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Pile foundations are usually subjected to cyclic loading which could possibly causes a significant degradation of the friction mobilised along the pile shaft. Most of the experimental studies devoted to analysing the behaviour of the pile-soil interfaces under cyclic loading tests are performed at a few hundred of cycles. However, a large number of cycles of the order of hundreds of thousands may cause a severe degradation of pile capacity. The present work aims to study the effect of cyclic loading parameters on the evolution of shaft friction of pile subjected to a large number of cycles. The experimental study is based on a physical modelling in a calibration chamber of axial cyclic loading of single pile jacked into sand under a large number of cycles, up to 105. It is found that cyclic amplitude, confining pressure and soil density have a significant effect on the evolution of skin friction along the pile shaft at a large number of cycles. [ABSTRACT FROM AUTHOR]

Objectives: The current study compared the outcome after orthopaedic surgeries in patients with rheumatoid arthritis receiving Janus kinase inhibitors (JAKis) versus biologic disease-modifying anti-rheumatic drugs (bDMARDs)., Methods: This was a retrospective observational study of Japanese patients with rheumatoid arthritis. Sixty-two patients with rheumatoid arthritis using JAKi preoperatively underwent orthopaedic surgeries. Using propensity score matching, these 62 patients were matched with 62 patients using bDMARDs preoperatively. The number of adverse events was counted. We also examined whether the drug-withholding period in the JAKi-treated group was associated with the occurrence of major postoperative adverse events, namely inflammatory flares and delayed wound healing., Results: JAKi-treated patients had a higher incidence of postoperative flares than bDMARD-treated patients (29% versus 12.1%, P = .01). The incidences of postoperative complications other than flares were not significantly different between the two groups. Among the JAKi-treated group, a longer perioperative drug-withholding period (≥11 days) was associated with a higher incidence of postoperative flares (P = .04). The incidences of delayed wound healing and surgical site infection were not associated with the duration of the JAKi-withholding period., Conclusions: JAKi-treated patients had a higher incidence of postoperative flares than bDMARD-treated patients. A total of ≥11 days of drug withdrawal was associated with postoperative flares., (© Japan College of Rheumatology 2024. Published by Oxford University Press.)

Introduction: Tumor size is an important factor in determining the appropriate clinical management of intradural-extramedullary schwannoma. A tumor volume reduction may be achieved by conservative targeted therapy instead of invasive surgery if a molecular event related to tumor size is discovered. Insulin-like growth factor II messenger RNA-binding protein 3 (IMP3), an oncofetal tumor-associated antigen that is expected to be a target for immunotherapy, was focused on in this study., Methods: The IMP3 status was assessed by immunohistochemistry in 64 samples of intradural-extramedullary schwannoma, and the correlation between IMP3 expression and tumor size was evaluated., Results: Immunohistochemically, high IMP3 expression was observed in ～85% of schwannomas. The maximum tumor diameter of the high IMP3 expression group was significantly larger than that of the low IMP3 expression group (34.3 mm vs 18.5 mm, p =0.002). The receiver operating characteristic curve demonstrated that a maximum tumor diameter of 24 mm was a predictable factor for IMP3 expression (sensitivity, 0.7; 1-specificity, 0.2; area under the curve, 0.82)., Conclusions: Upregulated IMP3 expression was associated with large tumor size, suggesting a possible therapeutic approach., Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest., (Copyright © 2023 The Japanese Society for Spine Surgery and Related Research.)

Purpose Symptomatic postoperative spinal epidural hematoma (POSEH) is a complication of spine surgery that occurs infrequently but may cause ongoing serious neurological damage. Due to the narrow entry portal, the risk of hematoma is increased after microendoscopic laminectomy (MEL) compared with conventional open surgery, and the risk might be even higher for multivertebral MEL (m-MEL). The purpose of this study was to clarify the factors affecting the development of POSEH after m-MEL and identify the optimal order for the decompression of vertebral bodies. Methods A total of 313 patients who underwent m-MEL from 2016 to 2020 were retrospectively assessed. The cohort comprised 238 patients who underwent two-level MEL, 67 who underwent three-level MEL, and eight who underwent four-level MEL. Symptomatic POSEH was defined as the presence of an epidural hematoma at the surgical site on MRI with symptoms such as lower extremity pain or muscle weakness. We elucidated the incidence of POSEH at each vertebral level and investigated the relationship between POSEH and possible risk factors such as clinical and operative variables. Results There were 41 patients in the POSEH group and 272 patients in the non-POSEH group. Seven patients in the POSEH group underwent reoperation. The occurrence of POSEH was related to the number of decompressed vertebral bodies. Patients who underwent L2/3 and L3/4 decompression at the end of the procedure also showed a higher incidence of POSEH at the surgical level. Conclusion In patients undergoing m-MEL, treatment of the upper lumbar vertebrae at the end of decompression surgery might be a risk factor for symptomatic POSEH. The incidence of POSEH was particularly increased at L2/3, suggesting that L2/3 decompression should not be performed at last and that careful hemostasis should be applied., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Soejima et al.)

Background: Rheumatoid arthritis (RA) often causes cervical spine lesions as the disease condition progresses, which induce occipital neuralgia or cervical myelopathy requiring surgical interventions. Meanwhile, patients with RA are susceptible to infection or other complications in the perioperative period because they frequently have comorbidities and use immunosuppressive medications. However, the risk factors or characteristics of patients with RA who experience perioperative complications after cervical spine surgery remain unknown. A risk factor analysis of perioperative complications in patients with RA who underwent primary cervical spine surgery was conducted in the present study., Methods: A total of 139 patients with RA who underwent primary cervical spine surgery from January 2001 to March 2020 were retrospectively investigated. Age and height, weight, serum albumin, serum C-reactive protein, American Society of Anesthesiologists Physical Status (ASA-PS), Charlson comorbidity index, medications used, cervical spine lesion, surgery time, bleeding volume, and procedures were collected from medical records to compare the patients with complications to those without complications after surgery. The risk factors for perioperative complications were assessed by univariate and multivariate logistic regression analysis., Results: Twenty-eight patients (20.1%) had perioperative complications. Perioperative complications were significantly associated with the following factors [data presented as odds ratio]: lower height [0.928, p=0.007], higher ASA-PS [2.296, p=0.048], longer operation time [1.013, p=0.003], more bleeding volume [1.004, p=0.04], higher rates of vertical subluxation [2.914, p=0.015] and subaxial subluxation (SAS) [2.507, p=0.036], occipito-cervical (OC) fusion [3.438, p=0.023], and occipito-cervical/thoracic (long) fusion [8.021, p=0.002] in univariate analyses. In multivariate analyses, lower height [0.915, p=0.005], higher ASA-PS [2.622, p=0.045] and long fusion [7.289, p=0.008] remained risk factors. High-dose prednisolone use [1.247, p=0.028], SAS [6.413, p=0.018], OC fusion [17.93, p=0.034], and long fusion [108.1, p<0.001] were associated with severe complications., Conclusions: ASA-PS and long fusion could be indicators predicting perioperative complications in patients with RA after cervical spine surgery. In addition, cervical spine lesions requiring OC fusion or long fusion and high-dose prednisolone use were suggested to be risk factors for increasing severe complications., (© 2022. The Author(s).)

