The prognosis for patients with refractory soft-tissue sarcoma (STS) is dismal. Anlotinib has previously shown antitumor activity on STS in preclinical and phase I studies. Patients 18 years and older, progressing after anthracycline-based chemotherapy, naïve from angiogenesis inhibitors, with at least one measurable lesion according to RECIST 1.1, were enrolled. The main subtypes eligible were undifferentiated pleomorphic sarcoma (UPS), liposarcoma (LPS), leiomyosarcoma (LMS), synovial sarcoma (SS), fibrosarcoma (FS), alveolar soft-part sarcoma (ASPS), and clear cell sarcoma (CCS). Participants were treated with anlotinib. The primary endpoint was progression-free rate at 12 weeks (PFR). A total of 166 patients were included in the final analysis. Overall, the PFR was 68%, and objective response rate was 13% (95% confidence interval, 7.6%-18%). The median progression-free survival (PFS) and overall survival (OS) were 5.6 and 12 months, respectively. The PFR, median PFS and OS were: 58%, 4.1 and 11 months for UPS ( = 19); 63%, 5.6 and 13 months for LPS ( = 13); 75%, 11 and 15 months for LMS ( = 26); 75%, 7.7 and 12 months for SS ( = 47); 81%, 5.6 and 12 months for FS ( = 18); 77%, 21 and not reached for ASPS ( = 13); 54%, 11 and 16 months for CCS ( = 7); and 44%, 2.8 and 8.8 months for other sarcoma ( = 23), respectively. The most common clinically significant grade 3 or higher adverse events were hypertension (4.8%), triglyceride elevation (3.6%), and pneumothorax (2.4%). No treatment-related death occurred. Anlotinib showed antitumor activity in several STS entities. The toxicity was manageable. .

Recent clinical trials have shown several multi-target tyrosine kinase inhibitors (TKIs) to be effective in the treatment of osteosarcoma. However, these TKIs have a number of targets, and it is yet unclear which of these targets has a key role in osteosarcoma treatment. In this review, we first summarize the TKIs that were studied in clinical trials registered on ClinicalTrials.gov. Further, we compare and discuss the targets of these TKIs. We found that TKIs with promising therapeutic effect for osteosarcoma include apatinib, cabozantinib, lenvatinib, regorafenib, and sorafenib. The key targets for osteosarcoma treatment may include VEGFRs and RET. The receptor tyrosine kinases (RTKs) MET, IGF-1R, AXL, PDGFRs, KIT, and FGFRs might be relevant but unimportant targets for osteosarcoma treatment. Inhibition of one type of RTK for the treatment of osteosarcoma is not effective. It is necessary to inhibit several relevant RTKs simultaneously to achieve a breakthrough in osteosarcoma treatment. This review provides comprehensive information on TKI targets relevant in osteosarcoma treatment, and it will be useful for further research in this field.

BackgroundThe advent of immune checkpoint therapy has been a tremendous advance in cancer treatment. However, the responses are still insufficient in patients with soft tissue sarcoma (STS). We aimed to identify rational combinations to increase the response to immune checkpoint therapy and improve survival.MethodsWhole-exome sequencing (WES) was performed in 11 patients with liposarcoma. Somatic copy number alterations (SCNAs) were analyzed at the gene level to identify obvious amplification patterns in drug-target genes. The expression and prognostic value of class I histone deacetylases (HDACs) was evaluated in 49 patients with sarcoma in our center and confirmed in 263 sarcoma samples from The Tumor Cancer Genome Atlas (TCGA) database. Q-PCR, flow cytometry and RNA-seq were performed to determine the correlations between class I HDACs, chidamide and PD-L1 in vitro and in vivo. The efficacy of combining chidamide with PD-1 blockade was explored in an immunocompetent murine model and a small cohort of patients with advanced sarcoma. Western blot, ChIP assay and dual luciferase assessment were applied in the mechanistic study.ResultsThe HDAC gene family was frequently amplified in STS. SCNAs in the HDAC gene family were extensively amplified in 8 of 11 (73%) patients with liposarcoma, based on a drug-target gene set, and we verified amplification in 76.65% (197/257) of cases by analyzing TCGA sarcoma cohort. Class I HDAC expression is associated with a poor prognosis for patients with STS, and its inhibition is responsible for promoting apoptosis and upregulating of programmed cell death ligand 1 (PD-L1). The HDAC class I inhibitor chidamide significantly increases PD-L1 expression, increased the infiltration of CD8+ T cells and reduced the number of MDSCs in the tumor microenvironment. The combination of chidamide with an anti-PD-1 antibody significantly promotes tumor regression and improves survival in a murine model. Moreover, chidamide combined with the anti-PD-1 antibody toripalimab is effective in patients with advanced and metastatic sarcoma, and the side effects are tolerable. Mechanistically, chidamide increases histone acetylation at the PD-L1 gene through the activation of the transcriptional factor STAT1.ConclusionsThe combination of chidamide and anti-programmed cell death 1 (PD-1) therapy represents a potentially important strategy for STS.

