Publications by authors named "Yukihide Iwamoto"

551 Publications

Malignant Transformation of Giant Cell Tumor of Bone 7 years After Initial Surgery: A Case Report and Literature Review.

JBJS Case Connect 2021 04 20;11(2). Epub 2021 Apr 20.

Department of Orthopaedic Surgery, Kyushu Rosai Hospital, Japan.

Case: A 64-year-old man with a history of giant cell tumor of bone (GCTB) in the fibula 7 years earlier developed a recurrence with histologic features of osteosarcoma. Both the primary GCTB and the secondary osteosarcoma were found to have the H3F3A gene mutation. Despite immediate above-the-knee amputation, the patient died of respiratory failure because of lung metastases 3 months later.

Conclusion: This is the first report of proven H3F3A mutation in both the primary GCTB and the secondary osteosarcoma in the same case. Clinicians should consider secondary malignancy in patients presenting with a lesion at the site of a previously treated GCTB after a long interval.
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http://dx.doi.org/10.2106/JBJS.CC.20.00417DOI Listing
April 2021

Cardiac Tamponade as an Unusual Initial Clinical Manifestation of CIC-DUX4 Sarcoma.

Am J Case Rep 2021 Feb 28;22:e929349. Epub 2021 Feb 28.

Department of Orthopedic Surgery, Kyushu Rosai Hospital, Kitakyushu, Fukuoka, Japan.

BACKGROUND CIC-rearranged sarcoma (CRS) is a recently described subset of undifferentiated small-round-cell sarcomas of bone and soft tissue. DUX4 is the most common gene involved in CRS. CRS usually presents in the soft tissue of the trunk and extremities, and is recognized as being clinically aggressive, with poor prognosis. Our case highlights an unusual presentation of CRS with cardiac tamponade. CASE REPORT A 48-year-old man presented with hypotension caused by hemorrhagic cardiac tamponade. ¹⁸F-fluorodeoxyglucose-positron emission tomography showed increased uptake in multiple lesions, including lesions in the left proximal humerus and several lymph nodes. Biopsy specimens of the humerus revealed proliferation of round-shaped cells. In addition, CIC-DUX4 gene rearrangement was detected by polymerase chain reaction and direct sequencing, leading to a diagnosis of cardiac tamponade caused by CRS. Although the patient received systemic chemotherapy as well as radiotherapy to the mediastinal lesion and left humerus, he died of progressive disease 12 months after diagnosis. CONCLUSIONS Because CRS is a recently proposed entity that is distinct from Ewing sarcoma, the clinical presentation and outcome of CRS has not been well documented in the literature. This is the first case report of CRS presenting as cardiac tamponade. Although cardiac tamponade due to metastatic sarcoma is extremely rare, CRS can be included in the differential diagnosis.
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http://dx.doi.org/10.12659/AJCR.929349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931773PMC
February 2021

Long-term outcomes of spinal meningioma resection with outer layer of dura preservation technique.

J Clin Neurosci 2021 Jan 13;83:68-70. Epub 2020 Dec 13.

Department of Orthopedic Surgery, Graduate School of Medical Sciences, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.

Spinal meningioma is a common benign intradural spinal tumor. It has been reported that the local recurrence rate after surgical resection increases with longer follow-up duration. Simpson grade 1 resection could reduce the risk of recurrence, but this procedure needs dural reconstruction, which would cause cerebrospinal fluid (CSF) leakage or iatrogenic spinal cord injury. Saito et al. reported dura preservation technique to reduce the risk of CSF leakage, in which the meningioma together with the inner layer of the dura is removed and the outer layer is preserved for simple dural closure. The long-term outcomes with this technique have never been investigated. In this study, we retrospectively analyzed the data of 38 surgically treated patients (dura preservation technique, 12 patients; Simpson grade 2 resection, 26 patients) to assess the long-term recurrence rate (mean, 121.5 months; range, 60-228 months). The local recurrence rate in the dura preservation group was 8.3% (1 of 12 cases), which was similar to that in Simpson grade 2 resection group (2 of 26 cases [7.7%]). Although this case series did not indicate the significant difference in the recurrence rates between the dura preservation group and Simpson grade 2 group, we consider that this technique still has advantages for surgically less invasiveness in terms of dural reconstruction which is necessary for Simpson grade 1 and higher possibility of complete resection of tumors compared with Simpson grade 2 resection.
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http://dx.doi.org/10.1016/j.jocn.2020.11.026DOI Listing
January 2021

Risk Factors of Periprosthetic Infection in Patients with Tumor Prostheses Following Resection for Musculoskeletal Tumor of the Lower Limb.

J Clin Med 2020 Sep 28;9(10). Epub 2020 Sep 28.

Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka-shi, Fukuoka 812-8582, Japan.

Tumor prostheses for the lower limb following resection of musculoskeletal tumors is useful limb salvage management; however, as compared with routine total joint replacement, an increased incidence of deep periprosthetic infection of tumor prosthesis has been observed. The risk factors for periprosthetic infection of tumor prosthesis remain unclear. This study examines the risk factors and outcomes of periprosthetic infection. This was a retrospective observational study including 121 patients (67 males and 54 females) who underwent tumor prosthesis of the lower limb after resection of musculoskeletal tumors between 1 January 2000 and 30 November 2018. Among a total of 121 tumor prostheses, 7 were total femurs, 47 were proximal femurs, 47 were distal femurs, and 20 were proximal tibias. The incidence of postoperative infection and its risk factors were analyzed. Forty-five patients (37%) had osteosarcoma, 36 patients (30%) had bone metastasis, and 10 patients (8%) had soft-tissue tumors invading the bone. The mean operating time was 229 min, and the mean follow-up duration was 5.9 years. Deep periprosthetic infection was noted in 14 patients (12%). In the multivariate analysis, the risk factors for postoperative infection were identified as being male (hazard ratio [HR], 11.2316; = 0.0100), soft-tissue tumor (HR, 52.2443; = 0.0003), long operation (HR, 1.0056; = 0.0184), and radiotherapy (HR, 6.5683; = 0.0476). The incidence of periprosthetic infection in our institution was similar to that of previous reports. Patients undergoing tumor prosthesis of the lower limb who were male, had a soft-tissue tumor, were predicted to have a long operation, and who underwent radiation, had an increased possibility of postoperative infection.
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http://dx.doi.org/10.3390/jcm9103133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601076PMC
September 2020