Aims  This study was aimed to compare the perioperative and postoperative outcomes of patients who underwent posterior decompression for multi-segmental lumbar spinal stenosis by microendoscopic laminotomy (MEL) versus spinous process-splitting laminotomy (SPSL) retrospectively. Methods We retrospectively reviewed 73 consecutive patients who underwent two or three levels MEL (n=51) or SPSL (n=22) for lumbar spinal stenosis between 2012 and 2018. The perioperative outcomes were operative time, intraoperative blood loss, length of postoperative hospital stay, complications, and reoperation rate. The postoperative outcomes were evaluated using a visual analog scale (VAS) and the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) scores at one year postoperatively. Results The mean follow-up time was 26.6 months in MEL and 35.6 months in SPSL. The mean operative time was significantly longer in MEL than SPSL (two levels, 183.6 ± 43.2 versus 134.8 ± 26.7 min, respectively; three levels: 241.6 ± 47.8 versus 179.9 ± 28.8 min, respectively). MEL's mean postoperative hospital stay was significantly shorter than SPSL (12.3 ± 5.9 versus 15.5 ± 7.2 days, respectively). There was no significant difference in the mean intraoperative blood loss, complication rate, reoperation rate, and postoperative outcomes between the two groups. Conclusions This study suggests that both techniques are effective in treating multi-segmental lumbar spinal stenosis. There was no significant difference between the two procedures in intraoperative blood loss (IBL), complications rate, reoperation rate, or improvement in VAS and Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) scores. MEL had an advantage in the postoperative hospital stay., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Oyama et al.)

Background: Preoperative chemotherapy is widely applied to high-grade localized soft tissue sarcomas (STSs); however, the prognostic significance of histological response to chemotherapy remains controversial. This study aimed to standardize evaluation method of histological response to chemotherapy with high agreement score among pathologists, and to establish a cut-off value closely related to prognosis., Methods: Using data and specimens from the patients who had registered in the Japan Clinical Oncology Group study, JCOG0304, a phase II trial evaluating the efficacy of perioperative chemotherapy with doxorubicin (DOX) and ifosfamide (IFO), we evaluated histological response to preoperative chemotherapy at the central review board., Results: A total of 64 patients were eligible for this study. The percentage of viable tumor area ranged from 0.1% to 97.0%, with median value of 35.7%. Regarding concordance proportion between pathologists, the weighted kappa coefficient (κ) score in all patients was 0.71, indicating that the established evaluation method achieved substantial agreement score. When the cut-off value of the percentage of the residual tumor area was set as 25%, the p-value for the difference in overall survival showed the minimum value. Hazard ratio of the non-responder with percentage of the residual tumor < 25%, to the responder was 4.029 (95% confidence interval 0.893-18.188, p = 0.070)., Conclusion: The standardized evaluation method of pathological response to preoperative chemotherapy showed a substantial agreement in the weighted κ score. The evaluation method established here was useful for estimating of the prognosis in STS patients who were administered perioperative chemotherapy with DOX and IFO., Trial Registration: UMIN Clinical Trials Registry C000000096. Registered 30 August, 2005 (retrospectively registered)., (© 2022. The Author(s).)

Background: The diagnosis of osteoporosis is based on bone mineral density measurements expressed as a percentage of the young adult mean (YAM) in Japan. Osteoporosis is defined as YAM <70%, and intervention is recommended at this cutoff. Because osteoporosis has a strong association with systemic metabolic disorders, we postulated that patients with YAM <70% had higher inflammatory biomarker concentrations owing to the higher systemic stress compared with YAM >70%., Method: We retrospectively reviewed 94 patients with low-trauma hip fractures. Blood examinations were performed on postoperative day (POD) 1 and POD 7. We used neutrophil lymphocyte ratio (NLR) and monocyte lymphocyte ratio (MLR) to evaluate postoperative recovery. After dividing the 94 patients into two groups according to a YAM cutoff of 70%, we compared the differences in NLR and MLR., Results: On POD 1, patients with YAM >70% had a median NLR of 5.7 and a median MLR of 0.66, which were significantly lower than for patients with YAM <70% (8.8 and 0.9, respectively). Similarly, on POD 7, patients with YAM >70% had a median NLR of 2.0 and a median MLR of 0.31, which were significantly lower than for patients with YAM <70% (3.5 and 0.43, respectively)., Conclusion: A YAM cutoff of 70% is an appropriate intervention threshold regarding postoperative recovery after hip fracture surgery. Mini-Abstract . Patients with YAM >70% showed lower NLR and MLR on POD 1 and POD 7. A YAM cuffoff of 70% is an appropriate intervention threshold regarding postoperative recovery after hip fracture surgery., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Hirofumi Bekki et al.)

Introduction: Due to the narrow portal of entry, microendoscopic laminectomy (MEL) is associated with a risk of postoperative spinal epidural hematoma (POSEH). This risk might be higher when performing multiple-level (m-) MEL. The purpose of this study is to clarify the incidence rate of POSEH following single-level (s-) and m-MEL by each interlaminar level and identify the risk factors for POSEH following m-MEL., Methods: A total of 379 patients underwent MEL of the lumbar spine (s-MEL, n=141; m-MEL, n=238). We determined the incidence of POSEH following s-MEL and m-MEL by each interlaminar level. For m-MEL, we clarified the correlation between POSEH and possible risk factors, such as operative findings, the sequence of operated interlaminar levels, and the preoperative cross-sectional dural area (CSA) on magnetic resonance imaging., Results: The incidence rate at L2/3 was significantly higher than that at L3/4 and L4/5. Patients who underwent L2/3 decompression at the end of the procedure showed a higher incidence of POSEH at the L2/3 level. Preoperative spinal stenosis was associated with POSEH at the L2/3 level, and CSA of 56 mm 2 was a predictive factor for POSEH. Logistic regression analysis revealed that both were significant risk factors., Conclusions: In patients undergoing m-MEL, the incidence of POSEH is highest at the L2/3 level, and treatment of the L2/3 level at the end of the procedure and the presence of spinal stenosis are risk factors for POSEH., Competing Interests: Conflicts of Interest: The authors declare that there are no relevant conflicts of interest., (Copyright © 2022 by The Japanese Society for Spine Surgery and Related Research.)

