Development of curative therapies for Ewing sarcomas by interdisciplinary cooperative groups in Europe.

Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.

The influence of tumor- and treatment-related factors on the development of local recurrence in osteosarcoma after adequate surgery. An analysis of 1355 patients treated on neoadjuvant Cooperative Osteosarcoma Study Group protocols.

BACKGROUND: Local recurrence (LR) in osteosarcoma is associated with very poor prognosis. We sought to evaluate which factors correlate with LR in patients who achieved complete surgical remission with adequate margins. PATIENTS AND METHODS: We analyzed 1355 patients with previously untreated high-grade central osteosarcoma of the extremities, the shoulder and the pelvis registered in neoadjuvant Cooperative Osteosarcoma Study Group trials between 1986 and 2005. Seventy-six patients developed LR. RESULTS: Median follow-up was 5.56 years. No participation in a study, pelvic tumor site, limb-sparing surgery, soft tissue infiltration beyond the periosteum, poor response to neoadjuvant chemotherapy, failure to complete the planned chemotherapy protocol and biopsy at a center other than the one performing the tumor resection were significantly associated with a higher LR rate. No differences were found for varying surgical margin widths. Surgical treatment at centers with small patient volume and additional surgery in the primary tumor area, other than biopsy and tumor resection, were significantly associated with a higher rate of ablative surgery. CONCLUSIONS: Patient enrollment in clinical trials and performing the biopsy at experienced institutions capable of undertaking the tumor resection without compromising the oncological and functional outcome should be pursued in the future.

[Reconstruction of the proximal femur with the MUTARS® system]. / Proximaler Femurersatz mit dem MUTARS®-System.

In the proximal femur a modular tumor prosthesis can be used today for reconstruction after resection of primary malignant bone tumors, metastatic lesions, and in revision surgery. The MUTARS® Münster system offers a high modularity and the possibility of combining it with the hip and knee revision system. Technical innovations, like hexagonal press fit bone anchorage, fine adjustment of rotation, silver coating of the surface of the prosthesis, and functional reconstruction with the help of a Trevira tube, guarantee a very good long-term survival of the prostheses and protection against the main complications such as aseptic loosening, deep infection, and instability.

[Is there a need of an additional extramedullary fixation in transverse subtrochanteric shortening in primary total hip arthroplasty for patients with severe hip dysplasia? Short-term experience in seven patients with congenital dislocation]. / Erfordert die transverse Osteotomie bei der subtrochantären Femurverkürzungsosteotomie in der Hüftprothesenimplantation hoher Dysplasiekoxarthrosen eine additive Osteosynthese? Kurzfristige Erfahrung bei 7 Hüften mit kongenitaler Luxation.

AIM: Total hip arthroplasty for high developmental hip dislocations should restore the anatomic hip centre by implanting the acetabular cup in the true acetabulum. The normalisation of the position of the hip may require femoral shortening to avoid the risk of neurological traction injury. In this study group a subtrochanteric transverse shortening with a cement-free stem (Alloclassic-SL) with a rectangular square diameter was used to secure rotation stability. METHOD: With this technique seven primary hip arthroplasties were performed in Crowe grade types III and IV. The age at time of operation averaged 41.7 years (range: 29 to 64 years). Average follow-up was 18 months. An average subtrochanteric resection of 4.2 cm (range: 3 to 5 cm) by a transverse subtrochanteric osteotomy without external fixation was performed. RESULT: There was one symptomatic stem loosening 15 months postoperatively. The average Harris hip score preoperatively of 43 points (range: 29 to 61 points) improved to a mean of 77 points (range: 66 to 90 points) at the time of follow-up. The hemispherical cups were implanted in all cases at the place of the original acetabular site. Meanwhile, there was no loosening on the acetabular side. All transverse osteotomies healed with evidence of union at the osteotomy site. At the last follow-up six of the seven Alloclassic-SL stems presented a secondary osseointegration. CONCLUSION: The subtrochanteric transverse shortening osteotomy in total hip arthroplasty is a safe and predictable method for restoring the anatomic centre in high development hip dislocation. The intramedullary stability will be secured by the distal rotation stability of the inherent cross-sectional geometry of this stem design without external stabilisation. A Z-shaped osteotomy of the subtrochanteric shortening or additional augmentation with allograft struts and cables is not necessary.

