miR-345-3p Modulates M1/M2 Macrophage Polarization to Inhibit Inflammation in Bone Infection via Targeting MAP3K1 and NF-κB Pathway.

Infection after fracture fixation (IAFF), a complex infectious disease, causes inflammatory destruction of bone tissue and poses a significant clinical challenge. miR-345-3p is a biomarker for tibial infected nonunion; however, the comprehensive mechanistic role of miR-345-3p in IAFF is elusive. In this study, we investigated the role of miR-345-3p in IAFF pathogenesis through in vivo and in vitro experiments. In vivo, in a rat model of IAFF, miR-345-3p expression was downregulated, accompanied by increased M1 macrophage infiltration and secretion of proinflammatory factors. In vitro, LPS induced differentiation of primary rat bone marrow-derived macrophages into M1 macrophages, which was attenuated by miR-345-3p mimics. miR-345-3p promoted M1 to M2 macrophage transition-it reduced the expression of cluster of differentiation (CD) 86, inducible NO synthase, IL-1ß, and TNF-α but elevated those of CD163, arginase-1, IL-4, and IL-10. MAPK kinase kinase 1 (MAP3K1), a target mRNA of miR-345-3p, was overexpressed in the bone tissue of IAFF rats compared with that in those of the control rats. The M1 to M2 polarization inhibited MAP3K1 signaling pathways in vitro. Conversely, MAP3K1 overexpression promoted the transition from M2 to M1. miR-345-3p significantly inhibited NF-κB translocation from the cytosol to the nucleus in a MAP3K1-dependent manner. In conclusion, miR-345-3p promotes the polarization of M1 macrophages to the M2 phenotype by inhibiting the MAP3K1 and NF-κB pathways. These findings provide insight into the pathogenesis and immunotherapeutic strategies for IAFF and offer potential new targets for subsequent research.

Radiologic findings of osteonecrosis, osteoradionecrosis, osteomyelitis and jaw metastatic disease with cone beam CT.

PURPOSE: The purpose of this study was to assess CBCT scans of patients with medication related osteonecrosis of the jaws (MRONJ), osteoradionecrosis (ORN), osteomyelitis (OM) and jaw metastatic disease (JM), evaluate the presence and extent of radiologic findings, identify radiologic parameters that may distinguish the four entities and last, introduce a new modified radiographic index (CRIm), in order to contribute to the diagnosis of these conditions. METHODS: Τwo major databases were retrospectively searched for fully documented and diagnosed CBCT scans of MRONJ, ORN, OM and JM from 2006 to 2019. 335 CBCT scans met the inclusion criteria and were assessed under standardized viewing conditions blindly by 2 observers. The CRIm index proposed in this study evaluates: lytic changes, sclerosis, periosteal bone formation, sequestration, non-healing extraction sockets and other findings which included: sinus implication, inferior alveolar canal implication and jaw fracture. Lytic changes, sclerosis, periosteal bone formation, sequestration and non-healing extraction sockets were scored as: absent (0), localized/single (1) and extensive/multiple (2). Each one of other findings were scored individually as: absent (0) and present (1). For statistical analysis t-test, Pearson's r correlation coefficient, one-way ANOVA and Bonferonni were performed. RESULTS: Extensive lytic changes were the most common finding, especially for ORN, where it occurred in all CBCT scans (100%). The mean value of the CRIm index differs significantly between CBCT scans with MRONJ and JM, as well as between those with OM and JM (Bonferroni p < 0.001). CONCLUSIONS: The new modified Composite Radiographic Index introduced in this study, appears to have improved an objective approach to the previously used Composite Radiographic Index by means of cumulative radiologic features. Τhe predominance of certain radiologic features in one or more of these entities may lead the diagnostician towards the correct diagnosis.

Radiomics method in the differential diagnosis of diabetic foot osteomyelitis and charcot neuroarthropathy.

