Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis.

Familial expansile osteolysis (FEO, MIM 174810) is a rare, autosomal dominant bone disorder characterized by focal areas of increased bone remodelling. The osteolytic lesions, which develop usually in the long bones during early adulthood, show increased osteoblast and osteoclast activity. Our previous linkage studies mapped the gene responsible for FEO to an interval of less than 5 cM between D18S64 and D18S51 on chromosome 18q21.2-21.3 in a large Northern Irish family. The gene encoding receptor activator of nuclear factor-kappa B (RANK; ref. 5), TNFRSF11A, maps to this region. RANK is essential in osteoclast formation. We identified two heterozygous insertion mutations in exon 1 of TNFRSF11A in affected members of four families with FEO or familial Paget disease of bone (PDB). One was a duplication of 18 bases and the other a duplication of 27 bases, both of which affected the signal peptide region of the RANK molecule. Expression of recombinant forms of the mutant RANK proteins revealed perturbations in expression levels and lack of normal cleavage of the signal peptide. Both mutations caused an increase in RANK-mediated nuclear factor-kappaB (NF-kappaB) signalling in vitro, consistent with the presence of an activating mutation.

Pigmented villo-nodular synovitis and giant-cell tumor of tendon sheaths: a binational retrospective study.

AIM: Pigmented villonodular synovitis is rare. Thus, we initiated a retrospective multi-center study regarding symptoms, location, type of disease, type of surgery, number of recurrences, use of adjuvant therapies and functional outcome. RESULTS: Ten centers contributed. Data from 173 patients were sampled. The disease was seen predominantly in joints, less frequently in tendon sheaths and bursae. Patients with articular lesions suffered mainly from the diffuse type. In tendon sheaths, the relation "diffuse versus nodular" was nearly 50 % each, in bursae most often the nodular type was found. Anatomically, mostly the knee was affected. Institutions with more than 20 patients had a lower rate of recurrence than those with less than 20 cases. Regarding the knee, there were less recurrences in joints treated with open synovectomy than in those treated arthroscopically. CONCLUSIONS: Since the rate of recurrence has been rather high, the use of adjuvant treatments (radiosynoviorthesis or radiotherapy) is recommended. In our study, the rate of their application was quite low. Patients who received an adjuvant therapy after primary surgery did not show any recurrence. In 14 % of patients in whom an adjuvant therapy had been used, after at least one recurrence, further recurrences were observed. Functional results were excellent in 84 % of patients. LEVEL OF EVIDENCE: Prognostic multi-center study, Level III.

[Preclinical evaluation of coated knee implants for allergic patients]. / Präklinische Ergebnisse beschichteter Knieimplantate für Allergiker.

BACKGROUND: 10-15% of the population show allergic reactions against skin contact to metals as nickel, cobalt or chromium and have thus a risk of not tolerating implants containing those materials. The relationship between periimplantary hypersensivity reaction and given cutaneous contact allergy is currently unknown. A new developed multilayer coating system is supposed to prevent long-term allergic reactions that may result from uncoated implants. METHODS: Stability and function (concerning bonding durability, wear and ion release to the serum) of the multilayer coating system has been examined in a test series. RESULTS: The specific architecture of the multilayer coating system evidences a very good bonding durability. The results of the test in the simulator show a reduction of wear of approximately 60% compared to the uncoated implants. Ion concentrations within the serum of the wear tests were by magnitudes lower than those measured in reference tests on uncoated components. CONCLUSION: The results of the preclinical evaluation prove that the durability and function of the multilayer coating system are as intended.

[Intraoperative localization of metastases with a hand-held gamma probe]. / Intraoperative Metastasenlokalisation mit einer handgeführten Gammasonde.

A 50-y-old male patient with prostate cancer showed two suspicious lesions in bone scintigrams. They were assessed to be bone metastases by biopsy of the os ilium. After i.v. injection of 99mTc-HMDP a probe-guided localization permitted optimal surgical treatment. A bone metastasis in the os ilium was confirmed. The intraoperative detection with a hand-held gamma probe permitted accurate and complete excision of the tumour; the bone defect could thus be reduced to a minimum.

Treatment with ibandronate preserves bone in experimental tumour-induced bone loss.

