WWP2 confers risk to osteoarthritis by affecting cartilage matrix deposition via hypoxia associated genes.

OBJECTIVE: To explore the co-expression network of the osteoarthritis (OA) risk gene WWP2 in articular cartilage and study cartilage characteristics when mimicking the effect of OA risk allele rs1052429-A on WWP2 expression in a human 3D in vitro model of cartilage. METHOD: Co-expression behavior of WWP2 with genes expressed in lesioned OA articular cartilage (N = 35 samples) was explored. By applying lentiviral particle mediated WWP2 upregulation in 3D in vitro pellet cultures of human primary chondrocytes (N = 8 donors) the effects of upregulation on cartilage matrix deposition was evaluated. Finally, we transfected primary chondrocytes with miR-140 mimics to evaluate whether miR-140 and WWP2 are involved in similar pathways. RESULTS: Upon performing Spearman correlations in lesioned OA cartilage, 98 highly correlating genes (|ρ| > 0.7) were identified. Among these genes, we identified GJA1, GDF10, STC2, WDR1, and WNK4. Subsequent upregulation of WWP2 on 3D chondrocyte pellet cultures resulted in a decreased expression of COL2A1 and ACAN and an increase in EPAS1 expression. Additionally, we observed a decreased expression of GDF10, STC2, and GJA1. Proteomics analysis identified 42 proteins being differentially expressed with WWP2 upregulation, which were enriched for ubiquitin conjugating enzyme activity. Finally, upregulation of miR-140 in 2D chondrocytes resulted in significant upregulation of WWP2 and WDR1. CONCLUSIONS: Mimicking the effect of OA risk allele rs1052429-A on WWP2 expression initiates detrimental processes in the cartilage shown by a response in hypoxia associated genes EPAS1, GDF10, and GJA1 and a decrease in anabolic markers, COL2A1 and ACAN.

Bone material strength index as measured by in vivo impact microindentation is normal in subjects with high-energy trauma fractures.

Bone material properties were assessed using impact microindentation in patients with high-energy trauma fractures. Compared to patients with low-energy trauma fractures, bone material strength index was significantly higher in patients with high-energy trauma fractures, and did not differ between patients with osteopenia and those with osteoporosis within each trauma group. INTRODUCTION: Impact microindentation (IMI) is a technique to assess tissue-level properties of bone at the tibia. Bone material strength index (BMSi), measured by IMI, is decreased in patients with low-energy trauma fractures, independently of areal bone mineral density (aBMD), but there is no information about BMSi in patients with high-energy trauma fractures. In the present study, we evaluated tissue-level properties of bone with IMI in patients with high-energy trauma fractures. METHODS: BMSi was measured 3.0 months (IQR 2.0-5.8) after the fracture in 40 patients with high-energy trauma and 40 age- and gender-matched controls with low-energy trauma fractures using the OsteoProbe® device. RESULTS: Mean age of high- and low-energy trauma patients was 57.7 ± 9.1 and 57.2 ± 7.7 years, respectively (p = 0.78). Fracture types were comparable in high- vs low-energy trauma patients. Lumbar spine (LS)-aBMD, but not femoral neck (FN)-aBMD, was higher in high- than in low-energy trauma patients (LS 0.96 ± 0.13 vs 0.89 ± 0.13 g/cm2, p = 0.02; FN 0.75 ± 0.09 vs 0.72 ± 0.09 g/cm2, p = 0.09). BMSi was significantly higher in high- than in low-energy trauma patients (84.4 ± 5.0 vs 78.0 ± 4.6, p = 0.001), also after adjusting for aBMD (p = 0.003). In addition, BMSi did not differ between patients with osteopenia and those with osteoporosis within each trauma group. CONCLUSION: Our data demonstrate that BMSi and LS-aBMD, but not FN-aBMD, are significantly higher in high-energy trauma patients compared to matched controls with similar fractures from low-energy trauma. Further studies of non-osteoporotic patients with high-energy trauma fracture with measurements of BMSi are warranted to determine whether IMI might help in identifying those with reduced bone strength.

Incidence and centralization of chordoma in the Netherlands: A nationwide study between 1991 and 2020.

