Treatment Of Bone Metastases Research Articles

A simple nanoplatform of thermo-sensitive liposomes and gold nanorods to treat bone metastasis through improved chemotherapy combined with photothermal therapy

Bone metastasis remains a clinical challenge and is still considered incurable. While nanoparticles-based drug delivery and photothermal therapy (PTT) show promise in treating subcutaneous solid tumor, their therapeutic outcome in treating bone metastasis is limited, due to the inaccessibility of bone metastatic site and the complexity of bone metastasis. Herein, we reported a simple nanoplatform composed of thermo-sensitive liposomes (TSL) and gold nanorods (GNR) to treat bone metastasis through improved chemotherapy combined with GNR-assisted PTT. Lipid combination of TSL was firstly tailored to regulate its stability under physiological condition as well as its sensitivity in responding to PTT-caused mild hyperthermia. The obtained TSL with loaded drug was then combined with GNR to form the nanoplatform through unsophisticated incubation. Cell experiments revealed that upon near-infrared (NIR) irradiation, the nanoplatform effectively inhibited the viability and migration ability of tumor cells through PTT, PTT-triggered thermo-sensitive drug release, and PTT-augmented sensitivity of tumor cells to drug. In a murine model of bone metastasis, the nanoplatform enabled effective delivery of loaded drug and GNR to bone metastatic site for rapid drug release upon local NIR irradiation. Through killing tumor cells and rebalancing the turnover of osteoclasts and osteoblasts, the nanoplatform largely preserved bone structure for pain relief and survival extension. Inspired by the simplicity of nanoplatform acquirement and treatment operation, the strategy of liposomes-based thermo-sensitive drug delivery in combination with GNR-assisted PTT is considered greatly promising in treating bone metastasis.

Harnessing curcumin and nanotechnology for enhanced treatment of breast cancer bone metastasis.

Breast cancer (BC) bone metastasis poses a significant clinical challenge due to its impact on patient prognosis and quality of life. Curcumin (CUR), a natural polyphenol compound found in turmeric, has shown potential in cancer therapy due to its anti-inflammatory, antioxidant, and anticancer properties. However, its metabolic instability and hydrophobicity have hindered its clinical applications, leading to a short plasma half-life, poor absorption, and low bioavailability. To enhance the drug-like properties of CUR, nanotechnology-based delivery strategies have been employed, utilizing polymeric, lipidic, and inorganic nanoparticles (NPs). These approaches have effectively overcome CUR's inherent limitations by enhancing its stability and cellular bioavailability both in vitro and in vivo. Moreover, targeting molecules with high selectivity towards bone metastasized breast cancer cells can be used for site specific delivery of curcumin. Alendronate (ALN), a bone-seeking bisphosphonate, is one such moiety with high selectivity towards bone and thus can be effectively used for targeted delivery of curcumin loaded nanocarriers. This review will detail the process of bone metastasis in BC, elucidate the mechanism of action of CUR, and assess the efficacy of nanotechnology-based strategies for CUR delivery. Specifically, it will focus on how these strategies enhance CUR's stability and improve targeted delivery approaches in the treatment of BC bone metastasis.

High-dose denosumab (Xgeva®) Associated Medication-Related Osteonecrosis of the Jaws (MRONJ): incidence and clinical characteristics in a retrospective analysis of 1278 patients.

High-dose denosumab (Xgeva®) is increasingly used for treating bone metastasis and various malignant diseases but carries the risk of medication-related osteonecrosis of the jaw (MRONJ). This study aimed to evaluate the incidence, risk factors, and clinical outcomes of MRONJ in patients treated with high-dose denosumab. A retrospective review was performed on 1278 patients who received high-dose denosumab at Severance Hospital, Seoul, South Korea, from September 2014 to February 2023. Data on the incidence of MRONJ, patient demographics, primary diseases, and treatment outcomes were analyzed. Among the 1278 patients (average age 64.72years; 728 males and 550 females) treated, 34 developed MRONJ, with a 2.66% incidence rate. The average age of those with MRONJ was 68.32years, and they received more Xgeva® injections on average (13.62) compared to the overall cohort. Factors such as age and the frequency of injections were significantly associated with the risk of MRONJ. Notably, the incidence of MRONJ did not significantly differ between those who underwent oral surgery and those with spontaneous MRONJ, especially if oral surgery occurred within 1month of injection. Surgical interventions have shown higher recovery rates in advanced MRONJ stages. This study confirmed a significant MRONJ incidence of 2.66% among high-dose denosumab recipients, highlighting the importance of careful patient selection, monitoring, and education, particularly in older and long-term treatment patients, to mitigate the risk of MRONJ.

