Georg Omlor

CT-guided radiofrequency ablation of osteoid osteoma and osteoblastoma: Clinical success and long-term follow up in 77 patients

The purpose of this study was to retrospectively evaluate long-term success of CT-guided radiofrequency ablation (RFA) in patients with osteoid osteoma (OO) and osteoblastoma (OB) including tumors in critical locations. Eighty-one CT-guided RFA procedures were performed in 77 patients with OO (65 patients) and OB (12) including 6 spinal and 15 intra/periarticular tumors. Procedural techniques included multiple needle positions, three-dimensional access planning, as well as, thermal protection techniques. Long-term success was assessed using a questionnaire including, among others, several VAS (visual analogue scale) scores. All patients completed 3-6 months follow-up, overall response to the questionnaire was 64/77 (83.1%). Primary success rate was 74/77 (96.1%) of all patients. Retreatment with RFA in 3 patients resulted in a secondary success rate of 77/77 (100%). Long-term follow-up (mean, 38.5 months; range, 3-92) revealed a highly significant (p<0.001) reduction of all assessed limitation scores reaching normal or almost normal values. One major complication, a cannula break leading to a secondary short hospital stay, occurred. In conclusion, RFA is a safe and effective long-lasting treatment of OO and OB. Advanced procedural techniques aid treating tumors in critical locations and in the coverage of larger tumors. Besides night pain, RFA also greatly improves other factors negatively affecting the quality of life.

Stimulation of gene expression and loss of anular architecture caused by experimental disc degeneration--an in vivo animal study.

Study Design. An external compression model was used to evaluate gene and protein expression in intervertebral discs with moderate disc degeneration. Objective. To determine messenger ribonucleic acid and protein expression levels of relevant disc components. Summary of Background Data. An animal model of mechanically induced disc degeneration was developed and characterized histologically. However, little is known at the molecular level in moderate disc degeneration. Methods. There were 8 New Zealand white rabbits subjected to monosegmental posterior compression to induce moderate disc degeneration. Twelve animals served as controls or sham controls. Discs were analyzed using immunohistochemistry for collagen type 1 (COL1), COL2, aggrecan, and bone morphogenetic protein-2/4 (BMP-2/4). For gene analysis, conventional and quantitative polymerase chain reactions were used for COL1A2, COL2A1, aggrecan, BMP-2, biglycan, decorin, osteonectin, fibromodulin, fibronectin, matrix metalloproteinase-13 (MMP-13), and tissue inhibitor of MMP-1. Gene expression for nontreated, sham-treated, and compressed discs was quantified in relation to the housekeeping gene glyceraldehyde-3-phosphate dehydrogenase. Results. Immunohistochemistry of compressed discs showed a loss of anular architecture, and a significant reduction of BMP-2/4 and COL2 positive cells. Gene expression analysis showed a significant up-regulation of COL1A2, osteonectin, decorin, fibronectin, tissue inhibitor of MMP-1, BMP-2, and MMP-13 in compressed discs. Conclusions. Experimental moderate disc degeneration is characterized by a loss of BMP-2/4 and COL2 positive cells, although gene expression of disc constituents, catabolic enzymes, and growth factors is stimulated to reestablish disc integrity.

Disc distraction shows evidence of regenerative potential in degenerated intervertebral discs as evaluated by protein expression, magnetic resonance imaging, and messenger ribonucleic acid expression analysis.

