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

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(P<0.001),bone 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.

Research Progress on the Bone Metastasis Mechanism of Prostate Cancer and Bone-Targeted Drugs

Prostate cancer is a common male malignant tumor,and bone metastasis is one of the common complications in the late stage of prostate cancer.The mechanism of prostate cancer bone metastasis is a complex process involving multiple factors and steps.In recent years,with in-depth research on the mechanism of prostate cancer bone metastasis and the development of new drugs,important progress has been made in the treatment of prostate cancer bone metastasis.Based on this,this article introduces the mechanism of prostate cancer bone metastasis and the research progress of several bone-targeted drugs to provide reference and inspiration for future research.

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

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://www.wjgnet.com 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 with GC.

Analysis of Clinicopathological Factors Associated with Bone Metastasis in Breast Cancer

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 cancer bone metastasis has its unique characteristics, which is helpful to choose the appropriate treat- ment for breast cancer patients with bone metastasis.

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

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.

The evaluation of Tracp5b as a marker for monitoring treatment results of bone metastasis in breast cancer patients

Objective ：To evaluate the sensitivity of serum tartrate-resistant acid phosphatase 5b（Tracp5b） activity in monitoring bisphosphonate treatment results of bone metastasis in breast cancer（BC） patients. Methods：The serum activities of Tracp5b, CEA, CA153 were measured in 58 BC patients, including 26 without bone metastasis, 32 with bone metastasis. The serum activities of TracpSb, CEA, CA153 were also measured in 19 patients with bone metastasis after 3 months of bisphosphonate treatment. Eighteen healthy women with age from 34 to 70 served as control. Results：Serum TracpSb was significantly elevated in patients with bone metastasis compared with that in all any other groups（P〈 0.05）. The sensitivity of TracpSb was 78.13% and the specificity was 86.36%. The sensitivity of CA153 was 37.50% and the specificity was 77.27%. The sensitivity of CEA was 21.88% and the specificity was 84.09%. The serum activity of TracpSb decreased significantly（P 〈 0.05） after 3 months of bisphosphonate treatment, while the levels of CA153 and CEA were unchanged. Conclusion：Serum Tracp5b activity is a useful diagnostic marker for bone metastasis in BC patients and can be used to evaluate the treatment results of bisphosphonate.

Efficacy and safety of radiotherapy combined with zoledronic acid in the treatment of lung cancer with bone metastasis: a meta-analysis

Objective: To evaluate the efficacy and safety of radiotherapy combined with zoledronic acid fOr the treatment of bone metastases. Methods: Use Pubmed, Cochrane Library, Embase, CBM, CNKI, Wanfang, Weipu tools to search-related databases at home and abroad. From 2013.1 to March 2019, radiotherapy combined with zoledronic acid and radiotherapy alone for bone metastasis of lung cancer were collected. Experimental studies;quality evaluation and data extraction for each of the included studies, and Cochrane risk bias assessment tools for quality evaluation of the literature. Data processing was performed using RevMan 5.3 and Stata 15.0 software, including risk ratio (OR), 95% CI, I2, and P values. Line sensitivity test, publication bias evaluation is using Egger's, Bgge's method quantitative calculation using Revman 5.3 and Stata 15.0 software for statistical analysis. Results: The total of 8 articles was included, and the number of cases was 703. The results of the meta-analysis showed that the radiotherapy, combined with the zoledronic acid group was effective in the treatment of lung cancer with bone metastasis. The meta-analysis was Z = 6.31 (P < 0.00001), OR (95% CI = 3.57, (2.41, 5.30)), the difference was statistically significant. The combined effect of bone metastases was better than that of the single-stage group. The meta-analysis results were Z = 3.18 (P = 0.001) and OR (95% CI = 3.21, (1.57, 6.59)), indicating the therapeutic effect of the two groups in the treatment of bone metastases. The difference is statistically significant. Adverse reactions include: (1) bone marrow suppression, blood toxicity;(2) fever and rash;(3) nausea, vomiting, and fatigue;(4) liver damage and loss of appetite, meta-analysis results are: bone marrow suppression, blood toxicity: Z =0.73 ( P = 0.47), OR (95% CI = 0.58 (0.13, 2.54));fever, rash: Z = 0.36 (P = 0.36), OR (95% CI = 1.3 (0.31, 5.38));nausea, vomiting, Weakness: Z = 0.29 (P = 0.77), OR (95% CI = 0.85 (0.27, 2.62));liver function damage and loss of appetite: Z = 0.00 (P = 1.00), OR (95% CI = 1.00 (0.17, 6.00)). The P values of the four meta-analyses were all greater than 0.05, and the difference was not statistically significant, indicating that the addition of zoledronic acid to the bone metastasis of lung cancer did not aggravate the changes of the above four adverse reactions. Conclusion: Radiotherapy combined with the zoledronic acid group is better than the single radiotherapy group in treating pain caused by bone metastasis. It can effectively treat bone metastasis and will not aggravate the occurrence of adverse reactions.

