Long-term results after semiconstrained distal radioulnar joint arthroplasty: A focus on complications.

Arthroplasty of the distal radioulnar joint (DRUJ) using a semiconstrained DRUJ implant yields good outcomes according to the literature. The aim of this study was to investigate the subjective, clinical and radiographic outcomes with a special focus on complications in nine patients with a mean follow-up of 6years and to compare them with our previously published 3-year follow-up results. No subjective or objective changes were seen between the 3-year and the 6-year follow-up. In the previous study, one implant loosening and two irritations of the superficial branch of the radial nerve occurred. We saw three complications that needed surgery in addition to the three complications already found 3years after surgery. One patient with a large ulna had loosening of the cemented ulnar stem and therefore the prosthesis was explanted. One patient had an allergic reaction to the metal alloy of the prosthesis, which also led to removal. One patient had an ulnar impaction syndrome caused by too-distal placement of the implant that needed revision. Prior studies reported low complication rates. In our study, six complications occurred in four out of nine patients, requiring reoperation including two revisions and two implant removals. A precise surgical technique is mandatory to avoid the otherwise frequent complications and potential implant failures. LEVEL OF EVIDENCE: IV.

Extending the limits of reconstructive microsurgery in elderly patients.

BACKGROUND: Population aging strongly affects the demographic development of industrialized countries. While microsurgical procedures were initially believed to be only feasible in patients of younger age because of the duration of the surgical procedure and the higher risk of vascular insufficiency due to age-related comorbidities, it has become evident that these procedures are beneficial even for patients at an advanced age. METHODS: We retrospectively investigated microsurgical procedures in a patient cohort (n = 25 with 27 free flaps) with a minimum age of 78 years with regard to patients' characteristics, flap survival, and postoperative surgical and medical complications. RESULTS: Median age was 81 years (IQR 6). Most defects were located in the head and neck region. The mean operation time was 384 min (standard deviation (SD) 131). Flap failure was observed in three cases (11%). The median length of hospital stay was 17 days (interquartile range (IQR) 8). The mean ASA score was 2.48. Patients' age and ASA group did not correlate. The mortality rate was 4%. Postoperative surgical complications were observed in 11 cases (41%), while 19 patients (70%) showed one or more medical complications. Higher ASA classes tended to show more postoperative complications. However, neither age nor operating time nor ASA status showed significant influence on the occurrence of postoperative medical or surgical complications. CONCLUSION: There is growing demand for structural and functional restoration using free tissue transfer in an aging population. If there are no alternative treatment options available promising similar structural and functional preservation, free tissue transfer is justifiably in very old patients despite a potentially increased flap failure. As such, free tissue transfer is used as a curative treatment concept aiming at a maximum of patients' independence and early ambulation. Occurrence of complications can be diminished by adequate patient selection and thorough perioperative care.

Regulation of melatonin 1a receptor signaling and trafficking by asparagine-124.

Melatonin is a pineal hormone that regulates seasonal reproduction and has been used to treat circadian rhythm disorders. The melatonin 1a receptor is a seven- transmembrane domain receptor that signals predominately via pertussis toxin-sensitive G-proteins. Point mutations were created at residue N124 in cytoplasmic domain II of the receptor and the mutant receptors were expressed in a neurohormonal cell line. The acidic N124D- and E-substituted receptors had high-affinity (125)I-melatonin binding and a subcellular localization similar to the neutral N124N wild-type receptor. Melatonin efficacy for the inhibition of cAMP by N124D and E mutations was significantly decreased. N124D and E mutations strongly compromised melatonin efficacy and potency for inhibition of K(+)-induced intracellular Ca(++) fluxes and eliminated control of spontaneous calcium fluxes. However, these substitutions did not appear to affect activation of Kir3 potassium channels. The hydrophobic N124L and N124A or basic N124K mutations failed to bind (125)I-melatonin and appeared to aggregate or traffic improperly. N124A and N124K receptors were retained in the Golgi. Therefore, mutants at N124 separated into two sets: the first bound (125)I-melatonin with high affinity and trafficked normally, but with reduced inhibitory coupling to adenylyl cyclase and Ca(++) channels. The second set lacked melatonin binding and exhibited severe trafficking defects. In summary, asparagine-124 controls melatonin receptor function as evidenced by changes in melatonin binding, control of cAMP levels, and regulation of ion channel activity. Asparagine-124 also has a unique structural effect controlling receptor distribution within the cell.