Meniscal ramp lesions should be considered in anterior cruciate ligament-injured knees, especially with larger instability or longer delay before surgery.

Knee Surg Sports Traumatol Arthrosc 2020 Nov 7;28(11):3569-3575. Epub 2020 Aug 7.

Department of Orthopaedic Surgery, Kyushu Rosai Hospital, 1-1 Sonekita-machi, Kokura-minami-ku, Kitakyushu, 800-0296, Japan.

Purpose: To determine the incidence of meniscal ramp lesions in an anterior cruciate ligament (ACL) injured knees and to clarify whether ramp lesions are related to chronic ACL deficiency and increased knee instability.

Methods: Consecutive ACL injured patients were evaluated arthroscopically for a ramp lesion via a trans-notch view and evidence of menisco-capsular injury was recorded. Other concomitant injuries to the knee were also noted. Incidence of meniscal ramp lesions, delay before surgery, and anterior-posterior stability was analyzed. All patients underwent bilateral KT-2000 evaluation.

Results: One hundred and three consecutive ACL injured patients with a mean age of 24 years were included in this study. In total, a ramp lesion was found in 10 knees (9.7%) via a trans-notch view. None of these lesions could be identified by the standard view from the anterolateral portal. Other medial meniscal lesions were found in 26 knees (25.2%) by standard arthroscopic viewing. The ramp lesion group had significantly longer delay before surgery with a median of 191 days (p < 0.01) as well as a larger side-to-side difference of KT-2000 measurement (7.3 ± 1.8 mm; p < 0.01), compared with the intact medial meniscus group (53 days and 5.5 ± 1.5 mm, respectively).

Conclusion: Ramp lesions that were identified using a trans-notch view were not visualized with standard arthroscopic views. Increased anterior tibial translation and longer delay before surgery were seen in knees with ramp lesions. Careful inspection of the posteromedial menisco-capsular region is required as hidden menisco-capsular lesions may occur which may result in residual knee instability.

Level Of Evidence: Level II.
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http://dx.doi.org/10.1007/s00167-020-06161-8DOI Listing
November 2020

Desmoplastic Fibroblastoma Invading the Humerus.

Case Rep Orthop 2020 23;2020:9780263. Epub 2020 May 23.

Department of Orthopaedic Surgery, Kyushu Rosai Hospital, Japan.

Desmoplastic fibroblastoma (DFB) is an uncommon, benign, soft tissue tumor. The tumor most often presents as a slowly growing, painless soft tissue mass and is usually small. There have been only a few reports of patients with DFB who presented with bone invasion. Herein, we report the case of a 66-year-old woman with DFB with bone invasion in her left axilla. A lump under the left axilla was detected and was associated with pain and limited range of motion (ROM) of the shoulder. Computed tomography showed a soft tissue mass with invasion of the adjacent left humerus. Magnetic resonance imaging revealed a lesion with low signal intensity on T1- and T2-weighted images, and weak internal enhancement on postcontrast T1-weighted images with fat suppression. Histologic evaluation of a preoperative needle biopsy revealed DFB with FOSL1 expression. The tumor was marginally excised. Postoperative outpatient follow-up demonstrated a significant improvement in pain and ROM of the shoulder and no recurrence after 1 year. Even though DFB with bone invasion can cause pronounced clinical symptoms with pain and limited ROM, we conclude that simple excision is an adequate treatment.
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http://dx.doi.org/10.1155/2020/9780263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271290PMC
May 2020

Assessment of baseline bone turnover marker levels and response to risedronate treatment: Data from a Japanese phase III trial.

Bone Rep 2020 Jun 25;12:100275. Epub 2020 Apr 25.

Department of Orthopedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Risedronate increases bone mineral density (BMD) and reduces fracture risk, but treatment response may depend on the baseline state of bone turnover. Data regarding the selection of therapeutic drugs or the prediction of therapeutic effects with baseline levels of bone turnover markers (BTMs) as a reference are insufficient. We hypothesized that when the baseline levels of BTMs are higher, baseline BMD might be lower, changes in BMD at 12 months after risedronate treatment might be higher, and the reduction of fracture incidence might be greater. This study aimed to analyze the data of a phase III clinical trial of risedronate from Japan to investigate the relationships between baseline BTM levels and (1) baseline BMD, (2) changes in BMD at 12 months after the start of treatment, and (3) the incidence of new vertebral fractures.

Methods: This post-hoc analysis included 788 postmenopausal women with osteoporosis whose baseline BTM levels as well as baseline and endpoint BMDs were measured. Relationships between baseline BTM levels and BMD at baseline and 12 months after risedronate treatment and new vertebral fractures were examined. One-way analysis of variance, two-tailed Student's -test, and Fisher's exact test were used to analyze the data.

