Yasuo Yazawa

Alveolar Soft Part Sarcoma in Japan: Multi-Institutional Study of 57 Patients from the Japanese Musculoskeletal Oncology Group

Objective: The clinical features and the management of alveolar soft part sarcoma (ASPS) are not well known. The efficacy of chemotherapy for soft tissue sarcoma, including high-dose ifosfamide and cisplatin, has not been established yet. Some reports suggest ASPS may occur primarily in bone. Methods: We report on a series of 57 patients with ASPS over 20 years. Their ages ranged from 7 to 75 years (mean 25). Results: There were 37 females and 20 males. Thirteen lesions (23%) showed bone involvement at the primary site, and 6 of them were diagnosed as bone tumors at presentation. Thirty-seven patients had distant metastases at presentation. Tumor size, bone involvement at the primary site and the presence of metastases at presentation were prognostic indicators (p < 0.05). Marginal excision with radiotherapy or wide excision without radiotherapy achieved good local control. Chemotherapy was performed in 47 patients with different regimens. Two patients treated with intra-arterial chemotherapy regimens responded partially, but intravenous chemotherapy with high-dose ifosfamide or cisplatin failed. Conclusions: ASPS can present primarily as a bone tumor. No advantage of chemotherapy with high-dose ifosfamide or cisplatin could be demonstrated.

Postoperative deep infection in tumor endoprosthesis reconstruction around the knee

BackgroundAlthough deep infection remains one of the most difficult complications to manage in the treatment of musculoskeletal tumor reconstructed with an endoprosthesis, limited information with respect to its incidence and risk factors has been reported.MethodsThis multicenter, retrospective, uncontrolled study reviewed the medical records of 82 patients who underwent reconstruction with an endoprosthesis or temporary spacer for bone-immature patients after resection of malignant bone tumor around the knee. Risk factors for deep infection and the impact of deep infection on prosthesis survival and oncological outcomes were analyzed. Deep infection was defined according to the Centers for Disease Control and Prevention (CDC) guidelines with minor modification.ResultsDeep infection occurred in 14 cases (17%), identified at a mean of 10.9 months (range <1 to 48 months) after initial surgery. Univariate analysis identified surface infection (P < 0.001) and skin necrosis (P < 0.001) as risk factors associated with deep infection. Conversely, tumor origin, chemotherapy, number of postoperative antibiotics, and length of bone resection were not associated with infection. Subclass analysis in femur cases identified a correlation between infection and the extent of partial resection of the quadriceps muscle (P = 0.04). In the multivariate analysis, surface infection represented an independent risk factor for deep infection (P = 0.03). Deep infection was a risk for endoprosthesis survival (P = 0.003) but did not affect the oncological outcome.ConclusionsA strong correlation between the condition of soft tissue and establishment of deep infection is suggested in this study. Although practical options for preventing deep infection seem limited, the present data allow a form of perioperative evaluation for patients with a higher risk of deep infection.

Phase 2 study of eribulin in patients with previously treated advanced or metastatic soft tissue sarcoma

Objective: Eribulin, a microtubule dynamics inhibitor, is approved for the treatment of patients with breast cancer and soft tissue sarcoma. We investigated the efficacy and safety of eribulin in Japanese patients with soft tissue sarcoma. Methods: This open‐label, multicenter, nonrandomized, Phase 2 study enrolled Japanese patients with measurable, advanced/metastatic soft tissue sarcoma of high/intermediate grade and ≥1 prior chemotherapy for advanced disease. Patients received eribulin mesilate 1.4 mg/m2 intravenously over 2‐5 minutes on Days 1 and 8 of a 21‐day cycle. The primary endpoint was progression‐free rate at 12 weeks. Secondary endpoints included overall survival, progression‐free survival and safety. Efficacy analyses were stratified by histology (liposarcoma or leiomyosarcoma, and other subtypes). Results: Overall, 52 patients were enrolled and 51 patients were treated. Patients with liposarcoma/leiomyosarcoma (n = 35) had similar characteristics to those with other subtypes (n = 16), except for a higher proportion of women (63% vs 38%, respectively) and patients with Eastern Cooperative Oncology Group performance status 0 (57% vs 44%). Progression‐free rate at 12 weeks was 60% in liposarcoma/leiomyosarcoma patients, 31% in other subtypes and 51% overall. Median progression‐free survival was 5.5 months in liposarcoma/leiomyosarcoma patients, 2.0 months in other subtypes and 4.1 months overall. Median overall survival was 17.0 months in liposarcoma/leiomyosarcoma patients, 7.6 months in other subtypes and 13.2 months overall. The most common Grade 3‐4 adverse events were neutropenia (86%), leukopenia (75%), lymphopenia (33%), anemia (14%) and febrile neutropenia (8%). Conclusion: Eribulin showed clinical activity with a manageable safety profile in previously treated Japanese patients with advanced/metastatic soft tissue sarcoma.