Study Design. An animal model of degeneration was used to determine the effects of disc distraction, and was evaluated with magnetic resonance imaging (MRI) as well as gene and protein expression levels. Objective. To investigate gene expression and MRI effects of distraction. Summary of Background Data. Disc degeneration can result from hyper-physiologic loading. Distracted discs with degeneration showed histologic signs of tissue recovery. Methods. There were 18 rabbits that underwent 28 days of compression (200 N) to induce moderate disc degeneration followed by 28 days of distraction (120 N; attached and loaded distraction device) or sham distraction (attached but unloaded distraction device). Comparison was performed with 56 days of compressed discs without distraction. Quantitative outcome measures were MRI signal intensity and gene expression analysis to determine: messenger ribonucleic acid levels for extracellular matrix genes, including collagen 1, collagen 2, biglycan, decorin, aggrecan, fibromodulin, and osteonectin; and matrix-regulative genes, including matrix metalloproteinase-13, tissue-inhibitor of matrix metalloproteinase-1, and bone morphogenetic protein (BMP)-2. Immunohistology was performed for collagen 2 and BMP-2 to label cells semiquantitatively by staining of the cell-surrounding matrix. Results. A total of 28 days of compression decreased signal intensity. Distraction over the same period reestablished physiologic signal intensity, however, a persistent reduction was found in sham distraction. Distraction resulted in gene expression up-regulation of collagen 1 (5.4-fold), collagen 2 (5.5-fold), biglycan (7.7-fold), and decorin (3.4-fold), while expression of fibromodulin (0.16-fold), tissue-inhibitor of matrix metalloproteinase-1 (0.05-fold), and BMP-2 (0.15-fold) was decreased, as compared with 56 days compression. Distracted discs showed more BMP-2 (19.67 vs. 3.67 in 56 days compression) and collagen 2 (18.67 vs. 11.33 in 56 days compression) positive cells per field. Conclusions. Distraction results in disc rehydration, stimulated extracellular matrix gene expression, and increased numbers of protein-expressing cells.

A new porcine in vivo animal model of disc degeneration: response of anulus fibrosus cells, chondrocyte-like nucleus pulposus cells, and notochordal nucleus pulposus cells to partial nucleotomy.

Study Design. In vivo animal study. Objectives. To describe a new porcine disc degeneration model, and to analyze disc remodeling and degeneration after nucleotomy with special view to the different nucleus pulposus (NP) cell types. Summary of Background Data. Thus far, predominantly smaller animals were used for disc degeneration models; however, such small discs were inappropriate to investigate cell implementation therapies. Though notochordal cells (NCs) are important for disc formation and maintenance, differences in the amount of NCs between human and animal discs have often been neglected. Methods. Twenty-four Goettingen minipigs underwent partial nucleotomy with a 16G biopsy cannula, to remove ∼10% of total NP volume. Animals were followed up for 3, or 24 weeks and analyzed by radiographs, MRIs, (immuno)histology, gene expression analysis, and biomechanical testing. Results. Three weeks after nucleotomy disc height was reduced by 26%, and magnetic resonance imaging signal intensity by 40%. At 24 weeks disc height was decreased by 32%. Increased degenerative changes were found in a histodegeneration score 3 and 24 weeks after nucleotomy, as well as considerable NP scarification after 3 weeks. In controls, cytokeratin-8 immunohistochemistry identified NCs in proximity to chondrocyte-like NP cells at approximately equal ratio. After nucleotomy, NCs were considerably reduced to <10% of total NP cells. Matrix genes were upregulated, except for aggrecan that decreased to 35% of initial values 3 weeks after nucleotomy. Matrix degrading factors (matrix metalloproteinases 13 and 3) were continuously upregulated, whereas transcripts of their inhibitors (tissue inhibitors of matrix metalloproteinase 2 and 3) were downregulated. No significant changes in segmental spinal flexibility or bone density were found after nucleotomy. Conclusion. We introduced a new disc degeneration model with relatively large discs that could be used for cell therapeutic approaches. The study gives further information about disc remodeling after nucleotomy and indicates the relevance of an altered cellular composition for the development of disc degeneration.

Expression of TRAIL and the death receptors DR4 and DR5 correlates with progression of degeneration in human intervertebral disks.

