is the most common cause of functional limitation, disability and poor quality of life in patients with lysosomal storage disease (LSD). In type 1 Gaucher disease (GD1) intraosseous ...lesions have a vascular involvement with obstruction and / or local hemorrhage, once established it, secondary irreversible sequels with structure changes are developed. The intimate mechanisms that induce these feared complications are only partially known and the risk factors are not well established. There has been speculation about the relationship between the type of genetic defect and the severity of the disease. The most frequent mutations found in the Spanish population are point direction changes in the GBA gene (c.1226A> G (N370S) and c.1448T> C (L444P). However, other types of mutations (nonsense, splicing, frameshift stop codon, deletions, insertions, recombination) that induce a lower residual enzyme activity and, consequently, a higher storage rate and therefore more intensity of symptoms are found.
Objective: To analyze the relationship between different missense mutation and the presence and developing of vascular bone lesions in GD 1 patients.
Patients and Methods: We have analyzed the data obtained in our LSD Unit over the last 20 years in the evaluation of bone disease by magnetic resonance imaging with semi-quantitative estimation of the involvement by S-MRI and BMB scores and determination of bone mineral density by ultrasound in 131 GD patients (Andrade-Campos et al 2016). Here we present a sub-study in 85 patients heterozygous for c.1226A> G comparing the data obtained related to their genetic characteristics. According to the genotype were classified the patients in three groups, A: c.1226A> G / c.1448T> C (34), B: c.1226A> G in heterozygosity with other missense mutation (34) and C: c.1226A> G mutation with other types (17). In addition to search for plasma biomarkers associated to bone disease and verify them we have applied a targeted proteomics strategy. We have transformed monocytes to osteoclasts from these groups of patients and by proteomics profiles we have compared with osteoclasts of healthy controls by isobaric tag for relative and absolute quantification (iTRAQ). Labelling with iTRAQ in combination with sample pre-fractionation and nano liquid chromatography-tandem MS was used for identification and quantification of the basal proteome. More than 700 proteins were identified with this strategy. To verify the quantification of the proteins identified we have selected the MRM (multiple reaction monitoring) strategy for differential quantification according their highly sensitive, reproducible and accurate.
Results: The mean age at diagnosis for each of the groups was similar. A: 30.85 (6-68)> 30 years: 19 (55.88%), C: 28.52 (4-56)> 30 years: 8 (47%) And significantly lower in B: 18.32 (3-60;> 30years: 10 (29.41%) (p = 0.01). The M/F ratio was balanced in group A (F: 52.9%) while there was predominance of females in group C (64.72%) and males in group B (64.70%). The proportion of splenectomized patients in groups A and B was similar (32.3%), whereas in group C was significantly higher (52.9%) (p = 0.01). Patients in groups A and B presented similar scores S-MRI and BMB 11,2 / 7,32 while group C showed a significant higher score 14.3 / 8.23 (p: 0.01) and higher incidence of osteopenia and osteoporosis. Only 17% of patients in group C and 20% in group B showed uncomplicated bone marrow infiltration compared to 50% in group A. The mean concentration of the biomarkers (chitotriosidase activity and CCL18/PARC) was similar between the three groups. The results of iTRAQ study has identified some target proteins with potential use as biomarkers that will be present in the meeting if the work is selected to be presented.
In conclusion, patients with genotype that include an allele with complex mutations, present greater risk of suffering vascular bone complications (osteonecrosis, infarctions, bone demineralization). It is important to consider these genetic characteristics to establish recommendations about the importance of diagnosis and early treatment as well as to avoid splenectomy and to follow up by annual MRI and DEXA. The standard biomarkers of the disease do not establish differences between risk groups. The protein expression analyzed has show differential expression of some proteins that need to be addressed by target proteomic strategy.
No relevant conflicts of interest to declare.
Bone effects are the most frequent cause of disability in Gaucher disease (GD). Magnetic resonance imaging (MRI) has improved the study of bone involvement making it possible to measure the extent of ...infiltration and to identify localized complications and other lesions. Here we describe the results of our analysis of all bone lesions registered in MRI studies performed in our GD Clinic.
A retrospective study was undertaken for all patients with types 1 and 3 GD who underwent MRI evaluation and correlated with clinical, molecular, and other follow-up information obtained from the Spanish GD Registry.
350 MRI studies of 131 GD patients were reviewed (males 53.4%). Mean age: 37.5years (range 13-74yr), 94.6% (124) were GD1 patients. 113/131 (86.3%) of patients presented with at least one bone effect (bone infiltration, bone crisis, avascular necrosis) were 79.4%, while 28.8% showed another bone lesion such as neuronopathic-like arthropathy, hemangioma, other ischemic phenomena, infection-related lesions, secondary neoplasia and tissue infiltration.
MRI is a routinely-used tool for the evaluation of GD lesions which improves the assessment of patients before and during therapy, identifies GD complications and finds other concomitant lesions. This work provides a new evaluation of MRI assessment in this complex rare disease.
