Publications by authors named "Hidetatsu Outani"

52 Publications

Impact of Surgical Resection and Reasons for Poor Prognosis of Pelvic Osteosarcoma Based on the Bone Tumor Registry in Japan.

Cancers (Basel) 2021 Jul 1;13(13). Epub 2021 Jul 1.

Musculoskeletal Oncology and Rehabilitation Medicine, National Cancer Center, Tokyo 104-0045, Japan.

Pelvic osteosarcoma has a poor prognosis compared to osteosarcomas in other locations, and the reasons for this remain unknown. Surgical resection of pelvic osteosarcoma is technically demanding and often results in dysfunction and complications. In this study, we investigated the reasons underlying the poor prognosis of pelvic osteosarcoma by comparing it to femoral osteosarcoma using data from the Bone Tumor Registry in Japan. We used propensity score analysis to determine whether surgical resection of pelvic osteosarcoma improved its prognosis. We demonstrated that pelvic osteosarcoma had a poor prognosis because it occurred more often in the elderly, often had larger tumor size, and had metastasis at presentation more often in comparison to femoral osteosarcoma. These three factors were also associated with the non-surgical treatment of pelvic osteosarcoma, which also led to a poor outcome. The overall survival rate was only comparable in pelvic osteosarcoma and femoral osteosarcoma in cases treated with surgical resection. Propensity score analysis revealed that surgical treatment improved the prognosis of pelvic osteosarcoma. As such, we propose that surgical resection should be considered based on tumor stage and patient age in order to improve the prognosis of pelvic osteosarcoma.
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http://dx.doi.org/10.3390/cancers13133320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268378PMC
July 2021

Giant cell tumor of bone - Analysis of 213 cases involving extra-craniofacial bones.

Pathol Int 2021 Jun 14. Epub 2021 Jun 14.

Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

We elucidated clinicopathological characteristics of giant cell tumor of bone (GCTB) in Japan, and significant clinicopathological factors for predicting local recurrence. Clinicopathological profiles of 213 patients with GCTB (100 male, 113 female) involving extra-craniofacial bones were retrieved. Pathological slides obtained at the initial surgery were reviewed. Fourteen pathological and five clinical features were statistically analyzed to disclose prognostic significance. Patient age ranged from 12-80 years (Average 38.7). Long bones were most frequently affected (86.4%), especially around the knee (62.9%). Histological features are basically similar to those previously reported. Within a follow-up period (24-316 months, average 106.1 months), the local recurrence rate is 29.1%. Metastasis has occurred in 9 patients. Cox regression analysis of representative clinicopathological features shows that younger age, higher mitotic count, smaller zones of stromal hemorrhage, considerable vascular invasion and absence of ischemic necrosis are significant predictors for local recurrence. Initial operative method (curettage) is a significant risk factor in univariate analysis but not by multivariate analysis (P = 0.053). Denosumab administration increases risk but not significantly (P = 0.053). Histone 3.3 G34W immunopositivity is not significant for predicting local recurrence.
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http://dx.doi.org/10.1111/pin.13107DOI Listing
June 2021

Efficacy and safety of TAS-115, a novel oral multi-kinase inhibitor, in osteosarcoma: an expansion cohort of a phase I study.

Invest New Drugs 2021 Jun 12. Epub 2021 Jun 12.

Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.

Background osteosarcoma is a rare, primary malignant bone tumour with limited available treatments for advanced or recurrent disease, resulting in a poor prognosis for patients. TAS-115 is a novel tyrosine kinase inhibitor under investigation in a phase I study in patients with solid tumours. We report data of osteosarcoma patients in the expansion cohort of this ongoing study. Patients and methods an analysis of this multicentre, open-label study was performed 6 months after the final patient was enrolled, and included patients aged ≥15 years, with unresectable or recurrent osteosarcoma, and who had refractory to standard therapy or for whom no standard therapy was available. TAS-115 650 mg/day was orally administered in a 5 days on/2 days off schedule. Results a total of 20 patients with osteosarcoma were enrolled. The most common adverse drug reactions (ADRs) were neutrophil count decreased (75%), aspartate aminotransferase increased (50%), and platelet count decreased (50%); 85% of patients had grade ≥ 3 ADRs. Long-term disease control (>1 year) with TAS-115 was achieved in three patients. The best overall response was stable disease (50%); no patient achieved a complete or partial response. Median progression-free survival was 3 months; 4-month and 12-month progression-free rates were 42% and 31%, respectively. Conclusion the safety and tolerability of TAS-115 and long-term disease stability for patients with unresectable or recurrent osteosarcoma were confirmed in this study, suggesting that TAS-115 is a promising novel therapy for advanced osteosarcoma patients. Trial registration number: JapicCTI-132333 (registered on November 8, 2013).
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http://dx.doi.org/10.1007/s10637-021-01107-4DOI Listing
June 2021

Impact of surgical resection on survival in patients with metastatic soft tissue sarcoma and comparison between synchronous and metachronous metastases.

J Orthop Sci 2021 May 20. Epub 2021 May 20.

Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.

Background: The role of local surgery in patients with metastatic soft tissue sarcoma (STS) remains unknown. The study aims to assess the clinical outcomes and impact of surgical resection on survival in patients with metastatic STS and elucidate the survival differences between synchronous and metachronous metastatic groups.

Methods: Among the 272 patients with STS treated between 2000 and 2018, 84 with synchronous or metachronous metastasis were included. Associations between overall survival and primary tumor resection and metastasectomy were assessed using multivariate Cox regression analyses to adjust for baseline differences between surgically and non-surgically treated patients. Propensity score matching was applied to compare synchronous and metachronous metastasis.

