Clinicopathologic and prognostic characteristics of tumor budding-like in giant cell tumor of bone.

BACKGROUND: Currently, tumor budding (TB) is defined as an important factor for a poor prognosis in various types of cancers. The authors identified a significant presence of TB-like structures at the tumor invasive front in giant cell tumor of bone (GCTB), which may have the same biologic function as TB. The objective of this report was to describe the distribution of TB in GCTB and investigate its correlation with clinicopathologic characteristics, the immune microenvironment, survival prognosis, and response to denosumab treatment. METHODS: This multicenter cohort study included 426 patients with GCTB who received treatment between 2012 and 2021 at four centers. Two independent pathologists performed visual assessments of TBL structures in hematoxylin-and-eosin-stained tumor sections. Immunohistochemistry was used to evaluate tumor-infiltrating lymphocyte subtypes (CD3-positive, CD4-positive, CD8-positive, CD20-positive, programmed cell death protein-1-positive, programmed cell death-ligand 1positive, and FoxP3-positive) as well as Ki-67 expression levels in 426 tissue samples. These parameters were then analyzed for associations with patient outcomes (local recurrence-free survival [LRFS] and overall survival [OS]), clinicopathologic characteristics, and response to denosumab treatment. RESULTS: High-grade TB was associated with poorer LRFS and OS in both patient groups. In addition, TB was correlated with various clinicopathologic features, tumor-infiltrating lymphocyte expression, and response to denosumab treatment. TB outperformed the traditional Enneking and Campanacci staging systems in predicting patient LRFS and OS. CONCLUSIONS: The current data support the assessment of TBL structures as a reliable prognostic tool in GCTB, potentially aiding in the development of personalized treatment strategies for patients.

Hypoxic Upregulation of IER2 Increases Paracrine GMFG Signaling of Endoplasmic Reticulum Stress-CAF to Promote Chordoma Progression via Targeting ITGB1.

Currently, the oncogenic mechanism of endoplasmic reticulum stress-CAF (ERS-CAF) subpopulation in chordoma remains unknown. Here, single-cell RNA sequencing, spatial transcriptomics, GeoMx Digital Spatial Profiler, data-independent acquisition proteomics, bulk RNA-seq, and multiplexed quantitative immunofluorescence are used to unveil the precise molecular mechanism of how ERS-CAF affected chordoma progression. Results show that hypoxic microenvironment reprograms CAFs into ERS-CAF subtype. Mechanistically, this occurrs via hypoxia-mediated transcriptional upregulation of IER2. Overexpression of IER2 in CAFs promotes chordoma progression, which can be impeded by IER2 knockdown or use of ERS inhibitors. IER2 also induces expression of ERS-CAF marker genes and results in production of a pro-tumorigenic paracrine GMFG signaling, which exert its biological function via directly binding to ITGB1 on tumor cells. ITGB1 inhibition attenuates tumor malignant progression, which can be partially reversed by exogenous GMFG intervention. Further analyses reveal a positive correlation between ITGB1high tumor cell counts and SPP1+ macrophage density, as well as the spatial proximity of these two cell types. Clinically, a significant correlation of high IER2/ITGB1 expression with tumor aggressive phenotype and poor patient survival is observed. Collectively, the findings suggest that ERS-CAF regulates SPP1+ macrophage to aggravate chordoma progression via the IER2/GMFG/ITGB1 axis, which may be targeted therapeutically in future.

Lymphocyte Infiltration Score and Spatial Characteristics Refined the Prognosis and Denosumab Treatment Responsiveness Indicators for Giant Cell Tumor of Bone.

