Yuta Taniguchi

Knee joint preservation surgery in osteosarcoma using tumour-bearing bone treated with liquid nitrogen

PurposeTo preserve the joint structure in order to maintain good limb function in patients with osteosarcoma, we perform epiphyseal or metaphyseal osteotomy and reconstruction using frozen autografts that contain a tumour treated with liquid nitrogen. There are two methods of using liquid nitrogen-treated autografts: the free-freezing method and the pedicle-freezing method. The purpose of this study was to evaluate the results of intentional joint-preserving reconstruction using the free-freezing method and the pedicle-freezing method in patients with osteosarcoma.MethodsBetween 2006 and 2014, we performed joint-preserving surgery (12 with the free-freezing method and six with the pedicle freezing method) to treat 18 cases of osteosarcoma (12 distal femurs and six proximal tibias) in patients who had achieved a good response to neoadjuvant chemotherapy.ResultsAmong the 18 patients (nine boys and nine girls) who had a mean age of 11.6 years, 13 remained continuously disease-free, three showed no evidence of disease, one was alive with the disease, and one died from the disease. Functional outcomes were assessed as excellent in 15 patients and poor in three, with a mean follow-up period of 46.1 months. The mean Musculoskeletal Tumour Society (MSTS) score was 90.2%. Except for one patient who underwent amputation, all patients could bend their knee through >90° flexion, and nine achieved full ROM. All but two patients could walk without aid, and 11 were able to run normally throughout the follow-up period. No intraoperative complications were observed, such as surrounding soft-tissue damage, neurovascular injury, or recurrence from frozen bone.ConclusionsJoint-preserving reconstruction using frozen autografts yielded excellent function in patients with osteosarcoma.

Intercalary frozen autograft for reconstruction of malignant bone and soft tissue tumours

PurposeIn 1999, we developed a technique using frozen autografts—tumour-containing bone treated with liquid nitrogen—for the reconstruction of malignant bone tumours. The purpose of this study was to evaluate the functional and oncological outcomes of frozen autografts for intercalary reconstruction of malignant bones and soft tissue tumours.MethodsThis retrospective study was designed to assess 34 patients of mean age 35 (range, 6–79) years. The mean follow-up period was 62 (24–214) months. The median length of the frozen autografts was 138.4 ± 60.39 (50–290) mm.ResultsPostsurgically, 20 patients remained disease-free, seven patients survived with no evidence of disease, five patients were alive with disease, and two patients died of disease. The five- and ten-year survival rates of the frozen autografts were 91.2% and the mean International Society of Limb Salvage score was 90%. Complete bony union was achieved in 97% of the patients. There were five cases of nonunion, six cases of fracture, two cases of deep infection and four cases of local recurrence.ConclusionUtilizing intercalary frozen autografts for patients with a nonosteolytic primary or secondary bone tumour without involvement of the subchondral bone is a good alternative treatment, because it is a straightforward biological technique and can provide excellent limb function.

Preoperative evaluation of the efficacy of radio-hyperthermo-chemotherapy for soft tissue sarcoma in a case series

Purpose Radio-hyperthermo-chemo (RHC) therapy, which combines radiotherapy, hyperthermia, and chemotherapy, for malignant soft tissue tumors has been introduced with the aim of decreasing the possibility of local recurrence after surgery. To avoid unnecessary neoadjuvant therapy and to plan the appropriate surgical treatment, surveillance of RHC therapeutic efficacy during treatment is necessary. In this study, we determined the optimal response criteria to evaluate the efficacy of RHC by comparing preoperative images before and after RHC with pathological evaluation of necrosis in the resected tumor. Patients and methods From 2004 to 2014, 20 patients were enrolled into this study. Needle biopsy revealed 6 cases of myxoid liposarcoma, 6 cases of undifferentiated pleomorphic sarcoma, 4 cases of myxofibrosarcoma, and 4 cases of synovial sarcoma. Based on the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or modified RECIST, we calculated the responses to RHC therapy by comparing pre- and post-RHC therapy images. In addition, resected specimens underwent pathological analysis to evaluate response based on tumor necrosis. The correlation between assessment based on preoperative images and resected tumors were evaluated by the Spearman’s rank-order correlation coefficient. Result From the surgical specimens, pathological assessment of necrosis in resected tumor were assessed as less than 50% (2 cases), 50–90% (9 cases), 90–99% (6 cases), and total necrosis (3 cases). Use of the RECIST 1.1 underestimated good responders as stable disease (SD) or progressive disease (PD) in 5 out of 15 cases; on the other hand, use of the modified RECIST did not underestimate the pathological assessment of necrosis. The correlations between responses based on preoperative images and those based on histological assessments were 0.23 (RECIST 1.1) and 0.76 (modified RECIST). Conclusion Because pathological responses can be underestimated using the RECIST 1.1, the modified RECIST, which take into consideration tumor viability, as assessed by contrast MRI, should also be considered when evaluating the efficacy of RHC.

