Cancer Bone Metastasis Research Articles

12214 Metastatic Functional Thyroid Carcinoma As An Unusual Cause Of Hyperthyroidism

Abstract Disclosure: S. Jimenez Salazar: None. N. Aristizabal Henao: None. C. Aguilar Londoño: None. N. Buitrago Gómez: None. S. Saldarriaga Betancur: None. D.L. Beltran: None. J.L. Torres: None. Background: Differentiated thyroid carcinoma (DTC) represents the most prevalent endocrine neoplasm. Less than 10% present distant metastases, with the lung (50%), and skeleton (25%) being the most frequently affected sites. The location of bone metastases predominates in the spine and pelvis; usually as osteolytic lesions, being more frequent in follicular thyroid cancer (FTC) (7-28%) than in patients with papillary thyroid cancer (PTC) (1.4-7%). In rare cases this metastasis can be functional and trigger a thyrotoxicosis syndrome with or without recombinant human TSH injections prior to therapy with 131-I. Clinical case: 59-year-old woman with a history of bone metastatic follicular thyroid cancer (FTC) presented with 1 month of palpitations, 4 kg weight loss, non-dysenteric diarrhea and progressive dyspnea. Her FTC had been diagnosed 8 years prior her consultation. In that time iodine refractoriness was considered due to the progression of bone lesions, and Sorafenib 800 mg per day was initiated, which was not tolerated due to severe dermatological manifestations, and the patient decided not to continue with TKI therapy. Since then, she has been treated with zoledronic acid and local radiotherapy as part of palliative care. On physical examination, she was tachycardic (150 bpm), and hypertensive (BP 160/100 mmHg). A suppressed TSH (<0.01 uUI/mL, n: 0.4-4 uUI/mL) with elevation of thyroid hormones (free T4 3.99 ng/dL, n: 0.8-2 ng/dL and total T3 480 ng/dL, n: 45-140 ng/dL) was documented, associated with a patient who had required a dose adjustment of levothyroxine from 700 mcg to 350 mcg weekly 2 months prior to admission. Additionally, she had a significantly elevated thyroglobulin (>5000 ng/mL, n: 0.1-64.1 ng/mL) with undetectable antithyroglobulin antibodies (1.09 UI/mL, n: 0-4.11 UI/mL). Considering the history of total thyroidectomy and the high tumor burden, secondary thyrotoxicosis due to functioning bone metastases of DTC was considered. Levothyroxine was discontinued, and propranolol was initiated for the control of adrenergic symptoms, along with methimazole, cholestyramine, and systemic steroids to control thyroid hormone production. 3 days after therapy adjustment dyspnea, palpitations, and thyroid function tests improved significantly (free T4 1.43 ng/dL, n: 0.8-2 ng/dL and total T3 178 ng/dL, n: 45-140 ng/dL). A new administration of therapy with 131-I 200 mCi was indicated. Antithyroid therapy and beta-blockers were continued with sustained biochemical control. Conclusion: Functional bone metastases of FTC can lead to high morbidity and mortality. Treatment consists of surgical cytoreduction of any large accessible metastatic lesion, therapy with 131-I, and high-dose antithyroid drugs to control hyperthyroidism. It is important to avoid the use of recombinant human TSH due to the risk of secondary thyrotoxicosis following its administration. Presentation: 6/2/2024

