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Evaluation of tumour necrosis during chemotherapy with diffusion-weighted MR imaging: preliminary results in osteosarcomas.

BACKGROUND: During successful chemotherapy of osteosarcomas tumour size does not diminish significantly because the therapy has limited impact on the mineralized matrix of the tumour. Treatment response is considered successful if, histologically, more than 90% of tumour cells show necrosis. OBJECTIVE: To determine if osteosarcomas change their water diffusion during preoperative chemotherapy in relation to the amount of tumour necrosis. MATERIALS AND METHODS: Eight patients (age 11-19 years) with histologically proven limb osteosarcoma underwent T1-weighted, fat-suppressed T2-weighted and contrast-enhanced T1-weighted spin-echo imaging together with diffusion-weighted EPI sequences (b = 700) at 1.5 T before and after five cycles of standard chemotherapy. Tumour volume and apparent diffusion coefficient (ADC) maps were calculated before and after chemotherapy. The degree of tumour necrosis after chemotherapy was assessed using the histological Salzer-Kuntschik classification (grades 1-6). RESULTS: During chemotherapy, the ADC values of osteosarcomas changed significantly. The ADC of untreated tumour was 2.1 +/- 0.4 x 10(-3) mm(2)/s (mean +/- SD) (95% CI 1.6-2.0). The ADC of chemotherapy-treated sarcomas was 2.5 +/- 0.4 x 10(-3) mm(2)/s (95% CI 1.8-2.2). Necrotic areas, which were confirmed by macroscopic examination, showed ADC values up to 2.7 x 10(-3) mm(2)/s. Four patients with little viable tumour tissue within the neoplasm (Salzer-Kuntschik grades 1-2) had an increase in ADC of 0.4 up to 0.7 x 10(-3) mm(2)/s. Four patients with larger areas of viable tumour (Salzer-Kuntschik grade 4) showed a lesser increase in ADC of 0.0 up to 0.3 x 10(-3) mm(2)/s. The differences in ADC values in tumour tissue before and after chemotherapy were highly significant (P = 0.01). CONCLUSION: During chemotherapy of osteosarcomas, tumour ADC changes are related to the degree of tumour necrosis.

Adolescent↗

Low-grade osteosarcoma of the ethmoid sinus.

Osteosarcoma uncommonly arises in craniofacial bones and has only rarely been reported to arise in the ethmoid sinus. Most primary osteosarcomas arising in paranasal sinuses are high-grade malignancies. A low-grade osteosarcoma arising in the ethmoid sinus has not previously been described. We report the clinical, radiological and histological findings of a case of low-grade (parosteal osteosarcoma-like) osteosarcoma which arose in the ethmoid sinus.

Adult↗

MR imaging based strategies in limb salvage surgery for osteosarcoma of the distal femur.

OBJECTIVE: To analyse to what extent MR imaging based decisions were correct in determining the surgical procedure in patients with osteosarcoma of the distal femur. DESIGN: We compared the findings on MR imaging that determined the surgical strategy with the actual surgical findings or histopathological specimen. We assessed to what extent MR images could be used to determine the surgical procedure in patients with osteosarcoma. PATIENTS: Between 1985 and 1992, 34 patients with an osteosarcoma were treated. Two patients had a low-grade osteosarcoma. Thirty-two patients with a high-grade osteosarcoma of the distal femur (17 stage IIB, 15 stage III) were included in this study. Surgical options consisted of either limb salvage surgery or ablative surgery, which included the Van Nes-Borggreve rotationplasty. Limb salvage surgery consisted of extra-articular or transarticular resection, followed by reconstruction. Surgery was planned depending on the local extent of the tumour as depicted on the MR studies, coupled with data from the biopsy, age, patient compliance and histological grade. Follow-up was available in all patients. Nine of 17 patients graded as IIB were alive with an average follow-up of 68 months (range 46-109 months), of whom one has metastases. No local recurrence was encountered. RESULTS: If no tumour involvement on MR imaging was found and this was used as a determining factor, this proved to be correct at subsequent analysis. We found that in eight of 11 cases, when MR images suggested a close relationship between tumour and nerve, an oncologically safe plane could be achieved during surgery. In three, a free plane could not be accomplished, as confirmed at histopathological examination. Hence, when nerve involvement was equivocal on MR imaging we found it valuable to reassess nerve involvement during surgery and reconsider limb salvage surgery. When the decisive factor was the vascular involvement and tumour extension was read as equivocal, it was possible to obtain a oncologically safe plane in six of 13 cases. When comprehensive tumour involvement of any structure was noted pre-operatively, it proved to be correct at histopathological examination, except for one case of assumed vascular involvement that proved to be free. CONCLUSIONS: If no tumour involvement of a structure was found on MR imaging and this was used as a determining factor, this proved to be correct. When nerve involvement was equivocal on MR imaging we found it valuable to reassess nerve involvement during surgery and reconsider limb salvage surgery. Extensive tumour involvement of any structure, as shown by MR imaging, could be used correctly as a decisive argument in planning a surgical procedure.

