Novel positioning guiders accurately assist in situ acetabular reconstruction for patients undergoing pelvic bone tumor resection.

PURPOSE: Acetabular reconstruction in situ after extensive pelvic resection is technically challenging. The aim of this study was to investigate the feasibility of positioning guiders for acetabular reconstruction following pelvic tumor resection and the clinical benefit brought by the approach. METHODS: The study included patients who underwent acetabular reconstruction following periacetabular tumor resection using a modular hemipelvic prosthesis. In the guider-assisted group (n = 14), guiders were designed and applied to assist acetabular reconstruction. In the traditional operation group (n = 18), the patients underwent the same surgery but without the guiders. The displacement of the hip rotation center before and after surgery was calculated. The complications and the Musculoskeletal Tumor Society-93 scores were documented. RESULTS: The overall displacement of the hip rotation center was significantly reduced in the guider-assisted group compared with the traditional operation group (13.83 ± 4.06 vs. 22.95 ± 9.18 mm in P = 0.000, 95%CI 3.90-12.96), especially in the anteroposterior axis (3.77 ± 3.03 versus 13.51 ± 9.43 mm in P = 0.000, 95%CI 3.45-13.09). Guider-assisted acetabular reconstruction reduced the risk of prosthesis dislocation compared with the traditional operation (dislocation risks: 1/14, 7.1% vs. 4/18, 22.2%). CONCLUSION: Positioning guiders can effectively and conveniently help place the modular hemipelvic prosthesis at the native position, which might potentially reduce the risk of prosthesis dislocation. LEVEL OF EVIDENCE: Therapeutic level III.

Effect of radiotherapy on local control and overall survival in spinal metastasis of non-small-cell lung cancer after surgery and systemic therapy.

Aims: Radiotherapy is a well-known local treatment for spinal metastases. However, in the presence of postoperative systemic therapy, the efficacy of radiotherapy on local control (LC) and overall survival (OS) in patients with spinal metastases remains unknown. This study aimed to evaluate the clinical outcomes of post-surgical radiotherapy for spinal metastatic non-small-cell lung cancer (NSCLC) patients, and to identify factors correlated with LC and OS. Methods: A retrospective, single-centre review was conducted of patients with spinal metastases from NSCLC who underwent surgery followed by systemic therapy at our institution from January 2018 to September 2022. Kaplan-Meier analysis and log-rank tests were used to compare the LC and OS between groups. Associated factors for LC and OS were assessed using Cox proportional hazards regression analysis. Results: Overall, 123 patients with 127 spinal metastases from NSCLC who underwent decompression surgery followed by postoperative systemic therapy were included. A total of 43 lesions were treated with stereotactic body radiotherapy (SBRT) after surgery and 84 lesions were not. Survival rate at one, two, and three years was 83.4%, 58.9%, and 48.2%, respectively, and LC rate was 87.8%, 78.8%, and 78.8%, respectively. Histological type was the only significant associated factor for both LC (p = 0.007) and OS (p < 0.001). Treatment with targeted therapy was significantly associated with longer survival (p = 0.039). The risk factors associated with worse survival were abnormal laboratory data (p = 0.021), lesions located in the thoracic spine (p = 0.047), and lumbar spine (p = 0.044). This study also revealed that postoperative radiotherapy had little effect in improving OS or LC. Conclusion: Tumour histological type was significantly associated with the prognosis in spinal NSCLC metastasis patients. In the presence of post-surgical systemic therapy, radiotherapy appeared to be less effective in improving LC, OS, or quality of life in spinal NSCLC metastasis patients.

First-Line Anlotinib Treatment for Soft Tissue Sarcoma in Chemotherapy-Ineligible Patients: An Open-label, Single-arm, Phase 2 Clinical Trial.

