Homeostatic Control of Sebaceous Glands by Innate Lymphoid Cells Regulates Commensal Bacteria Equilibrium.

Immune cells and epithelium form sophisticated barrier systems in symbiotic relationships with microbiota. Evidence suggests that immune cells can sense microbes through intact barriers, but regulation of microbial commensalism remain largely unexplored. Here, we uncovered spatial compartmentalization of skin-resident innate lymphoid cells (ILCs) and modulation of sebaceous glands by a subset of RORγt+ ILCs residing within hair follicles in close proximity to sebaceous glands. Their persistence in skin required IL-7 and thymic stromal lymphopoietin, and localization was dependent on the chemokine receptor CCR6. ILC subsets expressed TNF receptor ligands, which limited sebocyte growth by repressing Notch signaling pathway. Consequently, loss of ILCs resulted in sebaceous hyperplasia with increased production of antimicrobial lipids and restricted commensalism of Gram-positive bacterial communities. Thus, epithelia-derived signals maintain skin-resident ILCs that regulate microbial commensalism through sebaceous gland-mediated tuning of the barrier surface, highlighting an immune-epithelia circuitry that facilitates host-microbe symbiosis.

Disruption of the endopeptidase ADAM10-Notch signaling axis leads to skin dysbiosis and innate lymphoid cell-mediated hair follicle destruction.

Hair follicles (HFs) function as hubs for stem cells, immune cells, and commensal microbes, which must be tightly regulated during homeostasis and transient inflammation. Here we found that transmembrane endopeptidase ADAM10 expression in upper HFs was crucial for regulating the skin microbiota and protecting HFs and their stem cell niche from inflammatory destruction. Ablation of the ADAM10-Notch signaling axis impaired the innate epithelial barrier and enabled Corynebacterium species to predominate the microbiome. Dysbiosis triggered group 2 innate lymphoid cell-mediated inflammation in an interleukin-7 (IL-7) receptor-, S1P receptor 1-, and CCR6-dependent manner, leading to pyroptotic cell death of HFs and irreversible alopecia. Double-stranded RNA-induced ablation models indicated that the ADAM10-Notch signaling axis bolsters epithelial innate immunity by promoting ß-defensin-6 expression downstream of type I interferon responses. Thus, ADAM10-Notch signaling axis-mediated regulation of host-microbial symbiosis crucially protects HFs from inflammatory destruction, which has implications for strategies to sustain tissue integrity during chronic inflammation.

Stress-induced production of chemokines by hair follicles regulates the trafficking of dendritic cells in skin.

Langerhans cells (LCs) are epidermal dendritic cells with incompletely understood origins that associate with hair follicles for unknown reasons. Here we show that in response to external stress, mouse hair follicles recruited Gr-1(hi) monocyte-derived precursors of LCs whose epidermal entry was dependent on the chemokine receptors CCR2 and CCR6, whereas the chemokine receptor CCR8 inhibited the recruitment of LCs. Distinct hair-follicle regions had differences in their expression of ligands for CCR2 and CCR6. The isthmus expressed the chemokine CCL2; the infundibulum expressed the chemokine CCL20; and keratinocytes in the bulge produced the chemokine CCL8, which is the ligand for CCR8. Thus, distinct hair-follicle keratinocyte subpopulations promoted or inhibited repopulation with LCs via differences in chemokine production, a feature also noted in humans. Pre-LCs failed to enter hairless skin in mice or humans, which establishes hair follicles as portals for LCs.

Dysbiosis and Staphylococcus aureus Colonization Drives Inflammation in Atopic Dermatitis.

