Neo-adjuvant radiation and intratumoral immunotherapy followed by surgery-NARIS trial for extremity soft tissue sarcoma.

Extremity soft tissue sarcoma (ESTS) is a rare malignant nonepithelial disease, calling for combined modality treatments with surgery to further improve local control rates and long-term survival, especially in patients with multiple local recurrences with or without risk of amputation. In this double-arm, open-label, Phase II clinical trial, we will enroll 30 patients with pathologically confirmed ESTS without nodal involvement or distant metastases. Patients are randomly assigned to the combination treatment group or the radiation monotherapy group. Additionally, tumor and biological samples will be obtained directly before and after neoadjuvant therapy, allowing for studies of immune response and primary drug resistance mechanisms.Clinical Trial Registration: ChiCTR2200060659 (http://www.chictr.org.cn) (ClinicalTrials.gov).

[Box: see text].

Suppressing CHD1L reduces the proliferation and chemoresistance in osteosarcoma.

Osteosarcoma (OS) is the most common bone malignant tumor. However, the genetic basis of OS pathogenesis is still not understood, and occurrence of chemo-resistance is a major reason for the high morbidity of OS patients. Recently, chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) has been identified as a gene related to malignant tumor progression. Unfortunately, its effects on OS development and drug resistance are still not understood. In the study, we attempted to investigate the effects of CHD1L on tumorigenesis and chemoresistance in OS. We found that CHD1L expression was markedly up-regulated in OS samples, especially in cisplatin (cDDP)-resistant patients. We also showed that OS cells with CHD1L knockdown were more sensitive to cDDP treatment with lower IC50 values. In addition, we found that CHD1L deletion markedly reduced cell proliferation and induced apoptosis in OS cells with cDDP resistance. Moreover, the properties of cancer stem cells were highly suppressed in cDDP-resistant OS cells following CHD1L knockdown. Furthermore, multidrug resistance protein 1 (MDR-1) expression levels were dramatically decreased in OS cells with cDDP resistance when CHD1L was suppressed. Functional analysis indicated that CHD1L knockdown clearly restrained the activation of ERK1/2, protein kinase B (AKT) and NF-κB signaling pathways in cDDP-resistant OS cells. Consistently, animal experiments suggested that CHD1L suppression mitigated cDDP resistance in the generated in vivo xenografts. Collectively, CHD1L could modulate chemoresistance of OS cells to cDDP, and thus may be inspiring findings for overcoming drug resistance in OS.

Survival outcomes of patients with brain metastasis of osteosarcoma can be improved by aggressive multi-disciplinary interventions including chemotherapy.

BACKGROUND/OBJECTIVE: Brain metastasis in osteosarcoma (BMO) is rare and its clinical characteristics are often buried among studies on brain metastasis of bone and soft tissue sarcomas. The aim of the present study was to summarize the incidence, clinical characteristics, treatment and outcomes of patients with BMO. METHODS: This retrospective study included 7 patients with BMO who received treatment in our center between 2005 and 2019. The clinical medical records of the 7 patients, together with data of 70 BMO patients published in 33 articles and retrieved by means of PubMed and Medline, were analyzed, retrospectively. RESULTS: Data analysis of the 97 BMO patients showed a high correlation between the interval from the primary diagnosis to BMO occurrence and the interval from the primary diagnosis to prior metastases. Multivariate analysis showed that chemotherapy, radiotherapy and surgery were three main factors affecting the overall survival of BMO patients (HR = 0.427; HR = 0.372; HR = 0.296). Surgery combined with chemotherapy or radiotherapy offered a better overall survival than surgery alone. CONCLUSION: Patients with BMO may obtain survival benefits from regular neuroimaging and early aggressive multi-disciplinary interventions including surgical resection, postoperative radiotherapy and chemotherapy. SYNOPSIS: This is a retrospective study describing the characteristics of metastasic intervals, locations, clinical features and prognosis in 97 patients with brain metastasis of osteosarcoma (BMO). Multivariate analysis showed that chemotherapy was effective as surgery and radiotherapy for the treatment of BMO. Our findings emphasize the importance of regular neuroimaging and early aggressive multi-disciplinary interventions including surgical resection, postoperative radiotherapy and chemotherapy.

Expression profiling of long noncoding RNAs associated with vasculogenic mimicry in osteosarcoma.

