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Purpose: Anemia is relatively common in cancer patients, and is associated with poor survival in patients with various malignancies. However, how anemia would affect prognosis and response to neoadjuvant chemotherapy (NAC) in osteosarcoma (OS) is still without substantial evidence., Methods: We retrospectively analysed 242 patients with stage II OS around the knee joint in our institute. Changed hemoglobin (Hb) levels (before and after NAC) were recorded to assess the prognostic value in DFS (disease-free survival) and tumor response to NAC. Univariate and multivariate analyses were conducted to identify prognostic factors related with outcome in OS patients., Results: The mean Hb level significantly decreased after NAC (134.5 ± 15.3 g/L vs. 117.4 ± 16.3 g/L). The percentage of mild (21%), moderate (4.2%) and severe (0%) anemia patients markedly increased after NAC: 41%, 24% and 4.1% respectively. There was higher percentage of ≥ 5% Hb decline in patients with tumor necrosis rate < 90% (141 out of 161), compared with those with tumor necrosis rate ≥ 90% (59 out of 81). Further univariate and survival analysis demonstrated that Hb decline had a significant role in prediction survival in OS patients. Patients with ≥ 5% Hb decline after NAC had an inferior DFS compared with those with < 5% Hb decline., Conclusion: In osteosarcoma, patients with greater Hb decrease during neoadjuvant treatment were shown to have worse DFS and a poorer response to NAC than those without. Attempts to correct anemia and their effects on outcomes for osteosarcoma patients should be explored in future studies., (© 2024. The Author(s).)

Purpose: We investigated the safety and preliminary efficacy of anti-PD-L1 antibody (ZKAB001) as maintenance therapy for localized patients with high-grade osteosarcoma to reduce the risk of recurrence and metastasis., Patients and Methods: This open-label Phase I/II study was divided into dose-escalation Phase I and expansion Phase II. Phase I used a 3+3 design with ZKAB001 at three escalating doses ranging: 5, 10, 15 mg/kg every 2 weeks in 9 patients with localized high-grade osteosarcoma and Phase II tested 10 mg/kg in 12 patients for up to 24 cycles. Primary endpoints were safety and tolerability assessed using CTCAE4.0.3., Results: Between October 2018 and 2019, 21 eligible patients were enrolled and accepted ZKAB001 treatment: 9 in the dose-escalation phase, and 12 in expansion phase. Six patients with disease progression withdrew from this study and follow-up is ongoing. The MTD was not defined in Phase I. All doses had a manageable safety profile. The recommended dose in Phase II was set at 10 mg/kg. Most frequent immune-related adverse events were thyroiditis (76.2%) and dermatitis (42.9%). Only 1 (4.8%) of 21 patients had a Grade 3 skin rash. The median 3-year event-free survival (EFS) and overall survival (OS) were not established; however, 24-month EFS was 71.4% (95% confidence interval, 47.2-86.0) and 2-year OS was 100%. Preliminary efficacy data showed EFS benefits in patients with PD-L1 positive or an MSI-H sub-population., Conclusions: Switching to maintenance using ZKAB001 showed an acceptable safety profile and provided preliminary evidence of clinical activity in localized patients with osteosarcoma., (©2022 American Association for Cancer Research.)

Background: The clinicopathology of aneurysmal bone cysts (ABCs) secondary to osteosarcoma has not yet been reported. We conduct a retrospective review of ABCs secondary to osteosarcoma to characterize clinicopathology and influence on the survival of patients with Enneking stage IIB extremity osteosarcoma., Patients and Methods: A total of 300 patients with Enneking stage IIB extremity osteosarcoma were eligible for analysis. These cases were divided, according to the pathology of biopsy and magnetic resonance imaging (MRI), into ABCs group and no ABCs group. Patients (ABCs versus no ABCs) were compared using a 1:2 propensity score analysis to best match between groups. Clinicopathology and survival data were analyzed., Results: The total occurrence rate of secondary ABCs was 10.3%. A higher prevalence of pathological fractures was observed in the ABCs group (22.6%) compared with the no ABCs group (8.6%) (p = 0.032). Patients with ABCs were more likely to undergo amputation compared with patients without ABCs (p = 0.007). Those with secondary ABCs had poorer response to chemotherapy before and after propensity score matching (p = 0.006 and p = 0.048, respectively). Kaplan-Meier survival analysis showed that EFS and OS distributions were not significantly different between the two patient groups. ABCs were not significantly different in terms of EFS or OS in the multivariate analysis model (p > 0.05)., Conclusions: The presence of secondary ABCs was associated with increased occurrence rate of pathological fracture and high percentage of amputation. Moreover, patients with secondary ABCs had poorer response to chemotherapy. However, the presence of secondary ABCs did not influence survival of patients with Enneking stage IIB extremity osteosarcoma., (© 2021. Society of Surgical Oncology.)