Validation of radiographic response evaluation criteria of preoperative chemotherapy for bone and soft tissue sarcomas: Japanese Orthopaedic Association Committee on Musculoskeletal Tumors Cooperative Study

BackgroundThe radiographic evaluation of the response to preoperative chemotherapy for bone and soft tissue sarcomas is based mostly on the change in primary tumor size before and after chemotherapy, as is done for many solid cancers. Its prognostic correlation, however, has hardly been validated.MethodsWe conducted a retrospective validation study of the Japanese Orthopaedic Association (JOA) radiographic response evaluation criteria of preoperative chemotherapy for bone and soft tissue sarcomas as a JOA Committee on Musculoskeletal Tumors cooperative study. A total of 125 consecutive patients with high-grade bone (n = 77) and soft tissue (n = 48) sarcomas treated with neoadjuvant chemotherapy and definitive surgery in 25 tertiary referral hospitals were selected for the study. We investigated the correlation between the tumor size-based radiographic response evaluation criteria of preoperative chemotherapy for bone and soft tissue sarcomas provided by the JOA Committee on Musculoskeletal Tumors (hereafter called the JOA criteria) and the patients’ overall survival using the Kaplan-Meier method and the log-rank test.ResultsThe JOA criteria correlated relatively well with survival for malignant bone tumors (mostly comprising osteosarcoma and Ewing’s sarcoma) but not for soft tissue sarcomas, suggesting that the tumor size-based radiographic evaluation criteria for the response to preoperative chemotherapy in patients with soft tissue sarcomas is invalid.ConclusionsThe JOA criteria, based on the change in primary tumor size, is valid for malignant bone tumors but invalid for soft tissue sarcomas. Other new evaluation modalities of the response to preoperative chemotherapy using innovative functional imaging techniques are needed for soft tissue sarcomas.

Schedule-dependent interactions between paclitaxel and etoposide in human carcinoma cell lines in vitro

Abstract Clinical studies of paclitaxel in combination with etoposide against solid tumors have been carried out. The combination schedules used in these studies are different. We studied the cytotoxic effects of paclitaxel with etoposide against four human cancer cell lines in vitro to determine the optimal schedule of this combination at the cellular level. Cells were exposed simultaneously to paclitaxel and to etoposide for 24 h or sequentially to one drug for 24 h followed by the other for 24 h, after which they were incubated in drug-free medium for 4 and 3 days, respectively. Cell growth inhibition was determined by an MTT reduction assay. The effects of drug combinations at concentrations producing 80% inhibition (IC80) were analyzed by the isobologram method of Steel and Peckham. The cytotoxic effect of paclitaxel and etoposide was cell line- and schedule-dependent. Simultaneous exposure to paclitaxel and etoposide for 24 h produced additive effects in the lung cancer cell line A549 and ovarian cancer PA1 cells, and antagonistic effects in the breast cancer cell line MCF7 and colon cancer WIDr cells. Sequential exposures to paclitaxel followed by etoposide and vice versa produced additive effects in all four cell lines. These results suggest that maximum cytotoxic effects can be obtained with sequential administration, but not simultaneous administration, of paclitaxel and etoposide. These findings may have important clinical implications for this combination.

Intraabdominal desmoplastic small round cell tumor : results of ifosfamide-based chemotherapy

Intraabdominal desmoplastic small round cell tumor (IDSRT) is a rare neoplasm, which is malignant and typically occurs in young adults. Although IDSRT is chemotherapy-sensitive, most cases do not achieve a complete response (CR). Even if some cases achieve a CR, they often relapse and result in poor prognosis. We report two cases of IDSRT, in a 24-year-old man and a 23-year-old man, who were treated with ifosfamide-based chemotherapy. Case 1, a 24-year-old man, presented with an abdominal mass, and the diagnosis of the biopsy specimen at laparoscopy was IDSRT. He received 7 courses of ifosfamide-based chemotherapy, which obtained a partial response (PR). He had no surgical resection, except for the biopsy procedure, and he underwent a total of 21 courses of chemotherapy. He died 36 months after diagnosis because of tumor regrowth and peritoneal bleeding. Case 2, a 23-year-old man, whose biopsy material allowed a diagnosis of IDSRT, was treated with 18 courses of chemotherapy, using ifosfamide, that resulted in a PR. This was followed by resection of the abdominal lesions, and he received an additional 2 courses of adjuvant chemotherapy. Four months after, completion of these 2 courses, the tumor recurred, and he died of diffuse pulmonary metastasis 36 months after diagnosis. This case report examines the results of ifosfamide-based chemotherapy in our two patients.

Clinical outcomes of the KYOCERA Physio Hinge Total Knee System Type III after the resection of a bone and soft tissue tumor of the distal part of the femur

The KYOCERA Physio Hinge Total Knee System Type III (PHKIII) was developed to reconstruct bony defects of the distal femur. The PHKIII is originative in that the metallic parts are fully made of titanium alloy, and this prosthesis has a unique semi‐rotating hinge joint and was designed especially for people with the Asian physical body‐type. The clinical outcomes of the PHKIII after the resection of musculoskeletal tumors of the distal femur were evaluated.

