Publications by authors named "Kunkun Sun"

26 Publications

  • Page 1 of 1

Complete remission of metastatic osteosarcoma using combined modality therapy: a retrospective analysis of unselected patients in China.

BMC Cancer 2021 Mar 31;21(1):337. Epub 2021 Mar 31.

Musculoskeletal Tumor Center, Peking University People's Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, PR China.

Background: Complete surgical remission (CSR) is the best predictor of overall survival (OS) for patients with metastatic osteosarcoma. However, metastasectomy has not been widely implemented in China in the last decade due to various factors, and instead, most physicians choose hypofractionated radiotherapy to treat pulmonary lesions. This study aimed to retrospectively evaluate the outcomes of different local treatments for pulmonary lesions and identify the best local therapy strategies for these patients.

Methods: We reviewed the clinical courses of osteosarcoma patients with pulmonary metastases who were initially treated in two sarcoma centres in Beijing, China, from June 1st, 2009, to March 26th, 2020. With a median follow-up of 32.4 (95% confidence interval (CI): 30.8, 36.1) months, a total of 127 patients with 605 pulmonary nodules, all of whom had received local therapy and firstly achieved CSR or complete radiated/metabolic remission (CRR), were included in the analysis. A total of 102 patients with 525 nodules were initially diagnosed with resectable lung metastases, while 25 patients had 80 indeterminate nodules at presentation and relapsed with pulmonary metastases within 6 months after the completion of adjuvant chemotherapy.

Results: Eighty-eight of 127 (69.3%) patients had fewer than 5 nodules at the time of local therapy, with 48 of 127 (37.8%) located in the unilateral pleura. No patient underwent thoracotomy, and 42 of 127 patients (85 nodules) received video-assisted thoracoscopic surgery (VATS). In addition, 79 of 127 patients (520 nodules) received hypofractionated stereotactic body radiotherapy (RT), such as Gamma Knife radiosurgery or CyberKnife radiosurgery. The twelve-month event-free survival (EFS) (from local therapy to progression) rate of this entire study cohort was 35.6% (95% CI: 26.8, 44.4%), without a significant difference between the two groups (44.7% for VATS vs. 28.4% for RT, P = 0.755). Radiation-induced pneumonitis was observed in 62 of 86 (72.1%) patients, with one patient (1/86, 1.2%) in grade 4.

Conclusions: Our past data showed a similar prognosis with the use of hypofractionated radiotherapy and VATS for the treatment of pulmonary metastasis and no inferiority to thoracotomy regarding historical outcomes. Currently, high-resolution chest computed tomography (CT) provides sufficient information on nodules, and less invasive modalities can thus be considered for treatment.
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http://dx.doi.org/10.1186/s12885-021-08071-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010982PMC
March 2021

Constitutive GLI1 expression in chondrosarcoma is regulated by major vault protein via mTOR/S6K1 signaling cascade.

Cell Death Differ 2021 Feb 26. Epub 2021 Feb 26.

Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, China.

Hedgehog signaling plays a pivotal role in embryonic pattern formation and diverse aspects of the postnatal biological process. Perturbation of the hedgehog pathway and overexpression of GLI1, a downstream transcription factor in the hedgehog pathway, are highly relevant to several malignancies including chondrosarcoma (CS). We previously found that knocking down expression of GLI1 attenuates the disrupted Indian hedgehog (IHH) signal pathway and suppresses cell survival in human CS cells. However, the underlying mechanisms regulating the expression of GLI1 are still unknown. Here, we demonstrated the implication of GLI1 in SMO-independent pathways in CS cells. A GLI1 binding protein, major vault protein (MVP), was identified using the affinity purification method. MVP promoted the nuclear transport and stabilization of GLI1 by compromising the binding affinity of GLI1 with suppressor of fused homolog (SUFU) and increased GLI1 expression via mTOR/S6K1 signaling cascade. Functionally, knockdown of MVP suppressed cell growth and induced apoptosis. Simultaneous inhibition of MVP and GLI1 strongly inhibits the growth of CS in vitro and in vivo. Moreover, IHC results showed that MVP, GLI1, and P-p70S6K1 were highly expressed and positively correlated with each other in 71 human CS tissues. Overall, our findings revealed a novel regulating mechanism for HH-independent GLI1 expression and provide a rationale for combination therapy in patients with advanced CS.
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http://dx.doi.org/10.1038/s41418-021-00749-4DOI Listing
February 2021

Multiple primary tumors: a case report and review of the literature.

BMC Musculoskelet Disord 2020 Jun 22;21(1):394. Epub 2020 Jun 22.

Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, 100044, China.

Background: Multiple primary tumors, especially quadruple primary neoplasms is extremely rare. Fibrous dysplasia (FD), osteosarcoma (OS), and giant cell tumor of bone (GCTB) are three bone tumors with low incidence while primary pulmonary meningioma is a rare disease. In this case report, we present a unique synchronous occurrence of these four separate pathological conditions.

Case Presentation: A 53-year-old male previously underwent resection of OS of fifth rib and FD of eighth rib 1 year ago. Recently, a discontinuous pain at right knee developed. Serial X-ray films showed a progressively pure osteolytic lesion of proximal tibia which extended gradually. The incisional biopsy revealed that this tumor was confirmed as GCTB, and the tumor was successfully managed by extensive curettage and bone cement filling. The diagnosis of GCTB was re-confirmed by the postoperative histopathologic examinations. High-throughput sequencing from the GCTB exhibited a somatic mutation of H3.3A (G35W exon2). Germline testing revealed a germ-cell variant in gene of BRCA2 (exon 8 V220Ifs*4).

