BACKGROUND: Leukocyte Ig-like receptor B family 4 (LILRB4) as an immune checkpoint on myeloid cells is a potential target for tumor therapy. Extensive osteolytic bone lesion is the most characteristic feature of multiple myeloma. It is unclear whether ectopic LILRB4 on multiple myeloma regulates bone lesion.
METHODS: The conditioned medium (CM) from LILRB4-WT and -KO cells was used to analyze the effects of LILRB4 on osteoclasts and osteoblasts. Xenograft, syngeneic and patient derived xenograft models were constructed, and micro-CT, H&E staining were used to observe the bone lesion. RNA-seq, cytokine array, qPCR, the activity of luciferase, Co-IP and western blotting were used to clarify the mechanism by which LILRB4 mediated bone damage in multiple myeloma.
RESULTS: We comprehensively analyzed the expression of LILRB4 in various tumor tissue arrays, and found that LILRB4 was highly expressed in multiple myeloma samples. The patient\'s imaging data showed that the higher the expression level of LILRB4, the more serious the bone lesion in patients with multiple myeloma. The conditioned medium from LILRB4-WT not -KO cells could significantly promote the differentiation and maturation of osteoclasts. Xenograft, syngeneic and patient derived xenograft models furtherly confirmed that LILRB4 could mediate bone lesion of multiple myeloma. Next, cytokine array was performed to identify the differentially expressed cytokines, and RELT was identified and regulated by LILRB4. The overexpression or exogenous RELT could regenerate the bone damage in LILRB4-KO cells in vitro and in vivo. The deletion of LILRB4, anti-LILRB4 alone or in combination with bortezomib could significantly delay the progression of bone lesion of multiple myeloma.
CONCLUSIONS: Our findings indicated that LILRB4 promoted the bone lesion by promoting the differentiation and mature of osteoclasts through secreting RELT, and blocking LILRB4 singling pathway could inhibit the bone lesion.

Rationale: Bone destruction is a hallmark of multiple myeloma (MM) and affects more than 80% of patients. Although previous works revealed the roles of N6-methyladenosine (m6A) reader hnRNPA2B1 in the development of tumors, whether hnRNPA2B1 regulates bone destruction in MM is still unknown. Methods: Alizarin red S staining, TRAP staining, ELISA and quantitative real-time PCR assays were used to evaluate osteogenesis and osteoclastogenesis in vitro. X ray and bone histomorphometric analysis were preformed to identify bone resorption and bone formation in vivo. Exosome isolation and characterization were demonstrated by transmission electron microscopy, dynamic light scattering, immunofluorescence and flow cytometry assays. The interactions between hnRNPA2B1 and primary microRNAs were examined using RNA pull-down and RIP assays. Coimmunoprecipitation assay was used to test the interaction between hnRNPA2B1 and DGCR8 proteins. Luciferase assay was established to assess miRNAs target genes. Results: Here we show that myeloma cells hnRNPA2B1 mediates microRNAs processing and upregulates miR-92a-2-5p and miR-373-3p expression. These two microRNAs are transported to recipient monocytes or mesenchymal stem cells (MSCs) through exosomes, leading to activation of osteoclastogenesis and suppression of osteoblastogenesis by inhibiting IRF8 or RUNX2. Furthermore, clinical studies revealed a highly positive correlation between the level of myeloma cells hnRNPA2B1 and the number of osteolytic bone lesions in myeloma patients. Conclusions: This study elucidates an important mechanism by which myeloma-induced bone lesions, suggesting that hnRNPA2B1 may be targeted to prevent myeloma-associated bone disease.

BACKGROUND: ECD is a rare non-Langerhans cell histiocytosis with diverse and heterogeneous clinical manifestations, ranging from single-lesion forms to multi-system involvement, including slowly progressing unifocal forms to rapidly evolving life-threatening disease.
METHODS: A female patient presented with a 2-month history of fever. Imaging revealed multiple thromboses, bone destruction, an abnormal pituitary stalk, and clinical manifestations of diabetes insipidus. Excisional biopsy of a tibial lesion was sent for microscopic examination, and subsequent immunohistochemical testing was positive for expression of CD68 and CD163, and negative for expression of the immune markers CD1a, S100, and langerin. This confirmed the diagnosis of ECD. Treatment with methylprednisolone to inhibit the immune inflammatory response along with anti-cytokine therapy with an interleukin-6 antagonist resulted in satisfactory disease control.
CONCLUSIONS: We report a rare case of multiple thromboses, embolism, and multiple organ involvement as the main presentation of ECD, suggesting that ECD should be considered in patients presenting with multiple thromboses associated with multisystem damage. We successfully treated our patient with glucocorticoids and interleukin-6 antagonist. This patient\'s response to treatment suggests that hormone therapy and cytokine/chemokine therapy may be a potential novel treatment for patients with ECD without gene mutations.