7474 Demographic Patterns In Early Vertebral Fracture Diagnoses Among Women After Initiation Of Bisphosphonate Therapy

Abstract Disclosure: J.C. Lo: None. G.H. Tabada: None. M. Chandra: None. L.D. Carbone: None. T.C. Tan: None. J. Yang: None. E. Garcia: None. Introduction: Vertebral fractures (VFX) are a major osteoporotic fracture that identify women at high risk for subsequent fracture. However, less is known about demographic patterns in VFX diagnoses among women initiating osteoporosis therapy, including prior and subsequent VFX diagnoses. In this study, we examined racial and ethnic variation in VFX diagnoses among older women who initiated oral BP therapy in a large healthcare system. Methods: The study cohort included women aged 65-85y who initiated oral bisphosphonate (BP) therapy in 2008-2017, excluding those with selective bone disorders, metastatic cancer, multiple myeloma, kidney dialysis or transplant. Prior VFX diagnosis was based on ICD-9/10-CM diagnosis codes in the 5 years prior to or at BP initiation, excluding fracture codes related to open fracture or spinal cord injury. In the 2 years after BP initiation, new or initial encounter diagnoses of VFX were examined among those without prior VFX diagnoses. Findings were compared by race and ethnicity, overall and within age strata (65-74y, 75-85y). New VFX diagnoses after BP initiation were examined using Cox proportional hazard analyses, reporting hazard ratios (HR) with 95% confidence intervals (CI). Results: Among 50,870 women aged 65-85y (56.5% age <75y) who initiated BP (66.9% White, 16.7% Asian/PI, 11.9% Hispanic, 3.2% Black), 2819 (5.5%) had prior VFX diagnosis. By race and ethnicity, 4.5% of White, 2.3% of Asian/PI, 3.5% of Hispanic, and 4.1% of Black women aged 65-74y had prior VFX diagnosis, increasing to 7.9% of White, 6.6% of Asian/PI, 7.9% of Hispanic, and 6.3% of Black women aged 75-85y. During 2 years follow-up after BP initiation and stratified by age, the incidence of new VFX diagnosis (per 1000 person-years) was 8.9 (7.9-9.9) for White, 3.2 (2.3-4.5) for Asian/PI, 7.1 (5.3-9.5) for Hispanic, and 6.8 (3.8-12.3) for Black women aged 65-74y, and 17.4 (15.9-19.0) for White, 13.0 (10.2-16.6) for Asian/PI, 14.2 (11.2-18.1) for Hispanic, and 6.1 (3.1-12.2) for Black women aged 75-85y. Adjusting for age, prior clinical fracture, and BP initiation year, the risk of new VFX diagnosis among women aged 65-74y (White as reference) was much lower for Asian/PI women (HR 0.40, CI 0.28-0.57) but not Black (HR 0.70, CI 0.38-1.29) and Hispanic (HR 0.80, CI 0.59-1.10) women. For older women aged 75-85y, the risk was much lower for Black women (0.36 (CI 0.18-0.72) but not Asian/PI (0.78, CI 0.60-1.02) and Hispanic (0.83, CI 0.64-1.07) women. Conclusion: Compared to White women, much lower VFX diagnosis among younger but not older Asian/PI women and among older but not younger Black women were seen in the 2 years after BP initiation. While new VFX diagnoses may represent prevalent or incident VFX and underlying fracture risk and continuation of BP may differ by group, these pilot findings support the need for more studies examining ethnic variation in VFX among older women, including differences by age. Presentation: 6/3/2024

Mechanobiological cues to bone cells during early metastasis drive later osteolysis: a computational mechanoregulation framework prediction

Bone cells contribute to tumour metastasis by producing biochemical factors that stimulate tumour cell homing and proliferation, but also by resorbing bone matrix (osteolysis) that releases further stimulatory factors for tumour growth in a vicious cycle. Changes in the local mechanical environment of bone tissue occur during early metastasis, which might activate mechanobiological responses by resident bone cells (osteocytes) to activate resorption (osteoclasts) and thereby contribute to tumour invasion. The objective of this study is to investigate whether bone osteolysis is driven by early changes in the bone mechanical environment during metastasis by (a) implementing subject-specific FE models of metastatic femora to predict the mechanical environment within bone tissue during early metastasis (3-weeks after tumour inoculation) and then (b) applying mechanoregulation theory to predict bone tissue remodelling as a function of the evolving mechanical environment within bone tissue during breast cancer-bone metastasis. We implemented a global resorption rate derived from an experimental model, but the mechanoregulation algorithm predicted localised bone loss in the greater trochanter region, the same region where osteolysis was prevalent after three weeks of metastasis development in the animal model. Moreover, the mechanical environment evolved in a similar manner to that reported in separate subject-specific finite element models of these same animals by 6 weeks. Thus, we propose that early changes in the physical environment of bone tissue during metastasis may elicit mechanobiological cues for bone cells and activate later osteolytic bone destruction.

