Publications by authors named "Toru Wakamatsu"

35 Publications

Size effect of the guest cation on the AlO framework in aluminate sodalite-type oxides M[AlO](SO) (M = Sr and Ca) in the I43m phase.

Acta Crystallogr B Struct Sci Cryst Eng Mater 2021 Apr 25;77(Pt 2):186-192. Epub 2021 Feb 25.

Graduate School of Advanced Science and Engineering, Hiroshima University, Higashihiroshima 739-8526, Japan.

Sr[AlO](SO) (SAS) and Ca[AlO](SO) (CAS) are members of the aluminate sodalite-type oxides with the general chemical formula M[AlO](XO) (M is the guest cation and XO is the guest anion). To discuss the role of the guest cations (M = Sr and Ca) on the rotation of AlO in the oxygen tetrahedral framework in the I43m phase, the crystal structure parameters and the probability density function of the guest ions in SAS and CAS have been investigated via synchrotron radiation X-ray powder diffraction by considering Gram-Charlier expansions. The interatomic distances between the M and O ions evaluated from the maximum positions in the probability density distribution are almost equal to the sum of the ideal ionic radii of the M and O ions. This result suggests that the geometry of the AlO tetrahedral framework and the fluctuation of the guest ions are mainly caused by steric effects between the M and O ions.
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http://dx.doi.org/10.1107/S2052520621000238DOI Listing
April 2021

Primary breast angiosarcoma with disseminated intravascular coagulation is successfully treated with self-subcutaneous unfractionated heparin calcium injection: A case report.

Mol Clin Oncol 2021 May 17;14(5):104. Epub 2021 Mar 17.

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

Angiosarcoma is a rare sarcoma with a poor prognosis and is prone to disseminated intravascular coagulation (DIC), where DIC often interferes with chemotherapy. Primary angiosarcoma of the breast (PASB) is a type of angiosarcoma that is located in mammary parenchyma and is not associated with radiation exposure. The current study reported a 47-year-old female with DIC associated with PASB. The DIC of the patient relapsed during mono-chemotherapy with paclitaxel (PTX) after first-line anticoagulant therapy using thrombomodulin-α. The second-line danaparoid sodium therapy, followed by self-subcutaneous injection of unfractionated heparin calcium (UFH), resulted in long-term stabilization of DIC. Under this second-line anticoagulant therapy, the patient continued chemotherapy and chemoradiotherapy for >13 months in the outpatient setting without impairment of quality of life. The present case suggested that self-subcutaneous injections of UFH may be a useful therapeutic option for long-term control of DIC associated with PASB. However, further prospective clinical trails are needed to verify the efficacy of self-subcutaneous injection of UFH in similar settings.
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http://dx.doi.org/10.3892/mco.2021.2266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010513PMC
May 2021

Propofol midazolam for sedation during radiofrequency ablation in patients with hepatocellular carcinoma.

JGH Open 2021 Feb 22;5(2):273-279. Epub 2020 Dec 22.

Departmetn of Anesthesiology, Graduate School of Medicine Chiba University Chiba Japan.

Background And Aim: Standardization of the sedation protocol during radiofrequency ablation (RFA) in patients with hepatocellular carcinoma (HCC) is needed. This randomized, single-blind, investigator-initiated trial compared clinical outcomes during and after RFA using propofol and midazolam, respectively, in patients with HCC.

Methods: Few- and small-nodule HCC patients (≤3 nodules and ≤3 cm) were randomly assigned to either propofol or midazolam. Patient satisfaction was assessed using a 100-mm visual analog scale (VAS) (1 mm = not at all satisfied, 100 mm = completely satisfied). Sedation recovery rates 1, 2, 3, and 4 h after RFA were evaluated based on Modified Observer's Assessment of Alertness/Sedation (MOAA/S) scores; full recovery was defined as a MOAA/S score of 5.

Results: Between July 2013 and September 2017, 143 patients with HCC were enrolled, and 135 patients were randomly assigned to the treatment group. Compared with midazolam, propofol exhibited similar median procedural satisfaction (propofol: 73.1 mm, midazolam: 76.9 mm, = 0.574). Recovery rates 1 and 2 h after RFA were higher in the propofol group than in the midazolam group. Meanwhile, recovery rates observed 3 and 4 h after RFA were similar in the two groups. The safety profiles during and after RFA were almost identical in the two groups.

