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Undifferentiated pleomorphic sarcoma (UPS) has a favorable objective response rate to anti‐PD‐1 drugs compared with other sarcomas. Tertiary lymphoid structure (TLS) is a favorable prognostic factor and a biomarker for immune checkpoint inhibitors (ICIs). Nevertheless, there are limited data on the tumor microenvironment (TME) to support a good response to ICIs in sarcoma. Therefore, this study was conducted to investigate the impact of TLS on prognosis and TME. A total of 52 of UPS with wide resection were divided into intratumoral TLS, extratumoral TLS, and without TLS groups. Survival analysis and immunohistochemistry were performed to evaluate immune cells and immune checkpoint molecules, and multiplexed immunofluorescence was conducted to evaluate T‐cell exhaustion among the three groups. TLS was detected in 34 cases (65%), including 23 intratumoral TLS (44%) and 11 extratumoral TLS (21%) cases. Patients with TLS had significantly longer overall survival than those without TLS (log rank p = 0.020). The intratumoral TLS group had a significantly higher number of immune cells and higher expression of PD‐L1 and IDO‐1 than the without TLS group. Progenitor‐exhausted T cells were also observed in patients with UPS. In conclusion, these findings could help predict prognosis in patients with UPS. TLS was demonstrated to be a favorable prognostic factor in patients with UPS. Intratumoral TLS may be a biomarker for the response to ICIs, especially anti‐PD‐1 drugs. TLS was demonstrated to be a favorable prognostic factor in patients with UPS. Intratumoral TLS may be a biomarker for the response to ICIs, especially anti‐PD‐1 drugs. This study may pave the way for the prognostication of extensive resection in patients with UPS and the prognostication of ICI therapy.

Background: The prevalence of sarcopenia defined using the Asian Working Group for Sarcopenia (AWGS) criteria in Asian communities has not been fully addressed. Moreover, few studies have addressed the influence of sarcopenia on mortality. Methods: A total of 1,371 and 1,597 residents aged 65 years or older participated in health surveys in 2012 and 2017. Sarcopenia was determined using the AWGS definition. Factors associated with the presence of sarcopenia were assessed using a logistic regression model in participants in the 2012 survey. Subjects in the 2012 survey were followed-up prospectively for a median of 4.3 years. Mortality risk for subjects with sarcopenia was examined using the Cox proportional hazards model. Results: The crude prevalence of sarcopenia was 7.4% and 6.6% in participants at the 2012 and 2017 surveys, respectively; there was no significant difference between surveys (P = 0.44). The prevalence of sarcopenia increased significantly with age in both sexes (both P for trend <0.001). Subjects with sarcopenia were more likely to exercise less regularly, to intake less total energy, and to exhibit a disability in activity of daily living than those without. The multivariable-adjusted hazard ratio for all-cause mortality was 2.20 (95% confidence interval, 1.25–3.85) in subjects with sarcopenia, compared to those without. Conclusions: Approximately 7% of older subjects had sarcopenia in a community-dwelling older Japanese population. Moreover, subjects with sarcopenia had an increased mortality risk. Our findings suggest that a public health strategy for sarcopenia is needed to extend healthy life expectancy.

