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Hematology. American Society of... Nov 2018The myelodysplastic syndromes are collectively the most common myeloid neoplasms. Clonal hematopoiesis present in these diseases results in bone marrow failure... (Review)
Review
The myelodysplastic syndromes are collectively the most common myeloid neoplasms. Clonal hematopoiesis present in these diseases results in bone marrow failure characteristically seen in patients. The heterogeneity of myelodysplastic syndrome pathobiology has historically posed a challenge to the development of newer therapies. Recent advances in molecular characterization of myelodysplastic syndromes are improving diagnostic accuracy, providing insights into pathogenesis, and refining therapeutic options for patients. With the advent of these developments, appropriately chosen therapeutics or even targeted agents may be able to improve patient outcomes in the future.
Topics: Hematopoiesis; Humans; Myelodysplastic Syndromes
PubMed: 30504322
DOI: 10.1182/asheducation-2018.1.277 -
Journal of Clinical Laboratory Analysis Oct 2022Clinically, to make a definite diagnosis of aplastic anemia (AA), idiopathic cytopenia of undetermined significance (ICUS) or myelodysplastic syndrome (MDS), they should...
OBJECTIVE
Clinically, to make a definite diagnosis of aplastic anemia (AA), idiopathic cytopenia of undetermined significance (ICUS) or myelodysplastic syndrome (MDS), they should be distinguished from each other. AA and ICUS have some incidence to transform into MDS. Immunosuppressive therapy (IST) is effective in AA and partial ICUS patients, while other ICUSs are more likely to progress to MDS without response to IST. To date, we neither found a technical method that could easily identify AA from hypoproliferative MDS, nor a simple parameter that could indicate ICUS with a response to IST. Here, we detected the concentration of free immune checkpoints in bone marrow supernatant of AA, ICUS, and MDS patients, analyzed the differences of immune status among these three diseases, to try to find a way to predict the response to IST in ICUSs.
METHODS
Seventy-four novel patients were enrolled with newly diagnosed acquired bone marrow failure (including 29 AA patients, 11 ICUS patients, and 34 MDS patients), bone marrow supernatants were collected. Luminex liquid suspension array technology was used to measure the concentrations of 17 immune checkpoints to analyze the differences of immune status among these three diseases.
RESULTS
The levels of 17 free immune checkpoints were elevated in MDS and showed a strong correlation with each other, followed by ICUS, and with the weakest in AA. By drawing the ROC curve, we found eight immune checkpoints, including sCD40, sCD86/B7-2, sCTLA-4, sGITR, sHVEM, sPD-1, sTIM-3, and sTLR-2, could easily distinguish AA from hypoproliferative MDS. ICUSs with lower concentrations of these eight free immune checkpoints predicted a better IST response.
CONCLUSION
In conclusion, we found that there were notable differences in the immune status of AA, ICUS, and MDS. The concentrations of sCD40, sCD86/B7-2, sCTLA-4, sGITR, sHVEM, sPD-1, sTIM-3, and sTLR-2 could be used to identify AA and hypoproliferative MDS patients, as well as to distinguish ICUS patients who could benefit from IST.
Topics: Anemia, Aplastic; Biomarkers; Bone Marrow; Diagnosis, Differential; Humans; Myelodysplastic Syndromes
PubMed: 36086857
DOI: 10.1002/jcla.24677 -
Cartilage Oct 2019This study aimed to compile available data in medical literature about subchondral calcium phosphate injection, comparing results obtained with this technique, as well... (Review)
Review
PURPOSE
This study aimed to compile available data in medical literature about subchondral calcium phosphate injection, comparing results obtained with this technique, as well as indications, complications, and other important factors in treatment of bone marrow lesions.
DESIGNS
A literature review using PubMed and Medline database in order to identify works with terms "subchondral calcium phosphate injection," " subchondroplasty®," "bone marrow lesion," and "knee." Eight relevant articles were found.
RESULTS
A total of 164 patients with bone marrow lesion mainly on femoral condyle and tibial plateau recovered with significant functional improvement of knee after subchondral calcium phosphate treatment. Although 25% of them still had some type of pain complaint, they also showed improvement. There were few complications reported and return to activities occurred after 3 months on average.
CONCLUSIONS
Few studies evaluate the result of using subchondral calcium phosphate injection technique. However, all presented favorable results regarding pain and improvement of knee function. In addition, within 2 years, there was a 70% reduction in conversion to total knee arthroplasty in patients with previous surgical indication who choose calcium phosphate treatment.
