Synergistic upregulation of ADAMTS4 (aggrecanase-1) by cytokines and its suppression in knee osteoarthritic synovial fibroblasts.

The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family includes nine members with aggrecan-degrading activity, i.e., ADAMTS1, 4, 5, 8, 9, 15, 16, 18, and 20. However, their systematic expression profile in knee osteoarthritis (OA) synovium and effects of cytokines and growth factors on the expression in OA synovial fibroblasts remain elusive. In this study, expression of all nine aggrecanolytic ADAMTS species was assessed by quantitative real-time PCR in OA and control normal synovial tissues. OA synovial fibroblasts were treated with interleukin-1α (IL-1α), IL-1ß, tumor necrosis factor-α (TNF-α), transforming growth factor-ß (TGF-ß), vascular endothelial growth factor165, and heparin-binding epidermal growth factor, and analyzed for the expression of the ADAMTS species. The signaling pathways and inhibition of ADAMTS4 expression by high-molecular-weight hyaluronan, adalimumab, tocilizumab, and signaling molecule inhibitors were studied. ADAMTS1, 4, 5, 9, and 16 were expressed in OA synovium, but only ADAMTS4 expression was significantly higher in OA as compared to normal synovium. IL-1α, TNF-α, and TGF-ß markedly increased ADAMTS4 expression, while their effects were minimal for the other ADAMTS species. ADAMTS4 was synergistically upregulated by treatment with IL-1α and TNF-α, IL-1α and TGF-ß, or IL-1α, TNF-α and TGF-ß. The signaling molecules' inhibitors demonstrated that IL-1α-induced ADAMTS4 expression is predominantly through TGF-ß-associated kinase 1 (TAK1), and the TNF-α-stimulated expression is via TAK1 and nuclear factor-κB (NF-κB). The TGF-ß-promoted expression was through the activin receptor-like kinase 5 (ALK5)/Smad2/3, TAK1, and non-TAK1 pathways. Adalimumab blocked TNF-α-stimulated expression. ADAMTS4 expression co-stimulated with IL-1α, TNF-α and TGF-ß was abolished by treatment with adalimumab, TAK1 inhibitor, and ALK5/Smad2/3 inhibitor. These data demonstrate marked and synergistic upregulation of ADAMTS4 by IL-1α, TNF-α and TGF-ß in OA synovial fibroblasts, and suggest that concurrent therapy with an anti-TNF-α drug and inhibitor(s) may be useful for prevention against aggrecan degradation in OA.

Deletion of Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization (HYBID) Results in Attenuation of Osteoarthritis in Mice.

Hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID) is involved in cartilage destruction via HA depolymerization in human knee osteoarthritis. However, the role of HYBID in the progression of osteoarthritis remain elusive. This study sought to examine whether genetic depletion of Hybid could suppress surgically induced osteoarthritis of mouse knee joints. In osteoarthritis induced by medial collateral ligament transection with meniscus removal, articular cartilage destruction and osteophyte formation at the medial femoral-tibial joint were significantly inhibited in Hybid-deficient (Hybid-/-) mice compared with wild-type mice. Hybid was highly produced by synovial cells and articular chondrocytes in the osteoarthritis joints of wild-type mice. IL-1ß, IL-6, and tumor necrosis factor-α were up-regulated in the osteoarthritis joint tissues of both wild-type and Hybid-/- mice. Vascular density at the synovial and periosteal junction was significantly reduced in Hybid-/- mice compared with wild-type mice. High-molecular-weight HA accumulated in osteoarthritis joint tissues of Hybid-/- mice. Injections of high-molecular-weight HA to knee joints attenuated the cartilage destruction and osteophyte formation in wild-type mouse osteoarthritis group. Inhibition of cartilage destruction and osteophyte formation in Hybid-/- mice was also observed in destabilization of the medial meniscus model. These data are the first to demonstrate that cartilage destruction and osteophyte formation are suppressed in Hybid-/- mice and suggest that Hybid-mediated HA depolymerization is implicated for the progression of mechanically-induced knee osteoarthritis.

Blood cobalt ion level in patients with different sizes of cobalt/chrome femoral head with the Accolade TMZF stem.

