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Tomoki Nakamura, Kunihiro Asanuma, Tomohito Hagi, Akihiro Sudo Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu City, Mie, 514-8507, JapanCorrespondence: Tomoki Nakamura, Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan, Tel +81592315022, Fax +81592315211, Email tomoki66@clin.medic.mie-u.ac.jpBackground: Inflammation plays a critical role in the development, progression, clinical presentation, and diagnosis of tumours. We compared the usefulness of the high-sensitivity modified Glasgow prognostic score (HS-mGPS) and mGPS in predicting oncological outcomes in patients with soft tissue sarcomas (STSs) who underwent primary surgical tumour resection.Methods: Between 2002 and 2018, 144 patients were included in the study. The mean age of the patients was 63 years. The mean follow-up period was 76 months.Results: The disease-specific survival (DSS) at five years was 71.5% in all patients. When patients were divided into three groups according to the HS-mGPS and mGPS, those with a score of 1 or 2 had a poorer DSS than those with a score of 0, respectively. When we compared the survival rate among the 98 patients with both HS-mGPS and mGPS of 0 and 21 patients with HS-mGPS of 1 and mGPS of 0, there was no significant difference in the prognosis. In multivariate analysis, larger tumour size and higher mGPS remained significant.Conclusion: mGPS is a reliable system for identifying patients at high risk for death in patients with STSs.Keywords: soft tissue sarcoma, modified Glasgow prognostic score, high-sensitivity modified Glasgow prognostic score, oncological outcome, C-reactive protein, albumin

Tomoki Nakamura,1 Kunihiro Asanuma,1 Motoshi Takao,2 Takashi Yamanaka,3 Hiroshi Koike,4 Toyofumi F Chen-Yoshikawa,5 Satoshi Tsukushi,6 Hiroaki Kuroda,7 Eiji Kozawa,8 Masaaki Sano,9 Hisaki Aiba,10 Ryoichi Nakanishi,11 Akihito Nagano,12 Kenji Yamada,13 Yoji Shido,14 Katsuhisa Kawanami,15 Yuya Izubuchi,16 Akihiro Sudo,1 Yoshihiro Nishida4,17 1Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan; 2Department of Thoracic Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan; 3Department of Radiology, Mie University Graduate School of Medicine, Tsu, Mie, Japan; 4Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; 5Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan; 6Department of Orthopedic Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan; 7Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan; 8Department of Orthopedic Surgery, Nagoya Memorial Hospital, Nagoya, Aichi, Japan; 9Department of Thoracic Surgery, Nagoya Memorial Hospital, Nagoya, Aichi, Japan; 10Department of Orthopedic Surgery, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Aichi, Japan; 11Department of Oncology, Immunology and Surgery, Graduate School of Medical Sciences, Nagoya City University, Nagoya, Aichi, Japan; 12Department of Orthopedic Surgery, Gifu University Graduate School of Medicine, Gifu, Gifu, Japan; 13Department of Musculoskeletal Oncology, Okazaki City Hospital, Okazaki, Aichi, Japan; 14Department of Orthopedic Surgery, Hamamatsu Medical University, Hamamatsu, Sizuoka, Japan; 15Department of Orthopedic Surgery, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan; 16Department of Orthopedics and Rehabilitation Medicine, University of Fukui Faculty of Medical Sciences, Eiheiji, Fukui, Japan; 17Department of Rehabilitation, Nagoya University Hospital, Nagoya, Aichi, JapanCorrespondence: Tomoki NakamuraDepartment of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, JapanTel +81592315022Fax +81592315211Email tomoki66@med.mie-u.ac.jpPurpose: Here, we investigated the oncological outcomes of lung metastasectomy and/or radiofrequency ablation (RFA) of 92 patients with soft tissue sarcoma (STS) at nine institutions.Methods: The study cohort included 65 men and 27 women with a mean age of 59 years at the time of metastasis. The mean follow-up duration was 51 months. All patients underwent metastasectomy and/or RFA for lung metastasis.Results: The mean maximum size of the initial lung metastasis was 14.6 mm. At the initial evaluation, 41 patients had a single metastasis, whereas 51 patients had multiple metastases. The mean number of metastasectomies and/or RFA was 2 per patient. A total of 70 patients underwent lung metastasectomy, whereas the other 13 underwent lung RFA. The remaining nine patients underwent both RFA and metastasectomy. The 5-year post-metastatic survival rate was 52%. The patients who underwent complete treatment for the initial metastasis had better post-metastatic survival rates than those who underwent incomplete treatment. A univariate analysis of all possible prognostic factors for complete treatment confirmed the predictive value of disease-free interval, metastasis at initial presentation, distribution, tumor size, and number of lung metastases. Of the 92 patients, 74 underwent complete treatment for initial metastasis; in these patients, univariate and multivariate analyses showed that a smaller tumor size and single-lung metastasis were prognostic factors for superior post-metastatic survival. The patients with a smaller (< 11.5 mm) single metastasis had better post-metastasis survival. The 5-year post-metastatic survival rates were 89.9% for patients with a smaller (< 11.5 mm) single metastasis versus 22.7% for patients with larger (> 11.5 mm) and multiple metastases.Discussion: We propose that complete treatment for lung metastasis in patients with STS may improve post-metastatic survival rates. Furthermore, tumor number and size are important variables for clinical decision-making.Keywords: lung metastasis, metastasectomy, radiofrequency ablation, soft tissue sarcoma