PURPOSE: Standard treatment for patients with unresectable locally advanced or metastatic soft-tissue sarcoma (LA/M STS) is chemotherapy based on anthracyclines, but patient tolerance of chemotherapy is limited. The present trial (NCT03792542) investigated the use of anlotinib as first-line treatment for patients with advanced STS, in particular liposarcoma (LPS). PATIENTS AND METHODS: Eligible patients were previously untreated, pathologically confirmed, unresectable LA/M STS cases. Anlotinib was given orally at a dose of 12 mg once daily from day 1 to day 14 every 3 weeks until disease progression or intolerable adverse events (AEs) occurred. The primary endpoint was progression-free survival (PFS) and the secondary endpoints overall survival (OS), the objective response rate and the disease control rate (DCR). The safety profile was also evaluated. RESULTS: Forty patients were enrolled from April 2019 to Jun 2022 and are included in the intention-to-treat analysis. The median PFS was 6.83 months [95% confidence interval (CI): 4.17-8.71] and the median OS 27.40 months (95% CI: 16.43-not evaluable); 1 patient reached partial response and 26 attained stable disease, with a DCR of 67.5% (27/40). Median PFS and OS times for LPS patients were 8.71 and 16.23 months, respectively. Ten (25.0%) patients had treatment-related AEs ≥ grade 3, with in particular a higher incidence of hypertension (15.0%) and proteinuria (7.5%). CONCLUSIONS: The findings suggest a potential benefit in employing front-line anlotinib to treat patients with STS, who are not eligible for cytotoxic chemotherapy. Of note, the clinical outcomes for the LPS subgroup of patients were encouraging.

Investigating the synergy of Shikonin and Valproic acid in inducing apoptosis of osteosarcoma cells via ROS-mediated EGR1 expression.

BACKGROUND: Osteosarcoma is the most prevalent malignant bone tumour with a poor prognosis. Shikonin (SHK) is derived from the traditional Chinese medicine Lithospermum that has been extensively studied for its notable anti-tumour effects, including for osteosarcoma. However, its application has certain limitations. Valproic acid (VPA) is a histone deacetylase inhibitor (HDACI) that has recently been employed as an adjunctive therapeutic agent that allows chromatin to assume a more relaxed state, thereby enhancing anti-tumour efficacy. PURPOSE: This study was aimed to investigate the synergistic anti-tumour efficacy of SHK in combination with VPA and elucidate its underlying mechanism. METHODS/STUDY DESIGN: CCK-8 assays were utilized to calculate the combination index. Additional assays, including colony formation, acridine orange/ethidium bromide double fluorescent staining, and flow cytometry, were employed to evaluate the effects on osteosarcoma cells. Wound healing and transwell assays were utilized to assess cell mobility. RNA sequencing, PCR, and Western blot analyses were conducted to uncover the underlying mechanism. Rescue experiments were performed to validate the mechanism of apoptotic induction. The impact of SHK and VPA combination treatment on primary osteosarcoma cells was also assessed. Finally, in vivo experiments were conducted to validate its anti-tumour effects and mechanism. RESULTS: The combination of SHK and VPA synergistically inhibited the proliferation and migration of osteosarcoma cells in vitro and induced apoptosis in these cells. Through a comprehensive analysis involving RNA sequencing, PCR, Western blot, and rescue experiments, we have substantiated our hypothesis that the combination of SHK and VPA induced apoptosis via the ROS-EGR1-Bax axis. Importantly, our in vivo experiments corroborated these findings, demonstrating the potential of the SHK and VPA combination as a promising therapeutic approach for osteosarcoma. CONCLUSION: The combination of SHK and VPA exerted an anti-tumour effect by inducing apoptosis through the ROS-EGR1-Bax pathway. Repurposing the old drug VPA demonstrated its effectiveness as an adjunctive therapeutic agent for SHK, enhancing its anti-tumour efficacy and revealing its potential value. Furthermore, our study expanded the application of natural compounds in the anti-tumour field and overcame some of their limitations through combination therapy. Finally, we enhanced the understanding of the mechanistic pathways linking reactive oxygen species (ROS) accumulation and apoptosis in osteosarcoma cells. Additionally, we elucidated the role of EGR1 in osteosarcoma cells, offering novel strategies and concepts for the treatment of osteosarcoma.

Application of Metal-Based Nanomaterials in In Vitro Diagnosis of Tumor Markers: Summary and Prospect.

