Hypoxia activates SREBP2 through Golgi disassembly in bone marrow-derived monocytes for enhanced tumor growth.

Bone marrow-derived cells (BMDCs) infiltrate hypoxic tumors at a pre-angiogenic state and differentiate into mature macrophages, thereby inducing pro-tumorigenic immunity. A critical factor regulating this differentiation is activation of SREBP2-a well-known transcription factor participating in tumorigenesis progression-through unknown cellular mechanisms. Here, we show that hypoxia-induced Golgi disassembly and Golgi-ER fusion in monocytic myeloid cells result in nuclear translocation and activation of SREBP2 in a SCAP-independent manner. Notably, hypoxia-induced SREBP2 activation was only observed in an immature lineage of bone marrow-derived cells. Single-cell RNA-seq analysis revealed that SREBP2-mediated cholesterol biosynthesis was upregulated in HSCs and monocytes but not in macrophages in the hypoxic bone marrow niche. Moreover, inhibition of cholesterol biosynthesis impaired tumor growth through suppression of pro-tumorigenic immunity and angiogenesis. Thus, our findings indicate that Golgi-ER fusion regulates SREBP2-mediated metabolic alteration in lineage-specific BMDCs under hypoxia for tumor progression.

Changes in Spinal Instability After Conventional Radiotherapy for Painful Vertebral Bone Metastases.

OBJECTIVE: Precise assessment of spinal instability is critical before and after radiotherapy (RT) for evaluating the effectiveness of RT. Therefore, we retrospectively evaluated the efficacy of RT in spinal instability over a period of 6 months after RT, utilizing the spinal instability neoplastic score (SINS) in patients with painful spinal metastasis. We retrospectively evaluated 108 patients who received RT for painful vertebral metastasis in our institution. Mechanical pain at metastatic vertebrae, radiological responses of irradiated vertebrae, and spinal instability were assessed. Follow-up assessments were done at the start of and at intervals of 1, 2, 3, 4, and 6 months after RT, with the pain disappearing in 67%, 85%, 93%, 97%, and 100% of the patients, respectively. The median SINS were 8, 6, 6, 5, 5, and 4 at the beginning and after 1, 2, 3, 4, and 6 months of RT, respectively. Multivariate analysis revealed that posterolateral involvement of spinal elements (PLISE) was the only risk factor for continuous potentially unstable/unstable spine at 1 month. In conclusion, there was improvement of pain, and recalcification results in regaining spinal stability over time after RT although vertebral body collapse and malalignment occur in some irradiated vertebrae. Clinicians should pay attention to PLISE in predicting continuous potentially unstable/unstable spine.

High Fracture Rate of AVANTA Silicone Implant Following Arthroplasty of the Thumb MCP Joint of Rheumatoid Arthritis Patients with Boutonniere Deformities.

We retrospectively investigated the mid-term outcomes of arthroplasty using the AVANTA silicone implant for thumb metacarpophalangeal (MCP) joints with boutonniere deformity in patients with rheumatoid arthritis (RA). This study involved 36 thumbs of 33 RA patients with a mean follow-up period of 5.1 years (range, 2.0-13.3). Postoperatively, the mean extension was significantly increased and the mean flexion was significantly decreased (p<0.001, p<0.001, respectively), resulting in the mean arc of range of motion (ROM) shifting in the direction of extension after surgery. Implant fracture was observed in 10 thumbs (28%), and 4 of these (11%) underwent revision surgery. The survivorship with implant fracture and revision surgery as endpoints were 73.4% and 91.8% at 5 years, respectively. The preoperative arc of ROM and the postoperative flexion range of the implant-fracture group were significantly greater than those in the no-implant-fracture group (p=0.039, 0.034, respectively). These results suggest the importance of patient education and careful rehabilitation to prevent excessive flexion. Overall, the AVANTA silicone implant showed a relatively high rate of implant fracture at our institute.

Inhibitory Effect of a Tankyrase Inhibitor on Mechanical Stress-Induced Protease Expression in Human Articular Chondrocytes.

