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Sarcoma
Enrichment of Wee1/CDC2 and NF-κB Signaling Pathway Constituents Mutually Contributes to CDDP Resistance in Human Osteosarcoma
Zhengbo Hu, Lugen Li, Wenxing Lan, Xiao Wei, Xiangyuan Wen, Penghuan Wu, Xianliao Zhang, Xinhua Xi, Yufa Li, Liqi Wu, Wenhu Li, Xiaohong Liao
Cancer Res Treat. 2022;54(1):277-293.   Published online May 11, 2021
DOI: https://doi.org/10.4143/crt.2021.320
AbstractAbstract PDFPubReaderePub
Purpose
Osteosarcoma (OS) universally exhibits heterogeneity and cisplatin (CDDP) resistance. Although the Wee1/CDC2 and nuclear factor кB (NF-κB) pathways were reported to show abnormal activation in some tumor cells with CDDP resistance, whether there is any concrete connection is currently unclear. We explored it in human OS cells.
Materials and Methods
Multiple OS cell lines were exposed to a Wee1 inhibitor (AZD1775) and CDDP to assess the half-maximal inhibitory concentration values. Western blot, coimmunoprecipitation, confocal immunofluorescence, cell cycle, and Cell Counting Kit-8assays were performed to explore the connection between the Wee1/CDC2 and NF-κB pathways and their subsequent physiological contribution to CDDP resistance. Finally, CDDP-resistant PDX-OS xenograft models were established to confirm that AZD1775 restores the antitumor effects of CDDP.
Results
A sensitivity hierarchy of OS cells to CDDP and AZD1775 exists. In the highly CDDP-tolerant cell lines, Wee1 and RelA were physically crosslinked, which resulted in increased abundance of phosphorylated CDC2 (Y15) and RelA (S536) and consequent modulation of cell cycle progression, survival, and proliferation. Wee1 inhibition restored the effects of CDDP on these processes in CDDP-resistant OS cells. In addition, animal experiments with CDDP-resistant PDX-OS cells showed that AZD1775 combined with CDDP not only restored CDDP efficacy but also amplified AZD1775 in inhibiting tumor growth and prolonged the median survival of the mice.
Conclusion
Simultaneous enrichment of molecules in the Wee1/CDC2 and NF-κB pathways and their consequent coactivation is a new molecular mechanism of CDDP resistance in OS cells. OS with this molecular signature may respond well to Wee1 inhibition as an alternative treatment strategy.

Citations

Citations to this article as recorded by  
  • Wee1 inhibitor PD0166285 sensitized TP53 mutant lung squamous cell carcinoma to cisplatin via STAT1
    Qi Li, Wenjie Yang, Qingyi Zhang, Daoming Zhang, Jun Deng, Binxin Chen, Ping Li, Huanqi Zhang, Yiming Jiang, Yangling Li, Bo Zhang, Nengming Lin
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    Cellular Signalling.2023; 108: 110723.     CrossRef
  • Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process
    Yu-Li Su, Ling-Yi Xiao, Shih-Yu Huang, Chia-Che Wu, Li-Chung Chang, Yi-Hua Chen, Hao-Lun Luo, Chun-Chieh Huang, Ting-Ting Liu, Jei-Ming Peng
    Cells.2023; 12(11): 1471.     CrossRef
  • Network pharmacology-based research on the effect of angelicin on osteosarcoma and the underlying mechanism
    Yafang Zhang, Junqiang Wei, Lingwei Kong, Mingze Song, Yange Zhang, Xiangyu Xiao, Haiying Cao, Zhehong Li, Ning Yang, Yu Jin
    Aging.2023;[Epub]     CrossRef
  • Identification of Cell Subpopulations and Interactive Signaling Pathways From a Single-Cell RNA Sequencing Dataset in Osteosarcoma: A Comprehensive Bioinformatics Analysis
    Rong Wu, Xiaojie Dou, Haidong Li, Zhenguo Sun, Heng Li, Yuxin Shen, Wei Weng, Jikang Min
    Frontiers in Oncology.2022;[Epub]     CrossRef
  • MicroRNAs and osteosarcoma: Potential targets for inhibiting metastasis and increasing chemosensitivity
    Negin Soghli, Gordon A. Ferns, Fatemeh Sadeghsoltani, Durdi Qujeq, Tooba Yousefi, Mostafa Vaghari-Tabari
    Biochemical Pharmacology.2022; 201: 115094.     CrossRef
  • Inhibiting WEE1 and IKK-RELA Crosstalk Overcomes TNFα Resistance in Head and Neck Cancers
    Zhengbo Hu, Ramya Viswanathan, Hui Cheng, Jianghong Chen, Xinping Yang, Angel Huynh, Paul Clavijo, Yi An, Yvette Robbins, Christopher Silvin, Clint Allen, Pinar Ormanoglu, Scott Martin, Shaleeka Cornelius, Anthony Saleh, Zhong Chen, Carter Van Waes, Ethan
    Molecular Cancer Research.2022; 20(6): 867.     CrossRef
  • Epithelial to Mesenchymal Transition Relevant Subtypes with Distinct Prognosis and Responses to Chemo- or Immunotherapies in Osteosarcoma
    Yang Zhou, Gai Li, Hu Li, Fuchong Lai, Pingguo Duan, Ming Cheng, Fu Wang
    Journal of Immunology Research.2022; 2022: 1.     CrossRef
  • Proteasome Inhibitors and Their Potential Applicability in Osteosarcoma Treatment
    Cassidy M. Van Stiphout, Anita K. Luu, Alicia M. Viloria-Petit
    Cancers.2022; 14(19): 4544.     CrossRef
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Epidermal Growth Factor Receptor: Is It a Feasible Target for the Treatment of Osteosarcoma?
Jun Ah Lee, Yunmi Ko, Dong Ho Kim, Jung Sub Lim, Chang-Bae Kong, Wan Hyeong Cho, Dae-Geun Jeon, Soo-Yong Lee, Jae-Soo Koh
Cancer Res Treat. 2012;44(3):202-209.   Published online September 30, 2012
DOI: https://doi.org/10.4143/crt.2012.44.3.202
AbstractAbstract PDFPubReaderePub
PURPOSE
Features of epidermal growth factor receptor (EGFR) expression in osteosarcoma and in vitro efficacies of EGFR inhibitors against osteosarcoma cells were evaluated.
MATERIALS AND METHODS
Thirty biopsy samples of osteosarcoma patients were retrospectively analyzed for EGFR protein expression by immunohistochemistry. Relationships between EGFR expression and clinicopathologic characteristics and treatment outcomes were evaluated. Four osteosarcoma cell lines were analyzed for EGFR and p-EGFR expression by western blotting. Efficacies of gefitinib and BIBW2992 on osteosarcoma cells were evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Tyrosine kinase domains in exons 18 to 21 were sequenced and gene expression analyses of EGFR and PTEN were performed in four osteosarcoma cell lines.
RESULTS
EGFR protein was expressed in 27 (90%) samples (6 low, 12 intermediate, 9 high) and in three cell lines. Intermediate or high staining for EGFR was related to a tumor volume<150 mL (p<0.001) and histologic subtype other than osteoblastic type (p=0.03). However, EGFR expression was not associated with histologic response to preoperative chemotherapy or survival. Gefitinib and BIBW 2992 did not have any significant inhibitory effect on cell viabilities. DNA sequencing analysis revealed three osteosarcoma cell lines have single base changes at codon 2361 of exon 20 (G to A), without affecting translation results. Furthermore, no mutation was found to be associated with constitutive EGFR activation.
CONCLUSION
In the present study, gefitinib and BIBW2992 were not effective against osteosarcoma cells. However, as osteosarcoma cells express EGFR, further studies are necessary to explore the potential of other therapeutic agents targeting EGFR.

