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We describe the case of a primary open-angle glaucoma patient with re-elevated nocturnal sitting intraocular pressure (IOP) after restarting medical therapy due to a failing bleb. IOP was markedly higher than diurnal IOP during multiple-drug therapy in both eyes, but it did not increase in the left eye with a functional bleb without medical therapy after trabeculectomy with adjuvant mitomycin. However, nocturnal sitting IOP was re-elevated after restarting multiple-drug therapy due to a failing bleb, while diurnal IOP was maintained at a low level.

Malignant peripheral nerve sheath tumor (MPNST) often does not respond well to chemotherapy and develops against a background of NF1. The purpose of our study was to examine the efficacy of pazopanib against MPNST. Our study was designed as a physician-initiated phase II clinical trial in patients with advanced MPNST. Patients were registered from 11 large hospitals. The primary endpoint was set to clarify the clinical benefit rate (CBR) at 12 weeks according to response evaluation criteria in solid tumors (RECIST). Progression-free survival (PFS), overall survival (OS) and the CBR based on modified Choi evaluation at week 12 were set as secondary endpoints along with treatment-related safety. The study enrolled 12 patients. Median age was 49 years. Seven had Grade 2 and five Grade 3 according to the FNCLCC evaluation. Median follow-up period was 10.6 months. CBR at 12 weeks was both 50.0% (RECIST and Choi). The median PFS was 5.4 months for both RECIST and Choi, and the median OS was 10.6 months. Of special interest, the median PFS was 2.9 months for patients with FNCLCC Grade 2 and 10.2 months for Grade 3 (both RECIST and Choi). Grade 4 adverse events of neutropenia and lipase elevation were noted in one patient each. The results of this pazopanib therapy were generally better than those of any of the other single molecular targeted therapies reported previously. Although accumulation of more cases remains necessary, we conclude pazopanib treatment for MPNST to be a safe and promising treatment after doxorubicin-based chemotherapy., (© 2020 Union for International Cancer Control.)

The blood-brain barrier (BBB) protects the human brain from external aggression. Despite its great importance, very few in vitro models of the BBB reproducing its complex organization are available yet. Here we fabricated such a three-dimensional (3D) self-organized in vitro model of BBB microvasculature by means of a combination of collagen microfibers (CMF) and fibrin gel. The interconnected fibers supported human brain microvascular endothelial cell migration and the formation of a capillary-like network with a lumen diameter close to in vivo values. Fibrin, a protein involved in blood vessel repair, favored the further 3D conformation of the brain microvascular endothelial cells, astrocytes and pericytes, ensured gel cohesion and avoided shrinkage. The maturation of the BBB microvasculature network was stimulated by both the CMF and the fibrin in the hydrogel. The expression of essential tight-junction proteins, carriers and transporters was validated in regards to bidimensional simple coculture. The volume of gel drops was easily tunable to fit in 96-well plates. The cytotoxicity of D-Mannitol and its impacts on the microvascular network were evaluated, as an example of the pertinence of this 3D BBB capillary model for screening applications.

Competing Interests: Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Angiosarcoma (AS) is a rare and aggressive tumor with high rates of local recurrence and distant metastasis. Stewart-Treves syndrome (STS) is defined as AS arising in the setting of chronic lymphedema, and is extremely uncommon in the lower abdominal wall. Eribulin mesylate (eribulin) is a non-taxane microtubule inhibitor that has been approved in Japan for treating soft tissue sarcoma. The current study reports the case of a 76 year-old woman with STS in the lower abdominal wall who exhibited an excellent response to eribulin. Having undergone surgery and postoperative radiation therapy (RT) for cervical cancer 12 years earlier, the patient presented with a mass in her left lower abdominal wall, where chronic lymphedema had developed. Contrast-enhanced computed tomography revealed multiple enhancing nodules in the left lower abdominal wall and edema of the subcutaneous tissues in the whole lower abdomen. A histologic analysis of the specimens revealed AS, and she was diagnosed as STS. A total of 3 cycles of combination chemotherapy with gemcitabine and docetaxel were administered, but the patient discontinued treatment owing to severe adverse events. RT was performed for the tumor, but multiple reddish nodules appeared in the whole lower abdominal wall 3 months later. At this point, eribulin administration was offered. After 4 cycles of treatment, there was a clear reduction in the size of the nodules. All lesions were stable, no new lesions had developed, and the side effects of treatment were minor over the course of 1 year. The results reveal that eribulin may serve as a potential therapeutic option for the treatment of STS., (Copyright: © Imura et al.)

