Noriyoshi Kawaguchi

The concept of curative margin in surgery for bone and soft tissue sarcoma.

To clarify the safety margin in excision of bone and soft tissue sarcomas, a new evaluation method for surgical margins was drafted by the Bone and Soft Tissue Committee of the Japanese Orthopaedic Association in 1989. This new evaluation system was applied to 1329 patients with bone and soft tissue sarcomas, of whom 492 were excluded because of insufficient details, leaving 837 patients (901 surgeries) for the current study. Based on the results derived from analyzing these registered surgical margins, predictable safety margins under different conditions could be determined. When preoperative treatment is not done or is ineffective in high-grade sarcoma, a margin greater than 3 cm wide is necessary. When the preoperative modality is effective, a 2-cm wide margin is permissible. However, for recurrent sarcoma, whether low-grade or high-grade, a curative procedure is necessary. For low-grade sarcoma, obtaining an adequate wide margin is essential but partial marginal margins are acceptable at sites where barriers exist. When the margin is insufficient, radiotherapy should be used regardless of the tumor grade. Making a safety margin definitive through this system, an optimum treatment can be obtained and unnecessary adjunctive modalities can be avoided.

Pasteurized autologous bone graft in surgery for bone and soft tissue sarcoma

For skeletal reconstruction in surgery for bone tumors, pasteurization of bone has been used with favorable results over autoclaving or boiling. Twenty-three patients with primary malignant bone tumors and two patients with soft tissue sarcoma invading bone reconstruction surgery with pasteurized autologous bone graft comprised the study group. There were 16 females and nine males, between 7 and 77 years of age who were followed up for at least 3 years (mean, 52 months). The International Society of Limb Salvage graft evaluation method was used for evaluation of the radiographs. Fifteen patients (60%) had complete incorporation of the graft and eight patients (32%) had partial incorporation. Viability of the grafts was evaluated by bone scintigraphy. Of 22 patients evaluated, uptake was detected in 17 patients from approximately 6 months postoperatively after which it increased gradually. The functional results were assessed by the system of the Musculoskeletal Tumor Society, and the mean functional rating was 86%. Eighteen patients have been disease-free and seven have died of disease. Fracture (12%) and infection (20%) were the main complications. No local recurrence was detected. These results indicate that pasteurization of bone may be a useful option for reconstruction after resection of malignant bone tumors. The advantages of extracorporeal pasteurization include convenience of use, avoidance of intraspecies infection and allogenic reactions, and satisfactory bone remodeling.

New method of evaluating the surgical margin and safety margin for musculoskeletal sarcoma, analysed on the basis of 457 surgical cases

The evaluation of surgical margin is useful in determining the curative success of surgical treatment of musculoskeletal sarcoma and the degree to which later surgery will be reduced by the preoperative therapy. However, until recently no reliable evaluation method has been developed for these purposes. In this paper we propose a new method for evaluating the surgical margin as drafted in 1989 by the Bone and Soft Tissue Tumour Committee of the Japanese Orthopaedic Association (JOA). in this method, surgical margin was classified into four types based on the distance between the surgical margin and the reactive zone of the tumour. These classifications of surgical margin (in order of surgical extent) are curative wide margin (curative margin), wide margin, marginal margin, and intralesional margin. The surgical margin is said to be curative if the margin is more than 5 cm outside the reactive zone. It is referred to as wide if the margin is less than 5 cm. Similarly, a margin that is in the reactive zone is considered as marginal, and a margin passing through a tumour as intralesional. Moreover, wide margin is classified as adequate (at least 2 cm outside the reactive zone) or inadequate (1 cm). In our evaluation, a “thin” barrier is considered to be a 2-cm thickness of normal tissue, a “thick” barrier as a 3-cm thickness, and joint cartilage is said to be equivalent to a 5-cm thickness. In addition, a surgical margin that is outside a barrier, with normal tissue between the barrier and the reactive zone of the tumour, is considered to be curative. This method was applied in 457 cases (involving 499 surgeries) at the Cancer Institute Hospital to determine clinical significance in the treatment of musculoskeletal sarcoma (1979–1994). From the results of this study we were able to conclude that this evaluation method can be highly useful in clinical practice for establishing optimum surgery. Moreover, we found that the safety margin for high-grade musculoskeletal sarcoma is a curative margin providing an adequate wide margin of 3 cm or more when preoperative therapy is not performed or is not effective, while the safety margin for high-grade sarcoma that responds to preoperative chemo- or radiotherapy seems to be an adequate wise margin of 2 cm. Here, radiotherapy is more effective compared to chemotherapy for reducing surgical margin. An inadequate wide margin, however, combined with radiotherapy, is not enough to ensure local curative success following surgery for musculoskeletal sarcoma. Therefore, we have determined that these procedures should be used only when establishing a safety margin is difficult, even if ablasion or various reconstructive modalities are applied. On the other hand, for lowgrade sarcoma, an inadequate wide margin can be considered as safe.

