Bone Marrow Adipose Tissue.

Bone marrow (BM) acts as a dynamic organ within the bone cavity, responsible for hematopoiesis, skeletal remodeling, and immune system control. Bone marrow adipose tissue (BMAT) was long simply considered a filler of space, but now it is known that it instead constitutes an essential element of the BM microenvironment that participates in homeostasis, influences bone health and bone remodeling, alters hematopoietic stem cell functions, contributes to the commitment of mesenchymal stem cells, provides effects to immune homeostasis and defense against infections, and participates in energy metabolism and inflammation. BMAT has emerged as a significant contributor to the development and progression of various diseases, shedding light on its complex relationship with health. Notably, BMAT has been implicated in metabolic disorders, hematological malignancies, and skeletal conditions. BMAT has been shown to support the proliferation of tumor cells in acute myeloid leukemia and niche adipocytes have been found to protect cancer cells against chemotherapy, contributing to treatment resistance. Moreover, BMAT's impact on bone density and remodeling can lead to conditions like osteoporosis, where high levels of BMAT are inversely correlated with bone mineral density, increasing the risk of fractures. BMAT has also been associated with diabetes, obesity, and anorexia nervosa, with varying effects on individuals depending on their weight and health status. Understanding the interaction between adipocytes and different diseases may lead to new therapeutic strategies.

Detection of clonal plasma cells in POEMS syndrome using multiparameter flow cytometry.

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein [M-protein], and skin changes) is a rare systemic disorder characterized by various symptoms caused by underlying plasma cell (PC) dyscrasia. Detection of monoclonal PCs is mandatory for the diagnosis of POEMS syndrome; however, the usefulness of EuroFlow-based next-generation flow cytometry (EuroFlow-NGF) in POEMS syndrome for detecting monoclonal PCs in bone marrow (BM) and the gating strategy suitable for flow cytometry study of POEMS syndrome remain unknown. We employed EuroFlow-NGF-based single-tube eight-color multiparameter flow cytometry (MM-flow) and established a new gating strategy (POEMS-flow) to detect the monoclonal PCs in POEMS syndrome, gating CD38 broadly from dim to bright and CD45 narrowly from negative to dim compared to MM-flow. MM-flow detected monoclonal PCs in 9/25 (36.0%) cases, including 2/2 immunofixation electrophoresis (IFE)-negative cases (100%). However, POEMS-flow detected monoclonal PCs in 18/25 cases (72.0%), including 2/2 IFE-negative cases (100%). POEMS-flow detected monoclonal PCs with immunophenotypes of CD19- in 17/18 (94.4%). In six cases where post-treatment samples were available, the size of the clones was significantly reduced after the treatment (P = 0.031). POEMS-flow can enhance the identification rate of monoclonal PCs in POEMS syndrome and become a valuable tool for the diagnosis of POEMS syndrome.

Acute Myeloid Leukemia with Myelodysplasia - Related Changes after Isolated Myeloid Sarcoma.

BACKGROUND: As a tumor mass, a myeloid sarcoma consists of myeloid blasts and presents at an anatomical site other than the bone marrow. In about one quarter of cases, myeloid sarcoma happens without an underlying acute myeloid leukemia or other myeloid neoplasm, and it may precede or coincide with AML or form acute blastic transformation of MDSs, MPNs, or MDS/MPNs. METHODS: Herein, we described a rare case of acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), with WT1 mutation and high expression of TP53 after isolated myeloid sarcoma of lymph nodes showing a higher proportion of blasts, dysplasia of both megakaryocytes and granulocytes. CONCLUSIONS: The case highlights the importance of a bone marrow examination, including morphology, immunophenotyping, cytogenetic, and molecular examination in all cases to exclude the possibility of myeloid sarcoma, especially the morphological feature of bone marrow dysplasia in the early stage before AML.

Association of Preoperative Subchondral Bone Marrow Oedema with Outcomes after Lateral Unicompartmental Knee Arthroplasty.