Cancer, which presents with high incidence and mortality rates, has become a significant health threat worldwide. However, there is currently no effective solution for rapid screening and high-quality treatment of early-stage cancer patients. Metal-based nanoparticles (MNPs), as a new type of compound with stable properties, convenient synthesis, high efficiency, and few adverse reactions, have become highly competitive tools for early cancer diagnosis. Nevertheless, challenges such as the difference between the microenvironment of detected markers and the real-life body fluids remain in achieving widespread clinical application of MNPs. This review provides a comprehensive review of the research progress made in the field of in vitro cancer diagnosis using metal-based nanoparticles. By delving into the characteristics and advantages of these materials, this paper aims to inspire and guide researchers towards fully exploiting the potential of metal-based nanoparticles in the early diagnosis and treatment of cancer.

Human γδ T cells induce CD8+ T cell antitumor responses via antigen-presenting effect through HSP90-MyD88-mediated activation of JNK.

Human Vγ9Vδ2 T cells have attracted considerable attention as novel alternative antigen-presenting cells (APCs) with the potential to replace dendritic cells in antitumor immunotherapy owing to their high proliferative capacity and low cost. However, the utility of γδ T cells as APCs to induce CD8+ T cell-mediated antitumor immune response, as well as the mechanism by which they perform APC functions, remains unexplored. In this study, we found that activated Vγ9Vδ2 T cells were capable of inducing robust CD8+ T cell responses in osteosarcoma cells. Activated γδ T cells also effectively suppressed osteosarcoma growth by priming CD8+ T cells in xenograft animal models. Mechanistically, we further revealed that activated γδ T cells exhibited increased HSP90 production, which fed back to upregulate MyD88, followed by JNK activation and a subsequent improvement in CCL5 secretion, leading to enhanced CD8+ T cell cross-priming. Thus, our study suggests that Vγ9Vδ2 T cells represent a promising alternative APC for the development of γδ T cell-based tumor immunotherapy.

Metastasis of lung cancer?

BACKGROUND: Sarcoidosis is a multi-system, idiopathic, inflammatory disorder that affects the lungs in over 90% of patients. The incidence of bone lesions in sarcoidosis is only 1-13%. CASE REPORT: This study describes a 60-year-old woman with a previous history of thyroid cancer, and a more recent diagnosis of lung cancer with suspicious metastatic lesions, which were confirmed to be sarcoidosis. CONCLUSION: This case suggests that pulmonary neoplasms and pulmonary sarcoidosis can coexist and be easily confused. When lung cancer is accompanied by symmetric hilar lymph node enlargement and multiple lung nodules, sarcoidosis should be considered in addition to metastasis, and a biopsy should be performed for confirmation.

A Rare Case of Melanotic Schwannoma Occurred Intraosseous of Sacrum: A Literature Review.

BACKGROUND: Melanotic schwannoma is a rare tumor when it occurs in the sacrum. Though it is mostly classified as benign, the prognosis is unpredictable due to the possibility of recurrence and metastasis. Here, we reported a case of intraosseous of sacrum with good results and reviewed the literature. CASE PRESENTATION: A 33-year-old male patient complained of low back pain and was discovered to have an obstruction at S2. Following the necessary imaging diagnosis, we treated the patient with piecemeal excision in conjunction with extended curettage, and the frozen biopsy revealed that the tumor was melanotic schwannoma. The intraosseous portion of the lesion was curettaged using high-speed drill to enlarge the edge of curettage, and piecemeal excision for lesion within the sacral canal. After surgery, the patient received total 56Gy radiotherapy and frequent follow-up. After 15 months follow-up, there was no evidence of recurrence, and the nerve function was normal. CONCLUSION: Melanotic schwannoma that occurs intraosseous of the sacrum is extremely rare and lacks typical clinical manifestations; however it can be identified through careful pathological and imaging diagnosis. Intralesional extended curettage combined with radiotherapy can achieve a good local control with a satisfactory clinical effect in this rare disease.

Risk factor investigation for hip dislocation after periacetabular tumour resection and endoprosthetic reconstruction via thin-slice CT-based 3D model.

