Search Results (265)

Circulating tumour DNA (ctDNA) assays are increasingly applied in haematological malignancies for non-invasive genotyping, quantitative response assessment, measurable residual disease (MRD) detection, and relapse surveillance, often complementing bone marrow-based testing and, in selected scenarios, potentially reducing its frequency. Yet, translating ctDNA results into comparable clinical decisions across laboratories, platforms, and time remains challenging because ctDNA measurements are influenced by the definition of the measurand (for example, variant allele fraction versus mutant molecules per mL), pre-analytical variables, end-to-end workflow losses, and lineage-specific confounders such as clonal haematopoiesis of indeterminate potential (CHIP), therapy-related clonal haematopoiesis, and compartmental disease (marrow, plasma, cerebrospinal fluid, extramedullary sites). This review proposes a harmonisation framework for haematological ctDNA based on three linked concepts—metrological traceability, which connects reported values to reference systems with stated uncertainty, commutability, which ensures that reference materials behave like patient specimens across diverse workflows and fit-for-purpose reference materials that support calibration, and quality control, external quality assessment, and cut-off setting for intended uses such as early molecular response in large B-cell lymphoma, molecular MRD in acute myeloid leukaemia, and deep response monitoring in multiple myeloma. This framework is accompanied by harmonised CHIP-aware reporting rules for settings without matched cellular DNA and practical change-control/bridging strategies to preserve clinical decision thresholds when platforms or bioinformatic pipelines evolve. Full article

Background: Multiple myeloma (MM) is characterised by clonal expansion of plasma cells (PCs) in the bone marrow (BM). Disease assessment and monitoring typically rely on invasive, single-site procedures, such as BM biopsies (BMBs), which may inadequately capture intra- and extra-medullary spatial heterogeneity. Circulating plasma cells (CPCs), enriched from peripheral blood (PB), may represent a minimally invasive alternative or adjunct for molecular profiling. Objectives: This study aimed to evaluate the feasibility of using CPCs, enriched from PB, for mRNA analysis in plasma cell dyscrasia, including MM. A secondary objective was to assess whether mRNA expression levels of the endoplasmic reticulum (ER) stress sensors X-box-binding protein 1 (uXBP1) and activating transcription factor 6 (ATF6), and the chaperone-mediated autophagy marker Lysosomal-Associated Membrane Protein 2 (LAMP2A) by droplet digital PCR (ddPCR), were associated with resistance to the second-generation proteasome inhibitor (PI) carfilzomib (Cfz). Methods: Multiple myeloma (MM) cell lines (H929 and U266) and their carfilzomib-adapted derivatives were used to establish and validate droplet digital PCR (ddPCR) assays targeting ER stress (uXBP1, ATF6) and autophagy-related (LAMP2A) transcripts. Solid tumour cell lines, including serum-starved HeLa cells, served as biological controls to support assay specificity and sensitivity. Total RNA was extracted and reverse-transcribed to complementary DNA prior to analysis. Transcript levels were normalised to those of β-actin or GAPDH, as appropriate. ddPCR was performed using the BioRad QX200 system, with results reported as the normalised transcript copy number per microlitre of reaction. Matched bone marrow aspirate (BMA) and peripheral blood (PB) samples were collected at a single clinical time point from adults undergoing investigation for plasma cell dyscrasia between January 2021 and December 2023. Samples were obtained as part of standard clinical care and/or during treatment with Bortezomib (Btz) or Cfz. Mononuclear cells were isolated by density gradient centrifugation, and CD138⁺ plasma cells were enriched by fluorescence-activated cell sorting. Enrichment purity was assessed qualitatively by immunofluorescence microscopy using CD138 and CD117 markers. Samples yielding fewer than 1000 CD138⁺ plasma cells were excluded, resulting in 10 evaluable matched patient pairs. Results: Carfilzomib-adapted MM cell lines demonstrated reduced levels of uXBP1, ATF6, and LAMP2A mRNA compared to treatment-naïve cells. In matched BM and PB samples, uXBP1 mRNA levels were consistently lower in circulating PCs than in BM-derived PCs, whereas ATF6 mRNA levels were concordant between compartments. LAMP2A mRNA levels exhibited marked inter-patient heterogeneity. Conclusions: This study demonstrates the feasibility of using CPCs as a minimally invasive source for mRNA-based biomarker assessment and highlights ddPCR as a sensitive platform for quantifying ER stress and chaperone-mediated autophagy related transcripts in CPCs. Cfz adaptation was associated with reduced levels of uXBP1 and LAMP2A mRNA in MM cell lines. Future prospective studies evaluating the clinical utility of ER stress and chaperone-mediated autophagy associated transcripts in CPCs as predictors of resistance to PI are warranted. Full article