Do Mesenchymal Stem Cells Derived From Atypical Lipomatous Tumors Have Greater Differentiation Potency Than Cells From Normal Adipose Tissues

BackgroundThe p53 protein in mesenchymal stem cells (MSCs) regulates differentiation to osteogenic or adipogenic lineage. Because p53 function is depressed in most malignancies, if MSCs in malignancy also have p53 hypofunction, differentiation therapy to osteogenic or adipogenic lineage may be an effective treatment. We therefore wished to begin to explore this idea by evaluating atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) cells, because murine double minute 2 (MDM2) gene amplification, which leads to p53 hypofunction, is found in almost all ALT/WDLs.Questions/purposesWe compared osteogenic and adipogenic differentiation potency between MSCs isolated and cultured from normal adipose tissues and ALT/WDLs from the same patients.MethodsDuring tumor resections in six patients with ALT/WDL, we analyzed 3 mL of tumor, and for comparison, we harvested a similar amount of normal-appearing subcutaneous adipose tissue from an area remote from the tumor for comparison. Adipogenic differentiation potency was quantitatively assessed using spectrometry after oil red O staining. Osteogenic differentiation potency was semiquantitatively assessed by measuring a specific colored area after alkaline phosphatase (ALP) and alizarin red S staining. ALP is related to preosseous cellular metabolism, and alizarin red is related to calcium deposits in cell culture. There were three observers for each assessment, and each assessment (including induced-differentiation and histologic analysis) was performed in duplicate. We then analyzed the mechanism of the difference of osteogenic differentiation potency using the MDM2-specific inhibitor Nutlin-3 at various concentrations.ResultsIn terms of adipogenic differentiation potency, contrary to our expectations, more fatty acid droplets were observed in MSCs derived from normal fat than in MSCs derived from ALT/WDL, although we found no significant difference between MSCs derived from ALT/WDL and MSCs derived from normal fat; the mean differentiation potency values (normal adipose tissue versus ALT/WDL) (± SD) were 0.34 (SD, ± 0.13; 95% CI, 0.24–0.44) versus 0.25 (SD, ± 0.10; 95% CI, 0.18–0.33; p = 0.22). By contrast, we found greater osteogenic differentiation potency in MSCs derived from ALT/WDL than in MSCs derived from normal fat. The mean differentiation potency values (normal adipose tissue versus ALT/WDL) (±SD) based on ALP staining was 1.0 versus 17 (SD, ± 36; 95% CI, −2.8 to 38; p = 0.04). However, we found no differences based on alizarin red S staining; mean differentiation potency value (normal adipose tissue versus ALT/WDL) (± SD) was 1.0 versus 4.2 (SD, ± 4.8; 95% CI, 1.3–7.2; p = 0.58). The gap of osteogenic differentiation potency between MSCs from normal adipose tissue and ALT/WDL was decreased as MDM2-inhibitor Nutlin-3 concentration increased.ConclusionsMSCs derived from ALT/WDL had higher osteogenic differentiation potency based on ALP staining, which disappeared as Nutlin-3 concentration increased, suggesting that could be caused by amplified MDM2 in ALT/WDL. Future laboratory studies might mechanistically confirm the gene and protein expression, and based on the mechanism of the gap of differentiation potency, if p53 contrast between MSCs in tumor and normal tissue could be stimulated, less-toxic and more-effective differentiation therapy to MSCs in malignancies might be developed.

