Ends Of Long Bones Research Articles

024. Case Report: Giant Cell Tumor Intravertebra

Background: Giant cell tumor is a rare neoplasm that most frequently occurs at the end of long bones and accounts for approximately 5% of all primary bone tumors in adults. The prevalence of spinal giant cell tumors is estimated at 2%–15% of all spinal giant cell tumors. However, Giant cell tumor is a rare finding in the spine, especially in the pediatric population. Case: A 6-year-old male patient presented with back pain that had spread to both legs for 1.5 years and had worsened in the past 4 months. The pain is intermittent. The patient also felt tingling in the waist and legs, which then turned into a thickening feeling from the waist to the toes since the last 6 months. The patient also complained of weakness in both legs since 1 year ago. Currently the patient is only on bed rest. The patient cannot walk but can still stand with assistance. Defecation and urination remain within normal limits. History of previous trauma (-) Prolonged cough (-), bed wetting (-), headache (-), seizures (-), decreased consciousness (-), progressive weight loss (-), nausea (-) vomiting (-), history of contact with TB sufferers (-). Conclusion: Complete resection of tumor by laminectomy was performed successfully followed by spinal fusion with a pedicle screw. The screws were placed correctly at all four levels of Vertebrae. The decision was made to give stability for spine and it was scheduled to remove the pedicle screw one year follow-up after surgery. Histopathology results showed characteristic findings of giant cell tumor.

Depth-wise multiparametric assessment of articular cartilage layers with single-sided NMR.

Articular cartilage (AC) is a specialized connective tissue that covers the ends of long bones and facilitates the load-bearing of joints. It consists of chondrocytes distributed throughout an extracellular matrix and organized into three zones: superficial, middle, and deep. Nuclear magnetic resonance (NMR) techniques can be used to characterize this layered structure. In this study, devoted to a better understanding of the NMR response of this complex tissue, 20 specimens excised from femoral and tibial cartilage of bovine samples were analyzed by the low-field single-sided NMR-MOUSE-PM10. A multiparametric depth-wise analysis was performed to characterize the laminar structure of AC and investigate the origin of the NMR dependence on depth. The depth dependence of the single parameters T1, T2, and D has been described in literature, but their simultaneous measurement has not been fully exploited yet, as well as the extent of their variability. A novel parameter, α, evaluated by applying a double-quantum-like sequence, has been measured. The significant decrease in T1, T2, and D from the middle to the deep zone is consistent with depth-dependent composition and structure changes of the complex matrix of fibers confining and interacting with water. The α parameter appears to be a robust marker of the layered structure with a well-reproducible monotonic trend across the zones. The discrimination of cartilage zones was reinforced by a multivariate principal component analysis statistical analysis. The large number of samples allowed for the identification of the smallest number of parameters or their combination able to classify samples. The first two components clustered the data according to the different zones, highlighting the sensitivity of the NMR parameters to the structural and compositional variations of AC. Using two parameters, the best result was obtained by considering T1 and α. Single-sided NMR devices, portable and low-cost, provide information on NMR parameters related to tissue composition and structure.

Sustained release of MAPK14-targeting siRNA from polyelectrolyte complex hydrogels mitigates MSC osteogenesis in vitro with potential application in growth plate injury.

The growth plate is a cartilage structure at the end of long bones which mediates growth in children. When fractured, the formation of bony repair tissue known as a "bony bar" can occur and cause limb deformities. There are currently no effective clinical solutions for the prevention of the bony bar formation or regeneration of healthy growth plate cartilage after a fracture. This study employs previously developed alginate/chitosan polyelectrolyte complex (PEC) hydrogels as a sustained release vehicle for the delivery of short-interfering RNA (siRNA). Specifically, the siRNA targets the p38-MAPK pathway in mesenchymal stem cells (MSCs) to prevent their osteogenic differentiation. In vitro experimental findings show sustained release of siRNA from the hydrogels for 6 months. Flow cytometry and confocal imaging indicate that the hydrogels release siRNA to effectively knockdown GFP expression over a sustained period. MAPK-14 targeting siRNA was used to knockdown the expression of MAPK-14 and correspondingly decrease the expression of other osteogenic genes in MSCs in vitro over the span of 21 days. These hydrogels were used in a rat model of growth plate injury to determine whether siMAPK-14 released from the gels could inhibit bony bar formation. No significant reduction of bony bar formation was seen in vivo at the one concentration of siRNA examined. This PEC hydrogel represents a significant advancement for siRNA sustained delivery, and presents an interesting potential therapeutic delivery system for growth plate injuries and other regenerative medicine applications.