Smartphone step counts may capture real-world activities in patients' daily lives, and the self-monitoring of step counts may introduce healthier behavioral changes. We investigated the association between living arrangements (solitude/cohabiting) and residential location (urban/suburban) of patients and their preoperative and postoperative smartphone step counts following total hip arthroplasty (THA). Patients scheduled for THA at a university hospital from September 10, 2021, to December 5, 2023 were enrolled into the study from August 4, 2021, to November 10, 2023. We remotely monitored the patients' daily step counts from smartphone application until up to 365 days after THA. We used the moving average method and latent growth curve modeling to analyze the time-series data of the step count. Overall, 85 patients were included in this study. Comparing the 37 solitary and 48 cohabiting patients, the percentage of men was higher in the solitary group (27% vs. 8%, P = 0.037). There were no notable differences in the demographics between the 44 urban and 41 suburban patients. Urban patients experienced a 483-step per 2-week greater preoperative increase than suburban patients (P = 0.027) after adjusting for confounding factors. From postoperative 2 weeks to preoperative 12 weeks, the intercept was larger for urban patients than for suburban patients by 893 steps (P = 0.040). From postoperative 20 weeks to preoperative 50 weeks, the intercept was larger for solitary patients than for cohabiting patients by a difference of 1,360 steps (P = 0.027). Living arrangements and residential locations were associated with daily step counts before and after THA. Patients in urban areas had higher step counts after the initiation of step-count monitoring and during the early postoperative period. Solitary patients walked more than cohabiting patients. Our findings underscore the utility of smartphone step counts as objective outcome measures for patient assessment and encouraging healthier behavioral changes.

PurposeProgrammed death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1) are immunosuppressive proteins known to be associated with poor prognosis in various cancers. However, their expression and clinical relevance in osteosarcoma remain unknown. In this study, the relationships of PD-L1 and IDO1 expression with clinicopathological features and prognosis were explored.MethodsThe expression of PD-L1, IDO1, CD3, CD4, and CD8 in 112 formalin-fixed, paraffin-embedded tumor tissues collected by biopsy or surgical resection from 56 osteosarcoma patients was evaluated immunohistochemically. Moreover, four osteosarcoma cell lines were evaluated for the effects of IFNγ on PD-L1 and IDO1 mRNA expression by real-time reverse-transcription polymerase chain reaction.ResultsIn pre-neoadjuvant chemotherapy (NAC) primary specimens, 10 cases (17%) showed PD-L1 expression and 12 (21%) showed IDO1 expression. Six of ten cases (60%) with PD-L1 positivity co-expressed IDO1. In post-NAC metastatic lesions, the frequency of immunoexpression of PD-L1 and IDO1 was increased compared with that in pre-NAC specimens. PD-L1 and/or IDO1 expression was not associated with poor prognosis. PD-L1 immunoexpression was significantly associated with the infiltration of CD3+ T cells, CD4+ T cells, and CD8+ T cells; while, IDO1 immunoexpression was significantly associated with the infiltration of CD3+ T cells and CD4+ T cells. In all osteosarcoma cell lines, PD-L1 and IDO1 expression was upregulated by stimulation with IFNγ.ConclusionOur results suggest that the PD-L1 and IDO1 immune checkpoint inhibitors may provide clinical benefit in osteosarcoma patients with metastatic lesions after conventional chemotherapy.

BackgroundOsteosarcoma (OS) is the most common malignant bone tumor and the prognosis of advanced cases is still poor. Recently, there have been several reports suggesting the relationship between innate immunity and OS, but the detailed mechanism is unknown. We demonstrate the relationship between OS and Toll-like receptor 4 (TLR4) which is one of the most important factors in innate immunity.MethodsWe established a syngenic mouse tumor model using C3H/HeN, C3H/HeJ mouse and a highly metastatic OS cell line, LM8. TLR4 activation with lipopolysaccharide (LPS) was performed on both mice and its influence on the progression of OS was evaluated. We also performed CD8 + cells depletion to examine the influence on TLR4 activation effects.ResultsTumor volume of C3H/HeN mice was significantly smaller and overall survival of C3H/HeN mice was significantly longer than C3H/HeJ mice. We found more CD8+ cells infiltrating in lung metastases of C3H/HeN mice and depletion of CD8+ cells canceled the antitumor effects of LPS.ConclusionTLR4 activation by LPS increased CD8+ cells infiltrating into lung metastases and suppressed OS progression in the mouse model. TLR4 activation may suppress the progression of OS via stimulating CD8+ cells and can be expected as a novel treatment for OS.