Background/Objectives: Tenosynovial giant cell tumours (TGCT) are a group of mesenchymal tumours involving the synovium, bursae, and tendon sheaths, comprising two subtypes: nodular and diffuse. Although predominantly benign, diffuse forms can be locally aggressive, resulting in bone destruction. The pathogenesis of TGCTs is still poorly understood. The aim of this study was to systematically review the current literature on the factors, mechanisms, and markers involved in TGCT disease, focussing on their potential role in bone destruction. Methods: This systematic review was conducted using the PRISMA guidelines. A search was performed using PubMed, Scopus, and Cochrane Library, and all original scientific research into mechanisms/pathways/signalling involving TGCTs was included. Results: After the review process, 51 studies were included for data extraction. Extracted data included authorship, publication year, patient numbers and aetiology (nTGCT/dTGCT), demographics, investigative methods, and studied biological factors, mechanisms, and markers. Cross-tabulation of reported elements revealed 159 unique factors, with most appearing only once. Eight elements were reported five or more times: CSF1, CD68, Ki-67, MMP9, CD163, TRAP, TNF-α, and IL-1β. Although representing just 5% of all identified factors, these appeared in 69% of the included studies, highlighting their prominence in the literature. Conclusions: Apart from the well-known osteoclastogenesis factor CSF1, inflammatory cytokines (TNF-α and IL-1β) and monocyte–macrophage lineage makers (CD68, CD163) are signalling pathways key to TGCT disease progression and associated bone destruction. Full article

Background: Sinonasal mucosal melanoma is a rare and aggressive malignancy arising from the nasal cavity and paranasal sinuses, characterized by high local recurrence rates and poor survival. Skull-base and orbital progression can occur rapidly, particularly when preoperative imaging underestimates local extension. This paper reports a case of sinonasal mucosal epithelioid melanoma with fulminant postoperative skull-base breach and orbital invasion, highlighting its clinical course, management challenges, and histopathological features. Methods: A 60-year-old woman with progressive unilateral nasal obstruction, recurrent epistaxis, and headache underwent clinical evaluation, contrast-enhanced head MRI, CT, and PET-CT staging. Preoperative imaging demonstrated no intracranial or orbital invasion. Biopsy confirmed mucosal epithelioid melanoma with high proliferative activity (Ki-67 ~80–85%). The patient underwent extensive image-guided endoscopic resection with intraoperative cerebrospinal fluid leak repair. Results: Definitive histopathology confirmed pigmented epithelioid melanoma with extensive necrosis, bone invasion, and non-assessable resection margins due to specimen fragmentation (pT4a, Rx). Within two weeks postoperatively, CT and MRI demonstrated extensive local recurrence with cribriform plate destruction, anterior skull-base dural infiltration, and rapid orbital progression with optic nerve compression and loss of vision. Despite hemorrhage control and hypofractionated palliative radiotherapy (VMAT, 33 Gy in 11 fractions), the patient experienced progressive neurological decline, refractory pain, and recurrent tumour bleeding, and died approximately 4.5 months after initial presentation. Conclusions: In patients with sinonasal mucosal epithelioid melanoma, fulminant local progression with skull-base and orbital involvement may occur despite apparently limited preoperative imaging. When rapid vision loss, dural infiltration, and refractory nasal bleeding develop, structured palliation, hemorrhage control, and aggressive multimodal analgesia should be prioritized early alongside ongoing multidisciplinary decision-making. Full article