Expression of beta-catenin and p53 are prognostic factors in deep aggressive fibromatosis.

AIMS: To determine the prognostic significance of beta-catenin in aggressive fibromatosis and to identify potential molecular markers for new targeted therapies. METHODS AND RESULTS: A tissue microarray of 37 cases of deep aggressive fibromatosis was constructed and subjected to immunohistochemical analysis for beta-catenin, p53, smooth muscle actin (SMA), desmin, Ki67, c-erbB2, epidermal growth factor receptor (EGFR), c-kit, CD34 and S100. Complete clinical follow-up was available for 23 patients. Nuclear beta-catenin expression was associated with an increased rate of local tumour recurrence (60.0% 1-year and 0% 5-year event-free survival; P < 0.05). Furthermore, p53 expression was associated with an increased risk of tumour recurrence (50% 1-year event-free survival rate and 0% 5-years event-free survival rate, P < 0.05). The coexpression of p53 and beta-catenin was significantly correlated (P < 0.05). No statistically significant association was seen between MIB1 and p53 or beta-catenin expression, respectively. No expression of EGFR, c-erbB2 or c-kit was seen. CONCLUSIONS: The overexpression of beta-catenin and p53 is associated with a decreased event-free survival in deep aggressive fibromatosis. Further studies are required to establish whether these findings can lead to an improvement in the treatment of this rare neoplasm.

Interleukin-6, procalcitonin and TNF-alpha: markers of peri-prosthetic infection following total joint replacement.

This prospective study evaluates the role of new laboratory markers in the diagnosis of deep implant infection in 78 patients (41 men and 37 women) with a revision total knee or hip replacement. The mean age at the time of operation was 64.0 years (19 to 90). Intra-operative cultures showed that 21 patients had a septic and 57 an aseptic total joint replacement. The white blood cell count, the erythrocyte sedimentation rate and levels of C-reactive protein, interleukin-6, procalcitonin and tumour necrosis factor (TNF)-alpha were measured in blood samples before operation. The diagnostic cut-off values were determined by Received Operating Characteristic curve analysis. C-reactive protein (> 3.2 md/dl) and interleukin-6 (> 12 pg/ml) have the highest sensitivity (0.95). Interleukin-6 is less specific than C-reactive protein (0.87 vs 0.96). Combining C-reactive protein and interleukin-6 identifies all patients with deep infection of the implant. Procalcitonin (> 0.3 ng/ml) and TNF-alpha (> 40 ng/ml) are very specific (0.98 vs 0.94) but have a low sensitivity (0.33 vs 0.43). The combination of C-reactive protein and interleukin-6 measurement provide excellent screening tests for infection of a deep implant. A highly specific marker such as procalcitonin and pre-operative aspiration of the joint might be useful in identifying patients with true positive C-reactive protein and/or interleukin-6 levels.

The effect of rotationplasty on the ankle joint: long-term results.

In patients with rotationplasty the biomechanical conditions in the ankle joint are altered dramatically. By displacement and reduction of the weight-bearing area of the joint, the stress affecting its cartilage is increased. The use of an exoprothesis results in skin and soft tissue irritation. Due to these biomechanical changes, a prearthrotic deformity or skin problems could be expected. The current study examines changes in 21 patients treated with rotationplasty (mean follow-up 13.5 years) because of a malignant bone tumour or a femoral segmental defect. Local tenderness, skin and soft tissue changes, problems with exoprostheses, and pain was assessed by clinical examination and documented. Osseous changes were evaluated by plain X-ray. A MRI-scan was also obtained in five patients. Hardened skin and blisters were located at the main loading areas of the rotated foot. These changes could be reduced by optimizing the exoprosthetic fit. Radiographically, a slight asymptomatic attenuation of the articular space was observed in four patients and a slight coexistent subchondral sclerosis with small osteophytes in one patient. No degenerative changes were observed on X-ray and no cartilaginous changes were observed on MRI. The results suggest that the foot is able to adapt to the load changes after this procedure and that rotationplasty does not cause an inevitable arthrosis in the ankle joint.