Cancer-induced bone diseases are often associated with increased bone resorption and pathological fractures. In recent years, osteoprotective agents such as bisphosphonates have been studied extensively and have been shown to inhibit cancer-related bone resorption in experimental and clinical studies. The third-generation bisphosphonate, ibandronate (BM 21.0955), is a potent compound for controlling tumour osteolysis and hypercalcaemia in rats bearing Walker 256 carcinosarcoma. We have studied the effect of ibandronate given as an interventional treatment on bone strength and bone loss after the onset of tumour growth in bone. Our results suggest that it is capable of preserving bone quality in rats bearing Walker 256 carcinosarcoma cells. Since other bisphosphonates have produced comparable results in man after their success in the Walker 256 animal models our findings suggest that ibandronate may be a powerful treatment for maintaining skeletal integrity in patients with metastatic bone disease.

Joint preserving procedures and endoprostheses in hemophiliacs - indications and long term results.

Hemophilic arthropathy is the result of recurrent joint bleedings in patients with severe haemophilia A or B and von Willebrand Syndrome. Conservative orthopaedic treatment is preferred in every stage of the arthropathy. Synovectomy is indicated only after failure of the conservative regimen after 3 to 6 months in order to control synovitis and recurrent bleeding. This paper presents the indications, methods, and results of different joint preserving operations. Especially synovectomy of the elbow joint with or without radial head resection shows very good long term results. Radiosynoviorthesis is an alternative in certain cases. The end stages of hemophilic arthropathy are characterised by pronounced joint contractures. We achieved very good long term results by implanting total hip joints (n = 13) and total knee joints (n = 20) with a median follow up of 102 respectively 53 months. No perioperative complications like bleeding or infection were registrated. Only one aseptic loosening of a cemented cup occurred 14 years postoperatively as well as one septic loosening 14 months postoperatively in an HIV-positive haemophilic. Another HIV positive patient developed a hematogenic abscess on both operated on hips without loosening of the endoprosthesis. Bicondylar prosthesis (n = 14) showed 6 very good, 6 good and 2 fair results in the HSS-score. Only one subsidence of an uncemented tibia plateau without definitive loosening occurred 55 months later. The functional results of constrained knee endoprostheses (n = 6) were not as good (2 good, 2 fair, 2 poor). However, these patients suffered preoperatively from severe contractures and malalignments. Aseptic loosening or late infections did not occur even in case of HIV infections.

Structural demands on computer-based medical documentation in the hospital setting.

During the last years physicians are confrontated with a significant increase of their duties in clinical documentation. By law the medical diagnoses and procedures were linked with the aspect of liquidation. In consequence it is very important that physicians work out a detailled list of options concernig the features of the medical database, which has to cover the complete clinical data input and deliver flexible utilities for detailed evaluation. Beside documentation the system has to perform as an essential tool of clinical organisation and quality control to optimize the medical and commercial efficiency of the hospital. An open interface technology should be postulated to avoid a stand alone system in the long run.

Conservative treatment measures in hemophilic arthropathy.

Intraarticular bleeding and muscle bleeding occur spontaneously or as a result of trauma in hemophilia A or B. The most common sites for hemarthrosis are the knees joints, elbows and ankles joints. Resorption of intraarticular blood induces reactive hemophilic synovitis. Hyperplasia of the synovium can be followed by recurrent bleedings. These early reactions can change to a chronic synovitis and cause cartilage damage, finally resulting in a complete destruction of the joint. Since 1981 158 adults and 61 children with a hemophilia A or B were treated at the Center for hemophilic disorders Frankfurt in an interdisciplinary approach. Consequent prophylactic treatment with factor substitution can prevent the incidence of severe hemarthrosis. Minor joint bleedings are treated by adequate factor substitution, temporarily non-weight bearing of the extremity, application of ice-packs and physical therapy. More severe joint hemorrhages should be aspirated in order to reduce the acute synovitis. This is followed by a consequent physical therapy (joint and soft tissue techniques) and anti-inflammatory drugs. The goal is a sufficient muscular balance of the joint, the improvement of the coordination, and the proprioception. The chronic synovitis is less painful and poorly responses to conservative interventions. Local ice application, sytemic and local anti-inflammatory treatment support the physical therapy. Soft heel shock absorber, elastic and semi-rigid bandages prevent recurrent bleeding episodes by shock absorption and decrease of synovial impingement. Synovectomy is indicated in cases of chronic persistent synovitis. Radiosynoviorthesis (RSO), which is an alternative in certain cases, has been performed with great success in 12 cases in our hospital. In advanced arthropathy joint mobilization should be the emphasis of the physical therapy. Bandages, crutches and ortopaedic shoe devices improve the walking capacity.

Phenotypical characterization of c-kit receptor deficient mouse femora using non-destructive high-resolution imaging techniques and biomechanical testing.

