Published papers

Background: Due to the wide variations in location, size, local invasiveness, and treatment options, the complications associated with surgery for giant cell tumor of bone have been sporadically reported. For quality assessment, fundamental data based on large-scale surveys of complications under a universal evaluation system is needed. The Dindo-Clavien classification is an evaluation system for complications based on severity and required intervention type and is suitable for the evaluation of surgery in a heterogeneous cohort. Methods: A multi-institutional retrospective survey of 141 patients who underwent surgery for giant cell tumor of bone in the extremity was performed. The incidence and risk factors of complications, type of intervention for complication control, and impact of complications on functional and oncological outcomes were analyzed using the Dindo-Clavien classification. Results: Forty-six cases (32.6%) had one or more complications. Of them, 18 (12.8%), 11 (7.8%), and 17 (12.1%) cases were classified as Dindo-Clavien classification grade I, II, and III complications, respectively. There were no cases with grade IV or V complications. Progression in Campanacci grading (p = 0.04), resection (over curettage, p < 0.0001), reconstruction with prosthesis (p = 0.0007), and prolonged operative duration (p = 0.0002) were significant risk factors for complications. Complications had a significant impact on function (p < 0.0001). Differences in the impact of complication types and tumor location on function were confirmed. Complications had no impact on local recurrence and metastasis development. Conclusion: The Dindo-Clavien classification could provide fundamental information, under a uniform definition and classification system, on postoperative complications in patients with giant cell tumor of bone in terms of incidence, type of intervention for complication control, risk factors, and impact on functional outcome. The data are useful not only for preoperative evaluation for the risk of complications under specific conditions but also for quality assessment of surgery for giant cell tumor of bone.

Background: Dedifferentiated liposarcoma occurs predominantly in the retroperitoneum. Given the paucity of cases, information on the clinical characteristics of this entity in the extremities and trunk wall is quite limited. In particular, the significance of preoperative evaluation and principles of intraoperative management of the different components, i.e., well-differentiated and dedifferentiated areas, are still to be defined. Methods: Clinical characteristics, treatment outcomes, and risk factors for poor oncological outcomes in cases of dedifferentiated liposarcoma in the extremity or trunk wall were analyzed by a retrospective, multicentric study. Results: A total of 132 patients were included. The mean duration from the initial presentation to dedifferentiation was 101 months in dedifferentiation-type cases. The 5-year local recurrence-free survival, metastasis-free survival, and disease-specific survival rates were 71.6%, 75.7%, and 84.7%, respectively. Among 32 patients with metastasis, 15 presented with extrapulmonary metastasis. A percentage of dedifferentiated area over 87.5%, marginal/intralesional margin, and R1/2 resection in the dedifferentiated area were independent risk factors for local recurrence. Dedifferentiated areas over 36 cm2, French Federation of Cancer Centers Sarcoma Group grade III, and intralesional or marginal resection were independent risk factors for metastasis. A dedifferentiated area over 77 cm2 and lung metastasis were independent risk factors for disease-specific mortality. Conclusions: The typical clinical characteristics of dedifferentiated liposarcoma in the extremity and trunk wall were reconfirmed in the largest cohort ever. The evaluation of the dedifferentiated area in terms of grade, extension, and pathological margin, together with securing adequate surgical margins, was critical in the management of this entity.