Background: Identifying the factors related to low bone mineral density (BMD) can have significant implications for preventing hip fractures. The correlation between ascending aortic calcification and BMD has never been reported. Therefore, the purpose of the current study is to confirm the hypothesis that ascending aortic calcification can be used as a predictive factor for low BMD and to find a radiographic sign to show it., Method: Plain film and computed tomography (CT) images of the thorax were obtained from 91 patients with hip fractures. Using the images, the calcification line of the ascending aorta adjacent to the aortic arch was evaluated. A prominent calcification line confirmed by both plain film and CT was classified as +2. A line which was ambiguous on plain film but confirmed by CT was classified as +1. Cases with no calcification were categorized as 0 (control). We compared the classified score with the BMD and calculated the kappa coefficient to measure intraobserver reliabilities for this radiographic finding., Results: Twenty-eight patients showed a +2 line, twenty-four patients showed a +1 line, and thirty-nine patients showed 0 lines. The median BMD of each group was 0.37 for the +2 line, 0.45 for the +1 line, and 0.51 for the 0 line. The BMD for the +2 group was significantly lower than the others. The kappa coefficient was approximately 0.6 ( p < 0.01)., Conclusion: The imaging finding of calcification of the ascending aorta might be considered as a potential surrogate marker of low BMD. In such subjects, BMD might be ordered for the confirmation of diagnosis of osteoporosis. Mini-Abstract . The Aortic Arch Tail Sign, a calcification line on the ascending aorta, was relevant to low BMD in the current study. BMD can be ordered for the confirmation of diagnosis of osteoporosis in a subject incidentally found to have ascending aorta calcification on X-ray or CT., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Hirofumi Bekki et al.)

Introduction The coronavirus disease 2019 (COVID-19) pandemic has had immense impact on people and institutions, including the number of admissions to hospitals for surgery. Our aim in this study was to determine the impact of the pandemic on surgeries in a single institution located in Fukuoka, Japan, between 2019 and 2020. Methods We quantified the numbers of surgeries in both years according to three sites of injury (indoor, outdoor, and unknown), 14 disease categories, and 9 primary diseases using patients' medical records. We also compared the hospital cost per day in each month from March to November in both 2019 and 2020 and compared the change in these costs between the two years. Results The number of admissions in 2020 was 1,187 cases vs 1,282 cases in 2019. The average patients' age was higher in 2020 vs 2019 (69.7 ± 0.5 vs 67.5 ± 0.5 years, respectively; p = 0.004), with no gender differences (2020: 705 women and 482 men; 2019: 716 women and 566 men). We found no significant differences in the number of admissions by month between 2019 and 2020. The percentages of outdoor injuries were significantly lower in 2020 vs 2019 (29.8% vs 37.9%, respectively; p = 0.004), and we found significantly different rates when comparing 2020 and 2019 for degenerative disease (42.6% vs 37.4%; p = 0.007), trauma related to falls (34.4% vs 30.2%; p = 0.02), chronic disease (1.9% vs 3.7%; p = 0.005), and sports injuries (0.8% vs 3.7%; p < 0.0001). The rate of sports-related injury was significantly lower in 2020 (1.6%) than in 2019 (7.7%) (p < 0.0001). The daily hospital charge was $10,517.09 (US dollars) in 2020 vs $11,225.32 in 2019, and the charges in the months of April and June were significantly higher in 2020 vs 2019 (p = 0.003 and p = 0.001, for April and June, respectively). Both the number and rate of upper limb fractures were higher in 2020. Conclusions The COVID-19 pandemic is affecting some hospitals' revenue. Although the charges per day were sufficient in our institution in 2020, compared with 2019, some hospital beds were unused during this phase of the pandemic. Hospitals may increase the revenue by mixing both short-term and long-term patients' hospital stays effectively., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Bekki et al.)

Objective: Osteoarthritis (OA) is the most common age-related joint disease. With aging and in OA, the expression of FoxO transcription factors is reduced, diminishing their chondroprotective actions. In order to elucidate the molecular mechanisms by which FoxO1 protects chondrocytes, we sought to identify the genome-wide occupancy profile of FoxO1., Methods: We performed FoxO1 chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-Seq) on human primary chondrocytes. ChIP-Seq data were integrated with RNA sequencing (RNA-Seq) data sets. Bioinformatics results were confirmed in primary chondrocytes that were treated with a FoxO1 inhibitor., Results: Analysis of FoxO1 ChIP-Seq on human primary chondrocytes showed that pathways implicated in OA pathogenesis are mainly regulated by FoxO1 binding to tissue-specific enhancers with suboptimal binding sites (20% of the peaks), while more ubiquitous FoxO1 pathways are regulated at the promoter level through interaction with its canonical binding motif (7% of the peaks). Integrating FoxO1 occupancy data with RNA-Seq data comparing OA and healthy human cartilage revealed 428 putative FoxO1 target genes that are dysregulated in OA. Pathway analysis showed enrichment for genes belonging to the senescence pathway (logP = -6.73), extracellular matrix (ECM) pathway (logP = -12.97), and circadian clock pathway (logP = -6.30), which suggests that FoxO1 dysregulation plays an important role in their abnormal expression in OA. Using an inhibitor of FoxO1, we confirmed that FoxO1 regulates these pathways in cultured human chondrocytes., Conclusion: FoxO1 regulates ubiquitous and cartilage-specific genes in chondrocytes by using different mechanisms. The FoxO1 transcriptional network is a key player in regulating homeostasis, ECM, and circadian clock genes and plays an important role in the abnormal expression of these pathways observed in OA pathogenesis., (© 2020, American College of Rheumatology.)

Objective: NF-κB-dependent signaling is an important modulator in osteoarthritis (OA), and G protein-coupled receptor kinase 5 (GRK5) regulates the NF-κB pathway. This study was undertaken to investigate the functional involvement of GRK5 in OA pathogenesis., Methods: GRK5 expression in normal and OA human knee joints was analyzed immunohistochemically. Gain- or loss-of-function experiments were performed using human and mouse chondrocytes. OA was induced in GRK5-knockout mice by destabilization of the medial meniscus, and histologic examination was performed. OA was also induced in wild-type mice, which were then treated with an intraarticular injection of amlexanox, a selective GRK5 inhibitor, every 5 days for 8 weeks., Results: GRK5 protein expression was increased in human OA cartilage. In vitro, expression levels of OA-related factors and NF-κB transcriptional activation were down-regulated by suppression of the GRK5 gene in human OA chondrocytes (3.49-fold decrease in IL6 [P < 0.01], 2.43-fold decrease in MMP13 [P < 0.01], and 2.66-fold decrease in ADAMTS4 [P < 0.01]). Conversely, GRK5 overexpression significantly increased the expression of OA-related catabolic mediators and NF-κB transcriptional activation. On Western blot analysis, GRK5 deletion reduced IκBα phosphorylation (up to 4.4-fold decrease [P < 0.05]) and decreased p65 nuclear translocation (up to 6.4-fold decrease [P < 0.01]) in mouse chondrocytes. In vivo, both GRK5 deletion and intraarticular amlexanox protected mouse cartilage against OA., Conclusion: Our results suggest that GRK5 regulates cartilage degradation through a catabolic response mediated by NF-κB signaling, and is a potential target for OA treatment. Furthermore, amlexanox may be a major compound in relevant drugs., (© 2019, American College of Rheumatology.)

