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Fusions involving NTRK1, NTRK2, and NTRK3 are oncogenic drivers occurring in a spectrum of mesenchymal neoplasms ranging from benign to highly malignant tumors. To gain further insights into the staining profile with the pan-TRK assay, we analyzed a large number of soft tissue sarcomas and correlated our findings with molecular testing. Additionally, we expand the spectrum of NTRK-fusion tumors by reporting a mesenchymal lesion in the lung as well as a mesenchymal skin lesion in the spectrum of benign fibrous histiocytoma with NTRK—fusion. We retrospectively reviewed soft tissue sarcomas diagnosed at the Diagnostic and Research Institute of Pathology, Medical University of Graz, between 1999 and 2019, and cases from the consultation files of one of the authors (BLA). In total, 494 cases were analyzed immunohistochemically with pan-TRK antibody (clone EPR17341, RTU, Roche/Ventana) and positive cases (defined as any cytoplasmic/nuclear staining in more than 1% of tumor cells) underwent next-generation sequencing (NGS). Immunohistochemical staining was observed in 16 (3.2%) cases. Eleven cases with focal weak and moderate cytoplasmic/membranous or focal moderate to strong nuclear staining did not harbor an NTRK-fusion (three synovial sarcomas, three leiomyosarcomas, two extraskeletal myxoid chondrosarcomas, and one each: dedifferentiated liposarcoma, pleomorphic liposarcoma, and myxofibrosarcoma). Four cases showed strong diffuse nuclear and/or cytoplasmatic staining, and one case showed diffuse, but weak cytoplasmic staining. All these cases demonstrated an NTRK-fusion (LMNA-NTRK1, IRF2BP2-NTRK1, TMB3-NTRK1, ETV6-NTRK3, RBPMS-NTRK3). Pan-TRK assay (clone EPR17341, RTU, Roche, Ventana) immunohistochemistry serves as a reliable diagnostic marker that can also be expressed in non-NTRK-rearranged mesenchymal neoplasms. It can be used as a surrogate marker for identification of NTRK fusion, nevertheless, an RNA-based NGS for detection of the specific fusion should be performed to confirm the rearrangement, if patients are undergoing targeted therapy. Additionally, we identified NTRK-fusion-positive, primary mesenchymal tumors of the lung and the skin.

Cementless calcar-guided femoral short stems in total hip arthroplasty (THA) have become increasingly popular over the years. Early distal migration of femoral stems measured by Einzel-Bild-Roentgen Analyse, Femoral Component Analyse (EBRA-FCA) has been reported to be a risk factor for aseptic loosening. The aim of this study was to analyse axial migration behavior and subsidence of a new short stem (launched in 2015) over a follow-up period of 3 years. According to the study protocol, 100 hip osteoarthritis patients who consecutively received an unilateral cementless calcar-guided short stem (ANA.NOVA proxy) at a single department were prospectively included in this mid-term follow-up study. Thirteen patients were lost to follow-up, resulting in 87 patients with unilateral THA who fulfilled the criteria for migration analysis with EBRA-FCA. The cohort comprised 41 males (mean age: 60 ± 16.5; mean BMI (Body Mass Index): 30 ± 13) and 46 females (mean age: 61 ± 15.5; mean BMI: 27 ± 10). Seven standardized radiographs per patient were analyzed with EBRA-FCA. An average migration of 2.0 mm (0.95–3.35) was observed within the first 3 years. The median increase during the first year was higher than in the second and third year (1.2 mm [IQR: 0.5–2.15] vs. 0.3 mm [IQR: 0.1–0.6 mm] vs. 0.25 mm [IQR: 0.1–0.5 mm]. Detected migration did not lead to stem loosening, instability, dislocation, or revision surgery in any patient. A higher risk for subsidence was observed in male and heavyweight patients, whereas the female gender was associated with a lower risk. No correlation between migration and revision could be observed. Although moderate subsidence was detectable, the performance of the short stem ANA.NOVA proxy is encouraging. Yet, its use may be re-considered in overweight and male patients due to more pronounced subsidence.