Conclusion: Patient satisfaction was almost identical in patients receiving propofol and midazolam sedation during RFA. Propofol sedation resulted in reduced recovery time compared with midazolam sedation in patients with HCC. The safety profiles of both propofol and midazolam sedation during and after RFA were acceptable.
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http://dx.doi.org/10.1002/jgh3.12483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857294PMC
February 2021

Malignant gastrointestinal neuroectodermal tumor with BRAF mutation and a history of malignant melanoma: A case report.

Mol Clin Oncol 2021 Feb 4;14(2):23. Epub 2020 Dec 4.

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

Malignant gastrointestinal neuroectodermal tumors (GNETs), also called clear-cell sarcoma-like tumors of the gastrointestinal tract, are rare and highly aggressive tumors originating in the gastrointestinal tract. These tumors are generally immunohistochemically positive for S-100 protein (S-100) and SRY-related HMG-box 10 (SOX10), and often contain EWSR1-ATF1 or EWSR1-CREB1. The histological features of GNETs overlap with those of clear-cell sarcoma of the tendons and aponeuroses. However, GNETs immunohistochemically lack melanocyte-specific markers and often demonstrate positivity for CD56, synaptophysin and neuron-specific enolase. The present case reports a woman with a history of desmoplastic malignant melanoma exhibiting a BRAF mutation, which later transformed into a GNET of the small intestine with both a BRAF mutation and two subtypes of EWSR1-ATF1 fusion genes. Tumor cells were revealed to be weakly immunoreactive or negative for S-100 and SOX10, lacked markers of melanocytic differentiation and were focally positive for CD56. Combination therapy with dabrafenib mesylate and trametinib dimethyl sulfoxide proved to be temporarily effective against this tumor. The present case is relatively unique as, to the best of our knowledge, there is no case of GNET with a history of melanoma. Furthermore, there is no report of GNET exhibiting both a BRAF mutation and an EWSR1-ATF1 fusion gene. Further accumulation of similar cases is necessary to elucidate the pathological significance of this GNET having a BRAF mutation.
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http://dx.doi.org/10.3892/mco.2020.2185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739819PMC
February 2021

Eribulin Provides a Remarkable Effect in Trabectedin-Resistant Myxoid Liposarcoma.

Case Rep Orthop 2020 12;2020:8873185. Epub 2020 Nov 12.

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

Adriamycin-based chemotherapy is commonly used for malignant soft tissue sarcoma including myxoid liposarcoma. However, in the case of unavailability or failure of the adriamycin-based regimen, trabectedin or eribulin can produce a good antitumor effect for myxoid liposarcoma. We relate the experience of a 64-year-old female with myxoid liposarcoma, who noticed a nodule on her left thigh and visited our institute. At initial presentation, the tumor was 18.7 cm in diameter, and the magnetic resonance imaging (MRI) showed a malignant lipomatous tumor with a myxoid component. We recommended that she undergo treatment; however, she refused. Three years later, the tumor had grown larger, so she finally decided to undergo treatment. A needle biopsy revealed a myxoid liposarcoma. The tumor massively involved the neurovascular structures; we thus determined that hip disarticulation was inevitable. Two years later, metastases in the right thigh, left lung, right ileum, and abdominal space were pointed out and chemotherapy was initiated. Adriamycin was unusable due to cardiac dysfunction, so trabectedin was administered; however, the tumors progressed. Eribulin was subsequently started and has been considerably effective for more than 2 years without severe adverse effects. In conclusion, we experienced a case showing the remarkable and long-lasting effect of eribulin against trabectedin-resistant myxoid liposarcoma.
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http://dx.doi.org/10.1155/2020/8873185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683141PMC
November 2020

Analyses of Intermediate-Stage Hepatocellular Carcinoma Patients Receiving Transarterial Chemoembolization prior to Designing Clinical Trials.

Liver Cancer 2020 Sep 22;9(5):596-612. Epub 2020 Jul 22.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: Intermediate-stage hepatocellular carcinoma (HCC) has a high frequency of recurrence and progression to advanced stage after transarterial chemoembolization (TACE), particularly in patients with high tumor burden. Promising new results from immune checkpoint inhibitors (ICIs) and ICI-based therapies are expected to replace TACE, especially in HCC patients with high tumor burden.