Giant Cell Tumor of the Rib: A Report of Two Patients.

Giant cell tumor of the bone is a locally aggressive and rarely metastasizing tumor that typically affects the ends of long bones. Less than 1% of giant cell tumor of bone occur in the ribs. Our patients were a 32-year-old woman and a 45-year-old man and were detected following chest traumas. No bone alterations were detected in radiological studies performed immediately after local trauma. Six- and one- months, respectively, following chest trauma, both giant lytic heterogeneous masses arising on an anterior rib arc were radiologically observed. In the computerized tomography-guided needle biopsy, giant cell tumor of bone were diagnosed. Both tumors were completely removed by bloc resection including the adjacent ribs and posterior reconstruction were performed. One patient was preoperatively treated with denosumab. Neither local recurrences nor metastasis have been detected in follow-up. Despite its low frequency and its low degree of suspicion, giant cell tumor of bone should be included in the differential diagnosis of a rapid growing chest mass.

Biomaterials-Boosted Immunotherapy for Osteosarcoma.

Osteosarcoma (OS) is a primary malignant bone tumor that emanates from mesenchymal cells, commonly found in the epiphyseal end of long bones. The highly recurrent and metastatic nature of OS poses significant challenges to the efficacy of treatment and negatively affects patient prognosis. Currently, available clinical treatment strategies primarily focus on maximizing tumor resection and reducing localized symptoms rather than the complete eradication of malignant tumor cells to achieve ideal outcomes. The biomaterials-boosted immunotherapy for OS is characterized by high effectiveness and a favorable safety profile. This therapeutic approach manipulates the tumor microenvironments at the cellular and molecular levels to impede tumor progression. This review delves into the mechanisms underlying the treatment of OS, emphasizing biomaterials-enhanced tumor immunity. Moreover, it summarizes the immune cell phenotype and tumor microenvironment regulation, along with the ability of immune checkpoint blockade to activate the autoimmune system. Gaining a profound comprehension of biomaterials-boosted OS immunotherapy is imperative to explore more efficacious immunotherapy protocols and treatment options in this setting.

Large-Scale assessment of ChatGPT's performance in benign and malignant bone tumors imaging report diagnosis and its potential for clinical applications

ObjectiveThis study was designed to delve into the complexities involved in diagnosing of benign and malignant bone tumors and to assess the potential of AI technologies like ChatGPT in improving diagnostic accuracy and efficiency. The study also explores the few-shot learning as a method to optimize ChatGPT's performance in specialized medical domains such as benign and malignant bone tumors diagnosis. MethodsA total of 1366 benign and malignant bone tumors-related imaging reports were collected and diagnosed by 25 experienced physicians. The gold standard of diagnosis was established by combining clinical, imaging and pathological principles.These reports were then input into the ChatGPT model which underwent a few-shot learning method to generate diagnostic results. The diagnostic results of the physicians and the AI model were compared to evaluate the performance of ChatGPT. An experiment was conducted to assess the influence of different radiologist's reporting styles on the model's diagnostic performance. Furthermore, in-depth analysis of misdiagnosed cases was carried out, categorizing diagnostic errors and exploring possible causes. ResultsThe diagnostic results generated by ChatGPT showed an accuracy of 0.73, sensitivity of 0.95, and specificity of 0.58. After few-shot learning, ChatGPT demonstrated significant improvement, achieving an accuracy of 0.87, sensitivity of 0.99, and specificity of 0.73, bringing it much closer to the level of physician diagnostics. In an experiment analyzing the influence of the radiologist's reporting style, the model demonstrated higher sensitivity when interpreting reports written by high-level radiologists. In 56 benign cases, ChatGPT misdiagnosed them as malignant. Among these, 35 benign lesions- fibrous dysplasia and osteofibrous dysplasia- were incorrectly identified as metastatic tumors or osteosarcomas; 8 cases of myositis ossificans were wrongly diagnosed as extraosseous osteosarcoma. 7 cases of giant cell tumor of bone at the end of long bone were misdiagnosed as osteosarcoma by intermediate doctors. Chondroblastoma was misdiagnosed as malignant tumor in 6 cases −2 osteosarcoma and 4 chondrosarcoma-In this study, 23 osteosarcoma cases were misdiagnosed by ChatGPT as osteomyelitis; Chondrosarcoma was misdiagnosed as fibrous dysplasia or aneurysmal bone cyst in 8 cases. Four cases of spinal chordoma were misdiagnosed as spinal tuberculosis. ConclusionOur findings highlight the potential of ChatGPT in the diagnosis of benign and malignant bone tumors, offering advantages like enhanced efficiency and a reduction in missed diagnoses. However, the necessity of collaborative interactions between physicians and ChatGPT in practical settings was underscored. With an examination into AI's capacity in benign and malignant bone tumors diagnosis, this study lays the groundwork for future AI advancements in medicine. Additionally, the benefits of few-shot learning in fine-tuning ChatGPT applications in specialized fields were also demonstrated.