PURPOSE: The prognostic value of lymphocyte infiltration score (LIS) and its nearest neighbor distance to tumor cells (NNDTC) in giant cell tumor of bone (GCTB) is currently not well established. This study aims to characterize LIS and NNDTC and examine their correlation with denosumab treatment responsiveness, clinicopathologic features, and patient prognosis. METHODS: Using multiplexed quantitative immunofluorescence, LIS was evaluated in 253 tumor specimens, whereas NNDTC was computed using HALO software. Subsequently, we analyzed the association of these parameters with patient outcomes (progression-free survival [PFS] and overall survival [OS]), clinicopathologic features, and denosumab treatment responsiveness. RESULTS: Low LIS was indicative of both poor PFS and OS (both P < .001). In addition, LIS was significantly associated with sex (P = .046), Enneking staging (P < .001), Ki-67 expression (P = .007), and denosumab treatment responsiveness (P = .005). Lower CD8+ (tumor interior [TI]) NNDTC, and CD3+ (TI) NNDTC were associated with worse PFS (P = .003 and .038, respectively), whereas lower CD8+ (TI) NNDTC was associated with worse OS (P = .001), but CD8+ (tumor infiltrating margin) NNDTC had the opposite effect (P = .002). Moreover, NNDTC showed a correlation with several clinicopathologic features. Importantly, LIS outperformed Enneking and Campanacci staging systems in predicting the clinical outcomes of GCTB. CONCLUSION: These findings suggest that LIS is a reliable predictive tool for clinically relevant outcomes and response to denosumab therapy in patients with GCTB. These parameters may prove to be useful in guiding prognostic risk stratification and therapeutic optimization for patients.

The tumor-stroma ratio in giant cell tumor of bone: associations with the immune microenvironment and responsiveness to denosumab treatment.

BACKGROUND: Currently, there is limited understanding regarding the clinical significance of the tumor-stroma ratio (TSR) in giant cell tumor of bone (GCTB). Hence, we aimed to investigate the distribution of TSR in GCTB and explore its correlation with various clinicopathologic factors, immune microenvironment, survival prognosis, and denosumab treatment responsiveness. METHODS: We conducted a multicenter cohort study comprising 426 GCTB patients treated at four centers. TSR was evaluated on hematoxylin and eosin-stained and immunofluorescent sections of tumor specimens. Immunohistochemistry was performed to assess CD3+, CD4+, CD8+, CD20+, PD-1+, PD-L1+, and FoxP3+ TIL subtypes as well as Ki-67 expression levels in 426 tissue specimens. These parameters were then analyzed for their correlations with patient outcomes [local recurrence-free survival (LRFS) and overall survival (OS)], clinicopathological features, and denosumab treatment responsiveness. RESULTS: Low TSR was significantly associated with poor LRFS and OS in both cohorts. Furthermore, TSR was also correlated with multiple clinicopathological features, TIL subtype expression, and denosumab treatment responsiveness. TSR demonstrated similar predictive capabilities as the conventional Campanacci staging system for predicting patients' LRFS and OS. CONCLUSION: The results of this study provide evidence supporting the use of TSR as a reliable prognostic tool in GCTB and as a predictor of denosumab treatment responsiveness. These findings may aid in developing individualized treatment strategies for GCTB patients in the future.

Is Type 2 Diabetes Mellitus Associated with Spinal Degenerative Disorders?: Evidence from Observational and 2-Sample Mendelian Randomization Analyses.

BACKGROUND: Type 2 diabetes mellitus (T2DM) and spinal degenerative disorders (SDD) are common diseases that frequently coexist. However, both traditional observational studies and recent Mendelian randomization (MR) studies have demonstrated conflicting evidence on the association between T2DM and SDD. This comparative study explored and compared the association between T2DM and SDD using observational and MR analyses. METHODS: For observational analyses, cross-sectional studies (44,972 participants with T2DM and 403,095 participants without T2DM), case-control studies (38,234 participants with SDD and 409,833 participants without SDD), and prospective studies (35,550 participants with T2DM and 392,046 participants without T2DM with follow-up information until 2022) were performed to test the relationship between T2DM and SDD using individual-level data from the U.K. Biobank from 2006 to 2022. For MR analyses, the associations between single-nucleotide polymorphisms with SDD susceptibility obtained using participant data from the U.K. Biobank, which had 407,938 participants from 2006 to 2022, and the FinnGen Consortium, which had 227,388 participants from 2017 to 2022, and genetic predisposition to T2DM obtained using summary statistics from a pooled genome-wide association study involving 1,407,282 individuals were examined. The onset and severity of T2DM are not available in the databases being used. RESULTS: Participants with T2DM were more likely to have SDD than their counterparts. Logistic regression analysis identified T2DM as an independent risk factor for SDD, which was confirmed by the Cox proportional hazard model results. However, using single-nucleotide polymorphisms as instruments, the MR analyses demonstrated no causal relationship between T2DM and SDD. The lack of such an association was robust in the sensitivity analysis, and no pleiotropy was seen. CONCLUSIONS: Our results suggest that the association between T2DM and SDD may be method-dependent. Researchers and clinicians should be cautious in interpreting the association, especially the causal association, between T2DM and SDD. Our findings provide fresh insights into the association between T2DM and SDD by various analysis methods and guide future research and clinical efforts in the effective prevention and management of T2DM and SDD. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Complex immune microenvironment of chordoma: a road map for future treatment.