Results: Baseline BMD showed a significant upward trend when baseline BTM levels were lower in the analysis by tertiles. New vertebral fractures tended to occur in patients with prevalent vertebral fractures, but the relationship between new fractures and BTM levels was not statistically significant. Regardless of BTM types, BMD percentage increments (%) and increments (g/cm) with the 12-month treatment were high when pretreatment BTM levels were high (P < 0.0001), and a >5.0% increase in BMD was observed even if baseline BTM levels were within the normal range. A new vertebral fracture occurred in only six patients (0.77%), and there was not enough statistical power to clarify the relationship between baseline BTM levels and fracture risk reduction.

Conclusions: When pretreatment BTM levels increased, baseline BMD tended to be lower and the increase in BMD with 12-month risedronate treatment was higher. However, BMD could still be increased even if the baseline BTM levels are within the normal range. Combined with available evidence, baseline BTMs may not have an important role in deciding the optimal therapy. To elucidate the relationship between baseline BTM levels and long-term fracture risk, it will be necessary to conduct more large-scale studies with a longer follow-up period in severe osteoporotic patients with a high fracture risk.

Mini Abstract: We evaluated the significance of baseline bone turnover markers in the response to risedronate treatment. The increase in the bone mineral density (BMD) with the 12-month treatment may be higher when the state of bone turnover at baseline is higher, and BMD could still be increased even if the baseline bone turnover is within the normal range.
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http://dx.doi.org/10.1016/j.bonr.2020.100275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240327PMC
June 2020

Definitive radiation therapy in patients with unresectable desmoid tumors: a systematic review.

Jpn J Clin Oncol 2020 May;50(5):568-573

Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Desmoid tumors are rare soft tissue tumors. Wide local excision has been the standard surgical treatment for desmoid tumors. However, this procedure results in high local recurrence rates, so non-surgical treatments should be considered. The aim of this systematic review was to evaluate the effect of radiation therapy on patients with desmoid tumors, especially those with unresectable disease.

Methods: We evaluated studies published between 1 January 1990 and 31 August 2017 and cited in PubMed and Ichushi (in Japanese). All studies evaluating the effect of radiation therapy on desmoid tumors were included. Data regarding radiation dose, recurrence and adverse events were recorded.

Results: Among 218 identified studies, only 6 were finally included in this review. Local control was achieved in 253 of 317 patients with unresectable or unresected tumors who underwent definitive radiation therapy (the crude rate of local control was 79.8%). Toxicity was evaluated in patients who underwent definitive radiation therapy or surgery plus radiation therapy. One of the most common acute complications was skin toxicity. Frequent late complications of radiation therapy included fibrosis/contracture/joint stiffness, skin disorders, lymphedema and pain. Six patients developed secondary malignancies in the radiation field.

Conclusions: In patients treated unsuccessfully with surgery, watchful waiting and pharmacotherapy, radiation therapy may be an option as salvage therapy because of the high rate of local control. Because desmoid tumors frequently develop in young individuals, children and young patients who receive radiation therapy for the treatment of desmoid tumors should be followed up on a long-term basis with periodic monitoring for late radiation toxicities.
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http://dx.doi.org/10.1093/jjco/hyaa007DOI Listing
May 2020

Surgery-related predictable risk factors influencing postoperative clinical outcomes for thoracic myelopathy caused by ossification of the posterior longitudinal ligament: a multicenter retrospective study.

J Neurosurg Spine 2019 Dec 27:1-7. Epub 2019 Dec 27.

1Department of Orthopedic Surgery, Graduate School of Medical Sciences.

Objective: Compression of the spinal cord by thoracic ossification of the posterior longitudinal ligament (T-OPLL) often causes severe thoracic myelopathy. Although surgery is the most effective treatment for T-OPLL, problems associated with surgical intervention require resolution because surgical outcomes are not always favorable, and a small number of patients experience deterioration of their neurological status after surgery. The aim of the present study was to examine the surgery-related risk factors contributing to poor clinical outcomes for myelopathy caused by T-OPLL.

Methods: Data were extracted from the records of 55 patients with thoracic myelopathy due to T-OPLL at institutions in the Fukuoka Spine Group. The mean follow-up period was 5.3 years. Surgical outcomes were assessed using the Japanese Orthopaedic Association (JOA) scale. To investigate the definitive factors associated with surgical outcomes, univariate and multivariate regression analyses were performed with several patient-related and surgery-related factors, including preoperative comorbidities, radiological findings, JOA score, surgical methods, surgical outcomes, and complications.

Results: Neurological status improved in 33 patients (60.0%) and deteriorated in 10 patients (18.2%) after surgery. The use of instrumentation was significantly associated with an improved outcome. In the comparison of surgical approaches, posterior decompression and fusion resulted in a significantly higher neurological recovery rate than did anterior decompression via a posterior approach and fusion or decompression alone. It was also found that postoperative neurological status was significantly poorer when there were fewer instrumented spinal levels than decompression levels. CSF leakage was a predictable risk factor for deterioration following surgery.

Conclusions: It is important to identify preventable risk factors for poor surgical outcomes for T-OPLL. The findings of the present study suggest that intraoperative CSF leakage and a lower number of instrumented spinal fusion levels than decompression levels were exacerbating factors for the neurological improvement in T-OPLL surgery.
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http://dx.doi.org/10.3171/2019.10.SPINE19831DOI Listing
December 2019

Integrated exome and RNA sequencing of dedifferentiated liposarcoma.

Nat Commun 2019 12 12;10(1):5683. Epub 2019 Dec 12.

Laboratory of DNA Information Analysis, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan.