We describe a case of primary localized histiocytic sarcoma of the lumbar vertebrae in a four-toed hedgehog. The case showed aggressive osteolysis of lumbar vertebrae on radiography, and a soft-tissue mass effacing this region was noted, suggesting a neoplastic lesion. No metastatic lesions were apparent. Antemortem diagnosis was challenging, and necropsy was performed. Histopathological and immunohistochemical findings were consistent with localized histiocytic sarcoma. This report provides documentation of the clinical and pathologic features of an unusual form of histiocytic sarcoma localizing to lumbar vertebrae in a four-toed hedgehog.

We describe the stress analysis of silicon oxide (SiO 2 ) thin film using cathodoluminescence (CL) spectroscopy and discuss its availability in this paper. To directly measure the CL spectra of the film under uniaxial tensile stresses, specially developed uniaxial tensile test equipment is used in a scanning electron microscope (SEM) equipped with a CL system. As tensile stress increases, the peak position and intensity proportionally increase. This indicates that CL spectroscopy is available as a stress measurement tool for SiO 2 film. However, the electron beam (EB) irradiation time influences the intensity and full width at half maximum (FWHM), which implies that some damage originating from EB irradiation accumulates in the film. The analyses using Raman spectroscopy and transmission electron microscopy (TEM) demonstrate that EB irradiation for stress measurement with CL induces the formation of silicon (Si) nanocrystals into SiO 2 film, indicating that CL stress analysis of the film is not nondestructive, but destructive inspection.

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., (Copyright: © Imura et al.)

Objectives: It is challenging to know at the first which patients with desmoid fibromatosis (DF) are better suited to conservative or aggressive treatment. To investigate whether the low signal intensity bundles on T1- or T2-weighted images (WI), termed the "black fiber sign (BFS)," can predict non-progressive behavior in the conservative approach., Methods: This retrospective study included 59 patients with primary DF managed with wait-and-see approach from 2005 to 2018 and serial MR images were analyzed. Three observers blinded to the patient information verified the presence or absence of BFS on baseline T1 or T2WI. The likelihood of progression-free survival (PFS) after ascertaining the presence or absence of the BFS was estimated using the Kaplan-Meier method and analyzed with the log-rank test., Results: PFS was significantly higher in cases with BFS than without BFS on T1WI (p < 0.01), but there was no significant difference in PFS between cases with and without BFS on T2WI. Multivariable Cox proportional hazards analysis revealed that the absence of BFS on T1WI was a high-risk factor for progression (hazard ratio, 14.9; p < 0.01). Drastic tumor regression was apparent with significantly increased low-signal area in cases with BFS on T1WI. Intra- and interobserver reliabilities of BFS on T1WI were in almost-perfect agreement (κ > 0.8)., Conclusion: Our retrospective observational data support that presence of BFS in baseline MRI may be a predictor for progression-free survival of DF. BFS on T1WI is easily identifiable and can be utilized clinically in patients with DF., Key Points: • We proposed a new imaging marker for prediction of desmoid fibromatosis progression. • The absence of black fiber sign predicted a high risk of disease progression.

