Marrow Changes Research Articles

Secondary haematological dysplasia after CAR-T-cell therapy foracute lymphoblastic leukaemia in children.

The use of CAR-T is becoming more widespread in the treatment of haematological malignancies. In adults, secondary myelodysplastic syndromes (MDS) after CAR-T have been described. However, there are currently no data on the risk of MDS following CAR-T in children treated for acute lymphoblastic leukaemia (ALL). We studied all children treated with CAR-T cells at Hospital Sant Joan de Déu in Barcelona and those with persistent cytopenias were evaluated at the cytological, cytogenetic, and molecular levels to look for MDS. A total of 106 patients received CAR-T for ALL. Among 40 patients without early relapse or subsequent therapy after CAR-T, four fulfilled the WHO criteria for myelodysplasia. These four patients had received a haematopoietic stem cell transplantation (HSCT) prior to CAR-T and presented cytopenias with severe dysplastic changes in bone marrow after CAR-T. One patient had clonal MDS with high-risk cytogenetics arising from the host cells requiring a HSCT. Three patients had non-progressive dysplasia arising from the donor cells. Two are alive in complete remission with stable cytopenias and one succumbed to ALL relapse. This is the first description of post-CAR-T MDS and haematological dysplasia in children and highlights the need to monitor children with persistent post-CAR-T cytopenias.

Hematological picture of pediatric Sudanese patients with visceral leishmaniasis and prediction of leishmania donovani parasite load.

Visceral leishmaniasis (VL) is a systemic protozoan infection caused by Leishmania donovani (L. donovani) and transmitted by sand flies, causing macrophage invasion in the liver, spleen, and bone marrow. Diagnosis of VL is currently based on clinical signs, symptoms, and specific in-vitro markers and bone marrow investigations. However, VL's specific hematological and bone marrow manifestation in Sudanese pediatric patients is not well studied. To examine the blood and bone marrow characteristics in pediatric patients from Sudan who have VL. This is a retrospective hospital-based study with a sample of 107 consecutive Sudanese pediatric patients. The data focused on hematological and bone marrow results. We included only the completed records of the pediatric patients with VL in the Tropical Disease Teaching Hospital in Khartoum, Sudan from the period of 2016 to 2020. The majority of pediatric patients included in this study are below 5-years-old (n = 59, 55.2%). Moreover, anemia, thrombocytopenia, and leukopenia were among the prevalent characteristics in the population under study. To further analyze the data, we developed a machine learning model using boosted forest algorithms to predict L. donovani parasites load, with a mean accuracy of 0.88 for the training dataset and an accuracy of 0.46, 0.50, and 0.74 for mild, moderate, and severe L. donovani parasite load in the validation dataset. This study shows that the most common bone marrow change among Sudanese VL children was increased chronic inflammatory cells (n = 88, 82.2%) with present macrophage hemophagocytes (n = 103, 96.3%). While anemia and thrombocytopenia were the most common hematological changes. These results will hopefully lead to an early diagnosis and hence better management for Sudanese pediatric patients with suspected VL.

External Validation of SpineNetV2 on a Comprehensive Set of Radiological Features for Grading Lumbosacral Disc Pathologies

BackgroundIn recent years, the integration of Artificial Intelligence (AI) models has revolutionized the diagnosis of Low Back Pain (LBP) and associated disc pathologies. Among these, SpineNetV2 stands out as a state-of-the-art, open-access model for detecting and grading various intervertebral disc pathologies. However, ensuring the reliability and applicability of AI models like SpineNetV2 is paramount. Rigorous validation is essential to guarantee their robustness and generalizability across diverse patient cohorts and imaging protocols. MethodsWe conducted a retrospective analysis of MRI images of 1747 lumbosacral intervertebral discs (IVDs) from 353 patients (mean age, 54 ± 15.4 years, 44.5% female) with various spinal disorders, collected between September 2021 and February 2023 at X-Ray Service s.r.l. The SpineNetV2 system was used to grade 11 distinct lumbosacral disc pathologies, including Pfirrmann grading, disc narrowing, central canal stenosis, spondylolisthesis, (upper & lower) endplate defects, (upper & lower) marrow changes, (right & left) foraminal stenosis, and disc herniation, using T2-weighted sagittal MR images. Performance metrics included accuracy, balanced accuracy, precision, F1 score, Matthew's Correlation Coefficient, Brier Score Loss, Lin's concordance correlation coefficients, and Cohen's kappa coefficients. Two expert radiologists provide annotations for these discs. The evaluation of SpineNetV2′s grading is compared against expert radiologists' assessments. ResultsSpineNetV2 demonstrated strong performance across various metrics, with high agreement scores (Cohen's Kappa, Lin's Concordance, and Matthew's Correlation Coefficient exceeding 0.7) for most pathologies. However, lower agreement was found for foraminal stenosis and disc herniation, underscoring the limitations of sagittal MR images for evaluating these conditions. ConclusionsThis study highlights the importance of external validation, emphasizing the need for comprehensive assessments of deep learning models. SpineNetV2 exhibits promising results in predicting disc pathologies, with findings guiding further improvements. The open-source release of SpineNetV2 enables researchers to independently validate and extend the model's capabilities. This collaborative approach promotes innovation and accelerates the development of more reliable and comprehensive deep learning tools for the assessment of spine pathology.

