Education and employment in long-term survivors of high-grade osteosarcoma: a Japanese single-center experience.

OBJECTIVE: To investigate the status of education and employment of long-term survivors who became physically handicapped after treatment for high-grade osteosarcoma. METHODS: Of the osteosarcoma patients treated at our hospital, 41 patients aged less than 18 years at the initial presentation who were free of disease for 10 years or longer after the end of treatment were studied. The status of their education and employment was investigated via a questionnaire. RESULTS: Twenty-seven patients responded to the questionnaire (response rate, 65.9%). Of these patients, 73.1% (19/26) could return to the school they had attended before the disease, and 52% (13/25) graduated from college or university. The percentage of those who went to college or university was higher in the limb-sparing group. Seventy-two percent of the patients were engaged in clerical work, and the mean annual income was 4.01 million JPY (corresponding to about 24,000 EUR). No difference was noted in the status of employment between the amputation and limb-sparing groups. CONCLUSIONS: The percentage of patients who went to college or university was similar to the percentage in all Japanese. However, the status of the diseased limb appeared to affect school attendance. The mean annual income of the patients was comparable to that of the national average, and they experienced no major problems in their employment. Physical disabilities posed few problems in their daily living.

Predictors of long-term survival with pulmonary metastasectomy for osteosarcomas and soft tissue sarcomas.

AIM: The control of pulmonary metastases is important for long-term survival of the patients with osteosarcomas and soft tissue sarcomas. METHODS: To evaluate the efficacy of aggressive pulmonary metastasectomy for those patients, we reviewed 105 cases (44 osteosarcomas, and 61 soft tissue sarcomas) treated in our hospital. RESULTS: The number of metastases was only the significant risk factor for the curability of the metastasectomy (logistic regression analysis, P=0.0274). The 5-year and 10-year survival rate were 43.6% and 32%. The curability was only independent prognostic factor on multivariate analysis (P=0.0008). CONCLUSIONS: Early detection of pulmonary metastasis, multimodal perioperative treatment, and design for minimizing the volume of resected lung tissues will enable complete and repeat resections for the achievement of long-term survival.

Extraskeletal mesenchymal chondrosarcoma: an imaging review of ten new patients.

OBJECTIVE: Extraskeletal mesenchymal chondrosarcoma (EMC) is a rare soft-tissue tumor that most arises in young adults. Because of its rarity, few imaging studies have been reported to date. The purpose of this study was to elucidate the imaging features of this tumor. DESIGN: We conducted a multi-institutional study in cooperation with five referral cancer centers in Japan. Imaging findings of ten new EMC cases, including conventional radiography, computed tomography (CT), and magnetic resonance imaging (MRI), performed at each institute, were reviewed along with clinical features. PATIENTS: Ten patients with EMC, who had been treated at each hospital from 1990 to 2001, participated in this study. RESULTS AND CONCLUSIONS: Soft-tissue masses with well-demarcated, dense and granular calcification were most frequently observed on plain radiographs and CT scans. T2-weighted MR images most clearly depicted a two-component structure composed of calcified and uncalcified areas, and enhanced MRI showed inhomogeneous enhancement in both areas. Although the sensitivity and specificity of these findings are unknown, they might be characteristic and have diagnostic value for this rare tumor.

Surgical treatment for pancreatic metastasis from soft-tissue sarcoma: report of two cases.

We present two cases in which a soft-tissue sarcoma metastasized to the pancreas, but both patients survived as a result of repetitive surgical treatment during a 6- to 10-year period. The first case was a 29-year-old man who had a history of removal of mesenchymal chondrosarcoma in the left thigh in 1986 and who underwent distal pancreatectomy and the enucleation of a tumor in the head of the pancreas because of the development of three metastatic lesions in 1989. Afterward, although metastases were found in other organs, they were resected each time (for a total of five times) and the patient has survived over 10 years. The second case was a 40-year-old woman who had a history of the removal of synovial sarcoma in the right thigh and had 6 surgical resections of local or pulmonary recurrent tumors. She underwent pylorus-preserving pancreaticoduodenectomy in 1993 because of the development of a solitary metastatic lesion in the pancreas and survived more than 6 years after the pancreatectomy. Our report suggests, in selected cases, that long-term survival from pancreatic metastasis of soft-tissue sarcoma is expected as a result of curative resection. However, because pancreatic metastasis has a potential to recur in other organs, it is necessary to take aggressive surgical procedures repeatedly for the treatment of recurrences to improve prognosis after pancreatectomy.

