Philipp Lechler

The antiapoptotic gene survivin is highly expressed in human chondrosarcoma and promotes drug resistance in chondrosarcoma cells in vitro

BackgroundChondrosarcoma is virtually resistant to chemotherapy and radiation therapy. Survivin, the smallest member of the inhibitor of apoptosis protein family, is a critical factor for tumor progression and resistance to conventional therapeutic approaches in a wide range of malignancies. However, the role of survivin in chondrosarcoma has not been well studied. We examined the importance of survivin gene expression in chondrosarcoma and analysed its influences on proliferation, apoptosis and resistance to chemotherapy in vitro.MethodsResected chondrosarcoma specimens from which paraffin-embedded tissues could be extracted were available from 12 patients. In vitro experiments were performed in human chondrosarcoma cell lines SW1353 and Hs819.T. Immunohistochemistry, immunoblot, quantitative PCR, RNA interference, gene-overexpression and analyses of cell proliferation and apoptosis were performed.ResultsExpression of survivin protein was detected in all chondrosarcoma specimens analyzed, while undetectable in adult human cartilage. RNA interference targeting survivin resulted in a G2/M-arrest of the cell cycle and led to increased rates of apoptosis in chondrosarcoma cells in vitro. Overexpression of survivin resulted in pronounced resistance to doxorubicin treatment.ConclusionsThese findings indicate that survivin plays a role in the pathogenesis and pronounced chemoresistance of high grade chondrosarcoma. Survivin antagonizing therapeutic strategies may lead to new treatment options in unresectable and metastasized chondrosarcoma.

Spinal cord injury without radiologic abnormalities in adults: a systematic review.

BACKGROUND There is increasing evidence that spinal cord injury without radiologic abnormalities (SCIWORA) is underreported in adults. The increasing availability of magnetic resonance imaging (MRI) has added substantial information, but there remains considerable disagreement concerning definition as well as diagnostic and therapeutic measures. Furthermore, the interpretability of the literature is constrained by the lack of a reliable classification system based on the morphologic abnormalities visualized by MRI. A comprehensive systematic review was performed to identify all the data published concerning adults experiencing SCIWORA. To assess a potential correlation between clinical and imaging findings, we developed a novel MRI classification system. METHODS Database searches were conducted for studies on SCIWORA in adults using PubMed and OvidSP. Inclusion criteria were (1) traumatic spinal cord injury with neurologic deficit, (2) absence of fractures and/or dislocations of the spinal column, and (3) a mature skeleton. Data collected included clinical and radiologic findings. MRI patterns and clinical course were correlated. RESULTS Sixty-three articles reporting 1,393 patients were identified, of which 44 studies reported 1,132 cases with MRI imaging. At admission, neurologic deficit assessed by the American Spinal Injury Association impairment scale (AIS) in 567 patients was A in 19.1%, B in 18.5%, C in 39.7%, and D in 22.8%. At final follow-up, these were 6.5%, 4.8%, 20.1%, and 44.3%, respectively. In 7.1%, no MRI abnormalities (Type I) were detected, and 92.9% exhibited abnormal scan results (Type II). Of the latter, 11.7% revealed extraneural (Type IIa), 36.9% revealed intraneural (Type IIb), and 44.3% revealed combined abnormalities (Type IIc). Statistical analysis of neurologic impairment at admission and follow-up revealed significant differences in outcome between patients with different imaging findings. CONCLUSION This review emphasizes the prognostic value of spinal MRI for adults with SCIWORA. Using the MRI classification system in future reports will enhance comparability and interpretability and might improve our understanding of the condition. LEVEL OF EVIDENCE Systematic review, level IV+.

The influence of hip rotation on femoral offset in plain radiographs.

Background and purpose — Adequate restoration of femoral offset (FO) is critical for successful outcome after hip arthroplasty or fixation of hip fracture. Previous studies have identified that hip rotation influences the projected femoral offset (FOP) on plain anteroposterior (AP) radiographs, but the precise effect of rotation is unknown. Patients and methods — We developed a novel method of assessing rotation-corrected femoral offset (FORC), tested its clinical application in 222 AP hip radiographs following proximal femoral nailing, and validated it in 25 cases with corresponding computed tomography (CT) scans. Results — The mean FORC was 57 (29–93) mm, which differed significantly (p < 0.001) from the mean FOP 49 (22–65) mm and from the mean femoral offset determined by the standard method: 49 (23–66) mm. FORC correlated closely with femoral offset assessed by CT (FOCT); the Spearman correlation coefficient was 0.94 (95% CI: 0.88–0.97). The intraclass correlation coefficient for the assessment of FORC by AP hip radiographs correlating the repeated measurements of 1 observer and of 2 independent blinded observers was 1.0 and 1.0, respectively. Interpretation — Hip rotation affects the FOP on plain AP radiographs of the hip in a predictable way and should be adequately accounted for.