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.
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http://dx.doi.org/10.1038/s41467-019-13286-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6908635PMC
December 2019

Ten-year follow-up results of perioperative chemotherapy with doxorubicin and ifosfamide for high-grade soft-tissue sarcoma of the extremities: Japan Clinical Oncology Group study JCOG0304.

BMC Cancer 2019 Sep 6;19(1):890. Epub 2019 Sep 6.

Kyushu Rosai Hospital, Kitakyushu, 800-0296, Japan.

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 of DXR plus 10 g/m 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.
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http://dx.doi.org/10.1186/s12885-019-6114-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728960PMC
September 2019

Predictive factors of mortality of patients with fragility hip fractures at 1 year after discharge: A multicenter, retrospective study in the northern Kyushu district of Japan.

J Orthop Surg (Hong Kong) 2019 Sep-Dec;27(3):2309499019866965

1 Department of Orthopaedic Surgery, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.

Purpose: Fragility hip fractures (FHFs) are associated with a high risk of mortality, but the relative contribution of various factors remains controversial. This study aimed to evaluate predictive factors of mortality at 1 year after discharge in Japan.

Methods: A total of 497 patients aged 60 years or older who sustained FHFs during follow-up were included in this study. Expected variables were finally assessed using multivariable Cox proportional hazards models.

Results: The 1-year mortality rate was 9.1% (95% confidence interval: 6.8-12.0%, = 45). Log-rank test revealed that previous fractures ( = 0.003), Barthel index (BI) at discharge ( = 0.011), and place-to-discharge ( = 0.004) were significantly associated with mortality for male patients. Meanwhile, body mass index (BMI; = 0.023), total Charlson comorbidity index (TCCI; = 0.005), smoking ( = 0.007), length of hospital stay (LOS; = 0.009), and BI ( = 0.004) were the counterparts for females. By multivariate analyses, previous vertebral fractures (hazard ratio (HR) 3.33; = 0.044), and BI <30 (HR 5.42, = 0.013) were the predictive variables of mortality for male patients. BMI <18.5 kg/m (HR 2.70, = 0.023), TCCI ≥5 (HR 2.61, = 0.032), smoking history (HR 3.59, = 0.018), LOS <14 days (HR 13.9; = 0.007), and BI <30 (HR 2.76; = 0.049) were the counterparts for females.

Conclusions: Previous vertebral fractures and BI <30 were the predictive variables of mortality for male patients, and BMI <18.5 kg/m, TCCI ≥5, smoking history, LOS <14 days, and BI <30 were those for females. Decreased BI is one of the independent and preventable risk factors. A comprehensive therapeutic approach should be considered to prevent deterioration of activities of daily living and a higher risk of mortality.
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http://dx.doi.org/10.1177/2309499019866965DOI Listing
June 2020

Selective inhibition of mutant IDH1 by DS-1001b ameliorates aberrant histone modifications and impairs tumor activity in chondrosarcoma.

Oncogene 2019 10 12;38(42):6835-6849. Epub 2019 Aug 12.

Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.

Chondrosarcoma is the second most common malignant bone tumor. It is characterized by low vascularity and an abundant extracellular matrix, which confer these tumors resistance to chemotherapy and radiotherapy. There are currently no effective treatment options for relapsed or dedifferentiated chondrosarcoma, and new targeted therapies need to be identified. Isocitrate dehydrogenase (IDH) mutations, which are detected in ~50% of chondrosarcoma patients, contribute to malignant transformation by catalyzing the production of 2-hydroxyglutarate (2-HG), a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Mutant IDH inhibitors are therefore potential novel anticancer drugs in IDH mutant tumors. Here, we examined the efficacy of the inhibition of mutant IDH1 as an antitumor approach in chondrosarcoma cells in vitro and in vivo, and investigated the association between the IDH mutation and chondrosarcoma cells. DS-1001b, a novel, orally bioavailable, selective mutant IDH1 inhibitor, impaired the proliferation of chondrosarcoma cells with IDH1 mutations in vitro and in vivo, and decreased 2-HG levels. RNA-seq analysis showed that inhibition of mutant IDH1 promoted chondrocyte differentiation in the conventional chondrosarcoma L835 cell line and caused cell cycle arrest in the dedifferentiated JJ012 cell line. Mutant IDH1-mediated modulation of SOX9 and CDKN1C expression regulated chondrosarcoma tumor progression, and DS-1001b upregulated the expression of these genes via a common mechanism involving the demethylation of H3K9me3. DS-1001b treatment reversed the epigenetic changes caused by aberrant histone modifications. The present data strongly suggest that inhibition of mutant IDH1 is a promising therapeutic approach in chondrosarcoma, particularly for the treatment of relapsed or dedifferentiated chondrosarcoma.
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http://dx.doi.org/10.1038/s41388-019-0929-9DOI Listing
October 2019

Osteosarcoma in patients over 50 years of age: Multi-institutional retrospective analysis of 104 patients.

J Orthop Sci 2020 Mar 30;25(2):319-323. Epub 2019 May 30.

The Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.

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.
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http://dx.doi.org/10.1016/j.jos.2019.04.008DOI Listing
March 2020

Macrophage centripetal migration drives spontaneous healing process after spinal cord injury.

Sci Adv 2019 05 15;5(5):eaav5086. Epub 2019 May 15.

Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.

