Search Results (7,209)

Background: Nontuberculous mycobacteria (NTM) skin infections pose significant diagnostic challenges in clinical practice, due to nonspecific clinical/histopathological features and limitations of conventional pathogenic detection methods. Metagenomic next-generation sequencing (mNGS) offers a promising approach but requires further evaluation. Methods: A prospective pilot study at Peking Union Medical College Hospital enrolled 20 patients with cutaneous NTM infection, confirmed by positive skin culture or mNGS. All patients underwent thorough clinical assessment, skin biopsy for histopathology and culture, and mNGS testing of skin tissue. Treatment was based on identified species and disease extent. Treatment outcomes were tracked. Results: Among 20 patients (median age 45.5 years), fingers were the most common site affected (n = 10), followed by forearms (n = 7), hands (n = 4), and face (n = 4). Mycobacterium marinum was the predominant pathogen (n = 12), associated with fish bone puncture, followed by M. abscessus (n = 4). mNGS demonstrated a substantially higher positivity rate than culture (95% [19/20] vs. 30% [6/20]) and delivered results faster. Histopathology revealed granulomatous inflammation in all cases. Nineteen patients presented with non-disseminated disease; one immunocompromised patient (GATA2 deficiency) had disseminated M. abscessus infection. Treatment success was achieved in 17 patients (85%) with tailored antibiotic regimens. Adverse drug effects occurred in seven patients. Conclusions: In this pilot study of cutaneous NTM infections, mNGS enabled more rapid diagnosis relative to conventional culture. Clinical presentation and exposure history correlate with specific NTM species. Integrating mNGS with clinical assessment significantly improves diagnosis and management. Full article

Mesenchymal stromal cells (MSCs) have shown immunomodulatory effects and great promise in many inflammatory diseases such as acute respiratory distress syndrome (ARDS). However, several barriers to translation remain such as cell availability and potency. This study evaluates the therapeutic potentials of three types of MSCs, bone marrow-derived MSCs (BM-MSC), the human induced pluripotent stem cell-derived MSC wild type (iMSC WT) and β2 microglobulin-knockout iMSCs (iMSC B2M KO) with or without proinflammatory cytokine preconditioning. BM-MSC, iMSC WT and iMSC B2M KO were preconditioned with a proinflammatory cytokine cocktail (Cytomix: IL-1β, IFN-γ and TNF-α). Immunoregulatory biomarkers were analysed by flow cytometry and cytokines released by ELISA. MSC antimicrobial properties were analysed via CFU assays while the MSCs’ immunomodulatory effects were evaluated using macrophage activation and T cell proliferation assays. Proinflammatory cytokine preconditioning enhanced the therapeutic potency of all three types of MSCs by increasing immunomodulatory marker expression, enhancing the antimicrobial effects and improving MSC-mediated inhibition of T cell proliferation. These findings provided new insights into the therapeutic potencies of MSCs in inflammation. Further studies are required for in vitro characterisation of the MSCs and in vivo efficacy verification of these MSCs prior to their clinical application. Full article

Bone metastasis remains a major cause of morbidity in advanced cancer, driven not only by tumor–bone crosstalk but also by profound immune remodeling within the marrow. Myeloid-derived suppressor cells (MDSCs), including polymorphonuclear (PMN-MDSC) and monocytic (M-MDSC) subsets, are increasingly recognized as central effectors of this process, integrating inflammatory signals with metabolic and stromal cues to enforce immune suppression and support skeletal colonization. In this review, we synthesize current evidence that bone metastases transform the bone marrow into an “MDSC amplifier,” where vascular and endosteal niches, CXCL12-rich stromal compartments, hypoxia, and adipocyte-derived lipids collectively promote MDSC recruitment, persistence, and functional maturation. We discuss the dominant suppressive programs deployed by MDSCs in bone (e.g., arginase-1 activity, reactive oxygen/nitrogen species, and checkpoint ligand expression), and how these mechanisms converge to impair cytotoxic T-cell and NK-cell responses while fostering regulatory T-cell dominance. Importantly, because the marrow is a hematopoietic organ, bone lesions can also generate systemic consequences through myeloid spillover, providing a mechanistic basis for reduced responsiveness to immune checkpoint blockade in bone-dominant disease. We then evaluate pharmacologic strategies to target MDSCs in the context of bone metastasis, including approaches that block trafficking (e.g., CCR2/CXCR2 axes), deplete or reprogram suppressive myeloid states (e.g., STAT3-directed strategies, differentiation therapy), and disrupt bone-resorptive feedback loops (e.g., receptor activator of NF-κB ligand (RANKL) inhibition and bisphosphonates), emphasizing rational combinations and sequencing to limit marrow toxicity. Finally, we highlight emerging single-cell and spatial profiling tools that can resolve bone-specific heterogeneity in MDSCs and guide biomarker-driven, mechanism-informed therapeutic development. Full article