Multiple myeloma is characterized by osteolytic lesions caused by reduced bone formation and activated bone resorption. An important feature of myeloma is a failure of bone healing after successful treatment. In this work, clinical studies indicated a highly positive correlation between bone marrow bacteria abundance and bone lesion numbers of myeloma patients in complete remission. Coculture experiments demonstrated that marrow Escherichia coli (E. coli) promotes osteoclast differentiation and inhibits osteoblast differentiation. Mechanism studies showed that E. coli lipopolysaccharides (LPS) activated NF-κB p65 signaling and reduced phosphorylated smad1/5/9 binding ability with RUNX2 promoter, leading to decreased RUNX2 expression in osteoblast progenitors. Additionally, LPS enhanced phosphorylated NF-κB p65 binding ability with NFATc1 promoter, leading to increased NFATc1 expression in osteoclast progenitors. In vivo studies revealed E. coli contributes to osteolytic bone lesion, and elimination of E. coli infection assists healing of bone lesion in mouse model of myeloma in complete remission. These findings establish a heretofore unrecognized effect for E. coli in the genesis of myeloma bone disease and suggest a new treatment strategy.

Osteolytic destruction is a hallmark of multiple myeloma and impairs myeloma patients\' quality of life. However, the molecular mechanism underlying the pathogenesis of myeloma-associated bone disease remains unclear. In this study, we demonstrate the role of myeloma cell-expressed integrin α6 in bone. Integrin α6 binds to laminin 8 and epidermal growth factor receptor on mesenchymal stem cells (MSCs) to form a trimer complex and upregulates the secretion of osteolytic cytokines from both myeloma cells and MSCs, leading to enhanced bone resorption and reduced bone formation. Thus, this study elucidates an important mechanism for myeloma-induced bone lesions and implicates that targeting integrin α6 may be a viable approach for bone healing in myeloma patients.

BACKGROUND: Radiologists have difficulty distinguishing benign from malignant bone lesions because these lesions may have similar imaging appearances. The purpose of this study was to develop a deep learning algorithm that can differentiate benign and malignant bone lesions using routine magnetic resonance imaging (MRI) and patient demographics.
METHODS: 1,060 histologically confirmed bone lesions with T1- and T2-weighted pre-operative MRI were retrospectively identified and included, with lesions from 4 institutions used for model development and internal validation, and data from a fifth institution used for external validation. Image-based models were generated using the EfficientNet-B0 architecture and a logistic regression model was trained using patient age, sex, and lesion location. A voting ensemble was created as the final model. The performance of the model was compared to classification performance by radiology experts.
RESULTS: The cohort had a mean age of 30±23 years and was 58.3% male, with 582 benign lesions and 478 malignant. Compared to a contrived expert committee result, the ensemble deep learning model achieved (ensemble vs. experts): similar accuracy (0·76 vs. 0·73, p=0·7), sensitivity (0·79 vs. 0·81, p=1·0) and specificity (0·75 vs. 0·66, p=0·48), with a ROC AUC of 0·82. On external testing, the model achieved ROC AUC of 0·79.
CONCLUSIONS: Deep learning can be used to distinguish benign and malignant bone lesions on par with experts. These findings could aid in the development of computer-aided diagnostic tools to reduce unnecessary referrals to specialized centers from community clinics and limit unnecessary biopsies.
BACKGROUND: This work was funded by a Radiological Society of North America Research Medical Student Grant (#RMS2013) and supported by the Amazon Web Services Diagnostic Development Initiative.

