The characteristics of bone disseminated cells of 4T1 / 药学学报

Based on bone metastasis potential of mouse breast cancer 4T1 cells, the bone disseminated breast tumor cells 4T1 (B-4T1) were acquired through the screening of 6-mercaptopurine. The characteristics of B-4T1 were studied by morphological observation, proliferation assay, expression of epithelial and mesenchymal cell markers detection, transcriptome sequencing, and tumor formation experiments. The results showed that B-4T1 was round and spindle-shaped than primary 4T1 cells, and its proliferation rate was reduced, as well as epithelial cell adhesion molecule (EpCAM) and E-cadherin expression. The transcript level of N-cadherin was increased in the B-4T1, but not vimentin, indicating that B-4T1 had partial epithelial mesenchymal transition. Besides, B-4T1 had higher fatty acid metabolism and better tumor formation capacity. This study lays the experimental foundation for the basic study of metastasis in breast cancer. All animal experiments in this paper were conducted in accordance with the standards of the Animal Ethics Committee of China Pharmaceutical University.

Metástasis falángica en dedo anular derecho en paciente con antecedente de cáncer de colon etapa IV

Objetivo: Reportar un caso clínico de acrometástasis de cáncer de colon. Materiales y Métodos: Se obtiene información de la ficha clínica electrónica. Se realiza revisión de literatura, utilizando los términos "acrometastasis", "metástasis óseas", "metástasis en la mano", "metástasis en falanges". Resultados: Se presenta el caso de un paciente con antecedente de cáncer de colon sigmoides etapa IV sometido a resección de metástasis hepáticas, quimioterapia y radioterapia. Consulta por lesión ulcerada en dedo anular derecho, cuya biopsia indica metástasis de adenocarcinoma de colon. Se realiza amputación transfalángica proximal con biopsia que confirma diagnóstico. Discusión: Las metástasis en mano dan cuenta del 0,0070,2% de todas las metástasis a distancia. Se presentan como aumento de volumen doloroso de aspecto granulomatoso o asociado a ulceración con empeoramiento progresivo. El tratamiento tiene por objetivo el manejo del dolor y la preservación de la funcionalidad de la extremidad. Conclusión: El adenocarcinoma de colon, raramente, da metástasis falángicas. Corresponden a una manifestación tardía de la enfermedad con una alta tasa de mortalidad a 6 meses asociada. Se deben considerar como diagnóstico diferencial en pacientes oncológicos.

Objective: To report a clinical case of achrometastases of colon cancer. Materials and methods: Information is obtained from the electronic medical record. A literature review is performed, using the terms "achrometastases", "bone metastases", "hand metastases", "phalangeal metastases". Results: We present the case of a patient with a history of stage IV sigmoid colon cancer who underwent resection of liver metastases, chemotherapy and radiotherapy. Consultation due to an ulcerative lesion on the right ring finger, whose biopsy indicated colon adenocarcinoma metastases. Proximal transphalangeal amputation is performed with biopsy confirming diagnosis. Discussion: Hand metastases account for 0.007-0.2% of all distant metastases. They present as a painful increase in volume with a granulomatous appearance or associated with progressively worsening ulceration. The treatment aims to manage pain and preserve the functionality of the limb. Conclusion: Colon adenocarcinoma rarely gives phalangeal metastases. They correspond to a late manifestation of the disease with a high associated 6-month mortality rate. They should be considered as a differential diagnosis in cancer patients.

Factores pronósticos de metástasis ósea en pacientes con cáncer de próstata / Predictive factors for bone metastasis in patients with prostate cancer i: en

El adenocarcinoma de próstata es considerado una de las neoplasias más frecuentes en hombres mayores de 60 años, y su metástasis ósea constituye una de las complicaciones de peor pronóstico. Objetivo: Estimar los factores pronósticos de metástasis ósea en pacientes con cáncer de próstata. Métodos: Se realizó un estudio analítico de 73 pacientes con cáncer de próstata, asistidos en el Hospital Oncológico Conrado Benítez de Santiago de Cuba en el período 2018-2022. Entre las variables analizadas figuraron: edad, color de la piel, manifestaciones clínicas, tiempo de aparición de la metástasis ósea, grado de diferenciación celular, nivel de antígeno prostático específico y diagnóstico imagenológico. Resultados: En la serie predominó el grupo etario de 60-69 años (50,7 %) y el promedio de edad fue de 67 años; asimismo, prevalecieron los pacientes de piel negra, el dolor óseo como síntoma más frecuente y el diagnóstico imagenológico de metástasis ósea por tomografía axial computarizada (48,0 %). Se observó un aumento proporcional de los valores del antígeno prostático específico y de la puntuación de Gleason en relación con la aparición de metástasis. Conclusiones: Los factores pronósticos que permiten estimar la presencia de metástasis ósea en pacientes con cáncer de próstata son la edad avanzada, el color negro de la piel y los valores de antígeno prostático específico por encima de 20 ng/mL.

Prostate adenocarcinoma is considered one of the most frequent neoplasms in men over 60 years, and bone metastasis constitutes one of the complications with the worst prognosis. Objective: Estimate the predictive factors for bone metastasis in patients with prostate cancer. Methods: An analytic study of 73 patients with prostate cancer was carried out. They were assisted at Conrado Benítez Cancer Hospital in Santiago de Cuba during 2018-2022. The variables analyzed included: age, skin color, clinical manifestations, onset time of bone metastasis, degree of cellular differentiation, prostate-specific antigen level and imaging diagnosis. Results: In the series there was a prevalence of the 60-69 age group (50.7%) and the average age was 67 years; also, dark skinned patients, bone pain as more frequent symptom and imaging diagnosis of bone metastasis by computerized axial tomography prevailed (48.0%). A proportional increase of prostate-specific antigen values and Gleason punctuation was observed in relation to the metastasis onset. Conclusions: The predictive factors for estimating the presence of bone metastasis in patients with prostate cancer are the advanced age, black skin color and prostate-specific antigen values above 20 ng/mL.