Conclusions: This is a unique case with quadruple primary tumors. Germline mutation in gene of BRCA2 may be associated with the occurrence of multiple primary tumors in this patient.
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http://dx.doi.org/10.1186/s12891-020-03426-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310446PMC
June 2020

Apatinib for Treatment of Inoperable Metastatic or Locally Advanced Chondrosarcoma: What We Can Learn About the Biological Behavior of Chondrosarcoma from a Two-Center Study.

Cancer Manag Res 2020 15;12:3513-3525. Epub 2020 May 15.

Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.

Purpose: For patients who have chondrosarcoma in the unresectable setting, antiangiogenic agents are reportedly effective. This multicenter, retrospective study investigated the antitumor activity of apatinib in patients with unresectable chondrosarcoma to gain insight into the biological behavior of this disease.

Methods: All of the patients with unresectable chondrosarcoma who were diagnosed between October 1, 2009, and November 1, 2019, in two sarcoma centers affiliated with Peking University were evaluated. Relevant information was collected from the medical records at both centers, from which patients receiving apatinib for systemic therapy were selected for analysis.

Results: In total, efficacy analysis was conducted in 33 patients with a median follow-up time of 22.1 (Q1, Q3, 14.6, 23.0) months. There were 20/33 (60.0%) conventional chondrosarcomas (grades 2-3), 5/33 (15.2%) dedifferentiated chondrosarcomas, 4/33 (12.1%) mesenchymal chondrosarcomas, 3/33 (9.1%) extraskeletal myxoid chondrosarcoma, and 1/33 (3.1%) clear-cell chondrosarcomas with 87.9% in metastatic and 12.1% in locally advanced states. The objective response rate was 6/33 (18.2%). The median progression-free survival (PFS) was 12.4 months (Q1, Q3, 7.0, 21.2), while the median overall survival has not yet been reached. Rare variants of chondrosarcoma tended to have a longer PFS than conventional chondrosarcoma (0.06). Based on clinicopathological factors Cox and univariate analysis, only extraskeletal myxoid chondrosarcoma and baseline target lesions <60 mm benefited from the drug apatinib (=0.14 and =0.00), respectively. Grade 3 or higher adverse events were frequent in 11/33 (39.3%) of patients who discontinued apatinib due to deterioration of their general condition.

Conclusion: Apatinib had clinically meaningful activity in patients with inoperable high-grade chondrosarcoma. However, special caution should be made in managing toxicity due to the indolent behavior and slow growth pattern after using this drug. Patients with a smaller tumor size and extraskeletal myxoid chondrosarcoma subtype might benefit from this therapy more.

Clinical Trial Registration: Registered February 7, 2020, with clinicaltrials.gov: NCT04260113.
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http://dx.doi.org/10.2147/CMAR.S253201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237692PMC
May 2020

Apatinib plus camrelizumab (anti-PD1 therapy, SHR-1210) for advanced osteosarcoma (APFAO) progressing after chemotherapy: a single-arm, open-label, phase 2 trial.

J Immunother Cancer 2020 05;8(1)

Radiology Department & Nuclear Medicine Department, Peking University People's Hospital, Beijing, China.

Background: Results of our previous study showed high objective response but short-term activity of apatinib in advanced osteosarcoma. We aimed to investigate the activity of apatinib in combination with camrelizumab in patients with inoperable high-grade osteosarcoma progressing after chemotherapy.

Methods: This open-label, phase 2 trial was conducted at Peking University People's Hospital. We enrolled patients with advanced osteosarcoma progressed after chemotherapy. Patients received 500 mg apatinib orally once daily plus 200 mg camrelizumab by intravenous infusion every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) and clinical benefit rate at 6 months, which were based on RECIST V.1.1.

Results: 43 patients were enrolled between January 25 and September 4, 2018. With median follow-up time of 48.3 (Q1, Q3, 30.6, 66.6) weeks, 13 (30.23%, 95% CI 17.2%, 40.1%) of 43 patients were progression free at 6 months and the 6-month PFS rate was 50.9% (95% CI 34.6%, 65.0%). Until final follow-up, the objective response rate was 20.9% (9/43) and two patients with durable disease control were observed. Patients with programmed cell death 1 ligand-1 (PD-L1) tumor proportion score ≥5% and pulmonary metastases tended to have a longer PFS in comparison to the others (p=0.004 and 0.017, respectively). Toxic effects led to dose reductions, or interruptions, or both in 24 (55.8%) of 43 patients and permanent discontinuation in 4 (9.3%) patients. There were no treatment-related deaths.

Conclusions: Although the combination of apatinib and camrelizumab seemed to prolong PFS in comparison to single agent apatinib in treating advanced osteosarcoma, it did not reach the prespecified target of 6-month PFS of 60% or greater. Overexpression of PD-L1 and the presence of pulmonary metastases only were associated with longer PFS.

Trial Registration Number: NCT03359018.
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http://dx.doi.org/10.1136/jitc-2020-000798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7223462PMC
May 2020

Macrophages reduce the sensitivity of osteosarcoma to neoadjuvant chemotherapy drugs by secreting Interleukin-1 beta.

Cancer Lett 2020 06 24;480:4-14. Epub 2020 Mar 24.

Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China; Beijing Key Laboratory of Musculoskeletal Tumor, Beijing, People's Republic of China.

Osteosarcoma is a common, highly malignant tumor of the musculoskeletal system in young people. Compared with simple amputation in the past, the application of neoadjuvant chemotherapy significantly improved the 5-year survival rate and limb-salvage rate of tumor patients without metastasis. However, the survival rate of patients with metastatic disease treated with neoadjuvant chemotherapy has remained stagnant over the past 30 years despite repeated attempts of adding neoadjuvant chemotherapy agents into the regimen or enhancing the chemotherapy drug dose. In this study, we revealed that macrophages, stimulated by neoadjuvant chemotherapy agents, could reduce the sensitivity of osteosarcoma cells to the drugs. Furthermore, we found that this phenomenon was strongly related to the secretion of the interleukin-1beta by macrophages. Our findings may provide new ideas for improving the efficiency of neoadjuvant chemotherapy for osteosarcoma.
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http://dx.doi.org/10.1016/j.canlet.2020.03.019DOI Listing
June 2020

Genomic characterisation of pulmonary subsolid nodules: mutational landscape and radiological features.