Background/Objectives: Pediatric cancers are disorders of dysregulated development driven largely by genomic and epigenetic alterations. Precisely modeling these developmental differences is essential for understanding the unique biology of childhood cancers. Patient-derived organoids (PDOs) offer a powerful in vitro platform that recapitulates tumor heterogeneity, plasticity, microenvironment (including immune cells) and disease-relevant features. Methods: Here, we describe a step-by-step protocol for the establishment of PDOs from cells derived from pediatric brain tumors and extracranial solid tumor biopsies and bone marrow aspirates, including tumor processing, organoid culture/subculture, and cryopreservation. Results: Furthermore, we present the use of PDOs for further experimental analysis such as fluorescence imaging, Western blotting, flow cytometry, and immunohistochemistry (IHC) to investigate the underlying pathophysiology of tumorigenesis. Conclusions: Expanding the application of organoids to childhood malignancies holds exceptional promise for elucidating pediatric tumor biology and advancing therapeutic strategies, representing the long-overdue convergence of technology and clinical need. Full article

Background/Objectives: Advanced prostate cancer (PCa) evolves through adaptive mechanisms that sustain tumor growth despite the suppression of androgen receptor (AR) signaling. Accumulating evidence identifies activation of the hepatocyte growth factor (HGF)/MET pathway as a potential driver of PCa progression in advanced disease states characterized by AR-independence and therapeutic resistance. We review the biological and clinical evidence supporting MET as a context-dependent therapeutic target and discuss its implications for patient selection and combination strategies. Methods: A comprehensive narrative review of preclinical, translational, and clinical studies evaluating MET-directed therapies for PCa was performed. Results: Aberrant activation of the HGF–MET axis is frequently driven by autonomous paracrine and autocrine loops that sustain pathway activation during disease progression. MET overexpression is associated with adverse pathological features, increased tumor aggressiveness, bone metastasis, lineage plasticity, and resistance to AR-targeted treatments. Preclinical studies have demonstrated that AR suppression, tumor hypoxia and tumor–microenvironment interactions promote MET upregulation, supporting AR-independent growth and epithelial-to-mesenchymal transition. Clinical trials of MET inhibitors have shown modest activity as monotherapies, with the most consistent biological effects observed in bone-dominant disease. Recent studies indicate greater therapeutic potential when MET inhibition is incorporated into rational combination strategies targeting complementary molecular pathways. Emerging data further indicate that MET activation characterizes a biologically aggressive, AR-low or neuroendocrine-like disease state. These findings support a transition from empiric use of MET inhibitors toward precision, context-driven therapeutic development. Conclusions: MET is not a universal therapeutic target but defines a clinically relevant subset of aggressive, AR-indifferent PCa. Future development should focus on biomarker-guided patient selection and rational combination strategies. Integration of molecular profiling, imaging, and liquid biopsy approaches will be essential to identify patients most likely to benefit from MET-directed interventions. Full article