Malignant fibrous histiocytoma of bone: a retrospective EMSOS study of 125 cases. European Musculo-Skeletal Oncology Society.

In an effort to learn more about malignant fibrous histiocytoma (MFH) of bone and its prognosis with different treatment approaches, the European Musculo-Skeletal Oncology Society (EMSOS) initiated a retrospective survey among its members. Data requested included patient and treatment variables and outcome. The information on all patients with histologically proven, primary, localized osseous extremity MFH was analyzed if surgical tumor removal was performed and disease status was documented for at least one follow-up date. 125 such patients were evaluable (74 male, 51 female; median age 34 years; tumor site femur 81, tibia 26, humerus 12, other 6). Local treatment was surgery only (110) or surgery plus radiotherapy (15). Chemotherapy was used in 97/125. On last follow-up, 85 patients remained in remission, 33 had developed metastases, 6 a local recurrence, and 1 a combined relapse. With a median follow-up of 3.9 years for patients at risk, actuarial 5-year disease-free survival was 59%. In univariate analyses, younger age and the use of chemotherapy were associated with a more favorable outcome, as was limb-salvage surgery. 23 of 66 tumors with information on response to preoperative chemotherapy responded well (> 90% necrosis). Among these 23, only one relapsed.

The antigenic composition of Neospora caninum.

Neospora caninum is an apicomplexan parasite which causes neosporosis, namely stillbirth and abortion in cattle, and neuromuscular disease in dogs. Although N. caninum is phylogenetically and biologically closely related to Toxoplasma gondii, it is antigenically clearly distinct. In analogy to T. gondii, three stages have been identified. These are: (i) asexually proliferating tachyzoites; (ii) tissue cysts harbouring slowly dividing bradyzoites; and (iii) oocysts containing sporozoites. The sexually produced stage of this parasite has only recently been identified, and has been shown to be shed with the faeces from dogs orally infected with N. caninum tissue cysts. Thus dogs are definitive hosts of N. caninum. Tachyzoites can be cultivated in vitro using similar techniques as previously described for T. gondii. Methods for generating tissue cysts containing N. caninum bradyzoites in mice, and purification of these cysts, have been developed. A number of studies have been undertaken to identify and characterise at the molecular level specific antigenic components of N. caninum in order to improve serological diagnosis and to enhance the current view on the many open questions concerning the cell biology of this parasite and its interactions with the host on the immunological and cellular level. The aim of this paper is to provide an overview on the approaches used for detection of antigens in N. caninum. The studies discussed here have had a great impact in the elucidation of the immunological and pathogenetic events during infection, as well as the development of potential new immunotherapeutic tools for future vaccination against N. caninum infection.

[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.

Early infections in patients undergoing bone marrow or blood stem cell transplantation--a 7 year single centre investigation of 409 cases.