Surgical management of proximal fibular tumors: A report of 12 cases

Background/aim Aggressive benign or malignant tumors in the proximal fibula may require en bloc resection of the fibular head, including the peroneal nerve and lateral collateral ligament. Here, we report the treatment outcomes of 12 patients with aggressive benign or malignant proximal fibula tumors. Patients and methods Four patients with osteosarcoma and 1 patient with Ewings sarcoma were treated with intentional marginal resections after effective chemotherapy, and 4 patients underwent fibular head resections without ligamentous reconstruction. Clinical outcomes were investigated. Results The mean Musculoskeletal Tumor Society scores were 96% and 65% in patients without peroneal nerve resection and those with nerve resection, respectively. No patients complained of knee instability. Conclusion Functional outcomes after resection of the fibular head were primarily influenced by peroneal nerve preservation. If patients are good responders to preoperative chemotherapy, malignant tumors may be treated with marginal excision, resulting in peroneal nerve preservation and good function.

Long-term patient survival after the surgical treatment of bone and soft-tissue metastases from renal cell carcinoma

Aims The aims of this study were to evaluate the long‐term outcome of surgery for bone or softtissue metastases from renal cell carcinoma (RCC) and to determine factors that affect prognosis. Patients and Methods Between 1993 and 2014, 58 patients underwent surgery for bone or soft‐tissue metastases from RCC at our hospital. There were 46 men and 12 women with a mean age of 60 years (25 to 84). The mean follow‐up period was 52 months (1 to 257). The surgical sites included the spine (33 patients), appendicular skeleton (ten patients), pelvis (eight patients), thorax (four patients), and soft tissue (three patients). The surgical procedures were en bloc metastasectomy in 46 patients (including 33 patients of total en bloc spondylectomy (TES)) and intralesional curettage in 12 patients. These patients were retrospectively evaluated for factors associated with prognosis. Results The one‐, three‐, five‐, ten‐, and 15‐year overall survival (OS) rates were 89%, 75%, 62%, 48%, and 25%, respectively. The median survival time (MST) was 127 months for en bloc metastasectomy and 54 months for intralesional curettage and bone grafting. The median survival time was 127 months for the spine, 140 months for lesions of the appendicular skeleton, and 54 months for the pelvis. Multivariate analysis showed that non‐clear cell type RCC and metastases to more than two sites were independent risk factors for a poor prognosis. Conclusion Patients with bone or soft‐tissue metastases from a RCC have a reasonable prognosis, making surgical resection a viable option even in patients in whom the metastases are advanced.

Efficacy of radio-hyperthermo-chemotherapy as salvage therapy for recurrent or residual malignant soft tissue tumors

Abstract Background: Recurrence after wide excision or residual tumor after an unplanned excision of a malignant soft tissue sarcoma (STS) is a complex problem, due to a higher recurrence rate and poorer survival rate compared with primary resection. Regional hyperthermia was used, with the expectation that it will enhance the anti-tumor effects of chemotherapy and radiotherapy. This study aimed to assess the efficacy of neoadjuvant concomitant radiotherapy, hyperthermia, and chemotherapy (RHC) for salvage of recurrent or residual malignant STS. Methods: We identified 64 patients with recurrent or residual STS treated between 1994 and 2013. After excluding those with low-grade malignancy, with recurrent bone tumor in the soft tissues, with truncal STS, and who declined to participate, 23 patients (7 with recurrence and 16 with residual tumor) underwent RHC. The histologic diagnoses were undifferentiated pleomorphic sarcoma (n = 11), synovial sarcoma (n = 3), leiomyosarcoma and myxoid liposarcoma (n = 2 each), and other histologic types. As primary outcomes, the 5-year overall survival (OS), distant metastasis-free survival (D-MFS), and local control (LC) rates were evaluated by Kaplan-Meier analysis. Results: The median follow-up period was 112.3 months. The 5-year OS, D-MFS, and LC were 86.4%, 77.4%, and 86.7%, respectively. In the univariate analysis, tumor depth was considered as a negative prognostic factor for OS and D-MFS, and a positive margin was also a negative prognostic factor for OS, D-MFS LC with retained on Cox proportional hazards model in OS, and D-MFS. Conclusion: RHC is an effective option for salvage treatment of recurrent and residual STS.