Background/Objectives: The optimal management of bone-only progressive disease (PD) in metastatic breast cancer remains unclear for several reasons. Radiologic diagnosis of bone PD is complicated by the lack of standardized response assessment criteria, unspecific morphologic changes of the bone, and flare-up phenomena. Furthermore, bone-only disease and oligoprogression have been associated with favorable prognosis challenging a change of systemic treatment with the consequence of limited treatment options in the future. Additionally, bone-only metastatic disease is frequently excluded from clinical trials resulting in scarce data. This study aimed to assess the therapeutic management and outcome of bone-only PD in metastatic breast cancer patients in a real-world academic setting. Methods: A retrospective analysis of all breast cancer patients with bone metastases (BMs) and at least one event of radiologic evidence of bone-only PD and/or the occurrence of a skeletal-related event (SRE) who were treated at the Department of Obstetrics and Gynecology of the Medical University of Vienna, Austria, between 1 January 2015 and 14 December 2021 was performed. In cases of multiple bone-only PD events in one patient only the first event was considered for analysis. All cases with PD in organs other than the bone were excluded. The primary outcome of the study was to assess therapeutic measures of bone-only PD. Secondary outcomes were the time from bone-only PD to next bone PD (TTF BD) and overall survival (OS; time from bone-only PD to death). Predictors of TTF BD and OS were assessed as exploratory outcomes. Results: Out of a total of 308 breast cancer patients with BMs, 57 had at least one event of bone-only PD. In 59.3% of bone-only PD cases the systemic treatment was continued with a numerically higher rate if multiple metastatic sites were present (71.4% vs. 46.4%). In most bone-only PD events the bone-targeted agent (BTA) was continued (94.5%), independent of the total number of metastatic sites. In 24.1% radiotherapy (RT) was administered with similar rates between patients with bone-only and multiple metastatic sites. The median TTF BD was 6.3 months. In multivariate analysis no predictor for TTF BD could be identified including change of systemic treatment, RT, previous BTA treatment duration, number of previous treatment lines for the metastatic disease, number of metastatic sites and previous or current SRE. Median OS was 21.8 months. Number of previous treatment lines for the metastatic setting was significantly associated with OS with shorter OS in the more advanced disease stage (p-value = 0.0208). Conclusions: Systemic and BTA treatment were continued in the majority of bone-only PD cases. In 24.1% RT was administered. No association between change of systemic therapy and improved oncologic outcome was found. The study’s results are hypothesis-generating in terms of whether change of systemic treatment should be performed restrictively to avoid limited treatment options in the future. Similarly, radiotherapy did not ameliorate prognosis. Full article

Multiple myeloma (MM) is a malignancy of plasma cells that is characterized by a complex and spatially heterogeneous genomic landscape. Despite this complexity, clinical monitoring remains largely dependent on localized bone marrow (BM) assessments. This dependence creates a significant diagnostic gap, as the primary monitoring tools fail to account for the spatial and temporal heterogeneity that drives tumor relapse. Liquid biopsy can serve as an adjunctive approach in assessing the pan-clonal landscape in MM through the molecular profiling of circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs). In this review, we examine the clinical utility of liquid biopsy components in capturing mutational profiles, clonal evolution, treatment resistance mechanisms, and minimal residual disease (MRD), including early detection of relapse and extramedullary progression. We will further discuss current limitations, including variability in assay sensitivity, lack of standardization, and the need for prospective validation. Full article

Radiographic assessment plays an important role in the diagnosis of periodontal disease. However, intraoral radiographs often underestimate interproximal bone level. Cone beam CT (CBCT) has been shown to outperform 2D radiography in the detection of furcation involvement, but research on bone level measurements is scarce. This study aimed to assess the accuracy of CBCT and intraoral periapical radiographs (PARX) as diagnostic tools for evaluating bone morphology compared to clinical measurements in an open field setting. This prospective observational diagnostic accuracy study consisted of 29 patients who were planned for periodontal surgery. Pre-surgical assessment consisted of PARX and CBCT compared to open field measurements, using a periodontal probe prior to any bone correction. The following parameters were evaluated: CEJ-BD (cementoenamel junction-base of the defect), AC-BD (alveolar crest–base of the defect), furcation involvement, and bone morphology (angular vs. horizontal). Twenty-nine patients were included, and a total of 173 interproximal sites were assessed. The ICC for the primary variable (CEJ-BD) indicated poor reliability for PARX (0.47), while CBCT showed moderate reliability (0.63). For infrabony measurements, ICC values indicated poor reliability for PARX (0.38) and moderate reliability for CBCT (0.56). Regarding furcation involvement, periapical radiography showed fair agreement (κ = 0.32), whereas CBCT demonstrated substantial agreement (κ = 0.72). Bone morphology assessment showed slight agreement for PARX (κ = 0.11) and fair agreement for CBCT (κ = 0.40). CBCT provides more consistent and reliable assessments of bone level, defect morphology and furcation involvement compared to conventional periapical radiographs. Full article