BACKGROUND: Corrosion of stem-cobalt/chromium (Co/Cr) head interface and subsequent systemic Co ion complication have been a clinical concern after total hip arthroplasty (THA). The aim of this study is to investigate correlation between type of femoral head and blood Co ion level. METHODS: One hundred four patients with THA using accolade TMZF and Co/Cr femoral head (32-mm; 55 cases, 36-mm; 20 cases, dual mobility system (DM) with 22.2 or 28-mm inner head; 29 cases) participated in this study, and blood Co ion concentration test was performed in patients a minimum of four years after THA. RESULTS: DM group was significantly older than 32-mm and 36-mm group (DM: 73.9 ± 4.6, 32-mm: 63.3 ± 8.5, 36-mm: 66.8 ± 10.5). The median (interquartile range) blood Co concentration of each group was 32-mm group 0.26 µg/L (0.69), 36-mm group; 0.21 µg/L (0.30); and DM group 0.21 µg/L (0.13). There was a significant difference of Co concentration between DM and 32-mm group (p = 0.023). Abnormal values of the blood Co concentration (> 1 µg/L) were observed in the 32-mm group; 12 cases (21.8%), 36-mm group; 2 cases (10.0%); and DM group; 0 case (0%) (p = 0.018). CONCLUSIONS: Co blood concentration differed among the different sizes of Co/Cr femoral head. THA using DM is a safe option with low risk of complication from cobalt ion if it is used for elderly patients.

Acoustic characteristics of broaching procedure for post-operative stem subsidence in cementless total hip arthroplasty.

PURPOSE: Avoiding stem subsidence is crucial for achieving better outcome for cementless total hip arthroplasty (THA). The aim of this study was to develop a prediction model for the incidence of post-operative stem subsidence using full quantitative acoustic parameters in hammering sound during the broaching procedure and to assess the accuracy of this prediction model. METHODS: The acoustic parameters of the hammering sounds during a broaching procedure for 55 hips in 49 patients who underwent THAs with cementless taper-wedged stem were analysed. The stem subsidence was assessed at one month post-operatively, and the relationship between the acoustic parameters and the value of stem subsidence was investigated. RESULTS: The average stem subsidence was 2.15 ± 2.91 mm. The subsidence 3 mm or more was observed in eleven hips (20%), and 5 mm or more was observed in seven hips (12.7%). Basic patient's characteristics, preoperative femoral morphology and immediate post-operative canal fill ratio and stem alignment were not significantly related to the volume of stem subsidence. Nine acoustic parameters were significantly correlated with the value of subsidence. The prediction model for post-operative subsidence using only acoustic parameters during broaching procedure was established, and this model showed a positive prediction value of 100% and a negative prediction value of 90.6% for post-operative stem subsidence at 5 mm or more. CONCLUSION: Post-operative stem subsidence can be predicted by using acoustic parameters of the hammering sound during the broaching procedure. Our results suggest that we are at the start of a new era in which novel and innovative smart technologies can be used to assist in orthopaedic surgery.

Implication of HYBID (Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization) in Hyaluronan Degradation by Synovial Fibroblasts in Patients with Knee Osteoarthritis.

Cell migration-inducing hyaluronidase 1 (CEMIP), also known as hyaluronan (HA)-binding protein involved in HA depolymerization (HYBID), plays a role in HA degradation. CEMIP2, also known as transmembrane protein 2 (TMEM2), possessing a sequence similarity with HYBID, is reported as a hyaluronidase in mice. However, the expression of these molecules in osteoarthritic synovium and their involvement in HA degradation in synovial fluid (SF) from patients with knee osteoarthritis remain elusive. This study examined their expression in synovial tissue and the relationship with molecular weight of HA in SF in knee osteoarthritis patients. Quantification of mRNA demonstrated that HYBID expression is significantly (5.5-fold) higher in osteoarthritic synovium than in normal control synovium, whereas TMEM2 expression level is similar between the two groups. By immunohistochemistry, HYBID was localized mainly to CD68-negative and fibroblast-specific protein 1-positive synovial lining cells and sublining fibroblasts in osteoarthritic synovium. The mRNA expression levels of HYBID, but not TMEM2, in osteoarthritic synovium positively correlated with distribution of lower-molecular-weight HA with below 1000 kDa in SF. HA-degrading activity in osteoarthritic synovial fibroblasts was abrogated by siRNA-mediated knockdown of HYBID. Among the 12 factors examined, IL-6 significantly up-regulated the HYBID expression and HA-degrading activity in osteoarthritic synovial fibroblasts. These data suggest that HYBID overexpressed by IL-6-stimulated synovial fibroblasts is implicated in HA degradation in osteoarthritic synovium.

Remnant preservation provides good clinical outcomes after anterior cruciate ligament reconstruction.