Uso de imágenes KV CBCT del acelerador lineal Halcyon para la planificación de tratamientos de metástasis óseas con intensión paliativa / Use of KV CBCT images from the Halcyon linear accelerator for treatment planning of bone metastases with palliative intent

Las nuevas tecnologías para el tratamiento del cáncer con radiación ionizante tienen especial interés en mejorar la calidad de las imágenes para el posicionamiento adecuado del paciente con sistemas de radioterapia guiada por imagen IGRT. El sistema Halcyon cuenta con imágenes de tomografía computarizada de haz de cono CBCT. Estas imágenes podrían ser una opción para escenarios donde no se cuente con una Tomografía Computarizada CT o el equipo se encuentre en reparación o mantenimiento especialmente para escenarios de intensión paliativa. La diferencia en la distribución de dosis en imágenes CT y CBCT fue analizada en este estudio. Los resultados mostraron diferencias en las unidades Hounsfield UH, aunque no fueron estadísticamente significativas, el volumen irradiado mostro diferencias máximas de 3,92% que no supera el 4% permitido para tratamientos de intensión paliativa. En cuanto a las dosis dispersas al tejido sano la diferencia tampoco supera el 4%. Nuestro estudio mostro que las imágenes CBCT pueden ser una alternativa para el tratamiento de metástasis óseas, sin embargo, estas imágenes todavía no pueden remplazar las imágenes CT utilizadas para el cálculo de dosis en radioterapia

New technologies for the treatment of cancer with ionizing radiation are of particular interest in improving image quality for proper patient positioning with image-guided radiation therapy IGRT systems. IGRT image-guided radiation therapy systems. The Halcyon system features cone beam computed tomography CBCT imaging. These images could be an option for scenarios where a CT scan is not available or the equipment is under repair or maintenance especially for is under repair or maintenance, especially for palliative scenarios. The difference in the The difference in dose distribution in CT and CBCT images was analyzed in this study. The results showed differences in Hounsfield UH units, although not statistically significant, the irradiated volume showed maximum differences of 3.92%, which is the maximum difference of 3.92%. Differences of 3.92%, which does not exceed the 4% allowed for palliative treatments. As for the doses dispersed to healthy tissue the difference does not exceed the 4% allowed for palliative treatments. Our study showed that CBCT imaging can be an alternative for the treatment of metastases. an alternative for the treatment of bone metastases, however, these images cannot yet replace the CT images used for dose calculation. CT images used for dose calculation in radiotherapy

Association of bone lesions distribution with prognosis in renal cell carcinoma bone metastasis / 中华泌尿外科杂志

Objective:To investigate the association between bone lesions distribution and survival outcome and prognostic risk stratification in renal cell carcinoma bone metastasis (RCC-BM).Methods:The data of 122 RCC-BM patients admitted to Peking University People's Hospital between January 2009 and December 2019 were retrospectively reviewed. There were 100 males and 22 females, with a baseline age of (59.87±11.33) years old. According to the Memorial Sloan-Kettering Cancer Center (MSKCC)/Motzer score, patients were stratified into different risk groups using profiles at first bone metastasis diagnosis, with 20 (16.4%), 74 (60.6%) and 28 (23.0%) patients in favorable, intermediate and poor group, respectively. The spatial distribution of bone metastasis was investigated at the first bone metastasis diagnosis. The overall distribution patterns were as follows: locoregional group (lesions only involved thoracic and/or lumbar vertebrates) in 26 cases (21.3%), stochastic group (bone lesions randomly distributed) in 69 cases (56.6%), extensive group (with concomitant visceral metastasis) in 27 cases (22.1%). Metastatic site involvement was as follows: spine in 48 cases(39.3%), pelvis in 43 cases (35.2%), upper extremities in 22 cases (18.0%), and lower extremities in 20 cases (16.4%). Half (61 cases) of the enrolled patients had synchronous bone metastasis as their first bone metastases were diagnosed simultaneously with their renal tumors. Of all the patients, 99 (81.1%) accepted radical nephrectomy, 6 (4.9%) accepted partial nephrectomy, and the other 17 patients (13.9%) accepted the treatment of ablation or embolization. Eighty-two patients (67.2%) received definitive treatment for bone metastatic lesions, respectively. Forty patients (32.8%) accepted the palliative tumor reduction therapy. Thirty-two patients (26.2%) received tyrosine kinase inhibitor (TKI) or immune checkpoint inhibitor (ICI) medication, and 12 patients (9.8%) received local radiotherapy. Distribution variation and therapeutic strategies throughout the disease course until the last follow-up were recorded. Univariate analysis (chi-squared test, Mantel-Haenszel test), Kaplan-Meier survival analysis, and multivariate ordinal logistic regression were performed for the possible association.Results:Patients from the locoregional group (30.8%, 8/26) were prone to have higher risk stratification at first diagnosis than patients in the stochastic and extensive groups ( 20.8%, 20/96, P=0.107) as the marginal difference was found. At first bone metastasis diagnosis, RCC-BM patients with spinal involvement were more likely to have higher MSKCC risk stratification than those without spinal involvement [20.3%(15/48) vs. 17.6%(13/74), P<0.05]. Multivariate ordinal logistic regression showed that after adjusting for general data, bone metastasis sites, and concomitant visceral metastasis, RCC-BM patients with spinal involvement at first bone metastasis diagnosis were 3.3 times (95% CI 1.195-9.091, P<0.05)more likely to fall into the higher MSKCC risk group than those without spinal involvement.In those 93 cases with follow-up records, 20 (21.5%), 53 (57.0%), and 20 (21.5%) cases were in the locoregional group, stochastic group, and extensive group, respectively. The median overall survival time (mOS) of patients with pelvic involvement (36 cases) throughout the disease course was 32.0 months (95% CI 6.0-58.0), which was shorter than that of patients without pelvic involvement (57 cases, mOS 49.0 months, 95% CI 20.4-77.5, P<0.05). Conclusions:Spinal involvement (especially limited to thoracic and/or lumbar vertebrates) at first bone metastasis diagnosis and pelvic involvement throughout the disease course were associated with poor prognosis.