Intervertebral disks degenerate far earlier than other musculoskeletal tissues and apoptosis has been suggested to have a vital function in promoting the degeneration process that is strongly associated with back pain. However, the molecular mediators of apoptosis in the intervertebral disk are poorly understood. Fas/FasL, TRAIL/DR4, TRAIL/DR5 and TNF-α/TNFR1 are ligand/receptor pairs of the tumor necrosis factor/nerve growth factor family, which are able to induce apoptosis by trimerization of the receptor by its corresponding ligand. We investigated which of these molecules are expressed in intervertebral disks and whether their expression correlates to disk degeneration. Intervertebral disks from 28 donors (age 12–70 years) suffering from scoliosis, vertebrae fracture or disk degeneration were scored histologically for degeneration and analyzed for gene expression of FasL/Fas, TRAIL/DR4, TNF-α/TNFR1 and caspase 8. Protein expression of FasL and TRAIL was assessed by immunohistology and apoptotic cell death was quantified by poly(ADP-ribose) polymerase (PARP) p85 staining. Isolated disk cells were analyzed by flow cytometry for Fas, FasL, TRAIL, DR4 and DR5 expression. Gene expression of TRAIL (P=0.002) and caspase 8 (P=0.027) significantly correlated with degeneration. TRAIL expression further correlated with cellularity (P=0.04), muccoid matrix changes (P=0.009) and tears and cleft formation (P=0.019). FasL and TRAIL expression was confirmed by immunohistology and PARP cleavage was significantly associated with degeneration (P=0.027). Flow cytometry on isolated disk cells revealed correlations between DR4 and degeneration (P=0.014), DR4/DR5 double-positive cells and degeneration (P=0.019), as well as DR5 and changes in tissue granularity (P=0.03). This is the first study that shows that intervertebral disk cells express TRAIL, DR4 and DR5, which correlate to the degenerative state of the disk. Therefore, disk cells inherit the molecular machinery to induce and undergo cellular apoptosis, and the frequency of cytokine expression suggests that the TRAIL/DR4/DR5 axis is an important molecular mediator of apoptosis induction in disk tissue.

CT-guided radiofrequency ablation of osteoid osteoma: correlation of clinical outcome and imaging features

PURPOSE We aimed to retrospectively evaluate the computed tomography (CT) and magnetic resonance imaging (MRI) findings of patients with osteoid osteoma treated with CT-guided radiofrequency ablation (RFA) along with the clinical outcome and long-term success. MATERIALS AND METHODS Seventy-three CT-guided RFA procedures were performed in 72 patients. The long-term success was assessed using a questionnaire including several visual analog scale scores. The CT evaluation included pre- and immediate postprocedural imaging of all 72 patients, and MRI was performed in 18 patients with follow-up imaging (mean, 3.4±2.2 months). The evaluation criteria included nidus morphology and a correlation with markers of clinical success. RESULTS The primary technique effectiveness rate was 71/72 (99%). One relapse was successfully retreated, leading to a secondary technique effectiveness rate of 72/72 (100%). The long-term follow-up (mean, 51.2±31.2 months; range, 3-109 months) revealed a highly significant reduction of all assessed limitation scores (P < 0.001). The CT morphology was typical in all cases and did not change during the short-term follow-up. The follow-up MRI patterns varied considerably, including persistent nidus contrast enhancement in one-third (6/18) and persistent marrow edema in half (9/18) of the patients. None of the investigated MRI and CT patterns correlated with the clinical outcome. CONCLUSION The long-term outcome of CT-guided RFA of osteoid osteoma is excellent. There is no correlation of the CT and MRI patterns with the clinical outcome. Thus, the treatment decisions should not be solely based on the imaging findings. Investigators should also be aware of the variety of imaging patterns after RFA.

Depiction of the triangular fibro-cartilage in patients with ulnar-sided wrist pain: comparison of direct multi-slice CT arthrography and direct MR arthrography

