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End-stage ankle osteoarthritis causes severe pain and disability. There are no randomized trials comparing the 2 main surgical treatments: total ankle replacement (TAR) and ankle fusion (AF).To determine which treatment is superior in terms of clinical scores and adverse events.A multicenter, parallel-group, open-label randomized trial. (ISRCTN registry number: 60672307).17 National Health Service trusts across the United Kingdom.Patients with end-stage ankle osteoarthritis, aged 50 to 85 years, and suitable for either procedure.Patients were randomly assigned to TAR or AF surgical treatment.The primary outcome was change in Manchester-Oxford Foot Questionnaire walking/standing (MOXFQ-W/S) domain scores between baseline and 52 weeks after surgery. No blinding was possible.Between 6 March 2015 and 10 January 2019, a total of 303 patients were randomly assigned; mean age was 68 years, and 71% were men. Twenty-one patients withdrew before surgery, and 281 clinical scores were analyzed. At 52 weeks, the mean MOXFQ-W/S scores improved for both groups. The adjusted difference in the change in MOXFQ-W/S scores from baseline was -5.6 (95% CI, -12.5 to 1.4), showing that TAR improved more than AF, but the difference was not considered clinically or statistically significant. The number of adverse events was similar between groups (109 vs. 104), but there were more wound healing issues in the TAR group and more thromboembolic events and nonunion in the AF group. The symptomatic nonunion rate for AF was 7%. A post hoc analysis suggested superiority of fixed-bearing TAR over AF (-11.1 [CI, -19.3 to -2.9]).Only 52-week data; pragmatic design creates heterogeneity of implants and surgical techniques.Both TAR and AF improve MOXFQ-W/S and had similar clinical scores and number of harms. Total ankle replacement had greater wound healing complications and nerve injuries, whereas AF had greater thromboembolism and nonunion, with a symptomatic nonunion rate of 7%.National Institute for Health and Care Research Heath Technology Assessment Programme.

Oncohistones represent compelling evidence for a causative role of epigenetic perturbations in cancer. Giant cell tumours of bone (GCTs) are characterised by a mutated histone H3.3 as the sole genetic driver present in bone-forming osteoprogenitor cells but absent from abnormally large bone-resorbing osteoclasts which represent the hallmark of these neoplasms. While these striking features imply a pathogenic interaction between mesenchymal and myelomonocytic lineages during GCT development, the underlying mechanisms remain unknown. We show that the changes in the transcriptome and epigenome in the mesenchymal cells caused by the H3.3-G34W mutation contribute to increase osteoclast recruitment in part via reduced expression of the TGFβ-like soluble factor, SCUBE3. Transcriptional changes in SCUBE3 are associated with altered histone marks and H3.3G34W enrichment at its enhancer regions. In turn, osteoclasts secrete unregulated amounts of SEMA4D which enhances proliferation of mutated osteoprogenitors arresting their maturation. These findings provide a mechanism by which GCTs undergo differentiation in response to denosumab, a drug that depletes the tumour of osteoclasts. In contrast, hTERT alterations, commonly found in malignant GCT, result in the histone-mutated neoplastic cells being independent of osteoclasts for their proliferation, predicting unresponsiveness to denosumab. We provide a mechanism for the initiation of GCT, the basis of which is dysfunctional cross-talk between bone-forming and bone-resorbing cells. The findings highlight the role of tumour/microenvironment bidirectional interactions in tumorigenesis and how this is exploited in the treatment of GCT.

