Ein Jahr ist es her, da stürzte Olympiasiegerin Kristina Vogel beim Training auf der Radrennbahn so schwer, dass sie fast ums Leben kam. Seitdem ist die 28jährige querschnittgelähmt. Solche Unfälle sind zum Glück selten – denn bislang kann die Medizin wenig tun, wenn das Rückenmark so schwer verletzt ist. Aber es gibt neue, vielversprechende Ansätze. Am Universitätsklinikum Heidelberg wird jetzt in einer europaweiten klinischen Studie eine neue Antikörper-Therapie erforscht. Campus Reporter Nils Birschmann berichtet und sprach dabei mit Prof. Dr. med. Norbert Weidner.
Der Beitrag erschien in der Sendereihe "Campus-Report" – einer Beitragsreihe, in der über aktuelle Themen aus Forschung und Wissenschaft der Universitäten Heidelberg, Mannheim, Karlsruhe und Freiburg berichtet wird. Zu hören ist "Campus-Report" montags bis freitags jeweils um ca. 19.10h im Programm von Radio Regenbogen (Empfang in Nordbaden: UKW 102,8. In Mittelbaden: 100,4 und in Südbaden: 101,1).
Background: Although anterior cruciate ligament (ACL) tear-prevention programs may be effective in the (secondary) prevention of a subsequent ACL injury, little is known, yet, on their effectiveness and feasibility. This study assesses the effects and implementation capacity of a secondary preventive motor-control training (the Stop-X program) after ACL reconstruction.
Methods and design: A multicenter, single-blind, randomized controlled, prospective, superiority, two-arm design is adopted. Subsequent patients (18–35 years) with primary arthroscopic unilateral ACL reconstruction with autologous hamstring graft are enrolled. Postoperative guideline rehabilitation plus Classic follow-up treatment and guideline rehabilitation plus the Stop-X intervention will be compared. The onset of the Stop-X program as part of the postoperative follow-up treatment is individualized and function based. The participants must be released for the training components. The endpoint is the unrestricted return to sport (RTS) decision. Before (where applicable) reconstruction and after the clearance for the intervention (aimed at 4–8 months post surgery) until the unrestricted RTS decision (but at least until 12 months post surgery), all outcomes will be assessed once a month. Each participant is consequently measured at least five times to a maximum of 12 times. Twelve, 18 and 24 months after the surgery, follow-up-measurements and recurrence monitoring will follow. The primary outcome assessement (normalized knee-separation distance at the Drop Jump Screening Test (DJST)) is followed by the functional secondary outcomes assessements. The latter consist of quality assessments during simple (combined) balance side, balance front and single-leg hops for distance. All hop/jump tests are self-administered and filmed from the frontal view (3-m distance). All videos are transferred using safe big content transfer and subsequently (and blinded) expertly video-rated. Secondary outcomes are questionnaires on patient-reported knee function, kinesiophobia, RTS after ACL injury and training/therapy volume (frequency – intensity – type and time). All questionnaires are completed online using the participants’ pseudonym only. Group allocation is executed randomly. The training intervention (Stop-X arm) consists of self-administered home-based exercises. The exercises are step-wise graduated and follow wound healing and functional restoration criteria. The training frequency for both arms is scheduled to be three times per week, each time for a 30 min duration. The program follows current (secondary) prevention guidelines. Repeated measurements gain-score analyses using analyses of (co-)variance are performed for all outcomes.
Trial registration: German Clinical Trials Register, identification number DRKS00015313. Registered on 1 October 2018.
Background: Thigh pain and cortical hypertrophies (CH) have been reported in the short term for specific short hip stem designs. The purpose of the study was to investigate 1) the differences in clinical outcome, thigh pain and stem survival for patients with and without CHs and 2) to identify patient and surgery-related factors being associated with the development of CHs.
Methods: A consecutive series of 233 patients with 246 hips was included in the present retrospective diagnostic cohort study, who had received a total hip arthroplasty (THA) between December 2007 and 2009 with a cementless, curved, short hip stem (Fitmore, Zimmer, Warsaw, IN, USA). Clinical and radiographic follow-up, including the radiographic parameters for hip geometry reconstruction, were prospectively assessed 1, 3, and 6 to 10 years after surgery.