Nanoscale Stiffness Distribution in Bone Metastasis

Nanomechanical heterogeneity is expected to have an effect on elasticity, injury and bone remodelling. In normal bone, we have two types of cells (osteoclasts and osteoblasts) working together to maintain existing bone. Bone cancers can produce factors that make the osteoclasts work harder. This means that more bone is destroyed than rebuilt, and leads to weakening of the affected bone. We report here the first demonstration of the nanoscale stiffness distribution in bone metastases before and after treatment of animals with the bisphosphonate Risedronate, a drug which is currently used for the treatment of bone metastases in patients with advanced cancers. The strategy used here is applicable to a wide class of biological tissues and may serve as a new reflection for biologically inspired scaffolds technologies.

A nanoagent for concurrent therapy of breast cancer bone metastasis and cancer-induced bone pain through SLC7A11 interruption and photodynamic therapy

Bone metastasis,a life-threatening complication of advanced breast cancer,is often accompanied by debilitating pain(cancer-induced bone pain,CIBP)that severely impairs life quality and survival.The concurrent treatment of bone metastases and CIBP remains a clinical challenge because the therapeutic options are limited.In this study,we construct a near-infrared light-activated nano-therapeutic system to meet this conundrum.In detail,sorafenib(SRF)and photosensitizer(chlorin e6,Ce6)are encapsulated into mesoporous hydroxyapatite nanoparticles(HANPs),which are further functionalized with hyaluronic acid(HA)to obtain HA-SRF/Ce6@HANPs system.The designed nanoplatform destroys tumor cells in vitro and in vivo via the synergism of SRF(interrupting the exchange of cystine/glutamate by inhibiting SLC7A11)and photodynamic therapy(PDT,inducing reactive oxygen species generation).The decrease in tumor burden and reduction of extracellular glutamate significantly attenuate CIBP in mice model with developing bone cancer.Moreover,the combination of HA-SRF/Ce6@HANPs and PDT inhibit osteoclasts activation,promote osteoblast differentiation and accelerate bone repair.Overall,the nanoagent with good biocompatibility may provide an effective therapy method for the concurrent treatment of breast cancer bone metastasis and CIBP.

Technetium-99m-methylene diphosphonate single photon emission computed tomography/computed tomography combined with prostate-specific antigen/free prostate-specific antigen ratio for bone metastasis of prostate cancer

BACKGROUND Prostate cancer(PC)is one of the most common malignant tumors in men,and bone metastasis is one of its common complications,which seriously affects the quality of life and prognosis of patients.AIM To investigate the diagnostic value of technetium-99m-methylene diphosphonate(99mTc-MDP)single photon emission computed tomography(SPECT)/CT imaging combined with the serum prostate-specific antigen(PSA)/free PSA ratio for PC bone metastasis(PCBM).METHODS One hundred patients with PC who visited the Hospital of Chengdu University of Traditional Chinese Medicine from January 2020 to January 2022 were recruited as the experimental(Exp)group,while 30 patients with benign prostatic lesions(BPLs)were recruited as the control(Ctrl)group.All patients underwent 99mTc-MDP SPECT/CT imaging and serum PSA/fPSA testing.The SPECT/CT imaging results and serum PSA/fPSA ratios of patients were analyzed to evaluate their diagnostic values for PCBM.RESULTS The difference in general information of the patients was not obvious,showing comparability.The two methods showed no visible differences in negative predictive value and sensitivity for patients with PCBM,but had great differences in positive predictive value and specificity(P<0.05).The PSA/fPSA ratio of patients with PC in the Exp group was lower than those with BPLs,and patients with PCBM had a much lower PSA/fPSA ratio than those without PC(P<0.05).The results confirmed that the combined use of 99mTc-MDP SPECT/CT imaging and serum PSA/fPSA ratio achieved a detection rate of 95%for PCBM.CONCLUSION The combination of 99mTc-MDP SPECT/CT and PSA/fPSA ratio is accurate and reliable for the diagnosis of PCBM,which provides an important reference for clinical practice.