Koji Akeda, Norihiko Takegami, Junichi Yamada, Tatsuhiko Fujiwara, Akinobu Nishimura, Akihiro Sudo Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu, JapanCorrespondence: Koji AkedaDepartment of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, JapanTel +81-59-231-5022Fax +81-59-231-5211Email k_akeda@clin.medic.mie-u.ac.jpPurpose: Central sensitization (CS) is defined as the increased responsiveness of nociceptive neurons in the central nervous system to normal or subthreshold afferent input. CS has been proposed as an underlying mechanism of chronic pain in musculoskeletal disorders including low back pain (LBP). A Central Sensitization Inventory (CSI) has recently been developed for screening participants with CS. However, the association of CS with chronic LBP (cLBP) in the general population remains unknown. The purpose of this study was to investigate the association of CS with cLBP using the CSI in a population-based cohort of a Japanese mountain village.Participants and Methods: Participants aged more than 50 years were recruited from the inhabitants of a mountain village in Japan. Participants completed the following patient-reported outcome measures. Severity of CS was assessed by the CSI. LBP intensity was measured on a numerical rating scale (NRS). Health-related quality of life (QOL) was measured using the EuroQol 5-dimension (EQ-5D), EuroQol-visual analogue scales (EQ-VAS), and the Oswestry Disability Index (ODI). The association of CS and each parameter was statistically evaluated.Results: A total of 272 participants (average age: 72.1 years-old) were analyzed in this study, and 28.3% had cLBP. Average NRS, ODI and CSI scores were significantly higher in the cLBP group than in the without LBP (LBP−) group. There was a significant correlation between CSI and NRS scores (r=0.34, P< 0.0001), ODI (r=0.60, P< 0.0001), EQ5D (r=− 0.55, P< 0.0001) and EQ-VAS (r=− 0.52, P< 0.0001). A multiple regression analysis identified that ODI, EQ-VAS and age were factors significantly associated with CSI.Conclusion: The results of this study suggest that CS is involved in the pathological condition of cLBP in the local residents of a Japanese mountain village.Keywords: central sensitization, low back pain, Central Sensitization Inventory, general population

Tomoki Nakamura, Kunihiro Asanuma, Tomohito Hagi, Akihiro Sudo Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu, JapanCorrespondence: Tomoki Nakamura Department of Orthopaedic SurgeryMie University Graduate School of Medicine, Tsu, Mie, JapanTel +81-592315022Fax +81-592315211Email tomoki66@clin.medic.mie-u.ac.jpIntroduction: The median survival time of patients with advanced soft tissue sarcoma (STS) is typically < 12 months. Since 2012, physicians were able to administer second- and/or third-line treatment easily in Japan, following the approval of new drugs, namely, pazopanib, eribulin, and trabectedin. We investigated the real-life experience of adults with advanced STS who received systemic therapy after the approval of the aforementioned new drugs.Patients and Methods: We retrospectively evaluated 34 patients (median age: 66 years) with primary STS arising at the extremities/trunk or unresectable local and/or metastatic STS between 2012 and 2019. We evaluated the tumor response and patient survival after initial systemic treatment.Results: As first-line treatment, doxorubicin and ifosfamide and other drugs were administered to 7 and 27 patients, respectively. Of 31 patients with an evaluable tumor response, partial response was observed in 2 (6.5%) patients, and 16 (52%) patients showed stable disease at 8 weeks. The 1- and 2-year survival rates were 51.4% and 28.4%, respectively. The median overall survival (OS) time was 12.6 months. Tumor response to first-line therapy was related to patient prognosis.Conclusion: New drugs may be beneficial for patients with advanced STS. When patients cannot receive anthracycline-based chemotherapy because of a high risk of side effects, we believe that the aforementioned drugs may be administered as the first-line treatment.Keywords: soft tissue sarcoma, eribulin, pazopanib, trabectedin, efficacy, overall survival