Japan is undergoing a major population health transition as its society ages, and it continues to experience low birth rates. An aging Japan will bring new challenges to its public health system, highlighted as a model for universal health coverage (UHC) around the world. Specific challenges Japan's health care system will face include an increase in national public health expenditures, higher demand for health care services, acute need for elder and long-term care, shortage of health care workers, and disparities between health care access in rural versus urban areas. Blockchain technology has the potential to address some of these challenges, but only if a health blockchain is conceptualized, designed, localized, and deployed in a way that is compatible with Japan's centralized UHC-centric public health system. Blockchain solutions must also be adaptive to opportunities and barriers unique to Japan's national health and innovation policy, including its regulatory sandbox system, while also seeking to learn from blockchain adoption in the private sector and in other countries. This viewpoint outlines the major opportunities and potential challenges to blockchain adoption for the future of Japan's health care., (©Tim Ken Mackey, Hirofumi Bekki, Tokio Matsuzaki, Hiroshi Mizushima. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 09.01.2020.)

Undifferentiated sarcoma (US) is a frequent soft tissue sarcoma. Although the 10-year survival rate is around 60%, advanced US is highly resistant to chemo/radiotherapy. The tumor microenvironment (TME) is closely associated with tumor progression. However, few studies of infiltrated immune cells in US have been published. In this study, we evaluated tumor-associated macrophages (TAMs) and CD8-positive cytotoxic T lymphocytes (CTLs) in 28 cases of US. Iba1, CD163, and CD204 were used as markers for TAMs. The density of CTLs was positively correlated with the density of TAMs. However, a negative correlation was seen between the density of CTLs and the percentage of CD204-positive TAMs. We found no significant association between the density of Iba1-/CD204-/CD8-positive cells and clinicopathological factors. No significant correlation between immune cell infiltration and clinical outcome was observed. Although we found no significant association between immune cells and clinicopathological factors, these findings may provide new insight into the characterization of immune cells in the TME of US.

Study Design: Prospective cohort study., Purpose: The present study aimed to evaluate the difference in the preoperative curve flexibility between the supine and prone positions in patients with adolescent idiopathic scoliosis (AIS)., Overview of Literature: In AIS, a side-bending view is necessary to differentiate a structural curve from a nonstructural curve using the Lenke classification system. However, there are no published studies about which position, supine or prone, is more effective when evaluating preoperative curve flexibility using side-bending X-ray images in AIS patients., Methods: Radiographs were analyzed for 32 AIS patients (26 females, six males) who underwent posterior correction and fusion of their main thoracic (MT) curves. Cobb angles of MT, proximal thoracic (PT), and thoracolumbar/lumbar (TL/L) curves were measured preoperatively using upright, supine (anteroposterior and side-bending), and prone (posteroanterior and side-bending) X-rays., Results: The average Cobb angles of PT, MT, and TL/L curves on preoperative upright/supine/prone X-rays were 29.1°/26.7°/26.6°, 60.7°/48.5°/48.2°, and 41.0°/32.6°/33.1°, respectively. The average Cobb angles of PT, MT, and TL/L curves on supine/prone sidebending X-rays were 19.2°/20.3°, 36.3°/36.4°, and 13.9°/15.7°, respectively. The flexibility rates of PT, MT, and TL/L curves in supine/prone positions were 35.3%/32.5%, 40.6%/40.2%, and 71.7%/68.2%, respectively. Comparing flexibility rates in the prone position with those in the supine position in each case, the average ratios of PT, MT, and TL/L curves were found to be 1.0, 1.0, and 0.9, respectively. There were no statistically significant differences between supine and prone side-bending X-ray measurements. However, the Lenke classification in six of 32 patients (18.8%) differed between supine and prone positions because the TL/L curve in the supine position was slightly more flexible than in the prone position., Conclusions: Supine side-bending films may be suitable for the evaluation of preoperative curve flexibility in AIS, especially for lumbar modifier C.

Recent findings have shown the significance of CD163-positive macrophages in tumor progression, yet there have been few studies on the function of CD163 in macrophages. Here, we uncover the role of CD163 in macrophage activation using CD163-deficient mice and human samples. We detected CD163 in 62 undifferentiated pleomorphic sarcoma samples, in which a high percentage of CD163-positive macrophages was associated with decreased overall survival and higher histologic grade. We observed macrophage-induced tumor cell proliferation in cocultures of human monocyte-derived macrophages and leiomyosarcoma (TYLMS-1) and myxofibrosarcoma (NMFH-1) cell lines, which was abrogated by silencing of CD163. Tumor development of sarcoma (MCA205 and LM8) cells in CD163-deficient mice was significantly abrogated in comparison with wild-type (WT) mice. Coculture with WT peritoneal macrophages significantly increased proliferation of MCA205 cells but decreased in the presence of CD163-deficient macrophages. Production of IL6 and CXCL2 in CD163-deficient macrophages was suppressed in comparison with WT macrophages, and overexpression of CD163 in CD163-deficient macrophages induced production of IL6 and CXCL2. Silencing of IL6 but not CXCL2 abrogated macrophage-induced proliferation of MCA205 cells. Taken together, our results show that CD163 is involved in protumoral activation of macrophages and subsequent development and progression of tumors in mice and humans. Significance: Macrophage CD163-mediated induction of IL6 promotes tumor development and progression in murine and human malignant tumors. Cancer Res; 78(12); 3255-66. ©2018 AACR ., (©2018 American Association for Cancer Research.)

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.

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.

Recently developed molecular genetic techniques have led to the elucidation of tumor-specific genomic alterations and thereby the reclassification of tumor entities of soft tissue sarcoma. A solitary fibrous tumor-mimicking tumor with the AHRR-NCOA2 gene has been isolated as angiofibroma of soft tissue. As for small round cell sarcomas, novel fusion genes such as CIC-DUX4 and BCOR-CCNB3 have been identified in these tumor groups. SMARCB1/INI1 deficient tumors with round cell morphology are also expected to be reclassified in three types, based on the combination of their morphology and genotype. The identification of the MDM2 gene amplification in pleomorphic sarcomas has extended the entity of dedifferentiated liposarcoma (DDLS). Our recent molecular investigations elucidated candidates for novel therapeutic strategies. Activation of the Akt-mTOR pathway was correlated with poor prognosis or tumor grade in spindle cell sarcomas including malignant peripheral nerve sheath tumor. In vitro and in vivo studies of transcription factor Forkhead Box M1 (FOXM1) demonstrated the close correlation between aggressive biological behavior or chemosensitivity and FOXM1 expression in synovial sarcoma, so far. Finally, in regard to the investigation of cancer-testis antigens, myxoid/round cell liposarcoma and synovial sarcoma showed frequent and high expression of PRAME and NY-ESO-1., (© 2017 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd.)