Adolescent↗

Chondroblastic osteosarcoma: characterisation by gadolinium-enhanced MR imaging correlated with histopathology.

OBJECTIVE: To identify specific features of chondroblastic osteosarcoma on gadopentetate dimeglumine (Gd)-enhanced magnetic resonance (MR) imaging. DESIGN AND PATIENTS: Nine patients with chondroblastic osteosarcoma and a control group of 20 patients with conventional central osteosarcoma were included in this study. The histopathological findings of the surgical specimens were compared with enhancement patterns on static Gd-enhanced MR images. RESULTS: In chondroblastic osteosarcoma septonodular and peripheral rim enhancement represented tumour with a pure chondroid matrix. Non-enhancing and heterogeneous enhancing areas represented tumour with both chondroid and osteoid matrix. In the tumours in the control group enhancement was predominantly heterogeneous but in one it was homogeneous. All these areas corresponded to necrotic or viable osteoid tumour tissue or fibrovascular tissue in areas of necrosis. CONCLUSION: Gd-enhanced MR imaging can assist in obtaining diagnostic biopsy material of chondroblastic osteosarcoma by identifying both osteoid- and chondroid-forming areas.

Adult↗

Recurrent parosteal osteosarcoma of the talus in a 2-year-old child.

Parosteal osteosarcoma is an uncommon, low-grade malignant bone tumor and is found in an older age group than conventional osteosarcoma. We present a talar parosteal osteosarcoma that recurred twice in a 2-year-old child. To our knowledge, this is the youngest patient reported with a parosteal osteosarcoma. The talus is an unusual site for parosteal osteosarcoma. Inadequate resection due to a diagnosis of juxtacortical chondroma resulted in recurrence of the tumor. The age of the patient, the thick cartilaginous cap, and well-differentiated trabecular bone all contributed to the critical erroneous diagnosis.

Bone Neoplasms↗

Bifocal sclerosing osteosarcoma: unusual presentation and course.

Multifocal osteosarcoma is uncommon. Long-term survival of an incompletely treated case is exceptional. We report an unusual case of bifocal sclerosing osteosarcoma in a 38-year-old women that involved the left ilium and right proximal femur. The femoral lesion was resected. The tumor in the left ilium was not treated. She did not receive chemotherapy and has been free of metastases for 7 years. Recently, growth of the pelvic osteosarcoma has resulted in vascular compression and edema of the lower extremity. The patient's alkaline phosphatase has been elevated throughout. The tumor was HMB-45 positive, which has not been previously reported in osteosarcoma. The pathogenesis of multifocal osteosarcoma is discussed.

Adult↗

[P-glycoprotein expression in osteosarcoma].

One of the mechanisms by which multidrug resistance is mediated, is the mdr1 gene product, P-glycooprotein. Immunohistochemistry was performed for 63 osteosarcomas of 54 patients to investigate P-glycoprotein expression using the monoclonal antibody JSB-1. Most of the patients were children or adolescents who had received treatment under the framework of the Cooperative Osteosarcoma Study Group. In addition P-glycoprotein expression was assayed in five growth plates. Of all cases 68.5% stained positive for P-glycoprotein. Cases that had received chemotherapy showed a higher incidence (80.9%) of positive P-glycoprotein immunostaining than cases that had not received chemotherapy (66.6%). No relation could be established between P-glycoprotein expression and the response to chemotherapy, since the majority of P-glycoprotein positive biopsies showed a good response in the surgical specimen after chemotherapy. Furthermore, 42.9% of P-glycoprotein negative biopsies were classified as non-responders in the later surgical specimen. In addition to P-glycoprotein expression in osteosarcomas positive immunostaining was also detected in osteoblasts, osteocytes, osteoclasts as well as in some chondroblasts. The results indicate that P-glycoprotein expression in osteosarcomas also exists prior to chemotherapy and resembles the phenotype of normal bone tissue. However, the determination of P-glycoprotein by using immunohistochemistry in biopsies of osteosarcomas cannot predict the response to chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

Human xenograft osteosarcoma models with spontaneous metastasis in mice: clinical relevance and applicability for drug testing.

