Volker Ewerbeck

Stress fractures in adolescent competitive athletes with open physis

There have been no studies devoted exclusively to stress fractures in competitive athletes with immature skeletal systems so far. The object of this case series was to describe special features of stress fractures in athletes with immature skeletal systems, with special reference to sport-specific strain, diagnosis and treatment results. The study population was made up of 19 children and adolescents with a total of 21 stress fractures. The average observation period was 4.83xa0years [standard deviation (SD) 2.69] and the average age at diagnosis, 14.04xa0years (SD 4.7). The lower extremity was affected in most of our cases. In adolescent athletes, endurance sports appear to lead preferentially to stress fractures in the region of the metatarsal bones, while sports requiring sudden stops at high speed appear to increase the risk of fractures in the region of the tibial diaphysis (P=0.0322). Most (20 of 21) of the fractures in this study were treated conservatively with refraining from athletic activity and reduction of stress/weight-bearing for an average of 6.73xa0weeks (SD 2.91). In five cases the extremity was in addition immobilized in a plaster cast for 5.32xa0weeks (SD 2.21). Complete healing was achieved in 14 cases. In seven cases, however, the treatment did not lead to a satisfactory outcome. Most of the patients whose symptoms persisted over a long period had fractures in the tibia and were engaged in sports requiring frequent sudden stops. Our data suggest that stress fractures in athletes, whose skeletal systems are still immature, lead to a clinical picture that does not always culminate in a good outcome of treatment. We therefore recommend a thorough and early diagnostic investigation (including MRI) and consistent treatment whenever a patient’s history and clinical picture give any indication that a stress fracture might be present.

CD8+/FOXP3+-ratio in osteosarcoma microenvironment separates survivors from non-survivors: A multicenter validated retrospective study

Osteosarcoma is the most common primary bone tumor characterized by juvenile onset, tumor heterogeneity, and early pulmonary metastasis. Therapeutic improvement stagnates since more than two decades. Unlike major malignancies, biomarkers as prognostic factors at time of diagnosis are missing. Disease rareness hampers study recruitment of patient numbers sufficient to outweigh tumor heterogeneity. Here, we analyzed in a multicenter cohort the osteosarcoma microenvironment to reduce effects of tumor cell heterogeneity. We hypothesized that quantitative ratios of intratumoral CD8+T-cells to FOXP3+T-cells (CD8+/FOXP3+-ratios) provide strong prognostic information when analyzed by whole-slide imaging in diagnostic biopsies. We followed recommendations-for-tumor-marker-prognostic-studies (REMARK). From 150 included cases, patients with complete treatment were identified and assigned to the discovery (diagnosis before 2004) or the validation cohort (diagnosis 2004–2012). Highly standardized immunohistochemistry of CD8+ and FOXP3+, which was validated by methylation-specific gene analysis, was performed followed by whole-slide analysis and clinical outcome correlations. We observed improved estimated survival in patients with CD8+/FOXP3+-ratios above the median (3.08) compared to patients with lower CD8+/FOXP3+-ratios (p = 0.000001). No patients with a CD8+/FOXP3+-ratio above the third quartile died within the observation period (median follow-up 69 mo). Multivariate analysis demonstrated independence from current prognostic factors including metastasis and response to neoadjuvant chemotherapy. Data from an independent validation cohort confirmed improved survival (p = 0.001) in patients with CD8+/FOXP3+-ratios above 3.08. Multivariate analysis proofed that this observation was also independent from prognostic factors at diagnosis within the validation cohort. Intratumoral CD8+/FOXP3+-ratio in pretreatment biopsies separates patients with prolonged survival from non-survivors in osteosarcoma.