Results: Cortical hypertrophies were observed in 56% of the hips after a mean of 7.7 years, compared to 53% after 3.3 years being mostly located in Gruen zone 3 and 5. There was no significant difference for the Harris Hip Score and UCLA score for patients with and without CHs. Only one patient with a mild CH in Gruen zone 5 and extensive heterotopic ossifications around the neck of the stem reported thigh pain. The Kaplan Meier survival rate after 8.6 years was 99.6% (95%-CI; 97.1–99.9%) for stem revision due to aseptic loosening and no association with CHs could be detected. Postoperative increase in hip offset was the only risk factor being associated with the development of CHs in the regression model (ΔHO; OR 1.1 (1.0–1.2); p = 0.001).
Conclusions: The percentage of cortical hypertrophies remained almost constant in the mid-term compared to the short-term with the present cementless short hip stem design. The high percentage of cortical hypertrophies seems not be a cause for concern with this specific implant in the mid-term.
Level of evidence: Diagnostic Level IV
Background: The spine is the most frequent location of bone metastases. Local treatment aims at palliation of pain and, given the increased likelihood of long-term cancer survival, at local control. Kyphoplasty and intraoperative radiotherapy (Kypho-IORT) provided instantaneous pain relief in 70% of patients at the first day after the intervention and resulted in local control rates of > 93% at 1 year in a recently conducted phase I/II trial. To assess its clinical value, we designed a phase III trial which tests Kypho-IORT against the most widespread standard-of-care, external beam radiotherapy (EBRT), in patients with painful vertebral metastases.
Methods: This phase III study includes patients ≥50 years of age with up to 4 vertebral metastases and a pain score of at least 3/10 points on the visual/numeric analogy scale (VAS). Patients randomized into the experimental arm (A) will undergo Kypho-IORT (Kyphoplasty plus IORT with 8 Gy prescribed to 13 mm depth). Patients randomized into the control arm (B) will receive EBRT with either 30 Gy in 10 fractions or 8 Gy as a single dose. The primary end point is pain reduction defined as at least − 3 points on the VAS compared to baseline at day 1. Assuming that 40% of patients in the Kypho-IORT arm and 5% of patients in the control arm will achieve this reduction and 20% will drop out, a total of 54 patients will have to be included to reach a power of 0.817 with a two-sided alpha of 0.05. Secondary endpoints are evaluation of the percentage of patients with a pain reduction of at least 3 points at 2 and 6 weeks, local tumor control, frequency of re-intervention, secondary fractures/sintering, complication rates, skin toxicity/wound healing, progression-free survival (PFS), overall survival (OS) and quality of life.
Discussion: This trial will generate level 1 evidence on the clinical value of a one-stop procedure which may provide instantaneous pain relief, long-term control and shortened intervals to further adjuvant (systemic) therapies in patients with spinal metastases.
Trial registration Registered with ClinicalTrials.gov, number: NCT02773966. Registration date: 05/16/2016.
Background: Giant cell tumor of the bone (GCT) has high local recurrence rates and the prognosis is hard to predict. We therefore retrospectively analyzed clinical outcome and recurrences of 51 GCT cases focusing on the effects of adjuvant local use of hydrogen peroxide.
Methods: The series enclosed 51 advanced GCT cases of the upper and lower extremities (n = 27 Campanacci grade III; n = 24 grade II; n = 39 surgery at our institution, n = 12 elsewhere). Mean follow-up was 88.3 (± 62.0) months. Surgical details, histology, metastases, recurrences, and interview-based data on satisfaction and function including the Musculoskeletal Tumor Society (MSTS) score were evaluated. It was investigated whether hydrogen peroxide was additionally used or not to clean the tumor cavity after curettage as we hypothesized influence on recurrences. To analyze the underlying mechanisms, GCT-derived stromal cell lines were cultured in vitro and tested for cell viability and apoptosis after treatment with hydrogen peroxide. Statistical analysis was performed with Student’s t tests, analysis of variance (ANOVA) with post hoc testing, Mann-Whitney U tests, chi-square tests, Kaplan-Meier analysis, and multivariate Cox regression analysis.