Gaucher disease (GD) is the most common lysosomal storage disorder. The principal manifestations for its diagnosis and further monitoring include haematological manifestations such as anaemia, ...thrombocytopaenia, spleen enlargement, and bleeding disorders, among others. This review aims to summarise and update the role of haematological complications in GD diagnosis and follow-up, describe their management strategies, and to use these indicators as part of the diagnostic approach.
A systematic review following the recommendations of PRISMA-P 2020 was carried out. Publications indexed in the databases PubMed, Embase, Science Open, Mendeley, and Web of Science were electronically searched by three independent reviewers, and publications up to June 2021 were accessed. A total of 246 publications were initially listed, of which 129 were included for further review and analysis. Case reports were considered if they were representative of a relevant hematologic complication.
From the first review dated in 1974 to the latest publication in 2021, including different populations confirmed that the haematological manifestations such as thrombocytopaenia and splenomegaly at diagnosis of GD type 1 are the most frequent features of the disease. The incorporation of haematological parameters to diagnosis strategies increases their cost-effectiveness. Hematologic parameters are part of the scoring system for disease assessment and the evaluation of therapeutic outcomes, providing reliable and accessible data to improve the management of GD. However, cytopaenia, underlying coagulation disorders, and platelet dysfunction need to be addressed, especially during pregnancy or surgery. Long-term haematological complications include the risk of neoplasia and immune impairment, an area of unmet need that is currently under research.
Haematological features are key for GD suspicion, diagnosis, and management. Normalization of hematological parameters is achieved with the treatment; however, there are unmet needs such as the underlying inflammatory status and the long-term risk of hematologic neoplasia.
A 68-year-old woman was treated with an autogenous particulated bone graft from the anterior part of the mandible to elevate the right maxillary sinus floor, which was next to the alveolar ridge of ...an edentulous area, to facilitate dental implant placement. A rigid plate for anchorage was placed into the zygomatic bone. The maxillary right canine and the premolars were moved distally 6 months after the implant was placed and osteointegration of the bone graft had occurred. The Class II relationship was corrected. After tooth movement, the patient underwent multislice computed tomography to determine the mineral density of the bone graft and compare it with the opposite side of the maxilla. The mineral density showed values above normal for the posterior segment of the maxilla. Although the patient was taking bisphosphonate for treatment of osteoporosis, no related complications were noted during treatment.
Introduction: The Myelodisplastic syndromes (MDS) are a heterogeneous group of clonal hematological neoplasms characterized by a progressive bone marrow failure with an increased risk for ...transformation to acute myeloid leukemia (AML). The WHO 2008 classification and the revised international prognosis-scoring system (IPSS-R) had improved prognosis assessment and therapy. The IPSS-R is based on the cytogenetic risk scoring system focus into the presence of cytogenetic alterations. However more than 50% of MDS patients are diagnosed without cytogenetic abnormalities (diploid Cytogenetics, DC-MDS), different to their counterparts with abnormal karyotype (AK-MDS) they face problems for prognostication. Epigenetic tests like microRNAs (miRNAs) studies can found biomarkers for diagnostic, prognosis and potentially target therapy. The miRNAs implications on hematopoiesis are wide recognized. After an exploratory work of miRNAs implication on MDS patients, a cluster located inside the chromosome region 19q13.2-19q13.4 appears to be related with the outcomes and risk for transformation. Here there is described novel data incorporated into a combined model to improve prognostication of patients with DC-MDS.
Aims: To explore the usefulness of miRNAs determination to improve prognosis assessment in MDS patients.
Patients and Methods: Based on previous works (Andres-Coduras, et al, ELN 2012, Andrade-Campos et al, Blood 2015: 126(23): 1642), a miRNAs profile, composed by 19 miRNAs identified in 40 patients with MDS compared to controls was analyzed in 242 plasma samples obtained at diagnosis from patients with MDS, ethic committee and inform consent according Helsinki declaration signature were required. The miRNA profile included: hsa-miR-26a, hsa-miR-451, hsa-miR-99b, hsa-miR-24, hsa-miR-625, hsa-miR-15b, hsa-miR-19b, hsa-let-7e, hsa-miR-16, hsa-miR-140-3p, hsa-miR361-3p, hsa-miR-378 and hsa-miR-942; The 2-d(dCT) method and expression over 1.3 (-10Log) times were considered as overexpression.
Results: from 242 samples, 141 (62.4%) were males, mean age of the entire cohort: 73.3 (29-91 years). For DC-MDS patients (n=154), mean age 74 (33-91) years, 94 (61.0%) males. For WHO, Cytogenetic and IPSS-R risk classification see table 1. During follow-up (median 29 (2-76) months), 47 progressions (24 on DC-MDS group) and 108 deaths (64 in DC-MDS) were registered. For a median progression free survival (PFS) of 49.4 (42.4-56.3) months and 58.0 (52.0-64.5) months for AK-MDS and DC-MDS respectively, and overall survival (OS): 36.0 (29.6-42.6) months and 45.4 (40.9-49.8) months respectively.