AIMS: Dislocation of the hip remains a major complication after periacetabular tumour resection and endoprosthetic reconstruction. The position of the acetabular component is an important modifiable factor for surgeons in determining the risk of postoperative dislocation. We investigated the significance of horizontal, vertical, and sagittal displacement of the hip centre of rotation (COR) on postoperative dislocation using a CT-based 3D model, as well as other potential risk factors for dislocation. METHODS: A total of 122 patients who underwent reconstruction following resection of periacetabular tumour between January 2011 and January 2020 were studied. The risk factors for dislocation were investigated with univariate and multivariate logistic regression analysis on patient-specific, resection-specific, and reconstruction-specific variables. RESULTS: The dislocation rate was 13.9% (n = 17). The hip COR was found to be significantly shifted anteriorly and inferiorly in most patients in the dislocation group compared with the non-dislocation group. Three independent risk factors were found to be related to dislocation: resection of gluteus medius (odds ratio (OR) 3.68 (95% confidence interval (CI) 1.24 to 19.70); p = 0.039), vertical shift of COR > 18 mm (OR 24.8 (95% CI 6.23 to 128.00); p = 0.001), and sagittal shift of COR > 20 mm (OR 6.22 (95% CI 1.33 to 32.2); p = 0.026). CONCLUSION: Among the 17 patients who dislocated, 70.3% (n = 12) were anterior dislocations. Three independent risk factors were identified, suggesting the importance of proper restoration of the COR and the role of the gluteus medius in maintaining hip joint stability.Cite this article: Bone Joint J 2022;104-B(10):1180-1188.

Remotely Temporal Scheduled Macrophage Phenotypic Transition Enables Optimized Immunomodulatory Bone Regeneration.

Precise timing of macrophage polarization plays a pivotal role in immunomodulation of tissue regeneration, yet most studies mainly focus on M2 macrophages for their anti-inflammatory and regenerative effects while the essential proinflammatory role of the M1 phenotype on the early inflammation stage is largely underestimated. Herein, a superparamagnetic hydrogel capable of timely controlling macrophage polarization is constructed by grafting superparamagnetic nanoparticles on collagen nanofibers. The magnetic responsive hydrogel network enables efficient polarization of encapsulated macrophage to the M2 phenotype through the podosome/Rho/ROCK mechanical pathway in response to static magnetic field (MF) as needed. Taking advantage of remote accessibility of magnetic field together with the superparamagnetic hydrogels, a temporal engineered M1 to M2 transition course preserving the essential role of M1 at the early stage of tissue healing, as well as enhancing the prohealing effect of M2 at the middle/late stages is established via delayed MF switch. Such precise timing of macrophage polarization matching the regenerative process of injured tissue eventually leads to optimized immunomodulatory bone healing in vivo. Overall, this study offers a remotely time-scheduled approach for macrophage polarization, which enables precise manipulation of inflammation progression during tissue healing.

[Application of three-dimensional printed total scapula for reverse shoulder arthroplasty in treatment of scapular tumors].

Objective: To investigate the effectiveness of three-dimensional (3D) printed total scapula for reverse shoulder arthroplasty in the treatment of scapular tumors. Methods: Between November 2017 and December 2021, 5 patients with scapular tumors were treated by reverse shoulder arthroplasty with 3D printed total scapula. There was 1 male and 4 females. The age ranged from 44 to 59 years, with an average of 50.4 years. There were 2 cases of chondro sarcoma, 1 case of high-grade osteosarcoma, 1 case of lung cancer with scapular metastasis, and 1 case of ligamentoid fibromatosis recurrence. The disease duration was 4-8 months, with an average of 5.8 months. According to the Musculoskeletal Tumor Society (MSTS) scapular girdle classification criteria, 4 cases of tumors involved both S1 and S2 zones, and 1 case involved S2 zone. The tumor diameters ranged from 4.2 to 11.2 cm, with an average of 6.1 cm. The operation time, intraoperative blood loss, and blood transfusion were recorded. During follow-up, the MSTS score was used to evaluate the recovery of limb function of the patients. The sink depth of the affected shoulder, complications, and oncological outcomes were observed. The position of the prosthesis was reviewed by imaging. Results: The operation time ranged from 155 to 230 minutes, with an average of 189 minutes. The intraoperative blood loss was 100-1 500 mL, with a median of 600 mL. Two patients were received blood transfusion of 800 mL and 1 850 mL respectively during operation. All incisions healed by first intention, and no complications such as infection occurred. All patients were followed up 4-22 months, with an average of 13 months. Two patients died at 8 and 15 months after operation respectively due to multiple metastases and organ failure. At last follow-up, the MSTS score of all patients was 73%-83%, with an average of 77.4%. The affected shoulder was 2-4 cm lower than the contralateral side, with an average of 3 cm. Imaging examinations showed that no prosthesis loosening, dislocation, or fracture occurred during follow-up. Conclusion: Reverse shoulder arthroplasty with 3D printed total scapula can obtain good shoulder function and appearance. Patients have high acceptance and satisfaction with this surgical method.