Knee rotation-plasty for malignant musculoskeletal tumors occurring around the knee joint.

BACKGROUND: In addition to the wide excision of malignant musculoskeletal tumor around the knee joint, surgical methods, such as total knee arthroplasty and knee rotation-plasty are available. Therefore, this study was undertaken to clarify the usefulness of knee rotation-plasty. MATERIALS AND METHODS: At the Chiba Cancer Center, knee rotation-plasty was performed in 27 patients with malignant musculoskeletal tumor around the knee joint. Patients were divided into two groups: Group S, in which operations were performed as salvage surgery (8 patients), and Group I, in which operations were performed as initial surgery (19 patients). The lower limb function was investigated in 17 patients (7 patients in Group S and 10 patients in Group I). The lower limb function was assessed by the Knee Evaluation System of International Symposium on Limb Salvage and the Knahr's assessment. RESULTS: Lower limb function in Group S measured an average of 25.7 points (85.6%), while the lower limb function in Group I measured an average of 23.6 points (78.7%). The majority of patients in both groups were capable of walking without a cane or doing light exercise with below-the-knee prosthesis, revealing good lower limb function. CONCLUSION: Whether it is performed as salvage or initial surgery, knee rotation-plasty can be useful method for reconstruction of the knee after wide excision of malignant musculoskeletal tumor around the knee joint.

[High-dose chemotherapy with autologous peripheral blood stem cell transplantation (PBSCT) for refractory bone and soft tissue sarcomas].

High-dose chemotherapy with autologous peripheral blood stem cell transplantation was administered to 10 patients with refractory bone and soft tissue sarcoma (2 patients with primitive neuroectodermal tumor, 4 patients with Ewing's sarcoma, 3 patients with synovial sarcoma and one patient with osteosarcoma). Busulfan 4 mg/kg x 4, melphalan 140 mg/m2 and thiotepa 200 mg/m2 x 3 were used in the high-dose chemotherapy. Complications related to the treatment were limited to one patient who developed hepatic veno-occlusive disease, no serious complications were seen in the other patients. Four patients died of their disease, one patient was alive with the disease and 5 patients were alive with no evidence of disease. The prognosis for non-resectable primitive neuroectodermal tumor and Ewing's sarcoma is said to be very poor. However, there are some patients in whom the disease is kept in remission by high-dose chemotherapy with autologous peripheral blood stem cell transplantation, so this therapy may be a possible substitute for radical operation. With spindle cell sarcomas, the efficacy of this treatment was temporary, so it will be necessary to investigate frequent high-dose chemotherapy and to change the high-dose chemotherapy regimen.

The surgical management of sacrococcygeal chordoma.

BACKGROUND: Complete excision of sacrococcygeal chordoma is necessary at initial surgery due to its poor sensitivity to radiotherapy and chemotherapy. However, due to the anatomic characteristics of this tumor, intralesional excision tends to be employed, resulting in local recurrences in many patients. METHODS: The clinical features and results of surgical treatment of 13 patients with sacrococcygeal chordoma who were treated at the Chiba Cancer Center and Chiba University beginning in 1972 were analyzed. RESULTS: Intralesional excision was performed in eight patients, marginal excision in two patients, and wide excision in three patients. Local recurrence was observed in six patients, with a high proportion occurring in the gluteal muscles attached to the sacrum (the gluteus maximus muscle and piriform muscle). Seven patients died of their disease and six patients were alive with no evidence of disease. The 5-year survival rate was 81.8% and the 10-year survival rate was 29.1%. CONCLUSIONS: It is highly possible that residual chordoma infiltrating the gluteal muscles accounts mainly for the local recurrences. Therefore, a precise preoperative assessment of the tumor infiltration into the gluteal muscles by magnetic resonance imaging is important for the prevention of local recurrence. For complete tumor removal, a radical wide posterior surgical margin of the gluteal muscles should be employed. A less radical anterior surgical margin is sufficient because there is a firm presacral fascia anterior to the sacrum. The appropriate surgical margin for the complete removal of the chordoma differs according to the location of the tumor and tissues involved.

Two cases of osteosarcoma occurring as second malignancy of childhood cancer.

We report on two patients in whom osteosarcoma occurred as second malignancy of childhood cancer. One patient had a malignant teratoma and the other adrenocortical carcinoma as the primary cancer. The emergence of cancer in cured cases and long-term survival cases of childhood cancer may result in an increase in the number of osteosarcomas seen in adolescence occurring as second malignancy. Anti-cancer drugs in large does were used for the treatment of a malignant teratoma in the former. These anti-cancer drugs may be involved in the occurrence of the second malignancy. In the latter, the patient has the germ-line mutation of p53 tumor suppressor gene, so genetic factors are presumably related to the occurrence of the second malignancy.