OBJECTIVE: To determine whether the presence of preoperative subchondral bone marrow oedema (SBME) is associated with inferior outcomes after lateral unicompartmental knee arthroplasty (LUKA). STUDY DESIGN: Descriptive study. Place and Duration of the Study: Department of Orthopaedic Surgery, Chongqing Orthopaedic Hospital of Traditional Chinese Medicine, Chongqing, China, from January 2019 to June 2022. METHODOLOGY: Data on patients treated with LUKA were obtained from the Medical Registry Database. Two groups were made based on the presence and absence of SBME on preoperative magnetic resonance imaging (MRI). The visual analogue scale (VAS), American Knee Society Scores (AKSS), and rate of patient satisfaction were compared between the two groups. RESULTS: A total of 20 patients treated with LUKA were reviewed. The SBME was present in 9 cases and absent in 11 cases. Patients with SBME had inferior scores at preoperative evaluation and at 1, 3, and 6 months postoperatively. However, there was no significant difference between the groups at the 12-month follow-up. Eight (88.9%) patients with SBME were satisfied with the LUKA surgery versus 9 (81.8%) patients without SBME, showing no significant differences between groups. CONCLUSION: Presence of preoperative SBME is associated with inferior functional outcomes after LUKA within six months of follow-up. KEY WORDS: Bone marrow, Oedema, Knee, Arthroplasty, Outcome, Patient satisfaction.

Value of third-generation of VNCa dual-energy CT for differentiating diffuse marrow infiltration of multiple myeloma from red bone marrow.

This study aims to investigate the ability of bone marrow imaging using third-generation dual-energy computed tomography (CT) virtual noncalcium (VNCa) to differentiate between multiple myeloma (MM) with diffuse bone marrow infiltration and red bone marrow (RBM). Bone marrow aspiration or follow-up results were used as reference. We retrospectively reviewed 188 regions of interests (ROIs) from 21 patients with confirmed MM and diffuse bone marrow infiltrations who underwent VNCa bone marrow imaging between May 2019 and September 2022. At the same time, we obtained 98 ROIs from 11 subjects with RBM for comparative study, and 189 ROIs from 20 subjects with normal yellow bone marrow for the control group. The ROIs were delineated by 2 radiologists independently, the interobservers reproducibility was evaluated by interclass correlation coefficients. The correlation with MRI grade results was analyzed by Spearman correlation coefficient. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal threshold for differentiating between these groups and to assess diagnostic performance. There were statistically significant differences in VNCa CT values of bone marrow among the MM, RBM, and control groups (all P < .001), with values decreasing sequentially. A strong positive rank correlation was observed between normal bone marrow, subgroup MM with moderately and severe bone marrow infiltration divided by MRI and their corresponding CT values (ρ = 0.897, 95%CI: 0.822 to 0.942, P < .001). When the CT value of VNCa bone marrow was 7.15 HU, the area under the curve (AUC) value for differentiating RBM and MM was 0.723, with a sensitivity of 50.5% and a specificity of 89.8%. When distinguishing severe bone marrow infiltration of MM from RBM, the AUC value was 0.80 with a sensitivity 70.9% and a specificity 78.9%. The AUC values for MM, RBM, and the combined group compared to the control group were all >0.99, with all diagnostic sensitivity and specificity exceeding 95%. VNCa bone marrow imaging using third-generation dual-energy CT accurately differentiates MM lesions from normal bone marrow or RBM. It demonstrates superior diagnostic performance in distinguishing RBM from MM with diffuse bone marrow infiltration.

[Aprospective study of detection and clinical significance of bone marrow tumor cells in small cell lung cancer].