Background/Objectives: Bone metastases are a common complication of breast cancer. In our previous study, we reported that extracellular vesicles released by osteotropic human (MDA-MB-231) and murine (4T1) breast cancer cells disrupt bone homeostasis by enhancing osteoclast differentiation and impairing osteoblast function. Based on these findings, we investigated whether microRNAs contained within tumour-derived EVs could mediate these bone-altering effects. Methods: MDA-MB-231- and 4T1-EVs were tagged with the RNA-specific fluorophore SYTORNA and employed to treat mouse primary bone marrow macrophages (BMMs) and osteoblasts (OBs). We also performed RNAseq on MDA-MB-231- and 4T1-EVs to assess their miRNAs content. Finally, we evaluated the effect of selected miRNA-mimics on OBs, BMMs and HUVEC cells. Results: Fluorescence microscopy demonstrated EV-RNAs shuttling to recipient cells, while RNA sequencing on MDA-MB-231- and 4T1-EVs revealed that, of the top 20 expressed miRNAs, 10 were common. Among them, we first focused on the following four: miR-26a-5p, miR-24-3p, miR-29a-3p, and miR-29b-3p, which were linked to bone biology. We confirmed their presence in MDA-MB-231-/4T1-EVs by qPCR. Then, we evaluated their EV-mediated shuttling to BMMs and OBs using affinity tags. Among all the conditions tested, miR-29a and miR-29b were the best-shuttled miRNAs, with efficiency between 50–100% in both OBs and BMMs, both for MDA-MB-231- and 4T1-EVs. Finally, to test whether miR-29a and miR-29b could have a functional role in bone cells, OBs were transfected with miR-29a and 29b-mimics, discovering that this treatment reduced collagen1α1 and 1α2 mRNA as well as the OBs’ mineralisation ability, while the same miRNA mimics were found to have no effect on osteoclastogenesis or on in vitro angiogenesis. Conclusions: MDA-MB-231- and 4T1-EVs shuttle miRNAs to bone cells, which likely contributes to OBs’ activity impairment. Full article

Objective: Bone-modifying agents (BMA) are central to the prevention of skeletal-related events (SREs) in patients with cancer bone metastases, yet evidence guiding agent selection in very old patients remains limited. This study aimed to compare the effectiveness and safety of Denosumab versus bisphosphonates in patients aged ≥75 years with solid tumour-related bone metastases using a target trial emulation framework. Methods: We conducted a retrospective cohort study using the TriNetX Global Collaborative Network to emulate a hypothetical randomised trial. Patients aged ≥75 years with solid tumour-related bone metastases initiating Denosumab or bisphosphonates were included. After 1:1 propensity score matching (PSM), 10,662 patients were analysed in each treatment group. The primary outcome was time to first SRE. Secondary outcomes included individual SRE components, all-cause mortality, and safety events. Results: Among 21,324 matched patients (mean age, 75.6 years), bisphosphonate use was associated with a higher risk of SREs compared with Denosumab (hazard ratio [HR], 1.15; 95% CI, 1.06–1.25). The excess risk was driven by pathological fractures (HR, 1.28; 95% CI, 1.10–1.49), whereas other SRE components did not differ significantly. All-cause mortality was higher among bisphosphonate users (HR, 1.41; 95% CI, 1.33–1.49, p < 0.001). Hypocalcaemia occurred more frequently with Denosumab (5.7% vs. 2.4%), while risks of acute kidney injury and end-stage renal disease (ESRD) were similar. Findings were consistent across sensitivity and subgroup analyses. Conclusions: In patients aged ≥75 years with solid tumour-related bone metastases, Denosumab was associated with lower risks of skeletal-related events—particularly pathological fractures—and reduced all-cause mortality compared with bisphosphonates. These results extend randomised trial evidence to a clinically vulnerable population and support Denosumab as a preferred BMA in older adults. Full article

Hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2−) early breast cancer (EBC) is the most common breast cancer subtype and encompasses a biologically heterogeneous group of tumours. Endocrine therapy (ET) remains the cornerstone of treatment, but decisions regarding chemotherapy, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, and bone-modifying agents must be tailored to tumour biology, clinical stage, and menopausal status. REAL Canadian Breast Cancer Alliance (REAL Alliance), a pan-Canadian group of breast cancer specialists, convened to develop national clinical consensus recommendations for the systemic management of HR+/HER2− EBC. Using a structured consensus process, 28 recommendations were endorsed, spanning neoadjuvant and adjuvant systemic therapy, surgical considerations, and use of bisphosphonates. Key recommendations include the selective use of neoadjuvant chemotherapy for high-risk or locally advanced disease; genomic testing to guide chemotherapy decisions, particularly in postmenopausal patients; ET as the foundation of adjuvant therapy with intensification using CDK4/6 inhibitors in higher-risk patients; and adjuvant bisphosphonates in postmenopausal women to reduce recurrence and improve survival. These consensus recommendations provide practical, evidence-based guidance to support individualized, patient-centred management of HR+/HER2− EBC in the Canadian context. Full article

Background/Objectives: Accurate classification of primary bone tumors from radiographic images is essential for early diagnosis, appropriate treatment planning, and informed clinical decision-making. While deep convolutional neural networks (CNNs) have shown strong performance in medical image analysis, their high computational complexity often limits real-world clinical deployment. This study aims to develop a lightweight yet highly accurate model for multi-class bone tumor classification. Methods: We propose Bone-CNN, a computationally efficient CNN architecture specifically designed for radiograph-based classification of primary bone tumors. The model was evaluated using the publicly available Figshare Radiograph Dataset of Primary Bone Tumors, which includes nine distinct tumor classes ranging from benign to malignant lesions and originates from multiple imaging centres. Performance was assessed through extensive experiments and compared against established baseline models, including DenseNet121, EfficientNet-B0, and MobileNetV2. Results: Bone-CNN achieved a test accuracy of 96.52% and a macro-AUC of 0.9989, outperforming all baseline architectures. Both quantitative and qualitative evaluations, including confusion matrices and ROC curve analyses, demonstrated robust and reliable discrimination between challenging tumor subtypes. Conclusions: The results indicate that Bone-CNN offers an excellent balance between accuracy and computational efficiency. Its strong performance and lightweight design highlight its suitability for clinical deployment, supporting effective and scalable radiograph-based assessment of primary bone tumors. Full article

Background: Primary fibula tumours are rare, representing approximately 0.25% of all primary bone tumours. While benign lesions are often asymptomatic, malignant ones typically present with pain and functional impairment. Most tumours arise in the proximal third of the fibula, yet the literature regarding their epidemiology and clinicopathological features remains limited. This systematic review aims to synthesise current evidence on presentation, diagnosis, management, and prognosis of primary malignant tumours of the proximal fibula. Methods: A systematic review was conducted following PRISMA guidelines. PubMed, Scopus, and the Cochrane Register were searched on 28 October 2025 for English-language case reports and case series on primary malignant tumors of the proximal fibula. Two reviewers independently performed study selection and data extraction, collecting information on demographics, tumor characteristics, diagnostic approaches, treatments, and outcomes, with disagreements resolved by a third reviewer. Results: Thirty-three papers involving 228 patients (78 females, 128 males, 22 unknown) were included. The mean age at diagnosis was 22.8 years (range 4–79). The most common symptoms were painful mass and neurological complaints. Osteosarcoma and Ewing’s sarcoma were predominant histological types. Limb-sparing surgeries were most common, although 16 patients underwent amputation. At mean follow-up of 48.9 months, local recurrence occurred in 44 cases, and 12 developed distant metastases, most commonly in the lungs. Overall, 38 patients died, 37 due to disease progression. Conclusions: Primary malignant tumours of the proximal fibula, while rare, pose significant therapeutic challenges. Accurate diagnosis, appropriate multimodal treatment, and careful surgical planning are crucial to optimise oncological control and functional outcomes. Full article