Citations

Citations to this article as recorded by  
  • PD-L1, STAT3, IL6, and EGFR Immunoexpressions in High-Grade Osteosarcoma
    Nayla Rahmadiani, Eviana Norahmawati, Agustina Tri Endharti, Ailen Oktaviana Hambalie, Satria Pandu Persada Isma, Raffaele Vitiello
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  • 79 Download
  • 28 Crossref
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Case Report
Two Pediatric Osteosarcoma Cases with Delayed Methotrexate Excretion: Its Clinical Course and Management
Kang Min Lee, Hee Woo Lee, Seung Yeon Kim, Hyeon Jeong Lee, Dong Hwan Kim, Joongbum Cho, Dong Ho Kim, Jung Sub Lim, Jin Kyung Lee, Jun Ah Lee
Cancer Res Treat. 2011;43(1):67-70.   Published online March 31, 2011
DOI: https://doi.org/10.4143/crt.2011.43.1.67
AbstractAbstract PDFPubReaderePub
High-dose methotrexate (MTX) chemotherapy extends the duration of hospitalization and introduces the risks of serious complications related to delayed MTX excretion. The treatment of delayed MTX excretion is largely dependent on invasive measures such as hemodialysis because the clinical data regarding the efficacy or safety of carboxypetidase G2 is limited. We report here on the cases of two pediatric osteosarcoma patients with delayed MTX excretion and who were successfully managed using supportive measures. Potential life-threatening complications were prevented by administering high doses of leucovorin.

Citations

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  • 8,912 View
  • 53 Download
  • 3 Crossref
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Original Articles
Clinical Value of Ezrin Expression in Primary Osteosarcoma
Chan Kim, Eunah Shin, Soojung Hong, Hong Jae Chon, Hye Ryun Kim, Jung Ryun Ahn, Min Hee Hong, Woo Ick Yang, Jae Kyung Roh, Sun Young Rha
Cancer Res Treat. 2009;41(3):138-144.   Published online September 28, 2009
DOI: https://doi.org/10.4143/crt.2009.41.3.138
AbstractAbstract PDFPubReaderePub
Purpose

Ezrin is a membrane cytoskeletal linker protein and it is known to be associated with metastasis of primary osteosarcoma. The aim of this study is to determine the relationship between an ezrin expression and several key clinical parameters and to elucidate its potential prognostic value for patients with osteosarcoma.

Materials and Methods

Seventy patients with histologically confirmed osteosarcoma and who had no distant metastasis were enrolled between 1995 and 2005 at Yonsei Cancer Center, Severance Hospital, Korea. The clinical parameters were retrospectively reviewed and immunohistochemical staining (IHC) for ezrin was performed using the surgically resected specimens.

Results

Of the 70 tumor specimens, 39 (55.7%) revealed an ezrin expression. More of an osteoblastic histology and an elevated initial ALP level were observed in the ezrin positive patients than in the ezrin negative patients (p=0.008 and 0.001, respectively). The proportion of patients who favorably responded to neoadjuvant chemotherapy (≥90% necrosis) was significantly higher in the group of ezrin positive patients than that in the group of ezrin negative patient (72.2% vs 45.2%, respectively, p=0.024). The ezrin positive patients showed more frequent recurrence than did the ezrin negative patients (64.1% vs 35.5%, respectively, p=0.017). The patients with an ezrin expression also demonstrated poorer survival than did those patients without ezrin expression (5-year EFS: 31.7% vs 61.3%, respectively, p=0.023, 5-year OS: 53.4% vs 71.0%, respectively, p=0.022). When comparing EFS according to both an ezrin expression and chemoresponsiveness, there were trends that the ezrin negative/chemoresponsive group showed the best 5-year EFS (71.4%), followed by the ezrin negative/chemoresistant group (52.9%), the ezrin positive/chemoresponsive group (38.1%) and the ezrin positive/chemoresistant group (13.6%). These trends were statistically significant (p=0.036).

Conclusion

The expression of ezrin by IHC staining was found in 55.7% of the patients with metastasis-free osteosarcoma. Immunoreactivity to ezrin is a negative prognostic factor for survival for the patients suffering with osteosarcoma. Identifying an ezrin expression might offer a valuable piece of information when treating patients with primary osteosarcoma.