Objective: To investigate the detection of bone marrow tumor cells in small cell lung cancer (SCLC) patients and their relationship with clinical features, treatment response and prognosis. Methods: A total of 113patients with newly diagnosed SCLC from January 2018 to October 2022 at Beijing Chest Hospital were prospectively enrolled. Before treatment, bone marrow was aspirated and separately submitted for tumor cells detection by liquid-based cytology and disseminated tumor cells (DTCs) detection by the substrction enrichment and immunostaining fluorescence in situ hybridization (SE-iFISH) platform. The correlation between the detection results of the two methods with patients' clinical features and treatment response was evaluated by Chi-square. Kaplan-Meier method was applied to create survival curves and the Cox regression model was used for multivariate analysis. Results: The positive rate of bone marrow liquid-based cytology in SCLC was 15.93% (18/113). The liver and bone metastases rates were significantly higher (55.56% vs 11.58% for liver metastasis, P＜0.001; 77.78% vs 16.84% for bone metastasis, P＜0.001) and thrombocytopenia was more common (16.67% vs 2.11%, P=0.033) in patients with tumor cells detected in liquid-based cytology than those without detected tumor cells. As for SE-iFISH, DTCs were detected in 92.92% of patients (105/113), the liver and bone metastasis rates were significantly higher (37.93% vs 11.90% for liver metastasis, P=0.002; 44.83% vs 20.23 % for bone metastasis, P=0.010), and the incidence of thrombocytopenia was significantly increased (13.79% vs 1.19%, P=0.020) in patients with DTCs≥111 per 3 ml than those with DTCs＜111 per 3 ml. The positive rates of bone marrow liquid-based cytology in the disease control group and the disease progression group were 12.00% (12/100) and 46.15% (6/13), respectively, and the difference was statistically significant (P=0.002). However, the result of SE-iFISH revealed the DTCs quantities of the above two groups were 29 (8,110) and 64 (15,257) per 3 ml, and there was no statistical difference between the two groups (P=0.329). Univariate analysis depicted that the median progression-free survival (PFS) and median overall survival (OS) of liquid-based cytology positive patients were significantly shorter than those of tumor cell negative patients (6.33 months vs 9.27 months for PFS, P=0.019; 8.03 months vs 19.50 months for OS, P=0.019, P=0.033). The median PFS and median OS in patients with DTCs≥111 per 3 ml decreased significantly than those with DTCs＜111 per 3 ml (6.83 months vs 9.50 months for PFS, P=0.004; 11.2 months vs 20.60 months for OS, P=0.019). Multivariate analysis showed that disease stage (HR=2.806, 95%CI:1.499-5.251, P=0.001) and DTCs quantity detected by SE-iFISH (HR=1.841, 95%CI:1.095-3.095, P=0.021) were independent factors of PFS, while disease stage was the independent factor of OS (HR=2.538, 95%CI:1.169-5.512, P=0.019). Conclusions: Both bone marrow liquid-based cytology and SE-iFISH are clinically feasible. The positive detection of liquid-based cytology or DTCs≥111 per 3 ml was correlated with distant metastasis, and DTCs≥111 per 3 ml was an independent prognostic factor of decreased PFS in SCLC.

Day-21 bone marrow findings incorrectly designate residual leukaemia in FLT3-mutated acute myeloid leukaemia treated with intensive induction plus midostaurin: a morphology-focused study.

Early induction response assessment with day-21 bone marrow (D21-BM) is commonly performed in patients with FLT3-mutated acute myeloid leukaemia (AML), where detection of residual leukaemia (RL; blasts ≥5%) typically results in the administration of a second induction course. However, whether D21-BM results predict for RL at the end of first induction has not been systematically assessed. This study evaluates the predictive role of D21-BM morphology in detecting RL following first induction. Between August 2018 and March 2022, all patients with FLT3-AML receiving 7+3 plus midostaurin, with D21-BM performed, were identified. Correlation between D21-BM morphology vs D21-BM ancillary flow/molecular results, as well as vs D28-BM end of first induction response, were retrospectively reviewed. Subsequently, D21-BMs were subjected to anonymised morphological re-assessments by independent haematopathologists (total in triplicate per patient). Of nine patients included in this study, three (33%) were designated to have RL at D21-BM, all of whom entered complete remission at D28-BM. Furthermore, only low-level measurable residual disease was detected in all three cases by flow or molecular methods at D21-BM, hence none proceeded to a second induction. Independent re-evaluations of these cases failed to correctly reassign D21-BM responses, yielding a final false positive rate of 33%. In summary, based on morphology alone, D21-BM assessment following 7+3 intensive induction plus midostaurin for FLT3-AML incorrectly designates RL in some patients; thus correlating with associated flow and molecular results is essential before concluding RL following first induction. Where remission status is unclear, repeat D28-BMs should be performed.