Effects of 13-hydroxy SM5887 in combination with other anticancer agents on human tumor cell lines

SummaryA new anthracycline derivative, SM5887, in combination with commonly used anticancer agents was evaluated against T-cell leukemia MOLT-3 and human osteosarcoma MG-63 cell lines in culture. MOLT-3 and MG-63 cells were incubated with various concentrations of 13-hydroxy SM5887 (SM5887-OH, the active metabolite of SM5887) and other drugs for 3 and 4 days, respectively. Cell growth inhibition was determined by MTT assay. The antitumor effects of the drug combinations at 80% inhibitory concentration (IC80) were analyzed by the isobologram of Steel and Peckham. In MOLT-3 cells, SM5887-OH had additive effects with bleomycin, etoposide, doxorubicin, cisplatin, mitomycin-C, 4-hydroperoxy ifosfamide, 5-fluorouracil, cytarabine, and vincristine, whereas it had mainly protective (marked antagonistic) effects with methotrexate. In MG-63 cells, SM5887-OH had additive effects with bleomycin, etoposide, doxorubicin, cisplatin, mitomycin-C, 4-hydroperoxy ifosfamide; mainly subadditive (mild antagonistic) effects with 5-fluorouracil and cytarabine; and mainly protective (marked antagonistic) effects with vincristine and methotrexate. These findings suggest that SM5887 is suitable for simultaneous administration with bleomycin, etoposide, doxorubicin, cisplatin, mitomycin-C, or ifosfamide and not suitable for simultaneous administration with methotrexate. The effects of SM5887 in combination with 5-fluorouracil, cytarabine or vincristine may be variable, depending on cell lines. To find optimal combinations, further in vitro and in vivo studies of antitumor activity and toxicity appear to be warranted.

Bone versus soft-tissue sarcomas in the elderly

Purpose. To compare survival rates in the elderly with bone versus soft-tissue sarcomas. Methods. Records of 12 men and 8 women aged 70 to 91 (mean, 77) years with bone or soft-tissue sarcomas were retrospectively reviewed. The grade, size, location, and stage of the sarcomas, as well as their surgical margins, treatment modalities, local recurrence, metastasis, and prognosis were recorded. The mean follow-up period was 37 (range, 2–137) months. Their 5-year survival rates were estimated using the Kaplan-Meier method, and compared with 110 younger controls aged 9 to 69 (mean, 45) years during the same period. There was no significant difference between the older patients and younger controls regarding tumour grading (p=0.068, Chi squared test), stage, and pathological diagnosis. Results. Six patients had bone and 14 had soft-tissue sarcomas. Of the 6 bone sarcomas, 3 were malignant fibrous histiocytomas, 2 were osteosarcomas, and one was a chordoma; all were high grade, except for the chordoma. Of the 14 soft-tissue sarcomas, 9 were malignant fibrous histiocytomas, 3 were myxofibrosarcomas, one was a liposarcoma and one an extraskeletal osteosarcoma; all were high grade except for 2 of the myxofibrosarcomas and the liposarcoma. Of the 110 younger controls, 30 had bone and 80 had soft-tissue sarcomas; 44 were low grade and 66 were high grade. The 5-year survival rate was significantly lower in older patients than in younger controls (35% vs 65%, p=0.048). Regarding bone versus soft-tissue sarcomas, the 5-year survival rate was not significantly different among older patients (0% vs 52%, p=0.068) or younger controls (61% vs 66%, p=0.863). The difference was also not significant for older patients versus younger controls with bone sarcomas (0% vs 61%, p=0.284) or soft-tissue sarcomas (52% vs 66%, p=0.368), for older patients with high- versus low-grade sarcomas (17% vs 100%, p=0.314), for older patients with sarcomas located in the limbs versus the trunk (39% vs 38%, p=0.233), as well as for older patients versus younger controls with low-grade sarcomas (100% vs 92%, p=0.512) or high-grade sarcomas (17% vs 46%, p=0.269). Conclusion. Survival rates tend to be lower in older patients with sarcomas, especially when the sarcoma is of bone and high grade.

Pedicle freezing with liquid nitrogen for malignant bone tumour in the radius: a new technique of osteotomy of the ulna

We describe a new technique of pedicle freezing of the distal radius with malignant bone tumour and osteotomy of the normal ulna. The distal radius was sufficiently elevated to enable freezing without damaging adjacent tissues by releasing the distal radio-ulnar and radio-carpal joint and cutting the middle third of the ulna. The distal radius (including the tumour) was soaked in liquid nitrogen and the defect filled with iliac grafts. The ulna was repaired with plate and screws and was united at month 2. There was no local recurrence and the postoperative function score was 93%. This technique decreases the risk of non-union of the osteotomy site of the tumorous bone.