PURPOSE: To evaluate the association of remnant preservation (RP) and non-RP (NRP) with patient-reported outcome measures and subsequent graft rupture at a minimum 2-year follow-up after anterior cruciate ligament (ACL) reconstruction. METHODS: Patients in this retrospective study underwent primary isolated ACL reconstruction by the RP or NRP technique with a four- to five-strand hamstring tendon graft. Multivariate linear or logistic regression and Cox regression analyses were performed to compare the physical and psychological outcomes by the International Knee Documentation Committee subjective knee form (IKDC-SKF) and the Japanese Anterior Cruciate Ligament questionnaire 25 (JACL-25), respectively; satisfaction rate; and prognosticators of graft rupture. RESULTS: In total, 120 patients (mean age, 30.6 ± 12.7 years; 54 RP, 66 NRP) with a mean follow-up of 3.2 ± 1.6 years were enrolled in this study. At the latest postoperative follow-up, the RP group showed a mean IKDC-SKF score of 92.3 ± 8.5 and mean JACL-25 score of 13.2 ± 11.2, while these scores in the NRP group were 86.4 ± 12.2 and 24.4 ± 19.5, respectively (P = 0.016 and 0.007, respectively). No significant differences were found in the return-to-sports rate (RP vs. NRP, 79.5% vs. 67.5%) or satisfaction rate (RP vs. NRP, 89.2% vs. 74.4%) (n.s.); however, a significant difference was found in the rate of return to the preinjury sports level (RP vs. NRP, 64.1% vs. 37.5%; P = 0.014). The graft rupture rate was significantly higher in the NRP than RP group (9/66 vs. 1/54; hazard ratio 9.29; 95% confidence interval 1.04-82.81). Younger age (≤ 18 years) was the other important risk factor for graft rupture (hazard ratio 8.67; 95% confidence interval 2.02-37.13). CONCLUSION: Patients who underwent ACL reconstruction with the RP technique obtained somewhat better physical and psychological results than those who underwent ACL reconstruction with the NRP technique. With respect to clinical relevance, patients treated with the RP technique may obtain better outcomes in terms of graft rupture and return to the preinjury sports level than those treated with the NRP technique, but with no differences in overall return to sports or satisfaction. LEVEL OF EVIDENCE: IV.

Use of Dual Mobility Acetabular Component and Anterior Approach in Patients With Displaced Femoral Neck Fracture.

BACKGROUND: Although the antidislocation effect of total hip arthroplasty (THA) via the direct anterior approach (DAA) with dual mobility cup (DMC) for displaced femoral neck fracture (FNF) has already been reported, the clinical result of DMC-DAA-THA for displaced FNF in terms of mortality, complications, and walking ability are still unclear. METHODS: 106 cases with DMC-DAA-THA for displaced FNF were investigated of dislocation; perioperative complications; 3-, 6-, and12-month mortality rate; and pre/early postoperative walking ability. The walking ability was stratified into the following four categories: (1) use of a wheelchair (no walking), (2) walking alongside a support (including walkers designed for the elderly), (3) walking using one stick, and (4) unaided walking. RESULTS: There was no dislocation withing one-year postoperative. The 3-, 6-, and 12-month mortality rate was 2.8%, 4.7%, and 5.7%. Total complications occurred in 14 cases (14.7%). Although there was no revision surgery, two cases (1.9%) of intraoperative fracture treated without additional fixation, and one case of postoperative fracture was occurred. Among patients with preinjury walking category 2, 3, and 4 (total 94 cases), the number of patients who recovered same walking category at two-week postoperation was 56 cases (59.6%). CONCLUSIONS: Our study demonstrated that DMC-DAA-THA for displaced FNF offered quick recovery of walking ability with no dislocation and low one-year mortality rate. We believe that the combination of early postoperative recovery due to the minimal invasiveness of the DAA and decreased dislocation rate due to increased range of motion by DMC and adequate soft tissue tension by DAA contributed to null dislocation.

Validation and defining the minimal clinically important difference of the Japanese version of the IKDC Subjective Knee Form.