Aims: The present study aimed to evaluate the effectiveness of TACE with a view to design clinical trials comparing TACE and ICIs.

Methods: We retrospectively identified intermediate-stage HCC patients undergoing TACE from our database and subdivided patients into low- and high-burden groups based on three subclassification models using the diameter of the maximum tumor and the number of tumors. Clinical outcomes were compared between low- and high-burden intermediate-stage HCC.

Results: Of 1,161 newly diagnosed HCC patients, 316 were diagnosed with intermediate-stage disease and underwent TACE. The median overall survival from high-burden intermediate-stage disease was not significantly different by clinical course, reaching high tumor burden in all subclassification models. The prognosis of high-burden patients after initial TACE was poor compared with low-burden patients for two models (except for the up-to-seven criteria). In all three models, high-burden patients showed a poor durable response rate (DRR) both ≥3 months and ≥6 months and poor prognosis after TACE. Moreover, patients with confirmed durable response ≥3 months and ≥6 months showed better survival outcomes for high-burden intermediate-stage HCC.

Conclusions: Our results demonstrate the basis for selecting a population that would not benefit from TACE and setting DRR ≥3 months or ≥6 months as alternative endpoints when designing clinical trials comparing TACE and ICIs.
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http://dx.doi.org/10.1159/000508809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548915PMC
September 2020

A case of Stewart-Treves syndrome occurring in the abdominal wall successfully treated with eribulin: A case report.

Mol Clin Oncol 2020 Nov 20;13(5):49. Epub 2020 Aug 20.

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

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.
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http://dx.doi.org/10.3892/mco.2020.2119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453393PMC
November 2020

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

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

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

Clinical features and prognostic factors in patients with esophageal cancer with bone metastasis.

Oncol Lett 2020 Jan 22;19(1):717-724. Epub 2019 Nov 22.

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

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.
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http://dx.doi.org/10.3892/ol.2019.11142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6924156PMC
January 2020

Efficacy and safety of trabectedin for patients with unresectable and relapsed soft-tissue sarcoma in Japan: A Japanese Musculoskeletal Oncology Group study.

Cancer 2020 03 11;126(6):1253-1263. Epub 2019 Dec 11.

Department of Orthopaedic Surgery, The University of Tokyo Hospital, Tokyo, Japan.

Background: Although initial trabectedin (1.2 mg/m ) is safe and effective for patients with translocation-related sarcoma (TRS) in Japan, its efficacy in other types of soft-tissue sarcomas (STSs) remains unknown. This study retrospectively investigated its efficacy and safety through postmarketing surveillance of trabectedin in patients with unresectable and relapsed STS.

Methods: One hundred forty patients received intravenous trabectedin (1.2 mg/m on day 1 every 21 days) over the course of 24 hours. The primary endpoint was the efficacy and safety of trabectedin.

Results: Grade 3 or higher adverse events occurred in 100 patients (71%) and included hepatotoxicity (37.8%), neutropenia (32.8%), and rhabdomyolysis (3.6%). Patients at high risk for grade 3 or higher rhabdomyolysis (36%) were classified by height (≥170.3 cm) and age (≤32 years) through a classification and regression tree model (area under the curve, 0.9). The overall median progression-free survival (PFS) was 3.7 months; with respect to the histological type, the median PFS was 17.4 months for myxoid liposarcoma, 4.9 months for leiomyosarcoma, 5.6 months for synovial sarcoma, and 3.7 months for dedifferentiated liposarcoma. Histological type (liposarcoma/leiomyosarcoma [L-sarcoma] and TRS) and grade 3 neutropenia (but not grade 4) were associated with significantly improved PFS after trabectedin treatment (P = .003, P = .04, and P = .001). The median growth modulation index (GMI) was 0.91; 37 patients (36.7%) experienced a GMI > 1.33, and among patients with solitary fibrous tumors and undifferentiated pleomorphic sarcoma, 60% and 42.9%, respectively, had a GMI > 1.33. The median overall survival (OS) was 16.4 months. A GMI > 1.33 was associated with significantly improved OS (P = .0006).