Protective Effect of Endogenous ω-3 Polyunsaturated Fatty Acid Against Cisplatin Induced Myelosuppression

To investigate the protective effect of endogenous ω-3 polyunsaturated fatty acid (PUFA) against cisplatin-induced myelosuppression and the mechanism of reducing apoptosis in bone marrow nucleated cells using mfat-1 transgenic mice. The experimental animals were divided into 4 groups: wild-type mice normal control group, mfat-1 transgenic mice normal control group, wild-type mice model group and mfat-1 transgenic mice model group. The mice in the model group were injected intraperitoneally with 7.5 mg/kg cisplatin on day 0 and day 7 to construct a myelosuppression model, while the mice in the normal control group were injected intraperitoneally with an equal amount of saline, and their status was observed and their body weight was measured daily. Peripheral blood was taken after 14 day for routine blood analysis, and the content and proportion of PUFA in peripheral blood were detected using gas chromatography. Bone marrow nucleated cells in the femur of mice were counted. The histopathological changes in bone marrow were observed by histopathological staining. The apoptosis of nucleated cells and the expression level changes of apoptosis-related genes in the bone marrow of mice were detected by flow cytometry and fluorescence quantitative PCR. Compared with wild-type mice, mfat-1 transgenic mice showed significantly increased levels of ω-3 PUFA in peripheral blood and greater tolerance to cisplatin. Peripheral blood analysis showed that endogenous ω-3 PUFA promoted the recovery of leukocytes, erythrocytes, platelets and haemoglobin in peripheral blood of myelosuppressed mice. The results of HE staining showed that endogenous ω-3 PUFA significantly improved the structural damage of bone marrow tissue induced by cisplatin. Flow cytometry and PCR showed that, compared with wild-type mice model group, the apoptosis rate of bone marrow nucleated cells in mfat-1 transgenic mice was significantly reduced ( P < 0.001), and the expression of anti-apoptotic genes Bcl-2 mRNA was significantly increased ( P < 0.01), while the expressions of pro-apoptotic genes Bax and Bak mRNA were significantly reduced ( P < 0.001, P < 0.05). Endogenous ω-3 PUFA can reduce cisplatin-induced apoptosis in bone marrow nucleated cells, increase the number of peripheral blood cells and exert a protective effect against cisplatin-induced myelosuppression by regulating the expression of apoptosis-related genes.

Fetal microchimerism cells suppress arthritis progression by inducing CD14+ IL-10+ cells in pregnant experimental mice.

Fetal microchimerism occurs in the mother after a pregnancy. To investigate the role of fetal microchimerism cells (FMCs) in rheumatoid arthritis, we analyzed the population of fetal cells in pregnant experimental arthritis mice. We used EGFP+ fetuses, which were mated with either healthy female mice or CIA mice, and male C57BL/6J-Tg (Pgk1-EGFP)03Narl mice, to detect the population of FMCs in maternal circulation. The disease progression was determined by measuring the clinical score and histological stains during pregnancy. The fetal cells have been analyzed if expressing EGFP, CD45, and Scal by flow cytometry. We also detected the expression of CD14+ IL-10+ cells invivo and invitro. Our data showed that the pregnancy ameliorated the arthritis progression of CIA mice. The IHC stains showed the CD45 -Sca-1+ EGFP+ FMCs were expressed in the bone marrow and peripheral blood mononuclear cells (PBMC) at 14 gestation days. However, Treg and Tc cell populations showed no significant change in the bone marrow. The data showed the H2Kb + fetal cells induced CD14+ IL10+ cell populations increased in the bone marrow invitro and invivo. Our investigations demonstrated that the FMCs protected the CIA mice from cartilage damage and triggered an immunosuppressive response in them by increasing the number of CD14+ IL10+ cells. In conclusion, the FMCs could potentially exhibit protective properties within the context of inflammatory arthritis that arises during pregnancy.