BACKGROUND: Chordoma, a rare bone tumor, presents limited treatment options and patients typically exhibit poor survival outcomes. While immunotherapy has shown promising results in treating various tumors, research on the immune microenvironment of chordomas is still in its early stages. Therefore, understanding how the immune microenvironment of chordomas influences the outcomes of immunotherapy is crucial. METHODS: We employed single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, CellChat, gene set variation analysis, as well as calculation of immune features to further dissect the complex immune microenvironment of chordoma. RESULTS: Previous research by van Oost et al argued that compared with other sarcomas, chordomas typically exhibit an immunologically "hot" microenvironment, a conclusion with which we concur based on their research findings. Additionally, the authors suggest that T cell-mediated immunotherapy is feasible for the majority of chordomas. However, we are inclined to categorize them as an immune-excluded phenotype according to the latest classification methods, rather than persisting with the concepts of "cold" and "hot". Unlike them, we explored immune infiltration scores (IS), T lymphocyte scoring (TLS), and human leucocyte antigen class I (HLA-I) using Bulk RNA-seq data from 126 chordoma patients and found that higher IS, TLS, and higher HLA-I expression were associated with poorer patient prognosis. Additionally, CellChat analysis of scRNA-seq results from six chordoma patients revealed no direct interaction between T cells and tumor cells. CONCLUSIONS: These findings suggested that the efficacy of T cell-based immunotherapy may be limited or even ineffective for patients with chordoma.

Integrating single-cell and spatial transcriptomics reveals endoplasmic reticulum stress-related CAF subpopulations associated with chordoma progression.

BACKGROUND: With cancer-associated fibroblasts (CAFs) as the main cell type, the rich myxoid stromal components in chordoma tissues may likely contribute to its development and progression. METHODS: Single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, bulk RNA-seq, and multiplexed quantitative immunofluorescence (QIF) were used to dissect the heterogeneity, spatial distribution, and clinical implication of CAFs in chordoma. RESULTS: We sequenced here 72 097 single cells from 3 primary and 3 recurrent tumor samples, as well as 3 nucleus pulposus samples as controls using scRNA-seq. We identified a unique cluster of CAF in recurrent tumors that highly expressed hypoxic genes and was functionally enriched in endoplasmic reticulum stress (ERS). Pseudotime trajectory and cell communication analyses showed that this ERS-CAF subpopulation originated from normal fibroblasts and widely interacted with tumoral and immune cells. Analyzing the bulk RNA-seq data from 126 patients, we found that the ERS-CAF signature score was associated with the invasion and poor prognosis of chordoma. By integrating the results of scRNA-seq with spatial transcriptomics, we demonstrated the existence of ERS-CAF in chordoma tissues and revealed that this CAF subtype displayed the most proximity to its surrounding tumor cells. In subsequent QIF validation involving 105 additional patients, we confirmed that ERS-CAF was abundant in the chordoma microenvironment and located close to tumor cells. Furthermore, both ERS-CAF density and its distance to tumor cells were correlated with tumor malignant phenotype and adverse patient outcomes. CONCLUSIONS: These findings depict the CAF landscape for chordoma and may provide insights into the development of novel treatment approaches.

Global cluster analysis and network visualization in cancer-associated fibroblast: insights from Web of Science database from 1999 to 2021.