OBJECTIVES: Our study used a radiomics method to differentiate bone marrow signal abnormality (BMSA) between Charcot neuroarthropathy (CN) and osteomyelitis (OM). METHODS AND MATERIALS: The records of 166 patients with diabetic foot suspected CN or OM between January 2020 and March 2022 were retrospectively examined. A total of 41 patients with BMSA on MRI were included in this study. The diagnosis of OM was confirmed histologically in 24 of 41 patients. We clinically followed 17 patients as CN with laboratory tests. We also included 29 nondiabetic patients with traumatic (TR) BMSA on MRI as the third group. Contours of all BMSA on T 2 - and T1 -weighted images in three patient groups were segmented semi-automatically on ManSeg (v.2.7d). The T1 and T2 features of three groups in radiomics were statistically evaluated. We applied the multi-class classification (MCC) and binary-class classification (BCC) methodologies to compare results. RESULTS: For MCC, the accuracy of Multi-Layer Perceptron (MLP) was 76.92% and 84.38% for T1 and T2, respectively. According to BCC, for CN, OM, and TR BMSA, the sensitivity of MLP is 74%, 89.23%, and 76.19% for T1, and 90.57%, 85.92%, 86.81% for T2, respectively. For CN, OM, and TR BMSA, the specificity of MLP is 89.16%, 87.57%, and 90.72% for T1 and 93.55%, 89.94%, and 90.48% for T2 images, respectively. CONCLUSION: In diabetic foot, the radiomics method can differentiate the BMSA of CN and OM with high accuracy. ADVANCES IN KNOWLEDGE: The radiomics method can differentiate the BMSA of CN and OM with high accuracy.

Solitary bone plasmacytoma of the tibia presenting as chronic osteomyelitis: A rare case report and literature review.

RATIONALE: Plasmacytoma is a rare plasma cell dyscrasia that grows within the axial skeleton or soft tissue structures as solitary or multiple masses. The primary types are solitary plasmacytoma, including solitary bone plasmacytoma (SBP) and solitary extramedullary plasmacytoma, and multiple solitary plasmacytomas. SBP is characterized by localized proliferation of monoclonal plasma cells and is rare. However, SBP with chronic osteomyelitis is even rarer. PATIENT CONCERNS: A 47-year-old man previously diagnosed with chronic osteomyelitis presented with repeated discharge and ulceration in the front of his right tibia. DIAGNOSIS, INTERVENTIONS AND OUTCOMES: Lower extremity magnetic resonance imaging (MRI) and computed tomography (CT) examinations showed dead bone formation and surrounding inflammatory edema. Thus, the patient underwent dead bone excision and fenestration of the bone marrow cavity. The histopathologic examination results indicated plasmacytoma. Therefore, we administered radiotherapy with satisfactory results. LESSONS: Physicians should pay close attention to chronic osteomyelitis because it may be accompanied by plasmacytoma. Postoperative pathological and immunohistochemical examinations are crucial, and surgical resection of the lesion and local radiotherapy are effective treatment methods.

Comparison of the histopathological characteristics of diffuse sclerosing osteomyelitis of the mandible, chronic suppurative osteomyelitis, and craniofacial fibrous dysplasia.

BACKGROUND: There are relatively few reports on the histopathological characteristics of diffuse sclerosing osteomyelitis of the mandible (DSOM), which is difficult to distinguish from chronic suppurative osteomyelitis (CSO) and craniofacial fibrous dysplasia (CFD). This study aimed to summarize and compare the histopathological characteristics of DSOM, CFD, and CSO. MATERIALS AND METHODS: In this study, hematoxylin and eosin-stained sections of patients with DSOM, CSO, and CFD at the Peking University Hospital of Stomatology from 2015 to 2020 were retrieved. The histopathological characteristics were summarized, including new bone formation, inflammatory cell infiltration, bone trabecular morphology, osteoclasts, sequestrum, bacterial mass, and calcified spherules, similar to cementicles. The histopathological characteristics of DSOM, CSO, and CFD were compared, and the results were statistically analyzed. RESULTS: In total, 50, 13, and 10 patients with DSOM, CSO, and CFD were included in this study, respectively. In terms of new bone formation, both DSOM and CSO showed reactive bone formation (p = 1), whereas CFD mainly showed fiber osteogenesis (p < 0.001). The inflammatory cells of DSOM were mainly lymphocytes and plasma cells, whereas those of CSO were mainly lymphocytes and neutrophils (p < 0.001), and there was usually no inflammatory cell infiltration in the CFD specimens (p < 0.001). DSOM, CSO, and CFD showed irregular bone trabeculae (p = 0.045, p = 0.703) and active osteoclasts (p1 = 0.189, p2 = 0.256). DSOM showed a small amount of bacterial mass but no sequestrum; neither of which was found in CFD (p = 1, p = 1), but it was common in CSO (p = 0.011 and p = 0.025). DSOM and CSO showed smooth and regular basophilic lines (p = 0.308), whereas CFD showed a rough and irregular basophilic line (p < 0.001). CONCLUSIONS: The histopathological characteristics of the three diseases were partly similar, but there were evident differences. The main differences are the type of new bone formation, types and distribution of inflammatory cells, and presence of sequestrum and bacterial masses. These differences will help clinicians diagnose DSOM.