On the inflammatory response in metal-on-metal implants

BackgroundMetal-on-metal implants are a special form of hip endoprostheses that despite many advantages can entail serious complications due to release of wear particles from the implanted material. Metal wear particles presumably activate local host defence mechanisms, which causes a persistent inflammatory response with destruction of bone followed by a loosening of the implant. To better characterize this inflammatory response and to link inflammation to bone degradation, the local generation of proinflammatory and osteoclast-inducing cytokines was analysed, as was systemic T cell activation.MethodsBy quantitative RT-PCR, gene expression of cytokines and markers for T lymphocytes, monocytes/macrophages and osteoclasts, respectively, was analysed in tissue samples obtained intraoperatively during exchange surgery of the loosened implant. Peripheral T cells were characterized by cytofluorometry before surgery and 7 to 10xa0days thereafter.ResultsAt sites of osteolysis, gene expression of cathepsin K, CD14 and CD3 was seen, indicating the generation of osteoclasts, and the presence of monocytes and of T cells, respectively. Also cytokines were highly expressed, including CXCL8, IL-1ß, CXCL2, MRP-14 and CXCL-10. The latter suggest T cell activation, a notion that could be confirmed by detecting a small, though conspicuous population of activated CD4+ cells in the peripheral blood T cells prior to surgery.ConclusionOur data support the concept that metallosis is the result of a local inflammatory response, which according to histomorphology and the composition of the cellular infiltrate classifies as an acute phase of a chronic inflammatory disease. The proinflammatory environment, particularly the generation of the osteoclast-inducing cytokines CXCL8 and IL1-ß, promotes bone resorption. Loss of bone results in implant loosening, which then causes the major symptoms of metallosis, pain and reduced range of motion.

Primary stability of the Fitmore® stem: biomechanical comparison

PurposeAfter clinical introduction of the Fitmore® stem (Zimmer), we noticed the formation of cortical hypertrophies in a few cases. We questioned whether (1) the primary stability or (2) load transfer of the Fitmore® stem differs from other stems unassociated with the formation of hypertrophies. We compared the Fitmore® stem to the well-established CLS® stem.MethodsFour Fitmore® and four CLS® stems were implanted in eight synthetic femurs. A cyclic torque around the stem axis and a mediolateral cyclic torque were applied. Micromotions between stems and femurs were measured to classify the specific rotational implant stability and to analyse the bending behaviour of the stem.ResultsNo statistical differences were found between the two stem designs with respect to their rotational stability (pu2009=u20090.82). For both stems, a proximal fixation was found. However, for the mediolateral bending behavior, we observed a significantly (pu2009<u20090.01) higher flexibility of the CLS® stem compared to the Fitmore® stem.ConclusionHip stem implantation may induce remodelling of the periprosthetic bone structure. Considering the proximal fixation of both stems, rotational stability of the Fitmore® stem might not be a plausible explanation for clinically observed formation of hypertrophies. However, bending results support our hypothesis that the CLS® stem presumably closely follows the bending of the bone, whereas the shorter Fitmore® stem acts more rigidly. Stem rigidity and flexibility needs to be considered, as they may influence the load transfer at the implant–bone interface and thus possibly affect bone remodelling processes.

Improved Survival in Osteosarcoma Patients with Atypical Low Vascularization

BackgroundOsteosarcoma is considered a highly vascularized bone tumor with early metastatic dissemination through intratumoral blood vessels mostly into the lung. Novel targets for therapy such as tumor vascularization are highly warranted since little progress has been achieved in the last 30xa0years. However, proof of relevance for vascularization as a major prognostic parameter has been hampered by tumor heterogeneity, difficulty in detecting microvessels by immunohistochemistry, and small study cohorts. Most recently, we demonstrated that highly standardized whole-slide imaging could overcome these limitations (Kunz et al., PloS One 9(3):e90727, 2014). In this study, we applied this method to a multicenter cohort of 131 osteosarcoma patients to test osteosarcoma vascularization as a prognostic determinant.MethodsComputer-assisted whole-slide analysis, together with enzymatic epitope retrieval, was used for CD31-based microvessel quantification in 131 pretreatment formalin-fixed and paraffin-embedded biopsies from three bone tumor centers. Kaplan–Meier-estimated survival and chemoresponse were determined and multivariate analysis was performed. Conventional hot-spot-based microvessel density (MVD) determination was compared with whole-slide imaging.ResultsWe detected high estimated overall (pxa0≤xa00.008) and relapse-free (pxa0≤xa00.004) survival in 25xa0% of osteosarcoma patients with low osteosarcoma vascularization in contrast to other patient groups. Furthermore, all patients with low osteosarcoma vascularization showed a good response to neoadjuvant chemotherapy. Comparison of conventional MVD determination with whole-slide imaging suggests false high quantification or even exclusion of samples with low osteosarcoma vascularization due to difficult CD31 detection in previous studies.ConclusionLow intratumoral vascularization at the time of diagnosis is a strong predictor for prolonged survival and good response to neoadjuvant chemotherapy in osteosarcoma.