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    Anne Gomez-Brouchet, Corinne Bouvier, Anne-Valérie Decouvelaere, Frédérique Larousserie, Sébastien Aubert, Xavier Leroy, Jean-Marc Guinebretière, Aurore Coulomb, Elisabeth Cassagnau, Anne de Muret, Virginie Audard, Béatrice Marie, Gonzague de Pinieux
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    S. Gao, Y. Dai, M. Yin, J. Ye, G. Li, J. Yu
    Acta Biochimica et Biophysica Sinica.2011; 43(6): 455.     CrossRef
  • YY1 overexpression is associated with poor prognosis and metastasis-free survival in patients suffering osteosarcoma
    Filomena de Nigris, Licciana Zanella, Francesco Cacciatore, Anna De Chiara, Flavio Fazioli, Gennaro Chiappetta, Gaetano Apice, Teresa Infante, Mario Monaco, Raffaele Rossiello, Gaetano De Rosa, Marco Alberghini, Claudio Napoli
    BMC Cancer.2011;[Epub]     CrossRef
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    Shuhui Zheng, Jinghe Huang, Kewen Zhou, Chengxi Zhang, Qiuling Xiang, Zhi Tan, Tinghuai Wang, Xiaodong Fu, Jean-Marc Vanacker
    PLoS ONE.2011; 6(7): e22439.     CrossRef
  • Ezrin expression predicts local recurrence and development of metastases in soft tissue sarcomas
    Ana Carneiro, Pär-Ola Bendahl, Måns Åkerman, Henryk A Domanski, Anders Rydholm, Jacob Engellau, Mef Nilbert
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  • Immunoexpression of Ezrin and CD44 in Patients With Osteosarcoma
    Erica Boldrini, Stela Verzinhasse Peres, Sandra Morini, Beatriz de Camargo
    Journal of Pediatric Hematology/Oncology.2010; 32(6): e213.     CrossRef
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Clinical Characteristics and Treatment Results of Pediatric Osteosarcoma: The Role of High Dose Chemotherapy with Autologous Stem Cell Transplantation
Ji Won Lee, Hyery Kim, Hyoung Jin Kang, Han-Soo Kim, Sung-Hye Park, In-One Kim, Hyo Seop Ahn, Hee Young Shin
Cancer Res Treat. 2008;40(4):172-177.   Published online December 31, 2008
DOI: https://doi.org/10.4143/crt.2008.40.4.172
AbstractAbstract PDFPubReaderePub
Purpose

In this study, we investigated the clinical characteristics and treatment results of osteosarcoma during the past 7 years, and evaluated the role of high dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT).

Materials and Methods

We retrospectively analyzed the clinical data of patients who were diagnosed as osteosarcoma at our center from January, 2000 to December, 2007.

Results

The 5-year overall survival and event-free survival of the patients were 72.6% and 55.9%, respectively. Seventeen (41.5%) patients showed disease progression during treatment or relapse after the end of treatment. The patients who had metastasis at diagnosis or who had a lower grade of necrosis after neoadjuvant chemotherapy showed decreased overall and event-free survival. Four patients received ASCT after HDCT, and 3 of them are alive without disease.

Conclusions

The patients who relapsed or had refractory osteosarcoma or who had metastasis at diagnosis or a lower grade of necrosis after neoadjuvant chemotherapy showed poor prognosis. HDCT with ASCT could be an alternative treatment option for these patients.

Citations

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  • High‐dose chemotherapy followed by autologous stem cell transplantation in pediatric patients with relapsed osteosarcoma
    Sung Han Kang, Wanlim Kim, Jong Seok Lee, Jin Kyung Suh, Hyery Kim, Dong Kwan Kim, Se Hoon Choi, Hee Won Cho, Hee Young Ju, Keon Hee Yoo, Ki Woong Sung, Hong Hoe Koo, Sung Wook Seo, Ho Joon Im, Ji Won Lee, Kyung‐Nam Koh
    Pediatric Blood & Cancer.2023;[Epub]     CrossRef
  • Favorable outcome of high-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with nonmetastatic osteosarcoma and low-degree necrosis
    Kyung Taek Hong, Hyun Jin Park, Bo Kyung Kim, Hong Yul An, Jung Yoon Choi, Jung-Eun Cheon, Sung-Hye Park, Han-Soo Kim, Hyoung Jin Kang
    Frontiers in Oncology.2022;[Epub]     CrossRef
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    Mohammadreza Bordbar, Ali Sarfaraz, Sezaneh Haghpanah, Omidreza Zekavat, Soheila Zareifar, Tahereh Zarei
    Global Pediatric Health.2021;[Epub]     CrossRef
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    C R Hong, H J Kang, M S Kim, H Y Ju, J W Lee, H Kim, H-S Kim, S-H Park, K D Park, J D Park, H Y Shin, H S Ahn
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  • High‐dose chemotherapy with stem cell rescue in the primary treatment of metastatic and pelvic osteosarcoma: Final results of the ISG/SSG II study
    Kjetil Boye, Adalberto Brach Del Prever, Mikael Eriksson, Gunnar Sæter, Amelia Tienghi, Paula Lindholm, Franca Fagioli, Sigmund Skjeldal, Stefano Ferrari, Kirsten Sundby Hall
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  • LY294002 suppresses the malignant phenotype and sensitizes osteosarcoma cells to pirarubicin chemotherapy
    XIN HUA LONG, ZHEN HAO ZHONG, AI FEN PENG, LIANG BO ZHU, HENG WANG, GUO MEI ZHANG, ZHI LI LIU
    Molecular Medicine Reports.2014; 10(6): 2967.     CrossRef
  • Prognostic significance of early lymphocyte recovery in pediatric osteosarcoma
    Colin Moore, Don Eslin, Alejandro Levy, Jessica Roberson, Vincent Giusti, Robert Sutphin
    Pediatric Blood & Cancer.2010; 55(6): 1096.     CrossRef
  • Cryoimmunologic Antitumor Effects Enhanced by Dendritic Cells in Osteosarcoma
    Masanori Kawano, Hideji Nishida, Yasunari Nakamoto, Hiroshi Tsumura, Hiroyuki Tsuchiya
    Clinical Orthopaedics and Related Research®.2010; 468(5): 1373.     CrossRef
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The Survival of Osteosarcoma Patients 10 Years Old or Younger Is Not Worse than the Survival of Older Patients: A Retrospective Analysis
Jun Ah Lee, Dong Ho Kim, Jung Sub Lim, Kyung Duk Park, Won Seok Song, Soo-Yong Lee, Dae-Geun Jeon
Cancer Res Treat. 2007;39(4):160-164.   Published online December 31, 2007
DOI: https://doi.org/10.4143/crt.2007.39.4.160
AbstractAbstract PDFPubReaderePub
Purpose