Background Unplanned excisions (UE) of soft tissue sarcomas (STS) carry a high risk for local recurrence (LR) due to marginal/intralesional resections. However, there are reports about improved prognosis for UE patients who have re-resection compared with patients who undergo planned surgery. The present multicentre study was designed to define characteristics of UE patients and to investigate the impact of UE on subsequent therapy and patient outcomes. Methods A total of 728 STS patients (376 males, 352 females; mean age: 58 years) who underwent definite surgery at one of three tumour centres were retrospectively included. Time-to-event analyses were calculated with log-rank and Gray’s tests, excluding patients with primary metastasis ( n  = 59). A propensity-score (PS) of being in the UE group was estimated, based on differences at baseline between the UE group and non-UE group. An inverse-probability-of-UE weight (IPUEW) was generated and time-to-event analyses calculated after IPUEW weighting. Results Before referral, 38.6% of patients ( n  = 281) had undergone UE. Unplanned excision patients were younger ( p  = 0.036), rather male ( p  = 0.05), and had smaller ( p  < 0.005), superficially located tumours ( p  < 0.005). Plastic reconstructions ( p  < 0.005) and adjuvant radiotherapy ( p  = 0.041) more often were needed at re-resection. In univariable analysis, re-resected patients had improved overall survival (OS; p  = 0.027) and lower risk of distant metastasis (DM; p  = 0.002) than primarily resected patients, whereas risk of LR was similar ( p  = 0.359). After weighting for the IPUEW, however, differences in terms of OS ( p  = 0.459) and risk of DM ( p  = 0.405) disappeared. Conclusions The present study does not support prior findings of improved outcome for UE patients. Unplanned excisions have a major impact on subsequent therapy, yet they do not seem to affect negatively the long-term oncology outcome.

Myxoid liposarcoma (MLPS) is a rare soft tissue sarcoma characterized by histopathological variability, which poses challenges for accurate grading and treatment planning. This study evaluated the feasibility of an automated MRI-based pipeline that combines deep learning and radiomics for non-invasive tumor assessment. In a retrospective multicenter cohort of 48 patients with histologically confirmed MLPS, a 3D U-Net convolutional neural network was trained to perform automatic tumor segmentation on axial T2-weighted MR images. Radiomics features were subsequently extracted from the segmented volumes and used to train a Random Forest classifier for predicting tumor grade, defined by centralized histopathological review according to WHO criteria. The segmentation model achieved a median Dice similarity coefficient of 0.892. The radiomics-based grading classifier reached a mean area under the curve of 0.745, with an F1-score of 0.729 and a balanced accuracy of 0.723 in distinguishing high-grade from low-grade tumors. Most classification errors occurred in borderline or histologically heterogeneous cases. These findings suggest that automated segmentation and radiomics analysis may offer valuable support for MLPS grading and complement histopathology, particularly in diagnostically complex cases. Further prospective validation in larger cohorts is warranted.

PurposeSpinal fusion is used for treatment of spinal deformities, degeneration, infection, malignancy, and trauma. Reduction of motion enables osseous fusion and permanent stabilization of segments, compromised by loosening of the pedicle screws (PS). Deep implant infection, biomechanical, and chemical mechanisms are suspected reasons for loosening of PS. Study objective was to investigate the frequency and impact of deep implant infection on PS loosening.MethodsIntraoperative infection screening from wound and explanted material sonication was performed during revision surgeries following dorsal stabilization. Case history events and factors, which might promote implant infections, were included in this retrospective survey.Results110 cases of spinal metal explantation were included. In 29.1% of revision cases, infection screening identified a germ, most commonly Staphylococcus (53.1%) and Propionibacterium (40.6%) genus. Patients screened positive had a significant higher number of previous spinal operations and radiologic loosening of screws. Patients revised for adjacent segment failure had a significantly lower rate of positive infection screening than patients revised for directly implant associated reasons. Removal of implants that revealed positive screening effected significant pain relief.ConclusionsChronic implant infection seems to play a role in PS loosening and ongoing pain, causing revision surgery after spinal fusion. Screw loosening and multiple prior spinal operations should be suspicious for implant infection after spinal fusion when it comes to revision surgery.Graphical abstractThese slides can be retrieved under Electronic Supplementary Material.