Osteosarcoma cells derived from patients have been isolated and subsequently cultured for the past 35 years. To date though, there have been no major breakthroughs in the development of a model for osteosarcoma that uses orthotopic implantation of human osteosarcoma cells and that closely emulates the clinical progression of this debilitating and fatal disease. Such a model is long overdue given the devastating demographics (second highest cause of cancer-related death in the paediatric age group) of the ailment and the lack of solid options for control, if not cure, for the disease, as it also is the most common primary tumour of bone. Only then can more robust R & D be undertaken in the search for efficacious anti-osteosarcoma agents. This review tackles this conundrum and lists the variety of models (that use human osteosarcoma cells) available and the types of studies performed with these.

Adolescent↗

Impact of family structure on long-term survivors of osteosarcoma.

GOALS OF WORK: Long-term outcomes of osteosarcoma have dramatically improved with the use of modern combination therapies. Such aggressive treatments, however, entail chronic complications. In the present study, we assessed the functional, psychological, and familial status of long-term survivors of osteosarcoma treated at our institution. MATERIALS AND METHODS: Fifteen long-term survivors of osteosarcoma were evaluated for functional and psychological sequelae. Functional assessment was based on a method described by Enneking et al. Psychological assessment was based on General Health Questionnaire 28, Inventory Scale for Traumatic Neurosis, and Family System Test. MAIN RESULTS: Ten patients showed mild functional impairments; only five patients were handicapped more seriously. Depressive symptoms were diagnosed in four patients. A total of six patients revealed unbalanced family structures, including three of the four patients with depressive symptoms, all four patients with symptoms of posttraumatic stress disorder, and five of seven patients who showed poor emotional acceptance. CONCLUSIONS: Osteosarcoma survivors will generally recover good functional performance. Only a minority of them remain seriously impaired. One third of the patients present depressive symptoms and posttraumatic stress disorder. Poor coping is closely associated with unbalanced family structures. Therefore, the psychological and familial situation of patients with newly diagnosed osteosarcoma should be carefully assessed.

Adolescent↗

Osteosarcoma of bone.

The definition of osteosarcoma requires that a malignant tumor of bone produce osteoid or bony matrix. With this as a basic definition, osteosarcoma of bone can be divided into several clinicopathologic entities based on clinical, roentgenographic, and pathologic features. The tumors can be broadly divided into those arising within the bone and those arising on the surface of bone. Most intraosseous osteosarcomas are high-grade malignant tumors that occur in children and adolescents. A small number occur in older patients, and they may be related to a preexisting condition, such as Paget's disease or radiation. The site of the lesion has prognostic importance. Osteosarcoma of the jaws is associated with an especially good prognosis, whereas the same kind of tumor involving the skull has a very poor prognosis. Most osteosarcomas of the surface of bone are well or moderately differentiated and are associated with an excellent prognosis.

Bone Neoplasms↗

Management of osteosarcoma.

Improving cure rates for osteosarcoma continues to be a major challenge. The clinical management of individual patients is exacting and requires a skilled, experienced team including a surgeon, pathologist, oncologist, and radiologist, with support from specialist nurses and rehabilitation teams. Outcomes from treatment have improved little in 20 years and remain disappointing. Chemotherapy for osteosarcoma is among the most grueling of any given for solid tumors, and treatment of the primary tumor is associated with permanent disability of some degree in a significant proportion of patients. New systemic treatments remain beyond the horizon. In recognition of these difficulties, an international cooperation has begun with the opening of a randomized trial, European and American Osteosarcoma (EURAMOS) 1, in Europe and the United States. This study heralds a new era of clinical investigation into osteosarcoma, with the promise of valuable biologic insights and rapid evaluation of investigational strategies. Osteosarcoma should always be treated under the guidance of a specialist team, and we recommend that whenever possible, patients be offered entry into EURAMOS 1 or other well-designed clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗

Small cell osteosarcoma of bone: an immunohistochemical study with differential diagnostic considerations.