Bone Marrow and Peripheral Blood Mononuclear Cell Phenotype Changes after Cultivation and Autologous Infusion in Patients with Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is a condition affecting the liver and immune system. In this study, the impact of autologous bone marrow-derived mononuclear cell (BM-MNC) transplantation on PBC patients was investigated. Sixteen eligible PBC patients participated at the National Scientific Medical Center in Astana, Kazakhstan, between 2017 and 2022, and BM-MNCs were harvested from their anterior iliac crest. After isolating and cultivating the BM-MNCs, they were infused back into the patient's peripheral veins. Changes in BM-MNC and peripheral blood mononuclear cell (PB-MNC) phenotypes were assessed before and after a 24-hour cultivation period and 72 hours post-transplantation. We monitored liver function parameters over 6-month intervals and conducted flow cytometry analysis to assess CD markers on BM-MNCs before and after cultivation and PB-MNCs before and after transplantation. Statistical analysis included the Friedman test for liver parameters and the Wilcoxon signed-rank test for BM-MNC and PB-MNC comparisons. Our findings revealed significant reductions in liver function tests after multiple transplantations. Flow cytometry analysis before and after a 24-hour culture and autologous BM-MNC infusion revealed the expansion of specific cell populations, with significant increases in CD3+, CD4+, CD16+, CD20+, CD25+, CD34+, CD105+, CD73+, СD117+, and CD34+populations, while CD4+25+, CD34+105+, and CD4+FOXP3+ populations decreased. Interestingly, a contradictory finding was observed with a decrease in bone marrow CD34+105+ cell lines (P=0.03) alongside an increase in peripheral CD34+105+ population (P=0.03). In summary, our study shows that BM-MNC transplantation in PBC patients leads to changes in immune cell populations and liver function. These findings suggest potential therapeutic applications of BM-MNC transplantation in managing PBC and offer insights into the dynamics of immune cells associated with this treatment approach.

Idiopathic multicentric Castleman disease with marrow fibrosis and extramedullary hematopoiesis.

Idiopathic multicentric Castleman disease (iMCD) is a rare inflammatory disorder mediated by excessive proinflammatory cytokine signaling, most notably by interleukin 6 (IL-6). IL-6-induced extramedullary hematopoiesis (EMH) has been reported in murine models of iMCD. Herein we present four cases of iMCD with EMH in humans. The index case is a 24-year-old white woman who presented with pancytopenia, hepatosplenomegaly, and diffuse lymphadenopathy (LAD) with EMH in core lymph node biopsies. We then searched ACCELERATE, a Castleman disease (CD) natural history registry, and identified three additional CD cases with EMH reported in biopsies: A 23-year-old Asian man with fatigue, edema, LAD, and splenomegaly; a 20-year-old white man with fever, dyspnea, LAD, and hepatosplenomegaly; and a 50-year-old white man with constitutional symptoms, LAD, and myelodysplastic syndrome in bone marrow with a KRAS mutation. All four patients presented with thrombocytopenia and fever and/or markedly elevated C-reactive protein. Patient 1 had iMCD-NOS (not otherwise specified) with severe thrombocytopenia, reticulin fibrosis in bone marrow, small volume LAD and organomegaly but no anasarca. The other three patients had iMCD-TAFRO (thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly). Two had mixed CD and two had hypervascular CD in lymph nodes. All four had bone marrow hypercellularity and megakaryocyte hyperplasia and two had reticulin fibrosis. This case series demonstrates that EMH can be seen in CD, particularly in iMCD-TAFRO. Given the similarity of this finding to previous murine models of IL-6-induced marrow and lymph node changes we hypothesize that this is an IL-6-mediated phenomenon.

Diagnostic Value of Whole-Body MRI in Pediatric Patients with Suspected Rheumatic Diseases.