Osteosarcoma (OS) is the most common highly malignant bone tumor in teens. Vasculogenic mimicry (VM) is defined as de novo extracellular matrix-rich vascular-like networks formed by highly aggressive tumor cells. We previously reported the presence of VM and it is an unfavorable prognostic factor in OS patients. Long noncoding RNAs (lncRNAs) are aberrantly expressed in OS and involved in cancer cell VM. However, lncRNAs in VM formation of OS have not been investigated. We, therefore, profiled the expression of lncRNAs in highly aggressive OS cell line 143B compared with its parental poorly aggressive cell line HOS. The differentially expressed (DE) lncRNAs and messenger RNA (mRNAs) were subjected to constructed lncRNA-mRNA coexpressed network. The top-ranked hub gene lncRNA n340532 knockdown 143B cells were used for in vitro and in vivo VM assays. The annotation of DE lncRNAs was performed according to the coexpressed mRNAs by Gene Ontology and pathway analysis. A total of 1360 DE lncRNAs and 1353 DE mRNAs were screened out. lncRNA MALAT1 and FTX, which have known functions related to VM formation and tumorigenesis were identified in our data. The coexpression network composed of 226 lncRNAs and 118 mRNAs in which lncRNA n340532 had the highest degree number. lncRNA n340532 knockdown reduced VM formation in vitro. The suppression of n340532 also exhibited potent anti-VM and antimetastasis effect in vivo, suggesting its potential role in OS VM and metastasis. Furthermore, n340532 coexpressed with 10 upregulation mRNAs and 3 downregulation mRNAs. The enriched transforming growth factor-ß signaling pathway, angiogenesis and so forth were targeted by those coexpressed mRNAs, implying n340532 may facilitate VM formation in OS through these pathways and gene functions. Our findings provide evidence for the potential role of lncRNAs in VM formation of OS that could be used in the clinic for anti-VM therapy in OS.

Migration-inducing gene-7 independently predicts poor prognosis of human osteosarcoma and is associated with vasculogenic mimicry.

Vasculogenic mimicry (VM) is a special type of vascular channel formed by tumor cells without endothelial cell participation. Migration-inducing gene 7 (MIG-7) plays an important role in regulating VM. In this study, immunohistochemical staining was used to detect MIG-7 in tissue specimens from 141 primary osteosarcoma patients, and the relationship between MIG-7 and VM was examined. Survival analysis were performed to evaluate the prognoses. MIG-7 knockdown osteosarcoma cells were used for cell proliferation, apoptosis, migration, invasiveness and VM formation assays. A spontaneously metastasizing cell line-derived orthotopic xenograft mouse model was established to evaluate the effect of MIG-7 knockdown on tumorigenesis, VM formation and lung metastasis. MIG-7 expression was associated with VM formation. There were significant differences in overall and metastasis-free survival between the MIG-7-positive and MIG-7-negative groups. The MIG-7 expression was shown to be an independent indicator of both overall and metastasis-free survival. In vitro knockdown of MIG-7 dramatically reduced migration, invasion and VM formation in osteosarcoma cells without any significant effect on cell proliferation and apoptosis. MIG-7 knockdown also exhibited potent antitumor, antimetastasis and anti-VM effects in the orthotopic mouse model of 143B osteosarcoma. Therefore, MIG-7 serves as an independent unfavorable prognostic indicator in osteosarcoma patients and MIG-7 is an important mediator of osteosarcoma VM formation.

Application of SRT plus MR recession in supra-maximal esotropia from chronic sixth nerve palsy.

BACKGROUND: To investigate prognostic factors in patients with augmented superior rectus transposition (SRT) for sixth nerve palsy. METHODS: Thirteen patients who were diagnosed with sixth nerve palsy and underwent augmented SRT between January 2015 and February 2017 in EENT Hospital of Fudan University were reviewed retrospectively. Data including age, sex, etiology of the abducens nerve palsy, degree of pre- and postoperative deviation in the primary position, pre- and postoperative abduction deficit, any induced vertical or torsional deviations, reoperations, and other complications was collected. Patients with undercorrection of SRT surgeries received additional inferior rectus transposition (IRT) surgery. RESULTS: Mean esodeviation in primary position improved from 81.92△ to 30.54△ (p < 0.001) with a 1.54-unit improvement in abduction (p = 0.001). Six patients achieved alignment defined as esodeviation in primary position within 10△ of orthotropia and seven patients were undercorrected after the first SRT surgery. Multivariable linear regression analysis showed that among factors (disease duration, preoperative esodeviation, preoperative abduction deficit), only the degree of preoperative abduction deficit (ß = - 13.68) was the prognostic factor for success of SRT surgery. After IRT procedures, the mean esodeviation in primary position improved from 40△ to 8△ (p < 0.01). CONCLUSION: The degree of preoperative abduction deficit is the prognostic factor for augmented SRT for sixth nerve palsy. Patients with worse abduction deficit have a greater likelihood of needing a secondary operation, and IRT could be a good choice for reoperation after SRT.

Development and proposal of a scoring system for giant cell tumour of the bone around the knee.

