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W Winkelmann

Publications and source records attributed to W Winkelmann.

At least 55 records · Page 3Linked to original sources
PubMed2000

Apoptotic responsiveness of the Ewing's sarcoma family of tumours to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL).

We investigated the cytotoxic responsiveness of 40 cell lines derived from representatives of the Ewing's sarcoma family of tumours (ESFT), i.e., Ewing's sarcoma (ES), peripheral primitive neuroectodermal tumour (pPNET) and Askin tumour (AT), to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Incubation with TRAIL at 100 ng/ml induced cell death at 24 hr in 19 of 26 ES, 11 of 12 pPNET and 2 of 2 AT cell lines. Half-maximal cell death concentrations (IC(50) values) varied from 0.1 to 20 ng/ml. TRAIL displayed potent cytotoxic activity against freshly derived ESFT cell isolates. Cytotoxicity was associated with phosphatidylserine expression and internucleosomal DNA fragmentation, features characteristic of apoptosis. The apoptotic programme in the sensitive ESFT VH-64 cell line revealed TRAIL-induced activation of FLICE/MACH1 (caspase-8) and CPP32/Yama/apopain (caspase-3) and processing of the prototype caspase substrate poly(ADP-ribose) polymerase. In addition, TRAIL provoked a collapse of the mitochondrial transmembrane potential (DeltaPsi(m)), parallelled by a reduction in ATP levels and release of cytochrome c from mitochondria into the cytosol. Inhibition of caspase-8 and caspase-3 by zIETDfmk and zDEVDfmk, respectively, substantially prevented TRAIL-induced apoptosis. However, zIETDfmk, but not zDEVDfmk, reduced TRAIL-mediated DeltaPsi(m) dissipation, indicating that TRAIL causes mitochondrial dysfunction through caspase-8 acting upstream of mitochondria. While macromolecule synthesis inhibitors (actinomycin D, cycloheximide) augmented susceptibility to TRAIL in TRAIL-responsive cell lines, these agents did not render TRAIL-resistant cell lines susceptible to TRAIL. However, the proteasome inhibitor MG132 sensitised to TRAIL in resistant cell lines. Collectively, these results show that TRAIL initiates effective death in the vast majority (80%) of cell lines derived from ESFT. Since TRAIL provoked cell death in ESFT ex vivo, this cytokine may be a promising drug for the treatment of ESFT in vivo.

Adenosine Triphosphate↗
PubMed2000

Rotationplasty--surgical treatment modality after failed limb salvage procedure.

Twelve patients aged between 10.9 and 64.7 (mean 28.5) years with a malignant tumour of the knee region underwent a rotationplasty after failed primary limb salvage procedure. The reasons for failure which finally lead to surgery were recurrent infection in 10 patients and local recurrence of the tumour in 2. The number of operations before the rotationplasty was performed was between 2 and 23 (mean 6.7). According to the primary tumour site, 9 patients underwent a rotationplasty type A1, 3 patients type A2, and 1 patient type BII. In 9 patients the rotationplasty was successful, but 3 patients finally had to undergo amputation. Intraoperative preservation of the vessels was difficult in these 3 patients due to infection and oedema of the arteries or massive fibrous tissues after the previous surgery. After rotationplasty, 3 of 9 patients had to undergo additional surgery because of thrombosis, pseudarthrosis and infection (n = 5, range 1-2). The mean follow-up after rotationplasty was 34.9 (range 13-65) months. The mean functional status according to the MSTS criteria in patients after rotationplasty scored 21.3 of 30 points. In the group of amputees, the score was 19 (range 16-22). Concerning the health-related quality-of-life, the mean score in physical functioning was 76.3 in the group with a rotationplasty versus 50.0 in the group of amputees. Patients with a rotationplasty reached a higher score of global health status (77.1 vs 58.3). Based on the present results we are convinced that rotationplasty can be recommended as a treatment option after a failed limb salvage procedure.

Adolescent↗
PubMed2000

Plantar and dorsal foot loading measurements in patients after rotationplasty.