Application of radium-223 combined with new-generation hormonal agents in bone metastatic of prostate cancer / 中华泌尿外科杂志

Objective:To investigate the efficacy and safety of radium-223 in combination with new-generation hormonal agents in patients with bone metastases of prostate cancer.Methods:The clinical data of 17 patients (12 from the First Affiliated Hospital of Airforce Military Medical University and 5 from Xi'an International Medical Center Hospital) with metastatic castration-resistant prostate cancer(mCRPC) treated by radium-223 combined with new-generation hormonal agents from January 2021 to June 2022 were retrospectively analyzed. In all cases, the average age was (73.3±8.5) years old. Before treatment, the median prostate-specific antigen (PSA) was 15.7 (3.2, 36.5) ng/ml, the median alkaline phosphatase (ALP) was 131.5 (79.0, 430.7) U/L. All patients had ≥ 2 bone metastases but no visceral or lymph node metastases. The median number of bone scan lesions was 10(8, 15). Bone pain symptom was present in 16(94.1%) patients. There were 9 cases (52.9%) with Eastern Cooperative Oncology Group (ECOG) score of ≥2, 1 case (5.9%) with ECOG score of 1 and 6 cases (35.2%) with ECOG score of 0. All patients were treated with radium-223 (55 kBq/kg, injected every 4 weeks for a maximum of 6 cycles), of which 5 patients were combined with enzalutamide, 8 patients combined with apatamide and 4 patients combined with bicalutamide. PSA response (PSA decreased by ≥30% from baseline and maintained for at least 1 month), ALP response (ALP decreased by ≥30% from baseline and maintained for at least 1 month) and pain relief rates were analyzed. Imaging evaluation was performed before and after treatment to calculate the objective response rate of metastases. The incidence of treatment-related adverse effects and skeletal related event (SRE) were also recorded.Results:Eleven patients completed 6 courses, 3 patients completed 5 courses and 3 patients completed ≥4 courses. The median ALP after 1 month of last treatment was 83.2 (51.5, 126.5) U/L, which was significantly decreased than baseline. 12 patients (70.6%) showed an ALP response and the other 5 (29.4%) showed varying degrees of ALP elevation. PSA response was observed in 4 patients (23.5%), of which 2 (11.8%) had a continuous decrease and 2 (11.8%) had a late-stage increase in PSA. Pain relief was relieved in 15 cases (88.2%) during treatment, 1 case (5.9%) had worsening pain due to disease progression and 1 case (5.9%) had no change during treatment. The ECOG score decreased in 15 (88.2%) patients. The median number of bone metastases in patients decreased to 5 (4, 9). One patient (5.9%) had complete remission during treatment, 11 patients (64.7%) had a partial response, 4 patients (23.5%) were stable, and 1 (5.9%) showed imaging progression after 4 months of treatment. The overall objective remission response rate was 70.5% (12/17). Treatment-related hematologic adverse effects included anemia (1 case, 5.9%, grade 3), thrombocytopenia (1 case, 5.9%, grade 3) and leukopenia (1 case, 5.9%, grade 2). Non-hematologic adverse effects included fatigue (3 cases, 17.6%, 2 cases in grade 1, 1 case in grade 2), gastrointestinal bleeding (1 case, 5.9%, grade 3), diarrhea (1 case, 5.9%, grade 2) and fever (1 case, 5.9%, grade 1). Patients with grades 1 to 2 relieved with symptomatic management. Three cases (17.6%) were discontinued due to intolerance of grade 3 adverse reactions and 1 case (5.9%) terminated on its own. There was no SRE during treatment and follow-up.Conclusions:Radium-223 combined with New-generation hormonal agents has a high objective remission rate in patients with mCRPC, which could provide pain relief and improve quality of life. The incidence of adverse reactions was low and well tolerated.

Theraputic Effect and Quality of Life Assessment in Patients with Neuropathic Pain Due to Bone Metastasis from Hepatocellular Carcinoma Treated with Radiotherapy and Pregabalin / 肿瘤防治研究