INTRODUCTION: Chordomas are rare malignant bone tumors arising in the axial skeleton, with an incidence of 0.3-0.88 per million inhabitants. We studied the annual incidence rate and centralization of treatment for chordoma in the Netherlands. METHODS: We retrieved pathology excerpts from the PALGA nationwide Dutch Pathology Registry between 1991 and 2019 for patients with a chordoma to calculate incidence rates. From pathology reports we extracted patient age at diagnosis, sex, year of diagnosis, localization of primary tumor, histologic chordoma subtype (conventional including chondroid, poorly differentiated or dedifferentiated), center of diagnosis (bone tumor referral center (BTC) or other hospital), and partial identification of the BTCs. RESULTS: A total of 420 individual chordoma patients were identified in the given time period. The incidence of chordoma increased from 0.593 per million inhabitants between 1991-1995 to 1.111 from 2015-2019 (P = 0.001). Median age at diagnosis was 63 years (range 1-95), 252 patients (60%) were male. The proportion of samples analyzed in a BTC either primarily or secondary, as a consultation, revision or referral, increased significantly from 29.3% to 84.4% (P < 0.001). Most primary and secondary samples were analyzed at the Leiden University Medical Center (LUMC, 54.4% and 57% respectively). CONCLUSIONS: This study shows an increase in the standardized incidence of pathology proven chordoma in the Netherlands. We observed an increase in samples being analysed in the specialized BTCs as well, which is in line with current guidelines and will hopefully lead to more accurate diagnoses and optimal treatment plans for chordoma patients in specialized treatment centers.

A mobile app for postoperative wound care after arthroplasty: Ease of use and perceived usefulness.

BACKGROUND: Early postoperative discharge after joint arthroplasty may lead to decreased wound monitoring. A mobile woundcare app with an integrated algorithm to detect complications may lead to improved monitoring and earlier treatment of complications. In this study, the ease of use and perceived usefulness of such a mobile app was investigated. OBJECTIVE: Primary objective was to investigate the ease of use and perceived usefulness of using a woundcare app. Secondary objectives were the number of alerts created, the amount of days the app was actually used and patient-reported wound infection. METHODS: Patients that received a joint arthroplasty were enrolled in a prospective cohort study. During 30 postoperative days, patients scored their surgical wound by daily answering of questions in the app. An inbuilt algorithm advised patients to contact their treating physician if needed. On day 15 and day 30, additional questionnaires in the app investigated ease of use and perceived usefulness. RESULTS: Sixty-nine patients were included. Median age was 68 years. Forty-one patients (59.4%) used the app until day 30. Mean grade for ease of use (on a Likert-scale of 1-5) were 4.2 on day 15 and 4.2 on day 30; grades for perceived usefulness were 4.1 on day 15 and 4.0 on day 30. Out of 1317 days of app use, an alert was sent to patients on 29 days (2.2%). Concordance between patient-reported outcome and physician-reported outcome was 80%. CONCLUSIONS: Introduction of a woundcare app with an alert communication on possible wound problems resulted in a high perceived usefulness and ease of use. Future studies will focus on validation of the algorithm and the association between postoperative wound leakage and the incidence of prosthetic joint infection.

Multiflora and Gram-Negative Microorganisms Predominate in Infections Affecting Pelvic Endoprostheses Following Tumor Resection.

BACKGROUND: Periprosthetic infections after pelvic reconstruction are common, with reported rates ranging from 11% to 53%. Management of these infections is troublesome, as they commonly necessitate multiple surgical interventions and implant removal. The epidemiology and outcomes of these infections are largely unknown. The aim of this study was to analyze the causative microorganisms and the clinical outcome of treatment in a series of patients with pelvic endoprostheses affected by infection following tumor resection. METHODS: In this retrospective, multicenter cohort study, we identified all patients who developed an infection after endoprosthetic reconstruction in periacetabular tumor resection, between 2003 and 2017. The microorganisms that were isolated during the first debridement were recorded, as were the number of reoperations for ongoing infection, the antimicrobial treatment strategy, and the outcome of treatment. RESULTS: In a series of 70 patients who underwent pelvic endoprosthetic reconstruction, 18 (26%) developed an infection. The type of pelvic resection according to the Enneking-Dunham classification was type P2-3 in 14 (78%) of these patients and type P2 in 4 (22%). Median follow-up was 66 months. Fourteen (78%) of the 18 patients with infection had a polymicrobial infection. Enterobacteriaceae were identified on culture for 12 (67%). Of a total 42 times that a microorganism was isolated, the identified pathogen was gram-negative in 26 instances (62%). Microorganisms associated with intestinal flora were identified 32 times (76%). At the time of latest follow-up, 9 (50%) of the patients had the original implant in situ. Of these, 2 had a fistula and another 2 were receiving suppressive antibiotic therapy. In the remaining 9 (50%) of the patients, the original implant had been removed. At the time of final follow-up, 3 of these had a second implant in situ. The remaining 6 patients had undergone no secondary reconstruction. CONCLUSIONS: Infections that affect pelvic endoprostheses are predominantly polymicrobial and caused by gram-negative microorganisms, and may be associated with intestinal flora. This differs fundamentally from mono-bacterial gram-positive causes of conventional periprosthetic joint infections and may indicate a different pathogenesis. Our results suggest that prophylaxis and empiric treatment may need to be re-evaluated. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Trends in the surgical treatment of pathological fractures of the long bones: based on a questionnaire among members of the Dutch Orthopaedic Society and the European Musculo-Skeletal Oncology Society (EMSOS).