Background and Objectives: We investigated the clinical significance of indeterminate pulmonary nodules (IPNs) in patients diagnosed with nonmetastatic, high-grade localized osteosarcoma., Methods: We retrospectively analyzed the clinical data of 364 patients with nonmetastatic, high-grade localized osteosarcoma. Based on pulmonary computed tomography findings at presentation, the patients were categorized into the no-nodules and the IPNs group and were further categorized into subgroups based on age (<18 and ≥18 years). We performed an intergroup comparison of event-free survival (EFS) and overall survival (OS)., Results: At presentation, 276 (75.8%) patients showed no nodules, and 88 (24.2%) patients showed IPNs. The EFS and OS were similar between adults with IPNs (n = 54 [30.5%]) and without nodules (n = 123 [69.5%]) (p = .200 and p = .609, respectively). No significant intergroup difference in OS was observed in pediatric patients (p = .093). However, pediatric patients with IPNs (n = 34 [18.2%]) had poorer EFS than those without nodules (n = 153 [81.8%]) (p = .016). Multivariate analyses confirmed that IPNs were independently associated with poorer EFS in pediatric patients (hazard ratio 1.788, 95% confidence interval 1.092-2.926, p = .021)., Conclusions: This study showed that IPNs at presentation did not affect the survival of adults with nonmetastatic, high-grade localized osteosarcoma but were associated with poorer EFS in pediatric patients., (© 2020 Wiley Periodicals LLC.)

Osteosarcoma is the most frequent primary bone tumor with poor prognosis. Through RNA-sequencing of 100,987 individual cells from 7 primary, 2 recurrent, and 2 lung metastatic osteosarcoma lesions, 11 major cell clusters are identified based on unbiased clustering of gene expression profiles and canonical markers. The transcriptomic properties, regulators and dynamics of osteosarcoma malignant cells together with their tumor microenvironment particularly stromal and immune cells are characterized. The transdifferentiation of malignant osteoblastic cells from malignant chondroblastic cells is revealed by analyses of inferred copy-number variation and trajectory. A proinflammatory FABP4 + macrophages infiltration is noticed in lung metastatic osteosarcoma lesions. Lower osteoclasts infiltration is observed in chondroblastic, recurrent and lung metastatic osteosarcoma lesions compared to primary osteoblastic osteosarcoma lesions. Importantly, TIGIT blockade enhances the cytotoxicity effects of the primary CD3 + T cells with high proportion of TIGIT + cells against osteosarcoma. These results present a single-cell atlas, explore intratumor heterogeneity, and provide potential therapeutic targets for osteosarcoma.