Topics: Bone Marrow Diseases; Bone Substitutes; Calcium Phosphates; Humans; Injections, Intra-Articular; Knee Injuries; Knee Joint; Recovery of Function
PubMed: 29667853
DOI: 10.1177/1947603518770249 -
Molecular Genetics & Genomic Medicine May 2018ERCC6L2-associated disorder has recently been described and only five patients were reported so far. The described phenotype included bone marrow, cerebral, and... (Review)
Review
BACKGROUND
ERCC6L2-associated disorder has recently been described and only five patients were reported so far. The described phenotype included bone marrow, cerebral, and craniofacial abnormalities. The aim of this study was to further define the genetic and phenotypic spectrum of the disorder by summarizing the five published cases and an additional case that we identified through whole-exome sequencing performed at the University of Toronto.
METHODS
Clinical data was extracted from the Canadian Inherited Marrow Failure Registry. Whole exome sequencing was performed to identify causative mutations.
RESULTS
All six cases had homozygous truncating mutations either at or upstream of the helicase domain of ERCC6L2. All patients displayed bone marrow failure, learning or developmental delay and microcephaly. Our patient was unique in displaying features of cerebellar disease, including ataxia and dysmetria as well as an interval deterioration of the corpus callosum and generalized volume loss on MRI. Another unique feature of our patient was retinal dystrophy with macular involvement. Along with one other patient, our patient displayed craniofacial abnormalities by presenting with low-set prominent ears, a pointed prominent chin, and deep-set eyes. Leukemia is common among patients with inherited bone marrow failure, but thus far, none of the patients have developed this complication.
CONCLUSIONS
ERCC6L2-associated disorder is a multisystem disorder. The phenotype spectrum includes bone marrow failure, cerebral, and craniofacial abnormalities, as well as cerebellar and retinal abnormalities.
Topics: Adolescent; Adult; Anemia, Aplastic; Bone Marrow Diseases; Bone Marrow Failure Disorders; Canada; Child; Child, Preschool; Craniofacial Abnormalities; DNA Helicases; Developmental Disabilities; Exome; Female; Hemoglobinuria, Paroxysmal; Homozygote; Humans; Infant; Intellectual Disability; Male; Microcephaly; Mutation; Nervous System Malformations; Pedigree; Phenotype
PubMed: 29633571
DOI: 10.1002/mgg3.388 -
Frontiers in Immunology 2024Bone marrow failure (BMF) has become one of the most studied autoimmune disorders, particularly due to its prevalence both as an inherited disease, but also as a result... (Review)
Review
Bone marrow failure (BMF) has become one of the most studied autoimmune disorders, particularly due to its prevalence both as an inherited disease, but also as a result of chemotherapies. BMF is associated with severe symptoms such as bleeding episodes and susceptibility to infections, and often has underlying characteristics, such as anemia, thrombocytopenia, and neutropenia. The current treatment landscape for BMF requires stem cell transplantation or chemotherapies to induce immune suppression. However, there is limited donor cell availability or dose related toxicity associated with these treatments. Optimizing these treatments has become a necessity. Polymer-based materials have become increasingly popular, as current research efforts are focused on synthesizing novel cell matrices for stem cell expansion to solve limited donor cell availability, as well as applying polymer delivery vehicles to intracellularly deliver cargo that can aid in immunosuppression. Here, we discuss the importance and impact of polymer materials to enhance therapeutics in the context of BMF.
Topics: Humans; Polymers; Animals; Bone Marrow Diseases; Bone Marrow Failure Disorders; Biocompatible Materials
PubMed: 38694497
DOI: 10.3389/fimmu.2024.1396486 -
Hematology. American Society of... Dec 2016Clonal progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) remains a dreaded complication for a subset of patients with bone marrow failure... (Review)
Review
Clonal progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) remains a dreaded complication for a subset of patients with bone marrow failure (BMF). Recognizing risk factors for the development of MDS or AML would inform individualized treatment decisions and identify patients who may benefit from early or upfront hematopoietic stem cell transplantation. Now that next-generation DNA sequencing is available in the clinical laboratory, research has focused on the implications of germ line and somatic mutations for diagnosing and monitoring patients with BMF. Most germ line genetic BMF disorders are characterized by a high propensity to develop MDS or AML. Many affected patients lack the physical stigmata traditionally associated with the inherited marrow failure syndromes. Although any single inherited marrow failure disorder is rare, multiplexed genetic sequencing that allows simultaneous evaluation of marrow failure genes en masse demonstrated that, as a group, these inherited disorders compose a significant subset (5% to 10%) of patients with BMF. Early diagnosis of a germ line genetic marrow failure disorder allows individualized monitoring and tailored therapy. Recent studies of somatic variants in marrow failure revealed a high frequency of clonal hematopoiesis with the acquisition of mutations in genes associated with MDS or AML. Investigation of somatic mutations in marrow failure revealed important insights into the mechanisms promoting clonal disease but also raised additional questions. This review will focus on the evaluation and implications of germ line and somatic mutations for the development of clonal disorders in patients with BMF. Challenges and limitations of clinical genetic testing will be explored.