Seventy-nine cases of small round cell tumors involving bone were studied in an attempt to learn whether the immunohistochemical features of the lesions might allow distinction of small cell osteosarcoma from other potential differential diagnostic considerations, including Ewing's sarcoma, atypical Ewing's sarcoma, primitive neuroectodermal tumor, mesenchymal chondrosarcoma, lymphoma, and the Askin tumor. The tissues studied were all formalin-fixed, decalcified, paraffin sections from patients between the ages of 16 and 48 years. With one exception (a small cell osteosarcoma), none of the lesions was cytokeratin positive. Moreover, none of the lesions was epithelial membrane antigen, desmin, factor VIII-related antigen, synaptophysin, or Leu-M1 positive. Accordingly, strong positivity for these antibodies in a majority of tumor cells should prompt inclusion of tumor types other than those listed above in the differential diagnosis. Vimentin positivity was seen in a majority of the tumors studied irrespective of histologic type. Scattered tumor cells (< 25%) showed positivity with antibodies to muscle-specific actin and smooth muscle actin in several of the different tumor types studied. No lesions other than lymphoma were leukocyte-common antigen (LCA) positive; all but two lymphomas were LCA positive, while all but one lymphoma were L26 positive. One (lymphoblastic) lymphoma was LCA and L26 negative. S-100, neuron-specific enolase, and Leu-7 did not prove to be specific for "neural-associated" tumors, but rather appeared in some small cell osteosarcomas, Ewing's sarcomas, atypical Ewing's sarcomas, primitive neuroectodermal tumors, mesenchymal chondrosarcomas, lymphomas, and Askin tumors. Antibody to cell surface antigen HBA71 was positive in three Ewing's sarcomas (two typical and one atypical) and negative in small cell osteosarcoma (three cases), mesenchymal chondrosarcoma (two cases), and lymphoma (one case). While some guidance may be derived from analysis of immunohistochemical staining patterns in a given lesion, the results reported in the present study do not suggest that routine immunohistochemistry alone will permit distinction of these small cell tumors of bone from one another. The value of immunohistochemical studies appears to lie particularly in the use of antibodies to LCA and S-100 protein to distinguish lymphoma and mesenchymal chondrosarcoma, and perhaps antibody to HBA71 to distinguish neural family lesions (such as Ewing's sarcoma), from other small cell tumors, such as small cell osteosarcoma.

Adolescent↗

Familial osteosarcoma associated with 13;14 chromosomal rearrangement.

Two prepubertal sisters of American Indian origin developed osteosarcoma at 8 and 12 years of age. This familial occurrence, tumor onset prior to puberty, unusual tumor location in one who also had short stature, and ethnic background all suggest an inborn predisposition to bone cancer rather than a chance occurrence. Rearrangements involving chromosomes #13 and #14 were found in both the surviving proband and mother. Comparison of the arm ratio and prometaphase G-banding patterns of the rearranged chromosomes suggests either deletion of band 14q11.2 or pericentric inversion (with breakpoints at 13q12 and 14q11.2) in the proband's rearranged chromosome, but not in her mother's. Her mother, who had no malignancy, had a typical Robertsonian translocation [t(13;14)(p11;q11)]. Three previously reported children with chromosomal abnormalities developed osteosarcoma at unusually young ages, younger even than in reported sibships with osteosarcoma. The most frequently detected cytogenetic abnormalities in sarcoma tumor cells involve chromosomes #13 and #14. In addition, some cases of bilateral retinoblastoma and familial unilateral retinoblastoma, which are known to be at increased risk for osteosarcoma, are associated with tiny deletions on chromosome #13. Thus, there may be a causal relationship between constitutional loss or rearrangement of genetic material at these breakpoints on chromosomes #13 or #14 and development of osteosarcoma in this family that is similar to that seen in patients with small constitutional chromosomal deletions who develop Wilms' tumor and retinoblastoma.

Adolescent↗

Low level amplification of c-sis and c-myc in a spontaneous osteosarcoma model.

Canine and human osteosarcoma are very similar clinically, radiologically and pathologically. DNA extracted from canine osteosarcomas (n = 9) and normal canine control tissues (n = 17) was examined for amplification of the c-sis, c-myc, N-myc and c-H-ras protooncogenes. Statistically significant amplification of the c-sis and c-myc protooncogenes was evident in the tumor tissues as compared to the normal control tissues (P less than 0.05). DNA and total cellular RNA from cultured canine and human osteosarcoma and fibroblast cell lines were examined for amplification or enhanced expression of c-sis and c-myc. Very low levels of c-myc and c-sis DNA amplification were noted in canine osteosarcoma cells as compared to canine fibroblasts. Immunostaining of sections of human and canine osteosarcoma for the sis gene product, PDGF B, showed similar levels and patterns of expression in both populations of tumors.