Effect of colony‑stimulating factor in the mechanism of bone metastasis development (Review).

Bone metastasis (BM) is a common complication of cancer and contributes to a higher mortality rate in patients with cancer. The treatment of BM remains a significant challenge for oncologists worldwide. The colony‑stimulating factor (CSF) has an important effect on the metastasis of multiple cancers. In vitro studies have shown that CSF acts as a cytokine, promoting the colony formation of hematopoietic cells by activating granulocytes and macrophages. Other studies have shown that CSF not only promotes cancer aggressiveness but also correlates with the development and prognosis of various types of cancer. In recent years, the effect of CSF on BM has been primarily investigated using cellular and animal models, with limited clinical studies available. The present review discussed the composition and function of CSF, as well as its role in the progression of BM across various types of cancer. The mechanisms by which osteoclast‑ and osteoblast‑mediated BM occur are comprehensively described. In addition, the mechanisms of action of emerging therapeutic agents are explored for their potential clinical applications. However, further clinical studies are required to validate these findings.

Breast Cancer Bone Metastasis Therapy and Tumor‐Associated Bone Destruction Repair by Versatile Semiconducting Nanointegrators with X‐Ray Adjuvant

AbstractTumor progress and tumor‐associated osteolysis are two key issues of breast cancer bone metastasis, which makes it challenging for bone metastasis treatment. To settle these two issues concurrently, a versatile semiconducting nanointegrator (termed as SPNCpG/Ca) containing semiconducting polymer nanoparticle (SPN), Ca2+ and cytosine‐phosphate‐guanine (CpG) oligonucleotides conjugated on the surface via a singlet oxygen (1O2)‐responsive linker, is designed. The antitumor effect can be triggered with X‐ray irradiation as an adjuvant, in which SPN works as a radiosensitizer to produce 1O2 for radiotherapy and controlled release of CpG via disrupting 1O2‐responsive linkers. The Ca2+ accumulation via SPNCpG/Ca delivering causes tumor cell death and the released CpG activates immune response to realize immunotherapy. The combinational action of radiotherapy, Ca2+ overloading, and immunotherapy results in complete clearance of metastatic tumor cells in 4T1 breast cancer‐based bone metastasis mouse models. Furthermore, Ca2+ can accelerate osteogenesis of bone marrow mesenchymal stem cells while CpG inhibits osteoclast differentiation in the bone metastasis microenvironment to alleviate osteolysis, which synergistically contributes to repair of tumor‐associated bone destruction. SPNCpG/Ca represents a versatile therapeutic nanosystem with the abilities to treat bone metastasis and repair tumor‐associated bone destruction, providing a new tactic for bone metastasis therapy.

Exploring the key pathogenic mechanisms and potential intervention targets for Sophorae Flavescentis radix in managing bone metastasis of lung cancer based on network pharmacology and molecular docking techniques.