Background and Objectives: The diagnosis of rheumatic diseases in children is challenging and requires the use of advanced imaging examinations such as whole-body magnetic resonance imaging (MRI). Whole-body MRI allows visualization of bone marrow edema (BME), muscle edema, joint effusion and changes in the soft tissues surrounding the joints. The aim of this study was to collect and compare whole-body MRI findings, laboratory results and clinical manifestations of pediatric patients with suspected rheumatic disease. Materials and methods: In this retrospective single-center study, 33 patients who underwent whole-body MRI were included. Their age ranged from 9 to 17 years, and 24 (72.73%) of the patients were female. Patients were diagnosed as follows: juvenile idiopathic arthritis (27.27%), juvenile idiopathic inflammatory myopathies (21.21%), chronic nonbacterial osteomyelitis (21.21%) and other medical conditions (30.30%), such as arthritis associated with infection, scleroderma, Takayasu arteritis, polyarteritis nodosa and joint damage. Results: The most common symptom reported by 26 (79.79%) patients was pain. On physical examination, the limitation of joint mobility was examined in 17 (51.51%), swelling of the joints was observed in 12 (36.36%) patients and decreased muscle strength was noticed in 11 (33.33%) patients. An increase in the C-reactive protein (12%), erythrocyte sedimentation rate (9%), leukocyte count (9%) and creatine kinase (CK) (18%) was observed. Whole-body MRI revealed myositis (30%), joint effusion (27%) and BME (24%). The statistical analysis showed a significant relationship between myositis and the elevated CK level (p < 0.05). Conclusions: The most common symptom in the studied population was pain, while the limitation of joint mobility was found in more than half of patients. Myositis was the most commonly imaged lesion on the whole-body MRI and it was related to an increase in the CK level.

Multimodality imaging of bone marrow involvement in paediatric oncology

Identifying bone marrow involvement (with or without bone destruction) in children with cancer is essential for adequate diagnosis, prognostication, therapy planning, and response assessment. Imaging plays an increasing role, with MRI including DWI and [18F]FDG-PET/CT as the most commonly used imaging techniques. Interpretation of the paediatric bone marrow on imaging might be challenging because of age-related physiological changes in the bone marrow, as well as disease and therapy related effects. In this review, we discuss how the imaging techniques available may be employed to detect bone marrow involvement (BMI) in paediatric oncology. Furthermore, insights into physiological, disease and therapy related bone marrow changes in children that might influence bone marrow imaging interpretation will be provided.

Emerging opportunities to target inflammation: myocardial infarction and type 2 diabetes.

After myocardial infarction (MI), patients with type 2 diabetes have an increased rate of adverse outcomes, compared to patients without. Diabetes confers a 1.5-2-fold increase in early mortality and, importantly, this discrepancy has been consistent over recent decades, despite advances in treatment and overall survival. Certain assumptions have emerged to explain this increased risk, such as differences in infarct size or coronary artery disease severity. Here, we re-evaluate that evidence and show how contemporary analyses using state-of-the-art characterization tools suggest that the received wisdom tells an incomplete story. Simultaneously, epidemiological and mechanistic biological data suggest additional factors relating to processes of diabetes-related inflammation might play a prominent role. Inflammatory processes after MI mediate injury and repair and are thus a potential therapeutic target. Recent studies have shown how diabetes affects immune cell numbers and drives changes in the bone marrow, leading to pro-inflammatory gene expression and functional suppression of healing and repair. Here, we review and re-evaluate the evidence around adverse prognosis in patients with diabetes after MI, with emphasis on how targeting processes of inflammation presents unexplored, yet valuable opportunities to improve cardiovascular outcomes in this vulnerable patient group.

Proteomic screening identifies PF4/Cxcl4 as a critical driver of myelofibrosis.

Despite increased understanding of the genomic landscape of Myeloproliferative Neoplasms (MPNs), the pathological mechanisms underlying abnormal megakaryocyte (Mk)-stromal crosstalk and fibrotic progression in MPNs remain unclear. We conducted mass spectrometry-based proteomics on mice with Romiplostim-dependent myelofibrosis to reveal alterations in signaling pathways and protein changes in Mks, platelets, and bone marrow (BM) cells. The chemokine Platelet Factor 4 (PF4)/Cxcl4 was up-regulated in all proteomes and increased in plasma and BM fluids of fibrotic mice. High TPO concentrations sustained in vitro PF4 synthesis and secretion in cultured Mks, while Ruxolitinib restrains the abnormal PF4 expression in vivo. We discovered that PF4 is rapidly internalized by stromal cells through surface glycosaminoglycans (GAGs) to promote myofibroblast differentiation. Cxcl4 gene silencing in Mks mitigated the profibrotic phenotype of stromal cells in TPO-saturated co-culture conditions. Consistently, extensive stromal PF4 uptake and altered GAGs deposition were detected in Romiplostim-treated, JAK2V617F mice and BM biopsies of MPN patients. BM PF4 levels and Mk/platelet CXCL4 expression were elevated in patients, exclusively in overt fibrosis. Finally, pharmacological inhibition of GAGs ameliorated in vivo fibrosis in Romiplostim-treated mice. Thus, our findings highlight the critical role of PF4 in the fibrosis progression of MPNs and substantiate the potential therapeutic strategy of neutralizing PF4-GAGs interaction.