Traumatic spinal cord injury (SCI) brings numerous inflammatory cells, including macrophages, from the circulating blood to lesions, but pathophysiological impact resulting from spatiotemporal dynamics of macrophages is unknown. Here, we show that macrophages centripetally migrate toward the lesion epicenter after infiltrating into the wide range of spinal cord, depending on the gradient of chemoattractant C5a. However, macrophages lacking interferon regulatory factor 8 (IRF8) cannot migrate toward the epicenter and remain widely scattered in the injured cord with profound axonal loss and little remyelination, resulting in a poor functional outcome after SCI. Time-lapse imaging and P2X/YRs blockade revealed that macrophage migration via IRF8 was caused by purinergic receptors involved in the C5a-directed migration. Conversely, pharmacological promotion of IRF8 activation facilitated macrophage centripetal movement, thereby improving the SCI recovery. Our findings reveal the importance of macrophage centripetal migration via IRF8, providing a novel therapeutic target for central nervous system injury.
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http://dx.doi.org/10.1126/sciadv.aav5086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520026PMC
May 2019

A randomized phase III trial of denosumab before curettage for giant cell tumor of bone: Japan Clinical Oncology Group Study JCOG1610.

Jpn J Clin Oncol 2019 Apr;49(4):379-382

Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.

A randomized phase III trial was planned to commence in October 2017. Resectable giant cell tumor of bone (GCTB) without possible postoperative large bone defect has been treated by curettage with local adjuvant treatment, with the local recurrence rate found to be as high as 24.6-30.8%. The aim of this study is to confirm the superiority of preoperative denosumab for patients with GCTB without possible postoperative large bone defect. A total of 106 patients will be accrued from 34 Japanese institutions over 5 years. The primary endpoint is relapse-free survival (RFS). Secondary endpoints include overall survival, joint-preserved survival, local RFS, metastasis-free survival, adverse events, serious adverse events, surgical and postoperative complications, and discontinuation of denosumab. This trial is conducted by the Bone and Soft Tissue Tumor Study Group in the Japan Clinical Oncology Group and has been registered in the UMIN Clinical Trials Registry as UMIN000029451 [http://www.umin.ac.jp/ctr/index.htm].
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http://dx.doi.org/10.1093/jjco/hyz004DOI Listing
April 2019

Prospective comparison of various radiological response criteria and pathological response to preoperative chemotherapy and survival in operable high-grade soft tissue sarcomas in the Japan Clinical Oncology Group study JCOG0304.

World J Surg Oncol 2018 Aug 10;16(1):162. Epub 2018 Aug 10.

Kyushu Risai Hospital, Kitakyushu, 800-0296, Japan.

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).
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http://dx.doi.org/10.1186/s12957-018-1462-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6086997PMC
August 2018

Clinical outcome of primary giant cell tumor of bone after curettage with or without perioperative denosumab in Japan: from a questionnaire for JCOG 1610 study.

World J Surg Oncol 2018 Aug 8;16(1):160. Epub 2018 Aug 8.

Department of Orthopaedic Surgery, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.

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.
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http://dx.doi.org/10.1186/s12957-018-1459-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6083623PMC
August 2018

Nationwide multicenter follow-up cohort study of hip arthroplasties performed for osteonecrosis of the femoral head.

Int Orthop 2018 07 12;42(7):1661-1668. Epub 2018 May 12.

The Japanese Investigation Committee on Osteonecrosis of the Femoral Head under the Ministry of Health, Labour and Welfare of Japan, Chiyoda, Tokyo, Japan.

Purpose: To identify modifiable factors related to post-operative dislocation and reoperation in patients with osteonecrosis of the femoral head (ONFH) in a large cohort.

Methods: We studied 4995 hip arthroplasties: total hip arthroplasty (THA) was performed in 79% of patients; bipolar hemiarthroplasty (BP), 17%; total resurfacing arthroplasty (tRS), 3%; and hemi-resurfacing arthroplasty (hRS), 1%. A new type of BP (accounting for 49% of BPs) comprised a femoral component with a polished or smooth, small-diameter (approximately 10 mm) neck with a round or oval axial cut surface and no sharp corners.

Results: The infection rate was relatively low (0.56%) even though 58% of cases of ONFH were associated with systemic steroid use, a known risk factor for infection. Post-operative dislocation occurred in 4.3% of cases, with re-operation needed in 3.9%. The dislocation rate was related to surgery type: 5.2% in THA, 0.9% in BP, and 0% in tRS and hRS. Among total arthroplasties with six month or longer follow-up (3670 THAs and 159 tRSs), the risk factors for post-operative dislocation were younger (≤ 40 years) or older (≥ 62 years) age, higher body weight, posterolateral approach, and smaller prosthetic head diameter. Regarding the need for re-operation, higher body weight and surgery type were identified as risk factors.

Conclusions: The relatively high dislocation rate of 5.2% in THA is a cause for concern. The identified risk factors for dislocation should be considered when selecting THA for treatment. Prosthesis survivorship in hRSs was inferior to that in BPs or THAs. Body weight also affected the survivorship of hip arthroplasties.
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http://dx.doi.org/10.1007/s00264-018-3980-1DOI Listing
July 2018

Effect of cartilaginous endplates on extruded disc resorption in lumbar disc herniation.

PLoS One 2018 17;13(4):e0195946. Epub 2018 Apr 17.

Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: The aim of this study was to investigate the clinicopathologic features of lumbar disc herniation (LDH) with endplate degeneration and the association between cartilaginous fragments and inflammatory response to the herniated disc.

Summary Of Background Data: LDH often involves hyaline cartilage fragments pulled from the vertebral endplates. Modic changes are closely associated with LDH that contains hyaline cartilage, and cartilaginous endplates seem to affect resorption of the herniated disc.

Methods: A total of 78 patients who underwent microscopic discectomy between 9 and 16 weeks after an occurrence of LDH were reviewed. Modic changes, disc degeneration, high-intensity zone, and vertebral corner defect were evaluated using magnetic resonance imaging (MRI). Histopathological observations of cartilaginous endplates and inflamed granulation tissue in the herniated disc were made. In cases with inflamed granulation tissue, neovascularization and macrophage infiltration were also evaluated using immunohistochemical analysis.