The association between Femoral Tilt and impingement-free range-of-motion in total hip arthroplasty

BackgroundThere is a complex interaction among acetabular component position and antetorsion of the femoral stem in determining the maximum, impingement-free prosthetic range-of-motion (ROM) in total hip arthroplasty (THA). By insertion into the femoral canal, stems of any geometry follow the natural anterior bow of the proximal femur, creating a sagittal Femoral Tilt (FT). We sought to study the incidence of FT as measured on postoperative computed tomography scans and its influence on impingement-free ROM in THA.MethodsThe incidence of the postoperative FT was evaluated on 40 computed tomography scans after cementless THA. With the help of a three-dimensional computer model of the hip, we then systematically analyzed the effects of FT on femoral antetorsion and its influence on calculations for a ROM maximized and impingement-free compliant stem/cup orientation.ResultsThe mean postoperative FT on CT scans was 5.7° ± 1.8°. In all tests, FT significantly influenced the antetorsion values. Re-calculating the compliant component positions according to the concept of combined anteversion with and without the influence of FT revealed that the zone of compliance could differ by more than 200%. For a 7° change in FT, the impingement-free cup position differed by 4° for inclination when the same antetorsion was used.ConclusionsA range-of-motion optimized cup position in THA cannot be calculated based on antetorsion values alone. The FT has a significant impact on recommended cup positions within the concept of “femur first” or “combined anteversion”. Ignoring FT may pose an increased risk of impingement as well as dislocation.

The femoral neck-shaft angle on plain radiographs: a systematic review

ObjectiveThe femoral neck-shaft angle (NSA) is an important measure for the assessment of the anatomy of the hip and planning of operations. Despite its common use, there remains disagreement concerning the method of measurement and the correction of hip rotation and femoral version of the projected NSA on conventional radiographs. We addressed the following questions: (1) What are the reported values for NSA in normal adult subjects and in osteoarthritis? (2) Is there a difference between non-corrected and rotation-corrected measurements? (3) Which methods are used for measuring the NSA on plain radiographs? (4) What could be learned from an analysis of the intra- and interobserver reliability?Material and methodsA systematic literature search was performed including 26 publications reporting the measurement of the NSA on conventional radiographs.ResultsThe mean NSA of healthy adults (5,089 hips) was 128.8° (98–180°) and 131.5° (115–155°) in patients with osteoarthritis (1230 hips). The mean NSA was 128.5° (127–130.5°) for the rotation-corrected and 129.5° (119.6–151°) for the non-corrected measurements.ConclusionOur data showed a high variance of the reported neck-shaft angles. Notably, we identified the inconsistency of the published methods of measurement as a central issue. The reported effect of rotation-correction cannot be reliably verified.

Effect of Preexisting Cognitive Impairment on In-Patient Treatment and Discharge Management among Elderly Patients with Hip Fractures

Objective: To examine the influence of cognitive impairment on the functional outcomes and complication rates of patients with hip fracture during in-patient treatment. Methods: A total of 402 patients who were surgically treated for hip fractures were consecutively enrolled at a single trauma center. The patients were grouped according to their results on the Mini-Mental State Examination (MMSE), i.e., ≥20 points (group I) and ≤19 points (group II). Complication and in-hospital mortality rates as well as postoperative functional outcomes according to the Barthel Index (BI) were compared between the groups. A multivariate regression analysis was performed to control for additional factors. Results: 33% of the patients had MMSE scores ≤19 points. The complication rates were similar between the groups (p > 0.05). Likewise, the overall in-hospital mortality rates were similar between the patients in group I (4.5%) and those in group II (9.8%; β = 0.218, p < 0.740). Functional outcomes, as assessed by the BI, were lower in group II (β = -0.266, p < 0.001). The patients in group II were transferred to a rehabilitation clinic less frequently (52.3 vs. 76.0%, p < 0.001). Conclusions: Patients with lower MMSE scores are at a higher risk for poorer functional outcomes. Perioperative care should focus on the preservation of functional abilities to protect these patients from an additional loss of independence and disadvantageous clinical course.

Early magnetic resonance imaging in spinal cord injury without radiological abnormality in adults: a retrospective study.

BACKGROUND The purpose of this study was to describe the clinical and imaging characteristics of patients experiencing blunt spinal trauma without radiological abnormalities but transient or persistent neurological deficits. METHODS This retrospective study analyzed plain radiographs, computed tomographic scans, and magnetic resonance images of patients with spinal cord injury without radiological abnormality (SCIWORA) who were admitted to a Level I trauma center. Neurologic status, Frankel grade, and short-term patient outcome were assessed. RESULTS Of 1,604 patients experiencing blunt spinal trauma, 21 (12 men and 9 women) with a mean age of 35.5 years (range, 16.2–70.9 years) presented with a clinicoradiographic mismatch. Magnetic resonance imaging (MRI) was available in 15 patients. In seven patients (46.6%), MRI revealed either neural (n = 2, 13.3%) or extraneural (n = 5, 33.3%) spinal abnormalities. Importantly, in eight patients (53.3%), no spinal abnormalities were visible on MRI. Furthermore, subgroup analysis revealed no prognostic value regarding the presence or absence of detectable spinal injuries. CONCLUSION Spinal abnormalities were not detected on MRI in a substantial proportion of patients presenting with SCIWORA. The prognostic value of MRI findings in SCIWORA needs to be validated by future studies. LEVEL OF EVIDENCE Epidemiological study, level V.