Tomoki Nakamura,1 Jun Sugaya,2 Norifumi Naka,3 Hiroshi Kobayashi,4 Tomotake Okuma,5 Toshiyuki Kunisada,6 Kunihiro Asanuma,1 Hedetatsu Outani,7 Shunji Nishimura,8 Hiroyuki Kawashima,9 Toru Akiyama,10 Taketoshi Yasuda,11 Shinji Miwa,12 Akihiro Sudo,1 Takafumi Ueda13 1Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu 514-8507, Japan; 2Department of Musculoskeletal Oncology, National Cancer Center Hospital, Chuo-ku, Tokyo 104-0045, Japan; 3Musculoskeletal Oncology Service, Osaka International Cancer Institute, Chuo-ku, Osaka 541-8567, Japan; 4Department of Orthopaedic Surgery, The University of Tokyo Hospital, Bunkyo-ku, Tokyo 113-8655, Japan; 5Department of Musculoskeletal Oncology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Bunkyo-ku, Tokyo 113-8677, Japan; 6Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan; 7Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; 8Department of Orthopaedic Surgery, Kindai University Hospital, Osaka-Sayama, Osaka 589-8511, Japan; 9Division of Orthopaedic Surgery, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata 951-8510, Japan; 10Department of Orthopaedic Surgery, Saitama Medical Center, Jichi Medical University, Saitama, Saitama 330-8503, Japan; 11Department of Orthopaedic Surgery, University of Toyama, Toyama 930-0194, Japan; 12Department of Orthopaedic Surgery, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8641, Japan; 13Department of Orthopaedic Surgery, Osaka National Hospital, Chuo-ku, Osaka 540-0006, JapanCorrespondence: Tomoki NakamuraDepartment of Orthopedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, JapanTel +81-592315022Fax +81-592315211Email tomoki66@clin.medic.mie-u.ac.jpBackground: The outcomes of unplanned surgery for bone sarcomas have not been frequently discussed. However, it is important to recognize patterns, treatment, and clinical outcomes of unplanned surgeries for patients with bone sarcomas. This multicenter study aimed to characterize the clinical outcomes of patients with bone sarcomas who underwent unplanned surgeries.Patients and Methods: Data of 43 patients with bone sarcomas who underwent unplanned surgery between 2006 and 2017 were obtained from 23 hospitals in Japan. These included 18 cases of osteosarcoma, 9 of Ewing sarcoma, 8 of chondrosarcoma, and 6 of undifferentiated pleomorphic sarcoma. The study included 28 men and 15 women, with a mean age of 46 years. The mean follow-up duration was 59 months.Results: The main primary tumor sites were the femur (n = 19), spine (n = 6), pelvis (n = 5), tibia (n = 3), and humerus (n = 3). The primary diagnoses were benign bone tumor (n = 24), trauma (n = 7), bone metastasis (n = 5), osteomyelitis (n = 4), degeneration (n=2), and unknown (n = 1). As unplanned surgeries, curettage, with or without bone graft, was performed in 26 patients; internal fixation was performed in 7; spinal surgery in 5; arthroplasty in 4; and arthroscopy in one. Thirty-eight patients received additional standard treatments. Thirty-four of these patients underwent surgical tumor resections, including amputation (n = 10), and the remaining 4 received radiotherapy or carbon ion radiotherapy as additional standard treatments. The 5-year disease-specific survival (DSS) rates in patients with osteosarcoma, Ewing sarcoma, and chondrosarcoma were 65.5%, 58.3%, and 72.9%, respectively. Twelve (27.9%) patients developed local recurrences (LR); among the total 43 patients studied, the 5-year DSS rates were significantly worse for those who developed LR compared to those who did not (p = 0.03). The 5-year DSS rates in patients with and without LR were 44% and 73.8%, respectively.Conclusion: We recommend that patients who have undergone unplanned surgery be administered standard treatment, including the option of amputation because herein, LR was shown to be a risk factor for decreased DSS.Keywords: bone sarcoma, unplanned surgery, local recurrence, osteosarcoma, Ewing sarcoma, chondrosarcoma