Background: Osteosarcoma (OSA) is the most common type of bone cancer in canines. Novel therapies are required to prevent the growth, survival, and metastatic progression of this cancer, to increase life expectancy of patients. Immunohistochemical (IHC) studies and RNA sequencing help us gain a deeper understanding into the molecular mechanisms of the disease. Methods: We previously compared canine OSA tissues with patient matched non-tumour tissues, revealing 442 overexpressed genes within the samples. The present research used IHC staining for four of these genes in OSA tissues: G protein-coupled receptor 64 (GPR64), TOX High Mobility Group Box Family Member 3 (TOX3), Matrix Metallopeptidase 12 (MMP-12), and Forkhead Box F1 (FOXF1). H-scoring was performed to quantitatively assess protein expression and qualitatively contextualise staining locations. Additional analyses addressed whether gender or anatomical location of lesions (axial or appendicular tumours) affected protein expression. cBioPortal was employed to analyse expression and genetic alterations in patients. Results: GPR64, TOX3, MMP-12, and FOXF1 showed high mRNA expression and genetic alterations in people with OSA. GPR64, TOX3, MMP-12, and FOXF1 were all expressed in canine OSA with novel findings regarding cellular expression. Additionally, differential sex expression was revealed for GPR64 and TOX3. Potential biomarkers or therapeutic targets were identified. Conclusions: These studies, and subsequent analysis, have provided insights into the molecular mechanisms associated with OSA progression and revealed potential biomarkers for diagnostic and prognostic purposes. A deeper understanding of genetic and protein interactions will support and progress novel pathways towards diagnostic, prognostic, and treatment interventions for OSA in both veterinary and human medicine. Full article

Background. Glucocorticoid-induced osteoporosis represents a well-known type of secondary osteoporosis (SOp). While the most prevalent sub-category includes corticotherapy, another important contributor is represented by Cushing’s syndrome. In this traditional landscape, adrenal incidentalomas do not involve a standard cause of SOp, since most of them are non-functioning adrenal tumours (NFATs). Yet, 30–40% of them are not entirely “non-functioning”, due to mild autonomous cortisol secretion (MACS). Despite not being a guideline-based diagnosis, a lower ACTH might point to various NFATs/MACS complications. Objective. This study aimed to determine the relationship between the bone health status of post-menopausal women with NFATs/MACS and their baseline morning ACTH level. The bone health indicators were DXA, FRAX, and bone remodelling markers. Methods. This was a retrospective, real-life, transversal study in adult females who were hospitalized in a single tertiary centre of endocrinology. They were all anti-osteoporotic drug-naïve. The subjects underwent CT and DXA scanning and a 1 mg dexamethasone suppression test (DST). Results. The cohort (sample size of N = 84 patients, 61.49 ± 7.86 years) had a type 2 diabetes rate of 18%, arterial hypertension rate of 75%, and a dyslipidemia rate of 78%. Median ACTH was 11.89 pg/mL. The prevalence of MACS was 30.95%. The mean largest tumour diameter (LTD) was 2.25 ± 0.99 cm. ACTH correlated with second-day cortisol after the 1 mg DST (r = −0.301, p = 0.024), and LTD (r = −0.434, p < 0.001). ROC analysis for the bone resorption marker CrossLaps showed an AUC of 0.647 (p = 0.05), with the highest Youden index for the cut-off at 0.32 ng/mL (sensitivity 87.50%, specificity 39.50%). Bone impairment (osteoporosis + osteopenia) was found in 65% of patients, with an osteoporotic fracture prevalence of 4.76%. The lowest mean T-score (−1.12 ± 1.00) showed osteopenia, and the median trabecular bone score pointed a partially degraded microarchitecture [median (interquartile interval): 1.320 (1.230, 1.392)]. FRAX and FRAXplus estimations correlated with bone mineral density (BMD) at all three central DXA sites, regardless of the ACTH cut-off. Patients with a low ACTH (<10 pg/mL) displayed similar bone/adrenal features when compared to those with normal ACTH, except forbut they had a higher MACS rate (45.45% versus 21.57%, p = 0.021) and a larger LTD (2.67 ± 0.98 versus 1.98 ± 0.92 cm, p = 0.003). Fracture estimation showed that only in patients with a low ACTH, the 10-year fracture risk for major osteoporotic fractures (MOF) adjusted for lumbar BMD was lower than the risk for MOF adjusted for diabetes (p = 0.036), and the 10-year hip fracture risk was lower when adjusted for lumbar BMD (p = 0.007). ACTH correlated with lumbar BMD (r = 0.591, p = 0.002) only in the group with an ACTH < 10 pg/mL, suggesting its potential usefulness as a bone biomarker in these cases. On the other hand, MACS-negative subjects with a low ACTH versus those with a normal ACTH showed higher CrossLaps (0.60 ± 0.27 versus 0.42 ± 0.21 ng/mL, p = 0.022), indicating an elevated bone resorption even in patients with tumours that are regarded as true non-secretors. Conclusions. A subgroup of patients diagnosed with NFATs/MACS might be prone to skeletal damage, and biomarkers such as ACTH (specifically, suppressed ACTH) might serve as a surrogate pointer to help refine this higher risk in daily practice. Further research to address other ACTH cut-offs will place ACTH assays in the overall bone status evaluation in these patients, most probably not as a single biomarker, but in addition to other assays. Full article