Background Although chondrosarcoma is the second most common primary malignant bone tumor, treatment options are limited due to its extensive resistance to a chemo- and radiation therapy. Since shikonin has shown potent anticancer activity in various types of cancer cells, it represents a promising compound for the development of a new therapeutic approach. Methods The dose-relationships of shikonin and its derivatives acetylshikonin and cyclopropylshikonin on two human chondrosarcoma cell lines were measured using the CellTiter-Glo®. The changes in the cell cycle were presented by flow cytometry. Protein phosphorylation and expression apoptotic markers, MAPKs and their downstream targets were analyzed using western blotting and gene expression were evaluated using RT-qPCR. Results Chondrosarcoma cells showed a dose-dependent inhibition of cell viability after treatment with shikonin and its derivatives, with the strongest effect for shikonin and IC 50 values of 1.3 ± 0.2 µM. Flow cytometric measurements revealed a G 2 /M arrest of the cells after treatment. Protein and gene expression analysis demonstrated a dose-dependent downregulation of survivin and XIAP, and an upregulation of Noxa, γH2AX, cleaved caspase-8, -9, -3, and -PARP. Furthermore, the expression of various death receptors was modulated. As MAPK signaling pathways play a key role in tumor biology, their phosphorylation pattern and their corresponding downstream gene regulation were analyzed. Treatment with shikonin derivatives caused an inhibition of pSTAT3 and an increase of pAKT and the MAPKs pERK, pJNK, and pp38 in a dose-dependent manner. Conclusions These data demonstrated the significant anti-tumorigenic effect of shikonin derivatives in chondrosarcoma and encourage further research.

Soft tissue sarcomas (STS) constitute a rare tumour entity comprising over 50 histological subtypes. MicroRNAs (miRNAs) are short non-protein coding RNA molecules that regulate gene expression by targeting the 3’-untranslated region of messenger RNAs. They are involved in a variety of human diseases, including malignancies, such as endometrial cancer, osteosarcoma, bronchial carcinoma and breast cancer. In STS, various miRNAs are differentially expressed, thus contributing to development, progression and invasion. Therefore, the aim of the present review is to summarise current knowledge on the role of miRNAs in STS. Furthermore, the potential role of miRNAs as diagnostic, prognostic and predictive biomarkers is discussed.

IntroductionThe aim of this study was to compare the use of mobile-bearing, fixed-bearing, posterior-stabilized (PS) and medial pivot design to describe epidemiological differences and subsequent outcomes.Materials and methodsA systematic literature search was performed using the NORE website to identify the relevant arthroplasty registers. Inclusion criteria were the following: (1) reports had to be publicly available, (2) reports had to be written in German or English language, (3) differentiation between mobile- and fixed-bearing, posterior-stabilized, and if possible, medial pivot designs had to be possible from the present reports, and (4) data had to be reported for at least three consecutive years and the latest report had to be from the year 2020 to retrieve recent data.ResultsSix registries (England and Wales, Australia, Norway, New Zealand, Germany, Switzerland) offered sufficient data according to the inclusion criteria. In all countries, the dominant type of bearing used for total knee arthroplasty (TKA) was fixed-bearing, with percentages ranging from 60.8% to 84.1% in 2018, 63.6% to 85.7% in 2019 and 66.2% to 87.4% in 2020. A large variation was observed concerning mobile-bearing design, which showed a range from 2.8% to 39.2% in 2018, 2.6% to 36.4% in 2019 and 2.9% to 33.8% in 2020. Some variation was found regarding the use of PS TKA, as its percentage frequency ranged from 9.7% to 29.2% in 2018, 9.8% to 29.4% in 2019 and 10.1% to 28.5% in 2020. Medial pivot design had a share of 9.1% in 2018, 8.6% in 2019 and 8.4% in 2020 in Australia, while it only accounted for 1.4% in 2018, 2.1% in 2019 and 2.5% in 2020 in Germany.ConclusionThe comparison of arthroplasty registers from England and Wales, Australia, Norway, New Zealand, Germany and Switzerland revealed large differences regarding the application of posterior-stabilized designs, but also common ground considering the overwhelming use of fixed-bearing inserts, which, when inserted correctly, eradicate the potential complication of bearing dislocation. Arthroplasty registers offer a real-world clinical perspective with the aim to improve quality and patient safety.