BACKGROUND: This study aimed to validate and determine the minimal clinically important difference (MCID) in the Japanese version of the International Knee Documentation Committee Subjective Knee Form (Japanese IKDC-SKF) for patients with anterior cruciate ligament (ACL) injuries. METHODS: This prospective study was performed using the COnsensus-based Standards for the selection of health status Measurement INstruments (COSMIN) guideline to assess the measurement properties of reliability, responsiveness, validity, and interpretability of the Japanese IKDC-SKF. RESULTS: A total of 152 patients were enrolled in the study. The Japanese IKDC-SKF had excellent internal consistency [Cronbach's alpha (95% confidence interval, CI) was 0.90 (0.88-0.92), and the test-retest reliability [intraclass correlation coefficient, ICC2,1 (95% CI)] was 0.97 (0.94-0.98). The content validity (r), which was interpretable between the Japanese IKDC-SKF and the Japanese Anterior Cruciate Ligament questionnaire 25 was -0.87 (P < 0.001). The construct validity for the IKDC-SKF was 86% (six of seven hypotheses were consistent with the results), also indicating high validity. Responsiveness of the Japanese IKDC-SKF was confirmed, with an acceptable area under the curve of 0.81 and a large effect size (Cohen's d of 0.8). There were no floor or ceiling effects. The MCID for the Japanese IKDC-SKF for ACL injury was 10.7. CONCLUSIONS: Our results indicate that the Japanese version of the IKDC-SKF is a reliable, valid, and responsive measurement instrument with which to evaluate the physical function of patients with ACL injuries.

Does increased diameter of metal femoral head associated with highly cross-linked polyethylene augment stress on the femoral stem and cortical hypertrophy?

PURPOSE: Cortical hypertrophy (CH) after total hip arthroplasty (THA) is thought as a process of femoral cortical functional adaptation against the stem. However, no study has been performed to investigate the association between CH and femoral head size. The purpose of this study is to investigate the factors related to femoral CH around the cementless stem after THA. METHODS: THAs in 31 patients using 36-mm metal head and as a control, age-matched 62 THAs with 32-mm metal head have been analyzed. Radiographs were reviewed at four years to determine cortical thickness change from immediate post-operative one. Pre-operative and immediate post-operative radiographs were used to calculate the femoral morphology, canal fill ratio, stem alignment, and femoral and acetabular offset. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for CH. RESULTS: Patients with a 36-mm metal head had a significantly higher rate of severe CH (P = 0.001) than those with a 32-mm metal head. The multivariate logistic regression analysis with dependent variables of CH showed that the use of a 36-mm metal head had a significantly positive effect on CH. The odds ratio of a 36-mm metal head in mild CH was 2.517 (95% confidence interval, 1.032-6.143; P = 0.043), and that in severe CH was 8.273 (95% confidence interval, 2.679-25.551; P = 0.000). Age and the canal flare index were weakly and negatively influenced by mild CH. CONCLUSIONS: The use of a 36-mm metal head was the dominant risk factor for CH.

Physiologic Leg Bowing is not a Physiologic Condition but Instead is Associated with Vitamin D Disorders in Toddlers.

When children around 2-year-old show leg bowing without lower-limb radiographic abnormalities for rickets, the leg bowing is classified as "physiologic" genu varum without conducting a blood test. However, it has recently been suggested that toddlers who are diagnosed with physiologic genu varum may in fact have some form of bone metabolic disorder. In this 1:2 case-control study, blood samples were obtained from 33 toddlers with genu varum without radiographic abnormalities for rickets and 66 age- and gender-matched healthy children. Serum alkaline phosphatase (sALP), intact parathyroid hormone (siPTH), 25-hydroxy vitamin D [s25(OH)D], calcium (sCa), and inorganic phosphate (sP) were measured. s25(OH)D of the subjects with genu varum (24.8 ng/ml) were significantly lower than those of the control (33.6 ng/ml) (p < 0.001). The frequency of vitamin D insufficiency/deficiency (< 20 ng/ml) of the subjects with genu varum (39%) was significantly higher than that in the control (14%) (p = 0.004) (odds ratio by vitamin D insufficiency/deficiency: 4.1 [1.5-11.1, p = 0.004]). sCa in subjects with genu varum (10.2 ng/ml) were significantly higher than in control (9.8 ng/ml) (p < 0.001), as were sALP (1057 IU/l) and siPTH (28.4 pg/ml) (740 IU/l and 8.8 pg/ml in control, respectively; p < 0.001). siPTH levels were associated with s25(OH)D levels in subjects with genu varum (r = - 0.57, p < 0.001), while no association was observed in the control (r = 0.11, p = 0.36). Genu varum without radiographic abnormalities of rickets was associated with both vitamin D and bone-metabolic disorders in toddlers, indicating that physiologic genu varum is not a physiologic condition in toddlers.

Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis.