Background: Successful bipolar radiofrequency catheter ablation (RFCA) of refractory ventricular arrhythmias (VAs) has been reported. However, the efficacy, safety, and long-term outcomes of bipolar RFCA of VAs are not fully determined., Objective: The purpose of this study was to evaluate the effectiveness and safety of bipolar RFCA in treating refractory VAs during long-term follow-up., Methods: Eighteen patients who underwent bipolar RFCA for ventricular tachycardia (VT) at 7 institutions were retrospectively investigated. Underlying heart diseases included remote myocardial infarction (n = 3 [17%]) and nonischemic cardiomyopathy (n = 15 [83%]). Although unipolar RFCA was performed in all patients, either it failed to suppress VT or VT recurred. The interventricular septum, left ventricular free wall, and left ventricular summit were targeted for bipolar RFCA., Results: Acute success (VT termination and/or noninducibility) was achieved with bipolar RFCA in 16 patients (89%). Complications during the procedure included complete atrioventricular block (n = 2) and coronary artery stenosis (n = 1). One patient underwent chemical ablation after bipolar RFCA failure. At 12-month follow-up, VT reoccurred in 8 patients (44%). However, in patients with recurrence, VT burden had decreased: only 4 patients underwent re-RFCA, and only 1 of the 4 required chemical ablation. In the remaining 4 patients, re-RFCA was not required, as VT was controlled by medication or an implantable cardioverter-defibrillator., Conclusion: Bipolar RFCA is useful for acute suppression of refractory VT. Although VT recurrence rates during long-term follow-up were relatively high, we observed a significant reduction in VT burden., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Alveolar soft part sarcoma (ASPS), epithelioid sarcoma (ES), and clear cell sarcoma (CCS) are known to be chemoresistant tumors. The aim of this study was to investigate the effect of pazopanib on these chemoresistant tumors. This study is designed as a single-arm, multicenter, investigator-initiated phase II trial. Patient enrollment was undertaken between July 2016 and August 2018 at 10 hospitals participating in the Japanese Musculoskeletal Oncology Group. The primary end-point is the CBR (CBR, including complete or partial response and stable disease) at 12 weeks after treatment with pazopanib according to RECIST. Eight patients were enrolled within the period. The histological subtypes were 5 ASPS, 2 ES, and 1 CCS. The median follow-up period was 22.2 (range, 4.9-24.9) months. All patients initially received pazopanib 800 mg once daily. The CBRs were 87.5% (7 of 8) and 75.0% (6 of 8) according to RECIST and Choi criteria at 12 weeks after pazopanib treatment, respectively. The CBRs at 12 weeks according to RECIST were 80.0%, 100.0%, and 100.0% in ASPS, ES, and CCS, respectively. Partial response was observed in 1 ASPS according to RECIST and 3 ASPS and 1 ES according to Choi criteria at 12 weeks after pazopanib treatment. This study documented antitumor activity of pazopanib, especially in ASPS. These results support the frontline use of pazopanib for ASPS. Prospective data collection is desired using both RECIST and Choi criteria for these rare chemoresistant tumors., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

TAS-115 is a novel MET, VEGFR, FMS and PDGFR inhibitor, developed to improve the continuity of drug administration with a relatively short half-life. We assessed its tolerability, safety, pharmacokinetics, efficacy, and pharmacodynamics in patients with solid tumors. This open-label, dose-escalation phase I study of TAS-115 consisted of three parts: part 1 (TAS-115 was administered orally once daily [SID]); part 2 and an expansion part (SID in a 5 days on/2 days off [5-on/2-off] schedule for 21 days per cycle). In part 1 (200-800 mg SID administered to 21 patients), systemic exposure after single administration increased almost dose-proportionally. Three dose-limiting toxicities (DLTs) were observed in three patients: grade 3 rash (650 mg), thrombocytopenia with bleeding, and rash (800 mg). The maximum tolerated dose (MTD) was determined as 650 mg SID. In part 2, the 5-on/2-off schedule was evaluated at the MTD to improve treatment exposure. No DLTs were observed and no patients required treatment interruption in cycle 1. During part 2 and the expansion part (N = 61), grade ≥3 treatment-related adverse events were reported in 47 patients, with neutropenia (24.6%), hypophosphatemia (21.3%), anemia, and thrombocytopenia (14.8% each), and leukocytopenia (11.5%) occurring in ≥10% of patients. The best overall response was stable disease in 31 of 82 patients (37.8%). An apparent reduction in fluorodesoxyglucose-uptake and bone scan index was observed in some patients. TAS-115 was generally well tolerated, with manageable toxicities and recommended phase II dose was estimated as 650 mg SID, 5-on/2-off. Furthermore, promising antitumor activity was observed.