Can "domino" therapy effectively treat the infection around the prosthesis after the limb salvage surgery of bone tumor? - A study of sequential therapy.

BACKGROUND: Tumor resection and prosthetic replacement have become the treatments of choice for malignant bone tumors. Infections are the leading cause of failure of limb salvage surgeries. Therefore, treating infections around prostheses after limb salvage is essential and challenging. Our research team designed a "domino" sequential treatment plan to treat postoperative infections around tumor prostheses and evaluated its efficacy. PURPOSE: To introduce the new domino sequential treatment plan for postoperative infections of tumor prostheses, and evaluate the technical points of the plan and prognosis in medium- and long-term follow-ups. METHODS: Between January 2015 and August 2021, 14 patients were treated with prosthesis-preserving domino sequential therapy for peripheral prosthesis infections after bone-tumor limb salvage. The sample included eight cases of distal femur tumor, two of proximal tibia tumor, three of pelvic tumor, and one of middle femur tumor. We evaluated routine blood test results, C-reactive protein level, the erythrocyte sedimentation rate, and other indicators. X-rays and CT scans of the surgical site were obtained and the Musculoskeletal Tumor Society (MSTS) score was calculated. Treatment involved debridement and lavage of the prosthesis, and systemic and local antibiotics. RESULTS: The positivity rate of microbial culture was 78.6%. There were three cases of Staphylococcus aureus, one of Staphylococcus epidermidis, two of methicillin-resistant Staphylococcus epidermidis, one of methicillin-resistant Staphylococcus aureus, two of Acinetobacter baumannii, one of Streptococcus lactis (group C), one of Streptococcus mitis, and three with negative cultures. In three cases, sequential treatment failed to control the infection. The operation success rate was 78.6% (11/14). One case eventually required amputation, and another required long-term wound dressings. To control the infection, a third had to be treated using antibiotic bone cement combined with the "intramedullary nail reverse double insertion" technique. The MSTS scores of patients before infection debridement and at the last follow-up showed statistically significant differences (t = 5.312, p = 0.02). CONCLUSIONS: The prosthesis-preserving domino sequential method has certain advantages for treating bone-tumor limb salvage infections around the prosthesis. LEVEL OF EVIDENCE: Level IV, therapeutic.

Mutational characteristics of bone metastasis of lung cancer.

BACKGROUND: Roughly 30-40% of lung cancer (LC) patients develop bone metastasis during the course of disease. The genetic differences between primary LC and matched bone metastasis are not yet fully understood. METHODS: A total of 40 LC patients with bone metastasis were collected and 450 targeted cancer-related genes were sequenced for genomic-alteration (GA) identification. RESULTS: Among the 40 LC patients, 33 had adenocarcinomas and 7 had squamous cell carcinomas. The metastatic sites of the 33 lung adenocarcinomas (LUADs) were the pelvis (6 patients), spine (16 patients), and limbs (11 patients). A total of 425 and 422 GAs were detected in the primary and metastatic lesions, respectively. The most common GAs were epidermal growth factor receptor (EGFR) mutations, which had mutation rates of 85.0% and 72.5% in the primary and metastatic lesions, respectively, and tumor protein 53 (TP53) mutations, which had mutation rates of 52.5% and 67.5% in the primary and metastatic lesions, respectively. Metastases to the pelvis and spine were most commonly accompanied by factor receptor substrate 2 (FRS2), cyclin-dependent kinase 4 (CDK4), and murine double minute 2 (MDM2) amplification, and cyclin-dependent kinase inhibitor 2A (CDKN2A) deletion. The concordance between primary lung squamous cell carcinoma (LUSC) and corresponding metastasis was significantly higher than that of primary LUAD and corresponding metastasis (P=0.033). Compared to limb and pelvis metastases, the shared mutation in spine metastasis was significantly lower (P=0.016 and P=0.023, respectively). In matched primary LUSCs and bone metastasis lesions, there was no significant difference in the distribution of the tumor mutational burden (TMB) (P=0.9). Conversely, a significant difference of the TMB distribution was detected in pairs of primary LUAD and corresponding bone metastasis lesions (P=0.021). CONCLUSIONS: The consistency of mutation patterns between primary LC lesions and matched bone metastases may vary in terms of metastatic sites, but is very high in general. There was a significant difference in the TMB between primary LUAD and matched bone metastatic lesions. Our findings contribute to molecular understandings of primary LC and matched bone metastatic lesions.