This study aimed to assess whether a young age at the time of diagnosis with osteosarcoma has value to predict the prognosis.

Materials and Methods

Sixty-seven children with stage II osteosarcoma were stratified according to the age of 10. There were 32 preadolescents (≤10 years) and 35 adolescents (10<age≤15 years). The patients were analyzed for their clinical characteristics, the histologic response to preoperative chemotherapy, event-free survival (EFS) and the patterns of relapse.

Results

After a median follow-up of 54 months (range: 6~153 months), the 5-year EFS of the preadolescent and adolescent groups was 64.5±9.3% and 58.2±9.1%, respectively, and age did not have any statistical significance for survival (p=0.55). Cox regression analysis revealed that both the serum level of alkaline phosphatase and the histologic response to preoperative chemotherapy were significantly related to survival of the 67 patients. Those patients aged less than 7 years responded poorly to preoperative chemotherapy and their rate of amputation was 43%. However, their 5-year EFS was not statistically different from the older patients (57.1±18.7 vs 67.7±6.3%, respectively, p=0.58).

Conclusions

We could not find any statistical difference in the clinical characteristics and survival from osteosarcoma for the preadolescents and adolescents, so the current approach of having the same protocol for both groups of patients seems to be reasonable.

Citations

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  • Tumor necrosis drives prognosis in osteosarcoma: No difference in chemotherapy response and survival between chondroblastic and osteoblastic osteosarcoma
    Neel Patel, Joseph O. Werenski, Marcos R. Gonzalez, Marilee J. Clunk, Meagan R. McCadden, Alexis Richard, Ivan Chebib, Yin P. Hung, G. Petur Nielsen, Santiago A. Lozano-Calderon
    Surgical Oncology.2024; 57: 102155.     CrossRef
  • Limb salvage surgery has a higher complication rate than amputation but is still beneficial for patients younger than 10 years old with osteosarcoma of an extremity
    Yoichi Kaneuchi, Shinichirou Yoshida, Tomohiro Fujiwara, Scott Evans, Adesegun Abudu
    Journal of Pediatric Surgery.2022; 57(11): 702.     CrossRef
  • Molecular profiling of osteosarcoma in children and adolescents from different age groups using a next-generation sequencing panel
    G.M. Guimarães, F. Tesser-Gamba, A.S. Petrilli, C.R.P. Donato-Macedo, M.T.S. Alves, F.T. de Lima, R.J. Garcia-Filho, R. Oliveira, S.R.C. Toledo
    Cancer Genetics.2021; 258-259: 85.     CrossRef
  • Age and Tumor Location Predict Survival in Nonmetastatic Osteosarcoma in Upper Egypt
    Ahmed M. Morsy, Badawy M. Ahmed, Khalid M. Rezk, Islam K.-A. Ramadan, Amir M. Aboelgheit, Hanan A. Eltyb, Osama M. Abd Elbadee, Maha S. El-Naggar
    Journal of Pediatric Hematology/Oncology.2020; 42(2): e66.     CrossRef
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    Congda Li, Deying Ma, Jinhu Yang, Xiangbo Lin, Bo Chen
    Oncology Letters.2018;[Epub]     CrossRef
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    Hai-Yong Ren, Ling-Ling Sun, Heng-Yuan Li, Zhao-Ming Ye
    BioMed Research International.2015; 2015: 1.     CrossRef
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    Jianli Gu, Jitian Li, Manyu Huang, Zhiyong Zhang, Dongsheng Li, Guoying Song, Xingpo Ding, Wuyin Li
    Journal of Immunology Research.2014; 2014: 1.     CrossRef
  • Comparison between preadolescent and adolescent patients with high-grade osteosarcoma in China
    Weixiang Qi, Zan Shen, Lina Tang, Aina He, Yumei Yang, Feng Lin, Yang Yao
    The Chinese-German Journal of Clinical Oncology.2012; 11(5): 274.     CrossRef
  • The relation of tumour necrosis and survival in patients with osteosarcoma
    Xin Li, Adedayo O. Ashana, Vincent M. Moretti, Richard D. Lackman
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    Jennifer Worch, Katherine K. Matthay, John Neuhaus, Robert Goldsby, Steven G. DuBois
    Pediatric Blood & Cancer.2010; 55(2): 285.     CrossRef
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Overexpression of Metastatic Tumor Antigen in Osteosarcoma: Comparison between Conventional High-Grade and Central Low-Grade Osteosarcoma
Hye-Rim Park, Woon Won Jung, Hyun Sook Kim, Patrizia Bacchini, Franco Bertoni, Yong-Koo Park
Cancer Res Treat. 2005;37(6):360-364.   Published online December 31, 2005
DOI: https://doi.org/10.4143/crt.2005.37.6.360
AbstractAbstract PDFPubReaderePub
Purpose

The metastatic tumor antigen (MTA) gene is a recently identified metastasis-associated gene which has implications in the signal transduction or regulation of gene expression. However, the expression of MTA in osteosarcoma and its potential relationship with metastasis have not been examined, forming the basis of this study.