bcl-2 and p53 as novel biomarkers for predicting malignant transformation in chronic osteomyelitis.

PURPOSE: To find whether B-cell lymphoma 2 (bcl-2) and p53 proteins could be used as parameters to detect malignant transformation of chronic osteomyelitis. We also attempted to determine whether they could be used to differentiate between secondary squamous cell carcinoma (SCC) resulting from chronic osteomyelitis, and primary cutaneous squamous cell carcinoma. METHODS: Retrospective study was conducted during 5 years period, resulting in 7 patients in each group: secondary squamous cell carcinoma arising from chronic osteomyelitis, primary cutaneous squamous cell carcinoma, and chronic osteomyelitis patients. Immunohistochemistry staining with bcl-2 and p53 was performed with the pathologist blinded to the sample groups. RESULTS: Contingency coefficient test was performed to assess the correlation between the biomarker status (bcl-2 and p53) and the case groups. Significant moderate correlations of bcl-2 and p53 were found between groups of chronic osteomyelitis and squamous cell carcinoma arising from chronic osteomyelitis in terms of malignant transformation (p = 0.005 for bcl-2 and p = 0.031 for p53). Insignificant correlations of bcl-2 and p53 expression were found between primary cutaneous squamous cell carcinoma and secondary squamous cell carcinoma arising from chronic osteomyelitis group (p = 0.577). CONCLUSIONS: The expression of bcl-2 and p-53 is significantly correlated with chronic osteomyelitis malignant transformation into squamous cell carcinoma.

Central Skull Base Osteomyelitis: Multimodality Imaging and Clinical Findings from a Large Indian Cohort.

Background: Central or atypical skull base osteomyelitis (CSBO) often presents with severe unrelenting headache and progressive mono or polyneuritis cranialis. MRI and CT are used as initial imaging techniques but have a poor specificity and sensitivity. Objective: To analyze our cohort of CSBO. Materials and Methods: Over a 5-year period [2015-2020], we retrospectively analyzed the records of all patients with CSBO who had undergone a 3T MRI Brain, MR angiography, regional FDG PET-CT, and skeletal scintigraphy with 99mTc MDP/SPECT-CT. Surgical biopsy specimens were sent for bacterial and fungal cultures. Results: In total, 17 patients with CSBO were identified. Typically, 88% of patients presented with severe unilateral headache. All patients had at least a cranial mono or polyneuritis. The majority of patients were diabetic [64%]. MRI was normal in 42% of patients, whereas PET-CT and with 99mTc MDP scan and SPECT-CT were abnormal in all patients. Conclusion: Our series of CSBO showed a 40% mortality rate with significant morbidity and relentless progression. Patients required repeated PET CT and bone scans to detect regression of disease activity. The average duration of IV therapy ranged from 3 weeks to 9 months and oral therapy for around 2-3 months. Cure was defined after taking into account the original diagnosis, symptom resolution, and concordant reduction of tissue uptake on PET CT and 99mTc bone scan. The combination of MRI, FDG PET CT, and 99mTc bone scan with concurrent SPECT CT was able to detect disease and disease progression in all patients.

Vascular Analysis of Soft Tissues Around the Bone Lesion in Osteoradionecrosis, Medication-Related Osteonecrosis, and Infectious Osteomyelitis of the Jaw.