PURPOSE: The purpose of this study was to provide the surgeons with effective and reliable guidelines for surgical decision-making by establishing a scoring system for giant cell tumour (GCTSS) based on evidence and expert opinion. METHODS: The modified Delphi technique and analytic hierarchy process were used to establish the GCTSS. The GCTSS was defined and classified based on different surgical methods using data from 207 patients collected retrospectively between October 2003 and December 2014. Finally, prospective data of 40 patients between December 2014 and October 2015 were used to analyze concordance between score categorization and experts' consensus on surgical procedure. RESULTS: A novel GCTSS included pathological fracture, cortical bone destruction, tumour size, and articular surface involved. The total scores ranged from 1 to 12 points. The strategy for each patient was decided: a total score of 1-4 suggested intralesional curettage alone for excellent post-operative function; 5-9 points indicated intralesional curettage with internal fixation for less surgery-related complications; and 10-12 points indicated prosthesis replacement for long-term local control. The κ-statistic for the predictive validity of total score was 0.611. The κ coefficient of each group represented moderate or substantial agreement, which was acceptable. The intraclass correlation coefficient for inter- and intra-observer reliability of total score was 0.831 and 0.740, respectively. CONCLUSIONS: The novel GCTSS is a comprehensive scoring system with content validity that can aid surgeons in assessing the aggressiveness or severity of giant cell tumour and might become a prognostic tool for surgical decision-making.

Personalized Identification of Differentially Expressed Modules in Osteosarcoma.

BACKGROUND Osteosarcoma (OS), an aggressive malignant neoplasm, is the most common primary bone cancer mainly in adolescents and young adults. Differentially expressed modules tend to distinguish differences integrally. Identifying modules individually has been crucial for understanding OS mechanisms and applications of custom therapeutic decisions in the future. MATERIAL AND METHODS Samples came from individuals were used from control group (n=15) and OS group (n=84). Based on clique-merging, module-identification algorithm was used to identify modules from OS PPI networks. A novel approach - the individualized module aberrance score (iMAS) was performed to distinguish differences, making special use of accumulated normal samples (ANS). We performed biological process ontology to classify functionally modules. Then Support Vector Machine (SVM) was used to test distribution results of normal and OS group with screened modules. RESULTS We identified 83 modules containing 2084 genes from PPI network in which 61 modules were significantly different. Cluster analysis of OS using the iMAS method identified 5 modules clusters. Specificity=1.00 and Sensitivity=1.00 proved the distribution outcomes of screened modules were mainly consistent with that of total data, which suggested the efficiency of 61 modules. CONCLUSIONS We conclude that a novel pipeline that identified the dysregulated modules in individuals of OS. The constructed process is expected to aid in personalized health care, which may present fruitful strategies for medical therapy.

Promotion of tumour proliferation, migration and invasion by miR-92b in targeting RECK in osteosarcoma.

MicroRNAs play important roles in the development of cancers. Although miR-92b has been reported to promote the tumorigenesis of some cancers, its role in osteosarcoma remains unknown. In the present study, we focused on the expression, function and mechanisms of miR-92b in osteosarcoma development. The miRNA miR-92b was up-regulated in osteosarcoma cell lines and tissues; miR-92b up-regulation correlated with poor prognosis in osteosarcoma. Overexpression of miR-92b promoted osteosarcoma cell proliferation, migration and invasion, which was abrogated by miR-92b inhibition. Reversion-inducing, cysteine-rich protein with kazal motifs (RECK) was identified as the direct and functional target of miR-92b in osteosarcoma. Importantly, restoring RECK expression abrogated increases in cell growth, motility and invasiveness induced by miR-92b RECK was down-regulated in osteosarcoma tissues, and its expression level negatively correlated with miR-92b Collectively, our results indicate that miR-92b acts as an oncogenic miRNA and may be a therapeutic target in osteosarcoma.

Surgical treatment for pelvic giant cell tumor: a multi-center study.

BACKGROUND: The purpose of this study was to discuss the clinical results which related to the location of giant cell tumors (GCTs) in the pelvis so as to determine the ideal surgical treatment protocol. METHODS: We report 29 cases who accepted surgical treatment from five clinical centers during the last 12 years. All patients were divided into three groups according to tumor locations, and they were also classified into two groups in light of surgical treatments. The parameters for outcome evaluation consisting of general condition, surgical complications, local disease control, and Musculoskeletal Tumor Society (MSTS) 93 functional score had been analyzed, respectively. RESULTS: Surgical treatment in the acetabular area usually resulted in postoperative complications and poor function. One patient who accepted intralesional surgery and two who accepted wide resection had local recurrence. The mean functional score was 25.4 for the 8 patients who received intralesional surgery and 21.9 for the 21 patients who received wide resection. Surgical complications occurred in 1 patient who underwent intralesional surgery and the other 6 patients who underwent wide resection. CONCLUSIONS: We conclude that surgical treatment of pelvic GCTs in the acetabular area is difficult to select as it is always accompanied by complications and poor function. Compared to wide resection, intralesional surgery combined with a meticulous preoperative planning may lower the recurrence rate and obtain favorable postoperative functional results.