Bone remodelling is a physiological process influenced by mechanical stimuli such as those generated during orthodontic treatment. Biochemical markers allow the phases of remodelling to be identified, its progression to be assessed, alterations to be detected and scaffold-based tissue regeneration to be evaluated. This study reviews the main markers involved in bone formation and resorption, highlighting their clinical relevance. A literature search was conducted in biomedical databases, selecting studies that analysed crevicular gingival fluid samples in areas of tension and compression. The markers were classified according to their function and location, and their baseline values, temporal variations and methods of analysis were compiled. Among the markers of bone formation, Osteoprotegerin (OPG), Transforming Growth factor β1 (TGF-β1) and Interleukin 27 (IL-27) stand out; while resorption markers include Receptor Activator of Nuclear Factor appa β Ligand (RANKL), Tumour Necrosis Factor (TNF-α) and Interleukin 1β (IL-1β). The results show different expression patterns depending on the type of force applied and the timing of the follow-up, allowing molecular profiles associated with each phase of remodelling to be established. This characterisation improves our understanding of tooth movement and provides a basis for the development of more precise scaffolds and functional biomaterials in orthodontics. Full article

Background and Objectives: Multiple myeloma (MM) remains an incurable plasma cell malignancy with heterogeneous clinical outcomes. Although current prognostic systems integrate biochemical and cytogenetic parameters, they do not fully capture disease complexity. Adipocytes within the bone marrow microenvironment secrete adipokines that regulate inflammation, metabolism, and immune interactions and may influence disease progression. This study aimed to assess circulating adipokines and related microenvironmental mediators as potential biomarkers of disease activity and treatment response in MM. Materials and Methods: In this case–control, cross-sectional study, the serum levels of eight adipokine-related molecules—adiponectin, leptin, resistin, chemerin, adipsin, thrombospondin-1 (TSP-1), paraoxonase-1 (PON-1), and myeloperoxidase (MPO)—were measured in 40 MM patients and 38 age- and sex-matched healthy controls. Enzyme-linked immunosorbent assays (ELISA) and bead-based multiplex immunoassays were used. Associations with prognostic markers (serum β₂-microglobulin (sB2M), LDH, albumin, hemoglobin, renal function) and treatment response were analyzed using correlation and non-parametric statistical methods. Results: Compared to the controls, MM patients exhibited significantly higher circulating levels of adiponectin, resistin, chemerin, adipsin, TSP-1, and MPO, while leptin was decreased. Among clinical correlations, chemerin and PON-1 correlated positively with sB2M, TSP-1 correlated with LDH, and MPO correlated with M-protein and albumin. Resistin was lower in patients with renal impairment and an advanced disease stage. Adiponectin and TSP-1 were significantly lower in progressive disease compared to complete remission, suggesting their potential association with treatment response. Conclusions: This study demonstrates that multiple adipokines are dysregulated in MM and exhibit distinct associations with disease burden, renal function, and therapeutic response. Novel associations identified for TSP-1, PON-1, and adipsin highlight previously unrecognized microenvironmental pathways in MM biology. Adipokine profiling may complement established prognostic markers and provide new insights into the tumour microenvironment in MM. Full article