The Government of Western Australia, through the Geological Survey of Western Australia, is funding a passive seismic acquisition program, WA array, which has been designed to map Earth’s lithosphere at an optimal level of station spacing across the state of WA (over 2.5 million square kilometres).The program, which started on 1 July 2022 will involve the deployment of an “array” of 165 seismometers arranged in a grid pattern spaced at 40 kilometre intervals, moving progressively across the state over a period of ten years. Instruments will be relocated on an annual basis across nine regional areas.It is primarily designed to investigate the crustal and lithospheric mantle structure with the aim of identifying prospective regions for mineral exploration, especially in areas undercover. At the continental scale, the large lithospheric models will target the bulk lithospheric velocities and upper mantle discontinuities, which will provide direct information to better constrain tectonic deformation processes that operated through time. From the Archean nuclei to the Phanerozoic passive margins, WA is composed of many domains with a rich tectonic history; thus WA array will also provide an unprecedented opportunity to study lithospheric structure related to early Earth tectonics, Earth evolution and the Earth today.The results of the program will step change in our understanding of Western Australia’s lithospheric architecture. This knowledge will provide a sound scientific basis for mineral and energy exploration, but also for evaluating crucial land use decisions over the coming decades, at a time when large areas of the State are expected to accommodate renewable energy projects.In addition, the data will be used to evaluate the risks from seismic events, which would contribute to risk assessments for the placement industrial infrastructure such as pipelines and hydrogen generation and storage installations as well as building codes for housing and other buildings.The first deployment of stations is now in the ground with 158 stations currently running. The first results and raw data will become available at the end of 2024. We will present and discuss the design of the array, initial modelling status and model updates, and related program applications.

Benign bone-forming tumors comprise osteomas, osteoid osteomas, and osteoblastomas. Osteomas affect a wide age range and are usually discovered incidentally. They occur predominantly in the craniofacial skeleton and are classically composed of compact bone. Osteoid osteomas and osteoblastomas are painful lesions occurring in young patients. They are morphologically similar and characterized by FOS gene rearrangement and c-FOS expression at a protein level. Osteoid osteomas are usually smaller than 2 cm in maximum dimension with limited growth potential; osteoblastomas are larger than 2 cm and may be locally aggressive. Histologically both are composed of anastomosing trabeculae of woven bone.

This review provides an overview of the spectrum of tumors showing notochordal differentiation. This spectrum encompasses benign entities that are mostly discovered incidentally on imaging, reported as benign notochordal cell tumor, usually not requiring surgical intervention; slowly growing and histologically low-grade tumors referred to as conventional chordoma but associated with a significant metastatic potential and mortality; and more aggressive disease represented by histologically higher-grade tumors including dedifferentiated chordoma, a high-grade biphasic tumor characterized by a conventional chordoma juxtaposed to a high-grade sarcoma, usually with a spindle or pleomorphic cell morphology, and associated with a poor prognosis and poorly differentiated chordoma.

We evaluated long-term outcome in 40 patients with MDS or AML, transplanted from related or unrelated donors following conditioning with targeted busulfan (Bu, over 4 days), fludarabine (Flu, 120 [n=23] or 250 [n=17] mg/m(2)) and thymoglobulin (THY). Compared to 95 patients conditioned with Bu/Cyclophosphamide (Cy) without THY, BuFluTHY-conditioned patients had lower rates of chronic graft-vs.-host disease (GVHD). Adjusted hazard ratios (HR) for BuFlu(120)THY and BuFlu(250)THY-conditioned patients were 1.60 (95% confidence interval (CI) 0.66 to 3.86) and 1.87 (0.68 to 5.11), respectively, for relapse; 0.77 (0.30 to 1.99) and 1.32 (0.54 to 3.23) for non-relapse mortality; 0.81 (0.42 to 1.57) and 1.38 (0.72 to 2.57) for overall mortality; and 0.78 (0.30 to 2.05) and 1.62 (0.63 to 4.41) for relapse or death (failure for relapse-free survival). At one year, 45% of BuFlu(120 or 250)THY conditioned patients had mixed CD3+ chimerism compared to 0% with BuCy (p

Chondrosarcoma (CS) is a rare tumour type and the most common primary malignant bone cancer in adults. The prognosis, currently based on tumour grade, imaging and anatomical location, is not reliable, and more objective biomarkers are required. We aimed to determine whether the level of circulating tumour DNA (ctDNA) in the blood of CS patients could be used to predict outcome. In this multi‐institutional study, we recruited 145 patients with cartilaginous tumours, of which 41 were excluded. ctDNA levels were assessed in 83 of the remaining 104 patients, whose tumours harboured a hotspot mutation in IDH1/2 or GNAS. ctDNA was detected pre‐operatively in 31/83 (37%) and in 12/31 (39%) patients postoperatively. We found that detection of ctDNA was more accurate than pathology for identification of high‐grade tumours and was associated with a poor prognosis; ctDNA was never associated with CS grade 1/atypical cartilaginous tumours (ACT) in the long bones, in neoplasms sited in the small bones of the hands and feet or in tumours measuring less than 80 mm. Although the results are promising, they are based on a small number of patients, and therefore, introduction of this blood test into clinical practice as a complementary assay to current standard‐of‐care protocols would allow the assay to be assessed more stringently and developed for a more personalised approach for the treatment of patients with CS., In this multi‐institutional study, we detected the amount of circulating tumour DNA (ctDNA) in the blood of patients with chondrosarcoma. We recruited 145 patients, and ctDNA levels were assessed in patients with tumours carrying IDH1/2 or GNAS mutations. We found that ctDNA levels offered a more accurate identification of high‐grade tumours than pathology and were additionally associated with poor prognosis.