Front face fluorescence spectroscopy of typical Japanese soil powders (soil A: Typic Hapludand; soil H: Typic Hydraquent; soil Y: Typic Paleudult) has been conducted. Three dimensional excitation-emission matrix fluorescence spectra of the 100 wt% soils showed similar fluorescence patterns to each other. The fluorescence patterns were similar between the soil samples and their residues after extraction by NaOH solution for 60 min. In order to examine fluorescence extinction from a view point of whiteness of the soils, the soil powders were mixed with white and black diluents (Al 2 O 3 and Fe 3 O 4 ) and fluorescence spectra of the mixtures were measured at 450 nm excitation. At low levels of dilution with Al 2 O 3 (2-100 wt% of A; 50-100 wt% of H and Y), the fluorescence intensities increased with dilution. At high levels of dilution with Al 2 O 3 , the fluorescence intensities decreased with dilution. On the other hand, fluorescent intensities decreased by dilution with Fe 3 O 4 . These results suggested inner filter effect-like fluorescence extinction by (1) large amount of blackish organic compounds giving high total carbon value and (2) blackish non-fluorescent mineral compounds. In order to correct the fluorescence intensities of the mixtures containing the sample soils and the diluents, we preliminary applied a correction method based on the Kubelka-Munk theory using diffuse reflectance. The corrected fluorescence intensities of samples with white diluents (Al 2 O 3 ) were described by a simple fluorescence response model having saturation values., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

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., (© 2020 Wiley Periodicals, Inc.)

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., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

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 ( n  = 9), protruding fixation implant ( n  = 4), or fracture of the grafted bone ( n  = 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., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Satoshi Takenaka et al.)

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.

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) in vitro and in vivo 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., (©2019 American Association for Cancer Research.)

Background: Primary osteosarcoma in elderly patients are rare malignant tumors. Its optimal treatment has not yet been determined., Methods: This retrospective study included 104 patients aged >50 years with resectable, non-metastatic osteosarcoma treated by the members of the Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group. The effects of adjuvant chemotherapy were estimated by comparing outcomes in patients who received surgery plus chemotherapy with those who underwent surgery alone., Results: Median age at presentation was 59 years. Neoadjuvant and adjuvant chemotherapy was administered to 83 (79.8%) patients. Patients who underwent surgery plus chemotherapy and those who underwent surgery alone had 5-year overall survival (OS) rates of 68.6% and 71.7%, respectively (p = 0.780), and 5-year relapse free survival (RFS) rates of 48.2% and 43.6%, respectively (p = 0.64). Univariate analysis showed that resection with wide margins was significantly correlated with better prognosis., Conclusions: The addition of chemotherapy to surgery did not improve OS or RFS in patients aged >50 years with resectable, non-metastatic osteosarcoma. Surgery with wide margins was only significantly prognostic of improved survival. The effect of chemotherapy in elderly osteosarcoma patients was unclear., (Copyright © 2019 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

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., (Copyright: © Hagizawa et al.)

There have been few reports on bone metastases (BMs) from esophageal cancer (EC). The aim of the present study was to investigate the clinicopathological features and prognostic factors in patients with EC with BMs. The present study retrospectively collected data from 58 patients with BMs from EC who were treated at our institution between 2007 and 2016. Patient, tumor and BM-associated characteristics were analyzed. Kaplan-Meier survival curves were constructed and analyzed using the univariate log-rank test. Multivariate analyses were conducted using the Cox proportional hazards model. The median patient age was 67 years (range, 39-84 years). Multiple BMs were detected in 38 patients (65.5%) and 52 patients (89.7%) exhibited osteolytic BMs. Skeletal-related events (SREs) occurred in 53 patients (91.4%). The one-year overall survival (OS) was 25.3%, and the median OS was 5 months (range, 0-54). Univariate analyses revealed that performance status, visceral or brain metastasis, serum carcinoembryonic antigen (CEA), C-reactive protein, albumin level, and receipt of chemotherapy following BM diagnosis were significantly associated with OS. Multivariate analyses of these factors demonstrated that higher serum CEA levels and no chemotherapy were significant risk factors for poor OS. Multiple osteolytic BMs are frequently observed in patients with EC with BMs, and SREs commonly occur. The prognoses of patients with EC with BMs are poor, but chemotherapy administration following the BM diagnosis should confer a survival benefit., (Copyright: © Imura et al.)