OBJECTIVE: The present study investigated the plantar and dorsal foot loading patterns inside the prosthesis of patients after rotationplasty. DESIGN: In vivo foot pressure distribution measurements during free walking in rotationplasty patients at an average follow-up of 10.4 years after surgery. METHODS: Fourteen subjects participated in the study and were measured during free walking. Capacitive pressure sensitive insoles were worn inside the shaft of the prosthesis either on the plantar or the dorsal aspect of the foot. Between 5 and 15 steps (mean 10.5) during full gait were selected and averaged to present a typical loading pattern for the individual patient. RESULTS: The measurements were reproducible and indicated that the main loading areas of the rotated foot inside the prosthesis are medially on the dorsal aspect and in the heel and toe region or the heel and midfoot region on the plantar aspect. The dorsal loading area was smaller than the plantar area (P=0.003). The force was higher on the plantar than on the dorsal aspect (P=0.005) but the loading time was shorter (P=0.008). In patients with callosities the high pressure areas coincided with the affected regions. CONCLUSIONS: The information gained from the pressure measurements support the understanding of foot loading characteristics in this anatomically and biomechanically unusual situation. This knowledge may be used to support the fitting process of new prosthetic designs for patients after rotationplasty. RELEVANCE: Foot loading capacity is one of the main factors limiting the activity level of rotationplasty patients. Therefore, a better understanding of foot loading characteristics might help to prevent overloading of certain foot structures and eventually improve the prosthetic fit with a direct benefit to the individual patient.

Adolescent↗
PubMed2000

Diagnosis, treatment and outcome of patients with Askin-tumors.

Askin tumors are highly malignant small-round-cell tumors of the thoracopulmonary region, which occur rarely. Therefore, we report on our experiences with eight patients (5 male, 3 females), who were treated in our department between 11'94 and 10'97 (age: 9-40 years, mean age: 20.5 years). All Askin tumors were diagnosed by histological and immunohistochemical examinations as well as molecular genetic proof of characteristic translocations. In all patients, the tumor arose from the chest wall, infiltrating adjacent ribs and parts of the lung. At the time of first diagnosis, five patients did not reveal any metastases. One patient suffered from intrapulmonary metastases and two patients from an infiltration of the diaphragm and of adjacent vertebral bodies. Treatment consisted of a pre- and postoperative (radio-) chemotherapy according to the EVAIA protocol and a radical tumor resection in all patients. The postoperative course was uneventful in seven patients, one patient suffered from pneumonia after multiple wedge resections for intrapulmonary metastases. Four patients, in whom primary tumor resection was complete, are alive 14, 20, 35 and 84 months after first diagnosis - only one patient had to undergo a second operation for a local relapse 17 months after first diagnosis. The other 4 patients, who suffered from a very extensive primary tumor, expired 13, 17, 18 and 39 months after the diagnosis was made. Our data demonstrate that Askin tumors require an aggressive multimodality treatment consisting of pre- and postoperative chemotherapy, radical surgical resection and postoperative irradiation, which may be performed preoperatively in selected cases, too.

Adolescent↗
PubMed2000

Osteoarticular allograft in surgery for high-grade malignant tumours of bone.

We assessed the results of 17 limb-salvage procedures using osteoarticular allografts after wide resection of high-grade malignant bone tumours. All patients received chemotherapy. At the five-year follow-up, three patients had died from metastases. The allografts survived for five years in only seven patients all of whom had good function, ranging from 73% to 90% of normal. The allografts were removed because of fracture in seven patients and infection in one, and in all of these a second limb-salvage procedure was undertaken. With such a low rate of survival of osteoarticular allografts, we believe that their use in the management of high-grade malignant bone tumours should, at best, be considered a temporary solution.

Adolescent↗
PubMed2000

Electromyographic and gait analysis of forty-three patients after rotationplasty.