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.

We herein report an unusual case of Brodie's abscess of the radius in a child. A 13-year-old boy presented with pain on his right distal forearm. A plain radiograph showed an 8 cm translucent lesion in the distal radius. MRI showed a penumbra sign on the T1-weighted image, hyperintensity on T2-weighted images, and ring enhancement on the contrast-enhanced T1 image. 18 F-FDG PET/CT images showed an uptake at the margin of the radius. Curettage and iliac cancellous bone grafting were undertaken for Brodie's abscess. Bacteriological examinations were found to be negative, however, the pathologic diagnosis showed chronic osteomyelitis. Eight months after surgery, the patient was asymptomatic and there was no sign of recurrence of infection. For Brodie's abscess in a child, thorough debridement is mandatory in addition to cancellous bone grafting. Brodie's abscess should be considered in the differential diagnosis of a patient who presents with forearm pain and exhibit the radiolucent osteolytic lesion on simple radiography.

Myxofibrosarcoma (MFS) is characterized by abundant myxoid stroma, a wide spectrum of cytological atypia, and frequent local recurrence. Some soft tissue tumors with myxoid stroma can histologically mimic MFS, but have different biological behaviors. Here we sought to identify a useful diagnostic marker for MFS. After our analysis of the gene expression dataset from the Gene Expression Omnibus database, we focused on claudin 6 (CLDN 6). The status of CLDN 6 was assessed by immunohistochemistry in 61 samples of MFS and other (benign) myxoid soft tissue tumors (28 myxoma samples, 12 nodular fasciitis samples), 18 low-grade fibromyxoid sarcoma, 30 myxoid liposarcoma, 29 extraskeletal myxoid chondrosarcoma and 27 dedifferentiated liposarcoma with myxoid feature samples. The correlation between the expression of CLDN 6 and clinicopathological findings in MFS was also investigated. Immunohistochemically, high expression of CLDN 6 was observed in approx. 65% of the MFSs, whereas the benign soft tissue tumors did not show a high expression of CLDN 6. The expression of CLDN 6 in the MFS was significantly higher than those of other tumor specimens. Among the MFSs, the high expression of CLDN 6 was correlated with high FNCLCC grades and high AJCC stages. CLDN 6 may be useful for the differential diagnosis from benign myxoid tumor and for predicting the aggressive biological behavior of MFS., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

It is important to distinguish between leiomyosarcoma (LMS) and dedifferentiated liposarcoma (DDLS) in the retroperitoneum. The dedifferentiated component of DDLS shows an LMS-like morphology in some cases; thus, detailed evaluation is necessary to achieve an accurate diagnosis. Immunohistochemically, MDM2 and myogenic markers provide clues for the diagnoses. However, immunoreactivity for MDM2 and myogenic markers has not been well studied in retroperitoneal LMS and DDLS. Here, we compared the clinicopathological data of 20 retroperitoneal tumors initially diagnosed as LMS with that of 36 cases of retroperitoneal DDLS and conducted an immunohistochemical study. Four (20%) of the cases initially diagnosed as LMS were immunoreactive for MDM2. Fifteen cases (41.7%) of DDLS showed positive expression of two or more myogenic markers. The patients with LMS with MDM2 overexpression were older than the patients with LMS without MDM2 overexpression (P=0.0328). LMS with MDM2 overexpression showed a worse prognosis than DDLS (P=0.0408). No significant difference in prognosis was found between LMS without MDM2 overexpression and DDLS with myogenic differentiation. In conclusion, we recommend that systemic MDM2 expression analysis be performed in cases of retroperitoneal sarcoma. Overdependence on the expression of myogenic markers could lead to misdiagnosis in distinguishing LMS from DDLS., (Copyright © 2017 Elsevier GmbH. All rights reserved.)

CIC-DUX4 and BCOR-CCNB3 fusion-gene-associated small round cell sarcomas account for a proportion of pediatric small round cell sarcomas, but their pathological features have not been sufficiently clarified. We reviewed a large number of soft tissue tumors registered at our institution, retrieved the cases of unclassified tumors with a small round cell component, and subjected them to histopathological, immunohistochemical, and gene profile analysis. We reviewed 164 cases of unclassified tumors with a small round cell component and analyzed them by RT-PCR and FISH. Tumors positive for a specific fusion-gene were also subjected to histopathological and immunohistochemical examinations. We identified 16 cases of BCOR-CCNB3/CIC-associated (CIC-DUX4 or CIC gene rearrangement-positive) sarcomas. These included seven BCOR-CCNB3 sarcomas and nine CIC-associated sarcomas. Heterogeneous elements included a myxoid spindle cell component in three BCOR-CCNB3 sarcomas and an epithelioid cell component in two CIC-associated sarcomas (one CIC-DUX4-positive and one CIC-DUX4-negative sarcomas). Mitotic activity was low in both heterogeneous components. By immunohistochemistry, in seven BCOR-CCNB3 sarcomas expression of EMA was positive in two cases, of p63 in three, of CD56 in six, of TLE1 in seven, of NKX2.2 in two, of CCNB3 in seven, and of BCOR in six cases (one case could not be tested for BCOR). In nine cases of CIC-associated sarcoma, CD56 was expressed in five, alpha-smooth muscle actin in one, ERG in three, and CD99, WT1 and TLE1 each in eight cases. Both sarcoma types showed not only a small round cell component, but also a myxoid/epithelioid component with low mitotic activity.