CONTROLLING CELL ORGANIZATION IN WAVY ELECTROSPUN SCAFFOLDS FOR THE REGENERATION OF THE ANTERIOR CRUCIATE LIGAMENT

The anterior cruciate ligament (ACL) is the connective tissue located at the end of long bones providing stability to the knee joint. After tear or rupture clinical reconstruction of the tissue remains a challenge due to the particular mechanical properties required for proper functioning of the tissue. The outstanding mechanical properties of the ACL are characterized by a viscoelastic behavior responsible of the dissipation of the loads that are transmitted to the bone. These mechanical properties are the result of a very specialized graded extracellular matrix that transitions smoothly between the heterotypic cells, stiffness and composition of the ACL and the adjacent bone. Thus, mimicking the zonal biochemical composition, cellular phenotype and organization are key to reset the proper functioning of the ACL.We have previously shown how the biochemical composition presented to cells in electrospun scaffolds results in haptokinesis, reverting contact-guidance effects.[1] Here, we demonstrate that contact guidance can also be disrupted by structural parameters in aligned wavy scaffolds. The presentation of a wavy fiber arrangement affected the cell organization and the deposition of a specific ECM characteristic of fibrocartilage. Cells cultured in wavy scaffolds grew in aggregates, deposited an abundant ECM rich in fibronectin and collagen II, and expressed higher amounts of collagen II, X and tenomodulin as compared to aligned scaffolds. In-vivo implantation in rabbits of triphasic scaffolds accounting for aligned-wavy-aligned zones showed a high cellular infiltration and the formation of an oriented ECM, as compared to traditional aligned scaffolds.[2]

An Unusual Giant Osteochondroma of Distal Tibia: A Case Report with Literature Review

Introduction: Benign bone tumors like osteochondroma are common during skeletal maturity occurring usually at the ends of long bones, such as the distal femur, proximal humerus, and proximal tibia. The tumor can occur in sessile or pedunculated forms. Mass lesions occurring around the ankle can lead to chronic pain, pathological fractures, progressive erosion, and scalloping of adjacent bone. This report highlights a case of a progressively enlarging bony swelling around the distal tibia with uncommon radiological and histological presentation managed with en bloc excision. Case Report: A 30-year-old male with 3 years of progressive bony enlargement without any history of significant trauma presented to our tertiary care hospital. The radiological and histological investigations were performed and many varied differentials were proposed. The lesion was provisionally diagnosed to be a case of an uncommon form of osteochondroma and en bloc excision was done. The patient followed up for a period of 6 months and the patient had uneventful recovery with no recurrence. Conclusion: Osteochondromas in the distal tibia are infrequent occurrences among common skeletal tumors. Timely surgical intervention is recommended for symptomatic lesions or those causing compression or mass effects. Keywords: Osteochondroma, distal tibia, benign, tumor, fibular deformation, bizarre parosteal osteochondramatous proliferation.