Extra-skeletal osteosarcoma is a rare malignant soft tissue sarcoma which can cause a diagnostic challenge due to its non-specific presentation and soft tissue mineralisation, thus potentially mimicking conditions such as myositis ossificans. This review will outline the demographics, clinical presentation, key imaging features, differential diagnosis, management and outcomes of extra-skeletal osteosarcoma and serve as a reference to radiologists and other clinicians involved in the care of patients with soft tissue tumours and tumour-like lesions.

To identify magnetic resonance imaging (MRI) features which aid differentiation of low-grade chondral tumours (LGCT-enchondroma and grade 1 chondrosarcoma) from high-grade chondral tumours (HGCT) in patients with enchondromatosis. Approval from our local Research and Innovation Centre of The Institute of Orthopaedics was gained. Patients with enchondromatosis who had biopsy and/or resection of chondral lesions over a 13-year period were identified. The pre-biopsy MRI study was assessed by two experienced musculoskeletal radiologists for tumour origin (intramedullary or surface), cortical expansion, cortical destruction, bone marrow oedema, periosteal reaction, soft tissue mass and soft tissue oedema. MRI features were compared with the final histopathological diagnosis. The study group comprised 25 males and 16 females, with a mean age of 34.9 years (range 6–81 years). Fifty-nine lesions were assessed (12 patients had > 1 tumour treated), including 43 LGCT and 16 HGCT. Significant MRI features suggesting malignant transformation to HGCT for both observers included bone oedema (p = < 0.001 and 0.002), periosteal reaction (p = 0.01) and soft tissue oedema (p = 0.001 and 0.05). Cortical destruction and soft tissue mass were predictors of HGCT in major long bones, but no significant differentiating features were identified in the hands and feet. The presence of bone oedema, periosteal reaction and soft tissue oedema on MRI may indicate a high-grade malignant transformation of chondral tumours in patients with enchondromatosis.

Results of two parallel phase II trials of transplantation of unrelated umbilical cord blood or bone marrow from HLA-haploidentical relatives provided equipoise for direct comparison of these donor sources. Between June 2012 and June 2018, 368 patients aged 18-70 years with chemotherapy-sensitive lymphoma or acute leukemia in remission were randomly assigned to undergo cord blood (n=186) or haploidentical (n=182) transplant. Reduced intensity conditioning comprised total body irradiation with cyclophosphamide and fludarabine for both donor types. Graft-versus-host disease prophylaxis for cord blood transplantation was cyclosporine and mycophenolate mofetil and for haploidentical transplantation, post-transplant cyclophosphamide, tacrolimus and mycophenolate mofetil. The primary endpoint was 2-year progression-free survival. Treatment groups had similar age, sex, self-reported ethnic origin, performance status, disease and disease status at randomization. Two-year progression-free survival was 35% (95% CI, 28-42%) compared to 41% (95% CI, 34-48%) after cord blood and haploidentical transplants, respectively (p=0.41). Pre-specified analysis of secondary endpoints recorded higher 2-year non-relapse mortality after cord blood, 18% (95% CI, 13-24%) compared to haploidentical transplantation, 11% (95% CI, 6-16%), p=0.04. This led to lower 2-year overall survival after cord blood compared to haploidentical transplantation, 46% (95% CI, 38-53) and 57% (95% CI 49-64%), respectively (p=0.04). The trial did not demonstrate a statistically significant difference in the primary endpoint, 2-year progression-free survival, between the donor sources. While both donor sources extend access to reduced intensity transplantation, analyses of secondary endpoints, including overall survival, favor haploidentical bone marrow donors. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute; ClinicalTrials.gov number, NCT01597778).