Eur Respir J 2020 02 6;55(2). Epub 2020 Feb 6.

Biomedical Pioneering Innovation Center (BIOPIC), School of Life Sciences and Dept of Thoracic Surgery, People's Hospital, Peking University, Beijing, China

Background: Lung adenocarcinomas (LUADs) that display radiologically as subsolid nodules (SSNs) exhibit more indolent biological behaviour than solid LUADs. SSNs, commonly encompassing pre-invasive and invasive yet early-stage adenocarcinomas, can be categorised as pure ground-glass nodules and part-solid nodules. The genomic characteristics of SSNs remain poorly understood.

Methods: We subjected 154 SSN samples from 120 treatment-naïve Chinese patients to whole-exome sequencing. Clinical parameters and radiological features of these SSNs were collected. The genomic landscape of SSNs and differences from that of advanced-stage LUADs were defined. In addition, we investigated the intratumour heterogeneity and clonal relationship of multifocal SSNs and conducted radiogenomic analysis to link imaging and molecular characteristics of SSNs. Fisher's exact and Wilcoxon rank sum tests were used in the statistical analysis.

Results: The median somatic mutation rate across the SSN cohort was 1.12 mutations per Mb. Mutations in were the most prominent and significant variation, followed by those in , , and A. The differences between SSNs and advanced-stage LUADs at a genomic level were unravelled. Branched evolution and remarkable genomic heterogeneity were demonstrated in SSNs. Although multicentric origin was predominant, we also detected early metastatic events among multifocal SSNs. Using radiogenomic analysis, we found that higher ratios of solid components in SSNs were accompanied by significantly higher mutation frequencies in , , and , suggesting that these genes play roles in the progression of LUADs.

Conclusions: Our study provides the first comprehensive description of the mutational landscape and radiogenomic mapping of SSNs.
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http://dx.doi.org/10.1183/13993003.01409-2019DOI Listing
February 2020

Cytological and Proteomic Analysis of Wheat Pollen Abortion Induced by Chemical Hybridization Agent.

Int J Mol Sci 2019 Apr 1;20(7). Epub 2019 Apr 1.

College of Agriculture, Northwest A&F University, Yangling 712100, China.

In plants, pollen grain transfers the haploid male genetic material from anther to stigma, both between flowers (cross-pollination) and within the same flower (self-pollination). In order to better understand chemical hybridizing agent (CHA) SQ-1-induced pollen abortion in wheat, comparative cytological and proteomic analyses were conducted. Results indicated that pollen grains underwent serious structural injury, including cell division abnormality, nutritional deficiencies, pollen wall defect and pollen grain malformations in the CHA-SQ-1-treated plants, resulting in pollen abortion and male sterility. A total of 61 proteins showed statistically significant differences in abundance, among which 18 proteins were highly abundant and 43 proteins were less abundant in CHA-SQ-1 treated plants. 60 proteins were successfully identified using MALDI-TOF/TOF mass spectrometry. These proteins were found to be involved in pollen maturation and showed a change in the abundance of a battery of proteins involved in multiple biological processes, including pollen development, carbohydrate and energy metabolism, stress response, protein metabolism. Interactions between these proteins were predicted using bioinformatics analysis. Gene ontology and pathway analyses revealed that the majority of the identified proteins were involved in carbohydrate and energy metabolism. Accordingly, a protein-protein interaction network involving in pollen abortion was proposed. These results provide information for the molecular events underlying CHA-SQ-1-induced pollen abortion and may serve as an additional guide for practical hybrid breeding.
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http://dx.doi.org/10.3390/ijms20071615DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480110PMC
April 2019

Intraocular schwannoma: A case series of 3 patients.

Oncol Lett 2019 Jan 16;17(1):1274-1278. Epub 2018 Nov 16.

Department of Ophthalmology, Peking University People's Hospital, Beijing 100044, P.R. China.

Schwannoma is a proliferation of neoplastic Schwann cells. Schwannomas comprise 8-10% of all primary intracranial tumors. Primary intraorbital schwannoma arising from the ciliary nerves in the uvea, which accounts for 1-2% of all intracranial tumors, is a rare intraocular neoplasm. Intraocular schwannoma frequently masquerades as melanoma, reflecting the difficulty in clinically distinguishing it from malignant melanoma and the requirement for a histopathological diagnosis. The aim of the present study was to report a case series of 3 patients diagnosed with intraocular schwannoma at the Department of Ophthalmology, Peking University People's Hospital (Beijing, China). Patients with intraocular schwannoma were identified by searching the computerized database and patient medical records of the Department of Ophthalmology of Peking University People's Hospital. The patients (2 men and 1 woman; mean age, 34 years; age range, 25-48 years) were all treated by trans-scleral local resection, and schwannoma was confirmed by biopsy. The study found that choroidal schwannoma has a variety of clinical manifestations, with iridodialysis, subluxation of the lens and exudative detachment of the retina observed. The present study indicates that a pathological biopsy is required for diagnosis and that the optimal therapy is local resection.
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http://dx.doi.org/10.3892/ol.2018.9718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6313066PMC
January 2019

Identification of Antioxidant and Anti-α-amylase Components in Lotus (Nelumbo nucifera, Gaertn.) Seed Epicarp.

Appl Biochem Biotechnol 2019 Mar 24;187(3):677-690. Epub 2018 Jul 24.