Objective To evaluate the short-term efficacy and quality of life of primary hepatocellular carcinoma patients after radiotherapy and pregabalin treatment for neuropathic pain with bone metastasis. Methods 32 patients with primary hepatocellular carcinoma bone metastases were treated with radiotherapy combined with pregabalin treatment.Then, we prospectively studied the analgesic efficacy for neuropathic pain and quality of life, used the brief pain inventory and douleur neuropathique 4 questionnaire (DN4) to evaluate pain at baseline, one and two months after radiotherapy, assessed pain response using the international consensus endpoint definition of bone metastasis, and used European Organization for Research and Treatment of Cancer Research and Treatment Quality of Life Questionnaire (EORTC QLQ-C30) and bone metastasis module (QLQ-BM22) for quality of life assessment. Results One and two months after radiotherapy, the average DN4 score of neuropathic pain decreased, and the objective pain relief rates were 62.8% and 68.6%, respectively.The physical, emotional, social, and role functional scores of EORTC QLQ-C30 functional scale significantly increased in the first month after radiotherapy.Symptom scale of pain (P=0.015), insomnia (P=0.035), and loss of appetite (P=0.022) improved, and fatigue was aggravated (P < 0.05).Two months after radiotherapy, the mean overall health score and all functional scale scores significantly increased than those at baseline.The scores of all symptom scales decreased, except fatigue, constipation, and financial difficulties (P < 0.05).In addition, pain responders showed significant improvement in emotional function (P=0.025) and physical function (P=0.029) in the functional scale and in pain (P=0.014) and fatigue (P=0.035) in the symptom scale.The QLQ-BM22 score showed that the painful sites (P=0.021) and pain characteristics (P=0.04) of the responders significantly improved compared with those of nonresponders two months after radiotherapy. Conclusion Radiotherapy combined with pregabalin can relieve neuropathic pain caused by bone metastasis from primary hepatocellular carcinoma and greatly improve the quality of life, particularly in pain responders.

Approach for Advanced Cancer Patients with Bone Metastases by the Bone Metastasis Board: A Single-institution Retrospective Study

Prevention, early diagnosis, and early treatment of skeletal-related events (SREs) are important in the treatment of potential or current cases of bone metastasis. In August 2020, our hospital established the bone metastasis team and the bone metastasis board (BMB) started actively engaging in activities aimed at improving the outcome of bone metastasis. We retrospectively examined whether a combined modality therapy started in the diagnosis of bone metastases could prevent the onset of SREs and whether it could prolong survival and improve activities of daily living. The 75 advanced cancer patients who underwent BMB at our hospital from August 1, 2020 to July 31, 2022 were divided into two groups according to when BMB performed before and after SREs for comparative analysis. Numerical Rating Scale improved, however Performance Status did not improve in both groups, and there was no difference in survival between the both groups (15.3 vs. 9.0 months, HR: 0.74, 95%; CI: 0.42–1.29, p=0.29). In conclusion, patients who suffered from SREs from the time of bone metastasis diagnosis were treated early. However, the incidence of SREs after BMB in our hospital was 22.6%, and it is necessary to actively work to prevent SREs in the future.

Effect of Bushen Huoxuetang on Expression of Bax/Bcl-2 and Cleaved Caspase-3 in Nude Mice with Bone Metastasis of Breast Cancer / 中国实验方剂学杂志

ObjectiveTo study the effect of Bushen Huoxuetang on the apoptosis and the expression of B-cell lymphoma （Bcl-2）-associated X protein （Bax）/ Bcl-2 and cleaved cysteine-containing aspartate proteolytic enzyme-3 （cleaved Caspase-3） in the nude mouse model of bone metastasis of breast cancer， and explore the mechanism of Bushen Huoxuetang in inhibiting bone destruction. MethodThirty BALB/c female nude mice were randomly assigned into blank group （n=6） and model group （n=24）. The suspension of 4T1 breast cancer cells was injected into the tibia of mouse right lower limb to establish model of bone metastasis of breast cancer. The successfully modeled nude mice were randomly assigned into model group， Bushen Huoxuetang group， zoledronic acid group， and combined drug group， with 6 mice in each group. Bushen Huoxuetang was administrated at a dose of 36.67 g·kg-1， once a day， and zoledronic acid was administrated by subcutaneous injection at a dose of 100 μg·kg-1， twice a week. The combined drug group was administrated with the same doses of Bushen Huoxuetang group by gavage and zoledronic acid by subcutaneous injection. The mice in the blank group and the model group were administrated with the same volume of distilled water by gavage for 14 days. On the next day at the end of drug administration， the mice were sacrificed by cervical dislocation. The general situation and weight changes of the mice were examined. The right lower limb was collected， and X-ray scanning and hematoxylin-eosin （HE） staining methods were used for observation of pathological changes in the bone. The terminal deoxynucleotidyl transferase dUTP nick-end labeling （TUNEL） was employed to detect the apoptosis of bone tissue in nude mice， and Western blot to determine the expression of Bax/Bcl-2 and cleaved Caspase-3 in the bone tissue. ResultCompared with the blank group， the modeling reduced the body weight （P<0.01） and increased the right lower limb weight of the nude mice （P<0.01）. Compared with the model group， Bushen Huoxuetang， zoledronic acid， and their combination increased the body weight （P<0.01） and decreased the right lower limb weight （P<0.01）. Compared with the blank group， the other groups showed obvious tumor cell atypia， deep nuclear staining， and clear bone metastasis， and the model group showed obvious osteolytic damage in right lower limb and loss of proximal tibia and knee joint. Compared with the model group， Bushen Huoxuetang， zoledronic acid， and their combination reduced the osteolytic lesions in the right lower limb and recovered part of the bone structure， demonstrating an inhibitory effect on bone destruction. The TUNEL assay showed that the model group had lower apoptosis rate of bone metastatic tumor cells than the blank group， Bushen Huoxuetang group， zoledronic acid group， and combined drug group （P<0.01）. Compared with the blank group， the modeling down-regulated the expression of Bax and cleaved Caspase-3 （P<0.01） and up-regulated the expression of Bcl-2 （P<0.01）. Compared with the model group， Bushen Huoxuetang， zoledronic acid， and their combination up-regulated the expression of Bax （P<0.01） and cleaved Caspase-3 （P<0.05， P<0.01） and down-regulated the expression of Bcl-2 （P<0.05， P<0.01）. ConclusionBushen Huoxuetang may inhibit bone destruction in the nude mouse model of bone metastasis of breast cancer by up-regulating the expression of Bax， down-regulating the expression of Bcl-2， activating cleaved Caspase-3， and further inducing apoptosis.