[Limb lengthening with a fully implantable mechanical distraction intramedullary nail]. / Beinverlängerung mit einem voll implantierbaren mechanischen Verlängerungsmarknagel.

AIM: The morbidity of fixator-assisted distraction osteogenesis should be reduced by intramedullary lengthening devices. The ISKD (intramedullary skeletal kinetic distractor) is a new, fully implantable mechanical lengthening nail. In a prospective cohort trial the possibilities and limitations of the device used on femur and tibia are examined. METHODS: 22 patients with a mean age of 25 (range: 16-46) years were treated with an ISKD for femoral (n = 16) and tibial (n = 6) lengthening. The average leg length discrepancy was 48 (range: 25-80) mm. The follow-up was 21 (range: 7-37) months. Clinical and radiological results and complications were evaluated. RESULTS: The results of femoral and tibial applications of the ISKD are different. At the tibia, in three patients a pseudarthrosis occurred and slow callus formation was observed twice. An equinus contracture became evident in 2 patients. At the femur, in one case the lengthening was not accomplished with the device. Five patients were manipulated under anaesthesia at least once to achieve the aim of distraction. Three of these patients received retrograde implantation of the ISKD. An infection or interlocking screw failure was not observed either at the femur or the tibia. CONCLUSION: The ISKD reduces fixator-associated problems but incorporates its own difficulties which are mainly based on the guidance of the device. Careful patient advice in monitoring the lengthening process is mandatory. At the femur 8 cm of lengthening can be achieved but the nail tends to "block". Proper reaming and osteotomy techniques are important. A lengthening of more than 1 mm/day is recommended to prevent early consolidation. At the tibia weak callus formation and soft tissue contractures occur, therefore not more than 4 cm lengthening should be planned, the distraction speed has to be reduced noticeable below 1 mm/day and the initial immobilisation should be for more than a week.

[Minimally invasive treatment of osteoid osteoma with CT-guided radiofrequency ablation in long-term follow-up]. / Die minimalinvasive Therapie beim Osteoidosteom mittels CT-gesteuerter Thermokoagulation im Langzeitverlauf.

AIM: We treated 74 patients with symptomatic osteoid osteoma by CT-guided radiofrequency ablation (CT-RF) and investigated the rate of success and complications. PATIENTS AND METHODS: 74 patients were treated by CT-RF between March 1997 and August 2001. The nidus was first located by thin-cut CT sections and then penetrated by a 2 mm coaxial drill or an 11-gauge Jamshidi needle followed by insertion of the RF probe and heat application for a period of 4-6 minutes at 90 degrees C. We investigated the recurrence of pain, complications, hospital stay, duration of postoperative pain and function. RESULTS: Nine recurrences occurred after the initial procedure, and one after a second CT-RF (rate of primary success 87.8 %, rate of secondary success 88.8 %; 98.6 % success rate in all). There was one minor complication in one case. CONCLUSIONS: CT-guided RF ablation cured 73 of 74 patients (98.6 %). It is a safe, simple, cost effective and minimally invasive treatment, which has stood the test of a long-term follow-up and we suggest it to be the treatment of choice in most cases.

[Cartilage tumours of the bone. Diagnosis and therapy]. / Knorpelbildende Knochentumore. Diagnose und Therapie.

Primary malignant bone tumours are rare. The annual incidence of these tumours is 10 per 1 million. Nearly 30% of the primary malignant bone tumours are malignant cartilage tumours. The frequency of benign cartilage tumours cannot be definitely estimated because these tumours are normally clinically inapparent and therefore often diagnosed as an incidental finding. The cartilage tumours appear as benign lesions (e.g. chondroma), as borderline tumours (proliferative chondroma vs grade I chondrosarcoma) or as highly malignant chondrosarcoma (e.g. dedifferentiated chondrosarcoma). Commensurate with the different clinical and oncological manifestations of the cartilage tumours, there are wide differences in the treatment and clinical course of the individual tumour. This article discusses the problems in the diagnosis and treatment of cartilage tumours from an orthopaedic point of view.