High-Grade Chondrosarcoma of Nasal Septum-A Rare Case Report and Review of Literature

Chondrosarcoma of the nasal septum is a rare malignancy. Since 1927 to date, 69 cases of chondrosarcoma of nasal septum have been reported. In addition to the 70th case, we reported here. Mostly chondrosarcoma is present on the ends of long bones and 5-10% in the head-neck region. In our case, 50 years old female presented a bilateral nasal obstruction, and a biopsy was sent for nasal mass. Histomorphology suggested high-grade chondrosarcoma, which is positive for S-100 immunohistochemistry. Early intervention through radiology and biopsy will manage the patient with chondrosarcoma.

Failure in articular cartilage: Finite element predictions of stress, strain, and pressure under micro-indentation induced fracture

Articular cartilage is found at the distal end of long bones and is responsible for assisting in joint articulation. While articular cartilage has remarkable resistance to failure, once initially damaged, degeneration is nearly irreversible. Thus, understanding damage initiation is important. There are a few proposed mechanisms for articular cartilage failure initiation: (A) a single collagen fibril stress-based regime; (B) a rate-dependent regime captured by brittle failure at slow displacement rates (SDR) and ductile failure at fast displacement rates (FDR); and (C) a rate-dependent regime where failure is governed by pressurization fragmentation at SDR and governed by strain at FDR. The objective of this study was to use finite element (FE) models to provide evidence to support or refute these proposed failure mechanisms. Models were developed of microfracture experiments that investigated osmolarity (hypo-osmolar, normal osmolarity, and hyper-osmolar) and displacement rate (FDR and SDR) effects. Cartilage was modeled with a neo-Hookean ground matrix, strain-dependent permeability, nonlinear fibril reinforcement with viscoelastic fibril terms, and Donnan equilibrium swelling. Total stress, solid matrix stress, Lagrange strain, and fluid pressure were determined under the indenter tip at the moment of microfracture. Results indicated significant rate dependence across multiple outputs, which does not support (A) a single failure regime. Larger solid and fluid pressures at FDR than SDR did not support (C) a rate-dependent regime split by pressurization at SDR and strain at FDR. Consistent solid shear stresses at SDR and consistent third principal solid stresses at FDR support (B) the ductile-brittle failure regime. These findings help to shed light on the underlying mechanisms of articular cartilage failure, which have implications for the development of osteoarthritis.

Robust hyperparameter tuned deep Elman neural network for the diagnosis of osteosarcoma on histology images

Osteosarcomas are a type of bone tumour that can develop anywhere in the bone but most typically do so around the metaphyseal growth plates at the ends of long bones. Death rates can be lowered by early detection. Manual osteosarcoma identification can be difficult and requires specialised knowledge. With the aid of contemporary technology, medical photographs may now be automatically analysed and categorised, enabling quicker and more effective data processing. This paper proposes a novel hyperparameter-tuned deep learning (DL) approach for predicting osteosarcoma on histology images with effective feature selection mechanism which aims to improve the prediction accuracy of the classification system for bone tumor detection. The proposed system mainly consists of ‘6’ phases: data collection, preprocessing, segmentation, feature extraction, feature selection, and classification. Firstly, the dataset of histology images is gathered from openly available sources. Then Median Filtering (MEF) is utilized as the preprocessing step that enhances the quality of the input images for accurate prediction by eliminating unwanted information from them. Afterwards, the pre-processed image was segmented using Harmonic Mean-based Otsu Thresholding (HMOTH) approach to obtain the tumor-affected regions from the pre-processed data. Then the features from the segmented tumor portions are extracted using the Self-Attention Mechanism-based MobileNet (SAMMNet) model. A Van der Corput sequence and Adaptive Inertia Weight included Reptile Search Optimization Algorithm (VARSOA) is used to select the more relevant features from the extracted features. Finally, a Hyperparameter-Tuned Deep Elman Neural Network (HTDENN) is utilized to diagnose and classify osteosarcoma, in which the hyperparameters of the neural network are obtained optimally using the VARSOA. The proposed HTDENN attains the higher accuracy of 0.9531 for the maximum of 200 epochs, whereas the existing DENN, MLP, RF, and SVM attains the accuracies of 0.9492, 0.9427, 0.9413, and 0.9387. Likewise, the proposed model attains the better results for precision (0.9511), f-measure (0.9423), sensitivity (0.9345) and specificity (0.9711) than the existing approaches for the maximum of 200 epochs. Simulation outcomes proved that the proposed model outperforms existing research frameworks for osteosarcoma prediction and classification.