According to the Polarity Hypothesis, the presence or absence of a processing cost for Scalar Inferences (SIs) depends on their polarity. This hypothesis predicts, among other things, that the processing of lower-bounding SIs should not be affected by cognitive load the same way upper-bounding SIs are. To date, evidence in support of this prediction comes from the comparison between upper-bounding and lower-bounding SIs elicited by disparate scalar words. In this paper, we report on two dual-task experiments testing this prediction in a more controlled way by comparing upper-bounding and lower-bounding SIs arising from the same scalar words or scale-mates operating over the same dimension. Results show that, for these more minimal comparisons, lower-bounding SIs involve comparable cognitive demands as their upper-bounding counterparts. These findings challenge the idea that load effects are consistently modulated by SI polarity and suggest instead that these effects are relatively consistent across different types of SIs.

Kouji Kita,1 Tomoki Nakamura,1 Takashi Yamanaka,2 Keisuke Yoshida,1 Tomohito Hagi,1 Kunihiro Asanuma,1 Atsuhiro Nakatsuka,2 Akihiro Sudo11Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu, Japan; 2Department of Radiology, Mie University Graduate School of Medicine, Tsu, JapanBackground: Treatment of metastatic bone tumors is challenging due to the morbidity associated with patients with metastasis. The present case report described a patient with successful treatment of bone metastasis using cryoablation with plate and cementation to prevent fracture for bone metastasis of leiomyosarcoma in the mid-shaft of the femur.Case report: The metastatic tumor was located at intramedullary lesion of the femur. At first, cryoablation was performed under local anesthesia. After one week after cryoablation, curettage and fixation with plate and cementation were performed to prevent fracture. Tumor cells were not observed in the histopathological findings of the curettage tissue. Four years after cryoablation, there was no recurrence and the patient could walk without any support.Conclusion: We suggest that a tumor with limited cancellous bone and of a small size may undergo cryoablation. The prevention of fracture after cryoablation should be considered.Keywords: leiomyosarcoma, bone metastasis, cryoablation

Koji Akeda,1 Junichi Yamada,1 Erikka T Linn,2 Akihiro Sudo,1 Koichi Masuda2 1Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, Tsu City, Mie 514-8507, Japan; 2Department of Orthopaedic Surgery, University of California, San Diego, La Jolla, CA 92093-0863, USA Abstract: Low back pain (LBP) is now regarded as the first cause of disability worldwide and should be a priority for future research on prevention and therapy. Intervertebral disc (IVD) degeneration is an important pathogenesis of LBP. Platelet-rich plasma (PRP) is an autologous blood concentrate that contains a natural concentration of autologous growth factors and cytokines and is currently widely used in the clinical setting for tissue regeneration and repair. PRP has great potential to stimulate cell proliferation and metabolic activity of IVD cells in vitro. Several animal studies have shown that the injection of PRP into degenerated IVDs is effective in restoring structural changes (IVD height) and improving the matrix integrity of degenerated IVDs as evaluated by magnetic resonance imaging (MRI) and histology. The results of this basic research have shown the great possibility that PRP has significant biological effects for tissue repair to counteract IVD degeneration. Clinical studies for evaluating the effects of the injection of PRP into degenerated IVDs for patients with discogenic LBP have been reviewed. Although there was only one double-blind randomized controlled trial, all the studies reported that PRP was safe and effective in reducing back pain. While the clinical evidence of tissue repair of IVDs by PRP treatment is currently lacking, there is a great possibility that the application of PRP has the potential to lead to a feasible intradiscal therapy for the treatment of degenerative disc diseases. Further large-scale studies may be required to confirm the clinical evidence of PRP for the treatment of discogenic LBP. Keywords: intervertebral disc, intervertebral disc degeneration, platelet-rich plasma, PRP, low back pain

