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Fritzsching B.,University of Heidelberg | Fellenberg J.,University of Heidelberg | Moskovszky L.,Semmelweis University | Sapi Z.,Semmelweis University | And 12 more authors.
OncoImmunology | Year: 2015

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-prognosticstudies (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 D 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 D 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 nonsurvivors in osteosarcoma. © 2015 Taylor & Francis Group, LLC.

Ferraris S.,Polytechnic University of Turin | Miola M.,Polytechnic University of Turin | Bistolfi A.,University of Turin | Fucale G.,Center for Orthopedics and Traumatology | And 3 more authors.
Journal of Applied Biomaterials and Biomechanics | Year: 2010

Purpose: The purpose of this study is the evaluation of the differences and, eventually, of the advantages or disadvantages of manual formulations with respect to industrial ones. Methods: Medical-grade bone cements (Palacos R® and Palacos LV®), based on poly-methyl methacrylate (PMMA) and used clinically in several cemented prosthetic devices were manually enriched with gentamicin sulphate during preparation and then compared with a commercially-available, antibiotic-loaded cement (Palacos R+G®) by means of an in vitro antibacterial test (inhibition zone evaluation). The purpose of this study was to evaluate the differences and advantages or disadvantages, if any, of manual formulations compared to commercial ones. The use of a different antibiotic (vancomycin) alone or in addition to gentamicin-containing bone cements was also considered. Results and conclusion: The commercial formulation produces an inhibition zone that is a bit larger and more regular than the manually mixed preparation. The vancomycin halo is smaller but clearer than the gentamicin halo. The addition of vancomycin to gentamicin-containing bone cements does not significantly increase the halo dimensions but could be an interesting strategy in the prevention of multiple and resistant infections. © 2010 © Società Italiana Biomateriali.

Kasch R.,University of Greifswald | Mensel B.,University of Greifswald | Schmidt F.,University of Greifswald | Drescher W.,RWTH Aachen | And 4 more authors.
PLoS ONE | Year: 2012

Purpose: To evaluate changes in nucleus pulposus volume as a potential parameter for the effects of disc decompression. Methods: Fifty-two discs (T8 to L1) were extracted from 26 pigs and separated into thoracic (T8 to T11) and thoracolumbar discs (T12 to L1). The discs were imaged using 7.1 Tesla ultrahigh-field magnetic resonance imaging (MRI) with acquisition of axial T2-weighted turbo spin-echo sequences for determination of baseline and postinterventional nucleus pulposus volumes. Volumes were calculated using OsiriX® (http://www.osirix-viewer.com). After randomization, one group was treated with nucleoplasty, while the placebo group was treated with an identical procedure but without coblation current. The readers analyzing the MR images were blinded to the kind of procedure performed. Baseline and postinterventional volumes were compared between the nucleoplasty and placebo group. Results: Average preinterventional nucleus volume was 0.799 (SD: 0.212) ml. Postinterventional volume reduction in the nucleoplasty group was significant at 0.052 (SD: 0.035) ml or 6.30% (p<0.0001) (thoracic discs) and 0.082 (SD: 0.042) ml or 7.25% (p = 0.0078) (thoracolumbar discs). Nucleoplasty achieved volume reductions of 0.114 (SD: 0.054) ml or 14.72% (thoracic) and 0.093 (SD: 0.081) ml or 11.61% (thoracolumbar) compared with the placebo group. Conclusions: Nucleoplasty significantly reduces thoracic and thoracolumbar nucleus pulposus volumes in porcine discs. © 2012 Kasch et al.

Kasch R.,University of Greifswald | Mensel B.,University of Greifswald | Schmidt F.,University of Greifswald | Ruetten S.,Center for Orthopedics and Traumatology | And 5 more authors.
PLoS ONE | Year: 2012

Study Design: We assessed volume following nucleoplasty disc decompression in lower lumbar spines from cadaveric pigs using 7.1Tesla magnetic resonance imaging (MRI). Purpose: To investigate coblation-induced volume reductions as a possible mechanism underlying nucleoplasty. Methods: We assessed volume following nucleoplastic disc decompression in pig spines using 7.1-Tesla MRI. Volumetry was performed in lumbar discs of 21 postmortem pigs. A preoperative image data set was obtained, volume was determined, and either disc decompression or placebo therapy was performed in a randomized manner. Group 1 (nucleoplasty group) was treated according to the usual nucleoplasty protocol with coblation current applied to 6 channels for 10 seconds each in an application field of 360°; in group 2 (placebo group) the same procedure was performed but without coblation current. After the procedure, a second data set was generated and volumes calculated and matched with the preoperative measurements in a blinded manner. To analyze the effectiveness of nucleoplasty, volumes between treatment and placebo groups were compared. Results: The average preoperative nucleus volume was 0.994 ml (SD: 0.298 ml). In the nucleoplasty group (n = 21) volume was reduced by an average of 0.087 ml (SD: 0.110 ml) or 7.14%. In the placebo group (n = 21) volume was increased by an average of 0.075 ml (SD: 0.075 ml) or 8.94%. The average nucleoplasty-induced volume reduction was 0.162 ml (SD: 0.124 ml) or 16.08%. Volume reduction in lumbar discs was significant in favor of the nucleoplasty group (p<0.0001). Conclusions: Our study demonstrates that nucleoplasty has a volume-reducing effect on the lumbar nucleus pulposus in an animal model. Furthermore, we show the volume reduction to be a coblation effect of nucleoplasty in porcine discs. © 2012 Kasch et al.

Horstmann T.,Medical Park Bad Wiessee St. Hubertus | Horstmann T.,TU Munich | Listringhaus R.,Center for Orthopedics and Traumatology | Haase G.-B.,Center for Orthopedics and Traumatology | And 4 more authors.
Clinical Biomechanics | Year: 2013

Background Appropriate gait function is an important determinant of the outcome of total hip arthroplasty and relies on appropriate joint motion and muscle activity. The purpose of this study was to test the hypothesis that 6-month postoperative dynamic joint range of motion, time-distance measures and muscle activity in the operated limb in patients undergoing total hip arthroplasty differ from preoperative levels and are more similar to those observed postoperatively in the contralateral limb and in healthy subjects. Methods Basic time-distance gait measurements, knee and hip kinematics and electromyographic activity from eight hip muscles were obtained preoperatively and 6 months postoperatively in 52 patients undergoing total hip arthroplasty and in 24 age-matched healthy subjects during treadmill walking. Findings Postoperative dynamic hip range of motion for the operated limb (confidence interval differences [- 3.9; - 2.3 ]) and postoperative knee range of motion for both limbs (operated: [- 8.4; - 5.6 ]; contralateral: [- 8.1; - 5.3 ]) in patients with total hip arthroplasty were significantly lower than values for the control subjects (P < 0.001). Postoperative gait in patients with total hip arthroplasty was more symmetric than preoperative gait. Preoperative and postoperative electromyographic intensities were higher in patients with total hip arthroplasty than values for the control subjects (P < 0.001), and patients had different EMG patterns compared to the control group. Interpretation Pre- and postoperative differences not only in hip but also in knee kinematics emphasize the importance of evaluating the dynamic outcome of total hip arthroplasty by assessing joint motion of all lower extremity joints in both legs. © 2013 Elsevier Ltd.

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