OBJECTIVE: Pathological processes in bone can lead to fatal health consequences. Therefore, it is important to study factors that possibly influence the activity of bone cells. The mast cell is a normal component of bone, storing and producing many potent bioactive substances. One of the most important factors to influence mast cell number, function, and phenotype is the c-kit ligand. A defect of the c-kit receptor leads to mast cell deficiency. In literature oversight, evidence for the importance of mast cells in skeletal homeostasis is compiled. METHODS: To investigate the influence of c-kit receptor deficiency on bone mass, geometry, microstructure, and strength, 30 femora of profoundly c-kit receptor deficient mouse mutants and 30 control group animals aged 8-20 weeks were phenotypically characterized using peripheral quantitative computed tomography (pQCT), micro-computed tomography (microCT) and 3-point-bending. RESULTS: The femora of the c-kit receptor and therefore mast cell deficient animals were significantly altered in bone mass and geometry but not in bone density and microstructure. The mutants had a lighter femur with a thinner shape. The lower load bearing capacity of the femora of mast cell deficient mouse mutants is more likely explained by the smaller amount of bone material than due to a change in intrinsic material properties. TECHNICAL CONSIDERATIONS: With the little dimensions of mouse bones, it is of prime importance to have precise methods to phenotypically characterize the bone. The pQCT allows the separate assessment and analysis of trabecular and cortical bone density, as well as a statement about bone geometry. Beyond it, the microCT-technique delivers a 3-D analysis of bone microstructure, which so far was only achieved with 2-D histomorphometry. microCT is an efficient alternative to destructive histological preparations allowing further biomechanical testing of the same specimens to also deliver measures for bone strength.

Total hip replacement in patients with severe bleeding disorders. A 30 years single center experience.

Arthropathy of the hip is moderate in frequency in haemophiliac patients, but is less common than ankle, knee or elbow arthropathy. We report about our experience with total hip replacement in patients with severe bleeding disorders over a period of 30 years. Between July 1972 and 2002, 15 hips in 13 patients were replaced. The main bleeding disorders were Haemophilia A in ten patients and severe v. Willebrand disease in three patients. The mean follow-up was 132 months (range 12-363). We can demonstrate good long-term results, with only one aseptic loosening after 14 years and one septic loosening after 14 months in an HIV-positive patient. The Harris Hip Score increased from 48 points (32-66) preoperatively to 89 (76-100) postoperatively. In conclusion, total hip replacement performed in a specialised haemophiliac centre is a safe procedure, and results in pain relief and improvement of the quality of life in patients with severe bleeding disorders.

[Epiphyseal tumors]. / Tumoren der Epiphyse.

The epiphyses of bone have a different physiologic development and pathophysiology compared to the other skeleton. Hereby the very low incidence of primary bone tumors has to be noted. The analysis of our tumor register, including 2758 cases, and of the literature confirms the chondroblastoma as the most frequent bone tumor especially in the second decade of life. Besides this we find chondromas of the epiphysis in infancy. Osteoid osteomas and osteoblastomas as well as tumor-like lesions and osteomyelitis occur extremely rare. We had no case of a primary malignant bone tumor in our register. Moreover less than 10 cases of osteosarcoma of the epiphysis have been reported in the literature. The border between metaphysis and epiphysis can not be distinguished any more after closure of the epiphyseal growth plate so that primary and secondary bone tumors can develop in this region now. An isolated occurrence of tumor in the epiphysis is even rare in adolescence.

[Joint preserving operations and endoprosthetic joint substitutions in hemophiliacs. Indications and long term results]. / Gelenkerhaltende Operationen und endoprothetischer Gelenkersatz bei Blutern. Indikation und Langzeitergebnisse.

Hemophilic arthropathy is the result of recurrent joint bleedings in patients with severe haemophilia A or B and von Willebrand Syndrome. Conservative orthopaedic treatment is preferred in every stage of the arthropathy. Synovectomy is indicated only after failure of the conservative regimen after 3 to 6 months in order to control synovitis and recurrent bleeding. This paper presents the indications, methods, and results of different joint preserving operations. Especially synovectomy of the elbow joint with or without radial head resection shows very good long term results. Radiosynoviorthesis is an alternative in certain cases. The end stages of hemophilic arthropathy are characterised by pronounced joint contractures. We achieved very good long term results by implanting total hip joints (n = 13) and total knee joints (n = 20) with a median follow up of 102 respectively 53 months. No perioperative complications like bleeding or infection were registrated. Only one aseptic loosening of a cemented cup occurred 14 years postoperatively as well as one septic loosening 14 months postoperatively in an HIV positive haemophilic. Another HIV positive patient developed a hematogenic abscess on both operated on hips without loosening of the endoprosthesis. Bicondylar prosthesis (n = 14) showed 6 very good, 6 good and 2 fair results in the HSS-score. Only one subsidence of an uncemented tibia plateau without definitive loosening occurred 55 months later. The functional results of constrained knee endoprostheses (n = 6) were not as good (2 good, 2 fair, 2 poor). However, these patients suffered preoperatively from severe contractures and malalignments. Aseptic loosening or late infections did not occur even in case of HIV infections.