Results: The whole series had 21 recurrences (41%). Eleven recurrences were found (28%) after surgery at our institution. Kaplan-Meier analysis of cumulative recurrence-free survival revealed at 2 years follow-up 69% (72%, only our institution) and at 10 years follow-up 54% (68%, only our institution). Intralesional resection was performed by vigorous curettage, burring, and defect filling with either polymethylmethacrylate bone cement (n = 45) or cancellous bone from the iliac crest (n = 6). Univariate chi-square analysis showed significantly lower recurrence rate after bone cement filling (2.3-fold, p = 0.024). Cleaning of the lesion cavity with hydrogen peroxide significantly reduced recurrence rate (whole collective 2.9-fold, p = 0.004; our institution 2.8-fold, p = 0.04) and significantly increased cumulative recurrence-free survival rate (whole collective at 10 years follow-up 74% versus 31%, p = 0.002; our institution 79% versus 48%, p = 0.02) compared to cases without hydrogen peroxide treatment. In multivariate analysis, significant risk factors for recurrence were pathological fracture (hazard ratio 3.7; p = 0.04), high mitosis rate (hazard ratio 15.6; p = 0.01), and lack of hydrogen peroxide use (hazard ratio 6.0; p = 0.02). In vitro cell culture analyses found apoptotic nature of hydrogen peroxide induced GCT cell death.
Conclusions: The present series proved for the first time that additional cleaning of the tumor cavity with hydrogen peroxide before defect filling significantly reduced recurrence rate and significantly increased recurrence-free survival in advanced but intralesionally treated GCT cases.
Background: The aim of the study was to evaluate changes in plantar pressure distribution in feet affected by hallux valgus compared with their contralateral non-affected feet and with the feet of healthy control subjects.
Methods: Thirty-six patients with unilateral hallux valgus who were indicated for surgery and 30 healthy subjects were assessed on a pedobarographic instrumented treadmill for step length and width, mean stance phase, and plantar foot pressure distribution. Plantar pressure distribution was divided into eight regions.
Results: Significantly higher plantar pressures were observed in hallux valgus feet under the second and third metatarsal heads (p = .033) and the fourth and fifth toes (p < .001) than in the healthy control feet. Although decreased pressures were measured under the hallux in affected feet (197 [82–467] kPa) in contrast to the contralateral side (221 [89–514] kPa), this difference failed to reach statistical significance (p = .055). The gait parameters step width, step length, and single-limb support did not show any differences between hallux valgus and control feet.
Conclusion: Although the literature on changes in plantar pressures in hallux valgus remains divided, our findings on transferring load from the painful medial to the central and lateral forefoot region are consistent with the development of transfer metatarsalgia in patients with hallux valgus.
Background: Sufficient data on outcome of patients with clinically and radiologically aggressive enchondromas and atypical cartilaginous tumors (ACT) is lacking. We therefore analyzed both conservatively and surgically treated patients with lesions, which were not distinguishable between benign enchondroma and low-grade malignant ACT based upon clinical and radiologic appearance.
Methods: The series included 228 consecutive cases with a follow-up > 24 months to assess radiological, histological, and clinical outcome including recurrences and complications. Pain, satisfaction, functional limitations, and the musculoskeletal tumor society (MSTS) score were evaluated to judge both function and emotional acceptance at final follow-up.
Results: Follow-up took place at a mean of 82 (median 75) months. The 228 patients all had comparable clinical and radiological findings. Of these, 153 patients were treated conservatively, while the other 75 patients underwent intralesional curettage. Besides clinical and radiological aggressiveness, most lesions were histologically judged as benign enchondromas. 9 cases were determined to be ACT, while the remaining 7 cases had indeterminate histology. After surgery, three patients developed a recurrence, and a further seven had complications of which six were related to osteosynthesis. Both groups had excellent and almost equal MSTS scores of 96 and 97%, respectively, but significantly less functional limitations were found in the non-surgery group. Further sub-analyses were performed to reduce selection bias. Sub-analysis of histologically diagnosed enchondromas in the surgery group found more pain, less function, and worse MSTS score compared to the non-surgery group. Sub-analysis of smaller lesions (< 4.4 cm) did not show significant differences. In contrast, larger lesions displayed significantly worse results after surgery compared to conservative treatment (enchondromas > 4.4 cm: MSTS score: 94.0% versus 97.3%, p = 0.007; pain 2.3 versus 0.8, p = 0.001). The majority of lesions treated surgically was filled with polymethylmethacrylate bone-cement, while the remainder was filled with cancellous-bone, without significant difference in clinical outcome.
Conclusion: Feasibility of intralesional curettage strategies for symptomatic benign to low-grade malignant chondrogenic tumors was supported. Surgery, however, did not prove superior compared to conservative clinical and radiological observation. Due to the low risk of transformation into higher-grade tumors and better functional results, more lesions might just be observed if continuous follow-up is assured.