Conclusions: Initial trabectedin at 1.2 mg/m has clinically meaningful benefits for patients with L-sarcoma and certain histological subtypes of TRS.
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http://dx.doi.org/10.1002/cncr.32661DOI Listing
March 2020

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

Antiferroelectric to Antiferroelectric-Relaxor Phase Transition in Calcium Strontium Sulfoaluminate.

Inorg Chem 2019 Nov 6;58(22):15410-15416. Epub 2019 Nov 6.

Department of Physics , Nagoya University , Nagoya 464-8602 , Japan.

Structural phase transitions of calcium strontium sulfoaluminate series, (CaSr)[AlO](SO) ((CS)AS-) with = 0.80-1.00, are systematically investigated by powder X-ray diffraction, dielectric measurements, and pyroelectric measurements, to clarify a phase diagram of (CS)AS- ( = 0.80-1.00). A pure strontium sulfoaluminate, (CS)AS-1.00, is found to undergo three phase transitions, which take place successively on cooling from a prototypical cubic phase with the symmetry of 3̅. Though the room-temperature phase of (CS)AS-1.00 was previously reported to be of polar 2, the pyroelectric measurements clarified a nonpolar character of the crystal symmetry. The dielectric measurements suggest a possibility of an antiferroelectric ground state of (CS)AS- in the Sr-rich compositions. As decreases, the ground state changes to a short-range-ordered state, implying a unique phase transition from the antiferroelectric state to the antiferroelectric-relaxor state. The present study provides an intriguing playground for designing new ferro/antiferroelectric materials.
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http://dx.doi.org/10.1021/acs.inorgchem.9b02495DOI Listing
November 2019

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

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

Transarterial chemoembolization as a substitute to radiofrequency ablation for treating Barcelona Clinic Liver Cancer stage 0/A hepatocellular carcinoma.

Oncotarget 2018 Apr 20;9(30):21560-21568. Epub 2018 Apr 20.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background And Aim: Transarterial chemoembolization (TACE) is the standard procedure for treating Barcelona clinic liver cancer (BCLC) stage B hepatocellular carcinoma (HCC). However, it is often carried out in the treatment of BCLC stage 0/A HCC for various reasons. This study aimed to elucidate the prognosis for BCLC stage 0/A HCC patients treated with TACE or with radiofrequency ablation (RFA).

Materials And Methods: The prognosis of 242 BCLC stage 0/A HCC patients within Milan criteria who underwent initially TACE or RFA were retrospectively analyzed using propensity score matching analysis.

Results: The analyses of baseline patient characteristics revealed that the maximum tumor size and the proportion of BCLC stage A patients were significantly higher in patients treated with TACE than in those treated with RFA (<0.001 and 0.047, respectively). After adjusting these factors using propensity score matching (1:3 matching), patients treated with TACE (n=32) and those treated with RFA (n=96) were further analyzed. The local recurrence rate was significantly higher in the TACE group than in the RFA group (<0.001). However, the overall survival (OS) in HCC patients treated with TACE was comparable to that in HCC patients treated with RFA (1 year, 93.5 vs. 95.8%; 3 years, 75.4 vs. 85.8%; 5 years, 61.8 vs. 70.7%; =0.196). Multivariate analyses followed by univariate analyses revealed that serum bilirubin level (=0.032), serum albumin level (=0.008), HBV-DNA (=0.013), and tumor number (=0.021) were independent predictors of OS.

Conclusion: TACE can substitute RFA at least in some patients with BCLC 0/A HCC.
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http://dx.doi.org/10.18632/oncotarget.25108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940395PMC
April 2018

Henoch-Schönlein Purpura Complicated by Hepatocellular Carcinoma.

Intern Med 2017 Nov 25;56(22):3041-3045. Epub 2017 Sep 25.

Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Japan.

Although Henoch-Schönlein purpura (HSP) is known to be accompanied by malignancies, cases with hepatobiliary cancer are extremely rare. A 62-year-old man with palpable purpura rapidly extending to both lower legs was admitted to our hospital. He was undergoing follow-up for cirrhosis caused by chronic hepatitis B virus infection and hepatocellular carcinoma (HCC). He had renal dysfunction with hematuria and proteinuria and abdominal pain. Based on the clinical presentation and skin biopsy findings, he was diagnosed with HSP. The administration of steroids resulted in the rapid improvement of the patient's symptoms and he was discharged 12 days after admission.
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http://dx.doi.org/10.2169/internalmedicine.8885-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5725858PMC
November 2017

Characteristics of patients with sorafenib-treated advanced hepatocellular carcinoma eligible for second-line treatment.