Engineering Research Center of Ecology and Agricultural Use of Wetland, Ministry of Education, Yangtze University, Jingzhou, 434025, China.

Lotus seed epicarp, a byproduct of lotus seed production process, is usually discarded as a waste. In this study, antioxidant and anti-α-amylase activities of freeze-dried water and various methanol extracts of lotus seed epicarp were evaluated. The extract obtained by 80% methanol exhibited the strongest DPPH and ABTS radical scavenging activity and ferric reducing power, as well as the greatest inhibitory potential on α-amylase. The excellent antioxidant and α-amylase inhibitory activities of 80% methanol extract might be attributed to its highest concentrations of total phenolics, flavonoids, and condensed tannins. The inhibition kinetic analysis revealed that the 80% methanol extract was a reversible and uncompetitive-type inhibitor of α-amylase. Furthermore, based on MALDI-TOF-MS and thiolysis-HPLC-ESI-MS, the main active components present in 80% methanol extract were identified to be B-type heteropolymeric condensed tannins built up of mixtures of propelargonidins, procyanidins, and prodelphinidins, with the predominance of procyanidins and epicatechin as the main constitutive units. The results obtained suggested that lotus seed epicarp could be exploited as a potential source of natural antioxidants and α-amylase inhibitors.
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http://dx.doi.org/10.1007/s12010-018-2844-xDOI Listing
March 2019

Novel oncogene COPS3 interacts with Beclin1 and Raf-1 to regulate metastasis of osteosarcoma through autophagy.

J Exp Clin Cancer Res 2018 Jul 3;37(1):135. Epub 2018 Jul 3.

Musculoskeletal Tumor Center, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing, 100044, China.

Background: Expression of COP9 signalosome subunit 3 (COPS3), an oncogene overexpressed in osteosarcoma, has been demonstrated to be significantly correlated with tumor metastasis. However, the underlying mechanism by which COPS3 promotes metastasis of osteosarcoma and its role in autophagy remain unknown.

Methods: The expression of COPS3 was detected in primary osteosarcoma tissues and matching lung metastasis tissues by immunohistochemistry (IHC). The effect of COPS3 on the metastasis of osteosarcoma cells was investigated by transwell, wound healing assays and animal studies. Indicated proteins was analyzed by western blotting when COPS3 was knockdown or overexpressed. The COPS3 Interacting protein was determined by immunoprecipitation assay. The relationship between COPS3 and autophagy was detected by western blotting and immunofluorescence.

Results: We found that knockdown of COPS3 significantly reduced the lung metastasis of osteosarcoma cells in a mouse model, coinciding with downregulation of mitogen-activated protein kinase (MEK) and extracellular signal-regulated kinase (ERK) signaling. The silencing of COPS3 also inhibited the epithelial-mesenchymal transition (EMT) through the 90 kDa ribosomal S6 kinases (RSK), a family of signal transduction proteins downstream of MEK/ERK. Reciprocal immunoprecipitation assays revealed that COPS3 directly interacts with Raf-1, an upstream regulator of MEK/ERK. Surprisingly, Beclin1, an important autophagic protein, appeared in the COPS3-immunoprecipitates, along with the autophagic markers LC3-I and LC3-II. Loss of COPS3 completely inhibited HO-induced autophagic flux and reduced Beclin1 expression. Additionally, autophagy inhibitor or silencing of Beclin1 both decreased cell metastasis.

Conclusions: Taken together, these data reveal a novel function of COPS3 in the regulation of autophagy and highlight the relationship between autophagy and metastasis in osteosarcoma cells.
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http://dx.doi.org/10.1186/s13046-018-0791-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6029018PMC
July 2018

Low levels of ADAM23 expression in epithelial ovarian cancer are associated with poor survival.

Pathol Res Pract 2018 Aug 12;214(8):1115-1122. Epub 2018 Jun 12.

Gynaecologic Oncology Centre, Peking University People's Hospital, No. 11, Xizhimen nan Road, XiCheng District, Beijing, 100044, People's Republic of China. Electronic address:

Background: ADAM23, a member of the disintegrin and metalloprotease (ADAM) family, has been reported to be expressed in several types of tumours. Nevertheless, the exact role of ADAM23 in epithelial ovarian cancer (EOC) remains unclear. The aim of this study was to investigate ADAM23 expression in EOC and evaluate its clinicopathological and prognostic significance.

Methods: Immunohistochemistry (IHC), western blot and real-time PCR (RT-PCR) were used to analyse ADAM23 expression in 133 EOC, 42 benign ovarian tumour and 35 healthy control samples. Moreover, we evaluated the expression of ADAM23 in both public database (Oncomine and Kaplan-Meier plotter). The association between ADAM23 expression and various clinicopathological parameters was analysed.

Results: The levels of ADAM23 mRNA and protein expression were significantly lower in EOC tissues than in corresponding control tissues and benign ovarian tumours, verifying results from the Oncomine databases. The loss of ADAM23 expression was significantly correlated with an advanced International Federation of Gynecology and Obstetrics (FIGO) stage and lymph node metastasis. The IHC data in the EOC samples correlated with the RT-PCR data. Furthermore, patients with low ADAM23 expression had shorter progression-free survival (PFS) and overall survival (OS) than patients with high ADAM23 expression. The multivariate analysis indicated that ADAM23 was an independent predictor in patients with EOC.

Conclusions: Our results demonstrate that ADAM23 expression is likely involved in the progression of EOC and may provide potential diagnostic and prognostic information regarding EOC.
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http://dx.doi.org/10.1016/j.prp.2018.06.007DOI Listing
August 2018

Correction to: PD-1 axis expression in musculoskeletal tumors and antitumor effect of nivolumab in osteosarcoma model of humanized mouse.

J Hematol Oncol 2018 Mar 12;11(1):37. Epub 2018 Mar 12.