The Role of Biphosphonate and Denosumab in Bone Metastasis

Metastasis is a major contributor to cancer-related morbidity and mortality. Bone metastasis is prevalent and associated with pain and fractures, particularly in breast cancer where up to 80% of patients may be affected. Bisphosphonates, traditional anti-resorptive drugs, have been crucial in managing bone metastatic cancers. This article reviews the pathophysiology of bone metastasis, focusing on the invasion-metastasis cascade and the role of matrix metalloproteinases (MMPs). The formation of metastatic tissue in bones involves disrupting the balance of the bone remodeling process. The study delves into the three generations of bisphosphonates, elucidating their structural differences and mechanisms of action. First-generation bisphosphonates, such as etidronate and clodronate, lack nitrogen and interfere with cellular processes. Second-generation bisphosphonates, including alendronate and pamidronate, bind to nitrogen and inhibit farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway. Third-generation bisphosphonates like risedronate and zoledronate have a heterogeneous nitrogenous chain, enhancing anti-resorptive activity. Denosumab's distinct pharmacokinetics and potential risks upon discontinuation are discussed. The article emphasizes the need for clinicians to be vigilant about potential adverse effects, especially kidney toxicity with bisphosphonates, and to tailor treatment based on individual patient characteristics.

Calcium-mediated zoledronate loading onto carbon nanohorns.

Previously, we showed that the anti-osteoclast effect of zoledronate (ZOL), a type of bisphosphonate, is enhanced when it is used as a nanocomposite comprising ZOL, an "oxidized single-walled carbon nanohorn (OxCNH) with a spherical shape" and calcium phosphate (CaP). This nanocomposite, termed OxCNH-CaP-ZOL, is a potential therapeutic agent for patients with bone fragility associated with metastatic bone cancer. Because OxCNH-CaP-ZOL contains by-products that comprise CaP-ZOL nanocomposites, the aim of this study was to prepare more sophisticated nanocomposites lacking such by-products; it was achieved by reducing the availability of calcium and phosphate ions during the preparation process. In this new nanocomposite, ZOL loading onto OxCNH was mediated by Ca, and therefore it is referred to as OxCNH-Ca-ZOL. Because the amount of ZOL in OxCNH-Ca-ZOL was about half that in OxCNH-CaP-ZOL and murine macrophages (RAW264.7 cells) took up less OxCNH-Ca-ZOL than OxCNH-CaP-ZOL, the amount of ZOL inside RAW264.7 cells exposed to OxCNH-Ca-ZOL was less than that inside cells exposed to OxCNH-CaP-ZOL. Despite this drawback, OxCNH-Ca-ZOL had suppressive effects similar to OxCNH-CaP-ZOL on the viability of RAW264.7 cells. The reason for these phenomena is not clear; however, it could be due to the differences in the ZOL release rate between OxCNH-Ca-ZOL and OxCNH-CaP-ZOL. In addition, receptor activator of nuclear factor kappa-B ligand (RANKL)-induced differentiation of RAW264.7 cells into osteoclasts was suppressed by co-administration of RANKL with OxCNH-Ca-ZOL as effectively as with OxCNH-CaP-ZOL, and indeed, their effects were greater than those of free ZOL.

Prognostic assessment of patients with bone metastatic renal cell cancer treated with palliative radiotherapy.

The present study investigated the prognosis of patients who received palliative radiotherapy (RT) for bone metastases (BMs) from renal cell cancer (RCC), and assessed the prognostic factors specific to BMs from RCC. A total of 109 patients with RCC and BMs who underwent RT for the first time were included in the study. Prognostic factors were evaluated using multivariate analysis and a scoring system based on regression coefficients was devised. The median follow-up time was 9 months, and the 0.5-year overall survival (OS) rate was 73.0%. In the multivariate analysis, the significant prognostic factors were higher performance status (≥2), no control of the primary site, disseminated metastasis, lymph node metastasis and multiple BMs. A score of 1 point was assigned to each risk factor. The median OS times were 19.0 and 5.0 months in patients with a total score of ≤1 (n=49) and >1 (n=60), respectively (P<0.01). In conclusion, a comprehensive prognostic assessment using these factors may be useful for predicting the prognoses of patients with BMs from RCC. In addition, this scoring system may be useful in selecting the optimal RT dose.