We investigated the effects of a Tankyrase (TNKS-1/2) inhibitor on mechanical stress-induced gene expression in human chondrocytes and examined TNKS-1/2 expression in human osteoarthritis (OA) cartilage. Cells were seeded onto stretch chambers and incubated with or without a TNKS-1/2 inhibitor (XAV939) for 12 h. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 8% elongation, 30 min) was applied and the gene expression of type II collagen a1 chain (COL2A1), aggrecan (ACAN), SRY-box9 (SOX9), TNKS-1/2, a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), and matrix metalloproteinase-13 (MMP-13) were examined by real-time PCR. The expression of ADAMTS-5, MMP-13, nuclear translocation of nuclear factor-κB (NF-κB), and ß-catenin were examined by immunocytochemistry and Western blotting. The concentration of IL-1ß in the supernatant was examined by enzyme-linked immunosorbent assay (ELISA). TNKS-1/2 expression was assessed by immunohistochemistry in human OA cartilage obtained at the total knee arthroplasty. TNKS-1/2 expression was increased after CTS. The expression of anabolic factors were decreased by CTS, however, these declines were abrogated by XAV939. XAV939 suppressed the CTS-induced expression of catabolic factors, the release of IL-1ß, as well as the nuclear translocation of NF-κB and ß-catenin. TNKS-1/2 expression increased in mild and moderate OA cartilage. Our results demonstrated that XAV939 suppressed mechanical stress-induced expression of catabolic proteases by the inhibition of NF-κB and activation of ß-catenin, indicating that TNKS-1/2 expression might be associated with OA pathogenesis.

Influence of Janus kinase inhibitors on early postoperative complications in patients with rheumatoid arthritis undergoing orthopaedic surgeries.

OBJECTIVE: We retrospectively reviewed the records of rheumatoid arthritis (RA) patients who underwent orthopaedic surgery to examine the influence of the perioperative use of Janus kinase (JAK) inhibitors on early postoperative complications. PATIENTS AND METHODS: Thirty-two patients with RA under disease control with JAK inhibitors who underwent 49 orthopaedic procedures were included in the study. Patient records after surgery were investigated for surgical site infection (SSI), delayed wound healing (DWH), a flare-up of the disease, preoperative and postoperative absolute lymphocyte counts (ALCs), venous thromboembolism, and other postoperative complications. RESULTS: JAK inhibitors were continued during the perioperative period in 31 procedures. In the remaining 18 procedures, JAK inhibitors were discontinued perioperatively with a mean discontinuation period of 2.4 days. No instances of SSI were identified in any patient during at least 90 days' follow-up, while DWH was seen in one patient. Disease flare-up was noted in two patients after 3 and 9 days of discontinuation of JAK inhibitors, respectively. The ALCs significantly decreased on postoperative Day 1 (P < .0001), and there was a significant correlation between pre- and post-one-day ALCs (r = 0.75, P < .0001). CONCLUSION: JAK inhibitors seem to be safe during the perioperative period of orthopaedic surgery.

Metabolic adaptations of cancer in extreme tumor microenvironments.

Cancer cells are highly heterogeneous to adapt to extreme tumor microenvironments (TMEs). TMEs challenge cancer cells via hypoxia, nutrition starvation, and acidic pH, promoting invasion and metastasis concomitant with genetic, epigenetic, and metabolic alterations. Metabolic adaptation to an extreme TME could allow cancer cells to evade cell death and immune responses, as well as resulting in drug resistance, recurrence, and poor patient prognosis. Therefore, elucidation of the metabolic adaptation of malignant cancer cells within TMEs is necessary, however, most are still elusive. Recently, adaptation of cancer cells within the TME can be analyzed via cell-cell interactions at the single-cell level. In addition, information into organelle-organelle interactions has recently been obtained. These cell-cell, and organelle-organelle interactions demonstrate the potential as new cancer therapy targets, as they play essential roles in the metabolic adaptation of cancer cells to the TME. In this manuscript, we review (1) metabolic adaptations within tumor microenvironments through (2) cell-to-cell, and (3) organelle-organelle metabolic interactions.

Fracture Line Distributions of Undisplaced Distal Radius Fractures in Relation to Rupture of the Extensor Pollicis Longus Tendon.