Results: Among the 84 patients included, 69 (82%) and 41 (49%) underwent primary tumor resection and metastasectomy, respectively. The 2- and 5-year overall survivals of all patients after first detection of metastasis were 51.1% and 24.4%, respectively. Multivariate analysis showed that size <8 cm, grade <3, and number of metastases <4 were associated with longer overall survival. After adjusting for baseline demographic and tumor characteristics, primary tumor resection and metastasectomy still had favorable effects on survival. Tumor subtypes, grade, and number of metastases differed significantly between synchronous and metachronous groups. However, after adjusting for these valuables, both groups exhibited comparable survival.

Conclusions: Approximately one fourth of the patients with metastatic STS survived for >5 years. Our results showed that surgical resection of primary tumors or metastatic lesions had favorable impact on survival even after adjusting for patient backgrounds, with comparable survival observed between those with synchronous and metachronous metastases.
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http://dx.doi.org/10.1016/j.jos.2021.03.013DOI Listing
May 2021

ASO Author Reflections: What are the Survivorship and Prognostic Factors of Patients with Metastatic Solitary Fibrous Tumors?

Ann Surg Oncol 2021 Jul 9;28(7):3902-3903. Epub 2020 Nov 9.

Department of Orthopedic Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan.

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http://dx.doi.org/10.1245/s10434-020-09358-wDOI Listing
July 2021

Clinical Outcomes of Patients with Metastatic Solitary Fibrous Tumors: A Japanese Musculoskeletal Oncology Group (JMOG) Multiinstitutional Study.

Ann Surg Oncol 2021 Jul 4;28(7):3893-3901. Epub 2020 Nov 4.

Department of Orthopedic Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan.

Background: Although the unpredictable malignant behavior of solitary fibrous tumors (SFTs) has been recognized, the clinical features and prognosis of metastatic SFTs have not been well documented due to the extreme rarity of these cases. The aim of this study is to investigate the clinical features, prognostic factors, and optimal management of patients with metastatic SFTs.

Patients And Methods: Sixty patients with metastatic SFT were retrospectively reviewed. Univariate and multivariate analyses were performed to identify the factors associated with survival. Time to next treatment (TNT) was used to evaluate the effects of various chemotherapy regimens.

Results: A total of 34 male and 26 female patients (median age 55 years, range, 23-87 years) were included in the study. The median follow-up period after metastasis was 32 months (range 1-126 months). Tumor location and local recurrence were correlated with late metastasis. The 3- and 5-year overall survival rates were 72.7% and 49.2%, respectively. Primary tumor location, number of metastases, and metastasectomy were significantly associated with survival. Metastasectomy was the only significant variable on multivariate analysis. The TNT was significantly different among the various regimens.

Conclusions: Patients with metastatic SFTs had relatively longer survival periods compared with those with other metastatic soft-tissue sarcomas. Tumor location and number of metastases was associated with survival. Surgical resection of the metastatic lesions offers the best chance of survival, however further studies are warranted to define patients who would benefit from metastasectomy, and the most effective chemotherapeutic regimen for patients with metastatic SFTs remains unknown.
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http://dx.doi.org/10.1245/s10434-020-09306-8DOI Listing
July 2021

Prognostic factors and skeletal-related events in patients with bone metastasis from gastric cancer.

Mol Clin Oncol 2020 Oct 22;13(4):31. Epub 2020 Jul 22.

Musculoskeletal Oncology Service, Osaka International Cancer Institute, Osaka 541-8567, Japan.

The number of studies on bone metastasis (BM) from gastric cancer (GC) is currently limited. Therefore, the aim of the present study was to investigate the characteristics, skeletal-related events (SREs) and prognosis of GC in patients with BMs. Data from 60 patients with BMs from GC were retrospectively retrieved and patient-, tumor- and BM-related characteristics were analyzed. Kaplan-Meier survival curves were analyzed using the univariate log-rank test. Multivariate analyses were conducted using the Cox proportional hazards model. The median patient age was 63.5 years (range, 26-83 years). Visceral or brain metastases were observed at BM diagnosis in 61.7% of the patients. Multiple BMs were detected in 83.3% and SREs occurred in 76.7% of the patients. The median overall survival (OS) after BM diagnosis and SRE occurrence was 9 months (range, 0-43 months) and 5 months (range, 0-36 months), respectively. On multivariate analysis, poor Eastern Cooperative Oncology Group performance status (P=0.030), the administration of chemotherapy prior to BM diagnosis (P<0.001) and no chemotherapy after BM diagnosis (P=0.002) were significant prognostic factors for unfavorable OS, whereas the non-use of bone-modifying agents (BMAs) was the only independent prognostic factor for poor SRE-free survival (SRS; P=0.022). Among patients without SREs at BM diagnosis, the median SRS duration was 7 months (range, 0-43 months). In conclusion, chemotherapy may confer a survival benefit in GC patients with BMs. In addition, the prognosis for GC patients with BMs presenting with SREs is poor, but treatment with BMAs may prevent or delay the development of SREs.
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http://dx.doi.org/10.3892/mco.2020.2101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403842PMC
October 2020

Complication rate, functional outcomes, and risk factors associated with carbon ion radiotherapy for patients with unresectable pelvic bone sarcoma.

Cancer 2020 09 13;126(18):4188-4196. Epub 2020 Jul 13.

Research Center for Charged Particle Therapy, National Institute of Radiological Sciences, Chiba, Japan.

Background: To the authors' knowledge, carbon ion radiotherapy (CIRT) is one of the few curative treatments for unresectable pelvic bone sarcoma. The current study investigated the complications, functional outcomes, and risk factors of CIRT.

Methods: Of 112 patients who were treated with CIRT for unresectable pelvic bone sarcoma, the authors enrolled 29 patients who were without local disease recurrence or distant metastasis. The mean follow-up was 93 months. Complications, functional outcomes, and quality of life scores were assessed. Risk factors were analyzed, including the dose-volume histogram of the femoral head.