Background Few studies have investigated the correlation between shoulder kinematics and clinical outcomes in patients undergoing rotator cuff repair using dynamic analysis. This study assessed shoulder kinematics before and after surgical repair in patients with rotator cuff tears (RCTs) and determined the relationship among shoulder kinematics and between shoulder kinematics and clinical outcomes. Methods Ten patients with large-to-massive RCTs and 10 control participants were included. In vivo shoulder kinematics during scapular plane abduction were measured preoperatively and 1 year postoperatively using validated image-registration techniques and compared among the control, preoperative, and postoperative groups. Mixed models were used to compare the effects of the groups on shoulder kinematics, followed by Tukey’s honest significant difference test. Pearson’s correlation coefficient was used to identify the correlations among shoulder kinematics and between each kinematic and clinical outcome. Results The scapula, tilted more anteriorly preoperatively, was not different from the control group postoperatively. Additionally, the change in scapular posterior tilt (PT) throughout dynamic abduction was 18.17° ± 3.59° in the postoperative group, greater than that in the control group (11.54° ± 2.29°; p  = 0.0037). The postoperative change in PT significantly correlated with acromiohumeral distance (AHD) and rotator cuff integrity (Sugaya classification) (AHD: r = 0.71, p  = 0.023; Sugaya classification: r = − 0.75, p  = 0.013), but not preoperative change in PT. Functional score improved from preoperative to postoperative ( p  < 0.0001). Abduction angle and functional score significantly correlated with Sugaya classification (abduction angle: r = − 0.67, p  = 0.034; functional score: r = − 0.70, p  = 0.025) but not with shoulder kinematics. Mean superior translation of the humeral head and AHD throughout abduction changed from 1.77 ± 1.34 to 0.61 ± 1.37 and 1.44 ± 1.59 to 2.71 ± 2.27 mm, respectively, from preoperative to postoperative (both p  < 0.0001). Conclusions After the surgical repair of large-to-massive RCTs, glenohumeral stability normalized, and the more anteriorly tilted orientation of the scapula improved. Additionally, the preoperative increased scapular motion throughout dynamic abduction was further enhanced postoperatively. Interestingly, in postoperative patients, scapular motion toward PT during dynamic abduction correlated with minimum AHD and cuff healing.

Background After spinal cord injury (SCI), glial scarring is mainly formed around the lesion and inhibits axon regeneration. Recently, we reported that anti-β1 integrin antibody (β1Ab) had a therapeutic effect on astrocytes by preventing the induction of glial scar formation. However, the cellular components within the glial scar are not only astrocytes but also microglia, and whether or not β1Ab treatment has any influence on microglia within the glial scar remains unclear. Methods To evaluate the effects of β1Ab treatment on microglia within the glial scar after SCI, we applied thoracic contusion SCI to C57BL/6N mice, administered β1Ab in the sub-acute phase, and analyzed the injured spinal cords with immunohistochemistry in the chronic phase. To examine the gene expression in microglia and glial scars, we selectively collected microglia with fluorescence-activated cell sorting and isolated the glial scars using laser-captured microdissection (LMD). To examine the interaction between microglia and astrocytes within the glial scar, we stimulated BV-2 microglia with conditioned medium of reactive astrocytes (RACM) in vitro, and the gene expression of TNFα (pro-inflammatory M1 marker) was analyzed via quantitative polymerase chain reaction. We also isolated both naïve astrocytes (NAs) and reactive astrocytes (RAs) with LMD and examined their expression of the ligands for β1 integrin receptors. Statistical analyses were performed using Wilcoxon’s rank-sum test. Results After performing β1Ab treatment, the microglia were scattered within the glial scar and the expression of TNFα in both the microglia and the glial scar were significantly suppressed after SCI. This in vivo alteration was attributed to fibronectin, a ligand of β1 integrin receptors. Furthermore, the microglial expression of TNFα was shown to be regulated by RACM as well as fibronectin in vitro. We also confirmed that fibronectin was secreted by RAs both in vitro and in vivo. These results highlighted the interaction mediated by fibronectin between RAs and microglia within the glial scar. Conclusion Microglial inflammation was enhanced by RAs via the fibronectin/β1 integrin pathway within the glial scar after SCI. Our results suggested that β1Ab administration had therapeutic potential for ameliorating both glial scar formation and persistent neuroinflammation in the chronic phase after SCI.