Dual medial and anterior approach for excision of extraosseous synovial hip osteochondroma: a case report

BackgroundOsteochondromas are the most common benign bone tumors occurring near the end of long bones. In this case report, we demonstrate the successful treatment of a proximal femoral osteochondroma in a pediatric patient excised through a dual medial and anterior approach with no hip dislocation.Case presentationWe present the case of a white Arab 14-year-old boy with chronic hip pain and inability to ambulate. He failed conservative treatment and was referred to us after X-rays revealed two osseous masses. He was diagnosed with an intra-articular hip osteochondroma confirmed on magnetic resonance imaging and computed tomography scan. He was treated surgically with excision using two incisions: Smith-Petersen approach and Ferguson approach.ConclusionThis case presents the successful resection of a symptomatic pediatric proximal femoral osteochondroma, using dual medial and anterior approaches without the need for hip dislocation. This was optimal for both the safety and accessibility of this unusual condition.

Intra-articular injection of epigallocatechin (EGCG) crosslinks and alters biomechanical properties of articular cartilage, a study via nanoindentation.

Osteoarthritis and rheumatoid arthritis are debilitating conditions, affecting millions of people. Both osteoarthritis and rheumatoid arthritis degrade the articular cartilage (AC) at the ends of long bones, resulting in weakened tissue prone to further damage. This degradation impairs the cartilage’s mechanical properties leading to areas of thinned cartilage and exposed bone which compromises the integrity of the joint. No preventative measures exist for joint destruction. Discovering a way to slow the degradation of AC or prevent it would slow the painful progression of the disease, allowing millions to live pain-free. Recently, that the articular injection of the polyphenol epigallocatechin-gallate (EGCG) slows AC damage in an arthritis rat model. It was suggested that EGCG crosslinks AC and makes it resistant to degradation. However, direct evidence that intraarticular injection of EGCG crosslinks cartilage collagen and changes its compressive properties are not known. The aim of this study was to investigate the effects of intraarticular injection of EGCG induced biomechanical properties of AC. We hypothesize that in vivo exposure EGCG will bind and crosslink to AC collagen and alter its biomechanical properties. We developed a technique of nano-indentation to investigate articular cartilage properties by measuring cartilage compressive properties and quantifying differences due to EGCG exposure. In this study, the rat knee joint was subjected to a series of intraarticular injections of EGCG and contralateral knee joint was injected with saline. After the injections animals were sacrificed, and the knees were removed and tested in an anatomically relevant model of nanoindentation. All mechanical data was normalized to the measurements in the contralateral knee to better compare data between the animals. The data demonstrated significant increases for reduced elastic modulus (57.5%), hardness (83.2%), and stiffness (17.6%) in cartilage treated with injections of EGCG normalized to those treated with just saline solution when compared to baseline subjects without injections, with a significance level of alpha = 0.05. This data provides evidence that EGCG treated cartilage yields a strengthened cartilage matrix as compared to AC from the saline injected knees. These findings are significant because the increase in cartilage biomechanics will translate into resistance to degradation in arthritis. Furthermore, the data suggest for the first time that it is possible to strengthen the articular cartilage by intraarticular injections of polyphenols. Although this data is preliminary, it suggests that clinical applications of EGCG treated cartilage could yield strengthened tissue with the potential to resist or compensate for matrix degradation caused by arthritis.

Postcranial description of Wendiceratops pinhornensis and a taphonomic analysis of the oldest monodominant ceratopsid bonebed.