Background: Thyroid hormones influence bone metabolism, and autoimmune thyroid diseases may further impact skeletal homeostasis. Wnt signaling inhibitors, including Dickkopf-1 (DKK-1) and sclerostin (SOST), as well as osteoprotegerin (OPG), play key roles in regulating bone formation and resorption. This study aimed to evaluate circulating DKK-1, SOST, and OPG in women with newly diagnosed overt thyroid dysfunction. Methods: This cross-sectional study included 62 women with newly diagnosed, untreated overt thyroid dysfunction (35 hypothyroid and 27 hyperthyroid) and 33 age- and BMI-matched healthy controls. Serum levels of DKK-1, sclerostin, and OPG were measured using ELISA. Thyroid function and autoantibodies were assessed using automated immunoassays. Correlation analysis was performed to evaluate associations between variables. Results: Serum DKK-1 levels were significantly elevated in both hypothyroid and hyperthyroid women compared with controls (p < 0.001). Sclerostin levels showed a non-significant trend toward higher values. OPG levels were significantly increased in hyperthyroid patients and moderately elevated in hypothyroid patients. Significant positive correlations were observed between OPG and FT3 (r = 0.42, p = 0.001) and FT4 (r = 0.43, p = 0.001). In hypothyroid patients, OPG correlated positively with TgAb (r = 0.46, p = 0.007). A strong positive correlation was found between DKK-1 and SOST (p < 0.001), while DKK-1 was negatively associated with age (p < 0.05). Conclusions: Overt thyroid dysfunction is associated with significant alterations in circulating Wnt signaling inhibitors and OPG. These findings suggest a potential role of Wnt signaling and immune–bone interactions in thyroid-related changes in bone metabolism. Full article

Background and Clinical Significance: Dyskeratosis congenita (DC) is a rare inherited disorder classified as a telomere biology disorder and characterized by multisystem involvement, including bone marrow failure and mucocutaneous abnormalities. Oral manifestations such as leukoplakia, increased susceptibility to infection, and abnormal dental development have been reported; however, detailed descriptions of long-term oral functional management in pediatric patients remain limited. This report aims to describe the longitudinal oral management and imaging-based assessment of dental development in a child with DC and to discuss the clinical implications in the context of existing literature. Case Presentation: A female patient diagnosed with dyskeratosis congenita due to a heterozygous TINF2 mutation was followed from early childhood. She underwent hematopoietic stem-cell transplantation at five years of age and later required lung and liver transplantation. Long-term oral management included regular professional oral care, preventive strategies, and periodic imaging evaluation. Panoramic radiographs obtained over several years demonstrated generalized delayed eruption and incomplete root formation relative to chronological age, with apparent early arrest of root elongation. Discussion: This case highlights the potential association between telomere dysfunction, intensive systemic therapy in early childhood, and arrested odontogenesis. These findings suggest a possible association between telomere dysfunction, early intensive systemic therapy, and impaired root formation. Despite severe systemic disease, continuous preventive oral care and imaging-based monitoring were effective in maintaining oral health and detecting mucosal changes. Conclusions: Long-term preventive oral management combined with noninvasive imaging assessment may play an important role in preserving oral function and monitoring dental development in pediatric patients with dyskeratosis congenita. This case adds to the limited literature on longitudinal oral outcomes in this rare disorder. Full article