OBJECTIVE: The histopathological differences of the surrounding soft tissues in osteoradionecrosis of the jaw, medication-related osteonecrosis of the jaw as well as infectious osteomyelitis of the jaw patients were rarely investigated. Here, we focused on the vascular microarchitecture of the soft tissues around bone lesion and compared the microvessel difference of ORNJ, MRONJ, and IOMJ in a quantitative fashion. METHODS: A series of consecutive patients diagnosed as ORNJ, MRONJ, and acute/chronic IOMJ was retrospectively reviewed. All cases received preoperative cone bean computed tomography scans. Immunohistochemistry of CD34 was performed with the streptavidin-peroxidase method and the variables including vascular density, vascular area fraction, mean vessel lumen area, perimeter and diameter of the vessels as well as percentage of lumen less than 400 µm2 were analyzed. RESULTS: The results showed that the vascular-like structures were visible in more cases of acute/chronic IOMJ compared with ORNJ and MRONJ by hematoxylin-eosin staining. Quantitively, our results demonstrated the decreased vascular density, mean perimeter and diameter of the vessels but increased percentage of small vessels in ORNJ and MRONJ patients in contrast with IOMJ patients. CONCLUSIONS: Hypovascularity of surrounding soft tissues could play important roles in the etiology of IOMJ, ORNJ, and MRONJ, and microvessel profile may be a useful pathological diagnostic indicator to differentiate these 3 types of OMJ.

Two-Phase Deep Learning Algorithm for Detection and Differentiation of Ewing Sarcoma and Acute Osteomyelitis in Paediatric Radiographs.

BACKGROUND/AIM: Ewing sarcoma is a highly malignant tumour predominantly found in children. The radiological signs of this malignancy can be mistaken for acute osteomyelitis. These entities require profoundly different treatments and result in completely different prognoses. The purpose of this study was to develop an artificial intelligence algorithm, which can determine imaging features in a common radiograph to distinguish osteomyelitis from Ewing sarcoma. MATERIALS AND METHODS: A total of 182 radiographs from our Sarcoma Centre (118 healthy, 44 Ewing, 20 osteomyelitis) from 58 different paediatric (≤18 years) patients were collected. All localisations were taken into consideration. Cases of acute, acute on chronic osteomyelitis and intraosseous Ewing sarcoma were included. Chronic osteomyelitis, extra-skeletal Ewing sarcoma, malignant small cell tumour and soft tissue-based primitive neuroectodermal tumours were excluded. The algorithm development was split into two phases and two different classifiers were built and combined with a Transfer Learning approach to cope with the very limited amount of data. In phase 1, pathological findings were differentiated from healthy findings. In phase 2, osteomyelitis was distinguished from Ewing sarcoma. Data augmentation and median frequency balancing were implemented. A data split of 70%, 15%, 15% for training, validation and hold-out testing was applied, respectively. RESULTS: The algorithm achieved an accuracy of 94.4% on validation and 90.6% on test data in phase 1. In phase 2, an accuracy of 90.3% on validation and 86.7% on test data was achieved. Grad-CAM results revealed regions, which were significant for the algorithms decision making. CONCLUSION: Our AI algorithm can become a valuable support for any physician involved in treating musculoskeletal lesions to support the diagnostic process of detection and differentiation of osteomyelitis from Ewing sarcoma. Through a Transfer Learning approach, the algorithm was able to cope with very limited data. However, a systematic and structured data acquisition is necessary to further develop the algorithm and increase results to clinical relevance.

Florid cemento-osseous dysplasia-related osteonecrosis: A series of cases.

OBJECTIVE: The aim of this study was to assess the clinicopathological features of florid cemento-osseous dysplasia (FCOD)-related osteonecrosis highlighting their histopathological aspects and bone structure. METHODS: Twenty-two FCOD-related osteonecrosis cases were evaluated retrospectively. Osteonecrosis, osteomyelitis, bacterial colonization, bone resorption, reactive bone, osteon-like structure, lamellar bone, and basophilic lines were analyzed. Specific staining and fluorescence and polarized light microscopy analyses were also performed. RESULTS: The mandible was more affected by FCOD-related osteonecrosis. There was a predominance of African-Brazilian women in the fifth and seventh decades of life. Osteomyelitis was present in 82 % of cases whereas bone resorption and bacterial colonization were present in 100 % of FCOD-related osteonecrosis cases. Thick basophilic lines were seen in all cases (100 %). Actinomycosis and osteoclasts were not often. CONCLUSIONS: This study showed female adult preference, mandibular location, and some findings such as osteomyelitis, bone resorption, and bacterial colonization were histopathological features more frequent in FCOD-related osteonecrosis. In the absence of a close clinical and radiographic correlation, the morphology of the necrotized bone similar to cementum could help to recognize FCOD.