What enlightenment has the development of lung cancer bone metastasis brought in the last 22 years

BACKGROUND Lung cancer bone metastasis(LCBM)is a disease with a poor prognosis,high risk and large patient population.Although considerable scientific output has accumulated on LCBM,problems have emerged,such as confusing research structures.AIM To organize the research frontiers and body of knowledge of the studies on LCBM from the last 22 years according to their basic research and translation,clinical treatment,and clinical diagnosis to provide a reference for the development of new LCBM clinical and basic research.METHODS We used tools,including R,VOSviewer and CiteSpace software,to measure and visualize the keywords and other metrics of 1903 articles from the Web of Science Core Collection.We also performed enrichment and proteinprotein interaction analyses of gene expression datasets from LCBM cases worldwide.RESULTS Research on LCBM has received extensive attention from scholars worldwide over the last 20 years.Targeted therapies and immunotherapies have evolved into the mainstream basic and clinical research directions.The basic aspects of drug resistance mechanisms and parathyroid hormone-related protein may provide new ideas for mechanistic study and improvements in LCBM prognosis.The produced molecular map showed that ribosomes and focal adhesion are possible pathways that promote LCBM occurrence.CONCLUSION Novel therapies for LCBM face animal testing and drug resistance issues.Future focus should centre on advancing clinical therapies and researching drug resistance mechanisms and ribosome-related pathways.

Dual ligand-targeted Pluronic P123 polymeric micelles enhance the therapeutic effect of breast cancer with bone metastases

Bone metastasis secondary to breast cancer negatively impacts patient quality of life and survival.The treatment of bone metastases is challenging since many anticancer drugs are not effectively delivered to the bone to exert a therapeutic effect.To improve the treatment efficacy,we developed Pluronic P123(P123)-based polymeric micelles dually decorated with alendronate(ALN)and cancer-specific phage protein DMPGTVLP(DP-8)for targeted drug delivery to breast cancer bone metastases.Doxorubicin(DOX)was selected as the anticancer drug and was encapsulated into the hydrophobic core of the micelles with a high drug loading capacity(3.44%).The DOX-loaded polymeric micelles were spherical,123 nm in diameter on average,and exhibited a narrow size distribution.The in vitro experiments demonstrated that a pH decrease from 7.4 to 5.0 markedly accelerated DOX release.The micelles were well internalized by cultured breast cancer cells and the cell death rate of micelle-treated breast cancer cells was increased compared to that of free DOX-treated cells.Rapid binding of the micelles to hydroxyapatite(HA)microparticles indicated their high affinity for bone.P123-ALN/DP-8@DOX inhibited tumor growth and reduced bone resorption in a 3D cancer bone metastasis model.In vivo experiments using a breast cancer bone metastasis nude model demonstrated increased accumulation of the micelles in the tumor region and considerable antitumor activity with no organ-specific histological damage and minimal systemic toxicity.In conclusion,our study provided strong evidence that these pH-sensitive dual ligand-targeted polymeric micelles may be a successful treatment strategy for breast cancer bone metastasis.

Thymic carcinoid with multiple bone metastases:A case report

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.

Contribution of Bone Scintigraphy in the Metastatic Extension Assessment of Prostate Cancer: A Study of 288 Cases in the Nuclear Medicine Department of Idrissa Pouye General Hospital, Dakar