Invest New Drugs 2018 04 11;36(2):332-339. Epub 2017 Sep 11.

Department of Gastroenterology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.

Background Regorafenib has been investigated for its efficacy and safety as a second-line treatment in patients with advanced hepatocellular carcinoma (HCC). We assessed the characteristics of patients with HCC treated with sorafenib who might be eligible for second-line treatment in general and regorafenib in particular. Methods Patients with HCC treated with sorafenib were retrospectively analyzed. We defined second-line candidate patients as maintaining Child-Pugh A and ECOG-PS ≤1 at the time of sorafenib failure. We also defined regorafenib candidate patients as follows: 1) continuing sorafenib at the time of radiological progression, 2) maintaining Child-Pugh A and ECOG-PS ≤ 1 at the time of sorafenib failure, and 3) continuing sorafenib 400 mg or more without intolerable adverse events at least 20 days of the last 28 days of treatment. Results Of 185 patients, 130 (70%) and 69 (37%) were candidates for second-line treatment and regorafenib. Child-Pugh score 6 and ECOG-PS 1 at the time of starting sorafenib were significantly lower in both second-line treatment and regorafenib candidate patients. Moreover, hand-foot skin reaction and liver failure during sorafenib treatment were associated with significantly low and high probabilities, respectively, of both Child-Pugh score > 6 and ECOG-PS > 1 at the time of sorafenib failure. Conclusion Regorafenib candidate patients after sorafenib failure are limited, and generally fewer than those who are candidates for second-line treatment. A lower Child-Pugh score and a better ECOG-PS were predictors of eligibility for second-line therapy and regorafenib treatment in sorafenib-treated patients with advanced HCC patients.
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http://dx.doi.org/10.1007/s10637-017-0507-3DOI Listing
April 2018

Histone lysine methyltransferase G9a is a novel epigenetic target for the treatment of hepatocellular carcinoma.

Oncotarget 2017 Mar;8(13):21315-21326

Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.

Histone H3 lysine 9 dimethylation (H3K9me2) is mainly regulated by the histone lysine methyltransferase G9a and is associated with the repression of transcription. However, both the role of G9a and the significance of H3K9me2 in hepatocellular carcinoma (HCC) cells remain unclear. In this study, we conducted loss-of-function assay of G9a using short-hairpin RNA and pharmacological interference. Knockdown of G9a reduced H3K9me2 levels and impaired both HCC cell growth and sphere formation. However, transforming growth factor β1-induced epithelial mesenchymal transition (EMT) was not suppressed by G9a knockdown. Combined analyses of chromatin immunoprecipitation followed by sequencing and RNA-sequencing led to successful identification of 96 candidate epigenetic targets of G9a. Pharmacological inhibition of G9a by BIX-01294 resulted in both cell growth inhibition and induction of apoptosis in HCC cells. Intraperitoneal administration of BIX-01294 suppressed the growth of xenograft tumors generated by implantation of HCC cells in non-obese diabetic/severe combined immunodeficient mice. Immunohistochemical analyses revealed high levels of G9a and H3K9me2 in 36 (66.7%) and 35 (64.8%) primary HCC tissues, respectively. G9a expression levels were significantly positively correlated with H3K9me2 levels in tumor tissues. In contrast, in non-tumor tissues, G9a and H3K9me2 were only observed in biliary epithelial cells and periportal hepatocytes. In conclusion, G9a inhibition impairs anchorage-dependent and -independent cell growth, but not EMT in HCC cells. Our data indicate that pharmacological interference of G9a might be a novel epigenetic approach for the treatment of HCC.
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http://dx.doi.org/10.18632/oncotarget.15528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400586PMC
March 2017

Successful Treatment of Hepatocellular Carcinoma Complicated by Fanconi Anemia.

Case Rep Gastroenterol 2017 Jan-Apr;11(1):29-35. Epub 2017 Jan 27.

Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan.