Lung cancer often metastasizes to the bone, which significantly complicates treatment and worsens patient prognosis. Thus, new therapeutic strategies need to be established. Using network pharmacology and bioinformatics analysis, this study sought to determine the molecular targets and associated mechanisms of the traditional Chinese medicine (TCM) Sophorae Flavescentis radix in the treatment of lung cancer bone metastasis. The active components of Sophorae Flavescentis radix were screened using the TCM Systems Pharmacology (TCMSP) platform based on drug-likeness and oral bioavailability. The target genes of these active compounds were obtained from the DrugBank database. Differentially expressed genes (DEGs) between primary and bone metastatic lung cancer samples were screened in the GSE175601 dataset from the Gene Expression Omnibus (GEO) database using GEO2R. The intersecting DEGs from both groups were used to construct a Venn diagram to identify the candidate target genes. The expression and prognostic relevance of these genes were validated in The Cancer Genome Atlas (TCGA) database. The GeneMania and Search Tool for Recurring Instances of Neighbouring Genes (STRING) databases were used to generate the protein-protein interaction networks. Molecular docking was performed using the PubChem, Protein Data Bank (PDB), and CB-DOCK2 databases. A Gene Set Enrichment Analysis (GSEA) was conducted to explore the possible mechanisms of action. In the TCMSP database, 28 active compounds and 227 target genes of the Sophorae Flavescentis radix were identified. In total, 952 DEGs related to lung cancer bone metastasis were found in the GSE175601 dataset from the GEO database. Five common DEGs were identified via Venn diagram construction (i.e., F10, JUN, AKR1B1, MMP1, and CCND1). MMP1 was selected as the candidate gene. MMP1 was upregulated in lung cancer tissues, and patients with low MMP1 expression had better survival rates than those with high MMP1 expression (P<0.05). MMP1 has an affinity of -8.9 with luteolin. The GSEA results suggested that MMP1 might influence biological processes in lung cancer by participating in pathways such as chemokine signaling, apoptosis, Wingless/Integrated (Wnt) signaling, tumor protein p53-regulated cell cycle arrest, Hedgehog signaling, and mitogen-activated protein kinase signaling. Patients with lower MMP1 levels had prolonged overall survival and may serve as a novel predictive biomarker for lung cancer. Sophorae Flavescentis radix appears to exert therapeutic effects on lung cancer bone metastasis by inhibiting MMP1 expression and modulating the abnormal activation of the Wnt pathway. Our findings further extend the understanding of the pathogenic mechanisms and potential therapeutic interventions of Sophorae Flavescentis radix in lung cancer bone metastasis, providing a theoretical basis for clinical diagnosis and treatment research.

Melatonin Inhibits ET-1 Production to Break Crosstalk Between Prostate Cancer and Bone Cells: Implication for Osteoblastic Bone Metastasis Treatment.

Bone metastasis is the primary cause of death among patients with advanced prostate cancer (PCa). PCa tends to spread to bones and acquire the bone-like phenotype, causing osteoblastic bone metastasis. Unfortunately, there is no effective treatment for this condition. However, melatonin, which regulates our circadian rhythm, has been found to have anti-tumor properties. It has yet to be established whether it is effective in treating osteoblastic PCa metastasis. Our findings show that melatonin inhibits the production of endothelin-1 (ET-1) in osteoblastic PCa cells, suppressing osteoblast differentiation. Clinical results indicate that bone metastatic PCa patients have higher levels of ET-1 compared to nonmetastatic PCa patients. Furthermore, melatonin-induced miR-let-7f-5p inhibits ET-1-promoted osteoblast differentiation in osteoblastic PCa. Melatonin also suppresses the property of osteomimicry in osteoblastic PCa cells. Importantly, in the intratibia injection PCa metastasis model, melatonin decreased osteoblastic PCa tumor growth, inhibiting ET-1 production and osteoblast differentiation in vivo. Taken together, melatonin inhibits osteoblastic PCa-regulated osteoblastogenesis by reducing ET-1 production through upregulation of miR-let-7f-5p, while suppressing the property of osteomimicry in osteoblastic PCa. Melatonin therapy could be a promising approach to treating bone metastasis in osteoblastic PCa.