EWSR1 is fused to POU5F1 in a bone tumor with translocation t(6;22)(p21;q12).

POU5F1(OCT3/4) is a sequence‐specific transcription factor that is essential for keeping germ cells and embryonic stem cells in an immature and pluripotent status. In this article, we report that POU5F1 was fused to EWSR1 in a case of undifferentiated sarcoma derived from pelvic bone with chromosomal translocation t(6;22)(p21;q12). The EWSR1–POU5F1 chimera consists of exons 1–6 of EWSR1 and exons 2–5 and a part of exon 1 of POU5F1. The predicted amino acid sequence indicates that the chimera is composed of the N‐terminal QSY domain of EWS that functions as a transcriptional activation domain and the C‐terminal POU DNA‐binding domains derived from POU5F1. The t(6;22) tumor does not belong to any known categories of bone and soft‐tissue tumors (BSTs). It is suggested that EWS–POU5F1 may act as an oncogenic transcription factor and that its expression may contribute to undifferentiated and immature phenotypes of BST.

Malignant change secondary to fibrous dysplasia.

BackgroundMalignant change in fibrous dysplasia (FD) is very rare. This study was carried out to establish some characteristic clinical information about this disorder.MethodsFour cases with a malignant change in FD out of 128 cases with FD were surgically treated and followed up for a median period of 61.3 months. The mean age of the patients was 39.8 years. Clinical features, radiological findings, and the outcome were analyzed for each of the four cases.Results and conclusionThe sites of the lesions were tibia (2 cases), femur (1 case), and rib (1 case). The forms of FD were monostotic in one case and polyostotic in three cases. Radiologically, plain films and computed tomography (CT) showed osteolytic lesions with poorly delineated margins within and/or near areas having a ground-glass appearance. In the osteolytic lesions, simple cystic changes associated with old FD could be excluded by enhanced magnetic resonance imaging (MRI). Histopathologically, two cases were osteosarcoma, one case was malignant fibrous histiocytoma (MFH), and one case was fibrosarcoma. The management of this disease should be decided according to the type of primary high-grade bone sarcoma. One patient, with MFH, was dead of lung metastasis 13 months after surgery. The others are alive without disease.

Multiinstitutional phase II study of neoadjuvant chemotherapy for osteosarcoma (NECO study) in Japan: NECO-93J and NECO-95J

BackgroundOsteosarcoma is the most frequent primary malignant bone tumor. In Europe and the United States, its prognosis has been greatly improved by the use of multimodal treatment, including preoperative and postoperative chemotherapy as well as surgery. In Japan, however, only a few clinical studies on osteosarcoma have been carried out.MethodsTo evaluate the efficacy of neoadjuvant chemotherapy on nonmetastatic, operable osteosarcoma arising in the extremities, a prospective multiinstitutional phase II trial, the Neoadjuvant Chemotherapy for Osteosarcoma (NECO) study, was conducted. Preoperative chemotherapy included high-dose methotrexate (HD-MTX), cisplatin (CDDP), and adriamycin (ADR). If the induction therapy was assessed as not effective, high-dose ifosfamide (IFO) was added to the chemotherapy regimen. A total of 124 patients were enrolled in this trial, and ultimately 113 patients were eligible.ResultsThe 5-year overall survival (OAS) and event-free survival (EFS) rates in the NECO study were 77.9% and 65.5%, respectively. A good histological response to the induction chemotherapy resulted in favorable OAS (78.7%). The patients assessed as poor histological responders with progressive disease after the induction chemotherapy exhibited comparable outcomes (OAS 89.5%, EFS 68.2%). There were no significant differences between the OAS and EFS rates of the patients in terms of response to preoperative chemotherapy.ConclusionsWe analyzed the results of the intensive neoadjuvant chemotherapy and the effects of adding IFO on patients with osteosarcoma in Japan. The results suggest efficacy of the high-dose IFO addition to the standard three-drug chemotherapy regimen. However, a randomized clinical study is needed to establish the true impact of IFO on patients with osteosarcoma.

