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.

Combined modality treatment for osteosarcoma occurring as a second malignant disease. Cooperative German-Austrian-Swiss Osteosarcoma Study Group.

PURPOSE: The prognosis of osteosarcoma occurring as a second malignant disease (OS-SMD) is thought to be poor. We attempted to evaluate whether this holds true when OS-SMD is treated with combined modality therapy as developed for primary osteosarcoma and if factors that influence survival might be identified. PATIENTS AND METHODS: All patients with OS-SMD registered at the Cooperative German-Austrian-Swiss Osteosarcoma Study Group (COSS) study center between 1980 and June 1996 were evaluated for patient- and treatment-related factors, local and systemic outcome, and survival. Therapy was to be given according to contemporary COSS protocols for primary extremity osteosarcoma, including surgery and multiagent chemotherapy. RESULTS: Thirty patients with OS-SMD were registered (median latency period, 9 years 2 months). The first malignancies had been retinoblastoma (10 patients), sarcoma (10 patients), lymphoma (five patients), carcinoma (four patients), and medulloblastoma (one patient). Treatment for these malignancies had included radiotherapy in 24 patients, surgery in 20, and chemotherapy in 14. Twelve osteosarcomas were located axially and 18 were located in an extremity; 17 were radiation-related. Twenty-seven patients presented with localized disease; three presented with primary metastases (two skip, one lung). All 30 patients received chemotherapy, 29 with multiple drugs. Twenty-eight patients underwent operation. At 7 years, actuarial overall survival, survival free from osteosarcoma progression, and survival free from progression of any cancer were 50%, 34%, and 30%, respectively. In 24 patients with local tumor control, the corresponding values were 63%, 46%, and 38%. All seven local failures occurred in patients with axial osteosarcomas who did not undergo operation with wide surgical margins. CONCLUSION: Provided that local tumor control is achieved, OS-SMD treated with combined modality therapy may have a prognosis that approaches that of otherwise comparable primary osteosarcoma.

[Neoadjuvant therapy for localized osteosarcoma of extremities. Results from the Cooperative osteosarcoma study group COSS of 925 patients]. / Neoadjuvante Therapie des lokalisierten Osteosarkoms der Extremitäten. Erfahrungen der Cooperativen Osteosarkomstudiengruppe COSS an 925 Patienten.

BACKGROUND: Owing to twenty years of multicentric interdisciplinary cooperation, the COSS group has been able to collect data on a large group of osteosarcoma patients treated by neoadjuvant therapy. This paper reviews results achieved in patients with localized extremity tumors. INCLUSION CRITERIA: Registration into a completed neoadjuvant COSS-Study. Histologically confirmed, primary, localized, high-grade, central osteosarcoma of an extremity; age < 40 years; no pretreatment; interval diagnosis to chemotherapy < or = 3 weeks; no severe comorbidity. Chemotherapy: HD-methotrexate +/- doxorubicin +/- cisplatin +/- ifosfamide +/- BCD. Scheduled local therapy: Surgery. RESULTS: 925 evaluable patients from 101 institutions. Median age 15 years, m:f 1.4:1. Primary site: femur 510, tibia 251, humerus 100, fibula 51, other 13. Tumor-size < 1/3 of the involved bone 616, > or = 1/3 304. Definitive surgery in 903/925 cases, 443 limb salvage procedures. Good response (> 90% necrosis) in 469/806 (58.2%) evaluated tumors. Median follow-up for surviving patients: 5.42 years. Actuarial survival after 5 and 10 years: 72.5% (95%-CI 69.3-75.7) and 66.3% (62.5-70.0), relapse-free 62.1% (58.7-65.4) and 59.4% (55.8-63.0). 683/925 alive (601 first remission), 242 deceased (212 tumor progression, 30 other causes). 66.2% (97.3%) of all relapses within 2 (5) years. Prognosis correlates with tumor-size (< vs. > or = 1/3: 69.9% vs. 58.3% at 10 years) and -site (tibia: 74.2%, humerus: 54.5%) and -response (good vs. poor: 78.2% vs. 52.5%) (all p < 0.01). Actuarial 10-year survival by response grading I-VI according to Salzer-Kuntschik 80.9%, 82.8%, 71.1%, 60.7%, 47.7%, 27.3%. COSS-studies with preoperative 4-drug therapy more efficacious than less aggressive protocols. No impact of doxorubicin scheduling (sequential: rapid vs. 48 h-continuous infusion) or cisplatin scheduling (randomized: 5 h vs. 72 h-infusion) on prognosis detected. CONCLUSIONS: Intensive multiagent chemotherapy and delayed surgery for localized extremity osteosarcoma led to excellent oncologic results in the COSS-studies. Tumor-size, -site, and -response as well as the intensity of upfront chemotherapy correlated with outcome. Giving doxorubicin and cisplatin by continuous infusions did not result in discernible prognostic disadvantages.

Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group's protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs.

BACKGROUND: In an effort to intensify osteosarcoma therapy, systemic ifosfamide was added pre- and postoperatively to an already aggressive three-drug regimen. In a subgroup of patients, loco-regional treatment intensification was attempted by using the intraarterial route to give cisplatin. PATIENTS AND METHODS: Patients < or = 40 years at diagnosis of a localised, de novo high-grade central extremity osteosarcoma were eligible for inclusion into study COSS-86 if registered within three weeks from biopsy. Doxorubicin, high-dose methotrexate, and cisplatin were given to all patients. Patients who fulfilled one or more of three defined high-risk criteria received early systemic treatment intensification by adding ifosfamide as the fourth agent. Preoperatively, these high-risk patients received cisplatin either intraarterially or intravenously. RESULTS: 171 eligible patients were entered, of which 128 were stratified into the high-risk group. When all 171 were analysed by intention-to-treat, actuarial overall and event-free survival rates at ten years were 72% and 66%, respectively. No benefit of intraarterial cisplatin application was detected. Cumulative treatment toxicity was considerable. CONCLUSIONS: In a multicenter setting, intensive treatment of osteosarcoma according to protocol COSS-86 led to long-term disease-free survival for two thirds of patients. We saw no benefit of using the intraarterial route to administer cisplatin.

Ehlers-Danlos Syndrome Type VI (EDS VI): problems of diagnosis and management.

Ehlers-Danlos Syndrome Type VI (EDS VI) is a rare autosomal recessively inherited connective tissue disorder, which poses several problems of diagnosis and management. We report on a patient who developed severe kyphoscoliosis long before the diagnosis was reached. We conclude that early biochemical diagnosis and a timely operative procedure by extensive posterior instrumentation is the basis for successful management of this disorder.

Tumor size and prognosis in aggressively treated osteosarcoma.

PURPOSE: The aim of this retrospective analysis was to investigate the prognostic significance and optimal measures of tumor size in osteosarcoma treated with intensive neoadjuvant chemotherapy. PATIENTS AND METHODS: Initial anterior-posterior (AP) and lateral x-ray films of 128 patients treated within the trials Cooperative Osteosarcoma Study (COSS)-80, -82, and -86, were evaluated for the following three tumor diameters: length, width, and depth. Metastasis-free survival (MFS) analyses were performed in univariate and multivariate models with one, two, and three dimensions of the tumor as absolute or relative measures (tumor length, referred to bone length, plane and volume to body-surface area). RESULTS: Univariate analyses of MFS showed a high prognostic significance of all absolute measures. Relative measures, at best, showed a comparable predictive value. Cox regression analysis indicated the high prognostic significance of absolute tumor volume (ATV; P < .0001) and histologic response (P < .0001). None of 19 patients with an ATV < or = 70 cm3 and only four of 53 with an ATV < or = 150 cm3 relapsed, while in patients with an ATV more than 150 cm3, the relapse rate remained 40% to 60%, irrespective of further increase in volume. CONCLUSION: Initial tumor size is an important and easily obtainable prognostic factor in osteosarcoma and may serve as a basis for risk-adapted therapy. It is best represented by the absolute three-dimensional measure ATV. There is a cut-off point regarding the incidence of metastases at a tumor volume of approximately 150 cm3 as calculated from two-plane x-ray films.

[Solitary bone cysts. Morphologic variation, site, incidence and differential diagnosis]. / Solitäre Knochenzysten. Morphologische Variationsbreite, Lokalisation, Häufigkeit und Differentialdiagnose.

Analysis of 402 solitary bone cysts demonstrates the wide morphological variation of this cystic lesion with regard to histology and radiology. Aside from metaphyseal location in femur (33%) and humerus (23%), solitary bone cysts are also often located in calcaneus (11%), tibia (11%) and pelvis (10%). Most patients are in the second decade of life. Differentiation between this benign lesion and malignant bone tumors is very important in daily clinical routine. The diagnosis cannot be based solely on radiological findings because of the variation of solitary bone cysts and the special forms, such as calcifying solitary bone cyst. Therefore, exact histological diagnosis is of particular importance.

[Periosteal osteosarcoma. Histologic characteristics, preparation technique, growth pattern and differential diagnosis]. / Das periostale Osteosarkom. Histologische Charakteristika, Präparationstechnik, Wachstumsmuster und Differentialdiagnose.