Osteosarcoma is the most common malignant primary bone tumor that occurs most frequently in the second decade of life but rarely in patients over 40 years of age. The most common primary sites of osteosarcoma are the distal femur followed by proximal tibia and proximal humerus, and involvement of the wrist is extremely rare. Moreover, dedifferentiated osteosarcoma is also a rare condition that progresses to high-grade osteosarcoma from low-grade osteosarcoma, usually central low-grade osteosarcoma or parosteal osteosarcoma that bears MDM2 and/or CDK4 gene amplifications. We herein report an extremely rare case of dedifferentiated osteosarcoma arising in the distal ulna of an adult over 40 years of age. The patient was a 46-year-old man with a 2-month history of pain in his left swollen wrist. The initial radiological findings suggested a benign bone tumor in the distal ulna, and the lesion was marginally excised at the nearby hospital. Although the pathological diagnosis at the nearby hospital suggested a benign cartilaginous tumor, the tumor recurred in an aggressive manner 8 months after the initial surgery. The patient was referred to our hospital, and an incisional biopsy showed a high-grade osteosarcoma. The primary tumor was retrospectively re-evaluated at our hospital and diagnosed as low-grade osteosarcoma. Since neoadjuvant chemotherapy failed to shrink the tumor, the patient had to undergo below the elbow amputation to cure the disease. Although the tumor was negative for MDM2 nor CDK4, the definitive diagnosis of dedifferentiated osteosarcoma was made according to the clinical course and the histological findings. Lung metastases were found 10 months after the amputation, which were successfully treated by neoadjuvant chemotherapy and surgery. The patient has been doing well with no evidence of disease for 1 year and 6 months. Surprisingly, the literature review revealed that many low-grade osteosarcomas of the distal ulna progressed to high-grade dedifferentiated osteosarcomas. One should bear in mind that the diagnosis and treatment for bone-forming tumors of the distal ulna should be made very carefully because, although rare, it is possible that the tumor may initially appear as a benign or low-grade malignant tumor and may progress to high-grade osteosarcoma.

Perturbations to mammalian SWI/SNF (mSWI/SNF or BAF) complexes contribute to more than 20% of human cancers, with driving roles first identified in malignant rhabdoid tumor, an aggressive pediatric cancer characterized by biallelic inactivation of the core BAF complex subunit SMARCB1 (BAF47). However, the mechanism by which this alteration contributes to tumorigenesis remains poorly understood. We find that BAF47 loss destabilizes BAF complexes on chromatin, absent significant changes in complex assembly or integrity. Rescue of BAF47 in BAF47-deficient sarcoma cell lines results in increased genome-wide BAF complex occupancy, facilitating widespread enhancer activation and opposition of Polycomb-mediated repression at bivalent promoters. We demonstrate differential regulation by two distinct mSWI/SNF assemblies, BAF and PBAF complexes, enhancers and promoters, respectively, suggesting that each complex has distinct functions that are perturbed upon BAF47 loss. Our results demonstrate collaborative mechanisms of mSWI/SNF-mediated gene activation, identifying functions that are co-opted or abated to drive human cancers and developmental disorders.

Solitary metastasis of a carcinoma to carpal bone is extremely rare. Metastases of renal cell carcinoma (RCC) usually occur in a multiple fashion and there has been no report to date of a solitary metastasis to trapezium from RCC. The tumor was excised and reconstructed with iliac bone transplantation. 2 years and 6 months after surgery, there is no local recurrence with minimal functional loss.

Extraskeletal chondroma is defined as a rare, benign, cartilaginous tumor arising from soft tissues such as tendons, tendon sheath synovia, and joint capsules with no continuity to the periosteum or bone cortex. In histopathologic findings, the tumor exhibits many lobular structures and some parts similar to hyaline cartilage. Therefore, it is sometimes difficult to differentiate this tumor from low-grade chondrosarcoma because of their similar histopathologic findings. In order to prevent recurrence, it is necessary to remove the tumor as a whole, including the capsule, so as not to leave any remnants of the tumor. In this article, we report our treatment experience with a case of extraskeletal chondroma in the index finger of a 63-year-old patient.