Bone density in postmenopausal women with scoliosis is associated with markers of degenerative joint disease.

Bone mineral density (BMD) measured with dual x-ray absorptiometry (DXA) is the clinical standard for the diagnosis of osteoporosis and prediction of bone fracture risk. In the aging skeleton, osteoporosis is often concomitantly present with degenerative joint disease (DJD). In this study, we evaluated tissue-level changes in the differentially loaded concave (CC) and convex (CV) sides of the lumbar spine in a sample of postmenopausal women with scoliosis. We used a cumulative degeneration score to assess osteophyte formation, the severity of sclerotic morphology, and marrow changes as markers of DJD in the lumbar spine and examined the correlation between markers of DJD and BMD. More severe osteophyte growth and sclerosis were present on the CC side of the spine. The degenerative score (DS) was higher on the CC side of the lumbar spine compared with the CV side. While CC BMD was positively correlated with CC DS and marrow, CV DS was not correlated with CV BMD. Marrow changes were correlated with DS on the CC lumbar spine. These results highlight the importance of mechanoadaptive as well as broader inflammatory processes in the manifestation of degenerative changes and local mineral deposition at the lumbar spine. DXA-based BMD measurement of osteoporosis need to be contextualized within the biomechanical and degenerative conditions of a joint rather than using a strict threshold cutoff.

Metabolic abnormalities in the bone marrow cells of young offspring born to mothers with obesity.

Intrauterine metabolic reprogramming occurs in mothers with obesity during gestation, putting the offspring at high risk of developing obesity and associated metabolic disorders even before birth. We have generated a mouse model of maternal high-fat diet-induced obesity that recapitulates the metabolic changes seen in humans born to women with obesity. Here, we profiled and compared the metabolic characteristics of bone marrow cells of newly weaned 3-week-old offspring of dams fed either a high-fat (Off-HFD) or a regular diet (Off-RD). We utilized a state-of-the-art flow cytometry, and targeted metabolomics approach coupled with a Seahorse metabolic analyzer. We revealed significant metabolic perturbation in the offspring of HFD-fed vs. RD-fed dams, including utilization of glucose primarily via oxidative phosphorylation. We also show a reduction in levels of amino acids, a phenomenon previously linked to bone marrow aging. Using flow cytometry, we found changes in the immune complexity of bone marrow cells and identified a unique B cell population expressing CD19 and CD11b in the bone marrow of three-week-old offspring of high-fat diet-fed mothers. Our data also revealed increased expression of Cyclooxygenase-2 (COX-2) on myeloid CD11b, and on CD11bhi B cells. Altogether, we demonstrate that the offspring of mothers with obesity show metabolic and immune changes in the bone marrow at a very young age and prior to any symptomatic metabolic disease.

Role of End Plate Changes and Paraspinal Muscle Pathology in Lower Back Pain: A Narrative Review.

Degenerative changes of the lumbar intervertebral disc are the most significant causes of enduring lower back pain. The possibility of the diagnosis is limited in people with this low back pain. Therefore, it is essential to identify the relevant back pain subgroups. The paraspinal muscles, that is, the muscles that attach to the spine, are necessary for the proper functioning of the spine and the body; insufficiency can result in back pain. Lower back pain disorders are strongly associated with altered function or structure of these paraspinal muscles, especially fibrosis and fatty infiltration. Modic changes are the bone marrow changes of the end plate in the vertebral body seen on MRI. These are strongly related to degeneration of the disc and are common in individuals with back pain symptoms. Articles were selected from Google Scholar using the terms 'Modic changes,' 'end plate changes,' 'paraspinal muscles,' and 'lower back pain. ' This article compiled different studies aiming to enhance the comprehension of biochemical processes resulting in the development of lumbar pain. Search using the keywords 'Modic changes,'' end plate changes lower back pain,' 'paraspinal muscles lower back pain,' and 'Modic changes lower back pain' on Google Scholar yielded 33000, 41000, 49400, and 17,800 results, and 958, 118, 890 and 560 results on Pubmed respectively.