Myxoid liposarcoma (MLS) accounts for 20%‐30% of liposarcoma and the round cell component (RCC) is believed to be a specific poor prognostic factor. However, the RCC assessment criteria are vaguely defined and, therefore, are inconsistently employed by pathologists. In this study, we modified and applied two established grading systems to evaluate nuclear atypia (namely, the World Health Organization/International Society of Urological Pathology and the Fuhrman grading in renal cell carcinoma) in 64 MLS cases. Detailed software‐based assessments of the morphology and the cellularity were performed. DNA mutation analysis, comprehensive mRNA expression analysis, and immunohistochemistry were also performed. Our findings revealed that the high–nuclear‐grade group according to the modified Fuhrman grading system exhibited a significantly poor disease‐free survival (hazard ratio: 4.43; 95% confidence interval: 0.9‐22.6; p = 0.047). On the other hand, the cellularity was significantly higher in the modified Fuhrman high‐grade group (p = 0.010 at the percentage of the hypercellular area; p = 0.003 at the maximum cell density) but did not qualify per se as a poor prognostic factor in the survival analyses. Furthermore, the modified Fuhrman high‐grade group significantly expressed the cell cycle–related genes (such as FOXM1, PLK1, and CDK1). In conclusion, our analyses suggest that an evaluation focusing on nuclear morphology (rather than on cellular density) can be more reliable in predicting the MLS prognosis. The evaluation focusing on nuclear morphology (rather than on cellular density) can be more reliable in predicting the myxoid liposarcoma (MLS) prognosis. Modified Fuhrman grading is useful for the morphology evaluation. The high–nuclear‐grade group significantly expressed the cell cycle–related genes (such as FOXM1, PLK1, and CDK1).

Purpose Varus alignment is known as one of the major causes of medial compartment osteoarthritis (OA). Medial meniscus extrusion also plays a critical role in the in the development of OA. However, studies on the exact relationship between alignment parameters and medial meniscus extrusion are limited. Therefore, this study aimed to investigate this relationship in patients with knee OA. Methods Based on a retrospective analysis of the outpatient magnetic resonance imaging (MRI) database, 190 knees were identified to be examined using weight-bearing, whole-leg radiographs and MRIs within 3 months from the first consultation. Subsequently, various parameters of lower leg alignment were measured, which affected the knee varus in radiographs. Finally, a statistical analysis was performed to assess the relationships between the OA grade, distance of medial meniscus extrusion (MME), and alignment parameters; hip–knee–ankle angle (HKAA), percentage of mechanical axis (% MA), medial proximal tibial angle (MPTA), and joint line convergence angle (JLCA). The subjects were divided according to the presence or absence of MME (Group A: MME distance below 3 mm, Group B: MME distance 3 mm and above) to assess the differences in each alignment parameter correlated with MME distance between the groups. Results MME distance significantly increased with OA grade progression. HKAA, % MA, MPTA, and JLCA significantly correlated with medial meniscus extrusion distance ( r  = − 0.21, − 0.23, − 0.16, 0.3, respectively). Multiple regression analysis of each significant alignment combined with age, sex, and body mass index revealed that HKAA, % MA, MPTA, and JLCA were significant independent factors of MME distance ( P  = 0.008, 0.0026, 0.011, 0.0001, respectively). These significant findings were reinforced in group B. In contrast, the correlation between alignment parameters and medial meniscus extrusion distance was not significant in group A. Conclusion Varus alignment factors are related to MME distance especially in extruded meniscus knees, as the OA grade progressed. Therefore, the coexistence of varus alignment and MME can be the risk factors for OA progression. As the low MPTA was an independent alignment factor for generating varus alignment, patients with osteoarthritis of the knee with both, low MPTA and MME could be the appropriate candidates for early intervention by high tibial osteotomy. Level of evidence III.