Objective: To determine the additional benefit of MRI for children with flatfoot deformity assessed with weight-bearing radiographs in a specialist paediatric orthopaedic unit. Methods and materials: Patient cohort was obtained by searching the Radiology Information System for children referred for investigation of flatfoot. All patients with flatfoot on weight-bearing radiographs who had undergone MRI were included. Radiographs were classified by a consultant musculoskeletal radiologist as showing no underlying abnormality, talo-calcaneal coalition, calcaneonavicular coalition, accessory navicular or other abnormality. MRI studies were classified similarly by a different consultant musculoskeletal radiologist blinded to the radiographic findings. Results: 33 males and 24 females were included (mean age 12.5 years; range 3–18 years). 24 had bilateral abnormality, so 81 feet were assessed. Radiographs showed no specific abnormality (n = 51), talocalcaneal coalition (n = 6), calcaneonavicular coalition (n = 3), os naviculare (n = 12) or other abnormality (n = 9). MRI showed no specific abnormality (n = 40), talocalcaneal coalition (n = 10), calcaneonavicular coalition (n = 5), os naviculare (n = 12) or other abnormality (n = 14). Assuming MRI as the diagnostic gold-standard, additional relevant diagnostic information was identified in 19 (23.5%) cases, while in the 51 cases for which radiographs provided no specific diagnosis MRI confirmed no underlying abnormality in 31 (60.8%). Conclusion: MRI is a valuable adjunct to weight-bearing radiography for investigating paediatric flatfoot deformity. Advances in knowledge: MRI is of value in the assessment of paediatric flatfoot, additional diagnostic information to radiography being identified in 23.5% cases, while in 60.8% of cases for which radiographs provided no specific diagnosis MRI confirmed no underlying abnormality.

Objective: To determine the differential diagnosis of bone lesions causing hip pain in children and the association between radiographic features of aggression and MRI appearances with final diagnosis. Methods: Retrospective review of children with hip pain referred to a specialist musculoskeletal oncology service between September 2018 and December 2020. Patient demographics, lesion location, the radiographic and MRI features, and the final diagnosis, which was made either by image-guided biopsy, surgical curettage or based on typical imaging features were recorded. Statistical analysis examined the association between the Lodwick-Madewell score (determined from available radiographs) and MRI findings with final diagnosis. Results: Fifty-nine patients were included, 40 males and 19 females with mean age 10.9 years, (range 3–16 years). Final diagnoses were based on histology in 24 (40.7%) cases and imaging in 35 (59.3%) cases. Eighteen lesions (30.5%) were classed as non-neoplastic, 31 (52.5%) as benign and 10 (16.9%) as malignant, of which four were primary bone sarcomas. There was a significant association between the Lodwick-Madewell score and final diagnosis (p < 0.001). On MRI, bone marrow oedema, presence of a focal lesion, bone expansion and the presence of an extraosseous mass were all significantly associated with final diagnostic classification. Conclusion: The differential diagnosis of hip pain in children presenting to a bone tumour service is wide. Most cases are due to benign or non-neoplastic conditions, with only 10 out of 59 children having a malignant lesion. Radiography complemented by MRI plays a major role in differentiating non-neoplastic, benign neoplastic and malignant lesions and in determining the requirement for needle biopsy. Advances in knowledge: This is the first study to consider how imaging features relate to diagnosis in suspected paediatric hip tumours. Use of this information can help in determining which cases should undergo needle biopsy.

The Australian continent, being void of plate boundaries, is often perceived as seismically quiescent. However, around 100 magnitude three or larger earthquakes are typically recorded in Australia each year, with a magnitude 6+ occurring every 8-10 years. Such intra-plate activity can pose a significant risk as they are often non-periodic, poorly understood, and sporadically recorded by sparse seismic networks across vast continents. Within Australia the distribution of intra-plate seismicity is non-uniform, but instead tends to concentrate along certain weak zones of increased activity. One such region is the eastern margin of the Gawler Craton in South Australia, one of the oldest building blocks of the continent. Recently several new temporary seismic arrays have been deployed in the region, transforming data coverage across South Australia. So far over 70 new local events have been recorded that would otherwise have gone undetected by the national network. After relocation the pattern of earthquakes becomes more spatially defined and appears to be closely tied to the edge of the Gawler Craton. Supporting evidence suggests that these events may be associated with a trans-crustal scale fault system that adds new constraints on the poorly defined craton boundary.