Genomic characterization and outcome evaluation of kinome fusions in lung cancer revealed novel druggable fusions.

Kinase fusions represent an important type of somatic alterations that promote oncogenesis and serve as diagnostic markers in lung cancer. We aimed to identify the landscape of clinically relevant kinase fusions in Chinese lung cancer and to explore rare kinase rearrangements; thus, providing valuable evidence for therapeutic decision making. We performed genomic profiling of 425 cancer-relevant genes from tumor/plasma biopsies from a total of 17,442 Chinese lung cancer patients using next generation sequencing (NGS). Patients' clinical characteristics and treatment histories were retrospectively studied. A total of 1162 patients (6.66%; 1162/17,442) were identified as having kinase fusions, including 906 adenocarcinomas (ADCs) and 35 squamous cell carcinomas (SCCs). In ADC, 170 unique gene fusion pairs were observed, including rare kinase fusions, SLC12A2-ROS1, NCOA4-RET, and ANK3-RET. As for SCC, 15 unique gene fusions were identified, among which the most frequent were EML4-ALK and FGFR3-TACC3. Analyses of oncogenic mutations revealed a dual role for the gene fusions, CCDC6-RET and FGFR3-TACC3, in driving oncogenesis or serving as acquired resistance mechanisms to kinase inhibitors. In addition, our real-world evidence showed that patients with recurrent kinase fusions with low frequency (two occurrences) could benefit from treatment with kinase inhibitors' off-label use. Notably, patients with stage IV ADC who had novel RORB-ALK or AFF2-RET fusions, but no other known oncogenic driver mutations, demonstrated favorable clinical outcomes on tyrosine kinase inhibitors. Our data provide a comprehensive overview of the landscape of oncogenic kinase fusions in lung cancer, which assist in recognizing potentially druggable fusions that can be translated into therapeutic applications.

Anethole inhibits RANKL-induced osteoclastogenesis by downregulating ERK/AKT signaling and prevents ovariectomy-induced bone loss in vivo.

Postmenopausal osteoporosis is a chronic population health hazard systemic metabolic disease caused by excessive bone resorption and reduced bone formation. The activity between osteoblast and osteoclast, with their mutual effects, influence the procedure of normal bone remodeling. Over-activated osteoclast differentiation and function play a crucial role in excessive bone resorption. Hence, therapy strategies targeting osteoclast activity may promote the bone mass preservation and delay the osteoporosis process. Natural compound (anethole) is emerging as potential therapeutics for various metabolic diseases. The purpose of this study is to investigate the potential effects of anethole on RANKL-induced osteoclast formation and function in vitro and in vivo. Here, in vitro TRAP staining assay was performed to investigate the inhibitory effect of anethole on osteoclast differentiation. Bone pits resorption assay revealed that osteoclast-mediated bone resorption was inhibited by anethole. At mRNA and protein levels, anethole significantly reduced the expression of osteoclast-specific genes expression in a concentration- or time-dependent manner, including NFATc1, MMP-9, DC-STAMP, c-F, TRAP, CTR, Cathepsin K, and V-ATPase d2. Furthermore, intracellular signaling transduction assay indicated that anethole inhibited osteoclast formation via blocking ERK and AKT signaling. GSK3ß, the downstream signal of AKT, is simultaneously suppressed with anethole treatment. Based on ovariectomized (OVX) mice model, micro-CT and histological staining results suggested that anethole prevented estrogen deficiency-induced bone mass loss and increased osteoclast activity in vivo. In conclusion, our results show significant indications that anethole exhibits an osteoprotective effect and may be potential for the treatment of osteoporosis.