Isolated metastasis of the ascending ramus of the mandible of thyroid follicular carcinoma: a case report / 临床耳鼻咽喉头颈外科杂志

The mandibular metastatic spread of carcinoma from the thyroid gland is exceedingly rare. Follicular thyroid carcinoma is the second most common type of thyroid carcinoma，accounting for approximately 10% to 15% of all thyroid cancers. The prognosis of FTC is relatively satisfactory. Due to its rich blood transport, it is easy to metastasize hematological, with the main sites of metastasis are bone and lung. However，mandibular metastasis of thyroid follicular carcinoma is rare. We report a case of thyroid follicular carcinoma that metastasized to the ascending ramus of the mandible 21 years after surgery.The operation was successfully completed, and there was no recurrence during postoperative follow-up. Due to the absence of obvious clinical symptoms in the patient, the diagnosis and treatment were challenging. We have provided detailed radiographic and pathological images to facilitate understanding and discussion of the disease.

Pathogenesis of Bone Metastasis-caused Pain and Its Prevention and Treatment with Traditional Chinese Medicine： A Review / 中国实验方剂学杂志

Bone metastasis-caused pain （BMP） is a common complication of cancer， and the incidence has been on the rise with the increase in the overall prevalence of cancer， threatening the survival and quality of life of patients. BMP is a kind of special pain with the characteristics of inflammatory pain and neuropathic pain， but is different from the two. Therefore， its pathogenesis is very complicated， and it is of great significance to understand the pathogenesis. The currently available studies mainly focused on osteoclast activation， changes in the bone microenvironment， glial cell activation， spinal cord neuron activation， and miRNA dysregulation. Modern therapies include the three-step analgesics， bisphosphonates， palliative radiotherapy， and interventional therapy for bone metastases， which show definite efficacy in short term. However， the long-term effect is unsatisfactory due to the adverse reactions， addiction， and drug resistance. Studies have shown that traditional Chinese medicine （TCM） has definite curative effect on BMP， which is safe， enhances efficacy， reduces toxicity， and boosts immunity. Moreover， it exerts the effect through multiple components， multiple targets， and multiple pathways. As a result， it has unique advantages in the prevention and treatment of BMP and has become a research focus. This paper summarizes the research on the pathogenesis of BMP， the intervention of TCM （compound Chinese medicine prescriptions， Chinese medicinals， and monomers from Chinese medicinals）， and the mechanisms of TCM， such as inhibiting osteoclast activation， glial cell activation， and spinal cord neuron activation， regulating pain mediators and abnormal expression of microRNA， and anti-tumor， which is expected to further clarify the pathogenesis of BMP and provide ideas and methods for the effective prevention and treatment of BMP with TCM.

Correlation of Systemic Immune Inflammatory Index and Tumor Markers with Bone Metastasis of Lung Cancer / 肿瘤防治研究

Objective To evaluate the value of the systemic immune-inflammatory index (SII), CEA, Cyfra21-1, and NSE in predicting and diagnosing bone metastasis of lung cancer. Methods The clinical data of 618 patients with lung cancer were retrospectively analyzed. According to the bone metastasis at baseline, the data of the diagnosis group (patients with bone metastasis at baseline and patients without bone metastasis during follow-up) and the prediction group (patients with bone metastasis during follow-up and patients without bone metastasis during follow-up) were analyzed to determine the correlation between the above indicators and lung cancer bone metastasis. Results Predictive group: SII≥850 and NSE≥58.64 ng/ml were independent risk factors and independent predictors for lung cancer bone metastasis. The AUC of the combined SII+NSE model was 0.662, with a sensitivity of 54.5% and a specificity of 74.5%; it was superior to the predictive value of single factor (95%CI: 0.596-0.728; P < 0.001). Diagnostic group: lung adenocarcinoma, SII≥951.6, CEA≥5.14 ng/ml, NSE≥20.15 ng/ml, and Cyfra21-1≥3.94 ng/ml were independent risk factors for bone metastasis in lung cancer patients (P < 0.05). The AUC of SII alone in the diagnosis of lung cancer bone metastasis was 0.754. The AUC of the SII+Cyfra21-1 combined model was 0.82 which was the largest, with a sensitivity of 74% and a specificity of 78.5%; it was superior to any univariate AUC (P < 0.05). Conclusion The levels of SII, CEA, Cyfra21-1, and NSE in the bone metastasis group are significantly higher than those in the non-bone metastasis group. The predictive and diabnostic values would be improved further when SII combined with other single risk factors.