Reporting bone marrow biopsies for myelodysplastic neoplasms and acute myeloid leukaemia incorporating WHO 5th edition and ICC 2022 classification systems: ALLG/RCPA joint committee consensus recommendations.

The classification of myeloid neoplasms continues to evolve along with advances in molecular diagnosis, risk stratification and treatment of disease. An approach for disease classification has been grounded in international consensus that has facilitated understanding, identification and management of molecularly heterogeneous entities, as well as enabled consistent patient stratification into clinical trials and clinical registries over time. The new World Health Organization (WHO) and International Consensus Classification (ICC) Clinical Advisory Committee releasing separate classification systems for myeloid neoplasms in 2022 precipitated some concern amongst haematopathology colleagues both locally and internationally. While both classifications emphasise molecular disease classification over the historical use of morphology, flow cytometry and cytogenetic based diagnostic methods, notable differences exist in how morphological, molecular and cytogenetic criteria are applied for defining myelodysplastic neoplasms (MDS) and acute myeloid leukaemias (AML). Here we review the conceptual advances, diagnostic nuances, and molecular platforms required for the diagnosis of MDS and AML using the new WHO and ICC 2022 classifications. We provide consensus recommendations for reporting bone marrow biopsies. Additionally, we address the logistical challenges encountered implementing these changes into routine laboratory practice in alignment with the National Pathology Accreditation Advisory Council reporting requirements for Australia and New Zealand.

Transforming the Niche: The Emerging Role of Extracellular Vesicles in Acute Myeloid Leukaemia Progression.

Acute myeloid leukaemia (AML) management remains a significant challenge in oncology due to its low survival rates and high post-treatment relapse rates, mainly attributed to treatment-resistant leukaemic stem cells (LSCs) residing in bone marrow (BM) niches. This review offers an in-depth analysis of AML progression, highlighting the pivotal role of extracellular vesicles (EVs) in the dynamic remodelling of BM niche intercellular communication. We explore recent advancements elucidating the mechanisms through which EVs facilitate complex crosstalk, effectively promoting AML hallmarks and drug resistance. Adopting a temporal view, we chart the evolving landscape of EV-mediated interactions within the AML niche, underscoring the transformative potential of these insights for therapeutic intervention. Furthermore, the review discusses the emerging understanding of endothelial cell subsets' impact across BM niches in shaping AML disease progression, adding another layer of complexity to the disease progression and treatment resistance. We highlight the potential of cutting-edge methodologies, such as organ-on-chip (OoC) and single-EV analysis technologies, to provide unprecedented insights into AML-niche interactions in a human setting. Leveraging accumulated insights into AML EV signalling to reconfigure BM niches and pioneer novel approaches to decipher the EV signalling networks that fuel AML within the human context could revolutionise the development of niche-targeted therapy for leukaemia eradication.

Construction of immune-related gene pairs signature to predict the overall survival of multiple myeloma patients based on whole bone marrow gene expression profiling.

Multiple myeloma (MM) is a plasma cell dyscrasia that is characterized by the uncontrolled proliferation of malignant PCs in the bone marrow. Due to immunotherapy, attention has returned to the immune system in MM, and it appears necessary to identify biomarkers in this area. In this study, we created a prognostic model for MM using immune-related gene pairs (IRGPs), with the advantage that it is not affected by technical bias. After retrieving microarray data of MM patients, bioinformatics analyses like COX regression and least absolute shrinkage and selection operator (LASSO) were used to construct the signature. Then its prognostic value is assessed via time-dependent receiver operating characteristic (ROC) and the Kaplan-Meier (KM) analysis. We also used XCELL to examine the status of immune cell infiltration among MM patients. 6-IRGP signatures were developed and proved to predict MM prognosis with a P-value of 0.001 in the KM analysis. Moreover, the risk score was significantly associated with clinicopathological characteristics and was an independent prognostic factor. Of note, the combination of age and ß2-microglobulin with risk score could improve the accuracy of determining patients' prognosis with the values of the area under the curve (AUC) of 0.73 in 5 years ROC curves. Our model was also associated with the distribution of immune cells. This novel signature, either alone or in combination with age and ß2-microglobulin, showed a good prognostic predictive value and might be used to guide the management of MM patients in clinical practice.