Background: Mesenchymal stromal cells isolated from bone marrow (MSC) represent an attractive source of adult stem cells for regenerative medicine. However, thorough research is required into their clinical application safety issues concerning a risk of potential neoplastic degeneration in a process of MSC propagation in cell culture for therapeutic applications. Expansion protocols could preselect MSC with elevated levels of growth-promoting transcription factors with oncogenic potential, such as c-MYC. We addressed the question whether c-MYC expression affects the growth and differentiation potential of human MSC upon extensive passaging in cell culture and assessed a risk of tumorigenic transformation caused by MSC overexpressing c-MYC in vivo.
Methods: MSC were subjected to retroviral transduction to induce expression of c-MYC, or GFP, as a control. Cells were expanded, and effects of c-MYC overexpression on osteogenesis, adipogenesis, and chondrogenesis were monitored. Ectopic bone formation properties were tested in SCID mice. A potential risk of tumorigenesis imposed by MSC with c-MYC overexpression was evaluated.
Results: C-MYC levels accumulated during ex vivo passaging, and overexpression enabled the transformed MSC to significantly overgrow competing control cells in culture. C-MYC-MSC acquired enhanced biological functions of c-MYC: its increased DNA-binding activity, elevated expression of the c-MYC-binding partner MAX, and induction of antagonists P19ARF/P16INK4A. Overexpression of c-MYC stimulated MSC proliferation and reduced osteogenic, adipogenic, and chondrogenic differentiation. Surprisingly, c-MYC overexpression also caused an increased COL10A1/COL2A1 expression ratio upon chondrogenesis, suggesting a role in hypertrophic degeneration. However, the in vivo ectopic bone formation ability of c-MYC-transduced MSC remained comparable to control GFP-MSC. There was no indication of tumor growth in any tissue after transplantation of c-MYC-MSC in mice.
Conclusions: C-MYC expression promoted high proliferation rates of MSC, attenuated but not abrogated their differentiation capacity, and did not immediately lead to tumor formation in the tested in vivo mouse model. However, upregulation of MYC antagonists P19ARF/P16INK4A promoting apoptosis and senescence, as well as an observed shift towards a hypertrophic collagen phenotype and cartilage degeneration, point to lack of safety for clinical application of MSC that were manipulated to overexpress c-MYC for their better expansion.
Background: Several studies have emphasized the importance of restoring thoracic kyphosis (TK) in the setting of AIS, but very few have discussed changes in cervical spine alignment following surgery. Aim of this study was to evaluate reciprocal cervical alignment change after modification of global and regional thoracolumbar alignment with surgery in the setting of adolescent idiopathic scoliosis (AIS).
Methods: Baseline and 2-yrs follow-up radiographs of AIS patients (n = 81) were analysed measuring cervical parameters (upper cervical: C2-C0, McGregor Slope; lower cervical: C2-C7, C2-C7 sagittal vertical axis (SVA), C2-T3, C2-T3SVA, C2-T1Harrison (C2-T1Ha), T1 Slope (T1S)), thoracic, lumbar, pelvic and global alignment parameters. Post-operatively, patients were grouped twice; based on changes in TK and SVA. Cervical alignment was compared between groups. Pearson correlation was conducted to examine the relationship between changes in TK, SVA, and cervical alignment.
Results: Stratification by change in TK, revealed significant alteration of lower cervical alignment T1S [p < 0.001]), C2-T3 [p = 0.019], C2-T1Ha [p = 0.043]), but there was no reciprocal change in the upper cervical spine. Stratification by SVA revealed a significant coexisting change in the lower cervical spine (T1S [p < 0.001], C2-C7SVA [p = 0.034], C2-T3 [p = 0.023], C2-T3SVA [p = 0.001]). SVA change was not associated to a change in the upper cervical spine. The correlation analysis showed that with a post-operative increase in TK, the cervical spine became more lordotic. Changes in TK were significantly correlated with: ΔT1S, ΔC2-C7, ΔC2-T3, and ΔC2-T3SVA. Similarly, increased cervical kyphosis was found when SVA was decreased post-operatively. Furthermore, there was a significant correlation between change of SVA and both ΔC2-T3 and ΔC2-T3SVA.
Conclusions: In surgically treated AIS patients, changes in global and regional alignment of the thoracolumbar and cervical spinal segments exhibit interdependence. Thus, surgical planning with regard to sagittal deformity in AIS patients should account for the post-operative impact on cervical alignment.