BACKGROUND: A scientific and comprehensive analysis of the current status and trends in the field of cancer-associated fibroblast (CAF) research is worth investigating. This study aims to investigate and visualize the development, research frontiers, and future trends in CAFs both quantitatively and qualitatively based on a bibliometric approach. METHODS: A total of 5518 publications were downloaded from the Science Citation Index Expanded of Web of Science Core Collection from 1999 to 2021 and identified for bibliometric analysis. Visualized approaches, OriginPro (version 9.8.0.200) and R (version 4.2.0) software tools were used to perform bibliometric and knowledge-map analysis. RESULTS: The number of publications on CAFs increased each year, and the same tendency was observed in the RRI. Apart from China, the countries with the largest number of publications and the most cited frequency were mainly Western developed countries, especially the USA. Cancers was the journal with the largest number of articles published in CAFs, and Oncology was the most popular research orientation. The most productive author was Lisanti MP, and the University of Texas System was ranked first in the institutions. In addition, the topics of CAFs could be divided into five categories, including tumor classification, prognostic study, oncologic therapies, tumor metabolism and tumor microenvironment. CONCLUSIONS: This is the first thoroughly scientific bibliometric analysis and visualized study of the global research field on CAFs over the past 20 years. The study may provide benefits for researchers to master CAFs' dynamic evolution and research trends.

Clinicopathological characteristics and prognostic factors in axial chondroblastomas: a retrospective analysis of 61 cases and comparison with extra-axial chondroblastomas.

BACKGROUND: A comprehensive understanding of the clinical characteristics and prognostic factors associated with axial chondroblastoma (ACB) is still lacking. This study aimed to understand the clinical characteristics and prognostic factors of axial chondroblastoma (ACB) and compare them with extra-axial chondroblastoma (EACB). METHODS: A retrospective review of our institution's local database was conducted, encompassing a total of 132 CB patients, of which 61 were diagnosed with ACB and 71 with EACB. Immunohistochemistry was employed to evaluate the expression levels of vimentin, S100, and cytokeratin. RESULTS: ACB and EACB shared similar characteristics, with the exception of advanced age, tumor size, elevated Vim expression, incidence of surrounding tissue invasion, and postoperative sensory or motor dysfunction. While wide resection and absence of surrounding tissue invasion consistently showed a favorable association with survival in both ACB and EACB cohorts during univariate analysis, most parameters exhibited differential prognostic significance between the two groups. Notably, the significant prognostic factors for local recurrence-free survival in the ACB cohort included the type of resection and the presence of chicken-wire calcification. In the multivariate analysis of overall survival, the type of resection emerged as a significant predictor in the ACB cohort, whereas in the EACB group, the type of resection and the occurrence of postoperative sensory or motor dysfunction were predictive of overall survival. CONCLUSION: There may exist distinct biological behaviors between ACB and EACB, thereby providing valuable insights into the prognostic characteristics of ACB patients and contributing to enhanced outcome prediction in this particular patient population.

ChatGPT encounters multiple opportunities and challenges in neurosurgery.

BACKGROUND: ChatGPT, powered by the GPT model and Transformer architecture, has demonstrated remarkable performance in the domains of medicine and healthcare, providing customized and informative responses. In our study, we investigated the potential of ChatGPT in the field of neurosurgery, focusing on its applications at the patient, neurosurgery student/resident, and neurosurgeon levels. METHOD: The authors conducted inquiries with ChatGPT from the viewpoints of patients, neurosurgery students/residents, and neurosurgeons, covering a range of topics, such as disease diagnosis, treatment options, prognosis, rehabilitation, and patient care. The authors also explored concepts related to neurosurgery, including fundamental principles and clinical aspects, as well as tools and techniques to enhance the skills of neurosurgery students/residents. Additionally, the authors examined disease-specific medical interventions and the decision-making processes involved in clinical practice. RESULTS: The authors received individual responses from ChatGPT, but they tended to be shallow and repetitive, lacking depth and personalization. Furthermore, ChatGPT may struggle to discern a patient's emotional state, hindering the establishment of rapport and the delivery of appropriate care. The language used in the medical field is influenced by technical and cultural factors, and biases in the training data can result in skewed or inaccurate responses. Additionally, ChatGPT's limitations include the inability to conduct physical examinations or interpret diagnostic images, potentially overlooking complex details and individual nuances in each patient's case. Moreover, its absence in the surgical setting limits its practical utility. CONCLUSION: Although ChatGPT is a powerful language model, it cannot substitute for the expertise and experience of trained medical professionals. It lacks the capability to perform physical examinations, make diagnoses, administer treatments, establish trust, provide emotional support, and assist in the recovery process. Moreover, the implementation of Artificial Intelligence in healthcare necessitates careful consideration of legal and ethical concerns. While recognizing the potential of ChatGPT, additional training with comprehensive data is necessary to fully maximize its capabilities.