Topics: Anemia, Aplastic; Genetic Diseases, Inborn; Germ-Line Mutation; Humans; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes
PubMed: 27913465
DOI: 10.1182/asheducation-2016.1.74 -
BMC Pediatrics Oct 2023Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease which results in inherited bone marrow failure (IBMF) and is characterized by exocrine pancreatic...
BACKGROUND
Shwachman-Diamond syndrome (SDS) is an autosomal recessive disease which results in inherited bone marrow failure (IBMF) and is characterized by exocrine pancreatic dysfunction and diverse clinical phenotypes. In the present study, we reviewed the internationally published reports on SDS patients, in order to summarize the clinical features, epidemiology, and treatment of SDS.
METHODS
We searched the WangFang and China National Knowledge Infrastructure databases with the keywords "Shwachman-Diamond syndrome," "SDS," "SBDS gene" and "inherited bone marrow failure" for relevant articles published from January 2002 to October 2022. In addition, studies published from January 2002 to October 2022 were searched from the Web of Science, PubMed, and MEDLINE databases, using "Shwachman-diamond syndrome" as the keyword. Finally, one child with SDS treated in Tongji Hospital was also included.
RESULTS
The clinical features of 156 patients with SDS were summarized. The three major clinical features of SDS were found to be peripheral blood cytopenia (96.8%), exocrine pancreatic dysfunction (83.3%), and failure to thrive (83.3%). The detection rate of SDS mutations was 94.6% (125/132). Mutations in SBDS, DNAJC21, SRP54, ELF6, and ELF1 have been reported. The male-to-female ratio was approximately 1.3/1. The median age of onset was 0.16 years, but the diagnostic age lagged by a median age of 1.3 years.
CONCLUSIONS
Pancreatic exocrine insufficiency and growth failure were common initial symptoms. SDS onset occurred early in childhood, and individual differences were obvious. Comprehensive collection and analysis of case-related data can help clinicians understand the clinical characteristics of SDS, which may improve early diagnosis and promote effective clinical intervention.
Topics: Female; Humans; Infant; Male; Bone Marrow Diseases; Exocrine Pancreatic Insufficiency; Mutation; Phenotype; Shwachman-Diamond Syndrome; Signal Recognition Particle
PubMed: 37803383
DOI: 10.1186/s12887-023-04324-3 -
Current Opinion in Pediatrics Feb 2023Recent advances in diagnosis and treatment of inherited bone marrow failure syndromes (IBMFS) have significantly improved disease understanding and patient outcomes.... (Review)
Review
PURPOSE OF REVIEW
Recent advances in diagnosis and treatment of inherited bone marrow failure syndromes (IBMFS) have significantly improved disease understanding and patient outcomes. Still, IBMFS present clinical challenges that require further progress. This review aims to provide an overview of the current state of diagnosis and treatment modalities of the major IBMFS seen in paediatrics and present areas of prioritization for future research.
RECENT FINDINGS
Haematopoietic cell transplantation (HCT) for IBMFS has greatly improved in recent years, shifting the research and clinical focus towards cancer predispositions and adverse effects of treatment. Each year, additional novel genes and pathogenic variants are described, and genotype-phenotype mapping becomes more sophisticated. Moreover, novel therapeutics exploring disease-specific mechanisms show promise to complement HCT and treat patients who cannot undergo current treatment options.
SUMMARY
Research on IBMFS should have short-term and long-term goals. Immediate challenges include solidifying diagnostic and treatment guidelines, cancer detection and treatment, and continued optimization of HCT. Long-term goals should emphasize genotype-phenotype mapping, genetic screening tools and gene-targeted therapy.