Musculoskeletal Tumor Center, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China.

The original article [1] contained an error in Table 1 whereby the 'Positive' column in the 'PD-L1' Tumor type group of columns was mistakenly included at the beginning of the 'PD-L2' Tumor type group of columns.
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http://dx.doi.org/10.1186/s13045-018-0580-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5846231PMC
March 2018

PD-1 axis expression in musculoskeletal tumors and antitumor effect of nivolumab in osteosarcoma model of humanized mouse.

J Hematol Oncol 2018 02 6;11(1):16. Epub 2018 Feb 6.

Musculoskeletal Tumor Center, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing, 100044, People's Republic of China.

Background: Immune checkpoint inhibitors have led to a breakthrough in solid tumor immunotherapy, but related studies on musculoskeletal tumors are few, especially for PD-L2.

Methods: We examined expression of three molecular effectors of the PD-1 axis in 234 patients with musculoskeletal tumors, including osteosarcoma, chondrosarcoma, synovial sarcoma, and giant cell tumor. Survival analyses and potential mechanisms were investigated in osteosarcoma per the Gene Expression Omnibus (GEO) and immunohistochemistry analyses. In vivo, humanized mice were used to evaluate the effect of nivolumab on osteosarcoma.

Results: PD-L1, PD-L2, and PD-1 expression levels were significantly different between the histologic types of the musculoskeletal tumors. For osteosarcoma, PD-L1 was negatively correlated with prognosis, while PD-1 had a negative correlation tendency with overall survival (OS). Meanwhile, PD-L2 had a positive correlation trend with OS. Nivolumab inhibited osteosarcoma metastasis in humanized mice by increasing CD4+ and CD8+ lymphocytes and the cytolytic activity of CD8 lymphocytes in the lung but did not affect primary osteosarcoma growth.

Conclusion: We systematically detected the expression patterns of PD-L1, PD-L2, and PD-1 in musculoskeletal tumors for the first time and demonstrated the prognostic roles and underlying mechanisms of PD-1 axis in osteosarcoma. Furthermore, PD-1 blockade could effectively control osteosarcoma pulmonary metastasis in vivo. Therefore, the PD-1 axis may be a potential immunotherapeutic target for metastatic osteosarcoma.
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http://dx.doi.org/10.1186/s13045-018-0560-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801803PMC
February 2018

BMPR2 and HIF1- overexpression in resected osteosarcoma correlates with distant metastasis and patient survival.

Chin J Cancer Res 2017 Oct;29(5):447-454

Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing 100044, China.

Objective: Bone morphogenetic protein receptor 2 (BMPR2) and hypoxia-inducible factor 1-α (HIF1-α) existed abnormal expression in several types of cancer. However, their expressions and related roles in osteosarcoma are largely unknown.

Methods: To investigate the clinical significance of BMPR2 and HIF1-α in osteosarcoma, we analyzed their expression levels in 103 osteosarcoma specimens by immunochemistry. Meanwhile, we conducted a follow-up to examine the metastatic behavior and overall survival (OS) of osteosarcoma patients.

Results: Among 103 tissues, 61 cases had BMPR2-positive expression and 57 cases had HIF1-α positive expression. A significant correlation was noticed between BMPR2 and HIF1-α expression in osteosarcoma specimens (P=0.035). Receiver-operating characteristic (ROC) curves were calculated to investigate the predictive value of the two markers in tumor metastasis. By means of univariate and multivariate analysis, BMPR2 and HIF1-α expression, as well as higher tumor grade, were identified as significant risk factors for OS in patients with osteosarcoma. Kaplan-Meier survival analysis revealed that the patients with BMPR2 and HIF1-α positive expression had worse OS compared with patients with BMPR2-negative or HIF1-α-negative staining.

Conclusions: It can be concluded that BMPR2 and HIF1-α expression is highly correlated with metastatic behavior in patients with osteosarcoma and can serve as predictive markers for metastasis and OS of these patients.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2017.05.09DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5677136PMC
October 2017

BMPR2 promotes invasion and metastasis via the RhoA-ROCK-LIMK2 pathway in human osteosarcoma cells.

Oncotarget 2017 Aug 24;8(35):58625-58641. Epub 2017 Apr 24.

Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, 100044, China.

Bone morphogenetic protein receptor 2 (BMPR2) has been identified in several types of cancer. However, its role in osteosarcoma is largely unknown. We systematically investigated the role of BMPR2 in osteosarcoma cell lines, human tissue samples and xenograft models. The relationship between BMPR2 expression and osteosarcoma patients' survival was investigated by bioinformatics and clinical data. Wound healing assay and transwell assay were used to detect the changes of cell migration and invasion ability after BMPR2 transfection. In addition, downstream phosphoproteins were analyzed by iTRAQ-based phosphoproteomic analysis and verified by western blotting. , the effects of BMPR2 on the growth, formation and metastasis of 143B cells were observed by orthotopic transplantation of nude mice. Here, we demonstrated that BMPR2 expression was elevated in a majority of osteosarcoma tissues compared with normal bone tissue. Osteosarcoma patients with greater BMPR2 expressing level showed a poor overall survival. The depletion of BMPR2 in 143B cells markedly reduced the invasive capacity and metastatic potential . Mechanistically, we found that LIM domain kinase 2 (LIMK2) was phosphorylated and activated by BMPR2 and that this event was crucial for activation of the BMPR2-mediated signal pathway in osteosarcoma cells. Additionally, we demonstrated that BMPR2 could active LIMK2 through the RhoA/ROCK pathway and could also interact with LIMK2 directly. Taken together, our study revealed that BMPR2 functions as a prometastatic oncogene and with the activation of the RhoA-ROCK-LIMK2 pathway and may represent a potential therapeutic target for osteosarcoma.
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http://dx.doi.org/10.18632/oncotarget.17382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601680PMC
August 2017

Apatinib promotes autophagy and apoptosis through VEGFR2/STAT3/BCL-2 signaling in osteosarcoma.