Background: Metastasis is the leading cause of death in patients with osteosarcoma. Some of these patients fail to respond to chemotherapy and die of metastasis within a short period. Therefore, it is important to identify novel biomarkers to improve the diagnosis and treatment of osteosarcoma. TRIM7 is a member of the tripartite motif (TRIM) family protein that is involved in various pathological conditions including cancer; however, its role in osteosarcoma remains elusive., Methods: Cell proliferation, invasion and migration were measured by CCK-8 and Transwell. Immunoprecipitation and mass spectrometry analysis were used to identify candidate proteins associated with TRIM7. Immunoprecipitation, immunofluorescence, pull down and ubiquitination assay were performed to examine the regulation between TRIM7 and its candidate protein. m6A modification of TRIM7 was measured by RNA immunoprecipitation., Findings: TRIM7 expression was upregulated in osteosarcoma tissues and was an independent risk factor in predicting poor prognosis. TRIM7 regulates osteosarcoma cell migration and invasion through ubiquitination of breast cancer metastasis suppressor 1 (BRMS1). Moreover, chemoresistance was readily observed in osteosarcoma cells and in patient-derived xenograft (PDX) mice with higher TRIM7 levels. Loss of TRIM7 m6A modification was observed in osteosarcoma tissues. METTL3 and YTHDF2 were the main factors involved in the aberrant m6A modification of TRIM7., Interpretation: Overall, our findings show that TRIM7 plays a key role in regulating metastasis and chemoresistance in osteosarcoma through ubiquitination of BRMS1., Funding: This work was financially supported by grants of NSFC (81001192, 81672658 and 81972521) and National Key Research Project of Science and Technology Ministry (2016YFC0106204)., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: This study was performed to explore the relationship between various clinical factors and the prognosis of limb osteosarcoma., Methods: We retrospectively analyzed the clinical data of 336 patients with limb osteosarcoma treated from June 2000 to August 2016 at 7 Chinese cancer centers. Data on the patients' clinical condition, treatment method, complications, recurrences, metastasis, and prognosis were collected and analyzed. Kaplan-Meier analysis and Cox regression models were used to analyze the data., Results: The patients comprised 204 males and 132 females ranging in age from 6 to 74 years (average, 21.1 years). The overall 3- and 5-year survival rates were 65.0% and 55.0%, respectively. The 5-year overall survival rate was 64.0% with standard chemotherapy and 45.6% with non-standard chemotherapy. Cox regression analysis demonstrated that standard chemotherapy, surgery, recurrence, and metastasis were independent factors associated with the prognosis of limb osteosarcoma., Conclusion: The survival of patients with limb osteosarcoma can be significantly improved by combining standard chemotherapy and surgery. The overall survival rate can also be improved by adding methotrexate to doxorubicin-cisplatin-ifosfamide triple chemotherapy.

Osteosarcoma (OS) is the most commonly diagnosed bone tumor in young people with poor prognosis. At present, the mechanisms underlying tumorigenesis in OS are not well understood. The methionine adnosyltransferase 2B (MAT2B) gene encodes the regulatory subunit of methionine adenosyltransferase (MAT). Recent studies demonstrated that it is highly expressed in a number of human malignancies; however, is undefined in OS. In the present study, MAT2B expression was investigated in tumor samples and cell lines. In vivo and in vitro, lentivirus‑mediated small hairpin RNA was constructed to target the MAT2B gene and examine the role of MAT2B in OS proliferation. Microarray analysis was performed to examine the possible downstream molecular target of MAT2B in OS. MAT2B was markedly increased in OS specimens compared with the normal bone tissues, and it was additionally abundantly expressed in OS cell lines. Inhibition of MAT2B expression caused a marked decrease in proliferation and significant increase in apoptosis. In vivo, MAT2B silencing significantly inhibited OS cell growth. Microarray analysis suggested that epidermal growth factor receptor (EGFR) and proliferating cell nuclear antigen (PCNA) may function as downstream targets of MAT2B in OS, as confirmed by reverse transcription‑quantitative polymerase chain reaction assays and western blotting. Collectively, these results suggested that MAT2B serves a critical role in the proliferation of OS by regulating EGFR and PCNA and that it may be a potential therapeutic target and prognostic factor of OS.

De novo methotrexate (MTX)-resistance, whose underlying mechanism remains largely unknown, usually leads to very poor prognosis in patients with osteosarcoma (OS). In this study, we established the de novo MTX-resistant OS cell line SF-86 and identified the candidate gene spindle and kinetochore associated complex subunit 1 (SKA1) as potentially related to de novo MTX-resistance. Analysis of a cohort of 95 OS patients demonstrated that SKA1 overexpression significantly correlated with de novo MTX-resistance and poor 5-year survival. Mechanistically, SKA1 overexpression lead to a downregulation of folylpoly-γ-glutamate synthetase (FPGS), a key enzyme that converts MTX into its active form, MTX-PG. We further demonstrated that SKA1 interacts with DNA-directed RNA polymerase II subunit RPB3. ChIP analysis revealed that RPB3 binds the promoter region of the FPGS gene and triggers FPGS transcription upon MTX treatment in SW1353, a MTX-sensitive OS cell line lacking endogenous SKA1 expression. On the contrary, this process is blocked in SF-86 cells due to the formation of an inhibitory SKA1-RPB3 complex. Furthermore, downregulation of SKA1 levels restores MTX sensitivity in SF-86. Collectively, our study has established the de novo MTX-resistant cell line SF-86 and identified SKA1 as a novel regulator of FPGS, playing a key role in the development of de novo MTX-resistance in OS., (© 2019 Federation of European Biochemical Societies.)