To describe the MRI features of paediatric conventional central chondrosarcoma (CC-CS) and correlate with histological grade. A retrospective review of children/adolescents with histologically confirmed CC-CS. Data collected included age, sex, skeletal location, and histology from needle biopsy or resection, which was classified as atypical cartilaginous tumours/grade 1 CS (ACT/Gd 1 CS), high-grade chondrosarcoma (HGCS), and dedifferentiated chondrosarcoma (DD-CS). MRI studies were reviewed independently by 2 radiologists blinded to the histology grade, who graded the tumours as ACT/Gd 1 CS, HGCS, and DD-CS based on MRI features. The study included 7 males and 10 females with mean age 13.9 years (range 6–18 years). Tumours were located in the femur (n = 6), humerus (n = 3), tibia, ilium, scapula, and ulna (n = 1 each), and the small bones of the hands or feet (n = 4). Final histology grade was ACT/Gd 1 CS in 15 cases and HGCS in 2 (both grade 1 CS with focal transition to grade 2), 15 based on surgical specimens, 1 based on open biopsy, and 1 on needle biopsy alone. Predicted MRI grade for the 2 readers was ACT/Gd 1 CS in 11 cases each and HGCS in 6 cases each, indicating a mismatch between predicted MRI grade and histological grade in 8 (47%) cases (4 cases with one reader mismatch and 4 cases with both). MRI findings in paediatric CC-CS may be misleading, showing features suggestive of HGCS 7 of 17 (41.2%) of cases. This should be taken into consideration when planning surgical treatment.

To evaluate the role of pre-biopsy MRI for management planning in patients with atypical cartilaginous tumours (ACT) diagnosed on image-guided core needle biopsy (IGCNB). Retrospective review of patients diagnosed with ACT of the appendicular skeleton based on IGCNB who subsequently underwent surgical curettage or resection. Data collected included age, sex, skeletal location and surgical histology classified as ACT, high-grade chondrosarcoma (HG-CS) and dedifferentiated chondrosarcoma (DD-CS). Pre-biopsy MRI studies were reviewed independently by 2 radiologists blinded to surgical histology results and graded as ACT, HG-CS and DD-CS based on MRI features. The study included 24 males and 28 females (mean age 42.1 years; range 9–76 years). One patient had 2 lesions treated, making a total of 53 lesions. Tumours were located in the femur in 21 cases, humerus in 17, tibia in 9, radius in 4 and ulna and fibula in 1 each. Surgical histology was ACT in 41 cases, HG-CS in 10 and DD-CS in 2, indicating mismatch between IGCNB and surgical histology in 12/53 cases (22.6%). Predicted MRI grade for the 2 readers was ACT in 39 cases each, HG-CS in 13 and 14 cases and DD-CS in 1 and 0 cases. Sensitivity, specificity and accuracy of MRI for predicting HG-CS/DD-CS were 91%, 93% and 92%, respectively. Inter-observer correlation was very good (kappa = 0.94). Review of MRI findings in patients with ACT diagnosed on IGCNB is vital for identifying patients with a HG-CS/DD-CS and is recommended when planning surgical management or considering repeat IGCNB.

EWSR1-SMAD3 fibroblastic tumour is a recently described soft tissue lesion. To date, eight cases have been reported, all sited in superficial soft tissue, typically occurring in the hands and feet with a tendency for local recurrence if incompletely excised. No metastatic spread has been reported, and hence, these tumours are currently considered benign. Herein, we present the radiological and histological features of the first reported occurrence of this entity in bone: a 44-year-old man with a tumour in the right tibia, treated with en bloc resection and showing no signs of relapse at 7 years. This tumour should be added to the differential diagnosis of bone lesions which harbour EWSR1 gene rearrangement.