Objective: Myxofibrosarcoma has high frequency of local recurrence after surgery. To determine an optimal treatment for recurrent tumors, clinical features of recurrent cases should be characterized. Methods: We performed a retrospective analysis of 30 patients with recurrent myxofibrosarcoma who underwent surgery between 1999 and 2008. Results: A negative margin after surgery was achieved in only 12 patients (40.0%). The 5-year re-recurrence free-survival rate was 31.7%. The 5-year re-recurrence free survival for those with positive histological margin and those with negative margin were 9.8% and 62.3%, respectively, which indicated that a positive margin was the significant predictor of poor prognosis (P = 0.006). In 21 patients with recurrent myxofibrosarcoma in the extremities, 10 patients (47.6%) ultimately underwent amputation in the follow-up period and the 5-year amputation-free survival rate was 62.5%. The 5-year metastasis-free survival rates and the 5-year overall survival rates were 84.8% and 83.6%, respectively. Conclusions: In this study, the majority of recurrent cases could not achieve negative margins; notably, a positive margin is a significant poor prognostic indicator of local re-recurrence in patients with recurrent myxofibrosarcoma. To control local recurrence of myxofibrosarcoma was extremely difficult and amputation is often needed in the extremity cases.

BACKGROUND: Historically, local control of recurrent sarcomas has been limited to radiotherapy when surgical re-resection is not feasible. For metastatic carcinomas to the bone or soft tissue, radiotherapy and some interventional radiology treatment along with other systemic therapies have been widely advocated due to the possibility of disseminated disease. These techniques are effective in alleviating pain and achieving local control for some tumor types, but it has not been effective for prolonged local control of most tumors. Recently, cryoablation has been reported to have satisfactory results in lung and liver carcinoma treatment. In this study, we analyzed the clinical outcome of CT-guided cryoablation for malignant bone and soft tissue tumors to elucidate potential problems associated with this procedure. METHODS: Since 2011, 11 CT-guided cryoablations in 9 patients were performed for locally recurrent or metastatic bone and soft tissue tumors (7 males and 2 females) at our institute. The patients' average age was 74.8 years (range 61-86) and the median follow up period was 24.1 months (range 5-48). Histological diagnosis included renal cell carcinoma (n = 4), dedifferentiated liposarcoma (n = 2), myxofibrosarcoma (n = 2), chordoma (n = 1), hepatocellular carcinoma (n = 1), and thyroid carcinoma (n = 1). Cryoablation methods, clinical outcomes, complications, and oncological outcomes were analyzed. RESULTS: There were 5 recurrent tumors and 6 metastatic tumors, and all cases had contraindication to either surgery, chemotherapy or radiotherapy. Two and 3 cycles of cryoablation were performed for bone and soft tissue tumors, respectively. The average length of the procedure was 101.1 min (range 63-187), and the average number of probes was 2.4 (range 2-3). Complications included 1 case of urinary retention in a patient with sacral chordoma who underwent prior carbon ion radiotherapy, 1 transient femoral nerve palsy, and 1 minor wound complication. At the final follow up, 4 patients showed no evidence of disease, 2 were alive with disease, and 3 died of disease. CONCLUSIONS: Reports regarding CT-guided cryoablation for musculoskeletal tumors are rare and the clinical outcomes have not been extensively studied. In our case series, CT-guided cryoablation had analgesic efficacy and there were no cases of local recurrence post procedure during the follow-up period. Although collection of further data regarding use of this technique is necessary, our data suggest that cryoablation is a promising option in medically inoperable musculoskeletal tumors.

BACKGROUND: Leiomyosarcoma of bone (LMSoB) is a rare malignant bone tumor. This multicenter retrospective study was conducted to investigate the diagnosis and the clinical outcome of primary LMSoB in Japan. METHODS: Forty-eight patients (average age: 52 years [range 14-88 years]) with primary LMSoB who were treated at registered institutes in Japan between 1991 and 2014 were recruited. The median follow-up period was 44 months (range: 2-273). RESULTS: The 5-year overall survival rates and disease-free survival rates were 78.3% and 44.9%, respectively. Surgical treatment was performed in 42 patients, and R0 resection was achieved in 31 patients. Neoadjuvant chemotherapy was administered in 18 patients. The most common regimen (cisplatin-based chemotherapy) was administered in 15 patients, however, no patient achieved a good response in both radiological and histological evaluations. The presence of metastasis at the first visit and a lack of definitive surgery were significantly correlated with poor overall survival, and the surgical margin was a significant prognostic factor for disease-free survival. CONCLUSIONS: This study is the largest LMSoB case series ever reported. Surgical treatment with wide margins was the only treatment that proved to be effective, whereas adjuvant chemotherapy in the present setting did not improve the overall survival. J. Surg. Oncol. 2016;114:495-500. (c) 2016 Wiley Periodicals, Inc.

