The Outcome of Molecularly Targeted Therapy after Surgical Treatment of Spinal Metastasis.

The aim of this study was to investigate outcomes of molecularly targeted therapy after surgical treatment of spinal metastasis. Participants comprised 164 patients who underwent surgical treatment of spinal metastasis, divided according to whether molecularly targeted therapy was performed. We compared survival, local recurrence of metastasis detected by imaging, the disease-free interval, relapses of neurological deterioration, and the ability to walk between groups. Molecularly targeted drugs were administered to 39 patients after surgery (TT group) and were not administered to 125 patients (non-TT group). Median survival was significantly longer in the TT group (1027 days) than in the non-TT group (439 days, p < 0.01). Local recurrence occurred in 25 patients in the non-TT group and 10 patients in the TT group. The disease-free interval did not differ between groups. Neurological deterioration was observed in three patients in the non-TT group and no patients in the TT group. The ability to walk was preserved in 97.6% of patients in the TT group and 88% of patients in the non-TT group (p = 0.12). In conclusion, molecularly targeted drugs improve survival in patients with spinal metastasis but do not alter local control of metastatic tumors.

Incidence of Unrecognized Incidental Durotomy during Surgery for Malignant Spinal Tumor.

INTRODUCTION: Cerebral spinal fluid leak from durotomy is a well-known risk with spinal surgeries. The aim of this study is to identify the incidence of unrecognized incidental durotomy during posterior surgery for spinal metastases and its risk factors. METHODS: Participants comprised 75 patients who underwent posterior spine surgery for spinal metastases between January 2012 and December 2016. Cases with apparent durotomy noticed intraoperatively were excluded. Unrecognized durotomy was diagnosed as the presence of wide subcutaneous fluid retention on magnetic resonance imaging at least 3 months postoperatively. For comparison, 50 patients who underwent cervical laminoplasty due to cervical spondylotic myelopathy were examined using the same method. We also examined correlations between occurrence of durotomy and patient characteristics such as age, type of tumor, location of tumor (ventral or dorsal), extent of tumor, and history of radiotherapy before surgery. RESULTS: Unrecognized durotomy occurred in 21 cases of spinal metastasis (26.7%) and in 1 case of cervical spondylotic myelopathy (2%), representing a significant difference between groups. Age, type of tumor, location of tumor, extent of tumor, and history of radiotherapy before surgery did not correlate significantly with occurrence of durotomy. No local trouble was observed in durotomy cases, except in one case with subcutaneous local infection. CONCLUSIONS: The incidence of unrecognized incidental durotomy is significantly higher during surgery for spinal metastases than that during surgery for degenerative disease.

CTLA4-Ig Directly Inhibits Osteoclastogenesis by Interfering With Intracellular Calcium Oscillations in Bone Marrow Macrophages.

CTLA4-Ig (cytotoxic T-lymphocyte antigen 4-immunoglobulin; Abatacept) is a biologic drug for rheumatoid arthritis. CTLA4 binds to the CD80/86 complex of antigen-presenting cells and blocks the activation of T cells. Although previous reports showed that CTLA4-Ig directly inhibited osteoclast differentiation, the whole inhibitory mechanism of CTLA4-Ig for osteoclast differentiation is unclear. Bone marrow macrophages (BMMs) from WT mice were cultured with M-CSF and RANKL with or without the recombinant mouse chimera CTLA4-Ig. Intracellular calcium oscillations of BMMs with RANKL were detected by staining with calcium indicator fura-2 immediately after administration of CTLA4-Ig or after one day of treatment. Calcium oscillations were analyzed using Fc receptor gamma- (FcRγ-) deficient BMMs. CTLA4-Ig inhibited osteoclast differentiation and reduced the expression of the nuclear factor of activated T cells NFATc1 in BMMs in vitro. Calcium oscillations in BMMs were suppressed by CTLA4-Ig both immediately after administration and after one day of treatment. CTLA4-Ig did not affect osteoclastogenesis and did not cause remarkable changes in calcium oscillations in FcRγ-deficient BMMs. Finally, to analyze the effect of CTLA4-Ig in vivo, we used an LPS-induced osteolysis model. CTLA4-Ig suppressed LPS-induced bone resorption in WT mice, not in FcRγ-deficient mice. In conclusion, CTLA4-Ig inhibits intracellular calcium oscillations depending on FcRγ and downregulates NFATc1 expression in BMMs. © 2019 American Society for Bone and Mineral Research.

Negative feedback loop of bone resorption by NFATc1-dependent induction of Cadm1.

Trimethylation of histone H3 lysine 4 and lysine 27 (H3K4me3 and H3K27me3) at gene promoter regions critically regulates gene expression. Key developmental genes tend to exhibit changes in histone modification patterns from the H3K4me3/H3K27me3 bivalent pattern to the H3K4me3 monovalent pattern. Using comprehensive chromatin immunoprecipitation followed by sequencing in bone marrow-derived macrophages (BMMs) and mature osteoclasts, we found that cell surface adhesion molecule 1 (Cadm1) is a direct target of nuclear factor of activated T cells 1 (NFATc1) and exhibits a bivalent histone pattern in BMMs and a monovalent pattern in osteoclasts. Cadm1 expression was upregulated in BMMs by receptor activator of nuclear factor kappa B ligand (RANKL), and blocked by a calcineurin/NFATc1 inhibitor, FK506. Cadm1-deficient mice exhibited significantly reduced bone mass compared with wild-type mice, which was due to the increased osteoclast differentiation, survival and bone-resorbing activity in Cadm1-deficient osteoclasts. These results suggest that Cadm1 is a direct target of NFATc1, which is induced by RANKL through epigenetic modification, and regulates osteoclastic bone resorption in a negative feedback manner.