Pain threshold correlates with functional scores in osteoarthritis patients

Background and purpose — Pain sensitization may be one of the reasons for persistent pain after technically successful joint replacement. We analyzed how pain sensitization, as measured by quantitative sensory testing, relates preoperatively to joint function in patients with osteoarthritis (OA) scheduled for joint replacement. Patients and methods — We included 50 patients with knee OA and 49 with hip OA who were scheduled for joint replacement, and 15 control participants. Hip/knee scores, thermal and pressure detection, and pain thresholds were examined. Results — Median pressure pain thresholds were lower in patients than in control subjects: 4.0 (range: 0–10) vs. 7.8 (4–10) (p = 0.003) for the affected knee; 4.5 (2–10) vs. 6.8 (4–10) (p = 0.03) for the affected hip. Lower pressure pain threshold values were found at the affected joint in 26 of the 50 patients with knee OA and in 17 of the 49 patients with hip OA. The American Knee Society score 1 and 2, the Oxford knee score, and functional questionnaire of Hannover for osteoarthritis score correlated with the pressure pain thresholds in patients with knee OA. Also, Harris hip score and the functional questionnaire of Hannover for osteoarthritis score correlated with the cold detection threshold in patients with hip OA. Interpretation — Quantitative sensory testing appeared to identify patients with sensory changes indicative of mechanisms of central sensitization. These patients may require additional pain treatment in order to profit fully from surgery. There were correlations between the clinical scores and the level of sensitization.

Cortical hypertrophy with a short, curved uncemented hip stem does not have any clinical impact during early follow-up

BackgroundShort stems have become more and more popular for cementless total hip arthroplasty in the past few years. While conventional, uncemented straight stems for primary total hip arthroplasty (THA) have shown high survival rates in the long term, it is not known whether uncemented short stems represent a reasonable alternative. As cortical hypertrophy has been reported for short stems, the aim of this study was to determine the radiographic prevalence of cortical hypertrophy and to assess the clinical outcome of a frequently used short, curved hip stem.MethodsWe retrospectively studied the clinical and radiographic results of our first 100 consecutive THAs (97 patients) using the Fitmore® hip stem. Mean age at the time of index arthroplasty was 59xa0years (range, 19 – 79xa0years). Clinical outcome and radiographic results were assessed with a minimum follow-up of 2xa0years, and Kaplan-Meier survivorship analysis was used to estimate survival for different endpoints.ResultsAfter a mean follow-up of 3.3xa0years (range, 2.0 – 4.4xa0years), two patients (two hips) had died, and three patients (four hips) were lost to follow-up. Kaplan-Meier analysis estimated a survival rate of 100xa0% at 3.8xa0years, with revision for any reason as the endpoint. No femoral component showed radiographic signs of loosening. No osteolysis was detected. Cortical hypertrophy was found in 50 hips (63xa0%), predominantly in Gruen zone 3 and 5. In the cortical hypertrophy group, two patients (two hips; 4xa0%) reported some thigh pain in combination with pain over the greater trochanter region during physical exercise (UCLA Score 6 and 7). There was no significant difference concerning the clinical outcome between the cortical hypertrophy and no cortical hypertrophy group.ConclusionsThe survival rate and both clinical and the radiographic outcome confirm the encouraging results for short, curved uncemented stems. Postoperative radiographs frequently displayed cortical hypertrophy but it had no significant effect on the clinical outcome in the early follow-up. Further clinical and radiographic follow-up is necessary to detect possible adverse, long-term, clinical effects of cortical hypertrophy.