Results: Modic changes were observed in approximately one-third of the patients (26 cases: type 1, 7; type 2, 17; and type 3, 2). Cartilaginous endplates were observed in 32 cases (41%) and in the majority of cases with Modic changes compared with cases without Modic changes (65%, p = 0.001). Although inflamed granulation tissue was observed in 60 cases (77%), no significant differences were detected in patient age and the composition of the herniated material. Immunohistochemical analysis showed that fewer CD34-positive capillaries and CD68-positive cells were found in cases with cartilaginous fragments compared with those without cartilaginous fragments (p < 0.001). In addition, a higher immunoreactivity to CD34 and CD68 was found in herniated discs <25% of whose area was occupied by cartilaginous endplates compared with discs whose area was occupied at 25% or more (p < 0.001).

Conclusion: There is an association between LDH with endplate degeneration and cartilaginous herniation, with Modic type 2 predominating. Furthermore, neovascularization and macrophage infiltration, especially if the amount of cartilage is high, are likely to be less frequent in cartilaginous herniation, leading to failure in the spontaneous remission of clinical symptoms.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0195946PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5903620PMC
July 2018

Cancer-testis antigens are predominantly expressed in uterine leiomyosarcoma compared with non-uterine leiomyosarcoma.

Oncol Lett 2018 Jan 26;15(1):441-446. Epub 2017 Oct 26.

Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Fukuoka 812-8581, Japan.

Leiomyosarcomas account for ~24% of all adult sarcomas, and develop predominantly either in the uterus [uterine leiomyosarcoma (ULMS)] or in deep soft tissue or the retroperitoneum [non-uterine leiomyosarcoma (NULMS)]. Leiomyosarcomas are relatively chemoresistant tumors, and the prognosis of patients with leiomyosarcomas is poor. Cancer-testis (CT) antigens are considered promising immunotherapeutic targets because of their restricted expression in normal tissue, except in the testis. Little is known about the expression of CT antigens in leiomyosarcomas. In the present study, the protein expression of the CT antigens MAGE family member A (MAGEA)1, MAGEA3, MAGEA4, G antigen 7 (GAGE7) and cancer/testis antigen 1 (NY-ESO-1) in ULMS and NULMS were investigated using immunohistochemistry (IHC), and their expression profiles compared. In ULMS and NULMS, positive expression was observed in 11/32 (31%) and 1/31 (3%; MAGEA1), 15/32 (47%) and 5/31 (16%; MAGEA3), 11/32 (34%) and 3/31 (10%; MAGEA4), 23/32 (72%) and 11/31 (35%; GAGE7) and 3/32 (9%) and 0/31 (0%; NY-ESO-1), respectively. The ULMSs demonstrated significantly higher positive expression of MAGEA1 (P=0.0034), MAGEA3 (P=0.0141), MAGEA4 (P=0.0319) and GAGE7 (P=0.0054) compared with the NULMSs. The ULMSs also had significantly higher IHC scores for MAGEA1 (P=0.0023), MAGEA3 (P=0.0474), MAGEA4 (P=0.011), GAGE7 (P=0.0319) and NY-ESO-1 (P=0.0437). The results of the present study support the potential utility of MAGEA1, MAGEA3, MAGEA4 and GAGE7 in ULMS and GAGE7 in NULMS as immunotherapeutic targets.
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http://dx.doi.org/10.3892/ol.2017.7274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5769386PMC
January 2018

Anterolateral rotatory instability correlates tunnel position after anterior cruciate ligament reconstruction using bone-patellar tendon-bone graft.

World J Orthop 2017 Dec 18;8(12):913-921. Epub 2017 Dec 18.

Department of Orthopaedic Surgery, Kyushu University, Fukuoka 812-8582, Japan.

Aim: To quantitatively assess rotatory and anterior-posterior instability after anterior cruciate ligament (ACL) reconstruction using bone-patellar tendon-bone (BTB) autografts, and to clarify the influence of tunnel positions on the knee stability.

Methods: Single-bundle ACL reconstruction with BTB autograft was performed on 50 patients with a mean age of 28 years using the trans-tibial (TT) ( = 20) and trans-portal (TP) ( = 30) techniques. Femoral and tibial tunnel positions were identified from the high-resolution 3D-CT bone models two weeks after surgery. Anterolateral rotatory translation was examined using a Slocum anterolateral rotatory instability test in open magnetic resonance imaging (MRI) 1.0-1.5 years after surgery, by measuring anterior tibial translation at the medial and lateral compartments on its sagittal images. Anterior-posterior stability was evaluated with a Kneelax3 arthrometer.

Results: A total of 40 patients (80%) were finally followed up. Femoral tunnel positions were shallower ( < 0.01) and higher ( < 0.001), and tibial tunnel positions were more posterior ( < 0.05) in the TT group compared with the TP group. Anterolateral rotatory translations in reconstructed knees were significantly correlated with the shallow femoral tunnel positions (R = 0.42, < 0.01), and the rotatory translations were greater in the TT group (3.2 ± 1.6 mm) than in the TP group (2.0 ± 1.8 mm) ( < 0.05). Side-to-side differences of Kneelax3 arthrometer were 1.5 ± 1.3 mm in the TT, and 1.7 ± 1.6 mm in the TP group (N.S.). Lysholm scores, KOOS subscales and re-injury rate showed no difference between the two groups.