Materials and Methods

We compared the expression levels of the MTA1 protein between 32 cases of high-grade osteosarcomas and 21 cases of low-grade osteosarcomas by immunohistochemistry. In addition, the mRNA expression levels of MTA1, 2, 3 in these osteosarcoma cell lines and control fibroblasts were evaluated by real-time quantitative PCR.

Results

MTA1 immunoreactivity was present in 81.25% of high-grade osteosarcoma specimens. Its expression was predominantly localized to the nucleus or cytoplasm of osteosarcoma cells. Thirteen (86.6%) of 15 patients who died of osteosarcomas displayed strong MTA1 expression. Both primary bone and pulmonary metastatic lesions exhibited MTA1 expression. All low-grade osteosarcomas were negative for MTA1 except for focal weak reactivity in two cases. The tested high-grade osteosarcoma cell lines showed marked amplification of MTA1 and MTA2 mRNA compared to control cells.

Conclusion

These results suggest that MTA might be involved in the progression of high-grade osteosarcoma, particularly in hematogenous metastasis of osteosarcoma.

Citations

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  • Differential Outcomes and Biologic Markers of Radiation-Associated vs. Sporadic Osteosarcoma: A Single-Institution Experience
    Brittany L. Siontis, Jonathan B. McHugh, Emily Roberts, Lily Zhao, Dafydd G. Thomas, Dawn Owen, Laurence H. Baker, J. Sybil Biermann, Scott M. Schuetze, Rashmi Chugh
    Frontiers in Oncology.2020;[Epub]     CrossRef
  • Inhibition of Migration, Invasion and Drug Resistance of Pancreatic Adenocarcinoma Cells – Role of Snail, Slug and Twist and Small Molecule Inhibitors


    Ezgi Kaşıkcı, Esra Aydemir, Omer Faruk Bayrak, Fikrettin Sahin
    OncoTargets and Therapy.2020; Volume 13: 5763.     CrossRef
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    Wenzhe Si, Xujun Liu, Rui Wei, Yuan Zhang, Yang Zhao, Liyan Cui, Tianpei Hong
    Cell Death & Disease.2019;[Epub]     CrossRef
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    Minghui Li, Yajie Lu, Zuoyao Long, Mengyang Li, Jing Kong, Guojing Chen, Zhen Wang
    Journal of Bone Oncology.2019; 16: 100236.     CrossRef
  • Identification of candidate biomarkers that involved in the epigenetic transcriptional regulation for detection gastric cancer by iTRAQ based quantitative proteomic analysis
    Zhen Jiang, Xingwang Sun, Qiong Zhang, Xingli Ji, Qin Yu, Ting Huang, Daogang Chen, Hui Chen, Xiaohan Mei, Linyu Wang, Linyan He, Junhua Fang, Li Hou, Li Wang
    Clinica Chimica Acta.2017; 471: 29.     CrossRef
  • Significance of MTA1 in the molecular characterization of osteosarcoma
    Sung Sun Kim, Yong-Koo Park
    Cancer and Metastasis Reviews.2014; 33(4): 981.     CrossRef
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    Zhifeng Ning, Jinfeng Gan, Chaoying Chen, Dianzheng Zhang, Hao Zhang
    Cancer and Metastasis Reviews.2014; 33(4): 901.     CrossRef
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    Jian Liu, Haijuan Wang, Changzhi Huang, Haili Qian
    Cancer and Metastasis Reviews.2014; 33(4): 843.     CrossRef
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    Leena Strien, Marjut Leidenius, Päivi Heikkilä
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    Hye-Rim Park, Romulo Luis Cabrini, Eduardo Santini Araujo, Maria Luisa Paparella, Daniel Brandizzi, Yong-Koo Park
    Tumori Journal.2009; 95(1): 81.     CrossRef
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Phenylacetate Induces Growth Inhibition and Apoptosis of Human Osteosarcoma Cells
Jong Hyuk Park, Min Young Park, Ho Sung Park, Kyu Yun Jang, Myoung Ja Chung, Woo Sung Moon, Dong Geun Lee, Myoung Jae Kang
Cancer Res Treat. 2004;36(5):324-329.   Published online October 31, 2004
DOI: https://doi.org/10.4143/crt.2004.36.5.324
AbstractAbstract PDFPubReaderePub
Purpose

Phenylacetate has potent antiproliferative effects in many malignant tumors. However, the exact mechanism as to how phenylacetate induces cell growth arrest remains unclear and very little is known about its effects on human osteosarcoma cells. In this study, we investigated whether phenylacetate is effective against two osteosarcoma cell lines (HOS and U-2 OS) in vitro.

Materials and Methods

The viability of phenylacetate-treated cell lines was assessed by trypan blue exclusion assay, and the cell cycle distribution was measured by flow cytometry. To measure cell apoptosis, poly (ADP-ribose) polymerase cleavage assay and flow cytometry were employed. The expressions of cell cycle-regulatory proteins and the apoptosis-related genes were evaluated by western blot analysis.

Results

Phenylacetate was found to inhibit the growth of osteosarcoma cells, induce cell cycle arrest in the G1 phase, and induce apoptosis. A significant decrease in Bcl-2 expression and a mild up-regulation of Bax were also observed in both phenylacetate-treated cell lines. Reduced phosphorylation of the pRb and the increased expression of p21Cip1 were observed subsequent to treatment with phenylacetate.

Conclusion

These findings support the idea that phenylacetate may be an effective chemotherapeutic agent to be employed in the future against osteosarcoma, because phenylacetate acts to inhibit the growth of osteosarcoma cells through cell cycle arrest and apoptosis.