Identification of Nedd9 as a TGF-ß-Smad2/3 Target Gene Involved in RANKL-Induced Osteoclastogenesis by Comprehensive Analysis.

TGF-ß is a multifunctional cytokine that is involved in cell proliferation, differentiation and function. We previously reported an essential role of the TGF-ß -Smad2/3 pathways in RANKL-induced osteoclastogenesis. Using chromatin immunoprecipitation followed by sequencing, we comprehensively identified Smad2/3 target genes in bone marrow macrophages. These genes were enriched in the gene population upregulated by TGF-ß and downregulated by RANKL. Recent studies have revealed that histone modifications, such as trimethylation of histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3), critically regulate key developmental steps. We identified Nedd9 as a Smad2/3 target gene whose histone modification pattern was converted from H3K4me3(+)/H3K4me27(+) to H3K4me3(+)/H3K4me27(-) by TGF-ß. Nedd9 expression was increased by TGF-ß and suppressed by RANKL. Overexpression of Nedd9 partially rescued an inhibitory effect of a TGF-ß inhibitor, while gene silencing of Nedd9 suppressed RANKL-induced osteoclastogenesis. RANKL-induced osteoclastogenesis were reduced and stimulatory effects of TGF-ß on RANKL-induced osteoclastogenesis were partially abrogated in cells from Nedd9-deficient mice although knockout mice did not show abnormal skeletal phenotypes. These results suggest that Nedd9 is a Smad2/3 target gene implicated in RANKL-induced osteoclastogenesis.

[Mechanism of bone destruction in rheumatoid arthritis and perspectives of the treatment].

Rheumatoid arthritis (RA) is an autoimmune diseases characterized by inflammation and destruction of bone and cartilage. Osteoclastogenesis induced by inflammatory cytokines contributes to focal and systemic bone and cartilage destruction including secondary osteoporosis. Recent progress in treatment enables us to prevent disease activity. Not only anti-inflammatory management but also therapies directly targeting bone metabolism can further prevent bone destruction in RA.

Modified metacarpal shortening osteotomy of the midcarpal bone for preserving metacarpophalangeal joints in patients with rheumatoid arthritis.

Recent advances in medication choices have strikingly improved the management of rheumatoid arthritis. However, medication alone cannot place back already deformed joints. Thus, to prevent metacarpophalangeal (MP) joint destruction, joint deformity correction should be considered since mechanical stress induced by finger motions will eventually destruct the undestructed joint, with a possibility of recurrence and future implant arthroplasty in mind since RA still remains as a progressive disease. We report a modified metacarpal shortening osteotomy for correcting MP joint deformity. The advantage of our technique over previous osteotomies is that it easily allows for subsequent implant arthroplasty even after the recurrence of joint deformity/destruction. Major modifications include that the metacarpal is shortened at its mid-shaft and the osteotomy is performed vertical to the shaft and fixed with surgical wiring. We believe that combination therapy consisting of medication and surgery is preferable to prevent joint destruction, even in this age of biological agents.

Validity and responsiveness of a self-administered foot evaluation questionnaire in rheumatoid arthritis.

OBJECTIVES: A self-administered foot evaluation questionnaire (SAFE-Q) was developed by the Japanese Society for Surgery of the Foot (JSSF). The aim of this study is to evaluate the validity and responsiveness of the SAFE-Q in patients with rheumatoid arthritis (RA). METHODS: In total, 180 patients with RA answered the SAFE-Q. Of 180 patients, 34 answered the SAFE-Q twice, preoperatively and postoperatively, to assess responsiveness. Construct validity was tested by comparing the 5 SAFE-Q subscales and the JSSF standard rating system for the RA foot and ankle scale (JSSF-RA), a Japanese version of the Health Assessment Questionnaire (JHAQ), disease activity score in 28 joints (DAS28), simplified disease activity index (SDAI), and clinical disease activity index (CDAI). Responsiveness was examined by calculating the standardized response mean (SRM) and effect size (ES) 3 months after surgery. RESULTS: There were moderate correlations between the SAFE-Q and the JSSF-RA and JHAQ. Conversely, a low correlation was observed between the SAFE-Q and DAS28, SDAI, and CDAI. The responsiveness was high, with an SRM of 0.9 and ES of 0.7 for pain subscales. CONCLUSION: SAFE-Q is a useful tool for assessing the foot and ankle in RA patients.

Recent trends in orthopedic surgery aiming to improve quality of life for those with rheumatoid arthritis: data from a large observational cohort.

OBJECTIVE: To describe current trends in the numbers of rheumatoid arthritis (RA)-related surgeries. METHODS: The number of operations was determined for patients with RA in a large observational cohort [Institute of Rheumatology, Rheumatoid Arthritis (IORRA)] enrolled from 2001 to 2012. RESULTS: The total number of operations peaked in 2002 and gradually decreased thereafter, but began to increase again in 2008. The number of total knee replacements has decreased since 2003, while the number of wrist and foot arthroplasties and the number of artificial finger prosthesis surgeries have increased gradually. CONCLUSION: Our results suggest that the number of orthopedic surgeries may change in response to changes in the drug therapy for RA.