To compare direct multi-slice CT arthrography (MSCT-AG) and direct MR arthrography (MR-AG) of the wrist with regard to the depiction of the triangular fibro-cartilage (TFC). Fifteen consecutive patients with ulnar-sided wrist pain suspicious for TFC tear underwent both MSCT-AG and MR-AG of the wrist. Images obtained were evaluated by two radiologists in a blinded fashion for the depiction of six anatomical areas (radial, central and ulnar portion on the proximal and distal side) of the TFC by means of a five-point scoring system (1 = excellent visibility to 5 = not visible). Scores for MSCT-AG and MR-AG were compared using the Students t-test. Mean scores for MSCT-AG and MR-AG, respectively, were 2.5/2.0, 3.2/2.5 and 2.8/2.4 for the radial, central and ulnar portion of the TFC on its proximal side, and 2.7/2.0, 3.1/2.3 and 2.9/2.4 for the radial, central and ulnar portion on its distal side (n = 15). Paired Students t-test showed no significant difference between MSCT-AG and MR-AG (P > 0.05). In a first, small series, depiction of the TFC with MSCT-AG is comparable to that of MR-AG. Further evaluation of direct multi-slice CT arthrography of the wrist in a larger patient population would be promising.

Differential expression of TGF-β superfamily members and role of Smad1/5/9-signalling in chondral versus endochondral chondrocyte differentiation

Proteins of the transforming-growth-factor-β (TGF-β)-superfamily have a remarkable ability to induce cartilage and bone and the crosstalk of TGF-β - and BMP-signalling pathways appears crucial during chondrocyte development. Aim was to assess the regulation of TGF-β-superfamily members and of Smad2/3- and Smad1/5/9-signalling during endochondral in vitro chondrogenesis of mesenchymal stromal cells (MSC) relative to chondral redifferentiation of articular chondrocytes (AC) to adjust chondrocyte development of MSC towards a less hypertrophic phenotype. While MSC increased BMP4 and BMP7 and reduced TGFBR2 and TGFBR3-expression during chondrogenesis, an opposite regulation was observed during AC-redifferentiation. Antagonists CHRD and CHL2 rose significantly only in AC-cultures. AC showed higher initial BMP4, pSmad1/5/9 and SOX9 protein levels, a faster (re-)differentiation but a similar decline of pSmad2/3- and pSmad1/5/9-signalling versus MSC-cultures. BMP-4/7-stimulation of MSC-pellets enhanced SOX9 and accelerated ALP-induction but did not shift differentiation towards osteogenesis. Inhibition of BMP-signalling by dorsomorphin significantly reduced SOX9, raised RUNX2, maintained collagen-type-II and collagen-type-X lower and kept ALP-activity at levels reached at initiation of treatment. Conclusively, ALK1,2,3,6-signalling was essential for MSC-chondrogenesis and its prochondrogenic rather than prohypertrophic role may explain why inhibition of canonical BMP-signalling could not uncouple cartilage matrix production from hypertrophy as this was achieved with pulsed PTHrP-application.

Increased bone formation in a rabbit long-bone defect model after single local and single systemic application of erythropoietin.

Background and purpose — Delayed bone healing with non-union is a common problem. Further options to increase bone healing together with surgery are needed. We therefore evaluated a 1-dose single application of erythropoietin (EPO), applied either locally to the defect or systemically during surgery, in a critical-size rabbit long-bone defect. Material and methods — 19 New Zealand White rabbits received a 15-mm defect in the radius diaphysis. An absorbable gelatin sponge was soaked with saline (control group and systemic treatment group) or EPO (local treatment group) and implanted into the gap. The systemic treatment group received EPO subcutaneously. In vivo micro-CT analysis was performed 4, 8, and 12 weeks postoperatively. Vascularization was evaluated histologically. Results — Semiquantitative histomorphometric and radiological evaluation showed increased bone formation (2.3- to 2.5-fold) in both treatment groups after 12 weeks compared to the controls. Quantitative determination of bone volume and tissue volume showed superior bone healing after EPO treatment at all follow-up time points, with the highest values after 12 weeks in locally treated animals (3.0- to 3.4-fold). More vascularization was found in both EPO treatment groups. Interpretation — Initial single dosing with EPO was sufficient to increase bone healing substantially after 12 weeks of follow-up. Local application inside the defect was most effective, and it can be administered directly during surgery. Apart from effects on ossification, systemic and local EPO treatment leads to increased callus vascularization.