Calibration Markers for Digital Templating in Total Hip Arthroplasty

Digital templating with external calibration markers is the standard method for planning total hip arthroplasty. We determined the geometrical basis of the magnification effect, compared magnification with external and internal calibration markers, and examined the influence on magnification of the position of the calibration markers, patient weight, and body mass index (BMI). A formula was derived to calculate magnification with internal and external calibration markers, informed by 100 digital radiographs of the pelvis. Intraclass correlations between the measured and calculated values and the strength of relationships between magnification, position and distance of calibration markers and height, weight, and BMI were sought. There was a weak correlation between magnification of internal and external calibration markers (r = 0.297–0.361; p < 0.01). Intraclass correlations were 0.882–1.000 (p = 0.000) for all parameters. There were also weak correlations between magnification of internal and external calibration markers and weight and BMI (r = 0.420, p = 0.000; r = 0.428, p = 0.000, respectively). The correlation between external and internal calibration markers was poor, indicating the need for more accurate calibration methods. While weight and BMI weakly correlated with the magnification of markers, future studies should examine this phenomenon in more detail.

The oncofetal gene survivin is re-expressed in osteoarthritis and is required for chondrocyte proliferation in vitro

BackgroundRegulation of cell death and cell division are key processes during chondrogenesis and in cartilage homeostasis and pathology. The oncogene survivin is considered to be critical for the coordination of mitosis and maintenance of cell viability during embryonic development and in cancer, and is not detectable in most adult differentiated tissues and cells. We analyzed survivin expression in osteoarthritic cartilage and its function in primary human chondrocytes in vitro.MethodsSurvivin expression was analyzed by immunoblotting and quantitative real-time PCR. The localization was visualized by immunofluorescence. Survivin functions in vitro were investigated by transfection of a specific siRNA.ResultsSurvivin was expressed in human osteoarthritic cartilage, but was not detectable in macroscopically and microscopically unaffected cartilage of osteoarthritic knee joints. In primary human chondrocyte cultures, survivin was localized to heterogeneous subcellular compartments. Suppression of survivin resulted in inhibition of cell cycle progression and sensitization toward apoptotic stimuli in vitro.ConclusionsThe present study indicates a role for survivin in osteoarthritic cartilage and human chondrocytes. In vitro experiments indicated its involvement in cellular division and viability. Learning more about the functions of survivin in chondrocyte biology might further help toward understanding and modulating the complex processes of cartilage pathology and regeneration.

Bone Morphogenetic Protein 7 (BMP-7) Influences Tendon-Bone Integration In Vitro

Introduction Successful graft ingrowth following reconstruction of the anterior cruciate ligament is governed by complex biological processes at the tendon-bone interface. The aim of this study was to investigate in an in vitro study the effects of bone morphogenetic protein 7 (BMP-7) on tendon-bone integration. Materials and Methods To study the biological effects of BMP-7 on the process of tendon-bone-integration, two independent in vitro models were used. The first model involved the mono- and coculture of bovine tendon specimens and primary bovine osteoblasts with and without BMP-7 exposure. The second model comprised the mono- and coculture of primary bovine osteoblasts and fibroblasts. Alkaline phosphatase (ALP), lactate dehydrogenase (LDH), lactate and osteocalcin (OCN) were analyzed by ELISA. Histological analysis and electron microscopy of the tendon specimens were performed. Results In both models, positive effects of BMP-7 on ALP enzyme activity were observed (p<0.001). Additionally, similar results were noted for LDH activity and lactate concentration. BMP-7 stimulation led to a significant increase in OCN expression. Whereas the effects of BMP-7 on tendon monoculture peaked during an early phase of the experiment (p<0.001), the cocultures showed a maximal increase during the later stages (p<0.001). The histological analysis showed a stimulating effect of BMP-7 on extracellular matrix formation. Organized ossification zones and calcium carbonate-like structures were only observed in the BMP-stimulated cell cultures. Discussion This study showed the positive effects of BMP-7 on the biological process of tendon-bone integration in vitro. Histological signs of improved mineralization were paralleled by increased rates of osteoblast-specific protein levels in primary bovine osteoblasts and fibroblasts. Conclusion Our findings indicated a role for BMP-7 as an adjuvant therapeutic agent in the treatment of ligamentous injuries, and they emphasized the importance of the transdifferentiation process of tendinous fibroblasts at the tendon-bone interface.