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Level IV, therapeutic study. See the Instructions for Authors for a complete description of levels of evidence.

BackgroundWhether reconstruction is more beneficial after iliosacral bone tumor resection remains controversial. Because of high rates of complications and recurrence, few patients benefit from reconstruction. The aim of this study is to assess functional outcomes and to reveal changes in the ipsilateral hip joint after partial iliosacral resection.MethodsFrom 1998 to 2016, 21 patients aged 20–66 years underwent iliosacral resection, 18 without reconstruction (group 1) and 3 with reconstruction (group 2). Function was evaluated using the Musculoskeletal Tumor Society 1993 rating scale (MSTS 1993), and disability was measured using the Toronto Extremity Salvage Score (TESS). I-A distance was defined as the distance from the iliosacral joint to the upper line of the acetabulum along the curved line. Group 1 were subdivided into two groups: group 1A included the patients with a defect less than one-third of the I-A distance and group 1B the remainder. Acetabulum-head index (AHI) and center-edge angle (CE angle) were measured. The relationship between defect length and femoral head coverage was analyzed.ResultsThe mean follow-up was 67.3 months. Eighteen patients were included in group 1 and three in group 2. Preoperative data of the 3 groups were statistically equivalent. In addition, no difference of postoperative functional outcome has been highlighted. The final average MSTS 1993 score was 93.6% in group 1 and 93.3% in group 2. The mean TESS was 98 in group 1 and 98.5 in group 2. AHI and CE angle between groups 1 and 2 were not different. The AHI was 80 ± 5.4% in group 1A and 67 ± 9.0% in group 1B (t = − 3.740, P = 0.002), while the CE angle was 29 ± 5.9° in group 1A and 20 ± 6.3° in group 1B (t = − 3.172, P = 0.006) at the last follow-up. Regarding the limb-length discrepancy, group 1 and 2 were similar whereas group 1A and 1B were statistically different (group 1A: 0.7 ± 0.7 cm; group 2: 2.6 ± 1.0 cm; t = − 4.324, P = 0.001).ConclusionsIlio-sacral resection without reconstruction removing more than one- third of the I-A distance leads to an impairement of the limb-length discrepancy and an increase of the defect of the acetabular coverage without altering the functional outcome. Nevertheless, iliosacral resection without reconstruction could serve as a viable treatment option for pelvic type I-IV tumors.

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Vanadium compounds are promising anti-diabetic agents. Although BEOV was not able to succeed in phase II clinical trial, great progresses have been made in the past three decades on the discovery and development of anti-diabetic vanadium compounds. A vast of knowledge has been obtained on the molecular mechanisms of both the pharmacological and toxicological effects of vanadium complexes. It has been revealed that vanadium compounds exert insulin enhancement effects and cell protection via a multiple mechanism involving inhibition of PTP1B, activation of PPARs- AMPK signaling, regulation of unfolded protein responses (UPRs), and stimulation of antioxidant enzymes, while vanadium-induced oxidative stress and inflammatory response could primarily be attributed to vanadium toxicity. Based on the present results concerning the relationship between structures, biological activities and biochemical properties, the rationale for future design of anti-diabetic vanadium compounds has been discussed.