Topics: Child; Humans; Anemia, Aplastic; Bone Marrow Diseases; Congenital Bone Marrow Failure Syndromes; Fanconi Anemia; Bone Marrow Failure Disorders; Hemoglobinuria, Paroxysmal
PubMed: 36354296
DOI: 10.1097/MOP.0000000000001196 -
International Journal of Oncology Jan 2022Hypoplastic myelodysplastic syndrome (hMDS) and aplastic anemia (AA) are rare hematopoietic disorders characterized by pancytopenia with hypoplastic bone marrow (BM).... (Review)
Review
Hypoplastic myelodysplastic syndrome (hMDS) and aplastic anemia (AA) are rare hematopoietic disorders characterized by pancytopenia with hypoplastic bone marrow (BM). hMDS and idiopathic AA share overlapping clinicopathological features, making a diagnosis very difficult. The differential diagnosis is mainly based on the presence of dysgranulopoiesis, dysmegakaryocytopoiesis, an increased percentage of blasts, and abnormal karyotype, all favouring the diagnosis of hMDS. An accurate diagnosis has important clinical implications, as the prognosis and treatment can be quite different for these diseases. Patients with hMDS have a greater risk of neoplastic progression, a shorter survival time and a lower response to immunosuppressive therapy compared with patients with AA. There is compelling evidence that these distinct clinical entities share a common pathophysiology based on the damage of hematopoietic stem and progenitor cells (HSPCs) by cytotoxic T cells. Expanded T cells overproduce proinflammatory cytokines (interferon‑γ and tumor necrosis factor‑α), resulting in decreased proliferation and increased apoptosis of HSPCs. The antigens that trigger this abnormal immune response are not known, but potential candidates have been suggested, including Wilms tumor protein 1 and human leukocyte antigen class I molecules. Our understanding of the molecular pathogenesis of these BM failure syndromes has been improved by next‑generation sequencing, which has enabled the identification of a large spectrum of mutations. It has also brought new challenges, such as the interpretation of variants of uncertain significance and clonal hematopoiesis of indeterminate potential. The present review discusses the main clinicopathological differences between hMDS and acquired AA, focuses on the molecular background and highlights the importance of molecular testing.
Topics: Anemia, Hemolytic, Autoimmune; Bone Marrow Failure Disorders; Humans; Immunity; Myelodysplastic-Myeloproliferative Diseases; Prognosis
PubMed: 34958107
DOI: 10.3892/ijo.2021.5297 -
Diagnostic and Interventional Radiology... Jul 2020Diagnosis of bone marrow edema syndrome (BMES) can be challenging. There is sometimes uncertainty about the correct diagnosis of BMES on morphologic magnetic resonance... (Review)
Review
PURPOSE
Diagnosis of bone marrow edema syndrome (BMES) can be challenging. There is sometimes uncertainty about the correct diagnosis of BMES on morphologic magnetic resonance imaging (MRI), since subchondral findings like lines and spots can be misinterpreted as "beginning" or "possible" avascular osteonecrosis (AVN). The aim of our study was to systematically assess the temporal course of BMES from first diagnosis on MRI until the end of clinical symptoms and the full disappearance of bone marrow edema (BME) to determine whether subchondral lines and spots detected in these patients can develop into osteonecrosis.
METHODS
In a combined retrospective and prospective study, we retrieved serial MRI scans of hips and knees with BME from the hospital database. According to clinical and imaging data, all patients with degenerative, infectious/inflammatory, rheumatic, neoplastic conditions and those showing typical osteonecrosis were excluded. We collected all available MRI examinations from first detection of BME until its disappearance. In case edema had not fully resolved in the last available MRI scan, we performed an MRI with an additional dynamic contrast-enhanced (DCE-MRI) sequence. For each MRI scan, we recorded the severity of edema, the presence of subchondral hypointense lines and the presence of subchondral focal hypointense zones on T1-weighted images by two independent readers. The DCE-MRI scans were used to calculate parameter maps to assess the perfusion characteristics.
RESULTS
The study comprised 49 patients aged 22-71 years. In total, 171 morphologic and 5 DCE-MRI scans were evaluated. In 44 patients (89.8%), the BMES completely healed without remnants. In 18 of 49 patients (36.7%), a subchondral line was present in the first MRI exam. Nine patients (18.4%) developed a subchondral line within 1-5 months after the first MRI. In total, 27 out of 49 patients (55.1%) had subchondral lines (12 knees, 15 hips) during the timeframe of the study. All subchondral lines disappeared in the timeframe of the study. Subchondral focal hypointense zones were present in 14 out of 49 patients (28.6%): in 9 cases, subchondral focal hypointense zones disappeared after a median of 5.5 months (range, 1-85 months), while in 5 cases, subchondral focal lesions persisted until the end of the study (up to more than 85 months) without edema in the surrounding bone. All persisting subchondral focal lesions were hyperperfused. These 5 patients had associated meniscal lesions.
CONCLUSION
Our study shows that subchondral lines and spots found in patients with BMES do not develop into AVN. Subchondral lines, which resemble subchondral insufficiency fractures, are associated with BMES. Subchondral focal T1-hypointense zones do not represent AVN; most probably these areas represent reparative processes within the subchondral bone, where tensile and shear force overload is present due to altered biomechanics.
Topics: Adult; Bone Marrow Diseases; Cartilage Diseases; Contrast Media; Edema; Female; Hip Joint; Humans; Knee Joint; Magnetic Resonance Imaging; Male; Middle Aged; Osteonecrosis; Prospective Studies; Retrospective Studies; Severity of Illness Index; Time Factors
PubMed: 32558648
DOI: 10.5152/dir.2020.19188