Prognosis of osteosarcoma with pulmonary metastases at initial presentation is not dismal.

Prognosis of osteosarcoma has been improved markedly with the introduction of effective, intensive chemotherapy. However, there are many reports that indicate that the prognosis of osteosarcoma with pulmonary metastases at the initial presentation is poor. One hundred seventeen patients with osteosarcoma involving the extremities were treated at the Chiba Cancer Center from 1976 to 1995. Of these, nine (7.6%) patients had pulmonary metastases at initial presentation; these nine patients are the subjects of this article. There was an average of 0.9 pulmonary metastatic lesions at initial presentation seen on plain chest radiographs, an average 2.9 lesions seen on computed tomograms of the chest, and an average 12.7 lesions found at thoracotomy in these nine patients. The pulmonary metastatic lesions that could not be detected by computed tomography of the chest were resected by thoracotomy. Three patients died, and six patients are alive, with the 5-year survival being 64.8%. Intensive chemotherapy and aggressive surgical therapy were done for these patients with osteosarcoma with pulmonary metastases at initial presentation, and it is thought that this improved the prognosis of these patients. Pulmonary metastases of osteosarcoma at initial presentation do not always indicate a hopeless prognosis.

[The effects of high-dose ifosfamide in the treatment of bone and soft tissue sarcomas].

From January 1990 to December 1995 we treated 35 patients (pts) with bone and soft tissue sarcoma with ifosfamide (IFM). Sixteen patients had measurable metastatic pulmonary lesion and 9 had primary lesion. Histology of the tumor included osteosarcoma in 13 pts, Ewing sarcoma in 5 pts, malignant fibrous histiocytoma of bone in 2 pts, synovial sarcoma in 7pts, primitive neuroectodermal tumor in 2 pts, and other in 7 pts. The IFM at the dose of 12-18g/m2 (mean 15. 4g/m2) for 5 to 8 days continuous infusion was administered to patients in each treatment course. The uroprotector, mesna, was also given concomitantly in 60-100% dose of IFM. Eighteen pts received one course of IFM treatment. Other pts received 2 to 8 courses of IFM treatment at three to four week intervals. The overall response rate was 40% (PR in 14 pts, NC in 18 pts, and PD in 3 pts). The response rate of 13 pts with osteosarcoma was 54% (PR in 7 pts) and 30% in 15 pts with soft tissue sarcoma (PR in 5 pts).

Effects of ethane-1-hydroxy-1, 1 diphosphonate on Dunn osteosarcoma cells.

We investigated the effects of ethane-1-hydroxy-1, 1 diphosphonate (EHDP) on Dunn osteosarcoma cells in vivo and in vitro. In in vivo study, an increase of tumor volume was significantly suppressed in the EHDP administered groups compared with the control group. Histologically, Dunn osteosarcoma cells' viability was maintained after EHDP administration. However, fatty degeneration of tumor tissue was suspected in two of eight mice in the 5.0 mg/kg EHDP administered group. In vitro study, EHDP inhibited DNA synthesis and induced morphological changes, such as pycnotic cells. These findings show that the growth of Dunn osteosarcoma cells is inhibited by EHDP.

A reversed-flow latissimus dorsi musculocutaneous flap based on the serratus branch in primary shoulder reconstruction.

We report a case using the latissimus dorsi musculocutaneous flap based on the serratus branch in primary shoulder reconstruction. The reversed flow of the serratus branch maintained the circulation of the flap following acute disruption of the thoracodorsal vessels. Although our case was unusual, the reversed-flow latissimus dorsi flap based on its serratus branch may add a useful option in some cases.

Prognostic value of the doubling time of serum C-reactive protein and alkaline phosphatase levels in primary bone and soft tissue tumors.