Osteosarcoma pulmonary metastases are typically treated with resection and/or chemotherapy. We hypothesize that stereotactic radiosurgery (SRS) can be an alternative to surgery that can achieve high rates of local control with limited toxicity. From January 2005 to December 2013, 73 patients who developed pulmonary metastasis during period of adjuvant chemotherapy or follow-up were analyzed. 33 patients were treated by stereotactic radiosurgery using the body gamma-knife system. A total dose of 50 Gy was delivered at 5 Gy/fraction to the 50% isodose line covering the planning target volume, whereas a total dose of 70 Gy was delivered at 7 Gy/fraction to the gross target volume. The other 40 patients were treated by surgical resection. Four-year progression-free survival rate, four-year survival rate, median time of PRPFS (post-relapse progress-free survival) and PROS (post-relapse overall survival) in SRS group were parallel to that in surgical group. Patients tolerated gamma knife radiosurgery well. Our study demonstrates that SRS is well-tolerated with excellent local control and less complications. SRS should be considered as a potential option in patients with pulmonary metastases from osteosarcoma, especially in those who are medically inoperable, refuse surgery.

Ubiquitin carboxyl terminal hydrolase 1 (UCHL1), a member of the UCH class of DUBs, has been reported as either an oncogene or a tumor suppressor. However, the molecular mechanism underlying the biological function of UCHL1 in osteosarcoma is still unclear. This study was aimed at elucidating the roles of UCHL1 in regulating the biological behavior of osteosarcoma cells. In this study, we found that UCHL1 was elevated in osteosarcoma compared with normal bone tissue. Moreover, UCHL1 expression level was correlated with tumor maximum diameter, high rate of lung metastases and short survival time. Then, we found that knockdown of UCHL1 in osteosarcoma cell MG63 inhibited cell proliferation and significantly increased cell population in the G1 phase. Several cyclins promoting G1/S phase transition were reduced after UCHL1 knockdown, including cell cycle regulator cyclin D1, cyclin E1 and CDK6. Moreover, inhibition of UCHL1 in MG63 cells dramatically induced cell apoptosis. We also found that down-regulation of UCHL1 in MG63 significantly inhibited cell invasion. Then, we found that there was a positive correlation between UCHL1 expression level and the Akt and ERK phosphorylation status. Finally, in vivo data showed that knockdown of UCHL1 inhibited osteosarcoma growth in nude mice. These results indicate that UCHL1 could work as an oncogene and may serve as a promising therapeutic strategy for osteosarcoma., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: Local unresectable recurrence of osteosarcoma is one of the most challenging tumors to treat. High-intensity focused ultrasound (HIFU) is a new, noninvasive technique with potential to ablate and inactivate tumors. Treatment of solid tumors with HIFU has been reported. In this study, we assessed safety and efficacy of HIFU in treating local unresectable recurrence of osteosarcoma., Methods: We performed a retrospective analysis of 27 patients who had local unresectable recurrence of osteosarcoma from 2006 to 2010. Changes of biochemical markers and pain rating, response rate, disease control rate, local disease progression-free survival, progression-free survival (PFS) and overall survival (OS) were used to evaluate efficacy of HIFU treatment., Results: HIFU resulted in a significant change in alkaline phosphatase and lactic acid dehydrogenase and a remarkably relief in pain rating, without severe side effects. According to MRI examination 4-6 weeks after HIFU treatment, 2 (7.4%) patients had complete response (CR), 12 (44.4%) had partial response (PR), 9 (33.3%) had stable disease (SD) and 4 (14.8%) had progression disease (PD). The response rate was 51.8% and the local disease control rate was 85.2%. The 1-, 2-, and 3-year local disease control rates were 59.2%, 40.7% and 33.1%, respectively. The median local disease progression-free time was 14 months, the median progression-free time was 13 months and the median over-all survival time was 21 months. Patients without pulmonary metastasis had a better local disease control rate at 1-,2-,3-year and a longer local disease progression-free time, progression-free time, over-all survival time than patients with pulmonary metastasis., Conclusion: HIFU is a safe and noninvasive treatment for local unresectable recurrence of osteosarcoma, with good local control and without severe complications., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Pirarubicin (THP), a novel anthracycline derivative of doxorubicin (ADM), is effective in treating patients with advanced, relapsed or recurrent high-grade osteosarcoma. But its role in neoadjuvant/adjuvant chemotherapy of osteosarcoma is still not defined. We conducted a retrospective evaluation of THP-containing chemotherapy for osteosarcoma in comparison with ADM-containing chemotherapy to determine differences in efficacy and toxicities between THP- and ADM-containing regimens. From January 2008 to May 2011, 112 stage IIB limb high-grade osteosarcoma patients were treated in our institute. Fifty-four patients received a median 6 cycles of neoadjuvant/adjuvant chemotherapy consisted of THP (pirarubicin), DDP (cisplatin), IFO (ifosfamide) and MTX (methotrexate), while 58 patients received a median 6 cycles of neoadjuvant/adjuvant chemotherapy consisted of ADM (doxorubicin), DDP (cisplatin), IFO (ifosfamide) and MTX (methotrexate). Efficacy and toxicity of the 2 anthracyclines given as combination chemotherapy were assessed in these patients. The limb salvage rate, histologic response rate, 2-year recurrence rate, 2-year metastasis rate, 2-year disease-free survival rate, 2-year overall survival rate, median disease-free survival time (DFS) and median overall survival time (OS) in THP-containing group were similar to that in ADM-containing group. Toxicities were well balanced in two groups. No death related to chemotherapy was observed. Left ventricular ejection fraction was unchanged 1 and 2 years after chemotherapy in two groups. Efficacy and toxicity of THP-containing combination are similar to those of ADM-containing combination in neoadjuvant/adjuvant chemotherapy for stage IIB limb high-grade osteosarcoma.