Conclusion: Anterolateral rotatory instability significantly correlated shallow femoral tunnel positions after ACL reconstruction using BTB autografts. Clinical outcomes, rotatory and anterior-posterior stability were overall satisfactory in both techniques, but the TT technique located femoral tunnels in shallower and higher positions, and tibial tunnels in more posterior positions than the TP technique, thus increased the anterolateral rotation. Anatomic ACL reconstruction with BTB autografts may restore knee function and stability.
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http://dx.doi.org/10.5312/wjo.v8.i12.913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745434PMC
December 2017

SWI/SNF Chromatin-remodeling Complex Status in SMARCB1/INI1-preserved Epithelioid Sarcoma.

Am J Surg Pathol 2018 03;42(3):312-318

Departments of Anatomic Pathology.

The SWI/SNF chromatin-remodeling complex, which is composed of evolutionarily conserved core subunits such as SMARCB1/INI1 (INI1), SMARCA4/BRG1 (BRG1), SMARCC1/BAF155 (BAF155), and SMARCC2/BAF170 (BAF170), can be viewed as the prototype of an epigenetic regulator of gene expression that is involved in tumor suppression. Epithelioid sarcoma, which classified as a tumor of uncertain differentiation, shows an almost complete loss of INI1. However, some cases of epithelioid sarcoma have preserved INI1, and the clinicopathologic features of these cases are uncertain. To date, there has been no investigation focused on the SWI/SNF chromatin-remodeling complex in INI1-preserved epithelioid sarcoma cases. First, an investigation of INI1 immunoexpression statuses in 60 formalin-fixed paraffin-embedded epithelioid sarcoma specimens (proximal type, 29 cases; conventional type, 31 cases) was performed. In the available INI1-preserved epithelioid sarcoma cases, we analyzed the BRG1, BAF155, and BAF170 protein expressions. INI1 preservation was observed in 6 of 29 (21%) proximal-type and 2 of 31 (6%) conventional-type epithelioid sarcoma cases. Six cases of INI1-preserved epithelioid sarcomas of proximal type were available for further immunohistochemical study. One proximal type showed loss of BAF170, and 2 proximal-type cases revealed loss of BRG1 with preservation of the other remaining core subunit proteins. One proximal-type case showed a mosaic pattern of BRG1 and loss of BAF155. However, in the remaining 2 proximal-type cases, all core subunit proteins were preserved. Overall, these results suggest that loss of expression of SWI/SNF chromatin-remodeling complex proteins has an important role in tumorigenesis. The remaining 2 INI1-preserved epithelioid sarcoma cases may have had other abnormalities causing dysfunction of SWI/SNF chromatin remodeling.
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http://dx.doi.org/10.1097/PAS.0000000000001011DOI Listing
March 2018

Methotrexate-Related Lymphoproliferative Disorder Presenting with Severe Swelling of the Elbow Joint: A Case Report.

JBJS Case Connect 2017 Jul-Sep;7(3):e65

1Departments of Orthopaedic Surgery (T.H., M.O., M.E., T.M., Y.N., K.O., J.-i.F., A.O., and Y.I.), Hematology and Oncology (G.Y.), and Otorhinolaryngology (M.Y.), Kyushu University Hospital, Fukuoka, Japan2Departments of Anatomic Pathology and Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Case: A patient with rheumatoid arthritis (RA) who was being treated with methotrexate (MTX) therapy presented with severe swelling of the left elbow. Magnetic resonance imaging showed a tumor-like lesion around the elbow joint. Fluorodeoxyglucose positron emission tomography indicated multiple lesions in the lung and the lymph nodes. An open biopsy of a cervical lymph node was performed, and MTX-related lymphoproliferative disorder (MTX-LPD) was diagnosed. After cessation of the MTX therapy, the elbow swelling regressed, and the patient was in remission of MTX-LPD.

Conclusion: MTX-LPD should be considered in the differential diagnosis when a patient with RA develops severe joint swelling while on MTX therapy.
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http://dx.doi.org/10.2106/JBJS.CC.17.00002DOI Listing
August 2018

Genome-wide Association Study of Idiopathic Osteonecrosis of the Femoral Head.

Sci Rep 2017 11 8;7(1):15035. Epub 2017 Nov 8.

Division of Integrative Pathophysiology, Proteo-Science Center, Ehime University Graduate School of Medicine, Shitsukawa, Toon-city, Ehime, 791-0295, Japan.

Idiopathic osteonecrosis of the femoral head (IONFH) is an ischemic disorder that causes bone necrosis of the femoral head, resulting in hip joint dysfunction. IONFH is a polygenic disease and steroid and alcohol have already known to increase its risk; however, the mechanism of IONFH remains to be elucidated. We performed a genome-wide association study using ~60,000 subjects and found two novel loci on chromosome 20q12 and 12q24. Big data analyses identified LINC01370 as a candidate susceptibility gene in the 20q12 locus. Stratified analysis by IONFH risk factors suggested that the 12q24 locus was associated with IONFH through drinking capacity. Our findings would shed new light on pathophysiology of IONFH.
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http://dx.doi.org/10.1038/s41598-017-14778-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5678103PMC
November 2017

Characteristics of patients with fragility hip fractures in the northern Kyushu district in Japan: a multicenter prospective registry based on an electronic data capture system.

J Bone Miner Metab 2018 Sep 12;36(5):596-604. Epub 2017 Oct 12.

Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.