Chromatin remodeling factor encoded by ini1 induces G1 arrest and apoptosis in ini1 -deficient cells

Ini1/hsnf5 gene encodes INI1 protein, a chromatin remodeling factor associated with the SWI/SNF complex. In yeast, this complex modifies chromatin condensation to coactivate various transcriptional factors. However, in human, little is known about the SWI/SNF complex and INI1. To elucidate cellular functions of ini1, we constructed a recombinant adenovirus (AdexHA-INI1) capable of overexpressing INI1 in ini1-deficient cells. AdexHA-INI1 produced intranuclear INI1 in three ini1-deficient cell lines, changed their morphology, and decreased the proportion of viable cells. Flow cytometry and a BrdU incorporation assay showed that after the infection, growth of these cells was partially arrested at G1. In two of the three ini1-deficient cell lines, apoptosis was found to occur after the infection, as detected by the presence of cleaved poly (ADP-ribose) polymerase. To determine functional domains of INI1, we constructed plasmids expressing INI1 and its deletion mutants, which were used for a colony formation assay. Repeats 1 and 2 of INI1 were found to be required to suppress the growth of the three ini1-deficient cell lines. The results support the hypothesis that ini1 is a tumor suppressor gene and suggest a novel link between human SWI/SNF chromatin remodeling complex and apoptosis.

Possible association of p53 overexpression and mutation with high-grade chondrosarcoma.

Overexpression and point mutation of the p53 protein/ gene was investigated in a series of chondrosarcoma by an immunohistochemical approach, and direct sequencing of the genomic DNA. respectively. In 2 of the 16 cases studied, both of which were high grade chondrosarcomas (grade III), immunodetectable p53 was identified. Histologically. one was ordinary type and the other a clear cell variant. However, no positivity was observed in the other cases including nine of low grade, ordinary type, three of low grade, clear cell type, and two of extraskeletal myxoid chondrosarcoma. Direct sequencing, following polymerase chain reaction amplification of exons 5–9 of the p53 gene in 14 cases, in which fresh materials were available. successfully demonstrated base substitution mutations in only two cases with detectable p53 overexpression on immunohistochemistry. Their details were GTC (valine) to TTC (phenylalanine) at codon 157 in exon 5. and CGT (arginine) to CAT (histidine) at codon 273 in exon 8. No mutation was detected in the other 12 cases which were negative for p53 immunostaining. These findings strongly suggest that p53 mutation plays a crucial role in the biologically aggressive subtype, and possibly in the process of tumor progression in human chondrosarcoma.

Definition of the target sign and its use for the diagnosis of schwannomas.

The target sign is one of the characteristic imaging findings in schwannomas that distinguishes it from other soft tissue tumors, but its definition has varied in past studies. We defined the characteristic target sign on MRI and clarified its sensitivity and specificity based on histology. Of the 199 schwannomas reviewed, 162 (81%) showed biphasic macroscopic and microscopic patterns of central Antoni A and peripheral Antoni B cells; 118 (59%) also showed a biphasic pattern on MRI. Gadolinium-enhanced T1-weighted images showed central high intensity and peripheral low intensity, whereas T2-weighted images showed peripheral high intensity and central low intensity. Seventy-eight cases had cystic, hemorrhagic, or necrotic degeneration, which corresponded to high intensity on T2-weighted images and low intensity on gadolinium-enhanced T1-weighted images. Nine cases in which the degenerative area was only in the central portion of Antoni A showed a triphasic pattern. We defined the target sign as the biphasic or triphasic pattern on MRI, and the sign correlated with macroscopic and microscopic findings. The specificity of the target sign in schwannoma was 100% and the sensitivity was 59%; therefore, the target sign was characteristic of and helpful for the diagnosis of schwannomas.Level of Evidence: Level II, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence.

Surgical treatment of bone metastasis: indications and outcomes.

Due to advances in cancer treatment that prolong survival, there has been a noticeable increase in the prevalence of bone metastasis. Consequently, the likelihood of orthopedic surgeons encountering such tumors and the need for effective surgical treatment are also expanding. Although bone metastasis constitutes only one possible type of metastatic lesion, and while local control at a bone metastatic site alone may have little effect on total curability, the quality of life (QOL) of the patient cannot be ensured if local control is ignored. Therefore, it is important to achieve local control through multidisciplinary treatments aimed at both reduced surgery and at conservation of limb function. Surgical treatment may be indicated after a series of more conservative treatments. Among the main indications are pathologic fracture or a high risk of fracture of limb bones. Acute spinal cord injury caused by acute compression fracture from spinal metastasis is a relative indication. The occurrence of a solitary metastasis, for which extended survival may be anticipated, is also an indication for surgery to achieve local control. Appropriate local control is required to realize a predicted survival period. As well, the surgical method, resection margin, and supplementary treatments, and immediately effective reconstruction method should be selected accordingly.