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Recent trends in bone metastasis treatments:A historical comparison using the new Katagiri score system

World Journal of Clinical Cases 2024年第15期12卷 2499-2505页

作者： Kenji Matsuda Kazuhiro Shimazu Hanae Shinozaki Koji Fukuda Taichi Yoshida Daiki Taguchi Kyoko Nomura Hiroyuki Shibata Department of Clinical Oncology Akita University Graduate School of MedicineAkita 010-8543Japan Department of Environmental Health Science and Public Health Akita University Graduate School of MedicineAkita 010-8543Japan Department of Comprehensive Cancer Control Akita University Graduate School of MedicineAkita 010-8543Japan

BACKGROUND bone metastasis has various negative impacts.Activities of daily living(ADL)and quality of life(QOL)can be significantly decreased,survival may be impacted,and medical expenses may increase.It is estimated that at least 5%cancer patients might be suffering from bone metastases.In 2016,we published the Comprehensive Guidelines for the Diagnosis and Treatment of bone metastasis.Since then,the therapeutic outcomes for patients have gradually improved.As life expectancy is a major determinant of surgical intervention,the strategy should be modified if the prolongation of survival is to be achieved.AIM To monitor how bone metastasis treatment has changed before and after launch of our guidelines for bone metastasis.METHODS For advanced cancer patients with bone metastasis who visited the Department of Clinical Oncology at Akita University hospital between 2012 and 2023,parameters including the site and number of bone metastases,laboratory data,and survival time,were extracted from electronic medical records and the Katagiri score was calculated.The association with survival was determined for each factor.RESULTS Data from 136 patients were obtained.The 1-year survival rate for the poor prognosis group with a higher Katagiri score was 20.0%in this study,which was 6%and an apparent improvement from 2014 when the scoring system was developed.Other factors significantly affecting survival included five or more bone metastases than less(P=0.0080),and treatment with chemotherapy(Pbone modifying agents(P=0.0175)and immune checkpoint inhibitors(P=0.0128).In recent years,advances in various treatment methods have extended the survival period for patients with advanced cancer.It is necessary not only to simply extend survival time,but also to maintain ADL and improve QOL.CONCLUSION Various therapeutic interventions including surgical approach for bone metastasis,which is a disorder of locomotor organs,are increasingly required.Guidelines and scoring system for prognosis need to be revised promptly.

关键词： bone metastasis New Katagiri scoring system Prognosis Immune check point inhibitors Survival

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Clinical association between coagulation indicators and bone metastasis in patients with gastric cancer

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World Journal of Gastrointestinal Oncology 2023年第7期15卷 1253-1261页

作者： Xuan Wang Jing-Ya Wang Min Chen Juan Ren Xin Zhang Department of Radiotherapy and Oncology The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an 710061Shaanxi ProvinceChina Department of Gastroenterology Xi'an Children's HospitalShaanxi Research Institute for Pediatric DiseasesThe Affiliated Children's Hospital of Xi'an Jiaotong University and National Regional Medical Center for Children(Northwest)Xi'an 710003Shaanxi ProvinceChina Department of Surgical Oncology The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an 710061Shaanxi ProvinceChina

BACKGROUND bones are one of the most common target organs for cancer metastasis.Early evaluation of bone metastasis(BM)status is clinically significant.Cancer patients often experience a hypercoagulable state.AIM To evaluate the correlation between coagulation indicators and the burden of BM in gastric cancer(GC).METHODS We conducted a single-center retrospective study and enrolled 454 patients.Clinical information including routine blood examination and coagulation markers were collected before any treatment.Patients were grouped according to the status of BM.Receiver operating characteristic curves were used to assess diagnostic performance and determine the optimal cutoff values of the above indicators.Cutoff values,sensitivity and specificity were based on the maximum Youden index.Univariate and multivariate logistic regression analyses were used to evaluate the relationships between biomarkers and BM.RESULTS Of the 454 enrolled patients,191 patients were diagnosed with BM.The receiver operating characteristic curve analysis suggested that prothrombin time(PT)Wang X et al.Coagulation indicators predict bone metastasis WJGO https://*** 1254 July 15,2023 Volume 15 Issue 7[cutoff:13.25;sensitivity:0.651;specificity:0.709;area under receiver operating characteristic curve(AUC)=0.738],activated partial thromboplastin time(aPTT)(cutoff:35.15;sensitivity:0.640;specificity:0.640;AUC=0.678)and fibrin degradation products(FDP)(cutoff:2.75;sensitivity:0.668;specificity:0.801;AUC=0.768)act as novel predictors for BM.Based on multivariate logistic regression analysis,the results showed the independent correlation between PT[odds ratio(OR):3.16;95%confidence interval(CI):1.612-6.194;P=0.001],aPTT(OR:2.234;95%CI:1.157-4.313;P=0.017)and FDP(OR:3.17;95%CI:1.637-6.139;P=0.001)and BM in patients with GC.Moreover,age,carcinoembryonic antigen,erythrocyte and globulin were found to be significantly associated with BM.CONCLUSION Coagulation markers,namely PT,aPTT and FDP,might be potential predictors for screening BM in patients wi