Fresh Tissue Multi-omics Profiling Reveals Immune Classification and Suggests Immunotherapy Candidates for Conventional Chondrosarcoma.

PURPOSE: There is still no standard nonsurgical regimen for conventional chondrosarcoma (CHS). We aimed to identify whether any CHSs have a favored microenvironment for immunotherapy via multidimensional evaluation of the immunologic characteristics of this tumor. EXPERIMENTAL DESIGN: We obtained 98 newly-diagnosed CHS fresh tumors from several institutions and performed comprehensive analysis of data from CyTOF, whole-exome sequencing, and flow cytometry in 22 cases. Clinical data from immunotherapy responders and nonresponders were compared to explore possible biomarkers of immunotherapy response. Mechanism studies were conducted to interpret the biomarker phenotype. RESULTS: Based on the integrated data of single-cell CyTOF and flow cytometry, the CHS immune-microenvironment phenotypes were classified into three groups: subtype I, the "granulocytic-myeloid-derived suppressor cell (G-MDSC) dominant" cluster, with high number of HLA-DR- CD14- myeloid cells; subtype II, the "immune exhausted" cluster, with high exhausted T-cell and dendritic-cell infiltration; and subtype III, the "immune desert" cluster, with few immune cells. Immune cell-rich subtypes (subtype I and II) were characterized by IDH mutation, pathologic high grade, and peritumoral edema, while subtype I cases were exclusively featured by myxoid transformation. In clinical practice involving 12 individuals who received PD-1 antibody immunotherapy, all of the 3 cases with controlled diseases were retrospectively classified as subtype II. In mechanism, IDH mutation significantly elevated chemokine levels and immune-cell infiltration in immune-inactivated tumors. CONCLUSIONS: This study is the first to provide immune characterization of CHS, representing a major step to precise immunotherapy against this malignancy. Immunotherapy is promising for the "immune exhausted" subtype of patients with CHS.

A panel of eight mRNA signatures improves prognosis prediction of osteosarcoma patients.

ABSTRACT: Genetic alterations are vital to the progression of osteosarcoma carcinoma. The present study investigated a panel of gene signatures that could evaluate prognosis in osteosarcoma based on data from the Therapeutically Applicable Research To Generate Effective Treatments initiative. Osteosarcoma messenger RNA (mRNA) profiles and clinical data were downloaded from the therapeutically applicable research to generate effective treatments database. Patients with osteosarcoma were divided into two groups based on findings at diagnosis: with and without metastasis. Differentially expressed mRNAs were compared and analyzed between groups. Univariate and multivariate Cox regression analyses identified a set of eight mRNAs with the ability to classify patients into high-risk and low-risk groups with significantly different overall survival times. Further analysis indicated that the eight-mRNA signature was an independent prognostic factor after adjusting for other clinical factors. Receiver operating characteristic curve analysis demonstrated a good performance of the eight-mRNA signature. Further, the biological processes and signaling pathways of the eight-mRNA signature were reviewed using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes resources. Finally, the results of the TCGA analysis were verified by other cohorts from Gene Expression Omnibus database. The identification of an eight-mRNA signature not only provides a prognostic biomarker of osteosarcoma but also offers the potential of novel therapeutic targets for its treatment.

[Treatment of distal tibial tumor with vascularized fibula reconstruction].