Rupture of the extensor pollicis longus (EPL) tendon is a known complication after undisplaced distal radius fracture (DRF). However, no report has revealed the relationship between EPL tendon rupture and the fracture pattern. Thus, this study aimed to investigate the characteristics of fractures at risk of EPL tendon rupture using fracture line mapping of undisplaced DRFs. This study used computed tomography imaging data of undisplaced DRFs with (n=18) and without EPL tendon rupture (n=52). Fracture lines obtained from 3D reconstruction data were drawn manually after matching with a 2D template wrist model. Fracture maps represented the fracture line distribution by superimposing the fracture lines of all 70 patients. Heat maps showed the relative frequency of the fracture lines as a gradual color change. Fracture lines of cases with EPL tendon rupture were concentrated in the proximal border of Lister's tubercle. By contrast, fracture lines of cases without EPL tendon rupture were relatively dispersed.

CD30-targeted therapy induces apoptosis of inflammatory cytokine-stimulated synovial fibroblasts and ameliorates collagen antibody-induced arthritis in mice.

OBJECTIVE: It has been reported that levels of soluble CD30 in serum and joint fluid are significantly elevated in patients with rheumatoid arthritis (RA). This study aimed to investigate whether CD30 could be a therapeutic target for RA. METHODS: The expression and localization of CD30 were examined by immunohistochemical and double immunofluorescence staining on synovial tissue samples obtained from patients with RA or osteoarthritis (OA) during surgery. Changes in CD30 expression of fibroblast-like synoviocytes (FLS) from RA patients with or without TNFα and IL-1ß stimulation were examined by the polymerase chain reaction (PCR) and flow cytometry. Collagen antibody-induced arthritis (CAIA) was created in DBA/1 mice, and the therapeutic effect of brentuximab vedotin (BV) was examined by clinical score, histological findings and measurement of serum levels of SAA, IL-6, and TNFα. RESULTS: CD30 expression was significantly higher in samples from patients with RA than from those with OA. Double immunofluorescence showed a low rate of co-localization of CD30 with CD20 or CD90, but a high rate of co-localization of CD30 and CD138. CD30 mRNA expression was upregulated 11.7-fold in FLS following stimulation by inflammatory cytokines. The clinical scores of CAIA mice were significantly lower following both BV treatments, however, the histological scores of CAIA mice were significantly lower only following treatment with high dose BV (70 mg/kg). CONCLUSIONS: CD30 was expressed on immunocompetent cells in synovial tissue from RA patients and in cytokine-stimulated FLS in vitro. High dose BV (70 mg/kg) showed significant therapeutic effects in ameliorating inflammation and joint destruction in CAIA mice, but low dose BV (30 mg/kg) was insufficient.

Subjective and Objective Outcomes of Surgery for Rheumatoid Forefoot Deformities Under the Current Treatment Paradigm.

We investigated the clinical outcomes of surgical procedures for the treatment of forefoot deformities in patients with rheumatoid arthritis. Twenty feet in 16 women (mean age 62.1 years) underwent corrective osteotomy of the first metatarsal bone with shortening oblique osteotomy of the lesser metatarsophalangeal joints (joint-preservation group), while 13 feet in 12 women (mean age 67.4 years) underwent arthrodesis of the first metatarsophalangeal joint with resection arthroplasty of the lesser metatarsophalangeal joints (joint-sacrifice group); mean follow-up for each group was 25.8 and 23.8 months, respectively. The mean total Japanese Society for Surgery of the Foot (JSSF) scale improved significantly from 64.2 to 89.2 in the joint-preservation group (p < .001), and from 54.2 to 74.2 in the joint-sacrifice group (p = .003). In the joint-preservation group, the postoperative range of motion (ROM) of the joint, walking ability, and activities of daily living scores of the JSSF scale were significantly higher than those in the joint-sacrifice group (p = .001, p = .001, and p = .019, respectively). There were no differences in the subscale scores of the self-administered foot evaluation questionnaire between 2 groups either pre- or postoperatively. No differences in the postoperative complications were found between 2 groups. Although the joint-sacrificing procedure resulted in lower objective outcomes than the joint-preserving procedure regarding the ROM of the joint, the walking ability, and the level of activities of daily living, both procedures resulted in similar treatment outcomes when evaluated by the subjective measures.