Background: Osteoporosis is a chronic bone disease characterized by reduced bone mass and structural deterioration, increasing fracture risk and affecting patients’ quality of life (QoL). Pharmacological treatments are essential in managing osteoporosis; however, suboptimal prescribing patterns and poor medication adherence can limit therapeutic outcomes. This study primarily aimed to assess medication adherence among patients with osteoporosis using the MMAS-8, as well as prescribing patterns and patient beliefs. Methods: We conducted a single-center cross-sectional observational study at Saqr Hospital, Ras al Khaimah, UAE, between October 2024 and May 2025, enrolling 300 adults with clinically diagnosed osteoporosis and/or a bone mineral density T-score ≤ −2.5. Data were collected through structured interviews and medical-record review. Medication adherence was assessed using the 8-item Morisky Medication Adherence Scale (MMAS-8), and beliefs about medicines were measured using the Beliefs about Medicines Questionnaire (BMQ). Prescribing patterns were characterized by drug class, dose, and frequency, and prescribing appropriateness was evaluated using prescribed daily dose/defined daily dose (PDD/DDD) ratios based on WHO ATC/DDD standards. Predictors of adherence were examined using univariate and multivariable Firth penalized logistic regression. Results: The median age was 70 years (IQR 63–76), 89.0% of participants were female, and 32.0% had a prior fracture history. Denosumab was the most frequently prescribed anti-osteoporotic therapy (59.0%), followed by romosozumab (30.7%), whereas bisphosphonates and parathyroid hormone analogues were infrequently used (2.7% and 4.7%, respectively). Prescribed dosing closely aligned with WHO standards for all evaluated agents. Overall, 40.7% of patients were classified as adherent and 59.3% as non-adherent. Adherence was not significantly associated with age, gender, nationality, fracture history, polypharmacy, or most comorbidities. In contrast, medication beliefs demonstrated a strong relationship with adherence. In multivariable Firth regression, stronger medication concerns were independently associated with lower odds of adherence (adjusted OR 0.033, 95% CI 0.003–0.355; p = 0.0049), while having more than two comorbidities was also associated with reduced adherence (adjusted OR 0.076, 95% CI 0.008–0.688; p = 0.022). Conclusions: In this UAE real-world cohort, osteoporosis pharmacotherapy was dominated by injectable biologic agents and was prescribed in close agreement with standard dosing recommendations. However, medication adherence remained suboptimal. Patient beliefs, particularly treatment-related concerns, emerged as a more important determinant of adherence than demographic or most clinical characteristics. These findings highlight the need for belief-sensitive, patient-centered adherence interventions alongside optimized pharmacotherapy to improve osteoporosis outcomes in routine practice. Full article

The immunological composition of the microenvironment has shown relevance for diagnosis, prognosis, and therapy in solid tumors but remains underexplored in acute leukemias. We investigated the significance of the acute myeloid leukemia (AML) bone marrow microenvironment in predicting chemosensitivity and long-term remission in pediatric patients. We analyzed 32 non-promyelocytic pediatric AML patients at diagnosis using a NanoString PanCancer IO 360 assay, RNA sequencing, and deep-phenotype flow cytometry analyses. The findings were validated using the pediatric TARGET AML dataset. A short signature of three interferon (IFN)-related genes (GBP1, PARP12, and TRAT1) distinguished patients with chemosensitive disease and reduced minimal residual disease after induction chemotherapy. The signature stratified patients overall, and within the clinically defined “standard-risk” group, patients with high gene expression at diagnosis had significantly longer overall survival. The leukemia microenvironment associated with this signature showed enrichment of non-exhausted CD4⁺ and CD8⁺ T cytotoxic lymphocytes and expansion of CD8⁺ T effector memory cells re-expressing CD45RA (TEMRA) in patients with a favorable prognosis. Our results show the importance of the bone marrow microenvironment in pediatric AML and provide tools for a refined stratification of “standard-risk” patients, lacking adequate risk-oriented therapies. They also offer a promising guide for tackling immune pathways and exploiting immune-targeted therapies. Full article

Objective: To characterize the frequency, timing, patterns of first distant metastasis, and post-metastatic survival in uterine sarcoma using population-based registry data. Methods: This study included all patients diagnosed with uterine sarcoma between 2000 and October 2025 in the regional cancer registry of Saxony-Anhalt, Germany. Patients with carcinosarcoma were excluded. Metastatic disease was classified as primary (present at diagnosis or ≤3 months) or metachronous (>3 months). Metastatic patterns were analyzed based on the first metastatic presentation only. Overall survival (OS), recurrence-free survival (RFS), and post-metastatic OS were estimated using Kaplan–Meier methods. RFS was defined as the interval from confirmed tumor-free status after primary therapy to first recurrence or death, and was restricted to patients who achieved tumor-free status (n = 114). Multivariable Cox regression analyses for OS and RFS were performed with administrative censoring at 5 years. Results: A total of 155 patients with uterine sarcoma were included. During follow-up, 54 patients (34.8%) were diagnosed with metastatic disease, of whom 30 (55.6%) presented with primary metastatic disease. Lung was the most frequent site of first metastasis, followed by bone, peritoneum, and liver; 43.4% of metastatic patients had multiple synchronous metastatic sites at first presentation. Median time to first metastasis was short, with several metastatic sites showing median values of zero months, reflecting the high proportion of primary metastatic disease. Median post-metastatic OS was 12 months. Advanced FIGO (Fédération Internationale de Gynécologie et d’Obstétrique) stage and failure to achieve tumor-free status after primary therapy were independently associated with worse OS, whereas histologic subtype was not. Conclusions: In this population-based cohort, metastatic disease occurred in more than one-third of patients with uterine sarcoma and was frequently present at diagnosis. Lung metastases predominated as the first site of distant spread, and post-metastatic survival was poor. These findings underscore the importance of comprehensive staging at diagnosis and highlight the aggressive metastatic behavior of uterine sarcoma in real-world practice. Full article