Citations

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  • Evaluation of α-hydroxycinnamic acids as pyruvate carboxylase inhibitors
    Daniel J. Burkett, Brittney N. Wyatt, Mallory Mews, Anson Bautista, Ryan Engel, Chris Dockendorff, William A. Donaldson, Martin St. Maurice
    Bioorganic & Medicinal Chemistry.2019; 27(18): 4041.     CrossRef
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Efficacy of Pre- and Postoperative Chemotherapy in Patients with Osteosarcoma of the Extremities
Joo Hyuk Sohn, Sun Young Rha, Hei Cheul Jeung, Hyun Joon Shin, Young Suck Goo, Hyun Cheol Chung, Woo Ick Yang, Soo Bong Hahn, Kyu Ho Shin, Jin Sik Min, Byung Soo Kim, Jae Kyung Roh, Woo Ick Jang
Cancer Res Treat. 2001;33(6):520-526.   Published online December 31, 2001
DOI: https://doi.org/10.4143/crt.2001.33.6.520
AbstractAbstract PDF
PURPOSE
We evaluated the treatment efficacy including survival and recurrence, and factors associated with recurrence in osteosarcoma patients treated with preoperative chemotherapy, surgery, and adjuvant chemotherapy.
MATERIALS AND METHODS
Forty nine patients with osteosarcoma were treated with preoperative chemotherapy with intra-arterial cisplatin and adriamycin infusion for 3 cycles, followed by surgery. According to the pathologic response, if tumor was necrotized more than 90%, the same adjuvant chemotherapy was reintroduced for 3 cycles, and if the response was not enough, then the salvage regimen was introduced. Plain chest film and chest CT scan were taken monthly and every 3 months, respectively. When tumor recurred, the metastasectomy was performed whenever possible.
RESULTS
Forty three patients were evaluable with amedian follow up of 53 months. Five-year disease-free and overallsurvival rate was 47.0% and 66.9%, respectively. The recurrence was observed in 22 patients (51.2%) with median time of 12.5 months. Baseline alkaline phosphatase (ALP) was the only significant factor for recurrence (p=0.03) and the patients with the possibility of metastasectomy recurrence showed higher post-relapse survival compared to other treatment modalities (26 momths vs 5~12 months).
CONCLUSION
These results indicates that pre- and postoperative chemotherapy with intra-arterial cisplatin and adriamycin infusion showed comparable treatment efficacy and acceptable toxicities.