Results: Femoral head necrosis occurred in approximately 37% of patients, pelvic fractures were reported in 48% of patients, and neurological deficits were noted in 52% of patients. Femoral head necrosis was found to be significantly more prevalent among patients with periacetabular tumors (P = .018). The dose-volume histogram of the femoral head indicated tolerable volume percentages of the femoral head to be <33% for 40 grays (relative biological effectiveness) and 16% for 60 grays ( relative biological effectiveness). The mean Musculoskeletal Tumor Society score and Toronto Extremity Salvage Score were 53% and 64%, respectively, and the mean EuroQol 5 dimensions questionnaire index was 0.587. Patients aged >50 years and those with periacetabular tumors were found to have significantly lower Toronto Extremity Salvage Scores.

Conclusions: Femoral head necrosis, pelvic fracture, and nerve damage are common complications with the use of CIRT for pelvic bone sarcoma. To prevent femoral head necrosis, the radiation dose to the femoral head should be kept below the estimated tolerance curve presented in the current study. The functional outcome is nearly equivalent to that of surgery. CIRT may be a promising alternative to surgery for patients with unresectable pelvic bone sarcoma.
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http://dx.doi.org/10.1002/cncr.33082DOI Listing
September 2020

Clinical Outcomes of Osteoarticular Extracorporeal Irradiated Autograft for Malignant Bone Tumor.

Sarcoma 2020 30;2020:9672093. Epub 2020 Mar 30.

Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.

Methods: We retrospectively reviewed 33 patients who underwent osteoarticular ECIA after bone tumor resection from 1988 to 2014. We investigated complications, radiographic changes by the International Society of Limb Salvage graft evaluation criteria, and functional outcomes according to the Musculoskeletal Tumor Society scoring system.

Results: Fifteen patients were reoperated upon due to infection ( = 9), protruding fixation implant ( = 4), or fracture of the grafted bone ( = 2). The average radiographic evaluation score was 66.4%, and the median functional score was 23 (77%). The radiographic score for the proximal humerus or proximal tibia was lower than that for the other locations. The functional score was not different among the autograft sites but was related to the radiographic score.

Conclusion: Although osteoarticular ECIA is one of the reasonable surgical options for patients with tumors for which reliable prostheses are not available, we do not recommend osteoarticular ECIA as a routine procedure because of high complication rate.
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http://dx.doi.org/10.1155/2020/9672093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7149532PMC
March 2020

A long-term follow-up study of extracorporeal irradiated autografts in limb salvage surgery for malignant bone and soft tissue tumors: A minimum follow-up of 10 years after surgery.

J Surg Oncol 2020 Jun 4;121(8):1276-1282. Epub 2020 Apr 4.

Department of Orthopaedic Surgery, Ashiya Municipal Hospital, Ashiya, Hyogo, Japan.

Background And Objectives: The aim of this study is to assess the survival, function, radiographic appearance, and modes of failure of extracorporeal irradiated (ECI) autografts in a long-term setting.

Methods: We retrospectively reviewed 87 patients who were treated for bone and soft tissue tumors using ECI autografts between 1988 and 2009.

Results: The 56 patients had a minimum follow-up of 10 years, and the median follow-up period was 16.5 years. The reimplantation procedures included 24 osteoarticular grafts, 16 intercalary grafts, 10 autograft-prosthetic composite grafts, and 6 hemicortical grafts. The 15-year graft and event-free survival rates were 76.8% and 47.9%, respectively. Infection and structural failure were the most common reasons for additional surgery. The time for additional surgery was significantly longer in patients with composite grafts (P < .01). The median Musculoskeletal Tumor Society score and the International Society of Limb Salvage score were 80% and 84%, respectively.

Conclusions: ECI autografts are a durable option for reconstruction after resection of musculoskeletal tumors and provide good function over more than 15 years. Most graft failures occurred within 5 years of the index surgery. However, composite grafts showed a tendency to fail more than 10 years after the surgery.
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http://dx.doi.org/10.1002/jso.25918DOI Listing
June 2020

TAS-115 inhibits PDGFRα/AXL/FLT-3 signaling and suppresses lung metastasis of osteosarcoma.

FEBS Open Bio 2020 05 30;10(5):767-779. Epub 2020 Mar 30.

Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Japan.

Osteosarcoma is the most common malignant bone tumor in adolescence and childhood. Metastatic osteosarcoma has a poor prognosis with an overall 5-year survival rate of approximately 20%. TAS-115 is a novel multiple receptor tyrosine kinase inhibitor that is currently undergoing clinical trials. Using the mouse highly lung-metastatic osteosarcoma cell line, LM8, we showed that TAS-115 suppressed the growth of subcutaneous grafted tumor and lung metastasis of osteosarcoma at least partially through the inhibition of platelet-derived growth factor receptor alpha, AXL, and Fms-like tyrosine kinase 3 phosphorylation. We also show that these signaling pathways are activated in various human osteosarcoma cell lines and are involved in proliferation. Our results suggest that TAS-115 may have potential for development into a novel treatment for metastatic osteosarcoma.
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http://dx.doi.org/10.1002/2211-5463.12827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193166PMC
May 2020

Clinical outcomes of chondroblastoma treated using synthetic bone substitute: risk factors for developing radiographic joint degeneration.

World J Surg Oncol 2020 Mar 2;18(1):47. Epub 2020 Mar 2.

Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.

Background: Chondroblastoma (CB) is a rare locally aggressive bone tumor that commonly occurs in the epiphysis or apophysis of long bones. Although surgical treatment of CB carries potential risk for physeal or articular cartilage damage, risk factors for joint degeneration have not been well described. In addition, we have mainly used synthetic bone substitute (SBS) to fill the bone defect after intralesional curettage as treatment for CB. This study thus aimed to evaluate the incidence of and risk factors for adjacent-joint radiographic degeneration after SBS treatment for CB.