关键词： Gastric cancer bone metastasis Coagulation markers Risk factor Activated partial thromboplastin time Prothrombin time Fibrin degradation products

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Thymic carcinoid with multiple bone metastases:A case report

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World Journal of Clinical Cases 2024年第13期12卷 2275-2280页

作者： Chun-Qiao Chen Ming-Yue Huang Min Pan Qiu-Qiu Chen Fei-Fei Wei Hui Huang Department of Oncology People’s Hospital of GuilinGuilin 541000Guangxi Zhuang Autonomous RegionChina

BACKGROUND Thymic carcinoid(TC)is a rare entity among anterior mediastinal malignancies.TCs are neuroendocrine carcinomas that constitute approximately 2%–5%of all thymic epithelial tumors.CASE SUMMARY The study reported a rare TC with multiple bone metastases.A 77-year-old man presented with a 2-month history of lower back pain and weight loss of 5 kg.Magnetic resonance imaging scans revealed damage to the lumbar spine,sacrocaudal vertebrae and iliac crest,suggesting bone metastasis;computed tomography(CT)scan of the thorax showed a calcified anterior mediastinal mass;positron emission tomography-CT demonstrated multiple abnormal bone signals;and laboratory work-up showed no endocrine abnormalities.Fine-needle aspiration biopsy revealed predominantly single small,round to oval cells with scant cytoplasm and some loose clusters,suggesting endocrine manifestations.The pathological diagnosis was atypical carcinoid,which tend to originate from the thymus and was classified as intermediate-highly invasive.The patient underwent anlotinib-targeted therapy.Anlotinib(12 mg)was administered daily for 2 wk,after which the patient was allowed to rest for 21 d.Follow-up CT after one year demonstrated that the tumor had shrunk by approximately 29%after therapy.Treatment has a long stable disease benefit of more than 2.5 years.CONCLUSION These findings demonstrated that anlotinib is a promising treatment regimen for patients with TC and multiple bone metastases.

关键词： Thymic carcinoid Anlotinib Multitargeted tyrosine kinase inhibitor bone metastasis Case report

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bone-seeking nanoplatform co-delivering cisplatin and zoledronate for synergistic therapy of breast cancer bone metastasis and bone resorption

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Acta Pharmaceutica Sinica B 2020年第12期10卷 2384-2403页

作者： Yanjuan Huang Zhanghong Xiao Zilin Guan Zishan Zeng Yifeng Shen Xiaoyu Xu Chunshun Zhao School of Pharmaceutical Sciences Sun Yat-sen UniversityGuangzhou 510006China

The"vicious cycle"established between tumor growth and osteolysis aggravates the process of breast cancer bone metastasis,leading to life-threatening skeletal-related events that severely reduce survival and quality of life.To effectively interrupt the"vicious cycle",innovative therapeutic strategies that not only reduce osteolysis but also relieve tumor burden are urgently needed.Herein,a bone-seeking moiety,alendronate(ALN),functionalized coordination polymer nanoparticles(DZ@ALN)co-delivering cisplatin prodrug(DSP)and antiresorptive agent zoledronate(ZOL)via Zn2+crosslinking for combination therapy was reported.The versatile DZ@ALN with a diameter of about 40 nm can cross the fissure in the bone marrow sinus capillaries,and possesses an excellent bone-seeking ability both in vitro and in vivo.Additionally,DZ@ALN could synergistically inhibit the proliferation of cancer cells,suppress the formation of osteoclast-like cells and induce the apoptosis of osteoclasts in vitro.Importantly,it could preferentially accumulate in bone affected site,remarkably inhibit the proliferation of tumor cells,relieving bone pain,and significantly inhibit the activation of osteoclasts,protecting the bone from destruction in vivo,eventually leading to the breakdown of"vicious cycle"without inducing obvious systemic toxicity.This innovative nanoagent combines chemotherapy and osteolysis inhibition,exhibiting an inspiring strategy for effective treatment of bone metastasis.