Introduction: Prostate cancer is the most frequently diagnosed male malignancy and the fifth leading cause of cancer death in men worldwide. Since the advent of screening methods such as Prostate Specific Antigen (PSA) assay, digital rectal examination (DRE) and prostate biopsy, its incidence has increased significantly. The aim of our study was to analyse aspects of bone scintigraphy (BS) as part of the metastatic extension assessment of prostate cancer in Senegal. Patients and Methods: This was a retrospective descriptive and analytical study, running from January 1er 2022 to August 31 2023. Patients with histologically confirmed prostate cancer were included. Whole-body scans (WBS) were performed using a dual-head SPECT gamma camera (Mediso Nucline TM Spirit DH-V type), 3 hours after intravenous injection of 8 MBq/kg (555 to 740 MBq) of 99mTc-HMDP. Results: A total of 288 patients with a mean age of 68.37 ± 7.79 years were included. The median total PSA level was 97.6 ng/ml, with 144 patients having a level greater than or equal to 20 ng/ml. All patients had adenocarcinoma, and the Gleason score was available in 202 (70.13%) patients, 75.75% of whom had a score greater than or equal to 7. BS was contributory in 70.48% of cases, with 30.90% positive and 39.58% negative. The result was inconclusive in 85 patients (29.51%). The mean PSA for patients with a positive scan was 190.2 ng/ml and 40.6 ng/ml for those with a negative scan. Multiple metastatic lesions predominated (87.35% of cases). Metastatic lesions occurred preferentially in the axial skeleton, with a proportion of 68% versus 32% in the appendicular skeleton. Classification of bone metastases according to the SOLOWAY score revealed grade I (62.07%), grade II (35.63%) and grade IV (2.30%). Conclusion: In Senegal, prostate cancer is generally diagnosed in men of advanced age. The presence of bone metastases is frequent in its evolution, transforming a curable localized disease into a generalized disease with a compromised prognosis. Bone scintigraphy remains an essential part of the initial work-up and evaluation of response to treatment.

U-Net Based Dual-Pooling Segmentation of Bone Metastases in Thoracic SPECT Bone Scintigrams

In order to enhance the performance of the CNN-based segmentation models for bone metastases, this study proposes a segmentation method that integrates dual-pooling, DAC, and RMP modules. The network consists of distinct feature encoding and decoding stages, with dual-pooling modules employed in encoding stages to maintain the background information needed for bone scintigrams diagnosis. Both the DAC and RMP modules are utilized in the bottleneck layer to address the multi-scale problem of metastatic lesions. Experimental evaluations on 306 clinical SPECT data have demonstrated that the proposed method showcases a substantial improvement in both DSC and Recall scores by 3.28% and 6.55% compared the baseline. Exhaustive case studies illustrate the superiority of the methodology.

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

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.

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

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.

Brucine Inhibits Bone Metastasis of Breast Cancer Cells by Suppressing Jagged1/Notch1 Signaling Pathways

Objective： To examine the effects of brucine on the invasion, migration and bone resorption of receptor activator of nuclear factor-kappa B ligand（RANKL）-induced osteoclastogenesis. Methods： The osteoclastogenesis model was builded by co-culturing human breast tumor MDA-MB-231 and mouse RAW264.7 macrophages cells. RANKL（50 ng/m L） and macrophage-colony stimulating factor（50 ng/m L） were added to this system, followed by treatment with brucine（0.02, 0.04 and 0.08 mmol/L）, or 10 μmol/L zoledronic acid as positive control. The migration and bone resorption were measured by transwell assay and in vitro bone resorption assay. The protein expressions of Jagged1 and Notch1 were investigated by Western blot. The expressions of transforming growth factor-β1（TGF-β1）, nuclear factor-kappa B（NF-κB） and Hes1 were determined by enzyme-linked immunosorbent assay. Results： Compared with the model group, brucine led to a dose-dependent decrease on migration of MDA-MB-231 cells, inhibited RANKL-induced osteoclastogenesis and bone resorption of RAW264.7 cells（P 〈0.01）. Furthermore, brucine decreased the protein levels of Jagged1 and Notch1 in MDA-MB-231 cells and RAW264.7 cells co-cultured system as well as the expressions of TGF-β1, NF-κB and Hes1（P〈0.05 or P〈0.01）. Conclusion： Brucine may inhibit osteoclastogenesis by suppressing Jagged1/Notch1 signaling pathways.

Clinicopathological features and treatment of extremity bone metastasis in patients with endometrial carcinoma： a case report and review

Unlike other non-gynecologic solid tumors, such as breast cancer, lung cancer, metastasis to bone from endometrial carcinoma is rare, metastasis to extremity is extremely rare. We report a 51-year-old multiparous woman with FIGO Stage IVb Grade 2 endometrial adenocarcinoma which metastasized to left lower extremity bone. She received an amputation of left lower extremity below the knees, and a total abdominal hysterectomy and bilateral salpingo-oophorectomy, and followed by systemic chemotherapy, radiation therapy to the pelvis and progestational agent. She had a complete response to above treatments, and disease-free survival for 10 months. After recurrence, she received chemotherapy, radiotherapy and progestational agent once again. She had lived 56 months and is still alive by the time of report. Metastasis of endometrial carcinoma to extremity bone can rarely occur and should be considered when the patient with endometrial carcinoma complained of unexplained pain and swelling associated with extremity bone.

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

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.