Kazuma Okuno,1,2 Takao Matsubara,1 Tomoki Nakamura,1 Takahiro Iino,1 Takuya Kakimoto,1 Kunihiro Asanuma,1 Akihiko Matsumine,1,3 Akihiro Sudo1 1Department of Orthopedic Surgery, Mie University Graduate School of Medicine, Tsu, Mie, Japan; 2Department of Orthopedic Surgery, Ise Red Cross Hospital, Ise, Japan; 3Department of Orthopedic Surgery, Fukui University Graduate School of Medicine, Fukui, Japan Purpose: We investigated the effect of carbonic anhydrase IX (CA IX) inhibitor under hypoxia and normoxia in SaOS2 human osteosarcoma cell line. We also evaluated the expression of CA IX in 27 patients diagnosed with osteosarcoma.Materials and methods: CA IX expression in SaOS2 cells cultured under different oxygen tensions was analyzed by Western blotting. To evaluate the effect of CA IX inhibitor, MTS cell viability assay was performed after cells were treated with various concentrations of doxorubicin with or without a CA IX inhibitor. Finally, CA IX expression in patient-derived osteosarcoma samples was evaluated by immunohistochemistry.Results: Treatment with CA IX inhibitor significantly suppressed cell proliferation and migration under hypoxic conditions. CA IX expression was observed in 81% of 27 patients. The 5-year survival rates in patients with high and low stain scores were 43.8% and 81.8%, respectively.Conclusion: CA IX inhibitors have the potential to suppress cell proliferation, migration, and chemoresistance. Keywords: hypoxia, osteosarcoma, carbonic anhydrase IX, inhibitor

Experimental studies show that the tendency to derive Scalar Implicatures (SIs) varies considerably between individuals: some individuals accept sentences that are literally true but carry a false SI, while others systematically reject them. The question of what factors drive these differences is crucial to understanding the mechanisms involved in SIs and currently at the center of numerous discussions. To date, there is no agreement on how to quantify individual differences in SI rates. In this article, we show how a hierarchical Bayesian modelling approach can be used to quantify subjects' preferences observed in the results of a truth value judgement task that investigated intra-individual and inter-individual variability in the rates of upper-bounding and lower-bounding SIs associated with the -scale. The results provide further evidence that the robustness of an SI is modulated within individuals by certain linguistic features, such as the presence of negation.

Tomoki Nakamura,1 Akihiko Matsumine,1 Motoshi Takao,2 Atsuhiro Nakatsuka,3 Takao Matsubara,1 Kunihiro Asanuma,1 Akihiro Sudo1 1Department of Orthopedic Surgery, Mie University Graduate School of Medicine, 2Department of Thoracic Surgery, 3Department of Interventional Radiology, Mie University Hospital, Tsu, Japan Abstract: Metastasectomy represents the standard treatment for improving survival in patients with lung metastases (LMs) from bone (BS) or soft-tissue sarcoma (STS). Recently, radiofrequency ablation (RFA) of the LMs has been proved to be a useful option which can promise the similar effect to metastasectomy. The aim of this study was to determine prognostic factors, including tumor volume doubling time (TVDT), for post-metastatic survival in BS and STS patients treated with metastasectomy and/or RFA of the lung. Forty-eight patients with LMs were retrospectively reviewed. The mean age of the patients at the time of LMs was 56 years. The cohort comprised 27 male and 21 female patients. Eight of the 48 patients had LMs at the point of initial presentation. The mean follow-up period after commencing the treatment for LMs was 37 months. The mean maximum diameter of the initial LMs was 11 mm. The mean number of LMs was 4. The TVDT was calculated using a method originally described by Schwartz. At last follow-up, 5 patients had no evidence of disease, 3 patients were still alive with disease, and 32 patients had died of disease. The 3-year and 5-year post-metastatic survival rates were 32% and 16.8%, respectively. In a Cox univariate analysis, the size (P=0.04) and number of LMs (P