Methods: We retrospectively reviewed 48 patients treated for CB at our institutions between 1996 and 2017. Clinical data, radiographic images, treatments, and local recurrence were analyzed.

Results: We identified 40 patients [29 males and 11 females with a mean age of 19 years (range, 8-35 years)] who received SBS to fill the defect after curettage with a minimum follow-up of 1 year. The mean follow-up period was 71 months (range, 13-239 months). A total of 8 patients (20%) developed local recurrence. Radiographic analysis showed that 5 patients (16.7%) developed radiographic joint degeneration. Joint degeneration was significantly associated with the affected joint (p = 0.004).

Conclusions: Curettage and SBS filling had been found to be a reasonable treatment method for CB, which commonly occurs in the epiphysis or apophysis. Radiographic joint degeneration was not uncommon after CB treatment, especially in the talus and proximal humerus.
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http://dx.doi.org/10.1186/s12957-020-01829-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053063PMC
March 2020

Author Correction: Establishment of a novel human CIC-DUX4 sarcoma cell line, Kitra-SRS, with autocrine IGF-1R activation and metastatic potential to the lungs.

Sci Rep 2020 Jan 15;10(1):684. Epub 2020 Jan 15.

Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-019-55752-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6962364PMC
January 2020

Malignant peripheral nerve-sheath tumors in an adolescent patient with mosaic localized NF1: A case report.

Mol Clin Oncol 2020 Feb 17;12(2):155-159. Epub 2019 Dec 17.

Department of Orthopedic Surgery, Osaka International Cancer Institute, Osaka 541-8567, Japan.

Malignant peripheral nerve-sheath tumors (MPNSTs) are rare malignancies that are often observed in patients with neurofibromatosis type 1 (NF1). However, the occurrence of MPNST associated with mosaic localized NF1 is extremely rare. Previous reports have revealed that MPNST was associated with mosaic localized NF1 in only three patients who were >40 years of age. The present report details a 16-year-old man who presented with pain and a 3 cm mass on the medial side of the right knee. Magnetic resonance imaging revealed a circumscribed soft tissue tumor located in the subcutaneous tissue. His previous doctor believed that it was benign and conducted a marginal resection. However, postoperative histology results demonstrated spindle cell sarcoma, following which the patient was referred to The Osaka International Cancer Institute. Localized café-au-lait spots were identified in the affected leg, which inferred that the patient had NF1-related MPNST. A wide resection was performed to completely resect the residual tumor; however, a definitive histological diagnosis was challenging due to the small residual tumor. Hence, the genomic mutations of NF1 in the regional café-au-lait spots were analyzed. The result revealed an NF1 microdeletion and a consistently limited expression of NF1 in the tumor sample. Finally, the patient was diagnosed with MPNST with mosaic localized NF1. Local recurrence and distant metastasis were not observed 1.5 years after surgery. In conclusion, the present report presented MPNST in an adolescent patient with mosaic localized NF1. The occurrence of MPNSTs correlated with mosaic localized NF1 is extremely rare. However, it is of high-grade malignancy and therefore, its clinical features should be considered by orthopedists and pathologists.
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http://dx.doi.org/10.3892/mco.2019.1969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951113PMC
February 2020

Silent subperiosteal iliac hematoma with bone radiolucency in adolescent male athletes.

J Orthop 2020 Jan-Feb;17:198-202. Epub 2019 Aug 13.

Department of Orthopaedics, Osaka University Graduate School of Medicine, Japan.

Background: Subperiosteal hematoma of the iliac bone is reported as a rare disorder that specifically occurs in young patients after obvious trauma. This report presents seven cases of male adolescent athletes with subperiosteal iliac hematoma without blunt trauma that was identified as an incidental radiolucent lesion on the iliac bone mimicking neoplasm. The purpose of this report is to describe clinical features and radiological findings of silent subperiosteal hematoma of the iliac bone.

Subjects And Methods: We retrospectively reviewed the clinical data and radiological appearance of 7 patients who presented with subperiosteal hematoma of iliac bone.

Results: All seven patients had no obvious trauma and no serious symptoms. All patients were middle school or high school male students who regularly participated in vigorous sports activity; five soccer players, one baseball catcher, and one basketball player. The X-ray showed radiolucent lesion on the iliac bone. Lens-shaped mass without involvement of psoas muscle with ghost native cortex sign and overlying periosteal calcification on CT scan was characteristic radiological finding on subperiosteal iliac hematoma.

Conclusion: Subperiosteal iliac hematomas can be caused by vigorous sports activity in adolescence. This condition is not always associated with serious symptom. It can be identified as a radiolucent lesion mimicking a neoplasm.
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http://dx.doi.org/10.1016/j.jor.2019.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6919376PMC
August 2019

Eribulin Suppresses Clear Cell Sarcoma Growth by Inhibiting Cell Proliferation and Inducing Melanocytic Differentiation Both Directly and Via Vascular Remodeling.

Mol Cancer Ther 2020 03 3;19(3):742-754. Epub 2019 Dec 3.

Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.

Clear cell sarcoma (CCS) is a rare but chemotherapy-resistant and often fatal high-grade soft-tissue sarcoma (STS) characterized by melanocytic differentiation under control of microphthalmia-associated transcription factor (MITF). Eribulin mesilate (eribulin) is a mechanistically unique microtubule inhibitor commonly used for STS treatment, particularly liposarcoma and leiomyosarcoma. In this study, we examined the antitumor efficacy of eribulin on four human CCS cell lines and two mouse xenograft models. Eribulin inhibited CCS cell proliferation by inducing cell-cycle arrest and apoptosis, shrunk CCS xenograft tumors, and increased tumor vessel density. Eribulin induced MITF protein upregulation and stimulated tumor cell melanocytic differentiation through ERK1/2 inactivation (a MITF negative regulator) and Moreover, tumor reoxygenation, probably caused by eribulin-induced vascular remodeling, attenuated cell growth and inhibited ERK1/2 activity, thereby upregulating MITF expression and promoting melanocytic differentiation. Finally, downregulation of MITF protein levels modestly debilitated the antiproliferative effect of eribulin on CCS cells. Taken together, eribulin suppresses CCS through inhibition of cell proliferation and promotion of tumor differentiation by acting both directly on tumor cells and indirectly through tumor reoxygenation.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-0358DOI Listing
March 2020

Establishment of a novel human CIC-DUX sarcoma cell line, Kitra-SRS, with autocrine IGF-1R activation and metastatic potential to the lungs.