BACKGROUND: Rotationplasty is considered to be a treatment option for patients who have had a primary malignant bone tumor of the distal part of the femur or the proximal part of the tibia. The present study was performed to evaluate the muscle activity, the kinetics (range of motion of the hip and knee joints), and the kinematics (joint moments) after rotationplasty and to determine whether there was an association between these parameters and the functional outcome. METHODS: Forty-three patients who had been managed with rotationplasty for the treatment of a femoral or tibial bone tumor were evaluated clinically and functionally. The mean age (and standard deviation) at the time of follow-up was 24.4 +/- 10.7 years (range, eight to sixty-eight years), the mean age at the time of the procedure was 17.8 +/- 10.2 years (range, seven to sixty-three years), and the mean duration of follow-up was 6.7 +/- 4.9 years (range, 0.7 to eighteen years). Instrumented gait and electromyographic analyses were performed. The qualitative data were compared with the functional outcome, which was determined with the functional evaluation score of the Musculoskeletal Tumor Society. RESULTS: Gait analysis revealed a fairly normal walking pattern with a slight limp and a lateral lean of the trunk over the ipsilateral limb that led to a reduced joint moment in the hip (moment on involved side, 68 percent [compared with a control group]; moment on uninvolved side, 81 percent). The ranges of motion of the hips (uninvolved side, 42.0 +/- 8.2 degrees; involved side, 42.4 +/- 8.0 degrees) and the knees (uninvolved side, 59.7 +/- 5.0 degrees; involved side [former ankle joint], 58.1 +/- 11.6 degrees) were symmetrical even though the knee-motion pattern of the involved limb indicated a slightly reduced extensor mechanism in 51 percent (twenty-two) and a markedly reduced extensor mechanism in 35 percent (fifteen) of the forty-three patients. Electromyography revealed function of the muscles of the involved limb, with comparable amplitudes in the involved and uninvolved limbs. The leg muscles of the involved limb were active in the stance phase (the soleus and the lateral and medial heads of the gastrocnemius) and the swing phase (the peroneus longus and the tibialis anterior) according to their function in relation to the new knee joint. The patients had a good functional result, with a mean score of 23.9 +/- 2.7 of 30 points. With the numbers available for study, we could not show the duration of follow-up to be related to the overall outcome, but the age at the time of the operation was related to the total functional score as well as to gait and walking ability (p < 0.05). CONCLUSIONS: The results of the electromyographic and gait analyses demonstrated good functional restoration of gait following rotationplasty.

Adolescent↗
PubMed1999

Pelvic Ewing sarcoma: a retrospective analysis of 241 cases.

BACKGROUND: This article reports on 241 patients each with pelvic Ewing sarcoma registered for studies in Germany, Austria, and the Netherlands from January 1, 1981, until January 31, 1994. One hundred sixty-four patients had localized disease and 87 had metastases at diagnosis (PMP). Eighty-four patients with localized disease were entered on protocol (PP) and 80 were followed (FP). METHODS: Statistics included an analysis of event free survival by the Kaplan-Meier method and a Cox regression analysis of factors influencing prognosis. RESULTS: In the Kaplan-Meier analysis, on February 1, 1995, the event free survival (EFS) rate was 32% at 12 years for all patients, 54% for PP, 25% for FP, and 13% for PMP. Cox regression analysis showed that response to chemotherapy, initial metastases, and less intense therapy were significant prognostic factors. Among patients who had surgery for local control, the histologic response to chemotherapy was analyzed in the surgical specimen and had a significant influence on survival: EFS 69% for PP with good response compared with 47% (P = 0.11) for patients with poor response, and for FP 56% versus 13% (P = 0.002). All PP with small tumors had relapse free survival, compared with 69% of patients with medium-sized tumors and 36% of patients with tumors larger than 200 mL (P = 0.006). The initial tumor volume was a significant predictor of survival. CONCLUSIONS: Combined modality treatment has resulted in definitive improvement of prognosis for patients with localized pelvic Ewing sarcoma. However, the results for patients with metastases at diagnosis are still discouraging, and their treatment requires new approaches. Tumor load, responsiveness to chemotherapy, and adequate surgical margins are the major factors influencing the prognosis of patients with localized Ewing sarcoma of the pelvis.

Adolescent↗
PubMed1999

Evaluation of prognostic factors in a tumor volume-adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience. Cooperative Ewing Sarcoma Study.