BACKGROUND: Congenital scoliosis (CS) is a common vertebral malformation. Spondylocostal dysostosis (SCD) is a rare skeletal dysplasia characterised by multiple vertebral malformations and rib anomalies. In a previous study, a compound heterozygosity for a null mutation and a risk haplotype composed by three single-nucleotide polymorphisms in TBX6 have been reported as a disease-causing model of CS. Another study identified bi-allelic missense variants in a SCD patient. The purpose of our study is to identify TBX6 variants in CS and SCD and examine their pathogenicity. METHODS: We recruited 200 patients with CS or SCD and investigated TBX6 variants. We evaluated the pathogenicity of the variants by in silico prediction and in vitro experiments. RESULTS: We identified five 16p11.2 deletions, one splice-site variant and five missense variants in 10 patients. In vitro functional assays for missense variants identified in the previous and present studies demonstrated that most of the variants caused abnormal localisation of TBX6 proteins. We confirmed mislocalisation of TBX6 proteins in presomitic mesoderm cells induced from SCD patient-derived iPS cells. In induced cells, we found decreased mRNA expressions of TBX6 and its downstream genes were involved in somite formation. All CS patients with missense variants had the risk haplotype in the opposite allele, while a SCD patient with bi-allelic missense variants did not have the haplotype. CONCLUSIONS: Our study suggests that bi-allelic loss of function variants of TBX6 cause a spectrum of phenotypes including CS and SCD, depending on the severity of the loss of TBX6 function.

Segmental coupling effects during correction of three-dimensional lumbar deformity using lateral lumbar interbody fusion.

PURPOSE: Lateral lumbar interbody fusion (LLIF) has been performed to correct spinal deformity associated with lumbar degenerative disease. Although its usefulness has been studied, there are no reports of quantitative evaluation in three dimensions. Our purpose is to quantitate 3D deformity of the patients with lumbar degenerative disease and correction of the deformity by LLIF using patient-specific 3D CT models. METHODS: We measured the disc height and 3D alignment of the lumbar spine in 28 patients with degenerative disease undergoing LLIF using patient-specific 3D CT models created preoperatively and 3 months after surgery. The 3D alignment was calculated as wedge, lordosis and axial rotation angles at each motion segment. The disc height and the rotational angles were compared between before and after LLIF. RESULTS: A strong positive correlation was found between the wedge angle and the axial rotation angles (r = 0.718, P < 0.001) in the patients with lumbar degenerative disease preoperatively. The wedge and axial rotation angles decreased after surgery (P < 0.001 and P < 0.001, respectively). A positive correlation was found between the corrected wedge angle and the corrected axial rotation angle (r = 0.46, P < 0.001). CONCLUSION: The present study demonstrated positive correlations between the wedge deformity and the axial rotational deformity in the patients with lumbar degenerative disease. The axial rotational deformity was simultaneously corrected with LLIF only by leveling the intervertebral wedge deformity via cage insertion without additional correction procedure. These slides can be retrieved under Electronic Supplementary Material.

Increased Stiffness of Rotator Cuff Tendons in Frozen Shoulder on Shear Wave Elastography.

OBJECTIVES: To evaluate the stiffness and morphologic characteristics of the capsule, rotator cuff tendons and muscles, coracohumeral ligament (CHL), and long head of the biceps in patients with frozen shoulder using shear wave elastography (SWE) with B-mode ultrasound. METHODS: Thirty-two patients with frozen shoulder were divided into freezing and frozen phases. All patients had limitations of their range of motion without rotator cuff tears. Stiffness was measured by SWE in the supraspinatus (SSp) tendon, infraspinatus (ISp) tendon, SSp muscle, ISp muscle, teres minor muscle, upper and lower trapezius muscles, posterior capsule, CHL, and long head of the biceps. The posterior capsule and CHL thicknesses were also investigated with B-mode ultrasound. All values were compared in the affected and unaffected shoulders in each phase. RESULTS: The SWE values for the SSp and ISp tendons in the freezing phase and the CHL in the frozen phase were significantly greater on the affected side than the unaffected side (mean ± SD, 280.4 ± 125.3 versus 178.1 ± 73.3, 318.4 ± 110.7 versus 240.8 ± 91.5, and 287.2 ± 135.3 versus 214.1 ± 91.1 kPa, respectively; P < .05). The posterior capsule in both the freezing and frozen phases and the CHL in the frozen phase were significantly thicker on the affected side than the unaffected side (1.3 ± 0.2 versus 0.9 ± 0.3, 1.2 ± 0.4 versus 0.9 ± 0.3, and 4.4 ± 1.4 versus 3.3 ± 1.1 mm; P < .01). CONCLUSIONS: The SWE values of the both SSp and ISp tendons increased in the freezing phase, and that of the CHL also increased in the frozen phase. Not only the change in thickness of the capsule but also the change in stiffness of the rotator cuff may correlate with frozen shoulder.