The early centrosaurine ceratopsid, Wendiceratops pinhornensis, was discovered in Alberta, Canada in a medium density monodominant bonebed from the Oldman Formation (mid-Campanian, ~79 Ma). The bonebed contains abundant, well-preserved, adult-sized and some juvenile-sized postcranial material, allowing for the first description of a number of elements of the postcrania of this basal centrosaurine ceratopsid. The postcranial elements described are generally consistent with postcrania described for more derived centrosaurine taxa. However the rectangular-shaped distal terminus of the ischium previously considered to be an apomorphy of Wendiceratops. is shown to also be present in Medusaceratops, and thus may be a synapomorphy of basal centrsaurines. The bonebed represents a lag deposit within a mudstone-bearing overbank facies and contains individuals from multiple age classes. It contains over 95% ceratopsid remains, with all identifiable elements referable to Wendiceratops. The elements are completely disarticulated, but have undergone little weathering or abrasion (both Stage 0), although the ends of long bones and processes capped by cartilage in life frequently exhibit evidence of wet rot and breakage by hydrological reworking after decomposition. The taphonomy of the bonebed is consist with other monodominant centrosaurine bonebeds that have been interpreted as mass death assemblages preserving evidence of gregarious (herding) behavior. At approximately 79 million years old, the Wendiceratops bonebed is approximately two million years older than other ceratopsid bonebeds indicating that this bonebed is the oldest documented evidence of herding behavior in a ceratopsid.

Outcomes in Bone Giant Cell Tumors Treated With Surgical Resection With and Without Denosumab Injection: A Single-Institution Retrospective Study.

Background: Giant cell tumors of the bone (GCTB) are rare, benign, aggressive, recurrent tumors that are most often found at the ends of long bones. They account for 5% of all primary bone tumors and 20% of all benign bone tumors. The clinical features of GCTB include local swelling, pain, and limitations in joint movement. Approximately half of GCTB arise around the knee joint, affecting either the distal femur or proximal tibia. Tissue biopsy reveals an excess of multinucleated giant cells on a stromal cell background, indicating a diagnosis. Intralesional curettage is used to treat GCTB and is associated with minimal disability; however, local recurrence may occur in many patients. Resection and endoprosthetic repair or bone graft reconstruction are often used to treat GCTB near the joint. To our knowledge, there are currently no studies on this topic in the city of Jeddah, where we conducted our study. Our aim was to evaluate the outcome of surgical resection accompanied by denosumab injection compared to that of surgery alone in treating GCTB.Methods: All cases of GCTB at King Abdulaziz Medical City, Jeddah, between January 2008 and December 2018, that fulfilled the inclusion and exclusion criteria were included. All cases of GCTB in the pre-specified period were classified as surgical resection with denosumab injection or surgical resection alone. The outcomes of the two modalities were compared. Recurrence was investigated in patients belonging to both the groups.Results: Twenty-six cases that met the inclusion criteria were included in the study and the data were analyzed. The subjects were divided into two groups: denosumab and surgery (n = 7) and surgery alone (n = 19). Patients treated with denosumab and surgery had a higher recurrence rate (57%); however, the difference was not significant (p = 0.407).Conclusion: Our study showed that when comparing local recurrence after curettage in patients treated with denosumab and patients who did not receive it, preoperative denosumab therapy was associated with an increased incidence of local recurrence. We recommend a systematic review that can include more studies in this field to acquire more definitive results regarding this topic.

Aggressive giant cell tumour of the talus: a rare case report and challenges faced during its management

<p>Giant cell tumour (GCT) of the bone is a locally aggressive benign tumour that commonly occurs in the epiphyseal ends of long bones. Its occurrence in the small bones of the foot like the talus is rare. In this case report we described a case of aggressive GCT of the talus (Campanacci grade 3) in a twenty-one years old male diagnosed by the presence of a well-defined osteolytic lesion seen involving the talar body with cortical breach and soft tissue extension confirmed to be a GCT by closed needle biopsy. The patient was managed surgically by excision of the tumour mass in-toto along with the talus followed by tibio-calcaneal fusion using free fibular strut graft and Ilizarov frame. At 3 months follow up no evidence of fusion was seen and therefore secondary augmentation with a cortico-cancellous graft from the iliac crest was done to aid fusion and Ilizarov fixator was removed 6 months after the surgery. The patient at one year follow up had shown no signs of recurrence of the tumour and has a pain free, stable fused tibiocalcaneal joint with a bipedal unassisted gait. Our case report found excision of talus combined with tibio-calcaneal fusion using free fibular strut graft along with cortico cancellous iliac bone graft to have a good outcome in terms of aiding tibio-calcaneal arthrodesis and thereby providing pain relief and providing a stable foot to the patient.</p>