Anti-tumor effects of a nonsteroidal anti-inflammatory drug zaltoprofen on chondrosarcoma via activating peroxisome proliferator-activated receptor gamma and suppressing matrix metalloproteinase-2 expression

Surgical resection is the only treatment for chondrosarcomas, because of their resistance to chemotherapy and radiotherapy; therefore, additional strategies are crucial to treat chondrosarcomas. Peroxisome proliferator‐activated receptor gamma (PPARγ) is a ligand‐activated transcription factor, which has been reported as a possible therapeutic target in certain malignancies including chondrosarcomas. In this study, we demonstrated that a nonsteroidal anti‐inflammatory drug, zaltoprofen, could induce PPARγ activation and elicit anti‐tumor effects in chondrosarcoma cells. Zaltoprofen was found to induce expressions of PPARγ mRNA and protein in human chondrosarcoma SW1353 and OUMS27 cells, and induce PPARγ‐responsible promoter reporter activities. Inhibitory effects of zaltoprofen were observed on cell viability, proliferation, migration, and invasion, and the activity of matrix metalloproteinase‐2 (MMP2); these effects were dependent on PPARγ activation and evidenced by silencing PPARγ. Moreover, we showed a case of a patient with cervical chondrosarcoma (grade 2), who was treated with zaltoprofen and has been free from disease progression for more than 2 years. Histopathological findings revealed enhanced expression of PPARγ and reduced expression of MMP2 after administration of zaltoprofen. These findings demonstrate that zaltoprofen could be a promising drug against the malignant phenotypes in chondrosarcomas via activation of PPARγ and inhibition of MMP2 activity.

The usefulness of wide excision assisted by a computer navigation system and reconstruction using a frozen bone autograft for malignant acetabular bone tumors: a report of two cases

BackgroundDifficult resection of tumors from regions with complex local anatomy, such as the pelvis and sacrum, is likely to result in inadequate surgical margins (intralesional or marginal); this is because three-dimensional osteotomy is difficult particularly around the acetabulum. Additionally, removal of the joint makes reconstruction very difficult; thus, retention of good function also becomes difficult. In musculoskeletal oncology, computer navigation systems are still not widely used to prevent tumor-positive margins. We performed wide excision with guidance from a computer navigation system and reconstruction using frozen bone autografts for malignant pelvic bone tumors in two patients, and we obtained excellent functional and oncological outcomes. Here we present these patients and discuss our approach.Case presentationCase 1: A 12-year-old girl presented with Ewing sarcoma of the left pelvis (PI-II). We performed wide excision assisted by a computer navigation system with the osteotomy of the load surface of acetabulum and reconstruction using a frozen bone autograft. At the final follow-up, she showed excellent function and was alive without the disease. Moreover, she did not have osteoarthritis of the left hip joint.Case 2: A 71-year-old woman presented with dedifferentiated chondrosarcoma of the right pelvis (PII-III). We performed wide excision assisted by a computer navigation system with osteotomy avoiding load surface of the acetabulum and reconstruction using a frozen bone autograft; there was no tumor at the load surface. At the final follow-up, she showed good function, was alive without the disease, and did not have osteoarthritis of the left hip joint.ConclusionsWide excision assisted by a computer navigation system and reconstruction using a frozen bone autograft are very useful for the management/treatment of extremely difficult cases such as malignant pelvic bone tumors, particularly those including the acetabulum.

Efficacy and Limitations of F-18-fluoro-2-deoxy-D-glucose Positron Emission Tomography to Differentiate Between Malignant and Benign Bone and Soft Tissue Tumors

Background/Aim: Positron emission tomography (PET) using 18fluorine-labelled fluorodeoxyglucose (FDG), is the most widely applied molecular imaging technique in oncology. The present study assessed the efficacy and limitations of FDG-PET by comparing FDG accumulation in bone and soft tissue lesions, as well as histopathological features. Patients and Methods: The study included 122 patients with 165 lesions, as assessed by histopathological examinations. The maximum standardized uptake values (SUVmax) of benign lesions were compared to those of primary, recurrent, or metastatic sarcomas, as well as those of other malignancies. Results: The sensitivity, specificity, and accuracy of SUVmax for differentiation between benign lesions and primary sarcomas were 67.9%, 92.9%, and 80.4%, respectively. There were no significant differences between benign lesions and recurrent or metastatic sarcomas. Conclusion: Although FDG-PET is a useful imaging modality to differentiate primary sarcomas from benign lesions, it is difficult to differentiate residual or metastatic sarcomas from benign lesions.