Assessment of Predictive Biomarkers of the Response to Pazopanib Based on an Integrative Analysis of High-grade Soft-tissue Sarcomas: Analysis of a Tumor Sample from a Responder and Patients with Other Soft-tissue Sarcomas.

BACKGROUND: Soft-tissue sarcomas are a rare group of malignant tumors that usually are treated with surgical excision and radiation therapy, but recently, pazopanib, an oral tyrosine kinase inhibitor, has been used in patients with metastases who do not respond to standard chemotherapy regimens. Based on patients with advanced soft-tissue sarcomas who had received prior chemotherapy, several clinical studies have reported the survival and sensitivity (approximately 5% to 10% sensitive) of patients with soft-tissue sarcomas treated with pazopanib. Recently, next-generation sequencing (NGS) technologies have been used to provide a wide genetic information and to develop personalized medicine in cancer treatment. However, there are few reports and no genetic analyses of patients with soft-tissue sarcomas who had a complete response (CR) to pazopanib. QUESTIONS/PURPOSES: We described the clinicopathologic features of a patient with a rare, advanced soft-tissue sarcoma who achieved a CR to pazopanib treatment. Furthermore, integrative analyses using NGS and arrays were performed to elucidate characteristic alterations, including gene mutations, copy number changes, and protein expression that were associated with response to pazopanib. Additionally, functional analyses consisting of in vitro and in vivo assays were also performed to elucidate whether the identified alterations were associated with oncogenic abilities and drug responses. METHODS: In a sample from a 70-year-old woman with an advanced soft-tissue sarcoma treated for 1 month with 800 mg of oral pazopanib daily, CT scans demonstrated a CR to treatment. To our knowledge, there have been no patients with soft-tissue sarcomas among several clinical trials of pazopanib that have achieved a CR and therefore, our patient is considered to be extremely rare. We performed an integrative analysis including whole-exome sequencing, transcriptome sequencing, and phosphorylation profiling of receptor tyrosine kinases (RTK) using tumor samples from a patient with a CR matched to normal samples. From here on we will refer to this patient as having a CR, although a short term high-grade partial response may be more accurate. These analyses were performed using NGS and the phosphoreceptor tyrosine kinase (phospho-RTK) array. As a validation study, we also performed target sequencing using three samples from patients with long-term stable disease and two samples from patients with progressive disease who responded to pazopanib treatment. In addition, characteristic gene alterations that were identified according to the response to pazopanib in one patient with a CR, in three patients with long-term stable disease, and in 27 patients with high-grade soft-tissue sarcomas with different histologic subtypes and different responses to pazopanib were verified by quantitative real-time polymerase chain reaction. We conducted a focus formation assay to evaluate the transforming activities of these genomic alterations. RESULTS: In the patient with a CR to pazopanib, we identified several somatic mutations including Fms related receptor tyrosine kinase 1 (FLT1) p.G38S, platelet-derived growth factor receptor alpha (PDGFRA) p.T83S, and platelet-derived growth factor receptor beta (PDGFRB) exon 13 skipping. Amplification at chromosome 12q13-14 encompassing GLI family zinc finger 1 (GLI1) and cyclin-dependent kinase-4 (CDK4) was also detected. Furthermore, an elevated PDGFRB phosphorylation level was observed in the tumor. In target sequencing analyses in five patients, one of three patients with long-term stable disease had 12q13-14 amplification. The mRNA expression of GLI1, CDK4, and pazopanib targets including PDGFRA, PDGFRB, vascular endothelial growth factor receptor (VEGFR)1-3, and stem cell factor receptor (KIT) in samples from the patient with a CR, and 27 patients with high-grade soft-tissue sarcomas was verified. The expression of GLI1 was characteristically increased in the patient with a CR and in those with long-term stable disease relative to other patients with soft-tissue sarcomas. Overexpression of GLI1 showed strong transforming potential in 3T3 cells. Moreover, the overexpression of GLI1 upregulated the expression of the PDGFRB protein and promoted phosphorylation, which was dose-dependently inhibited by pazopanib. However, inhibition of GLI1-induced transformation by pazopanib was limited in the focus formation assay; therefore, mechanisms other than PDGFRB activation may contribute to transformation. CONCLUSIONS: We identified several gene alterations that might be associated with a CR and long-term stable disease in patients who received pazopanib for advanced soft-tissue sarcomas. We therefore believe that this distinct molecular profile warrants further investigation to identify predictive biomarkers of the response to pazopanib. CLINICAL RELEVANCE: Our findings identify molecular mechanisms that possibly explain the high sensitivity of soft-tissue sarcomas to pazopanib and may lead to the development of predictive biomarkers and novel therapies in patients with this and other types of soft-tissue sarcomas.