关键词： bone metastasis bone targeting Osteolysis Zoledronate Cisplatin

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Interactions between cancer cells and bone microenvironment promote bone metastasis in prostate cancer

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Cancer Communications 2019年第1期39卷 645-654页

作者： Xiangyu Zhang Department of Pathology Jining First People’s HospitalJining Medical UniversityNo.6 Jiankang RoadJining 272000ShandongP.R.China

bone metastasis is the leading cause of death in prostate cancer patients,for which there is currently no effective treatment.Since the bone microenvironment plays an important role in this process,attentions have been directed to the interactions between cancer cells and the bone microenvironment,including osteoclasts,osteoblasts,and bone stromal cells.Here,we explained the mechanism of interactions between prostate cancer cells and metastasis-associated cells within the bone microenvironment and further discussed the recent advances in targeted therapy of prostate cancer bone metastasis.This review also summarized the effects of bone microenvironment on prostate cancer metastasis and the related mechanisms,and provides insights for future prostate cancer metastasis studies.

关键词： Prostate cancer bone metastasis bone microenvironment Colonization Dormancy Reactivation Reconstruction Nuclear factor-κB ligand Androgen receptor Targeted therapy

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Predictive Value of Serum bone Sialoprotein and Prostate-specific Antigen Doubling Time in Patients with bone metastasis of Prostate Cancer

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2013年第4期33卷 559-562页

作者：王焱张晓飞戴吉郑咏池张明根何建军 The Medical Laboratory Dujiangyan People's Hospital Department of Nuclear Medicine The Second Xiangya HospitalCentral South University

Summary： This study aimed to evaluate the diagnostic and prognostic significance of serum bone sialoprotein （BSP） and prostate-specific antigen doubling time （PSADT） in patients with bone metastasis （BM） from prostate cancer （PC）. A total of 116 patients with PC, 120 patients with benign prostatic hyperplasia （BPH） and 120 healthy controls were enrolled in this study. PC patients were divided into bone metastasis （BM） group （n=56） and non-bone metastasis （NBM） group （n=60）. Serum BSP was detected by Sandwich ELISA. Severity of bone pain was evaluated using visual analogue score （VAS）. Serum f-PSA and t-PSA levels were measured by using electrochemiluminescence immunoassay （ECLIA）. PSADT was calculated according to the formula： PSADT=lg（2）/[log（PSA2）--log（PSA1）]. The mean serum BSP level in PC patients with BM was significantly higher than in PC patients without BM, BPH patients and controls （P〈0.001 for all）. Pearson＇s analysis showed that serum BSP level was posi- tively correlated with VAS in PC patients with BM （P〈0.05）. Receiver operating characteristics （ROC） analysis demonstrated that BSP discriminated patients with BM from those without BM at the cutoff value of 33.26 ng/mL. The sensitivity and specificity were 78.21% and 79.28%, respectively. The opti- mal cutoff value of PSADT was 131 days, with sensitivity of 85.69% and specificity of 85.36%. Kap- lan-Meier analysis revealed that subjects with higher BSP levels/shorter PSADT had a shorter BM-free period than those with lower BSP levels/longer PSADT. Serum BSP and PSADT are useful biomarkers for the diagnosis of BM from PC, and can be regarded as independent factors for predicting the progno- sis of BM from PC. Combined determination of BSP and PSADT can improve accuracy and positive rate of BM from PC significantly.

关键词： bone sialoprotein prostate cancer bone metastasis prognosis

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Effects of Brucine on Vascular Endothelial Growth Factor Expression and Microvessel Density in A Nude Mouse Model of bone metastasis Due to Breast Cancer

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Chinese Journal of Integrative Medicine 2012年第8期18卷 605-609页

作者：李平张梅马文静孙鑫靳福鹏 Department of Traditional Chinese Medicine Oncology Provincial Hospital of Anhui Medical University Department of Oncology Affiliated Hospital of Bengbu Medical College