This pilot study aims to determine if tumour heterogeneity assessed using magnetic resonance imaging (MRI) radiomics-based texture analysis (TA) can differentiate between lipoma and atypical lipomatous tumour (ALT)/well-differentiated liposarcoma (WDL). Thirty consecutive ALT/WDLs and 30 lipomas were included in the study, cases diagnosed both histologically and with murine double minute 2 (MDM2) gene amplification by fluorescence in situ hybridisation (FISH) in excision specimens. Multiple patient, MRI and MRTA factors were assessed. Heterogeneity was evaluated using a filtration-histogram technique-based textural analysis on single axial proton density (PD) and coronal T1-W images of the most homogenously fatty component of the lesion. Thirty-three percent of the diagnoses of ALT/WDL vs lipoma were confirmed using FISH MDM2 analysis. ALT/WDLs were statistically different from lipomas in location (site in the body and depth from skin surface) and fat content, with p values of 0.021, 0.001, and 0.021 respectively. Nine of 36 (25%) texture parameters had significant differences between ALT/WDLs and lipomas on axial PD MRTA, with the most significant results at medium and coarse texture scales particularly mean intensity (p = 0.003) at SSF = 6, and kurtosis (p = 0.012) at SSF = 5. A cut-off value of

A fusion between fibronectin 1 (FN1) and activin receptor 2A (ACVR2A) has been reported previously in isolated cases of the synovial chondromatosis. To analyze further and validate the findings, we performed FISH and demonstrated recurrent FN1-ACVR2A rearrangements in synovial chondromatosis (57%), and chondrosarcoma secondary to synovial chondromatosis (75%), showing that FN1 and/or AVCR2A gene rearrangements do not distinguish between benign and malignant synovial chondromatosis. RNA sequencing revealed the presence of the FN1-ACVR2A fusion in several cases that were negative by FISH suggesting that the true prevalence of this fusion is potentially higher than 57%. In soft tissue chondromas, FN1 alterations were detected by FISH in 50% of cases but no ACVR2A alterations were identified. RNA sequencing identified a fusion involving FN1 and fibroblast growth factor receptor 2 (FGFR2) in the case of soft tissue chondroma and FISH confirmed recurrent involvement of both FGFR1 and FGFR2. These fusions were present in a subset of soft tissue chondromas characterized by grungy calcification, a feature reminiscent of phosphaturic mesenchymal tumor. However, unlike the latter, fibroblast growth factor 23 (FGF23) mRNA expression was not elevated in soft tissue chondromas harboring the FN1-FGFR1 fusion. The mutual exclusivity of ACVR2A rearrangements observed in synovial chondromatosis and FGFR1/2 in soft tissue chondromas suggests these represent separate entities. There have been no reports of malignant soft tissue chondromas, therefore differentiating these lesions will potentially alter clinical management by allowing soft tissue chondromas to be managed more conservatively.

In addition to remarkable antitumor activity, chimeric antigen receptor (CAR) T-cell therapy is associated with acute toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Current treatment guidelines for CRS and ICANS include use of tocilizumab, a monoclonal antibody that blocks the interleukin (IL)-6 receptor, and corticosteroids. In patients with refractory CRS, use of several other agents as third-line therapy (including siltuximab, ruxolitinib, anakinra, dasatinib, and cyclophosphamide) has been reported on an anecdotal basis. At our institution, anakinra has become the standard treatment for the management of steroid-refractory ICANS with or without CRS, based on recent animal data demonstrating the role of IL-1 in the pathogenesis of ICANS/CRS. Here, we retrospectively analyzed clinical and laboratory parameters, including serum cytokines, in 14 patients at our center treated with anakinra for steroid-refractory ICANS with or without CRS after standard treatment with tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) CD19-targeting CAR T. We observed statistically significant and rapid reductions in fever, inflammatory cytokines, and biomarkers associated with ICANS/CRS after anakinra treatment. With three daily subcutaneous doses, anakinra did not have a clear, clinically dramatic effect on neurotoxicity, and its use did not result in rapid tapering of corticosteroids; although neutropenia and thrombocytopenia were common at the time of anakinra dosing, there were no clear delays in hematopoietic recovery or infections that were directly attributable to anakinra. Anakinra may be useful adjunct to steroids and tocilizumab in the management of CRS and/or steroid-refractory ICANs resulting from CAR T-cell therapies, but prospective studies are needed to determine its efficacy in these settings.