OBJECTIVE: To evaluate the effectiveness of vascularized fibula reconstruction in treatment of distal tibial malignant and invasive tumors. METHODS: Between March 2012 and January 2018, 11 patients with distal tibial malignant and invasive tumors were treated with vascularized fibula reconstruction. There were 7 males and 4 females with an average age of 20 years (range, 16-39 years). There were 8 cases of osteosarcoma, 2 cases of invasive giant cell tumor of bone, and 1 case of hemangioendothelioma. The tumors were rated as benign stage 3 in 2 cases and malignant stageⅠA in 1 case, stageⅡA in 4 cases, and stage ⅡB in 4 cases according to the Enneking staging. The disease duration was 1-6 months (mean, 2.7 months). The limb function was evaluated by Musculoskeletal Tumor Society (MSTS) score, and the distal and proximal union of the transplanted fibula and the diameter of the fibula were examined by imaging. RESULTS: All incisions healed by first intention. All patients were followed up 16-85 months (mean, 41 months). No tumor recurrence or metastasis occurred during the follow-up. The proximal and distal grafts in the 10 cases showed osseous healing, and the healing time was 7-12 months (mean, 10.1 months) at proximal end and 7-12 months (mean, 9.3 months) at distal end. In 1 case, the proximal end did not heal at 19 months, while the distal end healed at 13 months; proximal bone grafting was performed, and the proximal end healed. Among the 4 patients with distal screw fixation, 2 had peri-internal fixation fractures after graft healing, but no skin necrosis or infection occurred. All the 7 patients with distal steel plate fixation had no peri-internal fixation fracture, but 1 patient developed anterior tibial skin necrosis. At 12 months after operation, the diameter of fibula increased 1-5 mm (mean, 2.4 mm) by compared with that before operation. The MSTS score was 17-27 (mean, 22.8). CONCLUSION: Reconstruction of ankle joint with vascularized fibula can achieve satisfactory functional results, which is one of the feasible and worthy methods for the distal tibial malignant and invasive tumors.

Denosumab in Giant Cell Tumor of Bone: Current Status and Pitfalls.

Denosumab is a monoclonal antibody against RANK ligand for treatment of giant cell tumor of bone (GCTB). Clinical trials and case series have demonstrated that denosumab is relevant to beneficial tumor response and surgical down-staging in patients of GCTB. However, these trials or case series have limitations with a short follow-up. Recent increasing studies revealed that denosumab probably increased the local recurrence risk in patients treated with curettage. This may be caused by the thicken bone margin of tumor that trapped tumor cells from curettage. The direct bone formation by tumor cells in the margin after denosumab treatment also contributed to the local recurrence. in vitro studies showed denosumab resulted in a cytostatic instead of a true cytotoxic response on neoplastic stromal cells. More importantly, denosumab-treated GCTB exhibited morphologic overlap with malignancy, and a growing number of patients of malignant transformation of GCTB during denosumab treatment have been reported. The optimal duration, long term safety, maintenance dose, and optimum indications remain to be elucidated. With these concerns in mind, this review warns that the denosumab therapy of GCTB should be applied with caution.

Novel prognostic nomograms for female patients with breast cancer and bone metastasis at presentation.

BACKGROUND: There is a paucity of literature about prognostic evaluation for patients with breast cancer (BC) and bone metastasis at presentation. To date, little is known about how to accurately predict the prognosis of BC patients with bone metastasis at presentation. Thus, an accurate prediction tool of prognosis in this population is urgently needed. Our goal is to construct novel and prognostic nomograms for BC patients with bone metastasis at presentation. METHODS: We searched Surveillance, Epidemiology, and End Results (SEER) database for BC patients with bone metastasis at presentation between 2010 and 2016. Multivariate analysis was performed to obtain significantly independent variables. Then, novel prognostic nomograms were constructed based on those independent predictors. RESULTS: Tumor grade, histological type, primary tumor size, tumor subtype, surgery, chemotherapy and number of metastatic organs except bone were recognized as significantly independent variables of both overall survival (OS) and cancer-specific survival (CSS). Then those significant variables were integrated to construct nomograms for 3- and 5-year survival. Calibration plots for the 3- and 5-year survival in training and validation sets showed that the prediction curve was close to a 45 degree slash. The C-indices of OS in training and validation cohorts were 0.705 and 0.678, respectively. Similar results were observed for CSS in training and validation cohorts. CONCLUSIONS: Our proposed nomograms can effectively and accurately predict the prognosis of BC patients with bone metastasis at presentation, which provide a basis for individual treatments for metastatic lesions.