Objective： To study the effects of brucine on vascular endothelial growth factor （VEGF） expression and microvessel density （MVD） in a nude mouse model of bone metastasis due to breast cancer, and to assess the possible antitumor mechanism of brucine. Methods： A syringe needle was used to directly inject 0.2 mL monoplast suspension （with 2 × 106 human breast cancer cells contained） into the bony femoral cortex of the right hind leg for modeling. Twenty-five nude mice were randomized into five groups and administered with an intraperitoneal injection of saline or drug for 8 consecutive days： model group （0.2 mL normal saline）, low-dose brucine group （1.73 mg-kg^-1）, medium-dose brucine group （3.45 mgokg^-1）, high-dose brucine group （6.90 mg.kg^-1）, and thalidomide group （200 mg.kg^-1）. Diet and activity were recorded, and the tumors were harvested 5 weeks later. The percentage of VEGF-positive cells was determined with hematoxylin and eosin staining and immunohistochemical staining, and MVD expression was determined by optical microscopy. Results： The VEGF expressions in brucineor thalidomide-treated mice were significantly reduced as compared with mice in the model group （P〈0.01）. There were no significant difference between the high-dose brucine group and the thalidomide group （P〉0.05）. Significant difference was between the high- and low-dose brucine group （P〈0.05）. Further, VEGF expression was significantly increased in the low- and medium-dose brucine groups compared with the thalidomide group （P〈0.05）. The MVD values in the three brucine and thalidomide groups were significantly lower than that in the model group （P〈0.01）. The MVD values in the medium- and high-dose brucine groups were not significantly different from those in the thalidomide group （P〉0.05）, while the MVD value showed a significant increase in the low-dose group compared with the thalidomide group （P〈0.05）. Conclusion： Brucine could inhibit the growth of breast cancer to bone metastases, possibly by inhibiting tumor angiogenesis.

关键词： brucine breast cancer bone metastasis vascular endothelial growth factor expression microvessel density

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Analysis of Clinicopathological Factors Associated with bone metastasis in Breast Cancer

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Journal of Huazhong University of Science and Technology(Medical Sciences) 2013年第1期33卷 122-125页

作者：陈璟朱沭谢修帧郭山峰童良前周晟赵明鲜于志群朱小华熊伟 Department of Nuclear Medicine Tongji HospitalTongji Medical CollegeHuazhong University of Science and Technology School of Life Science Hainan Normal University Department of Pathology Tongji HospitalTongji Medical CollegeHuazhong University of Science and Technology Department of Orthopaedics Tongji HospitalTongji Medical CollegeHuazhong University of Science and Technology

Breast cancer is the second leading cause of cancer death in women today. Once breast can- cer metastasizes to bone, mortality increases. Thus, there is an urgent need to identify patients with high risk of bone metastasis, and to find predictive factors for the occurrence of bone metastasis at an earlier stage of breast cancer. Three hundred and sixty patients with pathologically proved breast cancer visit- ing the Department of Nuclear Medicine for whole body bone scan from January 2006 and January 2009 were investigated in this study. Clinicopathological information was obtained, which consisted of age, menopausal status, clinical staging, lymph node stage, histological grade, the expression of estro- gen receptor （ER）, progesterone receptor （PR） and epidermal growth factor receptor 2 （HER2）. Correla- tion between bone metastasis and the associated factors was tested by using the Chi-square test. A Cox multivariate analysis was used to assess the factors which independently contributed to survival after bone metastasis in breast cancer patients. Survival curves were drawn for metastasis-free interval and the independent factors which contributed to survival, using the Kaplan-Meier method. Twenty-four pa- tients were excluded from subsequent analysis. Three hundred and thirty-six enrolled patients ranged in age from 22 to 77 years （mean, 47.8 years）. ER/PR status [ER（＋） vs. ER（-）, 2,2=4.328, P=0.037; ER（＋）PR（＋） vs. ER（＋）PR（-）, ;（2=4.425, P=-0.035] and histological grade （;（2=7.131, P=0.028） were sig- nificantly associated with bone metastasis. ER status （;（2=8.315, P=0.004） and metastasis-free interval （;（2=6.863, P=-0.009） were independent prognostic factors for survival in breast cancer patients with bone metastasis. Our study suggested that ER/PR status and histological grade are risk factors for the development of bone metastasis in breast cancer patients. However, ER status and metastasis-free inter- val are independent prognostic factors for survival in breast cancer patients with bone metastasis. Breast

关键词： breast cancer bone metastasis bone scan risk factors

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A novel mouse model of human breast cancer stem-like cells with high CD44^＋CD24^–/lower phenotype metastasis to human bone

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Chinese Medical Journal 2008年第20期121卷 1980-1986页

作者： LING Li-jun WANG Shui LIU Xiao-an SHEN En-chao DING Qiang LU Chao XU Jian CAO Qin-hong ZHU Hai-qing WANG Feng Department of General Surgery First Affiliated Hospital of Nanjing Medical University Nanjing Jiangsu 210029 China Department of Pathology Nanjing Brain Hospital Affiliated to Nanjing Medical University Nanjing Jiangsu 210029 China Department of Nuclear Medicine First Nanjing Hospital Affiliated to Nanjing Medical University Nanjing Jiangsu 210006 China