BACKGROUND: The Cooperative Ewing Sarcoma Study (CESS 86), conducted by the German Society of Pediatric Oncology and Hematology (GPOH), was planned on the basis of the results of the preceding CESS 81 study. The prognostic significance of tumor volume in localized Ewing sarcoma of bone was well documented in the CESS 81 trial. As a consequence, the treatment intensity was adapted to volume in the follow-up CESS 86 trial: the four-drug combination used in CESS 81 was amended for patients with large tumor volume (> or = 100 ml), where ifosfamide was substituted for cyclophosphamide. PROCEDURE: From January 1986 to June 1991, 177 protocol patients with localized Ewing sarcoma of bone were registered in CESS 86. The prognostic implication of tumor volume and several covariates was evaluated using Kaplan-Meier life table analysis and Cox's proportional hazard model. RESULTS: The estimated 5- and 8-year event-free survival (EFS) rates were both 59%. Age, gender, tumor site, and a tumor volume of 100 ml did not distinguish groups of patients with different prognosis. However, the prognosis of patients with tumors >200 ml (8-year EFS rate: 42%) was significantly inferior compared to patients with tumors both of 100 to 200 ml (70%) and of <100 ml (63%). In contrast to CESS 81, the histological response to chemotherapy was no longer a significant prognostic factor (EFS: 64% for good and 50% for poor responders, respectively). CONCLUSIONS: Despite risk-adapted treatment intensity, tumor volume retained its prognostic significance; the cut point, however, was shifted toward larger volumes.

Adolescent↗
PubMed1999

Aneurysmal bone cysts of the spine.

Thirteen patients with aneurysmal bone cyst of the spine (excluding sacral lesions) were retrospectively reviewed. Treatment for aneurysmal bone cysts remains controversial, but surgical resection, irradiation, and embolization are common treatment modalities for those involving the spine. Of 102 patients with aneurysmal bone cysts, 15 had a lesion of the spine, including 2 sacral cases. Of the 13 patients with a lesion of the thoracic or lumbar spine, 9 underwent resection of the lesion, 2 curettage and cementation, and 2 only currettage. Eleven patients underwent segmental arthrodesis with instrumentation after treatment of the primary or recurrent lesion, while 2 patients underwent segmental arthrodesis using autogeneic bone. Nine patients did not develop a local recurrence after resection of the lesion. However, the 2 patients who underwent curettage alone developed local recurrences. None of 4 patients developed recurrences after curettage and cementation. After recurrence, 1 patient underwent additional resection with irradiation, and 1 patient underwent resection alone. At the final follow-up, all lesions were under control. In one patient, lumbar kyphosis developed after segmental arthrodesis with instrumentation, and arthrodesis was performed again. Radical resection of aneurysmal bone cysts of the spine with instrumentation is the optimal method of acquiring a high degree of local control and preventing spinal deformity.

Adolescent↗
PubMed1999

The 'Entlastungsgang'. A hip unloading gait as a new conservative therapy for hip pain in the adult.

'Entlastungsgang' is a gait modification aiming to unload the hip joint by producing a modified Duchenne-limp (straight spinal column, additional lifting of the pelvis on the side of the swinging leg and a consecutive side shift of the pelvis) and a wide stance gait. Sixteen patients suffering from hip pain caused mainly by hip dysplasia were investigated. They received daily gait training for 12 h combined with intensive physical therapy as in-patients for 3-4 weeks. The external muscle torque acting on the hip joint was determined by 3D-gait analysis before, during and after the gait training. We found a reduction of the muscle torque after gait training to 77.2% of the initial value. At an average follow up of 12 months we found a persisting reduction of the muscle torque to 87. 0% at spontaneous gait that was further reduced to 81.3% of the initial value. The hip score for two components of the Merle d'Aubigne and Postel score for pain and walking was significantly improved from 7.4 to 10.8 points.

Adult↗
PubMed1999

Limb salvage and outcome of osteosarcoma. The University of Muenster experience.