Tumor Growth Rate in Spinal Giant Cell Tumors of Bone and Association With the Immune Microenvironment and Denosumab Treatment Responsiveness: A Multicenter Study.

BACKGROUND: Currently, little is known about the prognostic value of tumor growth rate (TGR) in spinal giant cell tumors of bone (GCTB). OBJECTIVE: To investigate the correlation of TGR with clinicopathological features, immune microenvironment, prognosis, and response to denosumab treatment of spinal GCTB. METHODS: A total of 128 patients with spinal GCTB treated at 5 centers from 2011 to 2021 were included. TGR was assessed by 2 independent neuroradiologists using at least 2 preoperative thin-section magnetic resonance imaging scans at a minimum interval of 2 months. Immunohistochemistry was used to assess tumor-infiltrating lymphocyte subtypes for CD3, CD4, CD8, CD20, PD-1, PD-L1, and Foxp3. Then, these parameters were analyzed for their associations with patient outcomes (progression-free survival and overall survival), clinicopathological features, and denosumab treatment responsiveness. RESULTS: High TGR predicted both poor progression-free survival and overall survival (both P < .001). In addition, TGR was associated with postoperative neurological dysfunction ( P < .001), Enneking staging ( P = .016), denosumab treatment responsiveness ( P = .035), and the number of CD3 + ( P < .001), PD-1 + ( P = .009), PD-L1 + ( P < .001), and FoxP3 + tumor-infiltrating lymphocyte ( P = .02). Importantly, TGR outperformed the traditional Enneking, Campanacci, and American Joint Committee on Cancer staging systems in predicting the clinical outcomes of spinal GCTB. CONCLUSION: These data support the use of TGR as a reliable predictive tool for clinically relevant outcomes and response to denosumab therapy of spinal GCTB, which may be helpful in guiding prognostic risk stratification and therapeutic optimization of patients.

Clinicopathological and Prognostic Characteristics in Spinal Chondroblastomas: A Pooled Analysis of Individual Patient Data From a Single Institute and 27 Studies.

STUDY DESIGN: Retrospective pooled analysis of individual patient data. OBJECTIVES: Spinal chondroblastoma (CB) is a very rare pathology and its clinicopathological and prognostic features remain unclear. Here, we sought to characterize the clinicopathological data of a large spinal CB cohort and determine factors affecting the local recurrence-free survival (LRFS) and overall survival (OS) of patients. METHODS: Electronic searches using Medline, Embase, Google Scholar and Wanfang databases were performed to identify eligible studies per predefined criteria. A retrospective review was also conducted to include additional patients at our center. RESULTS: Twenty-seven studies from the literature and 8 patients from our local institute were identified, yielding a total of 61 patients for analysis. Overall, there were no differences in clinicopathological characteristics between the local and literature cohorts, except for absence or presence of spinal canal invasion by tumor on imagings and chicken-wire calcification in tumor tissues. Univariate Kaplan-Meier analysis revealed that previous treatment, preoperative or postoperative neurological deficits, type of tumor resection, secondary aneurysmal bone cyst (ABC), chicken-wire calcification and radiotherapy correlated closely with LRFS, though only type of tumor resection, chicken-wire calcification and radiotherapy were predictive of outcome based on multivariate Cox analysis. Analyzing OS, we found that a history of preoperative treatment, concurrent ABC, chicken-wire calcification, type of tumor resection and adjuvant radiotherapy had a significant association with survival, whereas only type of tumor resection remained statistically significant after adjusting for other covariables. CONCLUSION: These data may be helpful in prognostic risk stratification and individualized therapy decision making for patients.