Optimal production and purification of n.c.a.143Pr as a promising palliative agent for the treatment of metastatic bone pain

This study proposes the beta-emitting radioisotope 143Pr as a promising candidate for palliative treatment of metastatic bone pain due to its desirable physical decay characteristics. An optimized process was developed for the production and purification of non-carrier-added 143Pr using a medium flux research reactor. Calculations were performed to determine the optimal irradiation time and cooling period for irradiating 1 mg of natural cerium oxide to indirectly produce 143Pr through the decay of 143Ce. Following irradiation and cooling, extraction chromatography was employed to efficiently isolate 143Pr from the irradiated target material. A column containing Ln-resin was used along with nitric acid as the mobile phase and an optional oxidation step with NaBrO3/ascorbic acid to separate 143Pr from impurities such as 143Ce and 141Ce. Radionuclidic purity of over 99.995% was achieved as confirmed through gamma spectroscopy, demonstrating effective separation of 143Pr. Additional quality control analyses established the chemical and radiochemical purity of the purified 143Pr nitrate product. With a half-life of 13.6 days and maximum beta energy of 0.937 MeV, 143Pr exhibits favorable properties for palliative bone pain therapy. This study therefore provides a viable method for producing high-purity 143Pr through the optimized irradiation and purification processes described. Further investigation is warranted to explore potential clinical applications of 143Pr for palliation of metastatic bone cancer pain.

Effect of decalcification on immunohistochemical staining of trichorhinophalangeal syndrome type 1

AbstractTo evaluate the effect of different decalcification solutions on the immunohistochemical staining of trichorhinophalangeal syndrome type 1 (TRPS1), and to provide a reliable basis for the accurate diagnosis of bone metastasis of breast cancer. Due to the limited biopsy samples of bone metastatic cancer, 20 cases of invasive breast cancer were selected to simulate bone metastatic biopsy, dividing into four groups: undecalcified group, 30% formic acid group, 10% hydrochloric acid group and 10% nitric acid group. Immunohistochemical staining was performed after treatment for 2, 6, 18 and 24 h. There was no change in the proportion and intensity of TRPS1 cells in the formic acid decalcification group within 18 h, but decreased significantly after 24 h. The staining intensity of TRPS1 and the proportion of stained cells were significantly decreased in the hydrochloric acid decalcification group since 2 h treatment. The percentage and intensity of positive cells in the nitric acid decalcification group changed little or no change within 6 h, and then gradually decreased with the extension of time. Another three invasive breast cancer samples were used to compare the effects of different decalcification solutions on the same case. In brief, we conclude that the effect of 30% formic acid decalcification on TRPS1 staining is small when the time is less than 18 h. 10% nitric acid decalcification should be controlled within 6 h, which has little effect on TRPS1 staining, and 10% hydrochloric acid decalcification will lead to significantly less positive TRPS1 staining, so it is not recommended for breast bone metastasis tissue decalcification.

Early diagnostic value of ECT whole-body bone imaging combined with PINP and β-CTX for bone metastasis of lung cancer.

This research was aimed at investigating the early diagnostic value of emission computed tomograph (ECT) whole-body bone imaging combined with PINP and β-CTX for bone metastasis of lung cancer. Case data of 86 lung cancer patients were categorized into lung cancer with bone metastasis (LCWBM, 46 cases) and lung cancer without bone metastasis (LCWOBM, 40 cases) groups according to the presence or absence of bone metastasis. Patients' general information were collected. ECT whole-body bone imaging was used to detect bone metastases and the grading of the extent of disease (EOD) in both groups, and electrochemiluminescence was utilized to detect the serum levels of PINP and β-CTX. Spearman correlation analysis was employed to evaluate the correlation between EOD grading and PINP and β-CTX levels. Logistic univariate and multivariate regression was implemented to analyze the risk factors of bone metastasis of lung cancer. Receiver operating characteristic (ROC) curve was applied to analyze the diagnostic efficacy of the single test of ECT whole-body bone imaging, PINP, or β-CTX and the combination of the three tests. The differences in pathological type, clinical stage and EOD grading, the number of positive ECT cases, and the expression levels of PINP and β-CTX between the LCWBM and LCWOBM groups were statistically significant. In LCWBM patients with different EOD grading, the trends of the expression of PINP and β-CTX were grade 3 > grade 2 > grade 1 and grade 0. Further correlation analyses revealed that EOD grading showed a significant positive correlation with the PINP and β-CTX expression levels. Univariate logistic regression analysis demonstrated that adenocarcinoma, TNM stage IV, ECT positivity, and high expression of PINP and β-CTX were associated with bone metastasis of lung cancer, and multivariate logistic regression analysis indicated that ECT positivity, high expression of PINP and β-CTX were independent risk factors for bone metastasis of lung cancer. The area under the curve (AUC) of ECT, PINP, and β-CTX alone for the diagnosis of bone metastasis of lung cancer were 0.872, 0.888, and 0.874, respectively, and the AUC for the combined diagnosis of the three was 0.963, which was greater than that of any one of the individual indices, with a sensitivity of 86.96% and a specificity of 97.50% at a Youden index of 0.845. ECT whole-body bone imaging combined with PINP and β-CTX has high diagnostic value for bone metastasis of lung cancer.