Moderne digitale Radiografie der Ganzwirbelsäule bei Skoliose – Dosisreduktion und Qualitätskriterien

PURPOSEnTo reduce the radiation exposure of plain radiographs of the entire spine depending on specific indications, since these are frequently performed examinations of children and young adults with scoliosis and to determine objective quality control criteria to ensure accurate assessment.nnnMATERIALS AND METHODSnIn this prospective randomized study 323 patients underwent plain-radiography of the entire spine with standard and 50u200a% reduced dose. In an experimental pilot-study this target-dose was determined using an Alderson-Phantom. The evaluation of the experimental radiographs, as well as, the randomized plain-radiographs was conducted using the following criteria: endplates (Cobb-angle), spinal process and pedicel (rotation), lateral margin of the vertebral body (lateral alignment), identification of C7u200a/u200aS1 (perpendicular). Two radiologists evaluated these criteria using a score ranging from 1 (definitely assessable) to 4 (not assessable). If one single criteria was evaluated with a score of 3 or more points or more than 2 criteria with 2 points, the radiograph was scored as not assessable. The statistical analysis was conducted as a non-inferiority-trial.nnnRESULTSnSeven (2.4u200a%) of the 290 examined x-rays were scored as not assessable. There was no statistic inferiority between the examinations with standard or reduced dose, while singular assessment of the defined criteria was likewise dose-independent.nnnCONCLUSIONnPlain-radiography of the total spine in patients with scoliosis can be performed with a dose reduction of 50% without a loss of validity. The obtained quality control criteria were clinically applicable.

Quality-controlled dose reduction of full-leg radiography in patients with knee malalignment

ObjectiveDigital plain radiographs of the full leg are frequently performed examinations of children and young adults. Thus, the objective of this work was to reduce the radiation exposure dependent on specific indications, and to determine objective quality-control criteria to ensure accurate assessment.Materials and methodsInstitutional review board approval and informed consent of all participants were obtained. In this prospective, randomized controlled, blinded, two-armed single-center study, 288 evaluable patients underwent plain radiography of the full leg with standard and reduced doses. The evaluation of the plain radiographs was conducted using the following criteria: mechanical axis, leg length, and maturation of the epiphyseal plate. Two blinded radiologists evaluated these criteria using a score ranging from 1 (definitely assessable) to 4 (not assessable). If a single criterion had been evaluated with a score of 3 or more points or all criteria with 2 points, the radiograph was scored as “not assessable”. The study was designed as a non-inferiority trial.ResultsEleven (3.8xa0%) examined X-rays were scored as not assessable. The rate of non-assessable radiographs with 33xa0% reduced dose was significantly not inferior to the rate of non-assessable radiographs with standard dose. The evaluation of the quality criteria was dose independent.ConclusionsFull-leg plain radiography in patients with knee malalignment can be performed at 33xa0% reduced dose without loss of relevant diagnostic information.

Pelvic X-ray examinations in follow-up of hip arthroplasty or femoral osteosynthesis – Dose reduction and quality criteria

OBJECTIVEnDigital plain radiographs of the pelvis are frequently performed in follow-up examinations of patients who received total hip arthroplasty (THA) or osteosynthesis (OS). Thus, the purpose was to reduce the radiation dose and to determine objective quality control criteria to ensure accurate assessment.nnnMATERIALS AND METHODSnInstitutional review board approval was obtained. In this prospective randomized study, 289 patients underwent X-ray examination of the pelvis as follow up after receiving THA or OS with standard and reduced dose. The evaluation of the plain radiographs was conducted using the following criteria: bone-implant interface, implant-implant discrimination, implant-surface character and periarticular heterotopic ossification. Two radiologists evaluated these criteria using a score ranging from 1 (definitely assessable) to 4 (not assessable). If a single criterion had been evaluated with a score of 3 or more or more than 2 criteria with 2 points, the radiograph was scored as not assessable. The study was designed as non-inferiority-trial.nnnRESULTSnSeven (2.4%) examined X-rays were scored as not assessable. There was no statistical inferiority between the examinations with standard (0.365 mSv) or reduced dose (0.211 mSv). Reduced dose only led to limitations in the evaluation of ceramic components with low clinical impact in most scenarios.nnnCONCLUSIONnPlain radiography of the pelvis in patients with THA or OS can be performed with a dose reduction of about 42% without a loss of important information. The obtained quality control criteria were clinically applicable.