Background/Objectives: Metastatic bone disease (MBD) poses an increasing challenge in orthopaedic oncology due to prolonged survival. While clinical prognostic factors are well established, the role of socio-economic determinants remains unclear, particularly within universal healthcare systems. Methods: We retrospectively analysed 243 patients who underwent surgery for MBD (excluding spine) between 2005 and 2024 at a German sarcoma centre. Socio-economic indicators were derived from national databases and linked to patients’ residential districts. Survival was analysed using Kaplan–Meier estimates and Cox regression, adjusting for clinical confounders. Results: Median postoperative survival was 22 months. Several socio-economic indicators—income, education, and employment—were associated with survival in univariate analysis. In multivariate models, only residential area size remained independently significant (p = 0.047). Patients from villages (<2000 inhabitants) and large cities (>100,000) had poorer survival than those from small or medium-sized towns. This effect persisted after adjustment for tumour type, pathological fractures, and year of surgery. Conclusions: Within a universal healthcare system, residential area size was associated with survival after surgery for MBD, suggesting that regional disparities may persist despite equal formal access to care. Further studies integrating individual-level socioeconomic data are needed to identify mechanisms and guide interventions to reduce geographic inequalities. Full article

Background: Megaprosthetic replacement is widely used following tumour resection but remains challenged by periprosthetic joint infection (PJI) and variable functional outcomes. This narrative review aims to summarise current evidence on infection rates, prevention strategies, and functional outcomes following proximal humerus megaprosthetic reconstruction. We hypothesise that antibacterial coatings and improved soft-tissue techniques reduce infection rates and enhance functional recovery. Methods: A comprehensive narrative review of PubMed, Web of Science, and the Cochrane Library was performed using the terms proximal humerus, shoulder, bone tumor, sarcoma, neoplasm, infection, megaprosthesis, and endoprosthetic replacement. Reference lists were screened manually. Case reports and series with fewer than five patients were excluded. Twenty-seven clinical studies (more than 1100 patients; mainly osteosarcoma, chondrosarcoma, and metastatic lesions) were included and qualitatively analyzed. Results: The reported infection rates ranged from 4% to 20%, with higher risk in patients receiving adjuvant therapy. Silver-coated implants reduced PJI compared with uncoated designs (e.g., 11.2% → 9.2% in primary implants; 29.2% → 13.7% in revisions) without systemic toxicity. Alternative antibacterial coatings (e.g., silver- or copper-enriched hydroxyapatite) showed promising early results but remain supported by limited clinical data. Soft-tissue stabilization with Trevira tube or synthetic mesh improved joint stability and did not increase infection risk. Functional outcomes, usually assessed by MSTS or TESS, were moderate to good (≈60–80%) overall, with better scores when the deltoid and axillary nerve were preserved or when reverse total shoulder arthroplasty was possible. Conclusions: Proximal humerus megaprosthetic reconstruction benefits from meticulous soft-tissue handling, selective use of antibacterial technologies, and multidisciplinary management. The current literature is mainly retrospective, heterogeneous, and non-comparative. Prospective multicenter studies are needed to clarify the long-term effectiveness of silver or alternative coatings, soft-tissue reconstruction techniques, and emerging custom-made 3D-printed prostheses. Full article