Cell Death Dis 2017 08 24;8(8):e3015. Epub 2017 Aug 24.

Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.

The cure rate of osteosarcoma has not improved in the past 30 years. The search for new treatments and drugs is urgently needed. Apatinib is a high selectivity inhibitor of vascular endothelial growth factor receptor-2 (VEGFR2) tyrosine kinase, exerting promising antitumoral effect in various tumors. The antitumor effect of Apatinib in human osteosarcoma has never been reported. We investigated the effects of Apatinib in osteosarcoma in vitro and in vivo. Osteosarcoma patients with high levels of VEGFR2 have poor prognosis. Apatinib can inhibit cell growth of osteosarcoma cells. In addition to cycle arrest and apoptosis, Apatinib induces autophagy. Interestingly, inhibition of autophagy increased Apatinib-induced apoptosis in osteosarcoma cells. Immunoprecipitation confirmed direct binding between VEGFR2 and signal transducer and activator of transcription 3 (STAT3). Downregulation of VEGFR2 by siRNA resulted in STAT3 inhibition in KHOS cells. VEGFR2 and STAT3 are inhibited by Apatinib in KHOS cells, and STAT3 act downstream of VEGFR2. STAT3 and BCL-2 were downregulated by Apatinib. STAT3 knockdown by siRNA reinforced autophagy and apoptosis induced by Apatinib. BCL-2 inhibits autophagy and was apoptosis restrained by Apatinib too. Overexpression of BCL-2 decreased Apatinib-induced apoptosis and autophagy. Apatinib repressed the expression of STAT3 and BCL-2 and suppressed the growth of osteosarcoma in vivo. To sum up, deactivation of VEGFR2/STAT3/BCL-2 signal pathway leads to Apatinib-induced growth inhibition of osteosarcoma.
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http://dx.doi.org/10.1038/cddis.2017.422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596600PMC
August 2017

Combining of serial embolization and denosumab for large sacropelvic giant cell tumor: Case report of 3 cases.

Medicine (Baltimore) 2017 Aug;96(33):e7799

Musculoskeletal Tumor Center Department of Pathology, People's Hospital, Peking University, Beijing, China.

Rationale: Both serial arterial embolization (SAE) and denosumab have been proved to be effective in treatment for giant cell tumor (GCT). There is potential synergic effect of combining two methods. The purpose of current study is to justify a new treatment strategy of combination of SAE and denosumab as neoadjuvant or stand-alone treatment for large sacropelvic giant cell tumor.

Patient Concerns: Pelvic and sacral GCTs tend to be very large size and vascular. The concerns of surgical treatment were invasiveness of extensive surgery, intraoperative hemorrhage, nerve function jeopardized and local recurrence. However, SAE alone may not be adequate for complete removal of the tumor.

Diagnoses: All the three cases were proved to be GCT by core-needle biopsy. Post-treatment pathological change was confirmed by further biopsy.

Interventions: The patient in Case 1 diagnosed of large recurrent sacral GCT received 6 times of endovascular embolizations with 2-month interval and started on denosumab simultaneously after first session of embolization. The second case was a 22-year-old female presented with a massive iliosacral tumor. SAE was performed for 3 sessions and the denosumab was started simultaneously. The patients was on treatment for half year. Both patients experienced a dramatic decrease in symptoms and concomitant improvement in function after the first embolization and weekly injection of denosumab. Tumor removal was performed on patient in case 2. The last case was a pelvic GCT and the patient received SAE and denosumab for half year. The tumor was then removed with purpose of complete cure.

Outcomes: The first patient was still on denosumab with stable tumor. The other two patients were both free of recurrence after surgical removal of the tumors. No denosumab was used postoperatively.

Lessons: We reported the first three cases treated by combination of SAE and denosumab in the literature and aim to raise an alternative method for large GCT at challenging anatomical locations, for which surgery would carry significant risk. SAE and denosumab can synergically promote sclerosis and result in significant decrease in pain. It is reasonable to consider using SAE combined with denosumab neoadjuvantly to reduce the extensiveness and morbidity of surgery, however further investigation is warranted.
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http://dx.doi.org/10.1097/MD.0000000000007799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571708PMC
August 2017

Knockdown of long non-coding RNA HOTAIR increases miR-454-3p by targeting Stat3 and Atg12 to inhibit chondrosarcoma growth.

Cell Death Dis 2017 02 9;8(2):e2605. Epub 2017 Feb 9.

Musculoskeletal Tumor Center, Peking University People's Hospital, Beijing, People's Republic of China.

Current practices for the therapy of chondrosarcoma, including wide-margin surgical resection and chemotherapy, are less than satisfactory. Recently, emerging evidence has demonstrated that long non-coding RNAs (lncRNAs) have an essential role in the initiation and progression of tumors. As a typical lncRNA, HOTAIR is significantly overexpressed in various tumors. However, the function and potential biological mechanisms of HOTAIR in human chondrosarcoma remain unknown. Quantitative RT-PCR demonstrated that HOTAIR expression was upregulated in chondrosarcoma tissues and cell lines. High HOTAIR expression is correlated with tumor stage and poor prognosis. Functional experiments reveal that HOTAIR knockdown leads to growth inhibition of human chondrosarcoma cells in vitro and in vivo. In addition to cycle arrest and apoptosis, knockdown of HOTAIR inhibits autophagy, which favors cell death. Mechanistically, we demonstrated that HOTAIR induced DNA methylation of miR-454-3p by recruiting EZH2 and DNMT1 to the miR-454-3p promoter regions, which markedly silences miR-454-3p expression. Further analysis revealed that STAT3 and ATG12 are targets of miR-454-3p, initiate HOTAIR deficiency-induced apoptosis and reduce autophagy. Collectively, our data reveal the roles and functional mechanisms of HOTAIR in human chondrosarcoma and suggest that HOTAIR may act as a prognostic biomarker and potential therapeutic target for chondrosarcoma.
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http://dx.doi.org/10.1038/cddis.2017.31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5386479PMC
February 2017

Adenosine Triphosphate Regresses Endometrial Explants in a Rat Model of Endometriosis.