TNF-inhibitors or bisphosphonates in chronic nonbacterial osteomyelitis? - Results of an international retrospective multicenter study.

Chronic nonbacterial osteomyelitis (CNO) can cause significant morbidity, including bone pain and damage. In the absence of clinical trials, treatments include non-steroidal anti-inflammatory drugs, corticosteroids, TNF-inhibitors (TNFi) and/or bisphosphonates. In a retrospective chart review in the United Kingdom and Germany, we investigated response to TNFi and/or pamidronate. Ninety-one patients were included, receiving pamidronate (n = 47), TNFi (n = 22) or both sequentially (n = 22). Patients with fatigue [p = 0.003] and/or arthritis [p = 0.002] were more frequently treated with TNFi than pamidronate. Both therapies were associated with clinical remission at 6 months, and reduction of bone lesions on MRI at 12 months. While not reaching statistical significance, pamidronate resulted in faster resolution of MRI lesions. Fewer flares were observed with TNFi. Failure to respond to pamidronate was associated with female sex [p = 0.027], more lesions on MRI [p = 0.01] and higher CRP levels [p = 0.03]. Randomized clinical trials are needed to confirm observations and generate evidence.

Are Bacteria Just Bystanders in the Pathogenesis of Inflammatory Jaw Conditions?

PURPOSE: It is unclear whether certain bacteria initiate the development of inflammatory jaw conditions, or whether these diseases create a milieu for dysbiosis and secondary colonization of indigenous flora. At present, there are no comparative studies on the types of bacteria that colonize different inflammatory jaw conditions. Accordingly, this study aims to identify and compare the types of bacteria isolated in osteomyelitis, osteoradionecrosis, and MRONJ. METHODS: This is a retrospective cohort study of patients diagnosed with inflammatory jaw conditions. The predictor variables were classification of bacteria as oral flora, categorized herein as resident bacteria, non-resident bacteria, or opportunistic organisms. The outcome variables were a diagnosis of osteomyelitis, osteoradionecrosis, and MRONJ. Covariates were age, sex, penicillin allergy, a diagnosis of diabetes and a history of smoking. Data analysis was performed using ANOVA and chi-squared tests. RESULTS: A total of 105 patients with inflammatory jaw conditions were enrolled. The final sample size was 69 subjects of which 16 were diagnosed with osteomyelitis, 20 with osteoradionecrosis, and 33 with MRONJ. There was no difference in the frequency that resident bacteria were isolated. Non-resident bacteria, which included Staphylococcus and Enterococcus among others, were isolated more frequently at 75% in osteomyelitis compared to 60% in osteoradionecrosis and 48% in MRONJ cases. There is weak evidence of significant difference when comparing osteomyelitis and MRONJ cases (P = .08). Opportunistic organisms, which included Mycobacterium and Candida, were isolated more frequently in osteoradionecrosis at 30% compared to 12.5% in osteomyelitis and 12.12% in MRONJ cases. There is weak evidence of significant difference when comparing osteoradionecrosis and MRONJ cases (P = .1). CONCLUSION: Non-resident bacteria including Staphylococcus and Enterococcus may be more frequently isolated in patients with osteomyelitis, while opportunistic organisms like Mycobacterium and Candida may be more frequently found in patients diagnosed with osteoradionecrosis.

Increasing Cases of Chronic Nonbacterial Osteomyelitis in Children: A Series of 215 Cases From a Single Tertiary Referral Center.