One hundred thirty-six patients with non-metastatic high grade osteosarcoma treated from 1978 to 1994 in one institution with a multidisciplinary approach that included intravenous neoadjuvant chemotherapy were studied to evaluate which factors influence the outcome of modern orthopaedic therapy. Anatomic location, tumor volume, surgical margins, complications, and functional outcome were analyzed. Seventy-nine patients had a limb salvage procedure, 21 had a rotationplasty, and 33 had an amputation. Limb salvage consisted of 32 endoprostheses, 39 allograft replacements, six autograft replacements, and two shortening procedures. Three patients died during preoperative chemotherapy treatment. At a mean followup of 43 months, 81 patients continue to be disease free, three are alive after local recurrence, 17 are alive after having metastatic lesions, five are alive with metastatic lesions present, and 30 patients died of their disease. Forty-seven patients had pulmonary metastatic lesions, 14 had osseous metastatic lesions, three had abdominal metastatic lesions, two had lymphatic metastatic lesions, and eight patients had skip metastatic lesions. Prognosis correlated with chemotherapy response, surgical margins, and tumor volume. The minor complication rate for limb salvage was 4% and the major complication rate was 52%. Amputations had a 6% minor complication rate and 34% major complication rate. Rotationplasties had 10% minor and 48% major complication rates. The Musculoskeletal Tumor Society functional evaluation after limb salvage showed that 23 (38%) patients had more than 75% of the maximum functional score, 34 (56%) were from 50% to 75%, and three (5%) less than 50%. Of the rotationplasties, six (67%) were functionally better than 75% and three (33%) were functionally better than from 50% to 75%. In the group of amputations, 13 (56%) were from 50% to 75%, and 10 (44%) less than 50%. The extent of preoperative necrosis, surgical margins, and tumor volume are the most important prognostic factors. The increase in limb salvage procedures and the better long term survival of patients results in a higher rate of immediate and delayed complications. Functional outcome after rotationplasty is superior to limb salvage reconstruction and amputation.

Bone Neoplasms↗
PubMed1999

Cytotoxic effect of methotrexate and its solvent on osteosarcoma cells in vitro.

Bone tumours may recur locally even after wide surgical excision and systemic chemotherapy. Local control of growth may be accomplished by the addition of cytostatic drugs such as methotrexate (MTX) to bone cement used to fill the defect after surgery and to stabilise the reconstructive prosthesis. We have studied the elution kinetics of MTX and its solvent N-methyl-pyrrolidone (NMP) from bone cement and their biological activities in five cell lines of osteosarcoma and in osteoblasts, and compared them with the effects of the parent compounds alone and in combination. Our findings show that MTX is released continuously over months at concentrations highly cytotoxic to osteosarcoma cells and suggest that the impregnated bone cement would be effective in the long term. Proliferating osteoblasts, however, were much less sensitive towards MTX. The dose-response relationship for NMP and experiments with MTX/NMP-mixtures show that the eluted concentrations of solvent are not toxic and do not influence the effects of MTX. We suggest that bone cement containing MTX dissolved in NMP releases the drug in a suitable and effective way and may be of value in the treatment of bone tumours.

Antimetabolites, Antineoplastic↗
PubMed1999

Malignant tumor of the distal part of the femur or the proximal part of the tibia: endoprosthetic replacement or rotationplasty. Functional outcome and quality-of-life measurements.

BACKGROUND: The present study was performed to determine whether there is a difference, with regard to functional outcome and quality of life, between endoprosthetic replacement and rotationplasty for the treatment of malignant tumors of the distal part of the femur or the proximal part of the tibia. METHODS: Sixty-seven patients, between the ages of eleven and twenty-four years at the time of the diagnosis, had a malignant tumor of the distal part of the femur or the proximal part of the tibia. A rotationplasty was performed in thirty-three patients, and an endoprosthetic replacement was done in thirty-four patients. The median duration of follow-up was six years and one month (range, two years to sixteen years and two months). The scale developed by the Musculoskeletal Tumor Society was used to evaluate the functional results. Quality-of-life issues were assessed with the questionnaire developed by the European Organization for Research and Treatment of Cancer. RESULTS: The patients who had had a rotationplasty had a mean functional score, according to the system of the Musculoskeletal Tumor Society, of 24 points, and the patients who had had an endoprosthetic replacement had a mean score of 25 points. This difference was not found to be significant, with the numbers available (p = 0.47). Only one patient who had had a rotationplasty used an assistive device when walking long distances, whereas six patients who had had an endoprosthetic replacement used an assistive device. This difference was significant (p<0.001). The quality-of-life questionnaire revealed that the patients who had had a rotationplasty could participate in hobbies such as carpentry and sports as well as in other daily activities to a significantly greater degree than those who had had an endoprosthetic replacement (p = 0.001). Restriction in daily activities due to pain was significantly less common in the group that had had a rotationplasty than it was in the group that had had an endoprosthetic replacement (p = 0.047). CONCLUSIONS: Rotationplasty was not associated with any disadvantages with regard to function or quality of life in comparison with endoprosthetic replacement. It is possible that the psychosocial outcome is influenced by the fact that patients who have a rotationplasty know that additional operative intervention is not usually necessary. Despite good functional and quality-of-life results, the cosmetic appearance may be the most serious disadvantage of rotationplasty. The decision to perform this procedure must be made on a case-by-case basis.