Relationship between characteristics of spinopelvic alignment and quality of life in Japanese patients with ankylosing spondylitis: a cross-sectional study.

BACKGROUND: Studies on characteristic spinal deformities in Japanese patients with ankylosing spondylitis (AS) and data demonstrating a relationship between health-related quality of life (HRQOL) and spinopelvic alignment in these patients are lacking. METHODS: In this cross-sectional study, 50 patients with AS and without a surgical history, vertebral body fracture, or scoliosis as well as 30 control patients with degenerative lumbar kyphoscoliosis (DLKS) were included. Data collected included patient sex, age, spinopelvic parameters on sagittal full-spine standing radiographs, and HRQOL questionnaire responses. Student's t-test was used to compare the characteristics of spinopelvic parameters between the groups. A multiple regression analysis was performed to analyze correlations between spinopelvic parameters and HRQOL in the AS group. RESULTS: Global kyphosis (GK; T1-12 angle) was significantly greater in the AS group than in the DLKS group (P < 0.001), whereas the pelvic tilt (PT; posterior PT angle) was smaller in the AS group (P = 0.006). Radiographic parameters correlated with HRQOL in the AS group. Multiple regression analysis identified the sagittal vertical axis (SVA) and sacral slope (SS) as factors influencing the SRS-22 total score and SVA and GK as factors influencing Japanese Orthopaedic Association Back Pain Evaluation Questionnaire mental health (subdomain). CONCLUSIONS: Patients with AS did not use lumbar lordosis or posterior PT to compensate for their large thoracic kyphosis due to spinopelvic ankylosis. These patients showed a unique compensation pattern. The correlation/regression analysis revealed a correlation between radiographic parameters and HRQOL in patients with AS, with particular importance of SVA, SS, and GK for clinical results in AS.

Anatomic Analysis of the Attachment of the Posteroinferior Labrum and Capsule to the Glenoid: A Cadaveric Study.

PURPOSE: To measure the height of the posteroinferior glenohumeral ligament (PIGHL) attachment to the labrum and the depth of the posteroinferior labrum to the glenoid, macroscopically, and to investigate the morphology of the attachment of the posteroinferior labrum to the glenoid, histologically. METHODS: Fifty cadaveric shoulders without exposed subchondral bone on the glenoid and detached posterior labrum were used. We examined the frequency of the heights of the PIGHL attachments to the labrum and the length of the labral attachment on the glenoid rim at the 7, 8, 9, and 10 o'clock positions, macroscopically. According to morphology of the histological labral attachments, it was divided into 3 groups. Labra attached on the articular surface and the glenoid neck were defined as the SN type, while labra attached only to the glenoid neck constituted labra attached to the bone and side of the articular cartilage (Nc type) and labra attached only to bone (Nb type). RESULTS: The PIGHL attached from 7 o'clock to 9 o'clock in 48 shoulders (96%). The mean labral attachment at the 7 o'clock position was 6.3 ± 1.0 mm (range, 4.6-9.4 mm), which was significantly longer than at the other positions (P < .05). Histologically, the frequency of SN type attachment was 49 (98%) shoulders at the 7 o'clock position. CONCLUSIONS: The PIGHL attached between 7 and 9 o'clock in 96% of the shoulders. In 98% of the shoulders, the labrum did not attach to the articular surface, but attached to both the articular cartilage and the bone of the glenoid neck at 7 o'clock. CLINICAL RELEVANCE: The posteroinferior labrum should be repaired widely at the 7 o'clock position and not on the articular surface because the labrum attached anatomically to the glenoid neck.

Pelvic mobility before and after total hip arthroplasty.