Leukemia circulation kinetics revealed through blood exchange method.

Leukemias and their bone marrow microenvironments undergo dynamic changes over the course of disease. However, little is known about the circulation kinetics of leukemia cells, nor the impact of specific factors on the clearance of circulating leukemia cells (CLCs) from the blood. To gain a basic understanding of CLC dynamics over the course of disease progression and therapeutic response, we apply a blood exchange method to mouse models of acute leukemia. We find that CLCs circulate in the blood for 1-2 orders of magnitude longer than solid tumor circulating tumor cells. We further observe that: (i) leukemia presence in the marrow can limit the clearance of CLCs in a model of acute lymphocytic leukemia (ALL), and (ii) CLCs in a model of relapsed acute myeloid leukemia (AML) can clear faster than their untreated counterparts. Our approach can also directly quantify the impact of microenvironmental factors on CLC clearance properties. For example, data from two leukemia models suggest that E-selectin, a vascular adhesion molecule, alters CLC clearance. Our research highlights that clearance rates of CLCs can vary in response to tumor and treatment status and provides a strategy for identifying basic processes and factors that govern the kinetics of circulating cells.

Severe Infection Mimicking AML due to Bone Marrow Suppression: a Diagnostic Challenge.

BACKGROUND: Infection may lead to agranulocytosis due to bone marrow suppression. However, a rare case with infection presented with morphological features of acute myeloid leukemia (AML). METHODS: We report a case of extreme agranulocytosis due to severe infection mimicking acute myeloid leukemia. The case was definitively diagnosed by subsequent morphology, flow cytometry, and bone marrow biopsy, and subsequent successful anti-infective treatment confirmed the diagnosis. CONCLUSIONS: To date, no case of a patient diagnosed with severe infection mimicking AML has been reported. The case emphasizes the importance of an integrated diagnostic work-up, especially careful clinical observation and differential diagnosis.

[Minimal residual disease assessment and progress in multiple myeloma].

With the rapid iteration of multiple myeloma therapeutics over the last two decades, as well as increasing remission rates and depth of remission in patients, traditional methods for monitoring disease response are insufficient to meet the clinical needs of new drugs. Minimal residual disease (MRD) is a more sensitive test for determining the depth of response, and data from multiple clinical trials and meta-analyses show that a negative MRD correlates with a better prognosis than a traditional complete response. MM is at the forefront of MRD evaluation and treatment. MRD detection methods have been continuously updated. The current MRD assessment has three dimensions: bone marrow-based MRD testing, MRD testing based on images of residual metabolic of focal lesions, and peripheral blood-based MRD testing. The various MRD assessment methods complement one another. The goal of this article is to discuss the currently used MRD assays, the progress, and challenges of MRD in MM, and to provide a reference for clinicians to better use the techniques.

Clinical characterization of hemophagocytic lymphohistiocytosis caused by immune checkpoint inhibitors: a review of published cases.

OBJECTIVE: An association exists between immune checkpoint inhibitors and hemophagocytic lymphohistiocytosis (HLH). Therefore, the main objective of this study was to collect data on this rare but potentially life-threatening immune-related adverse reaction to identify the medications that cause it, the clinical characteristics, and effective treatments. METHODS: Literature in English and Chinese on immune checkpoint inhibitors causing HLH published from August 2014 to March 2024 was analyzed. Immune checkpoint inhibitors, immunotherapy, anti-PD-1, PD-L1 inhibitors, HLH, hemophagocytic lymphohistiocytosis, hemophagocytic syndrome keywords were used to find the literature on China Knowledge Network, Wanfang, PubMed and Emabase Databases. RESULTS AND DISCUSSION: Twenty-four studies were included, with a total of 27 patients (18 males and 9 females) with a mean age of 58 years (range 26-86). The mean time to the onset of symptoms was 10.3 weeks (7 days-14 months). The main clinical characteristics were fever, cytopenia, splenomegaly, methemoglobinemia, hypofibrinogenemia, and bone marrow biopsy showed phagocytosis. Twenty-two patients improved after the treatment with steroids, cytokine blocking therapy and symptomatic treatment, four patients died, and one patient was not described. CONCLUSION: HLH should be not underestimated as a potentially serious adverse effect of immune checkpoint inhibitors since appropriate treatments may save the life of patients.