A 42-year-old woman with liver tumors was referred to our hospital. Her condition was complicated by Fanconi anemia, and she had undergone total laryngectomy 8 years ago. On admission, contrast-enhanced computed tomography revealed hypervascular tumors in the right hepatic lobe. Ultrasound-guided tumor biopsy revealed that the tumor comprised moderately differentiated hepatocellular carcinoma. Although the patient exhibited preserved liver function (Child-Pugh A), complete blood count revealed severe pancytopenia. Eventually, the tumor was successfully treated by transcatheter arterial embolization (TAE). Both platelet transfusion and systemic administration of antibiotics were performed. She was discharged 35 days after TAE.
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http://dx.doi.org/10.1159/000454710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5301094PMC
January 2017

Impact of Radiofrequency Ablation-Induced Glisson's Capsule-Associated Complications in Patients with Hepatocellular Carcinoma.

PLoS One 2017 18;12(1):e0170153. Epub 2017 Jan 18.

Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: Radiofrequency ablation (RFA) is commonly used to locally treat hepatocellular carcinoma (HCC). However, when tumors are close to the Glisson's capsule, RFA may induce injury in this region, complicating therapeutic efforts. We investigated the impact of RFA-induced Glisson's capsule-associated complications on liver function and prognosis of HCC patients.

Methods: We retrospectively reviewed our patient database and found 170 early-stage HCC patients treated via RFA from April 2004 to December 2012. We defined RFA-induced Glisson's capsule-associated complication as lasting hepatic arterioportal (AP) fistula, major intrahepatic bile-duct dilatation (affecting two or more subsegments), or hepatic infarction. We also defined liver failure as initial occurrence of either total bilirubin increase (>3.0 mg/dL), uncontrolled ascites, or encephalopathy.

Results: In our cohort, 15 patients had RFA-induced Glisson's capsule-associated complications (incidence of related complications, with some overlap: lasting AP fistula, n = 9; major intrahepatic bile-duct dilatation, n = 7; and hepatic infarction, n = 2). The cumulative incidence of liver failure before stage progression was significantly higher and the median overall survival (OS) was significantly lower (52.3 months) in HCC patients with Glisson's capsule-associated complications than in those without Glisson's capsule-associated complications (95.0 months). In addition, multivariate analysis demonstrated that Glisson's capsule-associated complication was a significant independent factor associated with OS.

Conclusions: In this study, we have shown that early-stage HCC patients with RFA-induced Glisson's capsule-associated complications may have higher risks in poor prognosis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0170153PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5242538PMC
August 2017

Presence of non-hypervascular hypointense nodules on Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging in patients with hepatocellular carcinoma.

J Gastroenterol Hepatol 2017 Apr;32(4):908-915

Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background And Aims: Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) performed before curative therapy for hepatocellular carcinoma (HCC) can distinguish between intrahepatic distant recurrence and hypervascularization. This study aimed to retrospectively evaluate the presence of non-hypervascular hypointense nodules on hepatobiliary phase images from Gd-EOB-DTPA-enhanced MRI as a risk factor of the intrahepatic distant recurrence of early stage HCC following radiofrequency ablation (RFA).

Methods: A total of 132 patients who underwent preprocedural Gd-EOB-DTPA-enhanced MRI followed by initial RFA were retrospectively analyzed. Post-RFA intrahepatic distant recurrence, which excluded the hypervascularization of non-hypervascular hypointense nodules detected by preprocedural Gd-EOB-DTPA-enhanced MRI, was evaluated according to the presence of non-hypervascular hypointense nodules on preprocedural Gd-EOB-DTPA-enhanced MRI.

Results: Intrahepatic distant recurrence rates following RFA were higher in patients with non-hypervascular hypointense nodules (1-year: 22.5%, 2-year: 52.1%, 5-year: 89.1%) compared with in patients without non-hypervascular hypointense nodules (1-year: 7.0%, 2-year: 28.8%, 5-year: 48.7%). The presence of non-hypervascular hypointense nodules was associated with markedly increased cumulative recurrence rates of both identical and different subsegment intrahepatic distant recurrence, being an independent risk factor for post-RFA identical and different subsegment intrahepatic distant recurrence (identical: HR = 2.365, P = 0.027; different: HR = 3.276, P < 0.001).