Background/Objectives: Sarcopenia and impaired bone quality are increasingly recognized as important determinants of outcomes after liver transplantation (LT). However, longitudinal data describing early post-transplant musculoskeletal changes in patients with chronic hepatitis B virus (HBV) infection, particularly according to hepatocellular carcinoma (HCC) status, remain limited. Aim: To evaluate longitudinal changes in skeletal muscle mass and vertebral bone attenuation after LT in patients with chronic HBV infection and to assess the impact of concomitant HCC and clinical subgroups on these patterns. Methods: This retrospective, single-center study included 99 adult patients who underwent LT for chronic HBV infection (HBV alone, n = 59; HBV + HCC, n = 40) between January 2018 and December 2024. Contrast-enhanced abdominal computed tomography examinations obtained before transplantation and at approximately 6 (POD180) and 12 months (POD365) after transplantation were analyzed. Skeletal muscle was assessed using psoas muscle area (PMA) and psoas muscle index (PMI), while bone quality was evaluated using mean vertebral trabecular attenuation averaged across L1–4. Longitudinal changes were examined according to HCC status, sex, Child–Pugh class, and survival status. Results: Repeated-measures analyses of longitudinal changes demonstrated a significant decline in both PMA and PMI at POD180 and POD365 compared with pre-transplant values (PMA: p = 0.006; PMI: p = 0.009). These patterns were comparable between patients with HBV alone and those with HBV-related HCC, with no significant differences between groups (all p > 0.05). Male patients consistently exhibited higher PMA and PMI values than female patients across all assessed time points (both p < 0.001). In contrast, neither Child–Pugh class nor mortality status was associated with differences in PMA or PMI levels (all p > 0.05). L1–4 attenuation declined markedly by POD180 and remained below baseline at POD365 (p < 0.001). Although overall L1–4 values did not differ between disease groups (p = 0.109), the temporal pattern of L1–4 change differed according to survival status (p = 0.026), with a greater decline observed in non-survivors. Conclusions: In patients with chronic HBV undergoing LT, early post-transplant loss of skeletal muscle and vertebral bone attenuation is common and persists throughout the first year of follow-up. These changes occur similarly in patients with and without HCC. CT-based assessment of muscle and bone parameters, particularly L1–4 attenuation, may therefore support early post-transplant risk stratification. Full article

Psoriatic arthritis (PsA) is a systemic autoimmune inflammatory disease affecting both the joints and the skin, with the potential involvement of multiple organ systems. A hallmark feature of PsA is enthesitis—inflammation at the sites where tendons and ligaments insert into bone—which arises from a combination of mechanical stress and immune-mediated inflammation. Another defining characteristic of the disease is the paradoxical coexistence of bone erosion and new bone formation, distinguishing it from other inflammatory arthritides. The therapeutic landscape of PsA has evolved considerably over time. Non-steroidal anti-inflammatory drugs (NSAIDs) remain a cornerstone of symptom management, while conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as methotrexate, are widely used to control disease progression. The introduction of biologic agents has revolutionized PsA management, with TNF inhibitors, IL-17 inhibitors, and IL-23 inhibitors demonstrating efficacy across a broad range of clinical manifestations. More recently, targeted synthetic small molecules—including JAK inhibitors and TYK2 inhibitors—have expanded the armamentarium of available therapies. The overarching goals of treatment in PsA include the suppression of the underlying inflammatory process and the prevention of structural joint damage. The impact of each therapeutic option on cutaneous psoriasis is an additional and important consideration that guides individualized treatment options. Full article