Characteristics and outcome of infections associated with tumor endoprostheses.

INTRODUCTION: Infection associated with prosthesis used after tumor resection is a common and serious complication. The purpose of the current retrospective study was to describe the course of infection in patients with a tumor endoprosthesis and the determination of risk factors associated with failed limb salvage. MATERIAL AND METHODS: 30 patients with an infection associated with a tumor endoprosthesis were investigated with regard to treatment strategies, number and type of revision operations, duration of hospital stay, determination of risk factors associated with failed limb salvage and final outcome. RESULTS: Limb salvage related to the complication infection was achieved in 19 patients (63.3%). Two-stage reimplantation of an endoprosthesis was successful in 14 patients but subsequently failed in one patient. Out of 11 patients where limb salvage failed, an amputation was performed in 6 patients, a rotationplasty in 4, and stump lengthening procedure in 1 patient. A poor soft tissue condition was a significant (P<0.05) risk factor for failed limb salvage. No patient receiving chemotherapy with a poor soft tissue condition had limb salvage surgery. The mean number of revision operations per patients was 2.6. The mean duration of hospital stay was 68 days. CONCLUSION: Infection associated with prosthesis is a serious complication and is involved with long hospitalization. Limb salvage failed mostly in the case of a poor soft tissue condition. In these cases repeated revision surgery should be avoided and ablative surgery recommended at an early stage. Rotationplasty is an alternative to amputation in the case of an infection of the proximal or distal part of the femur.

Functional results and quality of life after treatment of pelvic sarcomas involving the acetabulum.

BACKGROUND: Limb salvage after resection of a pelvic sarcoma that involves the acetabulum represents a surgical challenge. The ideal method of reconstruction after acetabular resection remains a subject of controversy, and the outcome in terms of the impact of therapy is still unknown. The purpose of this study was to determine the impact of surgery on health-related quality of life and function after acetabular resection. METHODS: Eighty-one patients with a pelvic sarcoma underwent acetabular resection at a single institution. Functional evaluation and quality-of-life examination were performed in forty-five patients, and these patients comprised the study group. Quality of life was assessed with use of the European Organization for Research and Treatment of Cancer core quality-of-life questionnaire. Function was assessed with use of the Musculoskeletal Tumor Society system. RESULTS: The median age of the patients was 30.4 years at the time of the acetabular resection and 35.7 years at the time of follow-up. The median time interval from the index operation to the latest follow-up was sixty-nine months. At the latest follow-up evaluation, the mean functional status score was 14.5 points of a maximum of 30 points. In a comparison of endoprosthetic replacement and hip transposition following resection, significantly better functional results (p = 0.017) and a lower number of complications were found in patients who had a hip transposition. Quality-of-life assessment results were also better in patients with a hip transposition, especially in role functioning (p = 0.043). CONCLUSIONS: On the basis of the low complication rate and the good functional and quality-of-life results, hip transposition after acetabular resection seems to be the optimal technique for treating patients with a pelvic sarcoma involving the acetabulum.

Pitfalls in immunohistochemical assessment of EGFR expression in soft tissue sarcomas.