Staphylococcus aureus skin colonization is universal in atopic dermatitis and common in cancer patients treated with epidermal growth factor receptor inhibitors. However, the causal relationship of dysbiosis and eczema has yet to be clarified. Herein, we demonstrate that Adam17(fl/fl)Sox9-(Cre) mice, generated to model ADAM17-deficiency in human, developed eczematous dermatitis with naturally occurring dysbiosis, similar to that observed in atopic dermatitis. Corynebacterium mastitidis, S. aureus, and Corynebacterium bovis sequentially emerged during the onset of eczematous dermatitis, and antibiotics specific for these bacterial species almost completely reversed dysbiosis and eliminated skin inflammation. Whereas S. aureus prominently drove eczema formation, C. bovis induced robust T helper 2 cell responses. Langerhans cells were required for eliciting immune responses against S. aureus inoculation. These results characterize differential contributions of dysbiotic flora during eczema formation, and highlight the microbiota-host immunity axis as a possible target for future therapeutics in eczematous dermatitis.

Preoperative Denosumab Therapy Against Giant Cell Tumor of Bone is Associated with an Increased Risk of Local Recurrence After Curettage Surgery.

INTRODUCTION: Denosumab has been shown to be highly effective at suppressing the progression of giant cell tumor of bone (GCTB). However, recent studies have observed a potential increased risk of local recurrence after surgery following the use of denosumab, raising concerns on the use of this agent against GCTB in combination with surgery. METHODS: We retrospectively reviewed the medical records of 234 patients with GCTB who were surgically treated at multiple institutions from 1990 to 2017. Patient background, tumor characteristics, treatment methods, local recurrence-free survival rate, distant metastasis rate, oncologic outcome, and limb function at final follow-up were analyzed and compared between cases treated with and without denosumab. RESULTS: The 3-year local recurrence-free survival rate was significantly lower in patients who underwent preoperative denosumab therapy (35.3%) compared with those treated without denosumab (79.9%) (P < 0.001). Among patients who were preoperatively treated with denosumab, those who had a local recurrence all underwent curettage surgery. CONCLUSIONS: Preoperative denosumab therapy in combination with curettage surgery was significantly associated with an increased risk of local recurrence in Campanacci grade 3 tumors. Our data suggest that clinicians seeing GCTB patients should be aware to this increased risk when planning preoperative denosumab therapy.

Risk assessment of femoral pathological fracture in prostate cancer patients by computed tomography analysis.

INTRODUCTION: Prostate cancer often forms osteoblastic lesions that appear as a high-dense shadow upon X-ray. Although the lesions may seem to increase bone strength, pathological fracture occurs in one in four patients with prostate cancer. The aim of this study is to elucidate the factors that may increase the risk of pathological fracture in patients with prostate cancer metastases in the proximal femur by analyzing computed tomography data. MATERIALS AND METHODS: Computed tomography data of the femur of 62 prostate cancer patients were retrospectively analyzed. The patients were divided into three groups based on the presence or absence of femoral metastatic lesions and pathological fracture. Surgical specimens of the proximal femur collected from patients who had a pathological fracture were histologically analyzed. RESULTS: Bone density in the marrow area was increased in all cases with metastases compared with those with no metastases. Contrarily, the cortical bone density at the medial trochanter region was significantly lower in patients who had pathological fractures in the proximal femur than those who did not. Accordingly, histological analysis of the surgical specimens revealed that the affected cortical bone was osteopenic without any apparent new bone formation. CONCLUSION: These results indicate that prostate cancer is less effective in inducing bone formation in the cortex than in the marrow and that the decrease in the cortical bone density at the medial trochanter region leads to an increased risk of pathological fracture. Therefore, a previously undocumented risk factor for pathological fracture in prostate cancer patients is presented.

Regulation of osteoarthritis development by ADAM17/Tace in articular cartilage.