Single-Cell Analysis of Bone-Marrow-Disseminated Tumour Cells

Metastasis frequently targets bones, where cancer cells from the primary tumour migrate to the bone marrow, initiating new tumour growth. Not only is bone the most common site for metastasis, but it also often marks the first site of metastatic recurrence. Despite causing over 90% of cancer-related deaths, effective treatments for bone metastasis are lacking, with current approaches mainly focusing on palliative care. Circulating tumour cells (CTCs) are pivotal in metastasis, originating from primary tumours and circulating in the bloodstream. They facilitate metastasis through molecular interactions with the bone marrow environment, involving direct cell-to-cell contacts and signalling molecules. CTCs infiltrate the bone marrow, transforming into disseminated tumour cells (DTCs). While some DTCs remain dormant, others become activated, leading to metastatic growth. The presence of DTCs in the bone marrow strongly correlates with future bone and visceral metastases. Research on CTCs in peripheral blood has shed light on their release mechanisms, yet investigations into bone marrow DTCs have been limited. Challenges include the invasiveness of bone marrow aspiration and the rarity of DTCs, complicating their isolation. However, advancements in single-cell analysis have facilitated insights into these elusive cells. This review will summarize recent advancements in understanding bone marrow DTCs using single-cell analysis techniques.

Prognostic Value of PlGF Upregulation in Prostate Cancer.

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men worldwide, with metastasis, particularly to bone, being the primary cause of mortality. Currently, prognostic markers like PSA levels and Gleason classification are limited in predicting metastasis, emphasizing the need for novel clinical biomarkers. New molecules predicting tumor progression have been identified over time. Some, such as the immune checkpoint inhibitors (ICIs) PD-1/PD-L1, have become valid markers as theranostic tools essential for prognosis and drug target therapy. However, despite the success of ICIs as an anti-cancer therapy for solid tumors, their efficacy in treating bone metastases has mainly proven ineffective, suggesting intrinsic resistance to this therapy in the bone microenvironment. This study explores the potential of immunological intratumoral biomarkers, focusing on placental growth factor (PlGF), Vascular Endothelial Growth Factor Receptor 1 (VEGFR1), and Programmed Cell Death Protein 1 (PD-1), in predicting bone metastasis formation. we analyzed PCa samples from patients with and without metastasis by immunohistochemical analysis. Results revealed that PlGF expression is significantly higher in primary tumors of patients that developed metastasis within five years from the histological diagnosis. Additionally, PlGF expression correlates with increased VEGFR1 and PD-1 levels, as well as the presence of intratumoral M2 macrophages. These findings suggest that PlGF contributes to an immunosuppressive environment, thus favoring tumor progression and metastatic process. Results here highlight the potential of integrating these molecular markers with existing prognostic tools to enhance the accuracy of metastasis prediction in PCa. By identifying patients at risk for metastasis, clinicians can tailor treatment strategies more effectively, potentially improving survival outcomes and quality of life. This study underscores the importance of further research into the role of intratumoral biomarkers in PCa management.

Targeting RNA helicase DDX3X with a small molecule inhibitor for breast cancer bone metastasis treatment

Patients who present with breast cancer bone metastasis only have limited palliative treatment strategies and efficacious drug treatments are needed. In breast cancer patient data, high levels of the RNA helicase DDX3 are associated with poor overall survival and bone metastasis. Consequently, our objective was to target DDX3 in a mouse breast cancer bone metastasis model using a small molecule inhibitor of DDX3, RK-33. Histologically confirmed live imaging indicated no bone metastases in the RK-33 treated cohort, as opposed to placebo-treated mice. We generated a cell line from a bone metastatic lesion in mouse and found that it along with a patient-derived bone metastasis cell line gained resistance to conventional chemotherapeutics but not to RK-33. Finally, differential levels of DDX3 were observed in breast cancer patient metastatic bone samples. Overall, this study indicates that DDX3 is a relevant clinical target in breast cancer bone metastasis and that RK-33 can be a safe and effective treatment for these patients.

Excellent RAI therapeutic response on a patient presenting skull metastasis of follicular thyroid cancer after 15 years.