BACKGROUND: Trabectedin is reported to be particularly effective against translocation-related sarcoma. Recently, a randomized phase 2 study in patients with translocation-related sarcomas unresponsive or intolerable to standard chemotherapy was conducted, which showed clinical benefit of trabectedin compared with best supportive care (BSC). Extraskeletal myxoid chondrosarcoma (EMCS) and Mesenchymal chondrosarcoma (MCS) are very rare malignant soft tissue sarcomas, and are associated with translocations resulting in fusion genes. In addition, the previous in vivo data showed that trabectedin affect tumor necrosis and reduction in vascularization in a xenograft model of a human high-grade chondrosarcoma. The aim of the present analysis was to clarify the efficacy of trabectedin for EMCS and MCS subjects in the randomized phase 2 study. METHODS: Five subjects with EMCS and MCS received trabectedin treatment in the randomized phase 2 study. Three MCS subjects were allocated to the BSC group. Objective response and progression-free survival (PFS) were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by central radiology imaging review. RESULTS: The median follow-up time of the randomized phase 2 study was 22.7 months, and one subject with MCS was still receiving trabectedin treatment at the final data cutoff. The median PFS was 12.5 months (95 % CI: 7.4-not reached) in the trabectedin group, while 1.0 months (95 % CI: 0.3-1.0 months) in MCS subjects of the BSC group. The six-month progression-free rate was 100 % in the trabectedin group. One subject with MCS showed partial response, and the others in the trabectedin group showed stable disease. Overall survival of EMCS and MCS subjects was 26.4 months (range, 10.4-26.4 months) in the trabectedin group. At the final data cutoff, two of five subjects were still alive. CONCLUSIONS: This sub-analysis shows that trabectedin is effective for patients with EMCS and MCS compared with BSC. The efficacy results were better than previously reported data of TRS. These facts suggest that trabectedin become an important choice of treatment for patients with advanced EMCS or MCS who failed or were intolerable to standard chemotherapy. TRIAL REGISTRATION: The randomized phase 2 study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-121850 (May 31, 2012).

Selinexor is an orally bioavailable selective inhibitor of nuclear export that has been demonstrated to have preclinical activity in various cancer types and that is currently in Phase I and II clinical trials for advanced cancers. In this study, we evaluated the effects of selinexor in several preclinical models of various sarcoma subtypes. The efficacy of selinexor was investigated in vitro and in vivo using 17 cell lines and 9 sarcoma xenograft models including gastrointestinal stromal tumor (GIST), liposarcoma (LPS), leiomyosarcoma, rhabdomyosarcoma, undifferentiated sarcomas, and alveolar soft part sarcoma (ASPS). Most sarcoma cell lines were sensitive to selinexor with IC50s ranging from 28.8 nM to 218.2 nM (median: 66.1 nM). Selinexor suppressed sarcoma tumor xenograft growth, including models of ASPS that were resistant in vitro. In GIST cells with KIT mutations, selinexor induced G1- arrest without attenuation of phosphorylation of KIT, AKT, or MAPK, in contrast to imatinib. In LPS cell lines with MDM2 and CDK4 amplification, selinexor induced G1-arrest and apoptosis irrespective of p53 expression or mutation and irrespective of RB expression. Selinexor increased p53 and p21 expression at the protein but not RNA level, indicating a post-transcriptional effect. These results indicate that selinexor has potent in vitro and in vivo activity against a wide variety of sarcoma models by inducing G1-arrest independent of known molecular mechanisms in GIST and LPS. These studies further justify the exploration of selinexor in clinical trials targeting various sarcoma subtypes.