Abstract 2059: Therapeutic Delivery Of MICRORNA-369-3p Promotes Atherosclerosis Regression In Diabetic Mice By Regulating Bone Marrow Myeloid Progenitors

Introduction: Hyperglycemia-induced immunometabolic alterations promote myelopoiesis, increase proinflammatory monocytes, and impair atherosclerosis regression. Identifying critical factors to restore metabolic alterations and promote resolution of inflammation remains an unmet medical need. MicroRNAs (miRs) orchestrate multiple signaling events in macrophages and regulate inflammation. Using miR-seq, we identified miR-369-3p as a novel miR expressed higher in regressing mouse plaques. Hypothesis: Therapeutic administration of miR-369-3p promotes plaque regression of diabetes-associated atherosclerosis in mice. Aim: To identify the therapeutic benefits of miR-369-3p overexpression, and the mechanism by which it promotes plaque regression in diabetic mice. Methods: Ldlr-/ - mice were fed HFSC-diet for 12-weeks to develop atherosclerotic plaques and were switched to chow-diet for 6-weeks to induce regression. During regression, mice received either non-specific control mimic (NS-m) or miR-369-3p mimic (369-m) intravenously twice every week. Immunohistological, morphometric, and flow cytometric analyses were performed to define the changes in plaque, circulation, and bone marrow following 369-m delivery. Results: Therapeutic delivery of 369-m promoted plaque resolution in diabetic mice, evident by reduced plaque area and macrophage content when compared to NS-m injected mice. Circulating proinflammatory cytokines (IL1β, IL6 and TNF-α), total circulating monocytes, and M1 macrophages were decreased in lesions while M2 macrophages were increased in 369-m group. 369-m also increased plaque stability and increased FOXP3+ Tregs in plaques when compared to NS-m group. Bioinformatic analyses showed GPR91 and CEBPB as conserved miR targets. Mechanistically, we found that 369-m decreased bone marrow granulocyte-monocyte progenitor population (GMPs), resulting in less inflammatory monocytes, attributed to reduced CEBPB and GPR91 target expression in GMPs. Conclusion: miR-369-3p overexpression reduced plaque-inflammatory macrophages, bone marrow GMPs, and proinflammatory monocytes by regulating macrophage immunometabolism in diabetes-accelerated atherosclerosis in part by targeting CEBPB and GPR91.

E046 Lytic lesions; metastatic disease or gout?

Abstract Background/Aims Uric acid crystal deposition in the spine is uncommonly diagnosed, although the frequency of axial involvement is thought to be as high as 14-35%. Studies have shown that spinal gout is more common in men aged 35-75 years, with a history of chronic polyarticular tophaceous gout which is not optimally controlled being a key risk factor. Recent studies have shown that spinal gout is under and misdiagnosed due to its non-specific presentation of back pain or absence of symptoms. Our case report exemplifies this diagnostic challenge. Methods In this report we describe a case of a 79-year-old male with a history of polyarticular tophaceous gout, chronic kidney disease and previous renal carcinoma treated with curative radiotherapy. He presented with a 4-week history of progressive exertional dyspnoea and orthopnoea. He was commenced on intravenous diuretics which lead to an acute kidney injury, with his eGFR dropping to 14mL/min. His preadmission allopurinol and colchicine were held and clinically he developed a flare of gout affecting his right wrist and right second and third MCP joints. A CT scan of his abdomen and pelvis, carried out to investigate potential bowel obstruction, showed no evidence of obstruction but it did reveal multiple lytic lesions in the spine with potential extension into the spinal canal at T9 and L5. He did not have any back pain and his neurological examination was normal. Results A working diagnosis of spinal metastasis with potential cord compression was made and the patient was commenced on high dose steroids. He subsequently underwent an MRI whole spine which showed marrow abnormalities and destructive soft tissues changes affecting various facet joints in the thoracic and lumbar spine. The primary differential remained metastases but due to the unusual distribution of the marrow changes in which the vertebral bodies were completely spared, the initial CT images were reviewed on spectral scanning which demonstrated uric acid deposition in the affected facet joints. The diagnosis was confirmed as gout in the spine when a PET-CT scan revealed no potential primary source of malignancy. The gout flare in his hand settled with the steroids prescribed to treat the potential cord compression and he continued to deny suffering from back pain. Conclusion A literature search demonstrates that reports of spinal gout being described as lytic lesions on CT are rare. Spinal gout should be considered as a differential in a patient with facet joint lytic lesions on imaging, without involvement of the vertebral body and where no primary malignancy is found. Our case demonstrates how dual energy CT scanning can prevent the need for invasive biopsy in cases of diagnostic uncertainty in patients with a history of poorly controlled chronic tophaceous gout. Disclosure S.K. Stewart: None. D.J. Coulter: None. C. Masih: None.