The genomic characteristics of dedifferentiated liposarcoma (DDLPS) that are associated with clinical features remain to be identified. Here, we conduct integrated whole exome and RNA sequencing analysis in 115 DDLPS tumors and perform comparative genomic analysis of well-differentiated and dedifferentiated components from eight DDLPS samples. Several somatic copy-number alterations (SCNAs), including the gain of 12q15, are identified as frequent genomic alterations. CTDSP1/2-DNM3OS fusion genes are identified in a subset of DDLPS tumors. Based on the association of SCNAs with clinical features, the DDLPS tumors are clustered into three groups. This clustering can predict the clinical outcome independently. The comparative analysis between well-differentiated and dedifferentiated components identify two categories of genomic alterations: shared alterations, associated with tumorigenesis, and dedifferentiated-specific alterations, associated with malignant transformation. This large-scale genomic analysis reveals the mechanisms underlying the development and progression of DDLPS and provides insights that could contribute to the refinement of DDLPS management.

Approximately 60-70% of EWSR1-negative small blue round cell sarcomas harbour a rearrangement of CIC, most commonly CIC-DUX 4 . CIC-DUX 4 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 4 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 4 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.

A 69-year-old Japanese woman was admitted to our hospital with progressive muscle weakness and dysphagia. She was taking pitavastatin for dyslipidemia. Her serum creatine kinase was 6,300 U/L. Pitavastatin was stopped, but her symptoms deteriorated, and cardiac congestion appeared. A muscle biopsy showed necrotizing myopathy (NM), and anti-signal recognition particle (SRP) antibody was positive. 18 F-fluorodeoxyglucose-positron emission tomography showed an abnormal uptake, and magnetic resonance imaging showed abnormal gadolinium enhancement in the left ventricular wall. An endomyocardial biopsy revealed inflammatory cardiomyopathy. Steroid, tacrolimus, and intravenous immunoglobulins were effective against the symptoms. This is the first case of biopsy-proven secondary cardiomyopathy due to anti-SRP-positive NM.

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.

Background: Soft-tissue sarcomas (STS) are rare malignant tumors those are resistant to chemotherapy. We have previously reported the 3-year follow-up result on the efficacy of perioperative chemotherapy with doxorubicin (DXR) and ifosfamide (IFM) for high-risk STS of the extremities (JCOG0304). In the present study, we analyzed the 10-year follow-up results of JCOG0304., Methods: Patients with operable, high-risk STS (T2bN0M0, AJCC 6th edition) of the extremities were treated with 3 courses of preoperative and 2 courses of postoperative chemotherapy, which consisted of 60 mg/m 2 of DXR plus 10 g/m 2 of IFM over a 3-week interval. The primary study endpoint was progression-free survival (PFS) estimated by Kaplan-Meier methods. Prognostic factors were evaluated by univariable and multivariable Cox proportional hazards model., Results: A total of 72 patients were enrolled between March 2004 and September 2008, with 70 of these patients being eligible. The median follow-up period was 10.0 years for all eligible patients. Local recurrence and distant metastasis were observed in 5 and 19 patients, respectively. The 10-year PFS was 65.7% (95% CI: 53.4-75.5%) with no PFS events being detected during the last 5 years of follow-up. The 10-year overall survival was 78.1% (95% CI: 66.3-86.2%). Secondary malignancy was detected in 6 patients. The subgroup analysis demonstrated that there was significant difference in survival with regard to primary tumor size., Conclusions: Only a few long-term results of clinical trials for perioperative chemotherapy treatment of STS have been reported. Our results demonstrate that the 10-year outcome of JCOG0304 for patients with operable, high-risk STS of the extremities was stable and remained favorable during the last 5 years of follow-up., Trial Registration: This trial was registered at the UMIN Clinical Trials Registry as C000000096 on August 30, 2005.