Japanese version of Patient-Rated Elbow Evaluation is a useful outcome measure that potentially reflects hand function in patients with rheumatoid arthritis who underwent total elbow arthroplasty.

OBJECTIVES: We examined the relationship between the Japanese version of Patient-Rated Elbow Evaluation (PREE-J) and other established subjective and objective outcome measures in Japanese patients with rheumatoid arthritis (RA) who underwent total elbow arthroplasty (TEA). MATERIALS AND METHODS: This study involved 46 elbows of 40 RA patients. We collected clinical data 1 year after surgery, including the PREE-J, the Mayo Elbow Performance Score (MEPS), Disability of the Arm, Shoulder, and Hand (DASH), and Hand20. The correlation and responsiveness to PREE-J were evaluated compared with other outcome measures preoperatively and postoperatively. RESULTS: Almost all outcome measures were improved significantly after surgery. Preoperative PREE-J was significantly correlated with preoperative DASH, Hand20, and MEPS. Interestingly, postoperative PREE-J did not correlate with postoperative MEPS. Multiple regression analyses revealed that preoperative grip strength [B = -0.09; 95% confidence interval (95% CI) -0.17 to -0.01, p = 0.03] and preoperative Hand20 (B = 0.31, 95% CI 0.03-0.58, p = 0.03) were significant factors that might influence the postoperative PREE-J. CONCLUSIONS: The PREE-J was shown to correlate well with other preoperative outcome measures among the RA patients included in the current study. The postoperative PREE-J after TEA was influenced by the preoperative grip strength and function of the hand.

Relationship between clinical outcomes and nerve conduction studies before and after surgery in patients with carpal tunnel syndrome.

BACKGROUND: Nerve conduction study (NCS) is the only useful test for objective assessment of carpal tunnel syndrome (CTS). However, the relationship between pre- and postoperative NCS and clinical outcomes was unclear. This study aimed to determine whether pre- and postoperative (6 months) NCS could predict patient-oriented and motor outcomes (6 and 12 months postoperatively) in patients with CTS. METHOD: Of the 85 patients with CTS, 107 hands were analyzed from March 2011 to March 2020. All patients underwent open carpal tunnel release and were examined using the disabilities of the arm, shoulder and hand (DASH) questionnaire and grip strength (GS) preoperatively and 6 and 12 months postoperatively. Moreover, NCS was examined preoperatively and 6 months postoperatively. Distal motor latency (DML) and sensory conduction velocity (SCV) were the parameters used for NCS. The correlation coefficient between NCS and DASH or GS was calculated. A receiver operating characteristic curve was utilized to determine the NCS threshold value to predict DASH and GS improvement. RESULTS: The average scores of GS preoperatively and 6 and 12 months postoperatively were 21.3, 22.3, and 22.8, respectively. On the other hand, the average scores of DASH preoperatively and 6 and 12 months postoperatively were 28.8, 18.3, and 12.2, respectively. The average NCS scores (DML and SCV) preoperatively/6 months postoperatively were 7.3/5.4 and 27.8/36.7, respectively. Preoperative NCS did not correlate with DASH and GS. Postoperative SCV correlated with the change in grip strength (6-12 months, r = 0.67; 0-12 months, r = 0.60) and DASH (0-12 months, r = 0.77). Moreover, postoperative DML correlated with the change in DASH (6-12 months, r = - 0.33; 0-12 months, r = - 0.59). The prediction for the improvement of GS/DASH achieved a sensitivity of 50.0%/66.7% and a specificity of 100%/100%, at an SCV cutoff score of 38.5/45.0 or above. The prediction for improvement of GS/DASH achieved a sensitivity of 83.3%/66.7% and a specificity of 100%/66.7% at a DML cutoff score of 4.4/4.4 or below. CONCLUSION: NCS at 6 months postoperatively can be used to predict the improvement of clinical outcome after 6 months postoperatively in patients with CTS.

Differences between the root and horn cells of the human medial meniscus from the osteoarthritic knee in cellular characteristics and responses to mechanical stress.