Use of Multimodality Imaging in the Evaluation of Patients With Spondyloarthropathies and Sacroiliitis.

Spondyloarthropathy (SpA) is one of the most common causes of low back pain. It is caused by inflammatory arthritis in the spine, manifesting in various forms such as psoriatic arthritis (PsA), ankylosing spondylitis (AS), and sacroiliitis. A comprehensive systematic literature search was done to evaluate and compare MRI, CT, single-photon emission CT, PET, ultrasound (US) imaging, low-dose CT, and diffusion-weighted imaging (DWI) techniques in assessing SpAs. The search strategy was constructed by an analysis of key terms from relevant articles in MEDLINE ProQuest, Embase, and PubMed. The key terms used to search for these articles were "SpA," "sacroiliitis," "spondylitis," "psoriatic arthritis," "MRI," "CT scan," "x-ray," "magnetic resonance imaging," "computed tomography," "bone density," and "ultrasound." A total of 1,131 articles published in English between January 1, 2003, and October 15, 2023 were identified and screened for eligibility by members of the research team, which resulted in 69 total articles selected for the final review. US has played an important role in visualizing joint inflammation and enthesitis (inflammation of the enthesis), which are common features of PsA. Although MRI and CT are considered more reliable modalities for diagnosing active sacroiliitis, US imaging with Doppler flow can also be useful in conjunction with CT images to visualize abnormal blood flow in the sacroiliac joints, as well as other joints affected by inflammatory arthritis. MRI provides increased diagnostic confidence in the diagnosis of sacroiliitis in active AS patients when compared to CT. CT is more sensitive than plain radiographs. The PET activity score showed a good correlation in diagnosing inflammatory sacroiliitis but lacked in identifying structural lesions. CT has high diagnostic accuracy, but it exposes patients to a high radiation dose. MRI visualizes joint and tissue inflammation, bone, and bone marrow change and can identify peripheral inflammation in soft tissue and joints in patients diagnosed with PsA. MRI can also visualize bone marrow changes and subchondral edema, which can aid in the early diagnosis of ankylosing SpA and gauge disease severity. DWI and short-tau inversion recovery imaging are both MRI techniques used in detecting sacroiliitis. MRI and CT are shown to be reliable imaging modalities for the diagnosis of sacroiliitis; however, it was found that Doppler US played an accurate role in the diagnosis as well. MRI visualizes joints and tissue with the most precision, making it useful in evaluating patients with PsA, while PET CT is useful in the diagnosis of inflammatory sacroiliitis patients. There is limited literature available comparing the multiple modalities of imaging available for each SpA. The review's objective is to analyze imaging findings in patients diagnosed with sacroiliitis and SpAs. The findings in this literature review are valuable for properly assessing and diagnosing patients suffering from SpAs.

Comprehensive analysis of myelosuppression of pediatric patients receiving radiotherapy

Pediatric oncology management necessitates distinct strategies for radiotherapy due to the heightened sensitivity of pediatric bone marrow to radiation exposure compared to adults. Therefore, this study aimed to compare the risk of radiation-induced myelosuppression between pediatric and adult patients by analyzing the correlations between gender, age, active marrow distribution, and radiation-induced myelosuppression. The medical records of 49 pediatric patients aged &lt;15 years were retrospectively analyzed. Subgroup analyses based on sex and age were conducted to compare this pediatric patient data with data from adult patients reported in the literature. The observed rate of radiation-induced myelosuppression in the pediatric group was 59.18%, which was approximately twice the rate for the adult group (34%) reported in literature. Notably, the rates of leukopenia and granulocytopenia were observed in 53% and 45% of patients suffering from radiation-induced myelosuppression, respectively, compared to rates of thrombocytopenia and hemoglobinopenia observed in only 10% of patients, indicating that white blood cells and granulocytes are more sensitive indicators of radiation-induced myelosuppression. Our findings revealed that pediatric patients receiving radiotherapy in the head-and-neck regions face a higher risk of radiation-induced myelosuppression than adult patients due to the changes in active bone marrow during childhood development. Therefore, careful consideration of radiation-induced myelosuppression is essential during protocol optimization for pediatric patients receiving radiotherapy outside the pelvic region.