[Computer-assisted implant positioning in knee endoprosthetics. Kinematic analysis for optimization of surgical technique]. / Computergestützte Implantatpositionierung in der Knieendoprothetik. Kinematische Analyse zur Optimierung der Operationstechnik.

Modern approaches in knee endoprosthetics using computer-assisted navigation systems are based on matching procedures which refer to osseous anatomical landmarks. However, surface replacement techniques require a correct position of the implants in relation to the bone, as well as an optimal postoperative interaction of the ligaments and the surface design of the endoprosthesis. Functional aspects are of elementary importance. Insufficient design of the prosthetic surface or incorrect implantation overstresses ligamentous structures and result in functional disturbance, increased wear, and early loosening of the components. The present computer model permits a quantitative analysis of different implant positions. Distal positioning of the femoral component or insufficient resection of the tibial plateau results in a lag of extension. Increased distal resection of the tibial plateau produces marked translatory instabilities in the sagital plane which exceed the absolute height of the resection in millimeters. Monocondylar replacements with preservation of the ACL react kinematically more sensitively than bicondylar endoprostheses sacrificing the ACL. The results of this study are systematically summarized in an algorithm and indicate correction steps in order to avoid functional impairment. The computer model delivers in addition some basic data for optimized navigation procedures in knee surgery and demonstrates the importance of further developments in custom-made endoprosthetics.

Functional results after partial pelvic resection in Ewing's sarcoma of the ilium.

Ewing's sarcoma of the pelvis has an unfavourable prognosis. The clinical and functional results of 7 patients who had a Ewing's sarcoma of the pelvis stage IIB were reviewed. All patients received multiple-agent chemotherapy pre- and postoperatively (modified T6 and T2 protocol according to Rosen) and underwent local resection of the pelvic tumour. According to Enneking, five patients had a type IA resection, one patient type I and another type IIA. One patient received a course of radiation therapy postoperatively (50 Gy). Six of seven patients showed a good regression of the tumour after preoperative chemotherapy. One patient who had a giant-cell Ewing's sarcoma died of local recurrence and lung metastases 29 months postoperatively. The remaining six patients were monitored radiographically and clinically according to Enneking's functional evaluation score after a follow-up period of 136 months (range 40-199 months). All were free of disease and had neither local recurrence nor metastases. In five patients the functional results were rated as "good" or "excellent". The good results depend mainly on the reconstruction of the pelvic girdle and its mechanical stability.

[Structural requirements of computer-based medical documentation in a hospital setting]. / Strukturelle Anforderungen an eine EDV-gestützte medizinische Klinikdokumentation.

During the last years physicians are confronted with a significant increase of their duties in clinical documentation. By law the medical diagnoses and procedures were linked with the aspect of liquidation. In consequence it is very important that physicians work out a detailed list of options concerning the features of the medical database, which has to cover the complete clinical data input and deliver flexible utilities for detailed evaluation. Beside documentation the system has to perform as an essential tool of clinical organisation and quality control to optimize the medical and commercial efficiency of the hospital. An open interface technology should be postulated to avoid a stand alone system in the long run.

[Soft tissue sarcoma in adulthood]. / Weichgewebssarkome im Erwachsenenalter.

Soft tissue sarcomas (STS) represent a heterogenous group of malignant tumors arising in mesenchymal tissue and in the autonomal and peripheral nervous systems. Only 1% of all malignancies in adults are STS. Most of them are localized at the extremities, but they also occur in the abdomen and the thorax as well as at the abdominal and chest wall. They are usually surrounded by a pseudocapsule which contains tumor cells and they can exhibit a discontinuous growth pattern. Macroscopically undetectable branches might grow along given anatomical structures. Thus the whole sarcoma-related anatomic compartment should be judged as tumor-contaminated. The high rate of local failure is often caused by insufficiently extended primary resections. Lymph node metastases are rare. The main prognostic factors are histological grading, tumor size and surgical radicality. Diagnosis of STS is often made at a rather late state of tumor progression often too late for curative therapy. Early histological diagnosis is thus of great importance. The operation aims at the removal of the whole tumor bearing anatomic compartment. Even wide excisions of the sarcoma surrounded by 3 cm of tumor free tissue will lead to at least 60% local recurrencies. Excisions along the pseudocapsule (enucleation) will most likely leave parts of the tumor behind. Insufficient surgical radicality cannot be compensated for by adjuvant therapies. The resection should be carried out without compromises.