Abstract 932: Conditional p53 loss in chondrocytes leads to osteosarcoma in mice

Abstract Osteosarcoma (OS) is the most common primary malignant bone tumor in children and young adults. Lack of a basic understanding of OS etiology, and lack of a sensitive method to detect pulmonary micro-metastases are major obstacles impeding meaningful therapeutic advancement. Here we report the generation of genetically engineered lineage-tracing mouse OS models, in which p53 expressions were conditionally deleted or mutated in chondrocytes, indicating that OS can originate from chondrocyte-derived osteoblastic-lineage cells. OS incidence peaks during puberty when rapid bone growth occurs. Longitudinal bone growth is achieved through endochondral ossification, a process sustained by growth plates - cartilage discs at the ends of long bones. As bone lengthening, growth plate chondrocytes go through proliferation, differentiation, and maturation in sequential steps to provide a continuous supply of cartilage scaffolds for ossification. Besides, mature chondrocytes residing at chondral-osteo junctions, are themselves an innate source of osteoblasts directly participating in bone formation. Not only there is a close link between OS incidence and growth plate activity, primary OS is most frequently localized at the growing ends of long bones, such as at proximal tibia, distal femurs, and proximal humerus. Given these associations, we hypothesize that mice harboring p53 deletion initiated in mature chondrocytes may develop osteosarcoma, and if so chondrocytes to osteoblasts transformation may be a vulnerable process to genome instability triggers. We generated various chondrocyte-Cre driven lineage-tracing reporter mouse models, in which either Col10a1-Cre or Acn-CreERT2 were Cre drivers to induce p53 deleted, R245W hot spot, and p53 deleted/Rbhet alleles. To date Col10a1-Cre/p53fxfx/Rosa-tomato (Xp53KO) mice developed osteosarcoma with 100% penetrance (n=32). The mean latency in days is 273.3 ± 60.5 (195-330), in a similar range of Osx-cre/p53fxfx mice by CR Walkley, etc. The OS from Xp53KO mice histologically resemble human OS and possessed osteogenic and adipogenic differentiation capacities in vitro. Most notably, the Xp53KO mice developed OS in long bones and spines, no cranium-facial OS was detected. Regarding OS distributions, our Xp53KO OS mice show the closest resemblance to that of humans, compared to previous genetically engineered mouse OS models. Additionally, the transplanted OS from Xp53KO mice showed good response to cyclophosphamide treatment (n=7, 15mg/kg), but not to topotecan (n=7, 0.6mg/kg), vincristine (n=7, 1mg/kg) and rapamycin (n=7, 5mg/kg) treatments, analogous to human OS. With reporter (tomato) expressions, we can trace and isolate the OS ancestry cells from the onsets of deletions to osteosarcoma genesis at any stages, as well as mutant cells in distant sites. Our OS models may unveil critical insights into the development of OS as well as its dissemination. Citation Format: Xin Zhou, Zhaohui Xu, Yizheng Tu, Zhongting Zhang, Richard Gorlick. Conditional p53 loss in chondrocytes leads to osteosarcoma in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 932.

Differential regulation of IGF‐1 pathway and accelerated bone elongation in pre‐obese juvenile mice