Bone is the second most common site of metastasis for differentiated thyroid carcinoma (DTC). Bone metastasis (BMs) occur in about 10% of patients with DTC and is observed more often in follicular thyroid carcinoma (FTC) (7-28%) than papillary thyroid carcinoma (PTC) (1-7%). Bone metastasis is associated with unfavorable clinical outcomes mainly including skeletal-related events (SREs), such as pathologic fractures, bone pain, spinal cord compressions, and hypercalcemia, which negatively impact the quality of life of patients and reduce their life expectancy. Patients with BMs from DTC require comprehensive and multimodal treatment approaches, including radioiodine (RAI) therapy, palliative care, surgery, external beam radiotherapy, and targeted drug therapy. RAI therapy is the first-line treatment, despite being rather ineffective, especially in large BMs. The response to RAI therapy, either alone or in combination with BM focal treatment depends on iodine avidity. This study reports a rare case of metachronous skull bone metastasis from FTC in a 72-year-old female patient 15 years after initial treatment. The patient had an excellent response to RAI therapy, which resulted in the abnormal uptake disappearing. Following treatment, the patient has been disease-free for six years. This case confirms that a complete response to RAI treatment for BM depends on the degree of dedifferentiation of cancer cells, which highlights the need for long-term follow-up, especially for FTC patients.

Lung and bone metastases patterns in Ewing sarcoma: Chemotherapy improves overall survival.

Ewing sarcoma (ES) is a small round cell malignancy, mainly in the bone tissue, followed by the soft tissue. Lung metastases (LM) and bone metastases (BM) are the most common types of metastases. From 2010 to 2018, the Surveillance, Epidemiology, and End Results database diagnosed 242 cases of ES with LM, 186 cases of ES with BM, and 74 cases of ES with LM and BM. Univariate and multivariate logistic regression analyses were used to determine the risk factors for LM and/or BM, and Kaplan-Meier curves and Cox regression analysis were used to determine the prognostic factors for LM and/or BM. Tumor size ≥50 mm, N1 stage, BM, liver metastases, and surgical treatment were significantly correlated with LM; tumor size >100 mm, brain metastases, LM, surgical treatment, and chemotherapy were significantly correlated with BM; female, N1 stage, brain metastases, liver metastases, and surgical treatment were significantly correlated with LM and BM. Older age, BM, higher T stage, no surgical treatment, and no chemotherapy were harmful to the survival of ES patients with LM; older age, female, LM, and no chemotherapy were harmful to the survival of ES patients with BM; older age and no chemotherapy were harmful to the survival of ES patients with LM and BM. Larger tumor size, N1 stages, and organ metastases were significantly associated with ES patients with LM and/or BM. Chemotherapy is effective in improving the survival.

Bioinformatic prediction of miR-320a as a potential negative regulator of CDGSH iron-sulfur domain 2 (CISD2), involved in lung adenocarcinoma bone metastasis via MYC activation, and associated with tumor immune infiltration.

Ferroptosis, a form of regulated cell death associated with iron-dependent lipid peroxidation, plays a role in cancer progression. However, the specific mechanisms of ferroptosis in lung adenocarcinoma (LUAD) bone metastasis (BM) remain unclear. Using bioinformatics analysis, this study sought to identify the ferroptosis-associated genes involved in BM in LUAD, thus providing potential novel targets for the treatment of BM in LUAD. The RNA expression dataset GSE10799 was acquired from the Gene Expression Omnibus (GEO) database, and intersected with the ferroptosis dataset to identify ferroptosis-related differentially expressed genes (DEGs). The expression of candidate genes and their correlation with the prognosis of LUAD patients were validated in The Cancer Genome Atlas (TCGA) database. A protein gene interaction network was constructed using GeneMania and Retrieval of Interacting Genes/Proteins (STRING) databases. The association between the candidate genes and immune cells was assessed via TCGA and Tumor IMmune Estimation Resource (TIMER) databases. The potential mechanisms were elucidated by a gene set enrichment analysis (GSEA). The relevant microRNAs (miRNAs or miRs) that bind to the 3'untranslated region (3'UTR) end of candidate genes' mRNA was explored using the TargetScan database. The expression of these candidate miRNAs in LUAD was validated and the correlation between candidate miRNAs and candidate mRNAs was tested using the TCGA database. Finally, the clinical data of 40 LUAD patients were retrospectively analyzed to evaluate the clinical value of candidate gene expression for LUAD BM patients. In this research, 15 ferroptosis-related DEGs in LUAD BM were identified. TCGA database analysis indicated that patients with low levels of CDGSH iron-sulfur domain 2 (CISD2) in LUAD had better disease-specific survival (DSS), overall survival (OS), and a better progression-free interval (PFI) than those with high levels of CISD2. The TIMER database results show that the expression of CISD2 is correlated with the infiltration levels of various immune cells. The GSEA indicated that CISD2 might influence biological activity in LUAD by participating in cell-cycle regulation, mitochondrial translation, DNA damage repair, c-Myc (MYC) activation, and the P53 signaling pathway. Through the combined analysis of the TargetScan and TCGA databases, hsa-miR-320a was identified as the optimal upstream regulatory miRNA. The immunohistochemistry data indicated that the positive CISD2 expression rates and immunohistochemistry scores of the patients with BM were significantly higher than those of the patients without BM (P<0.05). The high expression of CISD2 is a significant risk factor for BM in LUAD. The downregulation of CISD2 expression may extend DSS, OS, and the PFI of LUAD patients. Thus, CISD2 could serve as a novel predictive biomarker for LUAD patients. Further, miR-320a might negatively regulate CISD2 and participate in LUAD BM by activating MYC. These data provide a potential perspective for developing anticancer therapies for LUAD-BM patients.