Sci Rep 2019 11 1;9(1):15812. Epub 2019 Nov 1.

Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Approximately 60-70% of EWSR1-negative small blue round cell sarcomas harbour a rearrangement of CIC, most commonly CIC-DUX. CIC-DUX sarcoma (CDS) is an aggressive and often fatal high-grade sarcoma appearing predominantly in children and young adults. Although cell lines and their xenograft models are essential tools for basic research and development of antitumour drugs, few cell lines currently exist for CDS. We successfully established a novel human CDS cell line designated Kitra-SRS and developed orthotopic tumour xenografts in nude mice. The CIC-DUX fusion gene in Kitra-SRS cells was generated by t(12;19) complex chromosomal rearrangements with an insertion of a chromosome segment including a DUX pseudogene component. Kitra-SRS xenografts were histologically similar to the original tumour and exhibited metastatic potential to the lungs. Kitra-SRS cells displayed autocrine activation of the insulin-like growth factor 1 (IGF-1)/IGF-1 receptor (IGF-1R) pathway. Accordingly, treatment with the IGF-1R inhibitor, linsitinib, attenuated Kitra-SRS cell growth and IGF-1-induced activation of IGF-1R/AKT signalling both in vitro and in vivo. Furthermore, upon screening 1134 FDA-approved drugs, the responses of Kitra-SRS cells to anticancer drugs appeared to reflect those of the primary tumour. Our model will be a useful modality for investigating the molecular pathology and therapy of CDS.
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http://dx.doi.org/10.1038/s41598-019-52143-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825133PMC
November 2019

Is the Width of a Surgical Margin Associated with the Outcome of Disease in Patients with Peripheral Chondrosarcoma of the Pelvis? A Multicenter Study.

Clin Orthop Relat Res 2019 Nov;477(11):2432-2440

Y. Tsuda, S. Evans, J. D. Stevenson, M. Parry, T. Fujiwara, M. Laitinen, H. Outani, L. Jeys, Royal Orthopaedic Hospital, Birmingham, UK M. Laitinen, Department of Orthopedics and Traumatology, Helsinki University Hospital, Helsinki, Finland H. Outani, Department of Orthopaedic Surgery, University of Osaka, Osaka, Japan.

Background: We attempted to resect peripheral chondrosarcoma of the pelvis with clear margins. Because of the proximity of vessels or organs, there is still concern that narrow surgical margins may have an adverse effect on disease outcomes. Although current guidelines recommend resection of histologic Grade II or Grade III chondrosarcomas with a "wide" margin, there are no specific recommendations for the adequate width of a surgical margin.

Questions/purposes: (1) What is the disease-specific and local recurrence-free survival of patients with peripheral chondrosarcoma of the pelvis treated with resection or amputation? (2) Is the width of a surgical margin associated with the outcome of disease in patients with peripheral chondrosarcoma of the pelvis? (3) Does the histologic grade as determined with a preoperative biopsy correlate with the final grade after resection? (4) What are surgical complications in these patients?

Methods: We retrospectively reviewed records from three international collaborating hospitals. Between 1983 and 2017, we resected 262 pelvic chondrosarcomas of all types. After reviewing the pathologic reports of these patients, we included 52 patients with peripheral chondrosarcomas of the pelvis who had an osteochondroma-like lesion at the base of the tumor and a cartilage cap with malignant cells in resected specimens. To be eligible for this study, a patient had to have a minimum of 1 year of follow-up. Two patients were excluded because they had less than 1 year of follow-up, leaving 50 patients for inclusion in this study. The median follow-up duration was 7.0 years (interquartile range 2.1-10 years). The median age was 37 years (IQR 29-54 years). The ilium was the most frequently affected bone (in 36 of 50 patients; 72%). The histologic status of the surgical margin was defined as microscopically positive (0 mm), negative < 1 mm, or negative ≥ 1 mm. Thirteen of the 50 patients (26%) had local recurrence. Seven of 34 patients had Grade I tumors, five of 13 had Grade II tumors, and one of three had a Grade III tumor. Nine of 16 patients had multiple local recurrences. Two patients with Grade I tumors and two with Grade II tumors died because of pressure effects caused by local recurrence.

Results: The 10-year disease-specific and local recurrence-free survival rates were 90% (95% confidence interval, 70-97) and 69% (95% CI, 52-81), respectively. A surgical margin ≥ 1 mm (n = 16) was associated with a better local recurrence-free survival rate than a surgical margin < 1 mm (n = 17) or 0 mm (n = 11) (10-year local recurrence-free survival: resection margin ≥ 1 mm = 100% versus < 1 mm = 52% [95% CI, 31 to 70]; p = 0.008). No patients with a surgical margin ≥ 1 mm had local recurrence, metastasis, or disease-related death, irrespective of tumor grade. Patients with local recurrence (n = 13) showed worse disease-specific survival than those without local recurrence (n = 37) (10-year disease-specific survival: local recurrence [+] = 59% [95% CI, 16 to 86] versus local recurrence [-] = 100%; p=0.001]). The preoperative biopsy results correctly determined the tumor grade in 15 of 41 patients (37%). The most frequent complication after surgery was local recurrence (13 of 50 patients, 26%). Deep infection was the most frequent nononcologic complication (four patients).