Diagnostic Value of Serum LncRNAs for Bone Metastasis in Lung Cancer / 肿瘤防治研究

Objective To investigate the expression of lncRNA HOTAIR, HOTAIR, CRNDE and AFAP1-AS1 in lung cancer patients with bone metastasis (LCWBM), and to elucidate the diagnostic value of lncRNAs for LCWBM. Methods Serum was collected from 38 LCWBM patients and 38 lung cancer without bone metastasis (LCWOBM) patients. Questionnaires were used to collect basic information of patients. Fasting peripheral venous blood of patients was collected to separate serum. qRT-PCR was used to measure the expression levels of four serum lncRNAs, and their diagnostic value for LCWBM was analyzed. Results The expression of serum HOTAIR was decreased in LCWBM patients, compared with LCWOBM patients (P < 0.05); the AUC of serum HOTAIR diagnosing LCWBM was 0.722 (sensitivity was 70.0%, specificity was 81.3%). And the level of serum HOTTIP was significantly increased in LCWBM patients, compared with LCWOBM patients (P < 0.05); AUC of serum HOTTIP diagnosing LCWBM was 0.784 (sensitivity was 100.0%, specificity was 45.5%). The AUC of serum HOTAIR combined with HOTTIP diagnosing LCWBM was 0.818 (sensitivity, specificity, positive predictive value and negative predictive value were 87.5%, 72.7%, 70.0% and 88.9%, respectively). Conclusion Serum lncRNA HOTAIR and HOTTIP might be potential diagnostic biomarkers for bone metastases in lung cancer patients.

Analysis of clinical features and prognostic factors of neuroblastoma with bone metastasis in infants / 中华实用儿科临床杂志

Objective:To summarize the clinical features of neuroblastoma (NB) with bone metastasis in infants and the prognostic factors.Methods:A retrospective analysis was performed on 32 patients aged ≤12 months who were enrolled in Beijing Children′s Hospital, Capital Medical University from January 2010 to December 2019 and had imaging findings suggesting signs of distant bone metastasis.The control group was included NB children, aged ≤12 months, who were admitted to Beijing Children′s Hospital, Capital Medical University during the same period, without signs of distant bone destruction.The clinical manifestations and auxiliary examinations of infants with bone metastasis were summarized, and the efficacy evaluation and survival analysis of infants with regular treatment and follow-up were conducted until December 31, 2020. Kaplan- Meier survival analysis was used for prognostic analysis, and Log Rank test was used for univariate prognostic analysis. Results:There were 32 NB infants with bone metastases, involving 12 males (37.5%) and 20 females (62.5%), accounting for 16.0% (32/200 cases) of infants diagnosed with NB du-ring the same period.The median age of onset was 9 (4.5-12.0) months.The main primary site included the retroperitoneal and adrenal region in 24 cases(75.0%) and mediastinum in 3 cases (9.4%). Among the 32 cases, 14 cases (43.8%) had simple bone metastasis, 19 cases (59.4%) had distant lymph nodes, 18 cases (56.3%) had bone marrow, and 3 cases (9.4%) had intracranial and meningeal metastasis.Bone metastasis mainly occurred in the skull, with 11 cases of single bone metastases and the remaining with 2 or more bone metastases.Compared with 168 NB infants without bone metastasis, the prognosis of those with bone metastasis was significantly worse [3-year overall survival(OS) rate 97.6% vs.82.7%, P=0.001]. Univariate analysis showed that the prognosis of NB children with bone marrow metastasis, meningeal and intracranial metastasis, MYCN gene amplification, and high-risk group was poor (all P<0.05). Two patients returned to the local hospital for treatment after diagnosis.A total of 30 children were recruited for efficacy evaluation and prognostic analysis.Twenty-nine children underwent surgery, of which 6 cases received surgery before chemotherapy and 23 cases received surgery after chemotherapy.One case received chemotherapy only.The mean course of chemotherapy was 6.2 (4-13) times.One case was treated with radiotherapy, 1 case was treated with Metaiodobenzylguanidine (MIBG) therapy, and 1 case was treated with stem cell transplantation.A total of 18 cases (62.1%) event-free survived, and 12 cases (40.0%) had a mean event at 7 (1.5-32.0) months.Among them, 7 cases survived and 5 cases died (16.7%). The expected 3-year event-free survival rate and OS rate were 57.1% and 82.7%, respectively. Conclusions:The most common sites of infant NB metastasis are bone and bone marrow, and the most common sites of bone metastasis are skull.Infants with bone metastasis had a worse prognosis than those without bone metastasis, and infants with bone and bone marrow metastasis had a worse prognosis than infants with single bone metastasis.

The osteogenic niche-targeted arsenic nanoparticles prevent colonization of disseminated breast tumor cells in the bone

Up to 70% of patients with late-stage breast cancer have bone metastasis. Current treatment regimens for breast cancer bone metastasis are palliative with no therapeutic cure. Disseminated tumor cells (DTCs) colonize inside the osteogenic niches in the early stage of bone metastasis. Drug delivery into osteogenic niches to inhibit DTC colonization can prevent bone metastasis from entering its late stage and therefore cure bone metastasis. Here, we constructed a 50% DSS6 peptide conjugated nanoparticle to target the osteogenic niche. The osteogenic niche was always located at the endosteum with immature hydroxyapatite. Arsenic-manganese nanocrystals (around 14 nm) were loaded in osteogenic niche-targeted PEG-PLGA nanoparticles with an acidic environment-triggered arsenic release. Arsenic formulations greatly reduced 4T1 cell adhesion to mesenchymal stem cells (MSCs)/preosteoblasts (pre-OBs) and osteogenic differentiation of osteoblastic cells. Arsenic formulations also prevented tumor cell colonization and dormancy via altering the direct interaction between 4T1 cells and MSCs/pre-OBs. The chemotactic migration of 4T1 cells toward osteogenic cells was blocked by arsenic in mimic 3D osteogenic niche. Systemic administration of osteogenic niche-targeted arsenic nanoparticles significantly extended the survival of mice with 4T1 syngeneic bone metastasis. Our findings provide an effective approach for osteogenic niche-specific drug delivery and suggest that bone metastasis can be effectively inhibited by blockage of tumor cell colonization in the bone microenvironment.