Phosphate Ion-Responsive and Calcium Peroxide-Based Nanomedicine for Bone-Targeted Treatment of Breast Cancer Bone Metastasis.

The treatment of breast cancer bone metastasis is an unresolved clinical challenge, mostly because currently therapeutic approaches cannot simultaneously block the tumor growth and repair the osteolytic bone injuries at the metastatic site. Herein, the study develops a novel nanomedicine to treat breast cancer bone metastasis. The nanomedicine is based on phosphate ion-responsive and calcium peroxide-based nanoparticles carrying the bone-targeting agent zoledronic acid on the surface and loaded with the photosensitizer indocyanine green. Following intravenous administration to a mouse model of breast cancer bone metastasis, the nanoparticles efficiently accumulate at the bone metastasis site, react with free phosphate ions, and form hydroxyapatite nanoaggregates and O2, while releasing the photosensitizer. Hydroxyapatite nanoaggregates elicit the remineralization of the collagenous bone matrix and trigger tumor cell apoptosis. Upon irradiating tumor-bearing legs with an 808nm laser source, the O2 and free photosensitizer produced 1O2 by the reaction of the nanoparticles with phosphate ions, further boosting the anti-tumor effect. Tumor killing hampers the vicious cycle at the site of bone metastasis, translating to osteolysis blockade and further encouraging the remineralization of bone matrix. This work sheds light on the development of a novel, safe, and efficient approach for the treatment of breast cancer bone metastasis.

Balancing the Scales: The Dual Role of Interleukins in Bone Metastatic Microenvironments.

Bone metastases, a common and debilitating consequence of advanced cancers, involve a complex interplay between malignant cells and the bone microenvironment. Central to this interaction are interleukins (ILs), a group of cytokines with critical roles in immune modulation and inflammation. This review explores the dualistic nature of pro-inflammatory and anti-inflammatory interleukins in bone metastases, emphasizing their molecular mechanisms, pathological impacts, and therapeutic potential. Pro-inflammatory interleukins, such as IL-1, IL-6, and IL-8, have been identified as key drivers in promoting osteoclastogenesis, tumor proliferation, and angiogenesis. These cytokines create a favorable environment for cancer cell survival and bone degradation, contributing to the progression of metastatic lesions. Conversely, anti-inflammatory interleukins, including IL-4, IL-10, and IL-13, exhibit protective roles by modulating immune responses and inhibiting osteoclast activity. Understanding these opposing effects is crucial for developing targeted therapies aimed at disrupting the pathological processes in bone metastases. Key signaling pathways, including NF-κB, JAK/STAT, and MAPK, mediate the actions of these interleukins, influencing tumor cell survival, immune cell recruitment, and bone remodeling. Targeting these pathways presents promising therapeutic avenues. Current treatment strategies, such as the use of denosumab, tocilizumab, and emerging agents like bimekizumab and ANV419, highlight the potential of interleukin-targeted therapies in mitigating bone metastases. However, challenges such as therapeutic resistance, side effects, and long-term efficacy remain significant hurdles. This review also addresses the potential of interleukins as diagnostic and prognostic biomarkers, offering insights into patient stratification and personalized treatment approaches. Interleukins have multifaceted roles that depend on the context, including the environment, cell types, and cellular interactions. Despite substantial progress, gaps in research persist, particularly regarding the precise mechanisms by which interleukins influence the bone metastatic niche and their broader clinical implications. While not exhaustive, this overview underscores the critical roles of interleukins in bone metastases and highlights the need for continued research to fully elucidate their complex interactions and therapeutic potential. Addressing these gaps will be essential for advancing our understanding and treatment of bone metastases in cancer patients.