Infections are a major cause of morbidity and mortality in patients undergoing high-dose therapy and subsequent autologous or allogeneic haemopoietic stem cell transplantation, despite the change from topical to systemic anti-infection prophylaxis and the introduction of growth factors and new antimicrobial drugs. We report our single centre experience with data from 409 patients treated at our unit from its opening in 1990 until May 1997. Three hundred and seventy-eight patients were transplanted for the first time, 12 patients were retransplanted or boosted and 19 patients were readmitted for miscellaneous reasons. 245 patients were allografted and 157 autografted. Antimicrobial prophylaxis was mainly quinolones, fluconazole plus amphotericin-B orally, aciclovir, and TMP/SMX or pentamidine. Three hundred and nineteen (78%) developed fever of significantly longer duration in the allogeneic setting with anti-CMV seropositivity. The most frequent infection was fever of unknown origin (50.6%), followed by septicaemia (12.5%) and pneumonia (11.0%). Pathogens isolated in 24.6% of the infections were mostly gram-positive bacteria (57.9%), followed by non-fermenting rods (11.2%), Aspergillus spp. and Candida spp. (10.3%, each). Cumulative response rate to antimicrobial therapy was 66.9%. Infections were responsible for 62.5% (25/40) of deaths after transplantation. Predominant pathogens were Aspergillus spp. (11), Candida spp. (four), and Pseudomonas spp. (three). None of the patients died from gram-positive bacterial infection. The risk of dying from infection was 11.2% after allografting and 0.8% after autotransplantation. Infections remain a major risk for early death after allogeneic transplantation of haemopoietic stem cells. Infection with gram-negative bacteria can be prevented by quinolone prophylaxis. Predominant pathogens are Aspergillus spp. Candida spp. and nonfermenting rods. Systemic infection with these pathogens is associated with a poor prognosis. Antimycotic prophylaxis and the therapy must be improved.

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.

Differential expression of cell surface- and dense granule-associated Neospora caninum proteins in tachyzoites and bradyzoites.

Morphologically, the tachyzoites and the tissue cysts of Neospora caninum are difficult to distinguish from those of other cyst-forming apicomplexan parasites such as Toxoplasma gondii. Several stage-specific antigens have been identified in T. gondii tachyzoites and bradyzoites, and respective antibodies are useful tools for discriminating between the 2 stages during tachyzoite-bradyzoite interconversion in T. gondii infections. Whereas several cell surface- and dense granule-associated proteins have been identified and characterized in N. caninum tachyzoites, not much is known about antigenic components expressed in N. caninum bradyzoites. In this study, the differential expression of the 2 N. caninum surface proteins Nc-p43 and Nc-p36 and the dense granule protein Nc-p33 (NCDG1) within tachyzoites and bradyzoites of N. caninum has been investigated.

Identification and characterisation of a dense granule-associated protein in Neospora caninum tachyzoites.

Neospora caninum is an apicomplexan parasite which is morphologically and ultrastructurally very similar to Toxoplasma gondii. In order to identify molecules involved in host cell entry and subsequent modification of the parasitophorous vacuole, a polyclonal antiserum directed against N. caninum tachyzoites was raised in a rabbit. Subcellular fractionation of tachyzoites was performed using the non-ionic detergent Triton-X-114. Membrane fractions were analysed by immunoblotting using the polyclonal antiserum. One of the immunoreactive protein bands had a mol. wt of 33,000 and was subsequently named Nc-p33. Affinity-purified anti-Nc-p33 antibodies were used to characterise this polypeptide using SDS-PAGE, isoelectric focusing, Western blot analysis and immuno-EM. Nc-p33 was found in two isolates of N. caninum (NC-1 and Liverpool), but could not be detected in T. gondii tachyzoites. Immunogold EM revealed that Nc-p33 constituted a dense granule-associated protein, and Western blotting demonstrated that Nc-p33 was most likely identical to the recently described antigen NCDG1. Shortly after invasion, this dense granule protein was targeted to the parasitophorous vacuole membrane, and, at later timepoints after infection, was also found on the parasitophorous vacuolar network. This suggested that Nc-p33 could play a functional role in the modification of the parasitophorous vacuole and its membrane.

The major 36 kDa Neospora caninum tachyzoite surface protein is closely related to the major Toxoplasma gondii surface antigen.

The tachyzoites and the tissue cysts containing bradyzoites of Neospora caninum and Toxoplasma gondii, respectively, are difficult to distinguish morphologically. Specific antigens have been identified in T. gondii tachyzoites and bradyzoites, some of which are stage-specifically expressed, and different functions have been attributed to some of them. A tachyzoite stage-specifically expressed surface protein is the major surface antigen 1 (SAG1) which has been shown to be involved in host cell attachment and invasion. Previously we have identified a cell surface-associated glycoprotein (p36) in N. caninum tachyzoites. The full length coding sequence of the cDNA coding for p36 was determined, and analysis of the deduced amino acid sequence demonstrated that p36 is closely related to SAG1. p36 is encoded by a single copy gene which produces a transcript of 1.4 kb. Immunogold labeling of resin-embedded parasites using polyclonal antibodies affinity-purified on a recombinant p36 fusion protein expressed in Escherichia coli showed that this protein is located exclusively on the tachyzoite cell surface. As SAG1 in T. gondii, p36 is expressed in the tachyzoite stage, but is absent from bradyzoites. p36 is recognized by antibodies present in sera of cows experimentally infected with N. caninum tachyzoites.