Corrigendum: Risk factors for tuberculous or nontuberculous spondylitis after percutaneous vertebroplasty or kyphoplasty in patients with osteoporotic vertebral compression fracture: A case-control study.

[This corrects the article DOI: 10.3389/fsurg.2022.962425.].

Risk factors for tuberculous or nontuberculous spondylitis after percutaneous vertebroplasty or kyphoplasty in patients with osteoporotic vertebral compression fracture: A case-control study.

Objectives: The contributing factors for spondylitis after percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP) remain unclear. Here, we sought to investigate the factors affecting spondylitis occurrence after PVP/PKP. We also compared the clinical characteristics between patients with tuberculous spondylitis (TS) and nontuberculous spondylitis (NTS) following vertebral augmentation. Methods: Literature searches (from January 1, 1982 to October 16, 2020) using MEDLINE, EMBASE, Google Scholar and Web of science databases were conducted to identify eligible studies according to predefined criteria. The local database was also retrospectively reviewed to include additional TS and NTS patients at our center. Results: Thirty studies from the literature and 11 patients from our local institute were identified, yielding a total of 23 TS patients and 50 NTS patients for analysis. Compared with NTS group, patients in the TS group were more likely to have a history of trauma before PVP/PKP treatment. Univariate analyses of risk factors revealed pulmonary tuberculosis and diabetes were significant factors for TS after PVP/PKP. Analyzing NTS, we found obesity, a history of preoperative trauma, urinary tract infection, diabetes and multiple surgical segments (≥2) were significantly associated with its occurrence following PVP/PKP treatment. Multivariate logistic analyses showed a history of pulmonary tuberculosis and diabetes were independent risk factors for TS after PVP/PKP, while diabetes and the number of surgically treated segments independently influenced NTS development. Conclusions: A history of pulmonary tuberculosis and diabetes were independent risk factors for TS. For NTS, diabetes and the number of surgically treated segments significantly influenced the occurrence of postoperative spinal infection. These data may be helpful for guiding risk stratification and preoperative prevention for patients, thereby reducing the incidence of vertebral osteomyelitis after PVP/PKP.

[Research progress on role of traditional Chinese medicine in hepatic fibrosis based on miRNA-mediated activation of NLRP3 inflammasome].

In recent years, liver fibrosis has become a hotspot in the field of liver diseases. MicroRNA(miRNA)-mediated Nod-like receptor pyrin domain containing 3(NLRP3) inflammasome activation is pivotal in the pathogenesis of liver fibrosis. The present study mainly discussed the role of miRNA-mediated NLRP3 inflammasome activation in the pathogenesis of liver fibrosis. Different miRNA molecules regulated liver fibrosis by mediating NLRP3 inflammasome activation, including miRNA-350-3 p(miR-350-3 p)/interleukin-6(IL-6)-mediated signal transducer and activator of transcription 3(STAT3)/c-myc signaling pathway, miR-148 a-induced autophagy and apoptosis of hepatic stellate cells via hedgehog signaling pathway, miR-155-mediated NLRP3 inflammasome by the negative feedback of the suppressor of cytokine signaling-1(SOCS-1), miR-181 a-mediated downstream NLRP3 inflammatory pathway activation through mitogen-activated protein kinase kinase(MEK)/extracellular signal-regulated kinase(ERK)/nuclear transcription factor κB(NF-κB) inflammatory pathway, miR-21-promoted expression of NF-κB and NLRP3 of RAW264.7 cells in mice by inhibiting tumor necrosis factor-α inducible protein 3(A20), and miR-20 b-promoted expression of IL-1ß and IL-18 by activating NLRP3 signaling pathway. Additionally, the anti-liver fibrosis mechanism of different active components in Chinese medicines(such as Curcumae Rhizoma, Glycyrrhizae Radix et Rhizoma, Aurantii Fructus, Polygoni Cuspidati Rhizoma et Radix, Moutan Cortex, Paeoniae Radix Alba, Epimedii Folium, and Cinnamomi Cortex) was also explored based on the anti-liver fibrosis effect of miRNA-mediated NLRP3 inflammasome activation.