[Conservative management of hemophilic arthropathy]. / Konservative Behandlungsmassnahmen der hämophilen Arthropathie.

Intraarticular bleeding and muscle bleeding occur spontaneously or as a result of trauma in hemophilia A or B. The most common sites for hemarthrosis are the knees joints, elbows and ankles joints. Resorption of intraarticular blood induces reactive hemophilic synovitis Hyperplasia of the synovium can be followed by recurrent bleedings. These early reactions can change to a chronic synovitis and cause cartilage damage, finally resulting in a complete destruction of the joint. Since 1981 158 adults and 61 children with a hemophilia A or B were treated at the Center for hemophilic disorders Frankfurt in an interdisciplinary approach. Consequent prophylactic treatment with factor substitution can prevent the incidence of severe hemarthrosis. Minor joint bleedings are treated by adequate factor substitution, temporarily non-weight bearing of the extremity, application of ice-packs and physical therapy. More severe joint hemorrhages should be aspirated in order to reduce the acute synovitis. This is followed by a consequent physical therapy (joint and soft tissue techniques) and anti-inflammatory drugs. The goal is a sufficient muscular balance of the joint, the improvement of the coordination, and the proprioception. The chronic synovitis is less painful and poorly responses to conservative interventions. Local ice application, systemic and local anti-inflammatory treatment support the physical therapy. Soft heel shock absorber, elastic and semi-rigid bandages prevent recurrent bleeding episodes by shock absorption and decrease of synovial impingement. Synovectomy is indicated in cases of chronic persistent synovitis. Radiosynoviorthesis (RSO), which is an alternative in certain cases, has been performed with great success in 12 cases in our hospital. In advanced arthropathy joint mobilization should be the emphasis of the physical therapy. Bandages, crutches and ortopaedic shoe devices improve the walking capacity.

[Secondary deformities after section of primary bone tumors of the spine in children and adolescents]. / Sekundäre Deformitäten nach Resektion primärer Knochentumoren der Wirbelsäule bei Kindern und Jugendlichen.

Primary bone tumors and tumor-like lesions of the vertebral column are rare in children. After operative tumor resection, 25 children under the age of 17 could be reviewed in a retrospective analysis. Malignant bone tumors occurred only twice in the region of the vertebral body. No deformity was registered in 9 of 16 cases after local tumor resection with and without laminectomy on one level. In contrast, after resection of one or both facets in combination with laminectomy cranial to L4 or thoracal, progressive kyphosis was found within 6-22 months postoperatively in four cases. This required a secondary fusion. After primary fusion and instrumentation, no deformity was registered. In nine cases with a location of the tumor in the vertebral body, only two patients developed a secondary instability of the spine. Both cases had no primary fusion. The other seven patients with initial fusion and instrumentation showed no deformity within 24 up to 127 months postoperatively. These results are compared with data from the current literature.

[Anti-osteolytic therapy preserves trabecular structure and mechanical properties of bone in tumor osteolysis]. / Eine antiosteolytische Therapie bewahrt die Trabekelstruktur und die mechanischen Eigenschaften des Knochens in Tumorosteolysen.

PURPOSE OF THE STUDY: Little is known about the effect of a tumor on the trabecular architecture, therefore we employed an animal model for the assessment of bone quality in tumor osteolysis to determine the alterations of the trabecular architecture in tumor osteolysis and after an interventional treatment with a bisphosphonate. METHODS: To assess the bone mass and the micro-architecture of the trabecular bone in tumor osteolysis we employed a micro-computed tomography system. For the assessment of the mechanical properties of the treated and non-treated tumor-bearing bones we used a torsion test. RESULTS: The presence of a tumor in bone resulted in a reduction of bone mass, stability and architectural parameters. An interventional treatment of the animals with a bisphosphonate increased the bone mineral content, mechanical and architectural parameters compared to the non-treated, tumor-bearing animals. CONCLUSIONS: These results clearly show a beneficial effect of an anti-osteolytic treatment with a bisphosphonate in regard of bone quality in tumor-induced osteolysis.