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by abnormalities in the α-galactosidase (Gal) A gene (GLA; MIM:300644). The reduced activity of the lysosomal enzyme, α-galactosidase A (α-Gal A) leads to classic early manifestations and vascular disease of the heart, kidneys, and brain. As a high-risk screening for symptomatic AFD using an enzymatic assay on dried blood spot samples, we enrolled 2325 individuals (803 females and 1522 males; median age: 66 years) with cardiac, renal, or neurological manifestations that met at least one of the following criteria: (a) family history of early-onset cardiovascular diseases; (b) typical classic manifestations, such as acroparesthesias, clustered angiokeratoma, cornea verticillata, and hypo-anhidrosis; (c) proteinuria; (d) receiving dialysis; (e) left ventricular hypertrophy on electrocardiography or echocardiography; or (f) history of stroke. Ninety-two patients displayed low α-Gal A activity. Four males and two females had different pathogenic GLA mutations (0.26%) including a novel mutation c.908-928del21. Four males (0.17%) harbored the GLA c.196G>C (p.E66Q) variant. This simple screening protocol using dried blood spot samples is useful for early diagnosis of AFD in high-risk and underdiagnosed patients suffering from various cardiac, renal, or neurological manifestations.

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., (© 2019 Professor P K Surendran Memorial Education Foundation. Published by Elsevier B.V. All rights reserved.)

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.

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.

Granular cell tumors (GCTs) are rare mesenchymal tumors that exhibit a characteristic morphology and a finely granular cytoplasm. The genetic alterations responsible for GCT tumorigenesis had been unknown until recently, when loss-of-function mutations of ATP6AP1 and ATP6AP2 were described. Thus, we performed whole-exome sequencing, RNA sequencing, and targeted sequencing of 51 GCT samples. From these genomic analyses, we identified mutations in genes encoding vacuolar H + -ATPase (V-ATPase) components, including ATP6AP1 and ATP6AP2, in 33 (65%) GCTs. ATP6AP1 and ATP6AP2 mutations were found in 23 (45%) and 2 (4%) samples, respectively, and all were truncating or splice site mutations. In addition, seven other genes encoding V-ATPase components were also mutated, and three mutations in ATP6V0C occurred on the same amino acid (isoleucine 136). These V-ATPase component gene mutations were mutually exclusive, with one exception. These results suggest that V-ATPase function is impaired in GCTs not only by loss-of-function mutations of ATP6AP1 and ATP6AP2 but also through mutations of other subunits. Our findings provide additional support for the hypothesis that V-ATPase dysfunction promotes GCT tumorigenesis., (© 2018 Wiley Periodicals, Inc.)

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.

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., (Copyright © 2018 The Japanese Orthopaedic Association. Published by Elsevier B.V. All rights reserved.)

Background: Although we and others have reported cases of patients with Anderson-Fabry disease (AFD) complicated by coronary spastic angina (CSA), the prevalence of CSA in these patients remains unknown. Methods and Results: We performed the acetylcholine-induced provocation test, according to the Japanese guidelines for the diagnosis and treatment of patients with CSA, in 9 consecutive patients having 5 independent AFD pedigrees. Coronary spasms were provoked in conjunction with symptoms and ECG ischemic changes in 8 of 9 (89%) patients with AFD., Conclusions: We found an unexpectedly high prevalence of CSA in patients with AFD.

We demonstrated the superradiance-to-polariton crossover of the blue excitons in Cu&#95;{2}O by varying the sample thicknesses instead of controlling the cavity quality factor. The crossover behavior was compared with unprecedented calculations based on the nonlocal optical response theory with the inclusion of three exciton resonances. The crossover thickness, found to be 177±2  nm, was smaller than the predicted value for a single resonance by a factor of 5. The fact that there was much larger longitudinal-transverse splitting (40±5  meV) than in the bulk implies a surprisingly fast radiative recombination even without a cavity structure.

Background: Cardiac sarcoidosis (CS) is a noncaseating granulomatous disease of unknown etiology. Lifelong immunosuppressive therapy, most frequently using corticosteroids, is a standard therapy to control hypersensitivity of immune reactions and prevent inflammation. However, it sometimes causes various systemic adverse effects and requires dose escalation. Thus, additional therapy may be required for the treatment of this disease. Recently, Propionibacterium acnes ( P. acnes ) was reported as one of the etiologic agents of CS, indicating that antibacterial drugs (ABD) may be effective for the treatment of CS. The objective of this study was to investigate the effect of ABD treatment, in addition to standard corticosteroid therapy, in patients with CS., Methods: The Japanese Antibacterial Drug Management for Cardiac Sarcoidosis (J-ACNES) trial was designed as a prospective, multicenter, randomized, open-label, controlled clinical trial. The patients will be randomized to receive either standard corticosteroid therapy plus ABD therapy (ABD group) or standard corticosteroid therapy (standard group). The primary endpoint is change in the total standardized uptake value at 6 months vs baseline using fluorine-18 fluorodeoxyglucose positron emission tomography and computed tomography. Secondary endpoints include efficacy, prognosis, and safety., Results: The results of this study are currently under investigation., Conclusion: The J-ACNES trial will be the first prospective study assessing the clinical benefit and safety of ABD therapy, in addition to corticosteroid treatment, in patients with CS. Our findings may improve treatment of patients with CS, as additional ABD therapy reduces recurrence of inflammation and elucidates the mechanism of sarcoidosis.