Synovial sarcoma (SS) is regarded as a relatively chemosensitive sarcoma, but the prognosis of advanced SSs remains poor. Here we identified highly expressed cancer-testis antigens that could be promising immunotherapy targets for SS, using a previously conducted cDNA microarray, and we assessed the clinicopathological or prognostic relationships of these antigens in SS. We compared the gene expression profiles of 11 SSs with those of 3 normal adipose tissues. Among the up-regulated cancer-testis antigens, we analyzed PRAME, MAGEA1, and MAGEA4 and another cancer-testis antigen (NY-ESO-1) together, by immunohistochemistry and real-time polymerase chain reaction in 108 SSs. Immunohistochemically, NY-ESO-1, PRAME, MAGEA4, and MAGEA1 were positive in 66 (61%), 93 (86%), 89 (82%), and 16 (15%) of 108 SSs, respectively, and 104 (96%) of 108 SSs showed the immunohistochemical expression of at least 1 of NY-ESO-1, PRAME, and MAGEA4. Moreover, the high expression of at least 1 of these 3 antigens was observed in 83% of the SSs. High expression of NY-ESO-1 and MAGEA4 was significantly correlated with the presence of necrosis and advanced clinical stage. The immunohistochemical expression of these cancer-testis antigens was not correlated with prognosis, but the coexpression of NY-ESO-1, PRAME, and MAGEA4 was significantly associated with adverse prognosis. The real-time polymerase chain reaction results were closely related to the immunohistochemical results: NY-ESO-1 (P = .0019), PRAME (P = .039), MAGEA4 (P = .0149), and MAGEA1 (P = .0766). These data support the potential utility of NY-ESO-1, PRAME, and MAGEA4 as immunotherapy targets and ancillary prognostic parameters, suggesting the possible benefit of the combined use of these cancer-testis antigens as an SS immunotherapy target., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway plays a role in various biological processes. Phosphorylated STAT3 (p-STAT3) functions as a transcriptional factor, and suppressor of cytokine signaling 3 (SOCS3) is a potential inhibitor of STAT3. Here, we analyzed the status of the JAK-STAT pathway in undifferentiated pleomorphic sarcoma (UPS)., Methods: We performed immunohistochemistry in 79 samples of UPS and Western blotting in 10 frozen samples. We also examined alterations in protein expression in the JAK-STAT pathway after the inhibition of phosphorylated Akt (p-Akt) or extracellular signal-regulated kinase (p-Erk) in vitro., Results: Immunohistochemically, p-STAT3 and SOCS3 were positive in 59.7 and 55.8%, respectively. Positivity for p-STAT3 was significantly correlated with a better prognosis (p = 0.0006) and negatively with SOCS3 expression (p = 0.0223). Positivity for SOCS3 was significantly correlated with a worse prognosis (p = 0.0001). Western blotting analysis revealed that p-STAT3 expression was lower in tumor than in normal tissue. In vitro results demonstrated that there was no detectable change in the expression of p-STAT3 regardless of the status of p-Akt or p-Erk., Conclusion: p-STAT3 may be a useful prognostic factor for UPS., (© 2016 S. Karger AG, Basel.)

Background and Purpose: Carbon-ion radiotherapy (C-ion RT) was effective therapy for inoperable spinal and paraspinal sarcomas. However, a significant adverse event following radiotherapies is vertebral compression fractures (VCFs). In this study, we investigated the incidence of and risk factors for post-C-ion RT VCFs in patients with spinal or paraspinal sarcomas., Material and Methods: Thirty consecutive patients with spinal or paraspinal sarcomas treated with C-ion RT were retrospectively reviewed. Various clinical parameters and the Spinal Instability Neoplastic Score (SINS) were used to evaluate the risk factors for post-C-ion RT VCFs., Results: The overall incidence of VCFs was 23% (median time: 7 months). Patients with VCFs showed a markedly higher SINS score (median value, 9 points) than those without VCF (5 points). The area under the receiver operating characteristic curve for the SINS score was 0.88, and the optimum SINS cut-off score was 8 points. The cumulative incidence of VCFs at 1 year was 9% for patients with a SINS score under 8 points, versus 80% for those with a SINS score of 8 points or higher ( p < 0.0001)., Conclusions: In patients with a SINS score of 8 points or higher, referral to a spine surgeon for stabilization and multidisciplinary discussion is appropriate.

Background and Purpose: Primary malignant spine/spinal tumors (PMSTs) are rare and life-threatening diseases. In this study, we demonstrated the advantage of volume-based 18 F-FDG PET/CT metabolic parameter, metabolic tumor volume (MTV), for assessing the aggressiveness of PMSTs., Materials and Methods: We retrospectively reviewed 27 patients with PMSTs and calculated SUV max , MTV, and total lesion glycolysis (TLG) to compare their accuracy in predicting progression-free survival (PFS) and overall survival (OS) by receiver operating characteristic (ROC) curve analysis. Univariate and multivariate analyses were used to compare the reliability of the metabolic parameters and various clinical factors., Results: MTV exhibited greater accuracy than SUV max or TLG. The cut-off values for PFS and OS derived from the AUC data were MTV 45 ml and 83 ml and TLG 250 SUV⁎ml and 257 SUV⁎ml, respectively. MTV above cut-off value, but not TLG, was identified as significant prognostic factor for PFS by log-lank test ( p = 0.04). In addition, MTV was the only significant predictive factors for PFS and OS in the multivariate analysis., Conclusions: MTV was a more accurate predictor of PFS and OS in PMSTs compared to TLG or SUV max and helped decision-making for guiding rational treatment options.

Aims: Angiofibroma of soft tissue (AFST) is a rare soft tissue neoplasm characterized by a fibroblastic cytomorphology and a prominent vascular structure. AFSTs possess a novel fusion gene, i.e. NCOA2-AHRR/AHRR-NCOA2 or GTF2I-NCOA2, providing a useful approach to diagnosing AFST. Morphologically, AFSTs span a wide spectrum, making diagnosis a challenge. The aim of this study was to review AFST cases and to report previously unknown histological features, which we confirmed by genetic analysis., Methods and Results: We reviewed 276 cases diagnosed as solitary fibrous tumours/haemangiopericytomas (232 cases), unclassified tumours of fibroblastic differentiation (36 cases), and recently diagnosed AFSTs (eight cases), and retrieved 13 cases compatible with AFST. Immunohistochemical staining was performed for these cases, all 13 of which were analysed by reverse transcription polymerase chain reaction and fluorescence in-situ hybridization. The histological findings were as follows: amianthoid fibres, extravasation of red blood cells, haemosiderin deposition, aggregates of foamy histiocytes, cystic change, necrosis, and haemorrhage. Immunohistochemically, the tumour cells were positive for epithelial membrane antigen (four of 13 cases), desmin (six of 13 cases), CD163 (13 of 13 cases), CD68 (seven of 13 cases), oestrogen receptor (13 of 13 cases), progesterone receptor (three of 13 cases), and STAT6 (one of 13 cases, weak nuclear staining), but they were negative for CD34, α-smooth muscle actin, muscle-specific actin, S100, pan-cytokeratin, MDM2, and CDK4. The AHRR-NCOA2 fusion gene was detected in eight cases, and NCOA2 gene rearrangement in nine cases., Conclusion: We revealed the previously unreported histological variation and immunohistochemical findings of AFST, and confirmed them by using genetic methods. The results suggested that AFST should be considered in the diagnosis of fibrous or fibrohistiocytic tumours with the above histological features., (© 2016 John Wiley & Sons Ltd.)