AIMS: The aim of this study was to assess the current trends in the estimation of survival and the preferred forms of treatment of pathological fractures among national and international general and oncological orthopaedic surgeons, and to explore whether improvements in the management of these patients could be identified in this way. MATERIALS AND METHODS: All members of the Dutch Orthopaedic Society (DOS) and the European Musculoskeletal Oncology Society (EMSOS) were invited to complete a web-based questionnaire containing 12 cases. RESULTS: A total of 96 of 948 members of the DOS (10.1%; groups 1 and 2) and 33 of 182 members of the EMSOS (18%; group 3) replied. The estimation of survival was accurate by more than 50% of all three groups, if the expected survival was short (< 3 months) or long (> 12 months). General orthopaedic surgeons preferred using an intramedullary nail for fractures of the humerus and femur, irrespective of the expected survival or the origin of primary tumour or the location of the fracture. Oncological orthopaedic surgeons recommended prosthetic reconstruction in patients with a long expected survival. CONCLUSION: Identifying patients who require centralized care, as opposed to those who can be adequately treated in a regional centre, can improve the management of patients with pathological fractures. This differentiation should be based on the expected survival, the type and extent of the tumour, and the location of the fracture. Cite this article: Bone Joint J 2018;100-B:1392-8.

Severity classification of Tenosynovial Giant Cell Tumours on MR imaging.

AIM: Current development of novel systemic agents requires identification and monitoring of extensive Tenosynovial Giant Cell Tumours (TGCT). This study defines TGCT extension on MR imaging to classify severity. METHODS: In part one, six MR parameters were defined by field-experts to assess disease extension on MR images: type of TGCT, articular involvement, cartilage-covered bone invasion, and involvement of muscular/tendinous tissue, ligaments or neurovascular structures. Inter- and intra-rater agreement were calculated using 118 TGCT MR scans. In part two, the previously defined MR parameters were evaluated in 174 consecutive, not previously used, MR-scans. TGCT severity classification was established based on highest to lowest Hazard Ratios (HR) on first recurrence. RESULTS: In part one, all MR parameters showed good inter- and intra-rater agreement (Kappa≥0.66). In part two, cartilage-covered bone invasion and neurovascular involvement were rarely appreciated (<13%) and therefore excluded for additional analyses. Univariate analyses for recurrent disease yielded positive associations for type of TGCT HR12.84(95%CI4.60-35.81), articular involvement HR6.00(95%CI2.14-16.80), muscular/tendinous tissue involvement HR3.50(95%CI1.75-7.01) and ligament-involvement HR4.59(95%CI2.23-9.46). With these, a TGCT severity classification was constructed with four distinct severity-stages. Recurrence free survival at 4 years (log rank p < 0.0001) was 94% in mild localized (n56, 1 recurrence), 88% in severe localized (n31, 3 recurrences), 59% in moderate diffuse (n32, 12 recurrences) and 36% in severe diffuse (n55, 33 recurrences). CONCLUSION: The proposed TGCT severity classification informs physicians and patients on disease extent and risk for recurrence after surgical treatment. Definition of the most severe subgroup attributes to a universal identification of eligible patients for systemic therapy or trials for novel agents.