BACKGROUND: New targeted cancer treatments acting against growth factor receptors such as the epidermal growth factor receptor (EGFR) necessitate selecting patients for treatment with these drugs. Besides carcinomas, soft tissue sarcomas (STS) express EGFR and might thereby be a promising target for this new therapeutic strategy. OBJECTIVE: To test and compare different EGFR antibodies to determine the frequency of EGFR expression in STS. METHODS: 302 consecutive specimens of STS were examined using the tissue microarray technique. EGFR expression levels were assessed by immunohistochemistry using five different commercially available antibodies. Gene amplification status was measured by fluorescence in situ hybridisation (FISH). Immunoreactivity and amplification status were correlated with clinicopathological features and follow up data available in 163 cases. RESULTS: EGFR expression frequency ranged between 0.3% and 52.9%, depending on the antibody and scoring method used. In all, 3.5% of the tumours showed egfr gene amplification by FISH, which correlated with EGFR expression for three antibodies. Only one antibody had independent prognostic value in multivariate analysis and correlated with an unfavourable outcome; egfr gene amplification status showed no correlation with clinical features. CONCLUSIONS: Frequency of EGFR immunopositivity in STS strongly depends on the antibody used, and only one of five antibodies tested predicted an unfavourable clinical outcome. This indicates that choice of primary antibody and scoring system have a substantial impact on the determination of EGFR immunoreactivity.

Treatment of primary malignant bone tumours of the distal tibia.

We treated 15 patients with primary malignant bone tumours of the distal tibia of which 14 were treated by limb salvage surgery. Reconstructions were done by allografts with or without microvascular fibula transfer, by bone transport, by fibula transfer alone or by endoprosthetic replacement. The most successful methods were bone transport and endoprosthetic replacement. However, serious complications with deep infections leading to secondary amputation occurred in four patients and in all reconstruction groups. After a mean follow up of 7 years, no local recurrence occurred, and all patients were alive and free of disease. After radical resection, bone transport in defects less than 15 cm is a viable option. In larger defects in children, allograft with vascularised fibula is an acceptable alternative, but amputation still has a role in this group. In adults, endoprosthetic replacement with proper soft tissue coverage is a viable option in cases with large bony defects.

[Corrective osteotomy of the humerus using perivascular axillary anesthesia according to Weber in a patient suffering from McCune-Albright syndrome]. / Oberarmkorrekturosteotomie bei einem Patienten mit McCune-Albright-Syndrom unter perivaskulärer axillärer Plexusanästhesie nach Weber.

We report on a 20-year-old patient with McCune-Albright syndrome suffering from global respiratory insufficiency who required continuous mask ventilation and where intubation had to be avoided. Perivascular axillary anesthesia according to Weber was performed for a double corrective osteotomy of the humerus. During plexus anesthesia the patient was positioned on the non-anesthesized side in a 15 degrees Trendelenburg position. An extension of analgesia was observed up to the complete upper arm region. Using the modified positioning an extension of brachial plexus anesthesia is possible.

Rotationplasty type BI versus type BIIIa in children under the age of ten years. Should the knee be preserved?

Type BI rotationplasty is currently indicated for children with tumours of the proximal femur whereas type BIIIa rotationplasty is reserved for those in which the entire femur has to be removed. Our aim was to compare these two types of rotationplasty and determine whether the knee should be preserved in children with tumours of the proximal femur. We compared the post-operative complications, oncological outcome, range of movement, Enneking score and radiographs of six children, who had undergone type BI rotationplasty with those of 12 who had undergone type BIIIa rotationplasty. Patients with type BI rotationplasty had a mean Enneking score of 21.6 compared with 24.4 in those with type BIIIa rotationplasty, and worse mean results in all of the parameters investigated. We conclude that type BI rotationplasty has a worse functional outcome and more complications than type BIIIa rotationplasty in children under the age of ten years.

Endoprosthetic replacement of the humerus combined with trapezius and latissimus dorsi transfer: a report of three patients.

INTRODUCTION: To improve the functional outcome after proximal and/or total humerus replacement, we combined the surgical procedures described by Bateman and Gerber. MATERIALS AND METHODS: In three patients after wide tumor resection, endoprosthetic replacement with a modular tumor endoprosthesis (MUTARS System) was performed. In addition to a capsular and muscular reconstruction using the Trevira tube, a trapezius transfer onto the Trevira tube in combination with a latissimus dorsi transfer onto the Trevira tube was performed. The patients were immobilized for 6 weeks after surgery with an abductor cast. RESULTS: After a follow-up of 1 year, there was no significant improvement of the shoulder function in comparison with patients who did not undergo the combined muscle transfer (control group n=16: mean abduction 37.5 degrees ; mean anteversion 35.0 degrees ; mean internal rotation 15.2 degrees ; mean external rotation 25.2 degrees ). CONCLUSION: In our patients, the combination of the Gerber and the Bateman procedures did not improve the shoulder function in patients with proximal and/or total humerus replacements. Therefore, the functional results do not justify two separate approaches and a prolonged operation time.