INTRODUCTIONChildhood obesity is driven, in large part, by increased dietary fat intake. Accelerated bone growth, a hallmark of juvenile obesity but one of its most overlooked complications, can lead to irreversible skeletal damage and chronic adult disability. Paradoxically, obese children typically have low to normal circulating levels of the growth promoting hormone insulin‐like growth factor‐1 (IGF‐1), despite their accelerated growth rate. However, IGF‐1 is both an endocrine and paracrine hormone that is essential for endochondral ossification, the process by which bones lengthen in cartilaginous growth plates at the ends of long bones. We previously reported that pre‐obese juvenile mice on a high‐fat diet have increased cell proliferation in growth plates without changes in serum IGF‐1, and before significant changes in body mass were evident. Our goal was to determine whether a high‐fat diet alters local IGF‐1 activity in growth plates by using gene set enrichment analysis on RNA sequencing (RNA‐Seq) data. We tested theHYPOTHESISthat juvenile mice on a high‐fat diet will exhibit an upregulation of IGF‐1 pathways in the growth plate.METHODSMale and female 3‐week old C57BL/6 mice were weaned on to high‐fat diet (60% kCal of fat) or control diets (10% kCal of fat) for 2 weeks and examined at 5‐weeks age when bones are elongating faster in high‐fat diet mice. We developed and validated a manual dissection technique to isolate proximal tibial growth plates from surrounding bone for RNA and protein analyses on cartilage. RNA was isolated from pooled left and right tibial growth plates and sent to the Marshall Genomics Core for next generation sequencing using an Illumina NextSeq 2000 Sequencer. Data were analyzed using fast gene set enrichment analysis (version 1.20.0) along with the reactome pathway database (version 78). Enrichment scores were calculated based on the degree to which genes in a given pathway were up‐ or down‐regulated in the RNA‐Seq data set. These scores are then normalized to account for the different number of genes involved in each pathway set and compared between diets.RESULTSOur data show that pathways regulating IGF‐1 transport and uptake by insulin‐like growth factor binding proteins (IGFBPs) were upregulated in mice on a high‐fat diet with a normalized enrichment score (NES) of 2.17 (Benjamini‐Hochberg adjusted p‐value<0.01). Components of this pathway included, among others, individual IGFBPs (Igfbp4 and Igfbp5) and an IGFBP protease inhibitor (Stc2).DISCUSSIONSignificant changes in the IGF‐1 pathway closely followed those involved in cell metabolism and muscle contraction, suggesting that regulating IGF‐1 activity could be a main driver of diet‐induced growth acceleration. These data are consistent with our hypothesis that a high‐fat diet increases local IGF‐1 activity in growth plates even though systemic IGF‐1 remains unchanged.SIGNIFICANCEThese data are relevant for understanding mechanisms of diet‐induced growth acceleration and provide important groundwork for subsequent efforts to identify specific components of the IGF‐1 pathway that could underlie rapid skeletal growth in juvenile obesity.

Gunshot trauma in human long bones: towards practical diagnostic guidance for forensic anthropologists.

In contrast to cranial gunshot trauma, diagnosis and interpretation of gunshot trauma to long bones remains difficult and controversial. The aim of this study is to review the published literature on fracture patterns resulting from gunshot trauma in human long bones, and to use the described characteristics to provide practical guidance for the forensic anthropologist. In order to achieve this, medical and forensic publications on this topic were reviewed. Several types of fractures, such as linear, oblique, comminuted and butterfly fractures, have been observed in either the shaft or the ends of long bones. Indirect fractures that are not caused by bullets striking bone directly but by bullet-induced forces to the surrounding soft tissue have been found as well. Some of these fractures are related to a specific context or mechanism which might help in the forensic reconstruction of events. It is recommended that future research should focus on available medical data to provide more detailed descriptions on fracture patterns for forensic purposes. Experimentation with bone surrogates and computer modelling might also provide better and more realistic reconstructions of gunshot trauma in the future and provide valuable insights for its diagnosis and interpretation in forensic anthropology.

La tumeur à cellules géantes des os en 2022

Giant cell tumors of bone (GCTs) are rare mesenchymal tumors classified as intermediate in the WHO 2020 classification, i.e. neither completely benign nor definitely malignant, due to recurrence (frequent) and pulmonary metastases (rare). They involve the end of long bones as well as the axial bones of mature skeletons. They are made of mononuclear stromal tumor cells of (pre-) osteoblastic phenotype, mononuclear cells of the monocyte-macrophage lineage and osteoclast-like multinuclear giant cells responsible for tumor osteolysis. In 95% of cases, the stromal cells have a specific mutation in the H3F3A gene which encodes histone H3.3. The mutated H3.3 G34W protein (90% of cases) can be easily detected by immunohistochemistry, even on small samples. Many tumors or bone pseudotumors contain osteoclast-like giant cells, cells of the bone microenvironment, and should not be confused with GCT: mainly brown tumor of hyperparathyroidism, aneurysmal bone cyst, chondroblastoma, non-ossifying fibroma and central giant cell granuloma.