Citations

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  • Loading comparison of two structures in the moving tube of a non-invasive prosthesis
    Jie Zhang, Ping Ye, Lizheng Zhang, Hongliu Wu, Tianxi Chi, Zhaohua Chang
    Technology and Health Care.2021; 29(5): 1001.     CrossRef
  • The multidisciplinary treatment of osteosarcoma of the proximal tibia: a retrospective study
    Junqi Huang, Wenzhi Bi, Gang Han, Jinpeng Jia, Meng Xu, Wei Wang
    BMC Musculoskeletal Disorders.2018;[Epub]     CrossRef
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    Yao Fei Wang, Jing Nan Shen, Xian Biao Xie, Jin Wang, Gang Huang
    Medical Oncology.2011; 28(S1): 636.     CrossRef
  • Comparison of Long-Term Outcome between Doublet and Triplet Neoadjuvant Chemotherapy in Non-Metastatic Osteosarcoma of the Extremity
    Soojung Hong, Sang Joon Shin, Minkyu Jung, Jaeheon Jeong, Young Joo Lee, Kyoo-Ho Shin, Jae Kyung Roh, Sun Young Rha
    Oncology.2011; 80(1-2): 107.     CrossRef
  • Clinical Value of Ezrin Expression in Primary Osteosarcoma
    Chan Kim, Eunah Shin, Soojung Hong, Hong Jae Chon, Hye Ryun Kim, Jung Ryun Ahn, Min Hee Hong, Woo Ick Yang, Jae Kyung Roh, Sun Young Rha
    Cancer Research and Treatment.2009; 41(3): 138.     CrossRef
  • Carboxypeptidase-G2 Rescue in a Patient with High Dose Methotrexate-induced Nephrotoxicity
    Eun Sil Park, Kyung Hee Han, Hyoung Soo Choi, Hee Young Shin, Hyo Seop Ahn
    Cancer Research and Treatment.2005; 37(2): 133.     CrossRef
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The Efficacy of Pre - operative Chamotherapy with Intra-arterial Cisplatin and Intravenous Adriamycin for High Grade Osteosarcoma
Sun Young Rha, Soo Jung Gong, Hee Cheol Chung, Kwang Yong Shim, Joong Bae Ahn, Nae Choon Yoo, Hyn Cheol Chung, Joo Hang Kim, Hae Kyung Roh, Jin Sik Min, Byung Soo Kim, Kyu Ho Shin, Woo Ick Yang, Chong In Lee
J Korean Cancer Assoc. 1999;31(1):134-143.
AbstractAbstract PDF
PURPOSE
Osteosarcoma is one of the most common juvenile malignant tumors in Korea. Combined modality treatment [pre-operative chemotherapy + surgery (limb salvage or amputation) + adjuvant chemotherapy] had improved the overall survival and quality of life. To improve the local control rate, we introduced pre-operative chemotherapy combined with intra-arterial (IA) cisplatin and continuous intravenous infusion (CI) of adriamycin. We evaluated the efficacy and feasibility, such as limb salvage rate, recurrence pattern and the survival impact, based on the histologic response of pre-operative chemotherapy.
MATERIALS AND METHODS
Fourty-one patients with histologically-proven high grade osteosarcoma of the extremities were enrolled from January 1990 to June 1996. Pre-operative chemotherapy, cisplatin 120 mg/m2 IA and adriamycin 75 mg/m2/72hrs CI, was administered for 3 cycles with 3 week interval, followed by surgery. Post-operative chemotherapy was applied by the tumor necrosis rate. If the tumor necrosis of the specimen was more than 90%, the same regimen af the preoperative one was administered for 3 cycles. A salvage regimen (Ifosfamide 7.5 gm/m2/5d IV + high dose MTX 10 gm/m2 IV VP-16 360 mg/m2/3d IV) was administered every 3 weeks for 6 cycles if the tumor necrosis was <90%.
RESULTS
Of 41 patients, 37 were evaluable for efficacy and toxicities, because 4 refused further chemotherapy after 1 or 2 cycles. Twenty-one patients were male and 16 female, with the median age of 16 years (8-41). The tumor locations were as follows: distal femur 20, proximal tibia 8, humerus 6, distal tibia 2 and 1 in proximal femur. All but one patient, who died of neutropenic sepsis, completed the planned pre-operative therapy. Of the 36 patients who received surgery, limb salvage surgery was possible in 30 patients (83.3%) and 27 patients (75%) showed a good response (10 with grade III, 27.8%; 17 with grade IV, 47.2%). With a median follow-up of 23 months, 3-year disease-free survival rate was 54.7% and overall survival rate was 78.3%. Of the 15 patients who recurred, the major metastatic site was the lungs. No operation-related mortality was observed. Most patients experienced grade III-IV nausea, vomiting and hematologic toxicities, which were reversible with supportive care.
CONCLUSION
Pre-operative chemotherapy combined with IA cisplatin and CI adriamycin induced higher good response rate without survival benefits. To improve the survival rate, the design of good salvage chemotherapy with a non-cross resistant regimen should be considered.
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The Survival Rate of Stage IIB Ostosarcoma after Neoadjuvant Chemotherapy ( Modified T10 Protocol )
Jae Do Kim, Jeong Soo Bae, Myung Rae Cho
J Korean Cancer Assoc. 1998;30(3):591-598.
AbstractAbstract PDF
PURPOSE
The survival rate according to the methods of treatment was significantly higher in the osteosarcoma patients in which limb salvage operation with neoadjuvant chemotheraphy. The purpose of this study is to analyze the results of treatment in the Stage IIB osteosarcoma patients who treated with modified T10 protocol.
MATERIALS AND METHODS
From Jun. 1990 to Oct. 1997, thirty eight cases of Enneking's stage IIB osteosarcoma in extremities, were treated with neoadjuvant chemotherapy by modified T10 protocol of Rosen. Their mean age was 22 years old (8 months to 55 years). And average duration of follow up is 29 months(10 manths to 88 months). The preoperative chemotherapy consisted of high dose methotrexate(HDMTX)(above 12 years old: 8 g/m2, below 12 years old: 12 g/m2), adriamycin(ADR)(30 mg/m2/day x 2), intraarterial cisplatin(CDDP)(100 mg/m2) or ifosfamide (IFO)(1.8 g/m2/day x5). The preoperative tailoring was performed according to the radiologic response after chemotherapy. If the patient revealed good response, we continued the chemotherapy next one more cycle and if not, stoped the chemotherapy or changed the cisplatin to ifosfamide. The postoperative chemotherapy consisted of HDMTX, adriamycin, ifosfamide or cisplatin with 4 cycles. According to the pathologic response to the pre-operative chemotherapy, we use HDMTX, ADR, CDDP in good response group and HDMTX, ADR, IFO in poor response group respectively.
RESULTS
On the latest follow up, 27 patients were continuous disease free(CDF 27/38), 4 patients were alive with disease(AWD) and 6 patients were died of disease(DOD) and I case was died of bone marrow and hepatic failure due to complication of chemotherapy. According to Kaplan-Meier's plot, the overall 5 years survival rate was 73.6%, and continuous disease free 5 years survival rate being 64%. The comparison of continuous disease free survival rates between good radiologic response group and poor response group showed 73% and 55%. The continuous disease free survival rates according to the pathologic response in good response group and poor were 90 % and 55%. During the chemotherapy, the most serious complications were leukocytopenia and bone marrow failure. These were controled by granulocyte colony stimulating factor(G-CSF) and leukotrophic agent. Other minor complications were nausea, vomiting, headache and extrapyramidal symptom, which were easily managed by simple conservative measure.
CONCLUSION
It was obtained that the overall 5 years survival rate was 73.6%, and continuous disease free 5years survival rate being 64% with modified T10 protocol.
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Treatment Result of Pediatric Osteosarcoma with Intraarterial Cisplatin
Hyoung Soo Choi, Hyoung Jin Kang, Jun Ah Lee, Hyo Heong Han, Hyeon Jin Park, Eun Sun Yoo, Woo Sun Kim, Hee Young Shin, In One Kim, Sang Hoon Lee, Hyo Seop Ahn, Han Koo Lee
J Korean Cancer Assoc. 1998;30(1):169-177.
AbstractAbstract PDF
PURPOSE
This study was performed to determine the outcome after treatment of osteosarcoma with intraarterial cisplatin as a preoperative chematherapy regimen.
MATERIALS AND METHODS
Twenty five patients with extremity osteosarcoma were treated with intraarterial cisplatin at Seoul National University Children's Hospital from January 1987 to April 1996. The dose of cisplatin was 130 mg/m2 and three to six courses were repeated two- to three-week intervals, Systemic doxorubicin was added to six of these patients. This was followed by surgical resection(limb salvage or amputation) and postoperative adjuvant chemotherapy.