OBJECTIVE: Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disease that is gaining recognition from clinicians and researchers. We aim to publish data from our cohort of patients with CNO living in the northwestern United States to increase the awareness of specific demographics, characteristics, and presentation of this rare disease. METHODS: A retrospective chart review was performed of our electronic medical records. Patients with complete chart records who met criteria for a diagnosis of CNO from 2005 to 2019 were included. Extracted data including patient demographics, bone biopsy results, and lesion locations on advanced imaging were analyzed. King County census data were used to calculate the annual new case rate within our center. RESULTS: A total of 215 CNO cases were diagnosed at our large tertiary pediatric hospital. The majority of cases were of White race residing in Washington's most populous county, King County. Most cases were diagnosed in 2016 to 2019, showing a significant increase in the annual case rate from 8 to 23 per million children in King County, though there did not appear to be a seasonal predilection. Biopsy rate decreased from 75% to 52%. One hundred fifty-two (71%) children had family history of autoimmunity. With increasing use of whole-body magnetic resonance imaging (WB-MRI), results showed 68% had multiple lesions. CONCLUSION: CNO has been diagnosed at an increased rate in recent years. WB-MRI may assist in identifying other lesions that may be asymptomatic on presentation. Bone biopsy is still required in some children at the time of diagnosis.

[Long-Term Survival of Patient Having Advanced Esophageal Cancer with Cirrhosis after Overcoming Anastomotic Leakage, Purulent Osteomyelitis, Cervical Lymph Node Recurrence, and Systemic Edema-A Surgical Case].

We report the surgical case of advanced esophageal cancer with cirrhosis in a patient who has been cancer-free for 6 years after overcoming anastomotic leakage, purulent osteomyelitis, cervical lymph node recurrence, and systemic edema. A 69-year-old woman visited our hospital and presented with the complaint of a food sticking sensation. Endoscopic findings showed a type 3 tumor in the middle thoracic esophagus. Esophagectomy was subsequently performed. Histopathological findings revealed poorly differentiated squamous cell carcinoma, Mt, 17×15 mm, type 3, pT3, pIM0, pPM0, pDM0, pRM0, pN2(7/18), pStage Ⅲ, and liver cirrhosis(F4, A1-2). Postoperative suture failure was observed; however, it conservatively improved in approximately 2 months. The patient had lower back pain since approximately 6 weeks after the surgery, and she was diagnosed with purulent spondylitis and was administered antibiotics. The patient was subsequently discharged 67 days after the surgery. One course of 5-FU+CDDP was administered as postoperative adjuvant chemotherapy. However, renal function deteriorated, and chemotherapy was discontinued. Four months after the surgery, cervical echography revealed recurrence in the left cervical lymph node, and docetaxel(DTX)was administered. Five DTX doses were administered, because of which the left cervical lymph nodes markedly shrunk. Moreover, the sixth dose of DTX resulted in febrile neutropenia and a large amount of abdominal pleural effusion. Consequently, the patient was hospitalized. Tolvaptan treatment was extremely effective, and the thoracic ascites disappeared. Esophageal cancer has not recurred, and the patient is being observed at an outpatient clinic 6 years after the surgery.

Clinical characteristics and outcomes of chronic nonbacterial osteomyelitis in children: a multicenter case series.

OBJECTIVE: The aim of this study was to evaluate demographic, clinical, laboratory, imaging, histopathology characteristics, and treatment responses of children with Chronic nonbacterial osteomyelitis (CNO). METHODS: Retrospective multi-center case series study of pediatric patients diagnosed with CNO treated at five tertiary centers in south China. RESULTS: Totally there were 18 patients diagnosed as CNO between 2014 and 2020. The median age of onset was 9.2 years (range 3.7-13.1) and 55.6% were female. Median delay in diagnosis was 10.9 months (range 1.0-72.0). The most frequent presenting symptoms were bone pain (100%) and fever (44.4%). Most patients had more than one lesion (median of 5, range 1-7). Most frequently affected bones were tibiofibula (88.9%) and femur (77.8%). The MRI characteristics mainly presented as bone edema and hyperintensity in bone marrow. Bone biopsy was conducted in 11 patients (61.1%) with inflammatory cells infiltration manifested as chronic osteomyelitis, and none showed bacterial infection or tumor. In treatment, non-steroid anti-inflamatory drugs (NSAIDs) is used as the first-line drug followed by steriods, methotexate (MTX), salazosulfadimidine (SASP), Bisphosphonates and TNF-α inhibitor. Two refractory cases received combination therapy with Bisphosphonates and TNF-α inhibitor, and achieved good therapeutic effect. CONCLUSIONS: The present study described a multicenter series of CNO from south China and highlighted the clinical features, laboratory tests, imaging characteristics and treatment outcomes. Increasing awareness of this disease is important to decrease time to diagnosis, improve access to treatment, and reduce complications.