BACKGROUND: Many histological, mechanical, and clinical studies have been performed on the medial meniscus posterior root attachment, as it often tears in patients with osteoarthritic knee. Medial meniscal root repair is recommended in clinical situations; however, to date, no studies have examined the differences between meniscal root and horn cells. The aim of this study was, therefore, to investigate the morphology, reaction to cyclic tensile strain, and gene expression levels of medial meniscal root and horn cells. METHODS: Meniscal samples were obtained from the medial knee compartments of 10 patients with osteoarthritis who underwent total knee arthroplasty. Root and horn cells were cultured in Dulbecco's modified Eagle's medium without enzymes. The morphology, distribution, and proliferation of medial meniscal root and horn cells, as well as the gene and protein expression levels of Sry-type HMG box 9 and type II collagen, were determined after cyclic tensile strain treatment. RESULTS: Horn cells had a triangular morphology, whereas root cells were fibroblast-like. The number of horn cells positive for Sry-type HMG box 9 and type II collagen was considerably higher than that of root cells. Although root and horn cells showed similar levels of proliferation after 48, 72, or 96 h of culture, more horn cells than root cells were lost following a 2-h treatment with 5% and 10% cyclic tensile. Sry-type HMG box 9 and α1(II) collagen mRNA expression levels were significantly enhanced in both cells after 2- and 4-h cyclic tensile strain (5%) treatment. CONCLUSIONS: Medial meniscal root and horn cells have distinct morphologies, reactions to mechanical stress, and cellular phenotypes. Our results suggest that physiological tensile strain is important to activate extracellular matrix production in horn cells.

The trend of treatment and conveyance system for upper extremity replantation in Japan: A nationwide population-based study from the Japan trauma data bank.

BACKGROUND: In Japan, microsurgical skill development and a system to transfer patients to an appropriate hospital for upper extremity amputation have been promoted; however, information about trends of replantation is limited. Therefore, the aim of this study was to clarify the trends in the treatment for upper extremity amputation using the Japan Trauma Data Bank (JTDB). METHODS: Data derived from JTDB (2004-2015) were used to quantify trends in the volume of replantation for upper extremity amputation including finger amputation. Trauma was diagnosed based on the Abbreviated Injury Scale code; a subgroup of patients who underwent replantation was delineated. We investigated patient demographics, infection rate, and characteristics of treating facilities. RESULTS: A total of 1240 patients underwent upper extremity amputation. Among these, 510 (41.1%) underwent replantation, and the rate of replantation did not change over the study period. The average age of patients who underwent or did not undergo replantation was 45.5 and 47.2 years, respectively. The proportion of the patients who were transferred to another hospital for treatment significantly decreased between 2004 (28.5%) and 2015 (16.3%) (P < 0.01). Time taken for transfer from the accident site to hospitals increased. The rate of patients who underwent replantation differed among different hospitals; however, higher-volume hospitals were more likely to perform replantation. CONCLUSION: The rate of patients transferred to another hospital decreased between 2004 and 2015; however, the rate of patients who underwent replantation remained unchanged. This suggests that the number of patients who were transported directly from the accident site to an appropriate hospital has increased, whereas the indication for care in each hospital remains unchanged. Common criteria for amputations are needed to address the differing rates of replantation among hospitals.

Detection of muscle fatigue caused by repeated posterior tongue lift movement from neck surface EMG: a pilot study.

BACKGROUND: Fatigue is an important factor for muscle strengthening in rehabilitation medicine. Frequency analysis has been regarded as the gold standard for muscle fatigue assessment in surface electromyography (EMG). However, there are no experiments quantifying fatigue with grouped discharge (GD), which is one of the historical phenomena observed in patients having fatigue, by using high sampling rate recording of EMG. OBJECTIVE: To investigate the effect of fatigue, which is induced by repeated posterior tongue lift movement (TLM), on the occurrence of GD peaks, thus, to provide possible basis as a parameter for future fatigue evaluation. METHODS: Nineteen healthy adults (9 men and 10 women) participated in this study. The muscle fatigue protocol consisted of repetitive posterior TLM and maximum voluntary contractions (MVC). Bilateral N-EMG (Neck surface EMG for measuring the muscle activity of the posterior tongue) was recorded. RESULTS: Subjective tongue fatigue at the end of the protocol was significantly higher than at beginning throughout the muscle fatigue protocol (p < .01). The frequency of occurrence of GD peaks was 0.9 ± 1.2 (per second) at the baseline in 33 of 38 subject sides, and significantly increased depending on fatigue progression (p < .01). CONCLUSION: It was shown that fatigue due to repetitive posterior tongue lifting resulted in significant increase in the frequency of occurrence of GD peaks. Especially, the nature of GD, showing very few occurrences at non-fatigue condition, might work as an advantageous property for its use in future absolute evaluation of fatigue phenomena.