External Validation and Update of the Risk Prediction Model for Denosumab-Induced Hypocalcemia Developed From a Hospital-Based Administrative Database.

Denosumab is used to treat patients with bone metastasis from solid tumors, but sometimes causes severe hypocalcemia, so careful clinical management is important. This study aims to externally validate our previously developed risk prediction model for denosumab-induced hypocalcemia by using data from two facilities with different characteristics in Japan and to develop an updated model with improved performance and generalizability. In the external validation, retrospective data of Kameda General Hospital (KGH) and Miyagi Cancer Center (MCC) between June 2013 and June 2022 were used and receiver operating characteristic (ROC)-AUC was mainly evaluated. A scoring-based updated model was developed using the same data set from a hospital-based administrative database as previously employed. Selection of variables related to prediction of hypocalcemia was based on the results of external validation. For the external validation, data from 235 KGH patients and 224 MCC patients were collected. ROC-AUC values in the original model were 0.879 and 0.774, respectively. The updated model consisting of clinical laboratory tests (calcium, albumin, and alkaline phosphatase) afforded similar ROC-AUC values in the two facilities (KGH, 0.837; MCC, 0.856). We developed an updated risk prediction model for denosumab-induced hypocalcemia with small interfacility differences. Our results indicate the importance of using data from plural facilities with different characteristics in the external validation of generalized prediction models and may be generally relevant to the clinical application of risk prediction models. Our findings are expected to contribute to improved management of bone metastasis treatment.

Factors associated with work sustainability in patients with bone metastasis.

Working while receiving cancer treatment is challenging for patients, with considerable impact on their quality of life (QOL). However, there have been no reports on the factors that prevent employment in patients with bone metastases. This study aimed to investigate the employment status and factors impacting the continued employment of patients with bone metastases. We analyzed clinical data from new patients consulting The University of Tokyo Hospital team for bone metastasis treatment between June 2015 and September 2017. Patients who were working at the time of cancer diagnosis (n=124) completed four QOL questionnaires. Factors associated with work sustainability were identified via univariate analysis and a chi-squared test. Multivariate logistic regression analysis was used for significant variables. Relationships between employment and QOL scales were investigated using the Wilcoxon rank-sum test, with P<.05 considered as statistically significant. Among the 124 patients, only 45 (36.3%) were still working when the questionnaire was administered. Multivariate analysis revealed temporary employment, lytic or mixed bone metastases, and lower limb or acetabular metastasis, as significant factors hindering work sustainability. The QOL scores were high in the continued employment group. However, the relationship between employment status and pain remains unclear. Lytic or mixed bone metastases and the lower limb and acetabular metastasis were significantly associated with employment resignation. Mobility difficulties may prevent patients with bone metastases from sustaining employment. Collaboration between rehabilitation professionals, oncologists, and workplaces is imperative to address this problem.