Animals↗

Increased expression of S100A6 is associated with decreased metastasis and inhibition of cell migration and anchorage independent growth in human osteosarcoma.

While most osteosarcoma patients have metastatic or micrometastatic lesions, less than 15% of them have clinically detectable metastatic diseases at presentation. To identify potential markers that may predict osteosarcoma metastasis, we analyzed the expression of S100A6 in 50 osteosarcoma cases and found that 84% of the analyzed specimens stained positive for S100A6. There is a trend towards decreased clinically evident metastasis with increased S100A6 staining. Overexpression of S100A6 in osteosarcoma cells decreases cell motility and anchorage independent growth on collagen gels. Our findings provide evidence that, while S100A6 is commonly overexpressed in human osteosarcoma, loss of its expression correlates with a metastatic phenotype.

Adolescent↗

Mutations in the mitochondrial DNA D-Loop region occur frequently in human osteosarcoma.

To explore the polymorphisms and mutations of mitochondrial D-Loop region in osteosarcoma and their possible association with carcinogenesis, direct DNA sequencing method was used to detect the variants of the mitochondrial D-Loop in 20 patients with osteosarcoma. We found mutations of the mitochondrial D-Loop in 14/20 (70%) of the tested osteosarcoma samples, including 34 novel mutations. We did not detect any new polymorphisms in osteosarcomas, nor was there any association between variants and the three histopathological subtypes. We identified 89 variant sites, most of which were within the hypervariable I and II (HV I and HV II) regions. These data suggest that mtDNA mutations within the D-Loop region, particularly the HV I and HV II segments, are a frequent event in osteosarcomas.

Bone Neoplasms↗

[Standards and Options for the use of radiation therapy in the management of patients with osteosarcoma. Update 2004].

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of French Cancer Centres (FNCLCC), the 20 French regional cancer centres, and specialists from French public universities, general hospitals and private clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and the outcome of cancer patients. The methodology is based on a literature review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVE: To update the SOR recommendations for the use of radiation therapy in the management of patients with osteosarcoma. This work was performed in collaboration with the French society against cancers in children and adolescent (SFCE). METHODS: Data have been identified by literature search using Medline (from January 1992 to October 2003). In addition several Internet sites were searched in October 2003. RESULTS: The 3 mains standards are: 1) local and exclusive curative irradiation is not indicated as primary treatment for osteosarcoma or for local and operable recurrence, except for lesion in inaccessible sites or if the patient refuses surgery; 2) local and prophylactic adjuvant irradiation is not indicated for the treatment of osteosarcoma after chemotherapy (neoadjuvant and/or adjuvant) and complete macro or microscopic surgery, except for non-operable R1 or R2 surgical resection; 3) whole-lung prophylactic irradiation is not indicated in non-metastatic osteosarcoma. Systemic metabolic radiotherapy for pain treatment, using samarium-153 ethylenediaminetetramethylene phosphonic acid (Sm-153-EDTMP) can be offered to patients with painful metastatic osteosarcoma or in case of recurrent bone sites inaccessible to local therapies (surgery, external irradiation).

Adolescent↗

Follow-up study of long-term survivors of osteosarcoma in the prechemotherapy era.

Osteosarcoma is the most common primary bone sarcoma. Several studies published in the 1960s established that approximately one fifth of patients survive when treated with surgery alone. There is no information, however, about the long-term consequences of osteosarcoma. It is especially relevant to know if these patients are at risk for a second malignancy. We reviewed all clinical records from long-term (defined as more than 10 years) osteosarcoma survivors treated at Mayo Clinic in the prechemotherapeutic era from 1900 to 1960. We re-reviewed histological sections for most cases. Patients or next of kin provided follow-up information during telephone interviews. Rates of second malignancy were compared with expected rates in the population at large. We identified 465 patients treated for osteosarcoma. Of these patients, 83 (17.8%) were long-term survivors, including 19 who were alive up to 65 years after treatment. Of the 7 patients with pulmonary metastases, 3 died. A second malignancy developed in 26 patients, 15 of whom died of the malignancy. Although long-term survivors of osteosarcoma have a higher incidence of a second malignant tumor than a normal population, this increase was not statistically significant. No demographic or histological variables predicted long-term survival.

Age Distribution↗