Spontaneous regression of tumors is very unusual and is defined as a partial or complete disappearance of metastatic tumors without any treatment. This phenomenon has been reported in almost all types of cancer. The patient was a 25-year-old woman who presented with multiple pulmonary nodules on her bilateral lungs on the annual chest roentgenograph. Simultaneously, a swelling mass on her subcutaneous inguinal region was observed. The diagnosis of the inguinal mass was extraskeletal myxoid chondrosarcoma. The inguinal mass and pulmonary nodules spontaneously regressed without any treatment after biopsy. The patient was doing well without evidence of recurrence at 1 year after the operation without any additional therapy. Our case is the first clinical one that indicated a possibility of histologic regression of extraskeletal myxoid chondrosarcoma.

Epithelioid sarcoma is a rare soft tissue sarcoma and usually resistant to chemotherapy. It has high rates of local recurrence and distant metastasis, and the prognosis after metastasis is poor. We report a case of multiple lung metastases of an epithelioid sarcoma originating in the inguinal area that we treated with the multikinase inhibitor pazopanib. The patient was a 38-year-old male who began to experience discomfort in his left inguinal area. Magnetic resonance imaging showed a tumor extended from the medial aspect of the wing of the left ilium along the iliopsoas muscle to its site of insertion on the femur. The histopathological diagnosis with a biopsy was proximal-type epithelioid sarcoma. Although a positron emission tomography examination showed fluorodeoxyglucose accumulation in the left inguinal tumor, there was no distant metastasis. Wide resection by a combined iliac resection procedure was performed. Twelve months after surgery, computed tomography revealed multiple nodules and a diagnosis of bilateral multiple lung metastases was made. Treatment with pazopanib 800 mg was started. After 2.5 months of treatment, a clear reduction in the size of the pulmonary metastases was shown. Thirty months after the start of pazopanib treatment, most of the metastases have disappeared, and no development of new lesions has been seen. Therefore, it appeared that pazopanib was capable of serving as one of the choices of therapeutic agents that should be taken into consideration for the treatment of advanced epithelioid sarcoma.

Pulmonary metastasis is the most significant prognostic determinant for osteosarcoma, but methods for its prediction and treatment have not been established. Using oligonucleotide microarrays, we compared the global gene expression of biopsy samples between seven osteosarcoma patients who developed pulmonary metastasis within 4 years after neoadjuvant chemotherapy and curative resection, and 12 patients who did not relapse. We identified argininosuccinate synthetase (ASS) as a gene differentially expressed with the highest statistical significance (Welch's t test, P = 2.2 x 10(-5)). Immunohistochemical analysis of an independent cohort of 62 osteosarcoma cases confirmed that reduced expression of ASS protein was significantly correlated with the development of pulmonary metastasis after surgery (log-rank test, P < 0.05). Cox regression analysis revealed that ASS was the sole significant predictive factor (P = 0.039; hazard ratio, 0.319; 95% confidence interval, 0.108-0.945). ASS is one of the enzymes required for the production of a nonessential amino acid, arginine. We showed that osteosarcoma cells lacking ASS expression were auxotrophic for arginine and underwent G(0)-G(1) arrest in arginine-free medium, suggesting that an arginine deprivation therapy could be effective in patients with osteosarcoma. Recently, phase I and II clinical trials in patients with melanoma and hepatocellular carcinoma have shown the safety and efficacy of plasma arginine depletion by stabilized arginine deiminase. Our data indicate that in patients with osteosarcoma, reduced expression of ASS is not only a novel predictive biomarker for the development of metastasis, but also a potential target for pharmacologic intervention.