Conclusions: We found a high local recurrence rate after surgical treatment of a peripheral pelvic chondrosarcoma, which was related to the width of the surgical margin. These local recurrences led to inoperable recurrent tumors and death. The tumor grade as determined by preoperative biopsy was inaccurate in 2/3 of patients compared with the final histologic assessment. Therefore, we believe every attempt should be made to achieve a negative margin during the initial resection to lessen the likelihood of local recurrence of peripheral chondrosarcoma of the pelvis of all grades. A margin of 1 mm or more appeared to be sufficient in these patients.

Level Of Evidence: Level III, therapeutic study.
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http://dx.doi.org/10.1097/CORR.0000000000000926DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903848PMC
November 2019

Favorable outcomes of localized synovial sarcoma patients with a high utilization rate of neoadjuvant and/or adjuvant chemotherapy.

Mol Clin Oncol 2019 Aug 21;11(2):151-156. Epub 2019 May 21.

Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.

Synovial sarcoma (SS) is considered to be a chemosensitive, soft tissue sarcoma. Therefore, neoadjuvant and/or adjuvant chemotherapy (N/AC) is used for the treatment of high-risk SS patients. However, the role of N/AC remains controversial. The present study aimed to review the clinical outcomes of surgically treated localized SS and investigate the effects of N/AC with long-term observation. The clinical outcomes of 54 patients with surgically treated localized SS were retrospectively analyzed. The median patient age was 42 years (range, 8-81 years), and the median follow-up period was 94 months for survivors (range, 7-220 months). A total of 38 patients (70%) received chemotherapy. Of these, 32 (59%) patients received neoadjuvant chemotherapy, 33 (61%) received adjuvant chemotherapy, and 27 (50%) received neoadjuvant and adjuvant chemotherapy. Fourteen patients (26%) received adjuvant radiotherapy. Three patients (6%) had local recurrence and 13 patients (24%) developed distant metastasis. The overall survival (OS) rates at 5 and 10 years were 87 and 84%, respectively. N/AC did not improve survival. In conclusion, we found satisfactory long-term OS among patients with a high utilization rate of N/AC. Further study should be necessary to evaluate which population of SS would benefit from N/AC.
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http://dx.doi.org/10.3892/mco.2019.1863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587004PMC
August 2019

Prognostic implication of adjuvant/neoadjuvant chemotherapy consisting of doxorubicin and ifosfamide in patients with extraskeletal osteosarcoma.

Int J Clin Oncol 2019 Oct 13;24(10):1311-1319. Epub 2019 Jun 13.

Department of Orthopaedic Surgery, National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka, 540-0006, Japan.

Background: Extraskeletal osteosarcoma (ESOS) is an extremely rare soft tissue sarcoma. Their prognosis remains poor. Our purposes were to identify the effective chemotherapeutic regimen for ESOS.

Methods: We retrospectively reviewed 16 patients with ESOS treated at the Osaka University Orthopaedic Oncology Group between 1992 and 2012. We extracted the clinical data on patients. Kaplan-Meier method and the log-rank test were used for survival analyses.

Results: Median age of the patients was 61.5 years (range 25-79 years). Wide local excision was performed for 11 patients and 9 patients were treated combined with chemotherapy. The 5-year disease-specific survival (DSS) rate was 53.9%. The 5-year DSS rates for patients treated with adjuvant/neoadjuvant chemotherapy or not were 66.7% or 25%, respectively (p = 0.0215). Furthermore, the 5-year DSS rates for patients treated with adjuvant/neoadjuvant chemotherapy consisting of doxorubicin and ifosfamide and those treated with other regimens were 100% or 40%, respectively (p = 0.0327).

Conclusion: The present study demonstrated that adjuvant/neoadjuvant chemotherapy, especially consisting of doxorubicin and ifosfamide, was potentially efficacious for ESOS. Further prospective study using this multimodality treatment approach to patients with ESOS should be strongly warranted.
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http://dx.doi.org/10.1007/s10147-019-01475-1DOI Listing
October 2019

Survival analysis of elderly patients with osteosarcoma.

Int Orthop 2019 07 22;43(7):1741-1747. Epub 2019 Apr 22.

Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

Background: Few studies have described the characteristics and prognostic factors of elderly patients with osteosarcoma. We retrospectively investigated clinico-pathological features and prognostic factors in osteosarcoma patients > 40 years old.

Methods: Patients with high-grade osteosarcoma > 40 years old who were treated at our institutions from 2000 to 2016 were recruited for this study. Information on patient, tumour, and treatment-related factors was collected and statistically analyzed. The median follow-up was 26.5 months (range, 5-139 months) for all patients.

Results: Fifty patients (30 males and 20 females) were included. The median age at diagnosis was 59.5 years (range, 41-81 years). The primary lesions were found in the limbs in 32 patients, trunk in 12, and craniofacial bones in six. Primary and secondary osteosarcoma occurred in 41 and 9 patients, respectively. Eight patients exhibited initial distant metastasis. Definitive surgery and chemotherapy were performed in 39 patients each. The rate of good responders after neoadjuvant chemotherapy was 38%. The five year overall survival (OS) rates for all patients and those without distant metastasis at diagnosis were 44.5% and 51.1%, respectively. Multivariate analysis showed that definitive surgery was the only significant prognostic factor in non-metastatic patients. The five year OS and disease-free survival (DFS) rates for non-metastatic patients who received definitive surgery were 64.3% and 60%, respectively. Among these patients, neoadjuvant and/or adjuvant chemotherapy significantly improved both OS and DFS.

