Orthopedic Division

Introduction
In the Orthopedic Division, patients with malignant bone and soft tissue tumors are treated by four orthopedic surgeons, and surgical treatment for metastatic bone cancer is also performed. X-ray diagnosis of bone disease is carried out by the same staff members. Adjuvant chemotherapy for high-grade bone and soft tissue sarcomas is performed mainly in the Orthopedic Division. Recently, we began a high dose chemotherapy followed by autologous peripheral blood stem cell transplantation (PBSCT) for advanced rhabdomyosarcma, Ewing sarcoma and other small round cell sarcoma in cooperation with clinical oncologists. The purpose of Orthopedic Division is to establish the standard therapy for highly malignant bone and soft tissue sarcomas and to preserve upper and lower extremity functions.

Routine Activities
Our Division consists of four staff orthopedic surgeons, two orthopedic surgical residents and one physiotherapist. The staff surgeons have outpatient clinics once or twice a week at both NCCH and NCCHE. Five to six major operations are performed weekly on Tuesday, Wednesday and Thursday.
A weekly conference is held on Tuesday in order to discuss the diagnosis, operative procedures, and chemotherapy of each patient with medical oncologists and radiation oncologists. A clinico-pathological conference focusing on surgically removed bone and soft tissue specimens is held with pathologists once a month. Multi-institutional telepathology or a TV conference on bone and soft tissue malignancies is held every three months.
Thirty-eight malignant bone tumors including osteosarcoma (18), chondrosarcoma (7), Ewing s sarcoma (3), malignant fibrous histiocytoma (2), and others, and 62 soft tissue sarcomas including malignant fibrous histiocytoma (16), liposarcoma (14), synovial sarcoma (5), extraskeletal myxoid chondrosarcoma (4), malignant peripheral nerve sheath tumor (3), epithelioid sarcoma (2), and others were treated in 2001. Limb sparing surgery was performed in 38 patients, and amputation was performed in 9 patients with bone and soft tissue sarcomas of an extremity.
This division serves as a registration center for soft tissue tumors in Japan. About 2,474cases of malignant soft tissue tumors were registered during the period from 1985 to 1994 with an average of 247 cases per year.

Research Activities
1. We reported a case of multiple primary cancers having a germline missense mutation of the p53 gene. The patient was a Japanese female and had a history of five different types of cancers (osteosarcomas of the left and right femurs, Paget carcinomas in the left and right breasts and lung adenocarcinoma). PCR/direct sequencing analysis revealed the presence of a nucleotide substitution, AGC(Ser) to AGG(Arg), at codon 106 of the p53 gene in DNA from non-cancerous breast tissue. This is the first case of germline p53 mutation at codon 106, and could contribute to establishing correlations between the types and locations of germline p53 mutations and their phenotypical consequences.
2. We investigated the prognostic relevance of a histological grading system based on the assessment of proliferative activity in adult soft-tissue sarcomas of the extremities, trunk, head, and neck. Our grading system included histological grading based on the modified Federation Nationale des Centres de Lutte contre le Cancer (FNCLCC) system using the MIB-1 score for the estimation of the proliferative potential of the tumors. Variables associated with overall survival were tumor site in the trunk, head and neck, mitosis count, necrosis, MIB-1 score, FNCLCC grade, modified FNCLCC grade using the MIB-1 score, and stage. In multivariate analysis, the modified grade proved to be the most significant predictor of shortened overall survival, in addition to tumor site in the trunk, head, and neck. Using MIB-1 to replace mitosis counts in the FNCLCC system improves grading of soft-tissue sarcomas, and this in conjunction with other important factors appear to be more accurate prognostic factors for survival, and for patient selection in investigational adjuvant treatment trials.

Clinical Trials
1. A clinical phase II study of adriamycin (ADR) +cyclophosphamide (CPA)/ ifosfamide (IF0) chemotherapy (JCOG1079) for advanced highly malignant soft tissue tumor started in 1999 is now ongoing.
2. A cooperative multicenter clinical trial for osteosarcoma of the extremities (NECO-95J) has been ongoing since 1995. Preoperative chemotherapy included high dose MTX with citrovorum factor rescue, ADR and CDDP (arm I) or IFO (arm II) were administered for 3 months preoperatively, and were continued for 4 to 5 months postoperatively.
3. Rhabdmyosarcoma protocol
4. Ewing s sarcoma/PNET protocol

Y. BEPPU

Table of Contents