Adipose-Derived Extract Suppresses IL-1ß-Induced Inflammatory Signaling Pathways in Human Chondrocytes and Ameliorates the Cartilage Destruction of Experimental Osteoarthritis in Rats.

We investigated the effects of adipose-derived extract (AE) on cultured chondrocytes and in vivo cartilage destruction. AE was prepared from human adipose tissues using a nonenzymatic approach. Cultured human chondrocytes were stimulated with interleukin-1 beta (IL-1ß) with or without different concentrations of AE. The effects of co-treatment with AE on intracellular signaling pathways and their downstream gene and protein expressions were examined using real-time PCR, Western blotting, and immunofluorescence staining. Rat AE prepared from inguinal adipose tissues was intra-articularly delivered to the knee joints of rats with experimental osteoarthritis (OA), and the effect of AE on cartilage destruction was evaluated histologically. In vitro, co-treatment with IL-1ß combined with AE reduced activation of the p38 and ERK mitogen-activated protein kinase (MAPK) pathway and nuclear translocation of the p65 subunit of nuclear factor-kappa B (NF-κB), and subsequently downregulated the expressions of matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4, IL-6, and IL-8, whereas it markedly upregulated the expression of IL-1 receptor type 2 (IL-1R2) in chondrocytes. Intra-articular injection of homologous AE significantly ameliorated cartilage destruction six weeks postoperatively in the rat OA model. These results suggested that AE may exert a chondroprotective effect, at least in part, through modulation of the IL-1ß-induced inflammatory signaling pathway by upregulation of IL-1R2 expression.

What Are the Results of Resection of Localized Dedifferentiated Liposarcomas in the Extremities?