Reprod Sci 2016 07 17;23(7):924-30. Epub 2016 Feb 17.

Gynecological Oncology Center, Peking University People's Hospital, Beijing, China

The aim of this study was to determine the effects of adenosine triphosphate (ATP) in a rat endometriosis model. After surgical induction of endometriosis, 3 rats were killed, and explants were measured in the remaining 19 rats, which were then randomly assigned to 4 groups. Group 1 (n = 4) received normal saline (2 mL/d intragastric [IG]), group 2 (n = 4) gestrinone (0.5 mg/kg/d IG), group 3 (n = 5) ATP (3.4 mg/kg/d IG), and group 4 (n = 6) ATP (1.0 mg/kg/d; intramuscularly), respectively. Four weeks after medication, they were euthanized to evaluate histological features of explants and eutopic uterine tissues. To test the effect of ATP on the growth of eutopic endometrium stromal cells, proliferation rates of hEM15A cells at 24, 48, and 72 hours after treatment with different concentrations of ATP and vehicle control were detected with the Cell Counting Kit-8 (CCK-8) method. There was a significant difference between pretreatment and posttreatment volumes within group 2 (positive control; P = .048) and group 4 (P = .044). On condition that pretreatment implant size was similar in both groups (P = .516), regression of explants in group 4 was significantly higher than that in group 1 (negative control; P = .035). Epithelial cells were significantly better preserved in group 1 than in group 3 (P = .008) and group 4 (P = .037). The CCK-8 assay showed no significant difference in proliferation among hEM15A cells treated with ATP and controls. These results suggest that ATP regresses endometriotic tissues in a rat endometriosis model but has no impact on the growth of eutopic endometrium stromal cells.
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http://dx.doi.org/10.1177/1933719115625847DOI Listing
July 2016

[The clinical-radiologic-pathologic features of imported pulmonary histoplasmosis].

Zhonghua Jie He He Hu Xi Za Zhi 2015 Jan;38(1):23-8

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Objective: To describe the clinical features and treatment of imported pulmonary histoplasmosis and therefore to improve the recognition and differential diagnosis of this disease.

Methods: The clinical data of 3 patients with imported pulmonary histoplasmosis in our hospital were collected and analyzed. Literatures published since 1989 were retrieved with 'pulmonary histoplasmosis' from PubMed, China National Knowledge Infrastructure (CNKI), Wanfang Data and VIP data, of which all the literatures about imported pulmonary histoplasmosis were reviewed. The clinical manifestations, diagnostic methods and treatment were summarized.

Results: All the 3 cases of imported pulmonary histoplasmosis were immunocompetent hosts, all were males, age were from 44-67 years, and had a history of exploring the cave or tunnel inhabited by bats in the epidemic areas. All of them developed influenza-like symptoms varying in severity after the onset of the disease. Pulmonary multiple nodules and mediastinal lymphadenopathy were found on chest images. One patient underwent percutaneous lung biopsy and the other two received video-assisted thoracoscopic lung biopsy. All the 3 patients showed consistent histopathological findings, such as granulomatous inflammation with necrosis. Pathogen culture with lung biopsy in the first case was identified as histoplasma. All the 3 cases were treated with itraconazole, and recovered with good prognosis. Thirteen literatures in English were obtained, which reported 60 cases with imported pulmonary histoplasmosis. Forty-two of them were males, 16 were females and 2 undefined. The range of their age was from 17-64 years. No imported pulmonary histoplasmosis was reported so far in Chinese literature. Common features of imported pulmonary histoplasmosis were consistent with our patients, including epidemiology, influenza-like symptoms and bilateral pulmonary nodules, recovery with or without antifungal therapy.

Conclusion: The epidemiologic history, influenza-like symptoms and bilateral pulmonary nodules provide valuable diagnostic clues for imported histoplasmosis. Clinical features with pathologic findings and good response to antifungal therapy could make the diagnosis even without pathogen detection if other etiology is unlikely.
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January 2015

Risk factors of recurrence for resected T1aN0M0 invasive lung adenocarcinoma: a clinicopathologic study of 177 patients.

World J Surg Oncol 2014 Sep 13;12:285. Epub 2014 Sep 13.

Department of Thoracic Surgery, Peking University People's Hospital, 11 Xizhimen Nan Ave, Beijing 100044, China.

Background: This study aimed at identifying risk factors of recurrence for completely resected pathologic T1aN0M0 lung adenocarcinomas.

Methods: We reviewed the records of 177 T1aN0M0 invasive adenocarcinoma patients, and re-classified achieved surgical specimens according to the new International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) lung adenocarcinoma classification. Impact on recurrence-free survival (RFS) for age, gender, smoking history, lymphovascular invasion (LVI) and new classification was analyzed by log-rank test and Cox regression. Two existing prognostic grouping schemes of new classification were compared, and subsequently, the correlation of high-grade group in the better prognostic grouping model with clinical data was investigated statistically.