Background A satisfactory animal model of breast cancer metastasizing to bone is unavailable. In this study, we used human breast cancer stem-like cells and human bone to build a novel “human-source” model of human breast cancer skeletal metastasis. Methods Human breast cancer stem-like cells, the CD44^＋/CD24^-/lower subpopulation, was separated and cultured. Before injection with the stem-like cells, mice were implanted with human bone in the right or left dorsal flanks. Animals in Groups A, B, and C were injected with 1×10^5, 1×10^6 human breast cancer stem-like cells, and 1×10^6 parental MDA-MB-231 cells, respectively. A positive control group （D） without implantation of human bone was also injected with 1×10^6 MDA-MB-231 cells. Immunohistochemistry was performed for determination of CD34, CD105, smooth muscle antibody, CD44, CD24, cytokine, CXC chemokine receptor-4 （CXCR4）, and osteopontin （OPN）. mRNA levels of CD44, CD24, CXCR4, and OPN in bone metastasis tissues were analyzed by real-time quantitative polymerase chain reaction （PCR）.Results Our results demonstrated that cells in implanted human bones of group B, which received 1×10^6 cancer stem-like cells, stained strongly positive for CD44, CXCR4, and OPN, whereas those of other groups showed no or minimum staining. Moreover, group B had the highest incidence of human bone metastasis （77.8%, P=0.0230） and no accompaniment of other tissue metastasis. The real-time PCR showed an increase of CD44, CXCR4, and OPN mRNA in metastatic bone tissues in group B compared with those of groups C and D, however the expression of CD24 mRNA in group B were the lowest. Conclusions In the novel “human source” model of breast cancer, breast cancer stem-like cells demonstrated a higher human bone-seeking ability. Its mechanism might be related to the higher expressions of CD44, CXCR4, and OPN, and the lower expression of CD24 in breast cancer stem-like cells.

关键词： breast cancer cancer stem-like cells human source bone metastasis animal model

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Multiplexed bioluminescence imaging of cancer cell response to hypoxia and inflammation in the caudal-artery injection model of bone metastasis during zoledronic acid treatment

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Journal of Cancer metastasis and Treatment 2021年第1期7卷 69-80页

作者： Misa Minegishi Takahiro Kuchimaru Kenji Nakagawa Tatsuhiro Isozaki Satoshi Fujimori Tetsuya Kadonosono Shinae Kizaka-Kondoh School of Life Science and Technology Tokyo Institute of TechnologyKanagawa 226-8501Japan Center for Molecular Medicine Jichi Medical UniversityTochigi 329-0498Japan.

Aim:Therapeutic agents suppressing bone remodeling have been clinically approved to delay metastatic progression and skeletal-related events in patients with bone metastasis.However,therapeutic agents including zoledronic acid(ZA)are insufficient to regress established bone metastasis.Therefore,new treatment strategies are desired,and unraveling the status of cancer cells during bone metastatic progression will help develop therapeutic strategies.Methods:We developed a unique multiplexed reporter system for bioluminescent imaging(MRS-BLI)using three luciferase reporter genes.This system allows for the noninvasive and quantitative monitoring of tumor growth and activities of nuclear factor-kappa B(NF-κB)and hypoxia-inducible factor(HIF),which are the key transcriptional factors in response to inflammation and hypoxia,respectively.PC-3/MRS-BLI,a human prostate cancer cell line that stably retains the MRS-BLI reporter genes,was applied to the caudal-artery injection model of bone metastasis to observe the status of cancer cells during bone metastasis development and ZA treatment(bone metastasis development:NF-κB and HIF are activated in cancer cells after migration to the bone marrow and are transiently reduced,followed by rapid activation before proliferation begins.ZA treatment suppresses the growth of metastasized cancer cells by suppressing NF-κB and HIF activities that may be indirectly induced by osteoclast activation.Conclusion:By visualizing the NF-κB and HIF activities of PC-3/MRS-BLI in bone,MRS-BLI has enabled new discoveries regarding the regulation of bone metastases.Further analysis of the progression of bone metastases using MRS-BLI may provide important information for developing new therapeutic strategies.

关键词： bone metastasis multiplexed bioluminescence imaging zoledronic acid nuclear factor-kappa B hypoxia inducible factor

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