BACKGROUND: Dedifferentiated liposarcoma (DDLPS) is a rare malignancy that transitions from an atypical lipomatous tumor to a sarcoma with a variable morphologic appearance. The behavior of this tumor in the retroperitoneum is aggressive, but the behavior of DDLPS in the extremities is less well-defined because it is rare. Few reports have assessed the imaging features and clinical outcomes of primary DDLPS in the extremities. QUESTIONS/PURPOSES: In patients with primary DDLPS of the extremity, we asked the following questions: (1) How frequently do additional primary malignancies occur in patients with DDLPS? (2) What is the rate of overall survival, metastases, and local recurrence in DDLPS? (3) What factors are associated with metastasis-free survival and local recurrence in DDLPS? METHODS: We defined DDLPS as a biphasic neoplasm that transitions from an atypical lipomatous tumor (ALT) to a sarcoma of variable morphologic appearance and histologic grades. We retrospectively evaluated the medical records of patients with DDLPS of the extremities who underwent surgery in our institution between 2003 and 2017. During that time, 16 patients were treated for this diagnosis; one was excluded from this study because the patient did not have an MRI, leaving 15 patients (nine men, six women; their median [range] age was 67 years [42 to 87]) for evaluation. All had a minimum of 2 years follow-up (median [range] 54 months [25 to 136]); 14 of 15 have been seen in the last 5 years (one patient, who was doing well at the time, was lost after 9 years of follow-up). In 11 patients, MRI demonstrated two components: an ALT component with high intensity on both T1-weighed and T2-weighted sequences and a dedifferentiated component low-to-intermediate intensity on T1-weighed and heterogeneous hyperintensity on T2-weighted sequence. Nine patients were evaluated using 2-deoxy-2-18F-fluoro-D-glucose positron emission tomography (FDG-PET) combined with CT (PET/CT). PET/CT showed a biphasic pattern with a close relationship to MRI findings. The dedifferentiated component presented with high FDG uptake (median [range] maximum standardized uptake value 5.1 [1.9 to 22.6]), while the atypical lipomatous tumor component showed almost no FDG uptake. In all patients, immunohistochemical studies of p16 and cyclin-dependent kinase-4 (CDK4) were investigated. Positive staining for both p16 and CDK4 were seen in 13 of 15 patients.We retrospectively evaluated the electronic medical records of all patients in our institution for the presence of additional primary malignancies, local recurrence-free survival, metastasis-free survival, and overall survival. The survival rate was estimated using the Kaplan-Meier method. The Wilcoxon exact test was used to determine the prognostic importance of the following survival variables: age, sex, maximum tumor size, radiotherapy, and surgical margin. RESULTS: Seven additional primary malignancies developed in five of 15 patients (two lung cancers, two sarcomas, one renal cell cancer, one uterine cancer, and one non-Hodgkin lymphoma). The 3- and 5-year metastasis-free survival rates were 86% (95% CI 0.67 to 1.00) and 75% (95% CI 0.49 to 1.00), respectively. With the numbers available, we found no factors associated with metastasis-free survival. The 3- and 5-year overall survival rates were 100% (95% CI 1.00 to 1.00) and 88% (95% CI 0.65 to 1.00), respectively. Three of 15 patients had local recurrence. The 3- and 5-year local recurrence-free survival rates were 86% (95% CI 0.67 to 1.00) and 75% (95% CI 0.49 to 1.00), respectively. Large (> 15 cm) tumors were more likely to have a local recurrence (p = 0.04). CONCLUSIONS: In this small series, we found that the extremities are a favorable site for DDLPS compared with the retroperitoneum, although we did not directly compare the two sites. This rare tumor has a relatively high likelihood of being associated with other malignancies. We believe patients should be assessed and monitored carefully for this possibility. In the future, larger studies are needed to better define predictors of local recurrence, although the tumor's size may be associated with a greater propensity for local recurrence. LEVEL OF EVIDENCE: Level II, prognostic study.

Prevalence of and Risk Factors for the Progression of Upper Cervical Lesions in Patients with Rheumatoid Arthritis.

We investigated the prevalence of and risk factors for the progression of upper cervical lesions (UCLs) in patients with rheumatoid arthritis (RA). A retrospective analysis of 49 patients with RA (4 males, 45 females) was conducted. The UCLs included atlanto-axial subluxation and vertical subluxation. We investigated the clinical factors including the Disease Activity Score 28 based on C-reactive protein (DAS28-CRP) and the modified Health Assessment Questionnaire-Disability Index as well as radiographic changes between the baseline (at May 2010 to April 2013) and final follow-up. Forty patients (81.6%) were classified as the non-progressive group, and the other 9 patients (18.4%) comprised the progressive group. The progressive group's final CRP values, baseline or final MMP-3 levels, DAS28-CRP, and rate of pre-existing lesions at baseline were all significantly higher than those of the non-progressive group (p=0.017, p=0.043, p=0.002, p=0.008, p<0.001, and p=0.008 respectively). A multivariate logistic regression analysis demonstrated that DAS28-CRP at baseline was a risk factor for radiographic progression (p=0.018, odds ratio: 2.54, 95% confidence interval: 1.17-5.51). Our findings indicate that higher disease activity might influence the progression of UCLs in patients with RA.

Intraoperative O-arm-navigated resection in musculoskeletal tumors.