INTRODUCTION: A disintegrin and metalloproteinase 17 (Adam17), also known as TNFα-converting enzyme (Tace), is a membrane-anchored protein involved in shedding of TNF, IL-6 receptor, ligands of epidermal growth factor receptor (EGFR), and Notch receptor. This study aimed to examine the role of Adam17 in adult articular cartilage and osteoarthritis (OA) pathophysiology. MATERIALS AND METHODS: Adam17 expression was examined in mouse knee joints during OA development. We analyzed OA development in tamoxifen-inducible chondrocyte-specific Adam17 knockout mice of a resection of the medial meniscus and medial collateral ligament (medial) model, destabilization of the medial meniscus (DMM) model, and aging model. We analyzed downstream pathways by in vitro experiments, and further performed intra-articular administration of an Adam17 inhibitor TAPI-0 for surgically induced mouse OA. RESULTS: Adam17 expression in mouse articular cartilage was increased by OA progression. In all models, Adam17 knockout mice showed ameliorated progression of articular cartilage degradation. Adam17 knockout decreased matrix metallopeptidase 13 (Mmp13) expression in both in vivo and in vitro experiments, whereas Adam17 activation by phorbol-12-myristate-13-acetate (PMA) increased Mmp13 and decreased aggrecan in mouse primary chondrocytes. Adam17 activation enhanced release of soluble TNF and transforming growth factor alpha, a representative EGF ligand, from mouse primary chondrocytes, while it did not change release of soluble IL-6 receptor or nuclear translocation of Notch1 intercellular domain. Intra-articular administration of the Adam17 inhibitor ameliorated OA progression. CONCLUSIONS: This study demonstrates regulation of OA development by Adam17, involvement of EGFR and TNF pathways, and the possibility of Adam17 as a therapeutic target for OA.

Cell-autonomous FLT3L shedding via ADAM10 mediates conventional dendritic cell development in mouse spleen.

Conventional dendritic cells (cDCs) derive from bone marrow (BM) precursors that undergo cascades of developmental programs to terminally differentiate in peripheral tissues. Pre-cDC1s and pre-cDC2s commit in the BM to each differentiate into CD8α+/CD103+ cDC1s and CD11b+ cDC2s, respectively. Although both cDCs rely on the cytokine FLT3L during development, mechanisms that ensure cDC accessibility to FLT3L have yet to be elucidated. Here, we generated mice that lacked a disintegrin and metalloproteinase (ADAM) 10 in DCs (Itgax-cre × Adam10-fl/fl; ADAM10∆DC) and found that ADAM10 deletion markedly impacted splenic cDC2 development. Pre-cDC2s accumulated in the spleen with transcriptomic alterations that reflected their inability to differentiate and exhibited abrupt failure to survive as terminally differentiated cDC2s. Induced ADAM10 ablation also led to the reduction of terminally differentiated cDC2s, and restoration of Notch signaling, a major pathway downstream of ADAM10, only modestly rescued them. ADAM10∆DC BM failed to generate cDC2s in BM chimeric mice with or without cotransferred ADAM10-sufficient BM, indicating that cDC2 development required cell-autonomous ADAM10. We determined cDC2s to be sources of soluble FLT3L, as supported by decreased serum FLT3L concentration and the retention of membrane-bound FLT3L on cDC2 surfaces in ADAM10∆DC mice, and by demonstrating the release of soluble FLT3L by cDC2 in ex vivo culture supernatants. Through in vitro studies utilizing murine embryonic fibroblasts, we determined FLT3L to be a substrate for ADAM10. These data collectively reveal cDC2s as FLT3L sources and highlight a cell-autonomous mechanism that may enhance FLT3L accessibility for cDC2 development and survival.

Angioleiomyoma of the extremities: correlation of magnetic resonance imaging with histopathological findings in 25 cases.