Periosteal osteosarcoma is a distinct bone tumor entity with characteristic morphological features within the group of juxtacortical osteosarcoma. Periosteal osteosarcoma is predominantly located in the long tubular bones, especially in the tibia and femur and is situated on the outer circumference of the tumor-bearing bone (saucerization phenomenon). In contrast to parosteal osteosarcoma, periosteal osteosarcoma is less differentiated and is believed to have a worse prognosis. In this work the histological features are described with predominantly chondroblastic differentiation of 14 cases with periosteal osteosarcoma. A horizontal preparation technique of periosteal osteosarcoma specimens allows comparison with computed tomography and is the optimal method to detect an invasion of the medullary cavity. Further studies are necessary to clarify if neoadjuvant chemotherapy could improve the prognosis of certain patients.

[Spastic paraparesis in Scheuermann disease: a case report]. / Spastische Paraparese bei Morbus Scheuermann. Eine Kasuistik.

A case of paraparesis due to Scheuermann's disease in a 17.5 years old boy suffering from a moderate dorsal kyphosis (Cobb angle 64 degrees) is reported. Etiologically, spastic paraparesis can be caused either by myelon compression due to extradural cysts, herniated dorsal discs, or direct myelon compression from the vertebral bodies. Radiologically, in addition an intraspinal lipom was suspected. Because of the neurological deficits surgical treatment was performed. Ventral release followed by an anterior spondylodesis was combined with a dorsal spondylodesis using the Harrington compression system. An intraspinal lipom could be excluded intraoperatively after laminectomy of the suspicious region. Three months postoperatively, no signs of any neurological deficits were observable. X-ray control demonstrated a solid spondylodesis with an Cobb angle of 38 degrees. Direct myelon compression or indirect myelon damage due to a reduced blood supply at the apex of kyphosis are supposed to be the pathophysiological pathway.

[The Borggreve rotation-plasty. A surgical method in therapy of malignant bone tumors and functional results]. / Die Umkehrplastik nach Borggreve. Eine Operationsmethode bei der Therapie maligner Knochentumoren und deren funktionelle Ergebnisse.

From 1980 to 1992, 39 Borggreve-rotation-plasties were performed in patients with malignant bone tumors at the Orthopaedic Clinic of the University of Hamburg. The rotation-plasty was first published in 1930 by Borggreve. Salzer (Wien) described the method in 1981 for the operative treatment of osteosarcomas about the knee. The rotation-plasty is feasible for tumors of the distal femur, even when other limb-saving procedures are impossible, e.g. due to skip metastases, insufficient soft tissue coverage or involvement of the knee joint. The procedure was done on 26 female and 13 male patients, the age ranging between 7 and 45 years with a mean age of 17 years. The histological diagnosis was osteosarcoma in 36 cases, MFH, Ewing's sarcoma and Giant cell tumor in one case, respectively. The operative technique was slightly modified, compared to the method described originally by Salzer. The range of error of the different preoperative imaging procedures was evaluated and compared with the tumor extent in the resected specimen. MRI was found to be most precise. We saw no local recurrencies. Three patients had early thromboses, two of those had to be amputated, slow preoperative compression of the popliteal vein being the main cause in both. One patient developed a lymphatic fistula ten years postoperatively, which was eliminated in a second operation. All patients are followed routinely in the oncologic outpatient service. The functional results were rates "excellent" or "good" for all patients in six of seven categories, according to the Enneking evaluation system.(ABSTRACT TRUNCATED AT 250 WORDS)

[The prognostic significance of tumor volume in osteosarcoma with neoadjuvant chemotherapy]. / Die prognostische Bedeutung des Tumorvolumens beim Osteosarkom unter neoadjuvanter Chemotherapie.

In a retrospective analysis on 128 patients from the trials COSS-80, -82, -85 and -86 initial x-ray pictures were evaluated for tumor diameters in three planes and the prognostic meaning on survival was assessed. In a subset of patients (n = 27) the measured values were compared to values obtained by CT-Scan and a good correlation (r = 0.69) was found. Several parameters for tumor size were defined: absolute tumor length (ATL), relative tumor length (RTL, proportion of tumor to the length of the involved bone), absolute tumor volume (ATV, calculated by the ellipsoid formula) and relative tumor volume (RTL, tumor volume referred to the body surface area) and univariate and multivariate survival analysis were performed. Univariate analysis of metastasis free survival (MFS) revealed a high prognostic significance of the ATL, the ATV and the RTV. The RTL in this patient group demonstrated a tendency only toward an inferior prognosis in larger tumors. None of the patients with a ATV < 70 ml (n = 19) and only one of 33 patients with an ATV < 100 ml relapsed. Cox regression analysis was performed including the variables age, sex, site and response (> 90% tumor necrosis) in 84 patients. ATL and RTL do not enter the model, while the response proves its significance as a valid prognostic factor with a p-value of 0.0004. Adding the ATV as the measure of tumor size to the model it enters as the first term (p = 0.0000) followed by the response (p = 0.0002).(ABSTRACT TRUNCATED AT 250 WORDS)