Recurrent Marginal Zone Lymphoma with Bone Marrow Involvement Detected by ¹8F-FDG PET/CT and Biopsy: A Diagnostic Challenge.

BACKGROUND Marginal zone lymphoma is a low-grade, B-cell, non-Hodgkin lymphoma. Bone marrow involvement (BMI) of leukemia or lymphoma can usually be displayed in fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (¹8F-FDG PET/CT) with high standardized uptake values (SUV), while diffuse homogeneous ¹8F-FDG bone marrow uptake (BMU) in PET/CT primarily reflects hyperplastic bone marrow status. This report is of a 74-year-old man presenting with anemia and a diagnosis of recurrent marginal zone lymphoma with bone marrow involvement identified with 18F-FDG PET/CT imaging and biopsy. CASE REPORT A 64-year-old man with severe anemia and body weight loss of 7 kg in 1 month was diagnosed with marginal zone lymphoma, stage III, in July 2011. He went into complete remission in April 2012 after 6 cycles of chemotherapy, with Hb restored. Anemia and diffuse homogeneous ¹8F-FDG BMU in PET/CT were then noted during a routine check-up in October 2021, and recurrent disease was established through positive biopsy of subcutaneous nodules and bone marrow. Subsequent complete remission after 6 cycles of combination therapy was validated with pathologically negative BMI, the resolution of the slightly enhanced ¹8F-FDG BMU in PET/CT, and restored hemoglobin. CONCLUSIONS This report has highlighted the importance of follow-up for patients with lymphoma and supports the diagnostic role of ¹8F-FDG PET/CT imaging and the pathological verification in identifying malignant involvement in bone marrow.

The emerging importance of skull-brain interactions in traumatic brain injury.

The recent identification of skull bone marrow as a reactive hematopoietic niche that can contribute to and direct leukocyte trafficking into the meninges and brain has transformed our view of this bone structure from a solid, protective casing to a living, dynamic tissue poised to modulate brain homeostasis and neuroinflammation. This emerging concept may be highly relevant to injuries that directly impact the skull such as in traumatic brain injury (TBI). From mild concussion to severe contusion with skull fracturing, the bone marrow response of this local myeloid cell reservoir has the potential to impact not just the acute inflammatory response in the brain, but also the remodeling of the calvarium itself, influencing its response to future head impacts. If we borrow understanding from recent discoveries in other CNS immunological niches and extend them to this nascent, but growing, subfield of neuroimmunology, it is not unreasonable to consider the hematopoietic compartment in the skull may similarly play an important role in health, aging, and neurodegenerative disease following TBI. This literature review briefly summarizes the traditional role of the skull in TBI and offers some additional insights into skull-brain interactions and their potential role in affecting secondary neuroinflammation and injury outcomes.

A case report of prostate cancer with leptomeningeal metastasis and bone marrow involvement.

BACKGROUND: Prostate cancer is the second most common cancer in men. Central nervous system (CNS) involvement in prostate cancer which manifests as cerebral, leptomeningeal, or dural involvement is uncommon and occurs late in the course of disease. CASE: A 60-year-old patient with castration resistant prostate cancer (CRPC) presented with headache and fatigue. Evaluation revealed bone marrow and leptomeningeal involvement. The patient treated by whole brain radiotherapy, leuprolide, weekly docetaxel and daily 1000 mg abiraterone. Complete blood count (CBC) and CNS symptoms improved and the patient is alive after 11 months with excellent performance status. CONCLUSION: Leptomeningeal involvement in prostate cancer is rare and is associated with a poor prognosis but the possibility of such event should be considered in patients with new onset progressive CNS symptoms. New treatment strategies such as combination of docetaxel and abiraterone added to androgen deprivation therapy (triplet therapy) might improve outcome in these patients.