Efficacy and safety of radium-223 in 48 patients with bone metastatic castration resistant prostate cancer / 中华泌尿外科杂志

Objective:To observe the efficacy and safety of radium-223 in metastatic castration resistant prostate cancer (mCRPC) with bone metastasis.Methods:The clinical data of 48 patients with mCRPC treated with radium-223(55 kBq/kg, once every 4 weeks, planned to use for 6 cycles)from February 2021 to May 2022 were analyzed retrospectively. All patients had symptomatic bone metastasis without visceral metastasis, which the number of bone metastasis was more than one site.They were all classified as IVb stage. The average age was 70.5 (ranging 49-90) years. The median PSA was 44.70(ranging 0.15-1 864.00) ng/ml. The median ALP was 162 (ranging 43-1 589) U/L. The median time from mCRPC diagnosis to radium-223 use was 10 (ranging 3-47) months. 9, 18 and 11 patients had received first-line, second-line and third-line treatment for mCRPC before enrollment respectively, 10 patients had received at least fourth-line treatment. 38 (79.1%), 31 (64.5%), 30 (62.5%) and 7 (14.6%) patients had used abiraterone, enzalutamide, docetaxel and olaparib before enrollment. The probability of PSA level decrease >30%, ALP level decrease >30%, symptom improvement rate, median overall survival (OS), as well as the occurrence of treatment-related adverse reactions and the reasons for withdraw treatment were analyzed.Results:The median follow-up time was 8 (ranging 1-16) months. 11 patients completed all 6 courses of treatment. The median number of completed courses was 4 (ranging 1-6). 27 patients (56.2%) received radium-223 and bone protection drugs (Bisphosphate/ Denosumab). PSA decreased by >30% was recorded in 10 patients (20.8%) and ALP decreased by >30% was recorded in 25 patients (52.1%). 23 cases (47.9%) reported bone pain relief during treatment. Among the 9 patients who had received first-line of mCRPC previously, 6 cases (66%) had relief of bone pain symptoms, and 4 cases (44%) had a decrease of PSA >30%. Among the 18 patients who had previously received second-line mCRPC treatment, 11 cases (61%) had relief of bone pain symptoms, and 4 cases (22%) had a decrease of PSA >30%. Among the 21 patients who had received third-line or more mCRPC treatment in the past, 6 (28.5%) had symptom relief, and 2 (9.5%) had PSA decrease >30%. The median overall survival (OS) was not reached, and the OS was estimated to be 12.5 months using the Kaplan-Meier method. The most common hematological adverse effects were thrombocytopenia (15 cases, 31.2%; grade 3 in 6 cases and grade 4 in 0), followed by leucopenia (11 cases, 22.9%; grade 3 in 4 cases and grade 4 in 1 case) and anemia (8 cases, 16.7%; grade 3 in 3 cases and grade 4 in 0). Non-hematological adverse reactions included fever in 1 case (2.1%), constipation in 4 cases (8.3%), nausea and vomiting in 10 cases (20.8%), diarrhea in 7 cases (14.6%), dizziness in 1 case (2.1%) and fatigue in 11 cases (22.9%). Seven cases were discontinued due to intolerable adverse reactions (median 2 courses), 14 cases were discontinued due to disease progression or death (median 2 courses), and 5 cases were discontinued due to other reasons (median 1 course).Conclusions:Radium-223 has a good performance in symptom control for mCRPC patients who have previously received first-line or second-line therapy. Due to the high incidence of hematological adverse reactions, more attention should be paid to the changes of hemogram during the treatment, and timely treatment should be carried out to improve the drug tolerance of patients.

The relationship between the serum markers and bone metastasis of initial diagnosed prostate cancer patients in different ISUP groups / 中华泌尿外科杂志

Objective:To investigate the relationship between the serum alkaline phosphatase (ALP), prostate specific antigen (PSA) and bone metastasis in initially diagnosed prostate cancer (PCa) patients in different ISUP(International Society of Urological Pathology)groups.Methods:The 368 initial diagnosed prostate cancer patients recruited from January 2013 to December 2018 were retrospectively analyzed, including 247 cases in the Third Affiliated Hospital of Sun Yat-sen University, 111 cases in the Yuebei People's Hospital Affiliated to Medical College of Shantou University and 10 cases in Shenzhen Hospital of Southern Medical University. According to whether there was bone metastasis at the initial diagnosis, it was divided into 230 cases in the bone metastasis group and 138 cases in the non bone metastasis group. There was no significant difference between the two groups in age [(71.9±9.4) years and (71.2±8.7) years], body mass index (BMI) [(23.1±3.7) kg/m 2 and (23.7±2.6) kg/m 2]. There were significant differences in PSA [(307.3±847.0) ng/ml and (84.5±257.3) ng/ml] and ALP [(174.5±270.8) U/L and (71.0±23.2) U/L] between the two groups. In different PSA subgroups, there were 45 cases in PSA <10 ng/ml, 35 cases in PSA 10-20 ng/ml and 288 cases in PSA >20 ng/ml. The differences of ALP and PSA between bone metastasis group and non-bone metastasis group based on different ISUP stratification were analyzed, ROC curves were used to predict their risks of bone metastasis. Results:There were 3(1.3%), 22(9.6%), 34(14.8%), 85(37.0%) and 86 (37.4%) prostate cancer patients with bone metastasis from ISUP group 1 to 5, and 14(10.1%), 19(13.8%), 29(21.0%), 32(23.2%) and 44(31.9%) without bone metastasis, respectively. There was significant difference in the serum ALP levels between the bone metastasis group and the boneless metastasis group in the ISUP group 4(157.6±207.7 vs. 66.5±17.0) and 5(189.4±257.5 vs. 69.2±18.4)( P<0.001) and PSA levels had difference in the ISUP group 3(240.3±313.0 vs. 42.4±42.1), 4(152.3±184.5 vs. 44.7±33.3) and 5(435.2±1006.3 vs. 60.8±84.8)( P<0.001). There was statistically significant between the bone metastasis group and the without(336.1±882.2 vs. 139.3±328.1) when PSA>20 ng/ml( P=0.006). ROC curve analysis: the cut-off values of ALP were 115.5, 109.0, 75.5 and 86.0 U/L from ISUP group 2 to 5 respectively, the sensitivity was 23.8%, 56.5%, 66.4% and 50.6% respectively, the specificity was 99.7%, 93.4%, 78.3% and 89.2% respectively, and the accuracy were 59.4%, 73.1%, 69.7% and 63.3%, respectively. The cut-off values of PSA were 39.5, 93.1, 54.2 and 28.9 ng/ml from ISUP group 2 to 5 respectively, the sensitivity was 64.4%, 68.4%, 87.4% and 88.3% respectively, and the specificity was 79.5%, 90.6%, 63.7% and 61.6% respectively, and the accuracy were 71.6%, 78.1%, 80.1% and 79.2%, respectively. Conclusion:ALP increased significantly in ISUP group ≥4 and PSA in ISUP group ≥3, which related to bone metastasis in patients with initial diagnosed prostate cancer.