Osteosarcoma (OS) is the most common primary malignant tumour of bone. Nearly 30-40% of OS patients have a poor prognosis despite multimodal treatments. Because the carcinogenesis of OS remains unclear, the identification of new oncogenes that control the tumourigenesis and progression of OS is crucial for developing new therapies. Here, we found that the expression of Mediator of RNA polymerase II transcription subunit 19 (Med19) was increased in OS samples from patients compared to normal bone tissues. Cyclin D1 and cyclin B1 are upregulated in Med19 positive OS tissues. Importantly, among 97 OS patients of Enneking stage IIB or IIIB, Med19 expression was correlated with metastasis (P<0.05) and poor prognosis (P<0.01). Med19 knockdown significantly induced growth inhibition, reduced colony-forming ability and suppressed migration in the OS cell lines Saos-2 and U2OS, along with the downregulated expression of cyclin D1 and cyclin B1. Med19 knockdown also induced apoptosis in Saos-2 cells via induction of caspase-3 and poly ADP-ribose polymerase (PARP). In addition, Med19 knockdown significantly suppressed tumour growth in an OS xenograft nude mouse model via suppression of cyclin D1 and cyclin B1. Simultaneously, Med19 downregulation decreased the expression of Ki67 and proliferating cell nuclear antigen (PCNA) in tumour samples from OS xenograft nude mice. Med19 depletion remarkably reduced tumour metastasis in a model of OS metastatic spreading. Taken together, our data suggest that Med19 acts as an oncogene in OS via a possible cyclin D1/cyclin B1 modulation pathway., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Stereotactic radiosurgery (SRS), such as body gamma knife, was reported to achieve excellent rates of local disease control with limited toxicity in many cases of primary or secondary pulmonary tumor, except osteosarcoma. To confirm the value of SRS in pulmonary metastases from osteosarcoma, we reviewed the experience from our institution (Department of Oncology, Affiliated Sixth People's Hospital, Shanghai) and compared the efficiency of SRS with that of surgical resection. From January 2005 to December 2012, we carried out a retrospective investigation of 58 patients (age, 8-59 years; mean, 25.2 years) who were diagnosed with non-metastatic osteosarcoma of the extremity and later developed pulmonary metastasis during the period of adjuvant chemotherapy or follow-up. Among them, 27 patients were treated by SRS using the body gamma-knife system. A total dose of 50 Gy was delivered at 5 Gy/fraction to the 50% isodose line covering the planning target volume, whereas a total dose of 70 Gy was delivered at 7 Gy/fraction to the gross target volume. The other 31 patients were treated by surgical resection. Two-year progression-free survival rate, two-year survival rate, median time of PRPFS (post-relapse progress-free survival) and PROS (post-relapse overall survival) in SRS group were parallel to that in surgical group. All 27 patients tolerated gamma knife radiosurgery well while only 9 patients had grades 1-2 pneumonitis. We believe SRS, compared with surgical resection, is effective and safe in treating pulmonary metastasis from osteosarcoma, especially for those patients who were medically unfit for a resection or who refused surgery.