We investigated the clinical relevance of doubling time (DT) of serum laboratory data obtained in routine clinical examination of patients with primary bone and soft tissue tumors, in comparison with major clinical and pathological parameters (age at presentation, sex, tumor size, location, clinical stage and histologic grade) by uni- and multivariate analyses. In 64 patients with primary bone and soft tissue tumors (primary bone tumors: 39, primary soft tissue tumors: 25) and 68 cancer patients, the pretreatment DT values of serum C-reactive protein (CRP), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), calcium (Ca), phosphate (P) levels were measured, as well as the erythrocyte sedimentation rate (ESR: mm/60 min); these values were then compared with overall survival, local recurrence-free survival and metastasis-free survival. Only DT of CRP and ALP (CRP-DT, ALP-DT) were found to be correlated with disease outcome in patients with primary bone and soft tissue tumors. In cancer patients, only CRP-DT showed a relation with clinical stage and histologic grade, but the ALP-DT in patients with bone metastasis was significantly shorter than that in patients with metastases at other sites or in those with no metastasis. Among all tumor patients, those with bone metastasis showed the shortest ALP-DT compared with those with lung, liver and brain metastasis. Univariate analysis showed that shorter CRP-DT and ALP-DT are associated with poor overall survival, and the development of local recurrence and metastasis. These findings suggest that pretreatment CRP- and ALP-DT could be additional prognostic parameters for disease outcome in patients with primary malignant bone and soft tissue tumors. However, in multivariate analysis, only ALP-DT, but not CRP-DT, was an independent prognostic parameter for these disease outcomes.

Establishment and characterization of a human malignant fibrous histiocytoma cell line.

Malignant fibrous histiocytoma is the most frequent soft tissue sarcoma. However, the pathogenesis still remains unclear, because there are very few human malignant fibrous histiocytoma cell lines available for precise cellular study. In this study, a human malignant fibrous histiocytoma cell line (MMF-1) was established from the pulmonary metastatic lesion of a 55-year-old man with malignant fibrous histiocytoma. Human cell line MMF-1 and its heterotransplanted tumor had almost the same characteristics as the original tumor morphologically and immunohistochemically. This cell line is expected to be a useful for studying the pathogenesis of malignant fibrous histiocytoma. The cloned cell lines (MMF-2 and MMF-3) also consisted of spindle-shaped, polygonal, and multinucleated giant cells, meaning that the fibroblast-like cells, histiocyte-like cells, and multinucleated giant cells seen in malignant fibrous histiocytoma were derived from a single tumor cell. Human cell line MMF-1 produced inflammatory cytokines, such as tumor necrosis factor-alpha, macrophage colony-stimulating factor, interleukin-8, and monocyte chemotactic and activating factor, that might be involved in the morphogenesis of malignant fibrous histiocytoma. Furthermore, the results of the analysis of human cell line MMF-1 suggested that malignant fibrous histiocytoma originated from a poorly differentiated fibroblast.

Ultrasonographic monitoring of the effects of preoperative chemotherapy in osteosarcoma and Ewing's sarcoma.

This study evaluates ultrasonography as a method of monitoring the effect of preoperative chemotherapy on two types of tumour. Changes in the size of tumours of 15 patients (13 osteosarcoma, 2 extraosseous Ewing's sarcoma) were monitored by this method, and the results compared with the histological examination of the resected specimens. Six patients in whom the tumour size increased towards the end of chemotherapy showed in inadequate histological response, whereas 6 of the 7 patients in whom the tumour decreased in size had a good histological response. Ultrasonography is of value as it can indicate the effect of preoperative chemotherapy on sarcoma by monitoring the size of the tumour, and it is simple and cheap to use.

Serum levels of laminin, type IV collagen and type III procollagen peptide as markers for detection of metastasis.

We investigated the clinical usefulness of serum laminin, type IV collagen and type III procollagen peptide (PIIIP) as markers for detection of metastasis in patients with primary or metastatic bone and soft part tumors. The subjects consisted of 28 patients with metastatic bone tumors, 18 with primary bone tumors (benign; 10, malignant; 8), 22 with primary soft part tumors (benign; 12, malignant; 10), 18 with cancer without metastasis (as controls to metastatic bone tumor) and 60 healthy controls. Elevated levels of serum laminin, type IV collagen and PIIIP were not associated with any specific histological subtype, tumor size or location, and were clearly related to evidence of metastasis. Mean serum concentrations of laminin, type IV collagen and PIIIP were significantly higher in patients with metastasis than in patients without metastasis. Positive correlations were observed among serum laminin, type IV collagen and PIIIP levels in tumor patients. The sensitivity values for laminin, type IV collagen and PIIIP in detecting metastasis were 83.7%, 83.3% and 80.5%, respectively, with specificity of 90.0%, 86.1% and 86.1%. When two of the three markers were evaluated in identical blood samples, combined sensitivity and specificity values exhibited further increases as compared to the sensitivity and specificity of each marker. The use of all three markers led to the best combined sensitivity and specificity. These findings suggest that the combination of these markers would be a valuable screening test in predicting metastasis.