Background: Soft tissue sarcomas (STS) are rare malignant tumors. The efficacy of preoperative chemotherapy for STS is evaluated using various tumor size-based radiological response criteria. However, it is still unclear which set of criteria would show the best association with pathological response and survival of the patients with STS., Methods: We compared radiological responses to preoperative chemotherapy for operable STS by the Response Evaluation Criteria in Solid Tumors (RECIST), modified RECIST, World Health Organization criteria, Japanese Orthopaedic Association criteria, and modified Choi criteria and analyzed the association with pathological response and survival using the data from the Japan Clinical Oncology Group (JCOG) study JCOG0304, a phase II clinical trial evaluating the efficacy of perioperative chemotherapy for STS in the extremities., Results: Seventy eligible patients in JCOG0304 were analyzed. The results demonstrated that none of the size-based radiological response criteria showed significant association with pathological response to preoperative chemotherapy for STS. The difference between overall survival of the patients assessed as partial response and stable disease/progressive disease by RECIST was not significant (hazard ratio 1.37, p = 0.63), and calculated C-index was 0.50. All other response criteria also could not exhibit significant association between radiological responses and survival., Conclusion: In the present study, none of the radiological response criteria analyzed demonstrated association of response to preoperative chemotherapy with pathological response or survival of the patients with operable STS. Further prospective investigation is required to develop criteria to evaluate not only tumor shrinkage but biological effects of preoperative chemotherapy for the patients with localized STS., Trial Registration: UMIN Clinical Trials Registry C000000096. Registered 30 August, 2005 (retrospectively registered).

Background: Giant cell tumor of bone (GCTB) is an intermediate tumor known to be locally aggressive, but rarely metastasizing. To plan a prospective study of GCTB, we performed a questionnaire survey for institutions participating in the Bone and Soft Tissue Tumor Study Group (BSTTSG) in the Japan Clinical Oncology Group (JCOG) in 2015., Methods: We reviewed 158 consecutive patients with primary GCTB treated with curettage without perioperative denosumab from 2008 to 2010 in Japan. We investigated local and distant recurrence rates after definitive curettage. We also investigated the recurrence rate after treatment with preoperative and/or postoperative denosumab with curettage in recent years. There were 40 patients treated with perioperative denosumab, and the factors affecting recurrence in them were investigated., Results: Answers were available from 24 of 30 institutions (80.0%) participating in JCOG BSTTSG. Thirty (19.0%) and 4 (2.5%) of 158 patients developed local and distant recurrence after curettage without perioperative denosumab from 2008 to 2010, respectively. Campanacci grade and embolization before surgery were significantly associated with increasing incidence of local recurrence after curettage (p = 0.034 and p = 0.022, respectively). In patients treated with perioperative desnosumab, 120 mg denosumab was administered subcutaneously for a median 6 (2-41) and 6 (1-14) times in preoperative and postoperative settings, respectively. The recurrence rates were 6 of 21 (28.6%), 2 of 9 (22.2%), and 0 of 10 (0.0%) in the preoperative, postoperative, and both pre- and postoperative denosumab treatment groups, respectively. With all of the preoperative treatments, administration exceeding five times was significantly associated with a decreased incidence of local recurrence after curettage (p < 0.001)., Conclusion: The recurrence rate of GCTB was still high after curettage, especially in Campanacci grade III, and improvements in the therapeutic strategy are needed in this cohort. There is a possibility that a sufficient dose of preoperative denosumab can reduce recurrence after curettage. Recently, we have started a clinical trial, JCOG1610, to investigate the efficacy of preoperative denosumab in patients who can be treated with curettage in GCTB.