OBJECTIVE: To identify the characteristic magnetic resonance imaging (MRI) findings in angioleiomyoma and to clarify its relationship with histopathological findings. MATERIALS AND METHODS: We retrospectively analyzed the MRI findings and pathological subtypes in 25 patients with subcutaneous angioleiomyoma of the extremities. Based on the previous reports, MRI findings that could be characteristic of angioleiomyoma were extracted. According to the World Health Organization classification, all cases were classified into three pathological subtypes: solid, venous, and cavernous. The relationship between MRI findings and pathological subtypes was analyzed. RESULTS: The pathological subtypes were solid (n = 10), venous (n = 11), and cavernous (n = 4). The following MRI findings were observed: (a) hypo- or iso-intense linear and/or branching structures on a T2-weighted image (positive total/solid/venous/cavernous: 19/5/10/4, respectively), which we defined as "dark reticular sign"; (b) peripheral hypointense rim on a T2-weighted image (positive total/solid/venous/cavernous: 19/7/8/4, respectively); and (c) presence of any adjacent vascular structures (positive total/solid/venous/cavernous: 6/3/3/0, respectively). Chi-square test showed a significant relationship between dark reticular sign and pathological subtypes (p = 0.0426). The dark reticular sign was found more frequently in the venous and cavernous types than in the solid type. The other MRI findings did not reveal a significant relationship between pathological subtypes. CONCLUSION: We present the largest case series exploring MRI findings in angioleiomyoma. The dark reticular sign was a characteristic MRI finding of angioleiomyoma and was seen in most of the venous and cavernous types, which may facilitate preoperative diagnosis.

Aging Aggravates the Progression of Muscle Degeneration After Rotator Cuff Tears in Mice.

PURPOSE: The purpose of this study was to evaluate the impact of aging on muscle degeneration after rotator cuff tear (RCT) in mice. METHODS: Young (12-week-old) and aged (50-to-60-week-old) female C57BL/6 mice were used (n = 29 for each group). The rotator cuff was transected, and the proximal humerus was removed to induce degeneration of the rotator cuff muscles. The mice were euthanized 4 and 12 weeks after the procedure (referred to as RCT-4wk mice and RCT-12wk mice, respectively) and compared with the sham-treated mice. The supraspinatus muscles were collected for histology, Western blot analysis, and gene expression analyses. RESULTS: There was a significant increase in fat tissue in aged RCT-4wk mice (P = .001) and aged RCT-12wk mice (P < .001) compared with sham-treated aged mice, and aged RCT-12wk mice had a significantly increased fat area ratio compared with aged RCT-4wk mice (P < .001). The fat area was significantly larger in both the aged RCT-4wk (P = .002) and RCT-12wk mice (P < .001) than in the corresponding young mice. Muscular fibrosis was significantly increased in aged RCT-12wk mice compared with aged sham-treated mice (P = .005) and young RCT-12wk mice (P = .016). There were also significant increases in the expression of perilipin and transcripts of adipogenic and fibrogenic differentiation markers in aged RCT mice compared with young RCT mice. CONCLUSION: The present results show that aging is critically involved in the pathology of muscular fatty infiltration and fibrosis after RCT, and muscular degeneration progresses over time in aged mice. CLINICAL RELEVANCE: Aging promotes the progression of muscle degeneration in a mouse RCT model. Furthermore, this study shows that muscle degeneration occurs in aged mice even without denervation and that the model described in the present study is a useful tool for studying the pathology of muscle degeneration.

Complications of surgery for giant cell tumor of bone in the extremities: Incidence, risk factors, management modality, and impact on functional and oncological outcomes.