Ceramic vertebral body replacement for metastatic spine tumors.

A modular ceramic spacer system was developed and used for vertebral body replacement in 21 patients with metastatic spine tumor in cervical (n = 10 cases), thoracic (n = 9), and lumbar spines (n = 2). All cases of cervical and lumbar spinal tumors underwent simultaneous use of a ceramic spacer and plate-screw fixation, and eight patients received additional posterior interventions in the thoracic spine. Postoperative radiation therapy was performed in all cases except two, which involved prostatic carcinoma. Complete or moderate pain relief was obtained in 19 patients, and 17 patients were able to walk after surgery. The average bed rest period was 11 days. Radiologically, a clear zone at the spacer-vertebral body interfaces and migration of the spacer was observed in four cases and one case, respectively. However, satisfactory pain relief and stabilization of the spine was obtained in an average follow-up time of 22.3 months. In all four autopsy specimens studied, the ceramic spacer showed firm connection with the vertebral body. This modular ceramic spacer system facilitates a relatively easy procedure, maintenance of spinal stability, early ambulation, and no interference with local radiation therapy.

Establishment of a cell line from a human giant cell tumor of bone.

A cell line (CG-1) was established from a specimen of a 21-year-old woman with giant cell tumor of bone. Inverted-phase microscopic analysis showed that the cultured cells were spindle-shaped in appearance. Multinucleated giant cells and macrophagelike round cells characterizing the histology of giant cell tumor of bone were not found. It is believed that the spindle-shaped cells were the neoplastic element of this tumor, because they were cultured more than 40 passages over the course of one year and subsequent cytogenetic analysis with a G-band technique showed constant loss of chromosomes 14 and 19. The cell line was found to produce several cytokines: M-CSF, IFN-gamma and TNF-alpha, as demonstrated by Western blotting analysis. These cytokines are known to show chemotactic, differentiation-inducing, and activating effects on macrophages. Because it has been recently reported in the literature that there are many infiltrated macrophages in giant cell tumor of bone, and because multinucleated giant cells are formed by fusion of macrophages, the newly established cell line may prove a useful system in studying the nature of giant cell tumor of bone.

[Toxic effects of ifosfamide in the treatment of bone and soft tissue sarcomas].

A total of 64 courses of ifosfamide (IFM) treatments for sarcoma patients were evaluated for toxic effects. A dose of 100 ml of 1/2 diluted Maalox by normal saline was instilled into urinary bladder with clump of catheter for 15 min for uroprotection instead of Mesna that was not available in Japan at that time. Forty-six courses of ifosfamide treatment in 12-16 g/m2 doses with daily Maalox instillation resulted only one hemorrhagic cystitis, while 18 courses at a dose of 6-10 g/m2 of IFM without Maalox eventuated in 5 cases of hemorrhagic cystitis. Forty-six courses of ifosfamide treatment at a dose of 12-16 g/m2 (mean dose of 14.4 g/m2) for 5 to 6 day continuous infusion were evaluated also for myelosuppression, nephrotoxicity, neurotoxicity, and other toxicities. Myelosuppression was acceptable, although the absolute neutrophil count of the 80% course was below 500. No patient showed neurotoxicity characterized by confusion or somnolence. No course resulted in abnormal serum creatinine elevation, although two of 46 courses caused an abnormal decrease of creatinine clearance. One patient had arrhythmia that required medical treatment after 5 courses of IFM treatment.

Differentiation of Dunn osteosarcoma cells in response to dibutyryl cyclic 3',5'-adenosine monophosphate.

We investigated the effects of dibutyryl cyclic adenosine 3',5'-monophosphate (Bt2cAMP) on the differentiation of Dunn osteosarcoma cells. Flow-cytometric analysis and DNA synthesis assay showed that Bt2cAMP decreased the cell population in the S phase in a time- and dose-dependent manner. Also, the cells showed distinct morphological and functional alterations; the cell morphology changed to a fibroblast-like appearance with long and thin protoplasmic processes, the knobs or blebs on both the cell membrane and nuclear membrane disappeared and the intracellular alkaline phosphatase activity increased. Moreover, Bt2cAMP-treated cells secreted a large quantity of fibronectin, which was deposited on the extended cell surface in the culture medium. Thus, Dunn osteosarcoma cells are differentiated morphologically and functionally by Bt2cAMP, and might be transformed to benign precursor cells.