Intensified conditioning regimen in bone marrow transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia.

We investigated an intensified conditioning regimen including fractionated total body irradiation (12 Gy), etoposide (30-45 mg/kg) and cyclophosphamide (120 mg/kg), followed by autologous (n = 5), allo-related (n = 13) or allo-unrelated (n = 6) bone marrow (n = 22) or peripheral stem cell (n = 2) transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. One patient received busulfan (16 mg/kg) instead of TBI. Nineteen patients were transplanted in 1CR, two in 2CR, one in 1PR and two in relapse. Major toxicity was mucositis grade II according to the Bearman scale in all patients. The treatment-related mortality was 25%, mainly due to infection or GVHD after allogeneic transplantation. After a median follow-up of 45 months (range 2-93), nine patients (37.5%) remain alive in CR. Nine patients (37.5%) relapsed and eight (33.3%) of these subsequently died. After autologous transplantation, four of five patients (80%) relapsed and died. Late relapse was seen after allogeneic, as well as autologous transplantation, at 33 and 59 months, respectively. The Kaplan-Meier estimate of leukemia-free survival for all patients is 38% at 3 years (95% CI: 18-58%) and 35% at 5 years (95% CI: 15-55%). For allogeneic transplants in first CR (n = 15) the estimate of disease-free survival was 46% at 3 years (95% CI: 19-73%) and 34% at 5 years (95% CI: 17-51%). Patients aged below 30 years had a better estimated overall survival at 3 years (61% vs 11%, P < 0.001). The bcr-abl fusion transcript (p210 vs p190 vs p210/190) did not affect disease-free or overall survival. In our experience, an intensified conditioning regimen seems to improve the results of bone marrow transplantation in patients with Ph+ acute lymphoblastic leukemia. However, the high relapse rate warrants novel approaches to enhance anti-leukemic efficacy.

Attitudes to current oral contraceptive use and future developments: the women's perspective.

OBJECTIVES: The study was planned to determine current trends in contraceptive usage and to examine the attitudes, needs and preferences of women with respect to oral contraceptives. METHODS: Semi-structured interviews were carried out with women (n = 1201, aged 16-45 years) in Germany, the UK and France. RESULTS: The study revealed that oral contraceptives were the most popular method of contraception employed, followed by condoms, and that the majority of respondents were aged 16-19 years when they first used an oral contraceptive. An important finding of the study was that an oral contraceptive was first used only after having sexual intercourse for the first time (within 1 year), emphasizing the importance of effective contraceptive information and education for adolescents. Regarding non-contraceptive health benefits, protection from ovarian and endometrial cancer was perceived by respondents to be of the greatest importance; however, few women were spontaneously aware of this benefit. When given a number of different oral contraceptive intake options to assess, the established 'once daily for 21 consecutive days' option remained the most popular, although a 'once weekly' alternative was cited by many women. When asked about the preferred frequency of menstrual bleeding, there was a polarization between women favoring the normal monthly bleed and those wanting a 'no-bleed' regimen. CONCLUSION: Women are poorly informed about oral contraceptive use, and are largely unaware of the important long-term non-contraceptive benefits. Many women would prefer alternative pill intake options and a significant number would favor a 'no-bleed' regimen.

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.

[Therapy-induced changes in osteosarcoma after neoadjuvant chemotherapy (COSS 86 Therapy Study). Correlation between morphologic findings and clinical follow-up]. / Therapie-induzierte Veränderungen an Osteosarkomen nach neoadjuvanter Chemotherapie (Therapiestudie COSS 86). Beziehungen zwischen morphologischen Befunden und klinischem Verlauf.