Aim: To investigate prognostic factors for long-term outcomes in Chinese patients with high-grade osteosarcoma of the extremities or trunk treated by multidisciplinary combined therapy., Methods: In total, 333 consecutive patients with non-metastatic or primary metastatic high-grade osteosarcoma of the extremities or trunk were retrospectively reviewed to analyze the correlation between survival and sex, age, site, histological type, clinical stage, alkaline phosphatase (ALP) level, preoperative chemotherapy or not, response to preoperative chemotherapy, postoperative chemotherapy cycles and manner of surgery. The combined therapy included preoperative and postoperative chemotherapy as well as limb salvage surgery or amputation., Results: The median survival time was 52 months for all 333 patients. Univariate analysis revealed that sex, ALP level, preoperative chemotherapy and cycle numbers of postoperative chemotherapy may influence the prognosis of high-grade osteosarcoma of the extremities or trunk. Multivariate analysis revealed that the female, a normal ALP level, preoperative chemotherapy with good response and ≥4 cycles of postoperative chemotherapy correlated with a better outcome., Conclusion: Preoperative chemotherapy is important in high-grade osteosarcoma treatment and a good response to it is an important marker of prognosis. It should be given with ≥ cycles of postoperative chemotherapy after surgery., (© 2012 Wiley Publishing Asia Pty Ltd.)

Aims: The objective of this study was to investigate the efficacy and toxic side effects of two combinations of methotrexate, cisplatin, doxorubicin and ifosfamide on treating Chinese osteosarcoma patients., Methods: A retrospective analysis was conducted of 185 osteosarcoma patients treated with the four drugs mentioned above. A total of 93 patients received the Italian therapeutic treatment (IOR-OS/N-5: Instituto Ortopedic Rizzoli-Section of Osteosacorma/Neoadjuvant chemotherapy-5) and the remaining 92 patients received the therapeutic treatment optimized by our department. We compared the efficacy and toxic side effects of these two therapies., Results: The limb salvage rates, 3-year recurrence rates and 3-year metastasis rates of IOR-OS/N-5 and our optimized treatment were 52.7 and 58.7%; 20.9 and 11.4% and 44.1 and 27.2%, respectively. The 3-year survival rates and the 3-year disease-free survival rates of IOR-OS/N-5 and our optimized treatments were 62.4 and 78.4%; and 53.6 and 67.8%, respectively. Overall survival and disease-free survival rates were significantly different between these two treatments (P = 0.032 and 0.024, respectively). Liver function with degree III and IV damage accounted for 35.2 and 16.6% of the total adverse reactions in the IOR-OS/N-5 and our optimized treatment groups, respectively. Degree III-IV neutropenia accounted for 22.6 and 40.0%, respectively, in the IOR-OS/N-5 and optimized treatments., Conclusion: The optimization of MTX, DDP, DOX and IFO based on Chinese patients' physiology increased the tolerance and efficacy for the treatment of osteosarcoma., (© 2011 Blackwell Publishing Asia Pty Ltd.)