Purpose Traumatic brain injury (TBI) represents a major contributor to global morbidity and mortality, and the optimization of diagnostic approaches continues to be a matter of considerable scientific debate. The S100 calcium-binding protein B (S100B) value is characterized by a high diagnostic negative predictive value (NPV) and is obtained without exporure to radiation. The aim of the study was to investigate the NPV of the S100B level in the patient cohort aged 75 and older with TBI and compare the results with a cohort of individuals below 75. The hypothesis was, that the S100B value would have a sufficiently high NPV in both patient groups, thereby serving as a diagnostic marker, but with a higher NPV in the below 75 age group. Materials and methods A retrospective study was conducted on 815 TBI patients from a Level I trauma center from April 2016 to May 2024. Both, S100B levels and CT scans were obtained within 30 min to 6 h post-trauma. Patients were divided into two groups: below 75 years and 75 years and older. S100B levels ≥ 0.105 µ/L were considered positive.NPV and sensitivity were calculated for both groups. Results Among the 815 patients, 76 had normal S100B and CT results, 13 had abnormal CT but normal S100B, 65 had elevated S100B and abnormal CT, and 661 had elevated S100B with normal CT. The overall NPV was 85.4% (95% CI 0.753, 0.909; p  < 0.01), with a sensitivity of 83.3% (95% CI 0.776, 0.919; p  < 0.01). In the under-75 group (574 patients), the NPV was 86.8% (95% CI 0.816, 1; p  < 0.01), and sensitivity was 76.2% (95% CI 0.5, 1; p  < 0.01). In the over-75 group (241 patients), the NPV was 77% (95% CI 0.622, 0.878; p  < 0.01), with sensitivity of 91.7% (95% CI 0.786, 0.938; p  < 0.01). The intervention rate was 0.3% in the under-75 group and 1.6% in the over-75 group. Conclusion We found a clear and significant correlation between a negative S100B level and normal CT scan. We believe that the determination of S100B levels significantly reduces the radiation exposure for TBI patients, especially in younger patients. However, its reliability varies by age, warranting further investigation in diverse populations and TBI severities.

Silver-coated megaprostheses are considered to reduce infection rate following reconstruction of bone defects in tumour surgery or revision arthroplasty. However, little is known about systemic silver exposure and possible side effects. The aim of this study was to analyse serum silver concentrations in patients with silver-coated megaprostheses over a prolonged time period. Between 2004 and 2016, 46 patients (52.2% female, mean age at surgery 47.1 ± 24.2 years) received silver-coated megaprostheses for septic (n = 26) or oncological (n = 17; main implant since 2013) indications, or aseptic loosening (n = 3). Blood was drawn from all patients within the first few days following surgery (without silver ion levels) and thereafter every 6 months at the outpatient department (with silver ion levels). Inductively coupled plasma mass spectrometry was used to determine silver ion levels. Median follow-up was 47.3 months (IQR: 16.1–78.9). Overall, 29 revision surgeries became necessary in 20 patients, equivalent to a cumulative complication rate of 63.0%. Revisions were most commonly for periprosthetic joint infections (PJIs, n = 12) and instability/soft tissue problems (n = 10). Revision-free implant survival was 81.4%, 42.3% and 35.2% at one, 5 and 10 years. Incidence of local argyria was 8.7% (n = 4). Silver ion levels at two or more consecutive time points during follow-up were available for 26 patients. An increment of silver levels within the first months (“run-in”) was observed, followed by an unspecific undulating course. Median initial and latest follow-up (median, 49.5 months) serum silver ion levels were 16.0 ppb (IQR: 9.1–29.1) and 7.4 ppb (IQR: 2.7–14.1), respectively. According to the multivariate mixed linear random-effects model, development of PJI was associated with significantly higher silver ion levels over time (p = 0.002), irrespective of time from surgery (p = 0.274). In the current series, a cumulative complication rate of 63.0% was observed for patients receiving silver-coated megaprostheses for septic of oncological indications. An overall unspecific course of silver ion concentration was present. Development of PJI was significantly associated with increased silver ion levels over time. Yet, no systemic complication associated to high silver levels occurred. It can be concluded that silver-coated implants constitute a safe solution for megaprosthetic reconstruction, but monitoring of silver concentrations is recommended.