Calcific myonecrosis is a rare soft tissue condition. The first case was reported in 1960, however, the precise pathophysiology of calcific myonecrosis remains unclear. The disease was thought to arise from compartment syndrome within a confined space resulting in necrosis and fibrosis, subsequent repeated intralesional hemorrhage, mass enlargement and calcification. Several previous reports have described calcific myonecrosis, which include the formation of calcific myonecrosis after a prolonged period of post trauma. Notably, calcific myonecrosis has typically been described in the lower legs and characteristic imaging findings have been indicated. Furthermore, surgical intervention carries a high risk of complications. In the present case report 2 cases of calcific myonecrosis that occurred after a prolonged period of time following a traumatic event that impacted the lower leg were reported. CT images revealed disruption of calcified fascia and disease expansion into the outside of the fascia. Previous reports have implied that there is late focal enlargement of calcific myonecrosis following earlier enlargement, which may be caused by herniation through muscle fascia. However, no previous publications have focused on images for evidence of late local enlargement. To the best of our knowledge, this is the first report focusing on fascial herniation of calcific myonecrosis using images. Analysis of this feature using images may aid clinicians to differentiate calcific myonecrosis from malignancies.

Objectives: The differential diagnosis between precapillary and postcapillary pulmonary hypertension (PH) is important for deciding on the appropriate therapeutic strategy. The aim of this study was to assess whether the atrial volume ratio can differentiate precapillary and post-capillary PH., Methods: Seventy-seven patients with PH who underwent transthoracic echocardiography (TTE) and right heart catheterization were retrospectively studied. Pulmonary hypertension was defined as a mean pulmonary arterial pressure of 25 mm Hg or higher by right heart catheterization. Patients with a pulmonary capillary wedge pressure higher than 15 mm Hg were classified as having postcapillary PH, and patients with a pulmonary capillary wedge pressure of 15 mm Hg or lower were classified as having precapillary PH. The atrial volume ratio derived from TTE was defined as right atrial volume divided by left atrial volume., Results: Forty-four (57%) of 77 patients had precapillary PH by the right heart catheterization classification. The atrial volume ratio was significantly higher in precapillary PH than in postcapillary PH (1.03 ± 0.69 versus 0.50 ± 0.19; P < .001). The area under the receiver operating characteristic curve of the atrial volume ratio for detecting postcapillary PH was 0.84 (95% confidence interval: 0.75-0.93). Adding the atrial volume ratio to the left ventricular ejection fraction yielded a high area under the curve of 0.90 (95% confidence interval, 0.83-0.96) for distinguishing precapillary and postcapillary PH., Conclusions: The atrial volume ratio assessed by TTE might be useful for differential diagnosis between precapillary and postcapillary PH., (© 2017 by the American Institute of Ultrasound in Medicine.)

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.

Clear cell sarcoma is an aggressive soft tissue sarcoma and highly resistant to conventional chemotherapy and radiation therapy. This devastating disease is defined by EWSR1-ATF1 fusion gene resulting from chromosomal translocation t(12;22)(q13;q12) and characterized by melanocytic differentiation. A marine-derived antineoplastic agent, trabectedin, inhibits the growth of myxoid liposarcoma and Ewing sarcoma by causing adipogenic differentiation and neural differentiation, respectively. In this study, we examined the antitumor effects and mechanism of action of trabectedin on human clear cell sarcoma cell lines. We showed that trabectedin decreased the cell proliferation of five clear cell sarcoma cell lines in a dose-dependent manner in vitro and reduced tumor growth of two mouse xenograft models. Flow cytometry and immunoblot analyses in vitro and immunohistochemical analysis in vivo revealed that trabectedin-induced G2/M cell cycle arrest and apoptosis. Furthermore, trabectedin increased the expression of melanocytic differentiation markers along with downregulation of ERK activity in vitro and the rate of melanin-positive cells in vivo. These results suggest that trabectedin has potent antitumor activity against clear cell sarcoma cells by inducing cell cycle arrest, apoptosis, and, in part, by promoting melanocytic differentiation through inactivation of ERK signaling. Our present study indicates that trabectedin is a promising differentiation-inducing agent for clear cell sarcoma., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)