Results: The 5-year recurrence-free rate was 83.7%. The LVI and new adenocarcinoma classification were significantly associated with 5-year RFS (P = 0.012; P = 0.022, respectively). The designation of papillary predominant subtype in the low-grade group, along with lepidic- and acinar predominant subtype had more prognostic significance than the model of combining papillary-, solid- and micropapillary predominant subtypes as the high-grade group (P = 0.005 versus P = 0.181). This high-grade group has increased risk of recurrence in a multivariate Cox regression (adjusted HR 2.815, 95% CI: 1.239 to 6.397, P = 0.013), and is associated significantly more with male gender (adjusted OR 2.214, 95% CI: 1.050 to 4.668, P = 0.037), and, with borderline significance, the presence of LVI (adjusted OR 2.091, 95% CI: 0.938 to 4.662, P = 0.071).

Conclusions: Our results showed that the solid- and micropapillary predominant subtype of IASLC/ATS/ERS classification remains the only risk factor for post-operative recurrence of T1aN0M0 adenocarcinomas, suggesting that they can be indicators of aggressive tumor behaviors.
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http://dx.doi.org/10.1186/1477-7819-12-285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4168167PMC
September 2014

Can surgical management of bone metastases improve quality of life among women with gynecologic cancer?

World J Surg Oncol 2014 Aug 5;12:250. Epub 2014 Aug 5.

Musculoskeletal Tumor Center, People's Hospital, Peking University, Beijing 100044, China.

Background: The evaluation, counseling, and management of gynecologic patients with bone metastasis remain a challenge for clinicians. In order to critically evaluate the role of surgery, we retrospectively analyzed the records of 18 patients surgically treated for metastatic gynecologic tumors of bone, focusing on quality of life, local tumor control, and survival.

Methods: Eighteen patients underwent surgical procedures for the treatment of bone metastases secondary to gynecologic cancer between September 2003 and April 2012. The primary cancer sites included the uterus (n = 10), the cervix (n = 5), and an ovary (n = 3). Patients were followed for an average period of 13.8 months (range, 2 to 34 months). A visual analog pain scale (VAS) and Eastern Cooperative Oncology Group (ECOG) performance status were evaluated both pre- and postoperatively.

Results: The median survival time following diagnosis of bone metastasis was 10.0 months. The mean VAS score was 5.8 preoperatively compared with 2.1, 3 months after surgery. The mean pre and postoperative ECOG performance status grades were 3.1 and 2.3, respectively.

Conclusions: The prognosis of gynecological cancer patients with bone metastasis is poor. Some patients had improvement in their quality of life after surgical intervention for bone metastases; however, novel integrated treatment modalities should be investigated.
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http://dx.doi.org/10.1186/1477-7819-12-250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4125343PMC
August 2014

A primary pulmonary glomus tumor complicated with hyperpyrexia and anemia.

Ann Thorac Surg 2013 Feb;95(2):e29-31

Department of Thoracic Surgery, Peking University People's Hospital, Beijing, PR China.

Pulmonary glomus tumors are extremely rare, with only 19 cases having been reported worldwide. The glomus body is considered to be related to the regulation of body temperature, but the reported cases were not associated with hyperpyrexia. Here, we describe a 28-year-old man with hyperpyrexia and anemia complicated with a coin lesion of the right lung. After resection of the upper lobe of the right lung by video-assisted thoracoscopic surgery, all of the patient's symptoms disappeared. The pathologic analysis reported a rare pulmonary glomus tumor. The disease had not recurred by 1 year after operation.
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http://dx.doi.org/10.1016/j.athoracsur.2012.08.117DOI Listing
February 2013

Epithelioid angiosarcoma of bone and soft tissue: a report of seven cases with emphasis on morphologic diversity, immunohistochemical features and clinical outcome.

Tumori 2011 Sep-Oct;97(5):585-9

Department of Pathology, Peking University People’s Hospital, No. 11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.

Aims And Background: Epithelioid angiosarcoma is a rare histopathologic variant of angiosarcoma characterized by an epithelioid morphology. This subset can histologically mimic non-vascular neoplasms and impose serious challenges in reaching a correct diagnosis, especially in the context of limited tissue sampling (e.g., needle core biopsy). To improve recognition of epithelioid angiosarcoma - and the spectrum of morphologic diversity associated with this rare variant - and to avoid a misdiagnosis, we describe the clinical, histopathologic, and immunohistochemical findings of cases of epithelioid angiosarcoma diagnosed at our institution.

Methods And Study Design: Seven cases of epithelioid angiosarcoma with appropriate pathologic material were identified from our archives. Immunohistochemistry was used to detect the expression of CD31, CD34, Factor VIII, cytokeratin, epithelial membrane antigen, vimentin, HMB45, CD1a, CD68, lysozyme, CD45, desmin, and smooth muscle actin in all cases. Follow-up information was obtained by reviewing medical records or by direct communication with family members.

Results: The lesions involved the bone (n = 4) and soft tissues (n = 3). Microscopically, all tumors had a predominantly diffuse growth pattern, with a focal nested architecture in 6 cases, which closely mimicked metastatic carcinoma. The initial biopsy was performed in 2 of 6 patients and revealed the presence of a malignant neoplasm suggestive of metastatic carcinoma. Immunohistochemically, the epithelioid endothelial cells usually showed strong reactivity for CD31 (7/7), variable or focal positive staining for CD34 (5/7), Factor VIII (4/7), cytokeratin (6/7), epithelial membrane antigen (2/7), vimentin (7/7), and CD68 (3/7). In contrast, they were negative for CD1a, HMB45, lysozyme, CD45, desmin, and smooth muscle actin. Three patients died of disease within one year of the diagnosis, 2 patients developed local recurrence or metastases, and another 2 were disease-free at this writing.

Conclusions: With any unusual epithelioid neoplasm displaying some or all of the morphologic features described above, epithelioid angiosarcoma should be included in the differential diagnosis. In such an instance, endothelial markers should be incorporated in the immunohistochemical analysis to avoid misdiagnosis, particularly with limited sampling.
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http://dx.doi.org/10.1700/989.10716DOI Listing
April 2012