Bacterial outer membrane vesicle-cancer cell hybrid membrane-coated nanoparticles for sonodynamic therapy in the treatment of breast cancer bone metastasis

Breast cancer bone metastasis is a terminal-stage disease and is typically treated with radiotherapy and chemotherapy, which causes severe side effects and limited effectiveness. To improve this, Sonodynamic therapy may be a more safe and effective approach in the future. Bacterial outer membrane vesicles (OMV) have excellent immune-regulating properties, including modulating macrophage polarization, promoting DC cell maturation, and enhancing anti-tumor effects. Combining OMV with Sonodynamic therapy can result in synergetic anti-tumor effects. Therefore, we constructed multifunctional nanoparticles for treating breast cancer bone metastasis. We fused breast cancer cell membranes and bacterial outer membrane vesicles to form a hybrid membrane (HM) and then encapsulated IR780-loaded PLGA with HM to produce the nanoparticles, IR780@PLGA@HM, which had tumor targeting, immune regulating, and Sonodynamic abilities. Experiments showed that the IR780@PLGA@HM nanoparticles had good biocompatibility, effectively targeted to 4T1 tumors, promoted macrophage type I polarization and DC cells activation, strengthened anti-tumor inflammatory factors expression, and presented the ability to effectively kill tumors both in vitro and in vivo, which showed a promising therapeutic effect on breast cancer bone metastasis. Therefore, the nanoparticles we constructed provided a new strategy for effectively treating breast cancer bone metastasis.Graphical

Response rate specific to bone metastasis of various cancers for immune checkpoint inhibitors: a systematic review.

Immune checkpoint inhibitors (ICIs) have improved the prognosis of patients with cancer, such as melanoma, renal cell carcinoma, head and neck cancer, non-small cell lung cancer (NSCLC), and urothelial carcinoma. The extension of life expectancy has led to an increased incidence of bone metastases (BM) among patients with cancer. BM result in skeletal-related events, including severe pain, pathological fractures, and nerve palsy. Surgery is typically required for the treatment of BM in patients with an impending fracture; however, it may be avoided in those who respond to ICIs. We systematically reviewed studies analyzing BM responses to treatment with ICIs. This study was conducted in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020 statement and registered in the UMIN Clinical Trials Registry (ID: UMIN000053707). Studies reporting response rates based on the Response Evaluation Criteria in Solid Tumors (RECIST) or the MD Anderson Cancer Center (MDA) criteria specific for BM in patients treated with ICIs were included; reports of fewer than five cases and review articles were excluded. Studies involving humans, published in English and Japanese, were searched. The PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched. Ultimately, nine studies were analyzed. The Risk of Bias Assessment tool for Non-randomized Studies was used to assess the quality of studies. Based on the MDA criteria, complete response (CR) or partial response (PR) was observed in 44-78% and 62% patients treated with ICIs plus denosumab for NSCLC and melanoma, respectively. According to the RECIST, CR or PR was recorded in 5% and 7-28% of patients treated with ICIs for renal cell carcinoma and urothelial carcinoma, respectively. Although response rates to ICIs for BM are poor, patients treated with ICI plus denosumab for bone metastases with impending fractures from NSCLC and melanoma are likely to avoid surgery to prevent fractures.

Practical management of renal cell carcinoma: integrating current approaches with advances in bone metastasis treatment.

Renal cell carcinoma (RCC) is a common type of tumor that can develop in the kidney. It is responsible for around one-third of all cases of neoplasms. RCC manifests itself in a variety of distinct subtypes. The most frequent of which is clear cell RCC, followed by papillary and chromophobe RCC. RCC has the potential for metastasis to a variety of organs; nevertheless, bone metastases are one of the most common and potentially fatal complications. These bone metastases are characterized by osteolytic lesions that can result in pathological fractures, hypercalcemia, and other complications, which can ultimately lead to a deterioration in quality of life and an increase morbidity. While nephrectomy remains a foundational treatment for RCC, emerging evidence suggests that targeted therapies, including tyrosine kinase inhibitors and T cell checkpoint inhibitors, may offer effective alternatives, potentially obviating the need for adjuvant nephrectomy in certain cases of metastatic RCC Bone metastases continue to be a difficult complication of RCC, which is why more research is required to enhance patient outcome.