BACKGROUND: Due to the wide variations in location, size, local invasiveness, and treatment options, the complications associated with surgery for giant cell tumor of bone have been sporadically reported. For quality assessment, fundamental data based on large-scale surveys of complications under a universal evaluation system is needed. The Dindo-Clavien classification is an evaluation system for complications based on severity and required intervention type and is suitable for the evaluation of surgery in a heterogeneous cohort. METHODS: A multi-institutional retrospective survey of 141 patients who underwent surgery for giant cell tumor of bone in the extremity was performed. The incidence and risk factors of complications, type of intervention for complication control, and impact of complications on functional and oncological outcomes were analyzed using the Dindo-Clavien classification. RESULTS: Forty-six cases (32.6%) had one or more complications. Of them, 18 (12.8%), 11 (7.8%), and 17 (12.1%) cases were classified as Dindo-Clavien classification grade I, II, and III complications, respectively. There were no cases with grade IV or V complications. Progression in Campanacci grading (p = 0.04), resection (over curettage, p < 0.0001), reconstruction with prosthesis (p = 0.0007), and prolonged operative duration (p = 0.0002) were significant risk factors for complications. Complications had a significant impact on function (p < 0.0001). Differences in the impact of complication types and tumor location on function were confirmed. Complications had no impact on local recurrence and metastasis development. CONCLUSION: The Dindo-Clavien classification could provide fundamental information, under a uniform definition and classification system, on postoperative complications in patients with giant cell tumor of bone in terms of incidence, type of intervention for complication control, risk factors, and impact on functional outcome. The data are useful not only for preoperative evaluation for the risk of complications under specific conditions but also for quality assessment of surgery for giant cell tumor of bone.

ADAM10 partially protects mice against influenza pneumonia by suppressing specific myeloid cell population.

The influenza virus infection poses a serious health threat worldwide. Myeloid cells play pivotal roles in regulating innate and adaptive immune defense. A disintegrin and metalloproteinase (ADAM) family of proteins contributes to various immune responses; however, the role of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. ADAM10 gene (Adam10)flox/flox/Lyz2-Cre (Adam10ΔLyz2) and control Adam10flox/flox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10ΔLyz2 mice exhibited a significantly higher mortality rate, stronger lung inflammation, and a higher virus titer in the lungs than control mice. Macrophages and inflammatory cytokines, such as TNF-α, IL-1ß, and CCL2, were increased in bronchoalveolar lavage fluid from Adam10ΔLyz2 mice following infection. CD11b+Ly6G-F4/80+ myeloid cells, which had an inflammatory monocyte/macrophage-like phenotype, were significantly increased in the lungs of Adam10ΔLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10ΔLyz2 mice. Seven days after infection, CD11b+Ly6G-F4/80+ lung cells exhibited significantly higher arginase-1 expression levels in Adam10ΔLyz2 mice than in control mice, whereas an arginase-1 inhibitor improved the prognosis of Adam10ΔLyz2 mice. Enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)/GM-CSF receptor signaling likely contributed to this process. Collectively, these results indicate that myeloid ADAM10 protects against influenza virus pneumonia and may be a promising therapeutic target.

Eribulin induces tumor vascular remodeling through intussusceptive angiogenesis in a sarcoma xenograft model.

Eribulin is a novel microtubule inhibitor that, similar to other types of microtubule inhibitors, induces apoptosis by inhibiting the mitotic division of cells. Besides this direct effect on tumor cells, previous studies have shown that eribulin has the potential to induce tumor vascular remodeling in several different cancers; however, the mechanisms underlying this phenomenon remain unclear. In the present study, we aimed to elucidate whether eribulin is effective against synovial sarcoma, a relatively rare sarcoma that often affects adolescents and young adults, and to histologically investigate the microstructure of tumor vessels after the administration of eribulin. We found that eribulin exhibits potent antitumor activity against synovial sarcoma in a tumor xenograft model and that tumor vessels frequently have intervascular pillars, a hallmark of intussusceptive angiogenesis (IA), after the administration of eribulin. IA is a distinct form of angiogenesis that is involved in normal developmental processes as well as pathological conditions. Our data indicate that IA is potentially involved in eribulin-induced vascular remodeling and thereby suggest previously unacknowledged role of IA in regulating the tumor vasculature after eribulin administration.

ADAM17 protects against elastase-induced emphysema by suppressing CD62L+ leukocyte infiltration in mice.

Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease and is associated with chronic pulmonary inflammation caused by cigarette smoking, with contributions from immune cells such as neutrophils, macrophages, and lymphocytes. Although matrix metalloproteinases are well known to contribute to emphysema progression, the role of a disintegrin and metalloproteinase (ADAM) family proteins, other major metalloproteinases, in disease pathogenesis is largely unknown. ADAM17 is a major sheddase that cleaves various cell surface proteins, including CD62L, an adhesion molecule that plays a critical role in promoting the migration of immune cells to the site of inflammation. In the present study, we aimed to investigate the potential role of ADAM17 and CD62L in the development of elastase-induced emphysema. Control and Adam17flox/flox/Mx1-Cre (Adam17ΔMx1) mice (8-10 wk old) were intratracheally injected with 5 units of porcine pancreas elastase and monitored for 35 days after injection. Lung alveolar destruction was evaluated by analyzing the mean linear intercepts of lung tissue specimens and by histopathological examination. Mean linear intercepts data indicated that the degree of elastase-induced emphysema was significantly more severe in Adam17ΔMx1 mice. Furthermore, flow cytometry showed that CD62L+ neutrophil, CD62L+ macrophage, and CD62L+ B lymphocyte numbers were significantly increased in Adam17ΔMx1 mice. Moreover, the pharmacological depletion of CD62L+ cells with a CD62L-neutralizing antibody ameliorated the extent of emphysema in Adam17ΔMx1 mice. Collectively, these results suggest that ADAM17 possibly suppresses the progression of emphysema by proteolytically processing CD62L in immune cells and that ADAM17 and CD62L could be novel therapeutic targets for treating pulmonary emphysema.

Characteristic cerebral structural changes identified using voxel-based morphometry in patients with post-surgical chronic myelopathic pain.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: Patients who undergo intramedullary spinal surgery occasionally experience post-surgical chronic pain; however, the underlying mechanisms are not yet completely understood. Therefore, this study aimed to identify the cerebral structural changes in patients with post-surgical chronic myelopathic pain using voxel-based morphometry. SETTING: Single university hospital in Tokyo, Japan. METHODS: Forty-nine patients who had undergone intramedullary spinal surgery between January 2002 and April 2014 participated in this study. Participants were classified into two groups based on their post-surgical chronic pain intensity: control (numeric rating scale score of <3) and pain (numeric rating scale score of ≥3) groups. We compared pain questionnaire and brain MRI between two groups. Brain MRI data of each participants was analyzed using voxel-based morphometry. RESULTS: Voxel-based morphometry revealed that the gray matter volume in the left supplementary motor area, left primary motor area, and left posterior cingulate cortex was higher in the pain group than that in the control group. In addition, the numeric rating scale score was significantly correlated with increased gray matter volume in the left primary motor area, left posterior cingulate cortex, and right superior parietal lobule. CONCLUSION: Present study elucidates the characteristic cerebral structural changes after an intramedullary spinal surgery using voxel-based morphometry and indicates that the structural changes in specific cerebral areas are associated with post-surgical chronic myelopathic pain.

Granulocyte-colony stimulating factor enhances load-induced muscle hypertrophy in mice.

Granulocyte-colony stimulating factor (G-CSF) is a cytokine crucially involved in the regulation of granulopoiesis and the mobilization of hematopoietic stem cells from bone marrow. However, emerging data suggest that G-CSF exhibits more diverse functions than initially expected, such as conferring protection against apoptosis to neural cells and stimulating mitogenesis in cardiomyocytes and skeletal muscle stem cells after injury. In the present study, we sought to investigate the potential contribution of G-CSF to the regulation of muscle volume. We found that the administration of G-CSF significantly enhances muscle hypertrophy in two different muscle overload models. Interestingly, there was a significant increase in the transcripts of both G-CSF and G-CSF receptors in the muscles that were under overload stress. Using mutant mice lacking the G-CSF receptor, we confirmed that the anabolic effect is dependent on the G-CSF receptor signaling. Furthermore, we found that G-CSF increases the diameter of myotubes in vitro and induces the phosphorylation of AKT, mTOR, and ERK1/2 in the myoblast-like cell line C2C12 after differentiation induction. These findings indicate that G-CSF is involved in load-induced muscle hypertrophy and suggest that G-CSF is a potential agent for treating patients with muscle loss and sarcopenia.

Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization Controls Endochondral Ossification through Hyaluronan Metabolism.

Hyaluronan (HA) plays an important role in the development and maintenance of tissues, and its degradation is implicated in many pathologic conditions. We recently reported that HA-binding protein involved in HA depolymerization (CEMIP; alias HYBID/KIAA1199) is a key molecule in HA depolymerization, but its developmental and pathologic functions remain elusive. We generated Hybid-deficient mice using the Cre/locus of crossover in P1 (loxP) system and analyzed their phenotypes. Hybid-deficient mice were viable and fertile, but their adult long bones were shorter than those of wild-type animals. Hybid-deficient mice showed lengthening of hypertrophic zone in the growth plate until 4 weeks after birth. There were fewer capillaries and osteoclasts at the chondroosseous junction in the Hybid-deficient mice compared with the wild-type mice. In situ hybridization demonstrated that Hybid was expressed by hypertrophic chondrocytes at the chondroosseous junction. Cultured primary chondrocytes expressed higher levels of Hybid than did osteoblasts or osteoclasts, and the Hybid expression in the chondrocytes was up-regulated after maturation to hypertrophic chondrocytes. High-molecular-weight HA was accumulated in the lengthened hypertrophic zone in Hybid-deficient mice. In addition, high-molecular-weight HA significantly reduced cell growth and tube formation in vascular endothelial growth factor-stimulated or -nonstimulated endothelial cells. HA metabolism by HYBID is involved in endochondral ossification during postnatal development by modulation of angiogenesis and osteoclast recruitment at the chondroosseous junction.

Wide-spread ignorance on the treatment of subcutaneous malignant tumors; a questionnaire-based study.

BACKGROUND: Subcutaneous malignant tumors are often treated by non-specialized clinicians in musculoskeletal oncology. While the resection of subcutaneous tumors appears technically feasible, unplanned resection of malignant tumors can result in a devastating clinical outcome. The aim of this study was to evaluate the potential estrangement in the awareness of and the treatment strategy for the patients with subcutaneous soft tissue tumors between musculoskeletal oncologists and non-specialized clinicians. METHODS: A questionnaire probing the clinical assessment of subcutaneous tumors was sent to orthopedic surgeons, dermatologists, plastic surgeons, and general surgeons. Results of the questionnaire were statistically analyzed. RESULTS: One hundred sixteen clinicians out of 150 responded to the questionnaire; the response rate was 77.3%. Among those, 46 clinicians had treated subcutaneous tumors. Thirty-nine of these 46 clinicians (27 musculoskeletal oncologists and 12 non-specialized clinicians) preoperatively performed enhanced MRI for diagnostic evaluation. Preoperative incisional biopsy to confirm the pathological diagnosis was performed by 36 of the 46 clinicians (29 musculoskeletal oncologists and seven non-specialized clinicians). These results indicate that musculoskeletal oncologists perform preoperative enhanced MRI (P = 0.08) and biopsy (P < 0.01) more frequently than non-specialized clinicians. The recognition rate of 'myxofibrosarcoma' was 60.8% among clinicians with an experience with sarcoma treatment (25 musculoskeletal oncologists and three non-specialized clinicians). The recognition rate of 'myxofibrosarcoma' between musculoskeletal oncologists and non-specialized clinicians was statistically significant (P < 0.01). CONCLUSIONS: Preoperative evaluations for subcutaneous tumors are more often inappropriate in non-specialized clinicians than those who are. Therefore, it will be mandatory to raise the awareness of this condition to improve the clinical outcome of patients with subcutaneous tumors.