BACKGROUND: Although emerging evidence has suggested that computer-assisted navigation allows surgeons to plan the optimal level of resection without compromising the surgical margins, the precise accuracy of the procedures has been unclear. The aim of this study was to investigate the accuracy and safety of the musculoskeletal tumor resection using O-arm/Stealth intraoperative navigation assistance. METHODS: A retrospective study of six patients with bone and soft tissue tumors who underwent surgical resection using O-arm/Stealth navigation system was performed. The histological diagnosis was osteosarcoma, metastatic bone tumor, leiomyosarcoma, undifferentiated sarcoma, and synovial sarcoma, respectively. Tumor resection was performed according to planned osteotomy planes determined on O-arm/Stealth three-dimensional intraoperative images. The resection accuracy, length of time for the procedures, surgical margins, and perioperative complications were evaluated. RESULTS: The distances between the entry and exit points for the planned and actual cuts were 1.5 ± 0.3 mm and 2.3 ± 0.3 mm, respectively, and the mean discrepancy of the osteotomy angle was 2.8 ± 1.2°. The mean length of time required for navigation was 14 min. A histological examination revealed clear margins in all patients. There were no complications related to navigation, and no patients developed local recurrence during a mean follow-up of 30.6 months. CONCLUSIONS: The O-arm/Stealth intraoperative CT navigation system provides safe and accurate osteotomy in musculoskeletal tumor resections. However, surgeons should keep in mind and be careful of minimal errors during osteotomy, which are around 2 mm from the planned line.

Inhibitory effect of JAK inhibitor on mechanical stress-induced protease expression by human articular chondrocytes.

OBJECTIVE: To investigate whether janus kinase (JAK) inhibitor exhibits a chondro-protective effect against mechanical stress-induced expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) and matrix metalloproteinase (MMPs) in human chondrocytes. MATERIALS AND METHODS: Normal human articular chondrocytes were seeded onto stretch chambers and incubated with or without tofacitinib (1000 nM) for 12 h before mechanical stimulation or cytokine stimulation. Uni-axial cyclic tensile strain (CTS) (0.5 Hz, 10% elongation, 30 min) was applied and the gene expression levels of type II collagen α1 chain (COL2A1), aggrecan (ACAN), ADAMTS4, ADAMTS5, MMP13, and runt-related transcription factor 2 (RUNX-2) were examined by real-time polymerase chain reaction. Nuclear translocation of RUNX-2 and nuclear factor-κB (NF-κB) was examined by immunocytochemistry, and phosphorylation of mitogen-activated protein kinase (MAPK) and signaling transducer and activator of transcription (STAT) 3 was examined by western blotting. The concentration of interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α in the supernatant was examined by enzyme-linked immunosorbent assay. RESULTS: COL2A1 and ACAN gene expression levels were decreased by CTS, but these catabolic effects were canceled by tofacitinib. Tofacitinib significantly down-regulated CTS-induced expression of ADAMTS4, ADAMTS5, MMP13, and RUNX2, and the release of IL-6 in supernatant by chondrocytes. Tofacitinib also reduced CTS-induced nuclear translocation of RUNX-2 and NF-κB, and phosphorylation of MAPK and STAT3. CONCLUSION: Tofacitinib suppressed mechanical stress-induced expression of ADAMTS4, ADAMTS5, and MMP13 by human chondrocytes through inhibition of the JAK/STAT and MAPK cascades.

Results of Total Elbow Arthroplasty with Cementless Implantation of an Alumina Ceramic Elbow Prosthesis for Patients with Rheumatoid Arthritis.

We investigated the long-term clinical results of total elbow arthroplasty (TEA) by cementless fixation of alumina ceramic unlinked elbow prostheses (J-alumina ceramic elbows: JACE) for the reconstruction of elbow joints with rheumatoid arthritis (RA). Seventeen elbows in 17 patients (aged 44-72 years, average 54.8) replaced by JACE TEA without bone cement were investigated. The average follow-up period was 10.7 (range, 1.0-19.3) years. Clinical conditions of each elbow before and after surgery were assessed according to the Mayo Elbow Performance Index (MEPI). Radiographic loosening was defined as a progressive radiolucent line of more than 1 mm that was completely circumferential around the intramedullary stem. The average MEPI significantly improved from 46.8 points preoperatively to 66.8 points at final follow-up (p=0.0226). However, aseptic loosening was noted in 10 of 17 elbows (58.8%) and revision surgery was required in 7 (41.2%). Most loosening was observed on the humeral side. With radiographic loosening and revision surgery defined as the end points, the likelihoods of prosthesis survival were 41.2% and 51.8%, respectively, up to 15 years by Kaplan-Meier analysis. The clinical results of JACE implantation without bone cement were disappointing, with high revision and loosening rates of the humeral component.