207 osteosarcomas were examined morphologically after neoadjuvant chemotherapy according to the COSS-86 protocol using representative slides of one whole tumor plane. The rate of responders 63%. In relapse-free patients both the whole tumors and the vital areas there of were smaller than in patients with relapse during a follow-up period of 5 years. Within the subgroup of osteoblastic osteosarcomas, metastases were observed following smaller tumors than in chondroblastic osteosarcomas. Therefore, in addition to degree of regression, histological subtype and tumor size should be considered in the prognostic evaluation of osteosarcomas.

Methotrexate pharmacokinetics and prognosis in osteosarcoma.

PURPOSE: The influence of methotrexate (MTX) pharmacokinetic parameters on the efficacy of high-dose MTX (HDMTX) in osteosarcoma was analyzed. PATIENTS AND METHODS: MTX serum peak values from 198 patients in 1,703 treatment courses and more detailed pharmacokinetic data from 185 patients in 1,045 treatment courses from the Cooperative Osteosarcoma Study Group (COSS) studies COSS-80, COSS-82, and COSS-86 were investigated. RESULTS: A mean threshold peak level of > or = 1,000 mumol/L for the repeated MTX courses of individual patients was found to correlate significantly to prognosis in study COSS-80 (18% v 64% actuarial 10-year disease-free survival [DFS], P = .0001). Six courses of HDMTX per patient who achieved peak values > or = 1,000 mumol/L were found to be sufficient for a full effect to be seen in DFS in COSS-80. The MTX peak level was found to correlate closely to the area under the curve (AUC). However, AUC was a less powerful determinator of prognosis than the mean threshold MTX peak value. In patients who received cisplatin (DDP) as one of the additional drugs to MTX, the peak values and AUC were significantly increased (1,396 v 1,276 mumol/L, P = .011; 6,684 v 5,820 h.mumol/L, P < or = .002) and only a few patients (6%) did not achieve mean threshold MTX peak values. In addition, following restriction of hydration fluid after the MTX infusion from 4.5 to 3.0 L/m2 per 24 hours, the early MTX half-life (t1/2) and the AUC, but not the MTX peak value, were significantly increased (3.4 v 3.05 hours, and 6,760 v 5,998 h.mumol/L, respectively, P < or = .002). CONCLUSION: MTX pharmacokinetics significantly influence the efficacy of MTX in osteosarcoma. Individual adaptation of the MTX dose to ensure a threshold peak serum level > or = 1,000 mumol/L does not seem necessary at a fixed dose of 12 g MTX/m2, restriction of hydration fluid to 3 L/m2 per 24 hours, and concomitant use of DDP within the drug regimen.

[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)

Osteosarcoma.

Findings from molecular genetic and cytogenetic investigations suggest that mutations in suppressor genes play a key role in osteosarcoma pathogenesis. RB and p53 are frequently involved and are speculated to be indispensable components. Alterations in putative suppressor genes on chromosomes 18q and 3q additionally may be involved in various patterns. The high resolution of magnetic resonance imaging in osteosarcoma imaging is confirmed, and the validity of dynamic gadolinium-enhanced imaging for estimation of tumor response is stated. The efficacy of single-drug high-dose methotrexate convincingly is shown to be 19%. Phase II trials with nonspecific immunostimulation using a synthetic liposomal mycobacterium-derived antigen (liposomal muramyl tripeptide phosphatidylethanolamine) do not yet allow us to draw conclusions on eventual efficacy. A novel and promising approach may be intervention in the endocrine or orthocrine and paracrine tumor growth regulation. Hypophysectomy in mice dramatically reduced plasma or insulin-like growth factor and local as well as systemic growth of transplanted osteosarcoma. The close interrelation between tumor response, surgical margins, and local control is demonstrated, as well as the fatal prognosis after local failure. Also, the validity of known risk factors in patients undergoing intensive chemotherapy has been confirmed. Interestingly, dose intensity was not found to influence prognosis.