BACKGROUND: This study aimed to identify the characteristic radiological signs for the diagnosis of Langerhans cell histiocytosis (LCH) of the bone.
METHODS: We retrospectively studied 82 cases of LCH with bone lesions confirmed by pathology. Clinical and radiological features of the patients were analyzed.
RESULTS: A total of 64 and 18 patients had single and multiple bone lesions, respectively. With regard to LCH with single bone lesions, 37.5% (24/64) of lesions were located in the skull and presented as bone destruction with or without soft tissue mass. The correct diagnosis rate of these lesions was 60.0% (9/15) in children and adolescents, but was only 22.2% (2/9) in adults. A total of 26.5% (17/64) of the solitary lesions were found in the spine. Of these, 88.2% (15/17) were located in the vertebral body and appeared to have different degrees of collapse, and 66.7% (10/15) of these lesions were correctly diagnosed. Of the unifocal lesions, 21.8% (14/64) were located in other flat and irregular bones and manifested as osteolysis. Only 21.4% (3/14) of these cases were correctly diagnosed. In total, 14.1% (9/64) of the isolated bone LCH lesions were located in the long bones. Of these, 77.8% (7/9) were located in the diaphysis and presented as central bone destruction with or without fusiform periosteal reaction and extensive peripheral edema, of which 42.9% (3/7) were correctly diagnosed before surgery or biopsy. With regard to LCH with multiple bony destructive lesions, 71.4% (10/14) of cases in children and adolescents were correctly diagnosed; however, all four cases among adults were misdiagnosed.
CONCLUSIONS: In all age groups, isolated diaphyseal destruction of the long bone with fusiform periosteal reaction and extensive peripheral edema, vertebra plana of the spine, and bevelled edge of skull defects accompanied by soft tissue masses strongly suggest LCH diagnosis. Moreover, the multiple bone osteolytic destruction in children and adolescents strongly suggests LCH diagnosis. Familiarity with these typical radiological signs of LCH is necessary to decrease misdiagnoses.

Several feasibility studies have reported that high-intensity focused ultrasound (HIFU) ablation can be applied to ease patients\' bone pain. However, the effect of HIFU ablation to palliate bone pain remains unclear. To evaluate the technique\'s success, efficacy, minor complication and major complication on patients suffering from bone pain, we searched the PubMed, MEDLINE, EMBASE and Cochrane Library databases from January 1998 to March 2019. Clinical studies that have assessed the association between bone pain and HIFU ablation were involved. We filtered out 28 feasibility studies, which reported the association between HIFU ablation and bone pain, including a total of 717 patients and 736 bone lesions. Overall, our results indicate that the rate of technique success of HIFU ablation was 93% (95% confidence interval [CI] 89%-96%) for patients with bone lesions. The technique efficacy rate of HIFU ablation for palliation of pain from bone lesions was 80% (95% CI 74%-87%) in all the patients, 96% (91%-100%) in the subgroup of retrospective studies and 77% (69%-85%) in the subgroup of prospective studies. In regard to HIFU ablation treatment safety, the hazard ratio for minor complication was 12% (95% CI 7%-17%), and the hazard ratio for major complication was 2% (95% CI 1%-3%). In conclusion, the summary rates for various considerations of using HIFU ablation for the palliation of bone pain are as follows: technique success is 93%, technique efficacy is 77%, minor complication is 12% and major complication is 2%. Our results suggest that extracorporeal HIFU ablation is a promising method for palliation of pain in bone lesions, with high technique success and efficacy, but low adverse events.

The outbreak of coronavirus disease 2019 (COVID-19) has posed a severe threat to global health management system since it has been detected in the human body. This pandemic was prompted by severe acute respiratory syndrome coronaviruses 2 (SARS-CoV-2) and rapidly developed into a public emergency with an alarming increase in cases and deaths. The increasing explorations to SARS-CoV-2 infection guide us to consider whether bone lesion is followed by this pathologic process. We especially focus on the underlying pathobiology that SARS-CoV-2 possibly mediated in bone remodeling and analyze the association of bone destruction with ACE2 in COVID-19 incidence, for preferable understanding the pathogenesis and providing necessary clinical management in orthopedics.

Prostate cancer is the most common malignant tumor with bone metastasis, and there is still no ideal treatment for bone metastasis of prostate cancer. In this study, a pH and GSH dual sensitive calcium phosphate-polymer hybrid nanoparticle (DTX@Cap/HP) was prepared to co-deliver zoledronate (ZOL) and docetaxel (DTX) to treat bone metastasis of prostate cancer. DTX@Cap/HP exhibited high bone binding affinity and released more DTX and ZOL in acidic and high GSH concentration environment. A large amount of DTX@Cap/HP was uptaken by PC-3 cell in acidic medium than that in neutral medium. DTX@Cap/HP obviously reduced PC-3 cell proliferation and bone lesion in in-vitro 3D model of bone metastases of prostate cancer. Besides, DTX@Cap/HP also exhibited stronger anti bone metastases of prostate cancer activity in vivo as compared with the same dose of DTX + ZOL, which resulted from the co-delivery of DTX and ZOL to bone metastases of prostate cancer by DTX@Cap/HP and the synergistic effects of DTX and ZOL. DTX@Cap/HP has great potential in the treatment of bone metastases of prostate cancer.