Abstract 280: Aberrant β-catenin signaling from the bone marrow niche leads to transformation of IDH1/2-mutant hematopoietic stem cells and compromises response to IDH1/2 inhibitors

Abstract Our purpose is to identify stromal-derived signals required for IDH1/2-mut hematopoietic stem cells (HSCs) to become leukemogenic. Mutations in IDH genes are found in 20% of acute myeloid leukemia (AML) patients and are not transformative. They produce the oncometabolite 2HG which inhibits key epigenetic regulators. We explored whether epigenetic changes in the bone marrow (BM) niche could provide cooperative signals to IDH-mut HSCs leading to their transformation and disease development. We found that 2HG is elevated in the BM plasma of MDS/AML patients with IDH1/2 mutations as compared to IDH-wt patients. Interestingly, 2HG is taken up by BM stromal cells (BMSCs) suggesting it may induce aberrant methylation patterns in them. Indeed, methylome analysis showed hypermethylation in BMSCs of AML patients with IDH1/2 mutations compared to wt. Among the most hypermethylated genes in the IDH-mut stroma are AXIN1, AXIN2 and NDK2, all negative regulators of β-catenin; this pathway activation was previously shown to cause MDS/AML in mice and present in 38% of patients. In agreement with these findings βcat activation in the stroma of IDH-mut vs IDH-wt AML patients showed a strong positive correlation as 50% of IDH-mut patients had activated βcat in their BMSCs. Inquiring whether stroma methylation precedes HSC transformation, we analyzed samples from healthy individuals with IDH-mut clonal hematopoiesis. They exhibited increased global and AXIN1 promoter methylation compared to samples without such clones, but not active βcat in osteoblasts, indicating this might be a later step along with disease development. In fact, transplantation of HSCs from Idh2-mut mice to recipients expressing active βcat in osteoblasts led to increase in blasts and shortened survival compared to wt mice transplanted with Idh2-mut HSCs. As many patients relapse following treatment with IDH inhibitors, we investigated a potential role for βcat signaling in treatment outcome. IDH-mut AML patients who do not respond to treatment with the IDHi present more frequently with activated βcat in osteoblasts compared to responders. Analyzing samples from the same patient pre- and post-treatment with IDHi, we found before treatment most patients were positive for βcat stromal activation, whereas after treatment, all patients with complete response were negative, while patients with progressive disease remained positive. Our model suggests IDH-mut HSCs secrete 2HG inducing epigenetic alterations in the niche, some of which cause activation of the βcat pathway. In turn, this additional signal leads to the transformation of HSCs to dysplastic cells and MDS/AML development. This work uncovers a new mechanism for transformation to MDS/AML and resistance to IDHi treatment. Thus, targeting βcat activation in the stroma, in combination with IDHi, could improve treatment outcome. Citation Format: Paraskevi Vgenopoulou, Luis Flores, Ioanna Mosialou, Junfei Zhao, X. Shawn Liu, Pamela Sung, Virginie Penard-Lacronique, Martin Carroll, Stavroula Kousteni. Aberrant β-catenin signaling from the bone marrow niche leads to transformation of IDH1/2-mutant hematopoietic stem cells and compromises response to IDH1/2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 280.

Reliability assessment of the OMERACT whole-body magnetic resonance imaging scoring system for juvenile idiopathic arthritis

Inter-reader reliability of a new scoring system for evaluating joint inflammation and enthesitis in whole body MRI (WBMRI) in juvenile idiopathic arthritis was tested. The scoring system grades 732 item-region combinations of bone marrow and soft tissue changes for commonly involved joints and entheseal sites. Five radiologists rated 17 WBMRI scans through an online rating platform. Item-wise reliability was calculated for 117 items with non-zero scores in >10 % of readings. Interquartile ranges of the five-reader Kappa reliability coefficients were 0.58–0.73 (range: 0.36–0.88) for the joints, 0.65–0.81 (range: 0.39–0.95) for the entheses, and 0.62–0.75 (range: 0.60–0.76) for chronic nonbacterial osteomyelitis-like lesions.