The Akt/mTOR and MAPK pathways play important roles in modulating cellular function in response to extracellular signals, and they are known to be activated in certain kinds of sarcomas. Few investigations have examined these pathways in dedifferentiated liposarcoma (DDLS), in relation to clinicopathological features. Clinicopathological and immunohistochemical analyses were conducted using 99 DDLS specimens. An in vitro study was also conducted to examine the antitumor effects of an mTOR inhibitor and a MEK inhibitor on two DDLS cell lines. The clinicopathological analyses revealed that the AJCC staging was a significant prognostic factor for overall survival and that the tumor size, depth, and location were significant prognostic factors for event-free survival. Phosphorylated Akt (pAkt), pmTOR, pS6RP, p4E-BP1, pMEK, and pERK expressions were positive in 57.4, 52.4, 71.4, 57.1, 84.1, and 50.8 % of the dedifferentiated component of the 63 primary DDLSs. Positive staining for pmTOR was significantly more frequent in the dedifferentiated component than the well-differentiated component. A univariate prognostic analysis revealed that pmTOR expression was associated with poor prognosis in the tumors in the retroperitoneum/ventral body cavity. The mTOR and MEK inhibitors dose-dependently inhibited the cell proliferation of both DDLS cell lines and decreased the expression of downstream pS6RP and pERK, respectively. The combined use of the two inhibitors enhanced antiproliferative activity. In conclusion, the Akt/mTOR and MAPK pathways were activated in DDLS specimens, and the inhibition of these pathways decreased cell proliferation in DDLS cell lines. Our findings suggest that these pathways could be a therapeutic target for patients with DDLS.

Study Design: A computed tomography study., Objective: The aim of the study was to clarify the position of the aorta relative to the spine in patients with Lenke type 1 adolescent idiopathic scoliosis., Summary of Background Data: Several authors have examined the position of the aorta in patients with scoliosis; however, their analysis included several types of curve. There is a possibility that the position of the aorta differs according to the scoliosis curve type., Methods: Thirty-eight patients with Lenke type 1 were analyzed. The angle (left pedicle aorta [LtP-Ao] angle) and distance (LtP-Ao distance) from the insertion point of the left pedicle screw to the aorta were measured from T4 through L2. The measured data were evaluated from 4 levels above to 4 levels below the apical vertebra. The difference between lumbar modifiers A and C was examined. Dangerous pedicles, which were defined as those in which the aorta entered the expected area based on the screw direction error and length, were counted from T10 to L2., Results: The aorta was located posterolaterally and adjacent to the vertebra at the middle thoracic level, and anteromedially and distant at the thoracolumbar level. LtP-Ao angle was largest at 1 level above the apical vertebra, and LtP-Ao distance was shortest at 2 levels above. LtP-Ao angle of Lenke 1A was significantly larger than 1C from T11 to L2, and LtP-Ao distance of 1A was significantly shorter than 1C from T11 to L1. When the screw length was 40 mm and the direction error was within 10°, there were a large number of dangerous pedicles at T11, regardless of the lumbar modifier., Conclusion: The direction error has a potential risk of injuring the aorta around the apical vertebra. The selection of screws of the proper length is necessary to avoid a breach of the anterior vertebral wall at thoracolumbar level, especially at T11., Level of Evidence: 3.

Background: Undifferentiated pleomorphic sarcoma (UPS) is a heterogeneous tumor group, and little is known about molecular target therapy for UPS. Heat shock protein 90 (HSP90) is an expressed chaperone that refolds certain denatured proteins under stress conditions. One of these proteins is Akt. The disruption of Akt signaling plays an important role in tumor progression. The present study's purpose was to analyze the HSP90 expression, Akt/mTOR pathway activation and the correlation between HSP90 expression and its pathway activation in UPS., Methods: The status of HSP90 and the profiles of the Akt/ mTOR pathway were assessed by immunohistochemistry in 79 samples of UPS, and these data were compared with clinicopathological and histopathological findings. The expressions of indicated proteins were assessed by Western blotting in five frozen samples. After treating UPS cells with the HSP90 inhibitor, we assessed the antitumor effect of the inhibitor., Results: Immunohistochemically, phosphorylated Akt (p-Akt), p-mTOR, p-S6RP and p-4EBP were positive in 57.3, 51.9, 54.5 and 57.1% of the UPS samples, respectively. The expressions of those phosphorylated proteins were correlated with each other. HSP90 expression was elevated in 56.4% of the samples and was correlated with p-Akt, p-mTOR and p-S6RP. The immunohistochemical results were confirmed by Western blotting. The HSP90 inhibitor led to decreased viability and invasiveness of the cells and inactivated the AKT/mTOR pathway in vitro., Conclusion: Elevated expression of HSP90 is a poor-prognosis factor and is involved in the activation of the Akt/mTOR pathway in UPS. HSP90 inhibition is a potential treatment option for UPS.

Recently, a novel fusion transcript, NAB2-STAT6, and its variants have also been reported to be specific diagnostic markers for solitary fibrous tumors (SFTs). In this study, we validated the existence of the NAB2-STAT6 fusion gene in SFTs and examined its relation with the pathological features. Frozen samples from 9 tumors were assessed for fusion gene. The detected fusion genes exhibited large intron sequences and the insertion of unknown and previously unreported sequences. The fusion genes were not detected in the 2 malignant cases with high-grade nuclear atypia, nuclear pleomorphism and necrosis, that was confirmed by multiplex PCR method. In addition, 1 of the 2 NAB2-STAT6 fusion gene-negative tumors showed amplification of the MDM2 and CDK4 genes. It was suggested that a certain proportion of tumors previously diagnosed as malignant SFTs with high-grade nuclear atypia lacking NAB2-STAT6 should be categorized into a special subtype of SFT, which is genetically different from conventional SFTs, and which cannot be apparently distinguished from dedifferentiated liposarcoma or undifferentiated pleomorphic sarcoma., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Few reports have described the involvement of syringomyelia associated with diastematomyelia in the etiology of neurological deficits. We reported a case with syringomyelia associated with diastematomyelia. A female patient with diastematomyelia was followed up clinically over 14 years. At the age of 8, she developed clubfoot deformity with neurological deterioration. Motor function of the right peroneus demonstrated grade 2 in manual muscle tests. Continuous intracanial bony septum and double cords with independent double dura were observed at upper thoracic spine. Magnetic resonance imaging revealed a tethering of the spinal cord and syringomyelia distal to the level of diastematomyelia. Extirpation of the osseum septum and duralplasty were performed surgically. She grew without neurological deterioration during 7 years postoperatively. A long-term followed up case with syringomyelia that was possibly secondary to the tethering of the spinal cord associated with diastematomyelia, and effective treatment with extirpation of the osseum septum and duralplasty was described.