Effect of Extracts from Veronica peregrine on Breast Cancer Cell-induced Osteoclastic Bone Metastasis via Inhibiting Runx2 Activation / 中国实验方剂学杂志

ObjectiveTo investigate inhibitory effect of extracts from Veronica peregrina （EVP） on the osteoclastic bone metastasis induced by breast cancer cells. MethodBone metastasis model was established by injection of MDA-MB-231 cells， a human breast cancer cell line， into the left ventricle of BALB/c nude mice. The expression of human cytokeratin-19 （Ck-19） gene in mouse bone marrow was determined by nested polymerase chain reaction（PCR） to assess the bone metastasis of MDA-MB-231 cells. To assess the effects of EVP on the activation of bone marrow macrophages （BMMs）， we counted the multinuclear cells and measured the secretion of Cathepsin K. Western blot was adopted to assess the effects of EVP on receptor activator of nuclear factor-κB （RANK）， Runt-related transcription factor 2 （ Runx2 ）， phosphorylated Runx2 （p-Runx2）， and matrix metalloproteinase-9 （MMP-9） in BMMs. Gelatin zymography was employed to determine the activities of matrix metalloproteinases （MMPs）. ResultCompared with that in the blank group， Ck-19 expression was down-regulated in EVP groups （P<0.05）. The multinucleated cells increased when the BMMs were induced by soluble receptor activator of nuclear factor-κB ligand （sRANKL）， which was inhibited by EVP （P<0.05）. The level of cathepsin K in the supernatant of sRANKL group increased compared with that of the blank group， while EVP groups had lower cathepsin K levels than sRANKL group （P<0.05）. Compared with the blank group， the sRANKL group showed up-regulated RANK expression， Runx2 phosphorylation， and MMP-9 expression （P<0.05）， while the expression levels of RANK， p-Runx2， and MMP-9 were down-regulated when the cells were incubated with EVP （P<0.05）. Furthermore， exposure of BMMs to sRANKL resulted in an increase in gelatin hydrolyzation compared with the blank group （P<0.01）， which， however， was reversed in EVP groups （P<0.05）. ConclusionEVP significantly inhibits bone marrow metastasis of MDA-MB-231 cells， which may be associated with the suppression of osteoclast activation by inhibiting Runx2 phosphorylation.

A new therapeutic approach for bone metastasis in colorectal cancer: intratumoral melittin

Background: Melittin has shown antiproliferative effects on tumor cells. Therefore, it comprises a valuable compound for studies on cancer treatment. To the best of our knowledge, no studies have reported melittin effects on bone metastasis. Herein, we propose an approach based on intrametastatic melittin injection to treat bone metastases in colorectal cancer. Methods: Following the characterization of melittin and antiproliferative tests in vitro, a single dose was injected through intrametastatic route into the mouse bone metastasis model. Following treatment, metastasis growth was evaluated. Results: A single dose of melittin was able to inhibit metastasis growth. Histological analysis showed necrosis and inflammatory processes in melittin-treated metastasis. Except by mild weight loss, no other systemic effects were observed. Conclusion: Our data suggest that melittin might be a promising agent for the future development of treatment strategies aiming to reduce the bone metastasis skeletal-related impact in colorectal cancer patients with bone metastasis.(AU)

A new therapeutic approach for bone metastasis in colorectal cancer: intratumoral melittin

Abstract Background: Melittin has shown antiproliferative effects on tumor cells. Therefore, it comprises a valuable compound for studies on cancer treatment. To the best of our knowledge, no studies have reported melittin effects on bone metastasis. Herein, we propose an approach based on intrametastatic melittin injection to treat bone metastases in colorectal cancer. Methods: Following the characterization of melittin and antiproliferative tests in vitro, a single dose was injected through intrametastatic route into the mouse bone metastasis model. Following treatment, metastasis growth was evaluated. Results: A single dose of melittin was able to inhibit metastasis growth. Histological analysis showed necrosis and inflammatory processes in melittin-treated metastasis. Except by mild weight loss, no other systemic effects were observed. Conclusion: Our data suggest that melittin might be a promising agent for the future development of treatment strategies aiming to reduce the bone metastasis skeletal-related impact in colorectal cancer patients with bone metastasis.