Conclusion: The presence of non-hypervascular hypointense nodules on hepatobiliary phase images from Gd-EOB-DTPA-enhanced MRI obtained prior to RFA is an important predictive factor of intrahepatic distant recurrence following RFA of HCC.
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http://dx.doi.org/10.1111/jgh.13622DOI Listing
April 2017

Analysis of Sorafenib Outcome: Focusing on the Clinical Course in Patients with Hepatocellular Carcinoma.

PLoS One 2016 18;11(8):e0161303. Epub 2016 Aug 18.

Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan.

Background: Treatment outcomes of sorafenib therapy may greatly vary depending not only on tumor spread but also on past clinical processes prior to sorafenib therapy and timing of sorafenib administration in the past clinical course of hepatocellular carcinoma (HCC). We evaluated the efficacy of sorafenib in patients with HCC, taking into account of their past clinical courses.

Methods: Patients with HCC treated with sorafenib as a first-line systemic therapy, whose courses documented from the time of the initial diagnosis, were retrospectively analyzed.

Results: Of the 123 patients receiving sorafenib therapy at an advanced-stage, baseline characteristics differed including the rate of hepatitis C virus, Child-Pugh class, and status of intrahepatic lesions according to stage progression processes. Overall survival (OS) in patients progressed directly from the early-stage (15.3 months) was significantly longer than that in patients diagnosed at the advanced-stage (5.3 months, P = 0.022) and progressed from the intermediate-stages (6.0 months, P = 0.041). Of 105 patients diagnosed at the intermediate-stage on past clinical courses, OS of starting sorafenib therapy before progression to the advanced-stage (67 patients) was significantly longer than for patients starting sorafenib therapy only after progression to the advanced-stage (38 patients) (P = 0.015).

Conclusion: Characteristic differences between past stage progression processes might affect prognosis in advanced-stage HCC patients receiving sorafenib. Switching to sorafenib therapy before progression to the advanced-stage appears more effective than that after progression to the advanced-stage in patients diagnosed in the intermediate-stage on past clinical courses prior to sorafenib administration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161303PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4990272PMC
July 2017

Successful Management of Acute Liver Failure Patients Waiting for Liver Transplantation by On-Line Hemodiafiltration with an Arteriovenous Fistula.

Case Rep Gastroenterol 2016 Jan-Apr;10(1):139-45. Epub 2016 May 19.

Department of Gastroenterology and Nephrology, Chiba University Graduate School of Medicine, Chiba, Japan.

On-line hemodiafiltration (OLHDF) is one of the treatment options in the management of acute liver failure (ALF) in Japan. It is essential to avoid infection in the management of ALF. In fact, infection is one of the prognostic factors in ALF. In this report, we present a middle-aged Japanese man with ALF associated with benzbromarone use. He was successfully managed without infection until liver transplantation by creating an arteriovenous fistula for OLHDF. Utilizing an arteriovenous fistula for OLHDF, rather than inserting a vascular access catheter, is a beneficial option to avoid infectious diseases in the management of ALF.
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http://dx.doi.org/10.1159/000445186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4929385PMC
July 2016

Fatal Diaphragmatic Hernia following Radiofrequency Ablation for Hepatocellular Carcinoma: A Case Report and Literature Review.

Case Rep Oncol 2015 May-Aug;8(2):238-45. Epub 2015 May 28.

Department of Gastroenterology and Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan.

An 81-year-old man was admitted to our hospital because of right quadrant abdominal pain. On admission, his liver function was Child-Pugh grade C (10 points). Computed tomography (CT) revealed a diaphragmatic herniation of bowel loops into the right thoracic cavity, accompanied by pleural effusion. Although diaphragmatic hernia was successfully repaired by emergency surgery, he died of liver failure 23 days after the surgery. A retrospective reading of CT images revealed the presence of diaphragmatic injury after radiofrequency ablation (RFA) which had been conducted 33 months before the development of diaphragmatic hernia. Of importance, the lesion of the diaphragmatic injury was located on the estimated needle track of RFA for hepatocellular carcinomas in segment 5 and segment 5/8, but not adjacent to their ablation areas. Subsequently, diaphragmatic perforation had been observed 24 months before admission. This suggests that diaphragmatic hernia caused by RFA is not necessarily due to thermal damage of ablation and is possibly life-threatening, at least in some patients with an impaired liver function.
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http://dx.doi.org/10.1159/000431310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4478306PMC
June 2015

Combined targeting of mTOR and c-MET signaling pathways for effective management of epithelioid sarcoma.