Adolescent↗
PubMed1998

Second malignancies after treatment for Ewing's sarcoma: a report of the CESS-studies.

PURPOSE: During recent years, more intensified systemic and local treatment regimens have increased the 5-year survival figures in localized Ewing's sarcoma to more than 60%. There is, however, concern about the risk of second malignancies (SM) in long-term survivors. We have analyzed the second malignancies in patients treated in the German Ewing's Sarcoma Studies CESS 81 and CESS 86. MATERIALS AND METHODS: From January 1981 through June 1991, 674 patients were registered in the two sequential multicentric Ewing's sarcoma trials CESS 81 (recruitment period 1981-1985) and CESS 86 (1986-1991). The systemic treatment in both studies consisted of a four-drug-regimen (VACA = vincristine, actinomycin D, cyclophosphamide, and adriamycin; or VAIA = vincristine, actinomycin D, ifosfamide, and adriamycin) and a total number of four courses, each lasting nine weeks, was recommended by the protocol. Local therapy in curative patients was either complete surgery (n = 162), surgery plus postoperative radiotherapy with 36-46Gy (n = 274), or definitive radiotherapy with 46-60Gy (n = 212). The median follow-up at the time of this analysis was 5.1 years, the maximum follow-up 16.5 years. RESULTS: The overall survival of all patients including metastatic patients was 55% after 5 years, 48% after 10 years, and 37% after 15 years. Eight out of 674 patients (1.2%) developed a SM. Five of these were acute myelogenic leukemias (n = 4) or MDS (n = 1), and three were sarcomas. The interval between diagnosis of Ewing's sarcoma and the diagnosis of the SM was 17-78 months for the four AMLs, 96 months for the MDS and 82-136 months for the three sarcomas. The cumulative risk of an SM was 0.7% after 5 years, 2.9% after 10 years, and 4.7% after 15 years. Out of five patients with AML/MDS, three died of rapid AML-progression, and two are living with disease. Local therapy (surgery vs. surgery plus postoperative irradiation vs. definitive radiotherapy) had no impact on the frequency of AML/MDS, but local therapy did influence the risk of secondary sarcomas. All three patients with secondary sarcomas had received radiotherapy; however, all three sarcomas were salvaged by subsequent treatment and are in clinical remission with a follow-up of 1 month, 4.3 years, and 7.5 years after the diagnosis of the secondary sarcoma. Thus far, SM contributed to less than 1 % (3/328) of all deaths in the CESS-studies. CONCLUSIONS: The risk of leukemia after treatment for Ewing's sarcoma is probably in the range of 2%. The risk of solid tumors also seems to be low within the first 10 years after treatment and remains in the range of 5 % after 15 years. In the CESS-studies, less than 1% of all deaths within the first 10 years after diagnosis were caused by SM. Effective salvage therapy for secondary sarcomas is feasible.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Multicentric malignant transformation of multiple exostoses.

We treated a patient with large multiple chondrosarcomas derived from multiple cartilaginous exostoses. One sarcoma originated in the left pubic bone and the other sarcoma in the posterior aspect of the greater trochanter of the left femur. Thirty months after hindquarter amputation, the patient is alive without relapse. This is the first report of a patient with synchronous multiple malignant transformation of multiple cartilaginous exostoses.

Aged↗