Osteoporosis has become a worldwide public health problem, in part due to the fact that it increases the risk of fragility hip fractures (FHFs). The epidemiological assessment of FHFs is critical for their prevention; however, datasets for FHFs in Japan remain scarce. This was a multicenter, prospective, observational study in the northern district of Kyushu Island. Inclusion criteria were age > 60 years with a diagnosis of FHF and acquisition of clinical data by an electronic data capture system. Of 1294 registered patients, 1146 enrolled in the study. Nearly one third of patients (31.8%) had a history of previous fragility fractures. The percentage of patients receiving osteoporosis treatment on admission was 21.5%. Almost all patients underwent surgical treatment (99.1%), though fewer than 30% had surgery within 48 h after hospitalization. Bone mineral density (BMD) was evaluated during hospitalization in only 50.4% of patients. The rate of osteoporosis treatment increased from 21.5% on admission to 39.3% during hospitalization. The main reasons that prescribers did not administer osteoporosis treatment during hospitalization were forgetfulness (28.4%) and clinical judgment (13.6%). Age and female ratio were significantly higher in patients with previous FHFs than in those without. There was a significant difference in the rate of osteoporosis treatment or L-spine BMD values in patients with or without previous FHFs on admission. In conclusion, this study confirmed that the evaluation and treatment of osteoporosis and FHFs is still suboptimal in Japan, even in urban districts.
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http://dx.doi.org/10.1007/s00774-017-0869-9DOI Listing
September 2018

MAGEA4 expression in bone and soft tissue tumors: its utility as a target for immunotherapy and diagnostic marker combined with NY-ESO-1.

Virchows Arch 2017 Sep 26;471(3):383-392. Epub 2017 Jul 26.

Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka, 812-8582, Japan.

Cancer-testis (CT) antigens have promise as targets for immunotherapy, because of their restricted expression in tumor or testis tissue. MAGEA4 is both a MAGE family member and a CT antigen, and has attracted attention as a potential immunotherapeutic target. We investigated MAGEA4 expression by immunohistochemistry in bone and soft tissue tumor specimens that consisted of 35 malignant or intermediate and 24 benign histological subtypes, in order to evaluate its possible utility as an immunotherapy target and its potential use as a diagnostic marker when combined with another CT antigen, NY-ESO-1. Among these tumors, MAGEA4 was detected in 82.2% of synovial sarcomas, 67.7% of myxoid liposarcomas, 43.8% of osteosarcomas, 41.4% of angiosarcomas, 24.6% of malignant peripheral nerve sheath tumors (MPNSTs), and 21.4% of chondrosarcomas. NY-ESO-1 expression was found in 88.2% of myxoid liposarcomas, 61.1% of synovial sarcomas, 31.3% of osteosarcomas, 21.4% of pleomorphic liposarcomas, 16.7% of desmoplastic small round cell tumors, and 14.3% of chondrosarcomas. Benign tumors and non-tumorous tissue, except for testis tissue, did not express MAGEA4 or NY-ESO-1. Combined use of MAGEA4 and NY-ESO-1 increased the sensitivity, specificity, positive predictive values, and negative predictive values for distinguishing synovial sarcoma from spindle cell tumors and other mimicking tumors, compared to individual use of MAGEA4 or NY-ESO-1. Our results support the immunotherapy targeting MAGEA4 or NY-ESO-1 can be an ancillary therapy in the above-mentioned tumors, and the potential utility of MAGEA4 as an ancillary diagnostic marker for synovial sarcoma combined with NY-ESO-1.
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http://dx.doi.org/10.1007/s00428-017-2206-zDOI Listing
September 2017

Alteration of PDGFRβ-Akt-mTOR pathway signaling in fibrosarcomatous transformation of dermatofibrosarcoma protuberans.

Hum Pathol 2017 09 13;67:60-68. Epub 2017 Jul 13.

Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. Electronic address:

Dermatofibrosarcoma protuberans (DFSP) is a cutaneous mesenchymal tumor of intermediate malignancy and fibroblastic/myofibroblastic differentiation. Fibrosarcomatous (FS) component is a high-grade component of DFSP. The detailed oncogenic difference between DFSP and FS components is not clear. We thus investigated the Akt-mTOR pathway in both components. We used 65 tumor samples obtained from 65 patients. The phosphorylation of Akt-mTOR pathway proteins (Akt, mTOR, 4EBP1, and S6RP) and PDGFRα/β was assessed by immunohistochemical staining, the results of which were confirmed by Western blotting. The immunohistochemical results were as follows: in ordinary DFSP components, p-PDGFRα-positive tumors were 41.9% (18/43 cases), p-PDGFRβ 55.8% (24/43 cases), p-Akt 51.2% (22/43 cases), p-mTOR 39.5% (17/43 cases), p-4EBP1 46.5% (20/43 cases), and p-S6RP 41.8% (18/43 cases); in DFSP components of FS-DFSP, 52.6% (10/19 cases), 47.4% (9/19 cases), 52.6% (10/19 cases), 36.8% (7/19 cases), 52.6% (10/19 cases), and 52.6% (10/19 cases); and in FS components, 45.5% (10/22 cases), 36.4% (8/22 cases), 72.7% (16/22 cases), 54.5% (12/22 cases), 72.7% (16/22 cases), and 68.2% (15/22 cases), respectively. There were significant positive correlations of the phosphorylation of most of the Akt-mTOR pathway proteins (p-Akt, p-mTOR, p-4EBP1, and p-S6RP) with each other (P < .05). Phospho-PDGFRβ was well correlated with the phosphorylation of Akt-mTOR pathway proteins in DFSP components of ordinary and FS-DFSPs, but these correlations were weaker in FS components. This study suggested the association of activation of Akt-mTOR pathway proteins and PDGFR with the progression of DFSP to FS. The Akt-mTOR pathway is thus a potential therapeutic target in imatinib-resistant DFSP/FS.
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http://dx.doi.org/10.1016/j.humpath.2017.07.001DOI Listing
September 2017