Mol Cancer 2014 Aug 7;13:185. Epub 2014 Aug 7.

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

Background: Epithelioid sarcoma (EpS) is a high-grade malignant soft-tissue sarcoma characterized by local recurrences and distant metastases. Effective treatments for EpS have not been established and thus novel therapeutic approaches against EpS are urgently required. mTOR inhibitors exert antitumor effects on several malignancies but AKT reactivation by mTOR inhibition attenuates the antitumor effects of mTOR inhibitors. This reactivation is receptor tyrosine kinase (RTK)-dependent due to a release of negative feedback inhibition. We found that c-MET was the most highly activated RTK in two human EpS cell lines, Asra-EPS and VAESBJ. Here we investigated the functional and therapeutic relevance of mTOR and/or c-MET signaling pathways in EpS both in vitro and in vivo.

Methods: We first examined the effects of an mTOR inhibitor, RAD001 (everolimus), on cell proliferation, cell cycle, AKT/mTOR signaling, and xenograft tumor growth in EpS cell lines. Next, we determined whether RAD001-induced AKT reactivation was blocked by silencing of c-MET or treatment with a selective c-MET inhibitor, INC280. Finally, we evaluated the antitumor effects of RAD001 combined with INC280 on EpS cell lines compared with either single agent or control in vitro and in vivo.

Results: Constitutive AKT phosphorylation was observed in Asra-EPS and VAESBJ cells. RAD001 suppressed EpS cell growth by inducing cell cycle arrest but enhanced AKT phosphorylation, which resulted in intrinsic resistance to mTOR inhibitors. In both EpS cell lines, RAD001-induced AKT phosphorylation was dependent on c-MET signaling. INC280 inhibited phosphorylation of c-MET and its downstream molecules, and decreased RAD001-induced phosphorylation of both AKT and ERK in EpS. Compared with a single agent or control, the combination of RAD001 and INC280 exerted superior antitumor effects on the growth of EpS cell lines in vitro and in vivo.

Conclusions: Targeting of mTOR and c-MET signaling pathways significantly abrogates the growth of EpS in preclinical models and may be a promising therapeutic approach for patients with EpS.
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http://dx.doi.org/10.1186/1476-4598-13-185DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249599PMC
August 2014

Deflection of vascular endothelial growth factor action by SS18-SSX and composite vascular endothelial growth factor- and chemokine (C-X-C motif) receptor 4-targeted therapy in synovial sarcoma.

Cancer Sci 2014 Sep 3;105(9):1124-34. Epub 2014 Sep 3.

Department of Biology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan; Department of Orthopedics, Graduate School of Medicine, Osaka University, Osaka, Japan.

Synovial sarcoma (SS) is a malignant soft-tissue tumor characterized by the recurrent chromosomal translocation SS18-SSX. Vascular endothelial growth factor (VEGF)-targeting anti-angiogenic therapy has been approved for soft-tissue sarcoma, including SS; however, the mechanism underlying the VEGF signal for sarcomagenesis in SS is unclear. Here, we show that SS18-SSX directs the VEGF signal outcome to cellular growth from differentiation. Synovial sarcoma cells secrete large amounts of VEGF under spheroid culture conditions in autocrine fashion. SS18-SSX knockdown altered the VEGF signaling outcome, from proliferation to tubular differentiation, without affecting VEGF secretion, suggesting that VEGF signaling promoted cell growth in the presence of SS18-SSX. Thus, VEGF inhibitors blocked both host angiogenesis and spheroid growth. Simultaneous treatment with VEGF and chemokine (C-X-C motif) (CXC) ligand 12 and CXC receptor 4 inhibitors and/or ifosfamide effectively suppressed tumor growth both in vitro and in vivo. SS18-SSX directs the VEGF signal outcome from endothelial differentiation to spheroid growth, and VEGF and CXC receptor 4 are critical therapeutic targets for SS.
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http://dx.doi.org/10.1111/cas.12469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462399PMC
September 2014