BACKGROUND: Pre-operative evaluation of pelvic motion using the sacral slope (SS) has been proposed for risk assessment of dislocation after total hip arthroplasty (THA). The purposes of this study were to elucidate the statistical characteristics of pre-operative and post-operative pelvic mobility and investigate the relationship between pre-operative spinopelvic factors and post-operative pelvic mobility. METHODS: Eighty-six patients with osteoarthritis were assessed. The parameters evaluated were lumbar lordosis angle and the SS in the standing and sitting preo-peratively and post-operatively. The pelvic mobility was defined as the difference in the SS between standing and sitting. The presence of osteoarthritis in the contralateral hip, spondylolisthesis, vertebral compression fracture and lumbar scoliosis was investigated. RESULTS: The median (interquartile range) pre-operative and post-operative pelvic mobility was 19.0 (13.75-27.0) and 16.0 (10.0-25.25), respectively, with significant difference. The pre-operative SS while standing and pre-operative pelvic mobility were associated with post-operative pelvic mobility (r = 0.409, P < 0.05 and r = 0.533, P < 0.05). The multivariate linear regression analysis showed that the following factors contributed to post-operative pelvic mobility: incidence of osteoarthritis in the contralateral hip, lumbar scoliosis, pre-operative SS while standing and pre-operative SS while sitting. CONCLUSION: The pre-operative and post-operative pelvic mobility is not equal and ranges widely among patients. In addition to assessment of pre-operative pelvic mobility, other pre-operative spinopelvic factors may also influence post-operative pelvic mobility, such as the SS while standing and sitting, the condition of the contralateral hip and the presence of scoliosis. Risk assessment for dislocation using these pre-operative factors may be useful before THA.

Bowing-head sign: rare but detectable in pre-catastrophic hip implant failure.

Recently, catastrophic failure (i.e., dissociation between the metal femoral head and stem due to stem neck deformation) after total hip arthroplasty (THA) has been reported. Early detection of this complication is very important, because it is accompanied by an increased cobalt concentration in the body, which might influence systemic conditions such as heart failure and immune system diseases. However, early detection of stem neck deformation is considered as difficult. In most cases in the literatures, the diagnosis was made at the time of acute dissociation. We report a case of early detection of stem neck deformation with the 'Bowing-head sign' before acute dissociation. The patient is a 71-year old woman complained of a clicking sensation in the right hip during regular follow-up after THA with a 32-mm cobalt/chromium head with polyethylene insert for osteoarthritis performed 7 years previously. The plain radiograph showed that the angle between the metal femoral head and the axis of the stem neck was not perpendicular ('Bowing-head sign'). Dynamic evaluation under fluoroscopy showed movement of the stem neck in the metal femoral head with hip abduction and adduction. Laboratory data showed abnormal serum cobalt (6.3 µg/L, normal < 1 µg/L) and chromium (3.8 µg/L, normal < 5 µg/L) levels. Considering those radiographic findings, deformation of the stem neck due to trunnionosis was diagnosed, and elective revision surgery was performed without any complications. Plain radiographs after THA should be assessed with attention to this complication, 'Bowing-head sign' must not be overlooked.

[Spinal Intradural Extramedullary Ependymoma:A Case Report].

Ependymoma is the most common primary intramedullary tumor of the spinal cord, accounting for a quarter of these tumors. We experienced a case of 'ependymoma of the spinal cord with a cystic lesion that presented as an intradural extramedullary tumor extending from the thoracic to lumbar vertebrae. In review of past literature on reports of spinal intradural extramedullary ependymoma, lesions spanning three or more vertebrae with cystic lesions were frequent, and about half were World Health Organization grade II or higher. Dissemination or recurrence of these tumors may occur after surgery. There is no consensus on postoperative adjuvant therapy for intradural extramedullary spinal ependymoma, but careful consideration should be given to the intraoperative findings and the characteristics of the tumor.

Locked wires fixator for fractures of the distal third of the radius and ulna in children.

BACKGROUND: Prevention of redisplacement is an issue after the treatment of fractures of the distal third of the radius in children. In this study, we used a locked wires fixator for this type of fracture and achieved favorable treatment outcomes. METHODS: The subjects were 8 children with fractures of the distal third of the radius (male: 7, female: 1, mean age: 9.0 years old) who underwent surgery with locked wires fixators and were able to be evaluated 12 months after surgery. Immobilization was not applied after surgery. The locked wires fixator or K-wire was removed when the bridging callus was observed on plain radiography 4-6 (mean 5.5) weeks after surgery in all patients. The presence of bone union, functional outcomes, and complications were investigated postoperatively. RESULTS: All patients achieved bone union without redisplacement excellent function. The pin site infection was observed in two patients. CONCLUSIONS: The locked wires fixator may be a new useful treatment method for fractures likely to cause postoperative redisplacement.