Primary multifocal osseous Hodgkin disease: a case report and review of the literature.

PURPOSE: Hodgkin disease (HD) typically involves the lymphatic system at one or more sites. Rarely, Hodgkin disease presents as an osseous lesion without involvement of lymph nodes. Therefore, the histologic diagnosis of osseous HD can be problematic. We present a rare case of multifocal osseous HD and a review the literature with special emphasis on treatment and prognosis. METHODS: Osteomyelitis and lymphoma are the main differential diagnoses and can only be excluded histologically by the presence of Sternberg Reed cells or by immunohistochemical examinations. This case reports a 21-year old man with a Hodgkin lymphoma located at the proximal femur and the proximal tibia. RESULTS: Staging studies revealed no other tumor manifestations. Regarding the Ann Arbor classification, the presented case should be a stage IV disease. The patient is without evidence of disease 4 years after curettage, local radiation therapy, and systemic chemotherapy despite the poor prognosis considering the Ann Arbor classification. CONCLUSION: Reviewing the few reported cases, osseous HD must be distinguished from systemic HD with diffuse bone marrow involvement and from osseous metastases in advanced stage of disease because it seems to have a better prognosis.

High level of beta-hCG simulating pregnancy in recurrent osteosarcoma: case report and review of literature.

PURPOSE: A high serum level of beta human chorionic gonadotropin (hCG) normally indicates pregnancy in healthy women. We were confused by this finding in one of our patients. This 18-year-old girl presented with amenorrhoea of 1-month duration, a positive pregnancy test and a high beta-hCG serum level although taking contraceptives. Pregnancy was excluded by ultrasound. Three years previously, she had had an osteosarcoma of the humerus. The tumour initially had been wide resected and had shown a good response to neoadjuvant chemotherapy with COSS-96-protocol. METHODS: We reviewed the original histological result and the literature about possible similar findings. We analysed therapeutic options and the value of beta-hCG levels as a therapy monitor. RESULTS: During examination we detected a recurrent osteosarcoma of the left humerus. The local relapse evidently expressed beta-hCG which, retrospectively, could only sparsely be shown in the primary resectate. After intralesional surgery, chemotherapy and radiotherapy levels of beta-hCG normalised. CONCLUSION: Osteosarcoma very rarely is able to produce a paraneoplastic syndrome by high levels of beta-hCG. This may well be of diagnostic value and offer an additional monitoring tool. It can indicate tumour recurrence and dedifferentiation.

[Rotationplasty in the surgical treatment plan of primary malignant bone tumors. Possibilities and limits]. / Umkehrplastik im operativen Behandlungsplan der primär malignen Knochentumoren. Möglichkeiten und Grenzen.

Long-term survival of patients with a malignant bone tumor increased with a combined therapeutic approach using chemotherapy and possibly radiation therapy. Today up to 80% of patients with an osteosarcoma or Ewing's sarcoma survive. Therefore, it is important that the functional outcome and the quality of life are good after resection of the tumor. Before the era of endoprosthetic devices, rotationplasty, which was introduced in 1974 by Salzer for surgery of malignant bone tumors and modified by Winkelmann, protected many patients from an amputation. Although many authors favor limb-saving procedures today, rotationplasty obtained excellent functional and psychosocial results. Rotationplasty can be recommended in tumors with a large soft tissue component, in tumors located in the proximal femur and proximal tibia, and in children under 10 years of age. Furthermore, rotationplasty can be used in patients in whom a limb-salvage procedure failed because of infection or repeated changes of the endoprosthesis.