Background: Cell-based immunotherapy shows the therapeutic potential in sarcomas, in addition to angiogenesis-targeted tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI). Multi-antigen stimulated cell therapy-I (MASCT-I) technology is a sequential immune cell therapy for cancer, which composes of multiple antigen-loaded dendritic cell (DC) vaccines followed by the adoptive transfer of anti-tumor effector T-cells. Methods: In this phase 1 study, we assessed MASCT-I plus camrelizumab (an ICI against PD-1) and apatinib (a highly selective TKI targeting VEGFR2) in patients with unresectable recurrent or metastatic bone and soft-tissue sarcoma after at least one line of prior systemic therapy. One MASCT-I course consisted of 3 DC subcutaneous injections, followed by 3 active T cell infusions administered 18–27 days after each DC injection. In schedule-I group, 3 DC injections were administered with a 28-day interval in all courses; in schedule-II group, 3 DC injections were administered with a 7-day interval in the first course and with a 28-day interval thereafter. All patients received intravenous camrelizumab 200 mg every 3 weeks and oral apatinib 250 mg daily. Results: From October 30, 2019, to August 12, 2021, 19 patients were enrolled and randomly assigned to schedule-I group (n = 9) and schedule-II group (n = 10). Of the 19 patients, 11 (57.9%) experienced grade 3 or 4 treatment-related adverse events. No treatment-related deaths occurred. Patients in schedule-II group showed similar objective response rate (ORR) with those in schedule-I group (30.0% versus 33.3%) but had higher disease control rate (DCR; 90.0% versus 44.4%) and longer median progression-free survival (PFS; 7.7 versus 4.0 months). For the 13 patients with soft-tissue sarcomas, the ORR was 30.8%, DCR was 76.9%, and median PFS was 12.9 months; for the 6 patients with osteosarcomas, the ORR was 33.3%, the DCR was 50.0%, and median PFS was 5.7 months. Conclusions: Overall, MASCT-I plus camrelizumab and apatinib was safe and showed encouraging efficacy in advanced bone and soft-tissue sarcoma, and schedule-II administration method was recommended. Trial registration: ClinicalTrials.gov, NCT04074564. [ABSTRACT FROM AUTHOR]

Purpose: The options for the second-line treatment of metastatic osteosarcoma are still limited. Anlotinib is a multi-kinase inhibitor which has shown promising efficacy and good tolerability in various cancer types. This retrospective study was conducted to evaluate the efficacy and safety of anlotinib combined with gemcitabine/docetaxel (GD) in patients with metastatic osteosarcoma who have failed first-line chemotherapy. Patients and Methods: The data of patients who received anlotinib combined with GD or GD were collected. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate and safety. Results: From July 2013 to November 2020, a total of 32 patients were enrolled, 13 received anlotinib combined with GD and 19 received GD. Median PFS was 9.0 months (95% CI 6.7– 39.1) in the combination group and 5.0 months (95% CI 1.2– 6.7) in the chemotherapy group. ORR were 38.4% and 15.8%, DCR were 69.2% and 38.1% in the combination and chemotherapy group, respectively. The most common adverse events included fatigue (78.9% in the combination group vs 69.2% in the chemotherapy group), hypertension (46.2% vs 10.5%), diarrhea (38.5% vs 21.1%), hypothyroidism (38.5% vs 15.8%), neutropenia (23.1% vs 36.8%) and AST elevation (30.8% vs 21.1%). The most common grade 3 or worse adverse events included hand-foot reaction (7.7% vs 5.3%), hypothyroidism (15.4% vs 0), neutropenia (0 vs 10.5%). Conclusion: The combination of anlotinib and GD showed favorable efficacy with manageable toxicities compared with GD in the second-line treatment for metastatic osteosarcoma. This combination therapy deserves further investigations in patients with osteosarcoma. [ABSTRACT FROM AUTHOR]

Introduction: Totally implanted ports (PORTs) have been widely used among patients with malignancy. Cardiac metastasis secondary to bone sarcoma and catheter-related right atrial thrombosis (CRAT) can be both present as cardiac masses. However, these two cardiac masses share very similar imaging characteristics. Methods: The features, treatments, and outcomes of 5 bone sarcoma pediatric patients with PORTs who suffered from cardiac masses in the right atrium were analyzed. Clinical data and histological characteristics of cardiac masses were also recorded. Results: Among 928 patients with malignancy and PORTs, 5 bone sarcoma pediatric patients were found to have cardiac masses in the right atrium. The catheter tips were located in the right atrium of 4 patients and the superior vena cava-right atrium junction (CAJ) of 1 patient. Four patients with good response to anti-tumor treatment had received surgical lumpectomies for pathologic identification and mass excision, with cardiac metastases among 1 patient and thromboses among 3 patients. The median time from venous access port implantation to cardiac mass detection for CRAT was 6.3 months (range: 4.7–6.8 months) and to diagnosis of or possible cardiac metastasis was 13.3 months (range: 11.2–15.4 months). Conclusion: The placement of a catheter tip into the right atrium should be avoided. The time from PORTs implantation to cardiac mass detection might serve as a potential tool to differentiate cardiac metastasis from CRAT. Surgical management may be an effective treatment for bone sarcoma pediatric patients who had good response to anti-tumor treatment and suffered from cardiac masses in the right atrium. [ABSTRACT FROM AUTHOR]