[Transcatheter embolization of tumors of the muscular and skeletal systems]. / Transkatheterale Embolisationen von Tumoren des Muskel- und Skelettsystems.

The value of transcatheter embolisation of tumours of the musculoskeletal system is discussed on the basis of 26 cases. All procedures were performed following diagnostic angiography (DSA). By preoperative vascular occlusion it was possible to prevent major blood loss during surgery, provided the operation was carried out within three days of embolisation. Reduction in size of some large inoperable metastases before radio-iodine therapy is another indication for embolisation. As a palliative measure, vascular occlusion can be used for reducing otherwise untreatable skeletal pain and for the management of arteriovenous malformations. Bleeding from a tumour can be controlled by vascular occlusion. Our results indicate that transcatheter embolisation is an effective and reliable technique.

Hydroxyapatite ceramic as a bone substitute.

We have used hydroxyapatite ceramic as a bone substitute for grafting in extensive bone replacement. Hydroxyapatite is composed of calcium phosphate and is incorporated into bone as a physiological mineral. It is not antigenic, carcinogenic or osteogenic. The material used in this study differs from other hydroxyapatite ceramics in that it is an interconnected porous system. Between 1981 and 1986 we used this material on forty five occasions in 44 patients. It was combined with autologous cancellous bone graft in 38 cases and used alone in a further seven. It was usually employed to fill defects after removal of bone cysts and for long fusions in patients with scoliosis. It was also used to fill bone defects after trauma, for non-union in the lumbosacral area, for anterior vertebral fusions, in limb sparing operations for malignant bone tumours, and in exchange operations after failed joint endoprostheses. We have not seen incompatibility or rejection of the implanted material. The rate of postoperative infection was higher than usual due to the selection of patients, but did not appear to be connected with the use of hydroxyapatite ceramic. We were able to review 36 patients up to sixty months after operation. The results are encouraging with no difference in progress compared with patients in whom simple autologous bone grafts had been used.

Scintigraphic evaluation of tumor regression during preoperative chemotherapy of osteosarcoma. Correlation of 99mTc-methylene diphosphonate parametric imaging with surgical histopathology.

The effect of preoperative chemotherapy (PCT) on the uptake of 99mTc-labeled diphosphonates into tumor bone was quantitatively assessed from serial scan studies of 30 osteosarcomas and correlated with the histomorphological changes determined from the surgical specimens. The parametric images of the tumor blood pool and labeled methylene diphosphonate (99mTc-MDP) plasma clearance by the tumor bone enabled a sensitive distinction to be made preoperatively between a good (greater than 90% tumor cell destruction) and a poor (less than 90% tumor cell destruction) tumor response. Overall accuracy in presurgical prediction of tumor regression was found to be 88% and 96% for the blood pool and 99mTc-MDP clearance measurements, respectively (P less than or equal to 0.0004). In addition, it proved possible to localize resisting areas of viable tumor up to 1.0 cm in diameter. Even at the half-way stage of PCT, a poor response could be reliably predicted (overall accuracy 91% and 100%, respectively; P less than or equal to 0.011). Therefore, 99mTc-MDP parametric imaging is a highly sensitive and specific modality for an objective and accurate assessment of tumor regression during PCT of osteosarcoma.

[Current indications for angiography of tumors of the muscular and skeletal systems]. / Aktuelle Indikationen zur Angiographie von Tumoren des Muskel- und Skelettsystems.

CT and MRI have greatly influenced the indications for angiography as a diagnostic method for tumours of the muscular and skeletal systems. 59 patients with bone and soft tissue tumours were examined by arteriography (DSA) and the indications for arteriography were compared with CT (32 cases) and MRI (15 cases). Particular attention was paid to the presence of vessel encasement. Arteriography is the definitive method for demonstrating vascular involvement. Tomographic methods demonstrate the topographic relationships of the tumour and neuro-vascular structures. Angiography can also be used as an interventional measure pre-operatively or for palliative embolisation.