During the multivariate analysis with the objective to assess the risk of progression/death, the cytogenetic risk, IPSS-R and overexpression of miRNAs Let-7e-5p, miR-99b-5p and miR-140-3p showed significant differences among all subgroups. Regarding miRNAs only Let-7e and miR-99b showed a normal distribution into the entire cohort, and considering that both are part of a cluster, a combined expression model analysis was carried out. The hazard ratio (HR) for risk to progression of the combined overexpression (Let-7e + miR-99b) was 2.9 for the entire cohort, HR 1.3 for AK-MDS, but for the DC-MDS group: HR: 4.5 confirmed by Cox regression (p=0.034), for OS the results were also significant (p=0.008) for the DC-MDS, but not for the AK-MDS, in which IPSS-R remain as the more predictive tool. Considering the fact that >50% of patients present DC-MDS with problems for the stratification, a combined model adding the overexpression of Let-7e+miR-99b-information to the IPSS-R was created in order to split the categories as follows: 1. Very low with miRNAs overexpression 2-Very low without miRNAs overexpression, 3-Low with miRNAs overexpression, 4-Low without miRNAs overexpression, 5- Intermediate with miRNAs overexpression, 6- Intermediate without miRNAs overexpression (see table 2). With this approach the predictive value of the combined system (IPSS-R & miRNAs) improves the AUC for ROC analysis= 0,786 for PFS and AUC (ROC)=0.752 for OS (both p<0.001), identifying patients at risk for progression or death independently of the IPSS-R category, with especial repercussion among the low and intermediate risk groups.
Conclusions: this model offers for the first time the possibility to improve the accuracy of IPSS-R and identified high-risk patients.
This work has been partially supported by FEHHA.
No relevant conflicts of interest to declare.
Background: The myelodisplastic syndromes (MDS) is a heterogeneous group of hematological neoplasms secondary to a clonal alteration in the hematological stem cell. There is a relationship with the ...elderly and their major clinical manifestations reflect a status of progressive bone marrow failure with cytopenias and an elevated risk to transformation to acute myeloid leukemia (AML). The WHO 2008 classification for myeloid malignancies and the use of the revised international prognosis-scoring system (IPSS-R) had permitted to improve both therapy and prognosis approaches. The IPSS-R use the new cytogenetic risk scoring system, based in the presence of cytogenetic alterations clinically implicated in patients' outcomes. However more than 50% of patients with MDS are diagnosed without cytogenetic abnormalities (normal karyotype, NK) and they are classified mostly in the good and intermedium risk categories of IPSS-R, different to their counterparts with cytogenetic abnormalities that are more precisely classified. Epigenetic studies and innovative techniques like multiparameter karyotype, molecular biology or wide genetic sequencing can found biomarkers or alterations related with MDS status in these patients. MicroRNAs (miRNAs) are small non-coding regulatory molecules that act on the promoting or silencing different cellular processes. Few years ago, their relationship with hematological malignancies was evidenced. Here there is described an exploratory work of miRNAs implication on MDS patients and their utility on diagnosis and classification of NK-MDS patients.
Aims: To explore the expression of a profile of miRNAs in patients with MDS and NK, assessing the role of them in the risk stratification.
Patients and methods: Based on previous works of our group (Andres-Coduras, et al, ELN 2012; Andres-Codura, et al, SEHH 2013), a miRNAs profile, composed by 14 miRNAs over more than 7,000 miRNAs, was identified, on 40 patients with MDS compared to controls. This profile was analyzed in 243 plasma samples from patients with MDS at diagnosis from the INBIOMED group, previously ethic committee and board approval were required and patients signed an inform consent according the Helsinki declaration revised in 2013. Here, we are presenting a subanalysis including only patients with NK. The miRNA profile included: hsa-miR-26a, hsa-miR-451, hsa-miR-99b, hsa-miR-24, hsa-miR-625, hsa-miR-15b, hsa-miR-19b, hsa-let-7e, hsa-miR-16, hsa-miR-140-3p, hsa-miR361-3p, hsa-miR-378 and hsa-miR-942.
Results: From 154 plasma of NK-MDS patients. All of them classified as very good, good and intermediate risk category by IPSS-R or low and intermedium-1 by IPSS, a total of 143 have associated follow-up information at 2 years of diagnosis. Thirty-seven patients evolved to AML or died in this time. 4 miRNAs differentially expressed (miRNA140-3p, miRNA-15b, miRNA-99b-5p and miRNA-361-3p) showed advantage to identified patients with MDS. Based in IPSS-R, patients were classified as good prognosis group (no candidates to therapy) and high risk group (candidates to therapy). An increase in both the expression of miR-140-3p and miR-99b-5p was able to identified patients with MDS and NK with good prognosis independently of IPSS-R risk category, improving the identification of patients with good outcomes (ROC curve for IPSS-R: 0,669 and for miRNAs model: 0,785), contrary, the underexpression of both miRNAs was a predictor of worse outcomes.
Comments: Here we describe a non-previously described signature of miRNAs that can improve the classification of MDS patients without cytogenetic alterations, especially for patients with good or intermediate risk group. miRNAs could be a good biomarkers during follow-up considering their variations and easy assessment.
Ramos:Amgen: Consultancy, Honoraria; GlaxoSmithKline: Honoraria; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria; Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.
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