RESULTS
Limb-salvage was possible in twenty of these twenty five patients. Pulmonary metastasis was present in five patients at diagnosis and developed later in three patients. In six patients treated with systemic doxorubicin, pulmonary metastasis was absent at diagnosis and during follow-up period. Local recurrence after limb salvage was occurred in one patient and treated with amputation and systemic chemotherapy. Seven patients died from pulmonary metastssis and one from unknown cause. The follow-up duration of these patients was three to eighty eight months(median twenty two months) and the overall five-year survival and event free survival rate were 62.1% and 57.5%, respectively.
CONCLUSION
These data demonstrate that intraarterial cisplatin can be used as an effective regimen preoperatively for pediatric patients with extremity osteosarcoma. The combined use of systemic doxorubicin is expected to improve survival in patients with pulmonary metastasis.
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Neoadjuvant Chemotherapy with High-dose Methotrexate , Adriamycin and Cisplatin for Non - Metastatic Osteosarcoma
Keun Seok Lee, Heung Moon Chang, Dae Seog Heo, Yung Jue Bang, Noe Kyeong Kim, Sang Hoon Lee, Eui Keun Ham, Han Ku Lee
J Korean Cancer Assoc. 1996;28(6):1092-1104.
AbstractAbstract PDF
three non-metastatic osteosarcoma patients were treated with high-dose methotrexate, adriamycin, and cisplatin from October 1987 to May 1993. Median age was 18. The ratio of male to female was 16: 7. The patients received methotrexate 8g/§³ IV, day 1 and 8 with leucovorin rescue, adriamycin 25mg/§³ IV day 16~18, and cisplatin 75mg/§³ IV day 16, After two cycles of neoadjuvant chemotherapy, operation was done and then six cycles of adjuvant chemotherapy were given with the same regimen. One patient developed lung metastasis after two cycles of neoadjuvant chemotherapy, and the other patient died from sepsis associated with chemotherapy-induced neutropenia before operation. Therefore, 21 patients underwent operation. Among them, l9 patients underwent limb salvage operation. Of the five patients who relapsed, two patients had lung metastasis and another two patients had local recurrence, and one patient had both lung and brain metastasis. One year, three year, and five year disease-free survival rate were 84%, 68%, and 68%. One year, three year, and five year survival rate were 91%, 64%, and 53%, respectively. The site of the primary lesion was the only significant prognosis factor. Patients with the lesion of distal femur had poor prognosis.Histologic responses were assessed in 17 patients. Observed histologic responses were grade I necrosis in 35%, grade II necrosis in 65%. There was no grade III or IV necrosis. The disease-free survival rates and overall survival rates were not significantly different between grade I necrosis group and grade II necrosis group. Toxicities grade III or IV were as follows: leukopenia 32%, thrombocytopenia 9%, hepatotoxicity 14%, and infection 6% with one chemotherapy-related death. The pharmacokinetics of high-dose methotrexate with leucovorin rescue were studied in l0 patients. The highest concentration was achieved at the end of infusion(6 hour). The decay of the plasma concentration of methotrexate after completion of the infusion followed a two-compartment model with a T(1/2)¥a of 3.4¡¾1.9 hours and T(1/2)¥a of 8.0¡¾2.6 hours. The clearance was 55¡¾13ml/min/§³ and the volume of distribution was 8.2¡¾3.0 L/§³. In conclusion, neoadjuvant chemotherapy with high-dose methotrexate, adriamycin, and cisplatin is effective for treatment of the patients of osteosarcoma with preserving the limb function.
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Effect of Combined Modality Treatment and Clinical Significance of P-Glycoprotein Overexpression in Patients with Osteosarcoma
Yong Seok Yun, Jae Kyung Roh, Hyun Cheol Chung, Jae Yong Cho, Kyoo Ho Shin, Soo Bong Han, Beom Seok Kim, Joon Oh Park, Soo Jung Gong, Sun Young Rha, Nae Choon Yoo, Joo Hang Kim, Jin Sik Min, Byung So
J Korean Cancer Assoc. 1996;28(6):1104-1117.
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Osteosarcoma is a highly malignant bone tumor and usually encountered in the first three decades of life. The Prognosis of osteasarcoma treated with surgery alone had been poor, with 20% of the patients surviving 5 years. The addition of adjuvant chemotherapy after surgery has siginificantly improved the outcome of osteosarcoma. The new concept of pre-operative chemotherapy has permitted histological assessment of treatment effect and limb salvage procedures. As the role of chemotherapy has been raised, the resistance of tumors to multiple drugs, such as p-glycoprotein overexpression, has become a major problem in the treatment of osteosarcoma. We retrospectively reviewed the clinical records of 53 patients with stage IIB osteosarcoma who were treated at Yonsei Medical Center and Yonsei Cancer Center between March 1, 1986 and June 30, 1996. The purpose of this study was to assess the efficacy and toxicity of cisplatin(IA)-adriamycin(IV) combination pre-operative chemotherapy and the clinical significance of p-glycoprotein status and histologic response as prognostic factors. Among 53 patients, 33 were male and 20 were female with a median age of 21 years(range: 5~61). The tumor locations were as follows: distal femur 24(45.3%), proximal tibia 17(32.1%), humerus 7(13.2%), proximal femur 3(5.4%), fibular 1(1.9%), radius 1(1.9%). Histologic subclassifications were as follows: osteoblastic type 42(78.2%), telangiectatic type 4(7.5%), chondrablastic type 3(5.7%), fibroblastic type 2(3.8%) and undetermined 2(2.8%). The three year overall survival and disease-free survival rates were 66.1% and 61.9% respectively in all patients. Thirty-two patients were treated by pre-operative cisplatin(IA)-adriamycin(IV) combination chemotherapy and 21 patients were taken only post-operative adjuvant chemotherapy. No significant difference was found between the two groups in probability of survival and recurrence rates. The histological response ta pre-operative chemotherapy was scored by degree of tumor necrosis. Twenty-two patients had a good response [grade IV, 13(40.6%);grade III, 8(25.0%)] and 11 patients had a poor response [grade II, 6(18.8%);grade I, 5(15.6%)]. The histological response was not significantly related to the probability of the survival rate. However, the recurrence rate was higher in the poor-response group(p=0.04). Overexpression of p-glycoprotein was found in tumors from 11 of l8 patients(61.1%) who were given only post-operative adjuvant chemotherapy. No relation was found between the p-glycoprotein expression and survival rate. The degree of tumor necrosis after pre-operative chemotherapy and initial serum alkaline-phosphatase level were considered as prognositic factors. Other clinicopathologic features including age, gender, anatomical site, histological subclassification,operation types,tumor size.p-glycoprotein expression were not associate with patient outcome. Treatment-related side effects were relatively tolerable and reversible by conservative treatment. Pre-operative cisplatin(IA)-adriamycin(IV) combination chemotherapy in our study did not show improved survival than conventional post-operative chemotherapy with limited follow-up duration. The degree of histologic response after chemotherapy and the initial alkaline phosphatase level were found to be the major predictor for tumor recurrences, while p-glycoprotein overexpression did not alter the clinical outcome. Further studies are warranted to improve the efficacy of adjuvant chemotherapy and to evaluate the significance of multiple resistance gene overexpression in osteosarcoma.
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Cancer Res Treat : Cancer Research and Treatment
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