The poly(ADP-ribose) polymerase-1 protein (PARP-1) functions in DNA repair, maintenance of genomic stability, induction of cell death, and transcriptional regulation. We previously analyzed alterations of the PARP1 gene in 16 specimens of human germ cell tumors, and found a heterozygous sequence alteration that causes the amino acid substitution Met129Thr (M129T) in both tumor and normal tissues in a single patient. In this study, aberration of the PARP1 gene and protein was further analyzed in human germ cell tumor cell lines. We found a nonheterozygous sequence alteration that causes the amino acid substitution Glu251Lys (E251K) located at a conserved peptide stretch of PARP-1 in cell line NEC8. Sequencing of 95 samples from Japanese healthy volunteers revealed that all the samples were homozygous for the wild-type alleles at M129T and E251K. The M129T allele is thus suggested to be a rare single-nucleotide polymorphism (SNP). We observed a decrease in auto-poly(ADP-ribosyl)ation activity of PARP-1 proteins harboring M129T or E251K amino acid substitution, but the difference was not statistically significant. The levels of PARP-1 and poly(ADP-ribosyl)ation were heterogeneous among germ cell tumor cell lines. The SNPs of the PARP1 gene, as well as differences in the levels of PARP-1 and poly(ADP-ribosyl)ation of proteins, may influence germ cell tumor development and responses to chemotherapy and radiotherapy.

Osteosarcoma (OS) is the most frequent primary malignant bone tumor of children and young adults. Although the introduction of combined neoadjuvant chemotherapy has markedly improved survival, the outcome of OS patients with distant metastasis and/or poor response to chemotherapy is still unsatisfactory. Therefore there is a need to develop new therapeutic agents that suppress OS cell proliferation with higher efficacy. The protein kinases are a family of genes that play critical roles in various signaling pathways. Some cancer cells show addiction to constitutive activation of certain signaling pathways for proliferation and survival. To identify new drug targets for OS, we screened a panel of small interfering RNAs (siRNAs) that target 691 genes encoding human protein kinases and related proteins. We found that different constructs of siRNA specifically targeting polo-like 1 kinase (PLK1) significantly caused mitotic cell cycle arrest and subsequent apoptotic cell death in a variety of OS cell lines. siRNA targeting PLK1 also suppressed the growth of OS xenografts established in immunodeficient mice. Recently, phase I clinical trials of PLK1 chemical inhibitors have been reported. Our results indicate that PLK1 is a promising molecular target for pharmacologic intervention in OS.

BACKGROUND: Hemipelvectomy for massive malignancy can result in large soft tissue defects that cannot be reconstructed using conventional posterior flaps. For such cases, reconstruction methods, including a latissimus dorsi flap or a rectus abdominis myocutaneous flap, may be applied, resulting in donor site morbidity. Recent innovations in plastic surgery have resulted in the development of novel reconstruction modalities based on "the spare part concept," applying tissues from amputated limbs. METHODS: Five subjects with pelvic malignant tumors underwent hemipelvectomy with reconstruction using the spare part concept. Femoral artery-based myocutaneous flap and free fillet lower leg flap were used for three and two cases, respectively. The clinical results, including postoperative complications and oncological outcomes, were assessed. RESULTS: The mean follow-up period was 43.2 months (range 12-94 months). No local recurrence was encountered in any cases throughout follow-up. As of the final follow-up, three patients remained alive and two patients were dead due to distant metastasis. Minor postoperative infection was observed in two cases. CONCLUSIONS: The femoral artery-based myocutaneous flap and the free fillet lower leg flap are both useful, safe options for reconstruction of the large defect following extensive hemipelvectomy for malignant bone and soft tissue tumors. The present data support the continued application of these flap reconstruction techniques based on the spare part concept.

Synovial sarcoma is a relatively common soft tissue sarcoma with an aggressive clinical course. Although surgery is currently the first treatment modality, improvement of adjuvant chemotherapy is deemed essential to improve the clinical outcome. Nuclear factor-kappaB (NF-kappaB) is constitutively activated in various cancer cells and has emerged as a potential therapeutic molecular target; however, the possible involvement of NF-kappaB in the pathology of sarcomas remains to be clarified. Herein we examined the effects of a novel NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) on two synovial sarcoma-derived cell lines, HS-SY-II and SYO-1. The growth of both cell lines was completely inhibited by DHMEQ and apoptosis was induced at 10 microg/ml. Additionally, we found that DHMEQ showed additive effects when used in combination with other cytotoxic agents. These observations indicate that inhibition of NF-kappaB activity may serve as a potential therapeutic target for synovial sarcoma.