Osteosarcoma (OS) is the most common primary bone sarcoma, chemoresistance becomes an obstacle to its treatment. Metabolic reprogramming is a hallmark of malignancy, targeting the metabolic pathways might provide a reasonable therapeutic strategy for OS. Here we demonstrated that Ailanthone (AIL), a major component of the Chinese medicine Ailanthus altissima, significantly suppressed OS cell growth in vitro and in vivo. Furthermore, AIL dose-dependently inhibited cell migration and invasion, induced cell cycle arrest and apoptosis in OS cells. Combined transcriptomics, proteomics and metabolomics analyses revealed that AIL induced widespread changes in metabolic programs in OS cells, while the serine biosynthetic pathway (SSP) was the most significantly altered pathway. qRT-PCR and Western blot assay confirmed that the transcript and protein levels of the SSP genes (PHGDH , PSAT1 and PSPH) were downregulated dose-dependently by AIL. In addition, we found out that many downstream pathways of the SSP including the one-carbon pool by folate, purine metabolism, pyrimidine metabolism, DNA replication and sphingolipid metabolism were downregulated after AIL treatment. In the revere test, PHGDH overexpression but not exogenous serine supplementation clearly attenuated the effects of AIL on OS cells. Taken together, AIL exerts antitumor effects on OS through mediating metabolic reprogramming, at least in part, by suppressing the SSP. Our findings suggest that AIL could emerge as a potential therapeutic strategy in OS. [ABSTRACT FROM AUTHOR]

Aim To investigate prognostic factors for long-term outcomes in Chinese patients with high-grade osteosarcoma of the extremities or trunk treated by multidisciplinary combined therapy. Methods In total, 333 consecutive patients with non-metastatic or primary metastatic high-grade osteosarcoma of the extremities or trunk were retrospectively reviewed to analyze the correlation between survival and sex, age, site, histological type, clinical stage, alkaline phosphatase ( ALP) level, preoperative chemotherapy or not, response to preoperative chemotherapy, postoperative chemotherapy cycles and manner of surgery. The combined therapy included preoperative and postoperative chemotherapy as well as limb salvage surgery or amputation. Results The median survival time was 52 months for all 333 patients. Univariate analysis revealed that sex, ALP level, preoperative chemotherapy and cycle numbers of postoperative chemotherapy may influence the prognosis of high-grade osteosarcoma of the extremities or trunk. Multivariate analysis revealed that the female, a normal ALP level, preoperative chemotherapy with good response and ≥4 cycles of postoperative chemotherapy correlated with a better outcome. Conclusion Preoperative chemotherapy is important in high-grade osteosarcoma treatment and a good response to it is an important marker of prognosis. It should be given with ≥ cycles of postoperative chemotherapy after surgery. [ABSTRACT FROM AUTHOR]

Aims: The objective of this study was to investigate the efficacy and toxic side effects of two combinations of methotrexate, cisplatin, doxorubicin and ifosfamide on treating Chinese osteosarcoma patients. Methods: A retrospective analysis was conducted of 185 osteosarcoma patients treated with the four drugs mentioned above. A total of 93 patients received the Italian therapeutic treatment (IOR-OS/N-5: Instituto Ortopedic Rizzoli-Section of Osteosacorma/Neoadjuvant chemotherapy-5) and the remaining 92 patients received the therapeutic treatment optimized by our department. We compared the efficacy and toxic side effects of these two therapies. Results: The limb salvage rates, 3-year recurrence rates and 3-year metastasis rates of IOR-OS/N-5 and our optimized treatment were 52.7 and 58.7%; 20.9 and 11.4% and 44.1 and 27.2%, respectively. The 3-year survival rates and the 3-year disease-free survival rates of IOR-OS/N-5 and our optimized treatments were 62.4 and 78.4%; and 53.6 and 67.8%, respectively. Overall survival and disease-free survival rates were significantly different between these two treatments ( P = 0.032 and 0.024, respectively). Liver function with degree III and IV damage accounted for 35.2 and 16.6% of the total adverse reactions in the IOR-OS/N-5 and our optimized treatment groups, respectively. Degree III-IV neutropenia accounted for 22.6 and 40.0%, respectively, in the IOR-OS/N-5 and optimized treatments. Conclusion: The optimization of MTX, DDP, DOX and IFO based on Chinese patients' physiology increased the tolerance and efficacy for the treatment of osteosarcoma. [ABSTRACT FROM AUTHOR]