Background: Ezetimibe ameliorates serum low-density lipoprotein cholesterol (LDL-c) and it has been approved for the treatment of hypercholesterolemia. However, the effects of ezetimibe on specific biomarkers have not been fully clarified in obese Japanese patients., Methods: A total of 101 patients (47 males and 54 females) were registered in this study during 2011 and 2012. All patients were over 20 years old, were obese [body mass index (BMI) ≥ 25 kg/m(2)] and had hypercholesterolemia (LDL-c ≥ 120 mg/dl). After excluding 10 subjects (7 who dropped out and 3 with missing data), 91 patients (39 males and 52 females) were analyzed. They were treated with 10 mg ezetimibe once a day for 24 weeks and were evaluated at 12 and 24 weeks., Results: Following 12 weeks of ezetimibe therapy, BMI (p < 0.001), waist circumference (p < 0.001), total cholesterol (p < 0.001), LDL-c (p < 0.001), non high-density lipoprotein cholesterol [HDL-c] (p < 0.001), triglycerides (p < 0.05) and remnant-like particle cholesterol (RLP-c; p < 0.001) were significantly decreased. Following 24 weeks of ezetimibe therapy, BMI (p < 0.05), waist circumference (p < 0.001), total cholesterol (p < 0.001), LDL-c (p < 0.001), non HDL-c (p < 0.001), triglycerides (p < 0.05), RLP-c (p < 0.001), insulin (p < 0.05) and hepatocyte growth factor (HGF; p < 0.05) were significantly decreased. In contrast, HDL-c (p < 0.001) was significantly increased., Conclusions: Ezetimibe ameliorated not only atherogenic lipid profiles but also anthropometric factors, insulin resistance and biomarkers such as HGF. Ezetimibe may have pleiotropic effects on obese patients with hypercholesterolemia.

Background: There is a growing body of evidence that blood pressure (BP) level is one of the major determinants of cardiovascular morbidity and mortality in individuals, including elderly people. However, to achieve a target BP level in the elderly is more difficult compared with patients aged <65 years. Current guidelines recommend combination drug therapy with different modes of action for the treatment of elderly patients with moderate hypertension (HT). However, the optimal combination regimen is not well established in elderly HT., Hypothesis: We hypothesized that combination therapy of telmisartan plus amlodipine would exert favorable cardiometabolic actions in elderly HT., Methods: Seventeen elderly patients with essential HT who failed to achieve a target home BP level with treatment of 5 mg amlodipine plus 80 mg valsartan or 8 mg candesartan for at least 2 months were enrolled. Then the patients were assigned to replace their valsartan or candesartan with 40 mg telmisartan. The subjects were instructed to measure their own BP at home every day during the study periods., Results: Replacement of valsartan or candesartan by telmisartan in amlodipine-treated elderly hypertensive patients showed a significant reduction in morning home systolic BP and evening home systolic and diastolic BP at 12 weeks. Switching to telmisartan significantly increased serum adiponectin level., Conclusions: Our present study suggests that combination therapy with telmisartan plus amlodipine may exert more beneficial cardiometabolic effects in elderly patients with HT compared with valsartan or candesartan plus amlodipine treatment., (© 2011 Wiley Periodicals, Inc.)

There is accumulating evidence that blood pressure (BP) control significantly reduces the risk of future cardiovascular events in patients with essential hypertension. However, strict BP control is often difficult to maintain, and half of hypertensive patients fail to attain BP goals on single-drug therapy. Therefore, current guidelines recommend combinations of drugs that have complimentary mode of actions for treatment of patients with moderate hypertension. In this study, we examined in hypertensive patients uncontrolled by the combination treatment with 5 mg amlodipine plus 80 mg valsartan or 8 mg candesartan whether additional BP lowering could be achieved by switching to 5 mg amlodipine plus 40 mg telmisartan. Forty-seven patients with essential hypertension who failed to achieve a target BP level by the treatment of 5 mg amlodipine plus 80 mg valsartan or 8 mg candesartan for at least 2 months were enrolled. Replacement of valsartan or candesartan by telmisartan showed a significant reduction in both mean clinic systolic and diastolic BP at 4, 8 and 12 weeks; BP level decreased from 143.7/82.3 mmHg at baseline to 135.4/77.5 mmHg at 12 weeks. Furthermore, in 8 patients of valsartan group, switching to telmisartan significantly reduced central BP by 11.8 mmHg. Our present study suggests that combination therapy with telmisartan plus amlodipine may be more beneficial than valsartan or candesartan plus amlodipine treatment for controlling brachial and central BP, which could lead to more favorable cardiovascular outcomes with this drug combinations.

In order to detect an exercise induced asynergy, cross-sectional echocardiography was performed during multistage maximal bicycle ergometer stress test in the supine position. 1) Left ventricular (LV) asynergy occurred earlier than or simultaneously with the appreciable ST segment change. 2) In patients with angina, LV asynergy appeared in the area of dominant coronary stenosis, while ST depression was seen in V3-6 as well as II, III and aVF, despite of the localized area of asynergy. 3) In patients with myocardial infarction, LV asynergy increased or extended over or around the infarcted area except one case, ST segment elevated in the leads over the infarction with abnormal Q waves and depressed in the reciprocal leads. These observations revealed that ST depression does not necessarily mean an occurrence of new ischemia over the corresponding area in myocardial infarction. Thus exercise cross-sectional echocardiography was demonstrated to be a good method to detect an exercise induced ischemia and would be particularly valuable in view of the coronary artery bypass.

Three dimensional assessment of the site of myocardial infarct was performed using cross-sectional echocardiography in 68 patients with old myocardial infarction. Patients with a history or electrocardiographic findings suggestive of double or multiple infarctions were excluded from the study. In patients with abnormal Q waves in V1 to V3, a regional wall motion abnormality (asynergy) was observed in the anterior portion of the interventricular septum (IVS) and the anterior free wall of the left ventricle (LV) which was extended from the base to apex. Most of them had a significant stenosis in the left anterior descending artery (LAD) distal to the first diagonal branch. Patients with Q waves in V1 to V5 or V6 showed extensive asynergy in the anterior IVS, anterior and lateral free walls of the LV extended from the base to apex. LAD stenosis proximal to the first diagonal branch seemed to be the corresponding coronary lesion. In patients with Q waves in V3 to V5 or V6, asynergy was limited to the apical half of the anterior wall of the LV. In patients with Q waves in II, III and a VF, asynergy was observed in the basal half of the posterior wall and the posterior portion of the IVS.

Exercise two-dimensional (2-D) echocardiography was performed in patients with suspected coronary artery disease, and exercise induced left ventricular asynergy was evaluated qualitatively and was compared with the coronary artery stenosis and electrocardiographic ST changes. Subjects were 12 patients with angina of effort, 8 patients with spontaneous angina, 8 patients with chest pain syndrome with the normal coronary artery, and 7 patients with hypertrophic cardiomyopathy (HCM). Cases with myocardial infarction were excluded from this study. 1) Left ventricular asynergy during exercise was observed in 10 and ST depression in 11 of 12 patients with angina of effort. In patients with spontaneous angina, left ventricular asynergy and ST depression during exercise were observed in 2 of 8 patients without anginal pain, and both patients had coronary artery stenosis of 90% or more. 2) Exercise induced asynergy was also observed in 4 of 7 patients with HCM without coronary artery stenosis. It seemed likely that the markedly hypertrophied myocardium and impairment of left ventricular compliance and relaxation may induce relative myocardial ischemia.