Conclusions: Complete surgical resection and intensive chemotherapy should be performed for osteosarcoma patients > 40 years old despite distinct clinicopathological characteristics from those of younger patients.
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http://dx.doi.org/10.1007/s00264-019-04332-yDOI Listing
July 2019

Rectotumoral fistula formation occurring more than 5 years after carbon ion radiotherapy for sacral chordoma: A case report.

Mol Clin Oncol 2019 May 5;10(5):487-491. Epub 2019 Mar 5.

Musculoskeletal Oncology Service, Osaka International Cancer Institute, Osaka, Osaka 541-8567, Japan.

Chordoma is a rare tumor that originates from the notochord. Half of chordomas involve the sacral region. Surgery is considered to be the standard treatment for sacral chordoma. However, carbon ion radiotherapy (CIRT) has recently emerged as a promising treatment for unresectable sacral chordoma. Little is known about the long-term complications of CIRT. We present two cases of rectotumoral fistula formation that occurred >5 years after CIRT for sacral chordoma. We considered two possible explanations for fistula formation: radiation enterocolitis after CIRT might cause formation of the fistula long-term, and tumor regrowth might compress the rectum and cause fistula formation. A biopsy in Case 1 showed that regrowth tumor was post-CIRT. It is important to be aware of the possibility of rectal complications after CIRT, and if found, resection of the rectum should be considered. This is a first report of rectotumoral fistula formation that occurred >5 years after CIRT for sacral chordoma.
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http://dx.doi.org/10.3892/mco.2019.1821DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449880PMC
May 2019

Long-term outcomes and prognostic factors of pulmonary metastasectomy for osteosarcoma and soft tissue sarcoma.

Int J Clin Oncol 2019 Jul 26;24(7):863-870. Epub 2019 Feb 26.

Department of General Thoracic Surgery, Osaka University Graduate School of Medicine, 2-2 (L5), Yamadaoka, Suita, Osaka, 565-0871, Japan.

Background: The prognostic factors of pulmonary metastasectomy in patients with osteosarcoma and soft tissue sarcoma remain controversial. The purpose of our analysis was to explore the prognostic factors and outcomes of patients with osteosarcoma and soft tissue sarcoma who underwent pulmonary metastasectomy at our institution.

Methods: We reviewed the data of 44 patients who underwent resection of pulmonary metastases from 1996 to 2016 at our institution. The Kaplan-Meier method, log-rank test and multivariate Cox hazard model were used for comparison and survival analyses.

Results: There was no perioperative mortality. The median post-metastasectomy overall survival was 24.8 months, and the 5-year overall survival rate of all patients was 43.5%. The 5-year survival rate of the patients who underwent repeat thoracotomies was 60.0%. Incomplete resection, a largest tumor size > 2 cm and a disease-free interval < 12 months were associated with poor survival in multivariate analyses. Among eight patients, who underwent repeat pulmonary resection, two remain alive with no evidence of disease. These patients had the longest DFI and DFI-2 (time from first pulmonary metastasectomy to the diagnosis of recurrent pulmonary metastasis), respectively.

Conclusion: The survival of patients with a relatively long disease-free interval, small tumor size and complete resection was favorable following the treatment of osteosarcoma and soft tissue sarcoma with pulmonary metastasectomy. Repeat pulmonary metastasectomies also provide favorable prognosis in select patients.
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http://dx.doi.org/10.1007/s10147-019-01422-0DOI Listing
July 2019

Localized synovial sarcoma: A single institutional study of 191 patients with a minimum follow-up of 5 years for survivors.

J Surg Oncol 2019 Jun 20;119(7):850-855. Epub 2019 Feb 20.

Oncology Service, Royal Orthopaedic Hospital, Birmingham, United Kingdom.

Purpose: Factors affecting long-term outcomes of synovial sarcoma (SS) remain unknown. Here, we aimed to investigate the long-term oncological outcomes and prognostic factors in a large group of patients with surgically-treated localized SS.

Patients And Methods: Between 1980 and 2011, 191 patients (94 males and 97 females) were treated at a single hospital with a minimum follow-up of 5 years for survivors. The median age was 35 years (range, 3-80 years), and the median follow-up period was 83 months (range, 3-235 months).

Results: Disease-specific survival was 76.4% and 60.4% at 5 and 10 years, respectively. Local recurrence occurred in 23 patients at a median of 33 months (range, 6-158 months), and metastasis occurred in 73 patients at a median of 20 months (range, 2-166 months). In multivariate analysis, grade 3 tumors sized ≥5 cm were significantly associated with worse survival. Ten patients (5.2%) developed metastasis more than 5 years after surgery.

Conclusion: Tumor size and grade govern prognosis in surgically-treated localized SS in long-term settings. If adequately treated patients have not developed metastases for 5 years after surgery, the risk of subsequently developing metastases was lower than previously reported.
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http://dx.doi.org/10.1002/jso.25417DOI Listing
June 2019

Clinical outcomes and significant factors in the survival rate after decompression surgery for patients who were non-ambulatory due to spinal metastases.

J Orthop Sci 2019 Mar 25;24(2):347-352. Epub 2018 Oct 25.

Musculoskeletal Oncology Service, Osaka International Cancer Institute, 3-1-69 Otemae, Chuuou, Osaka 541-8567, Japan.

Background: The development of effective chemotherapy regimens and molecular targeting agents are improving the overall survival rates in patients with cancer. However, patients who are non-ambulatory due to metastatic epidural spinal cord compression (MESCC) may be assessed as unable to tolerate chemotherapy secondary to poor performance status. This means that the ambulatory status of patients with cancer might be significant for survival time.

Methods: We investigated the functional outcomes and factors influencing overall survival in 31 patients who were non-ambulatory due to MESCC and underwent decompression surgery. The functional outcome was determined by the Frankel grading system.

Result: Twenty-one patients (68%) improved by at least 1 Frankel grade; 17 patients (55%) became ambulatory postoperatively. Most of postoperatively ambulatory patients could undergo postoperative chemotherapy (14/17, 82%). On the other hand, only a few postoperatively non-ambulatory patients could undergo postoperative chemotherapy (2/15, 13%). We observed a complication rate of 35.5% with specific complications including wound infection, pneumonia, and deep vein thrombosis/pulmonary embolus. The median survival duration was 7.0 months. Factors that significantly affected the overall survival in univariate analyses were revised Tokuhashi score (RTS) ≥ 4, postoperative chemotherapy, ambulatory status, and complications (RTS ≥ 4, P < 0.05; postoperative chemotherapy, P < 0.001; ambulatory status, P < 0.001; complications, P < 0.01).

Conclusions: Decompression surgery for patients who are non-ambulatory due to MESCC directly contributes to functional outcomes and may indirectly contribute to overall survival. If non-ambulatory patients who are assessed as unable to tolerate chemotherapy due to poor performance status regain the ability to walk by decompression surgery, they will have a chance to receive postoperative chemotherapy, thereby increasing their chances of prolonging survival. However, postoperative complications may shorten their survival; therefore, we should carefully consider the surgical indications. RTS is useful for judging the surgical indication.
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http://dx.doi.org/10.1016/j.jos.2018.10.003DOI Listing
March 2019

A pseudoaneurysm of the popliteal artery probably pierced by a bone spike arising in the spontaneously regressed osteochondroma: A case report.

J Orthop Sci 2021 May 11;26(3):514-520. Epub 2018 Oct 11.

Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan; Musculoskeletal Oncology Service, Osaka International Cancer Institute, 3-1-69, Otemae, Chuo-ku, Osaka, 541-8567, Japan. Electronic address:

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http://dx.doi.org/10.1016/j.jos.2018.09.006DOI Listing
May 2021

Clinical Features and Prognosis of Patients With the Bone Metastasis of Pancreatic Cancer: A Single-Institutional Cohort Study.

Pancreas 2018 08;47(7):e43-e46

Department of Orthopedic Surgery Osaka University Graduate School of Medicine Musculoskeletal Oncology Service Osaka International Cancer Institute Osaka, Japan Department of Surgery Osaka International Cancer Institute Osaka, Japan Musculoskeletal Oncology Service Osaka International Cancer Institute Osaka, Japan Department of Hepatobiliary and Pancreatic Oncology Osaka International Cancer Institute Osaka, Japan Musculoskeletal Oncology Service Osaka International Cancer Institute Osaka, Japan Department of Surgery Osaka International Cancer Institute Osaka, Japan Department of Hepatobiliary and Pancreatic Oncology Osaka International Cancer Institute Osaka, Japan Department of Orthopedic Surgery Ashiya Municipal Hospital Hyogo, Japan Musculoskeletal Oncology Service Osaka International Cancer Institute Osaka, Japan Musculoskeletal Oncology Service Osaka International Cancer Institute Osaka, Japan.

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http://dx.doi.org/10.1097/MPA.0000000000001098DOI Listing
August 2018

Atypical femoral fracture associated with bone-modifying agent for bone metastasis of breast cancer: A report of two cases.

J Orthop Surg (Hong Kong) 2017 Sep-Dec;25(3):2309499017727916

Musculoskeletal Oncology Service, Osaka International Cancer Institute, Osaka, Japan.

Atypical femoral fractures (AFFs) are recently observed as a complication of long-term bone-modifying agent (BMA; bisphosphonate or denosumab) therapy for bone metastases. We describe the cases of two women diagnosed with breast cancer who developed incomplete AFF associated with BMAs prescribed for bone metastases. Radiographs of their femurs revealed thickening of the lateral subtrochanteric cortex, and tomosynthesis revealed a visible fracture line in the thickened cortex. They were initially treated with conservative management; however, the incomplete fracture resulted in a complete fracture. These cases highlight two major implications. First, symptomatic incomplete AFF associated with BMAs prescribed for bone metastases should be treated with surgical prophylaxis, given the fact that fracture healing is expected to require a longer duration and an incomplete fracture might potentially progress to a complete fracture during long-term conservative management. Second, tomosynthesis is useful in identifying radiolucent fracture lines that are reliable predictors of fracture propagation.
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http://dx.doi.org/10.1177/2309499017727916DOI Listing
March 2018

Clinical outcomes of patients with epithelioid sarcomas: impact and management of nodal metastasis.

Int J Clin Oncol 2018 Feb 10;23(1):181-188. Epub 2017 Aug 10.

Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka, 565-0871, Japan.

Purpose: An epithelioid sarcoma is a rare histological subtype of a soft tissue sarcoma with a high local recurrence rate, which frequently shows lymph node metastasis. However, because of the rarity of this tumor, the impact of nodal metastasis and its appropriate management remain unclear. The present study investigated the clinical outcomes of patients with epithelioid sarcomas, with a focus on lymph node metastasis.

Methods: We retrospectively evaluated the clinical outcomes of 27 patients with epithelioid sarcomas treated between 1985 and 2015. The log-rank test was used to assess the prognostic variables.

Results: The overall local recurrence rate was 33%, and the estimated overall 5-year survival rate was 62%. Hand and foot locations were associated with favorable overall survival. During the follow-up period, new nodal metastasis was noted in 14 patients (52%). The incidence of local recurrence was higher in patients with new nodal metastasis than in patients who did not develop nodal metastasis. The development of new nodal metastasis had a tendency to worsen survival; however, this association was not statistically significant. Lymphadenectomy did not affect overall survival.

Conclusions: Peripheral tumor location is associated with a better prognosis. The development of new nodal metastasis tends to be associated with poor prognosis; however, among patients with nodal metastasis, resection of the metastatic lesions has a low impact on survival.
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http://dx.doi.org/10.1007/s10147-017-1179-xDOI Listing
February 2018
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