Epidemiology, etiopathogenesis, and management of MRONJ: A European multicenter study

IntroductionThe purpose of this European multicenter study was to describe the general characteristics and risk factors of MRONJ lesions as well as their clinical diagnosis and management at different European Oral and Maxillofacial Surgery centers, in order to minimize selections biases and provide information about the epidemiology, etiopathogenesis, and the current trends in the treatment of MRONJ across Europe. Materials and methodsThe following data were registered for each patient: gender; age at MRONJ diagnosis; past medical history; indication for antiresorptive or antiangiogenic therapy; type of antiresorptive medication; local risk factor for MRONJ; MRONJ Stage; anatomic location and symptoms; treatment; surgical complications; recurrence. ResultsA total of 537 patients (375 females, 162 males) with MRONJ were included. Statistically significant associations were found between patients with metastatic bone disease and recurrences (P < 0.0005) and between advanced MRONJ stages (stages 2 and 3) and recurrences (P < 0.005). Statistically significant associations were also found between male gender and recurrences (P < 0.05), and between MRONJ maxillary sites and recurrences (P < 0.0000005). ConclusionsA longer mean duration of antiresorptive medications before MRONJ onset was observed in patients affected by osteoporosis, whereas a shorter mean duration was observed in all metastatic bone cancer patients, and in particular in those affected by prostate cancer with bone metastases or multiple myeloma. Surgery plays an important role for the management of MRONJ lesions.

Evaluation of Changes in Activities of Daily Living and Quality of Life of Patients with Bone Metastasis Who Underwent Conservative Therapy through Bone Metastasis Cancer Boards.

Background and Objectives: Changes in activities of daily living (ADL) and quality of life (QOL) of patients with bone metastasis who underwent surgical treatment through Bone Metastasis Cancer Boards (BMCBs), a recent multidisciplinary approach for managing bone metastases, have been reported; however, no reports exist on patients who undergo conservative treatment. In this study, we aimed to evaluate these patients' ADL and QOL and examine the factors influencing changes in these parameters. Materials and Methods: We retrospectively reviewed 200 patients with bone metastases who underwent conservative therapy through BMCBs between 2013 and 2021. A reassessment was conducted within 2-8 weeks after the initial assessment. Patients' background and changes in performance status (PS), Barthel Index (BI), EuroQol five-dimension (EQ-5D) scores, and Numerical Rating Scale (NRS) scores were initially assessed. Furthermore, we categorized patients into two groups based on improvements or deteriorations in ADL and QOL and performed comparative analyses. Results: Significant improvements in EQ-5D (0.57 ± 0.02 versus [vs.] 0.64 ± 0.02), NRS max (5.21 ± 0.24 vs. 3.56 ± 0.21), and NRS average (2.98 ± 0.18 vs. 1.85 ± 0.13) scores were observed between the initial assessment and reassessment (all p < 0.001). PS (1.84 ± 0.08 vs. 1.72 ± 0.08) and BI (83.15 ± 1.68 vs. 84.42 ± 1.73) also showed improvements (p = 0.06, and 0.054, respectively). In addition, spinal cord paralysis (odds ratio [OR]: 3.69, p = 0.049; OR: 8.42, p < 0.001), chemotherapy (OR: 0.43, p = 0.02; OR: 0.25, p = 0.007), and NRS average scores (OR: 0.38, p = 0.02; OR: 0.14, p < 0.001) were independent factors associated with ADL and QOL. Conclusions: Patients with bone metastases who underwent conservative treatment through BMCBs exhibited an increase in QOL without a decline in ADL. The presence of spinal cord paralysis, absence of chemotherapy, and poor pain control were associated with a higher risk of deterioration in ADL and QOL.

Difficulties Nurses Report in Caring for Patients with Bone Metastases and Their Expectations after Participating in a Bone Metastasis Cancer Board: A Questionnaire Study.

Patients with bone metastases often face physical, mental, and social challenges that require multidisciplinary management. To improve treatment and practice, we conducted a questionnaire survey to assess nurses' opinions of problems related to caring for patients with bone metastases. In addition, we investigated nurses' perceptions of bone metastases after participating in a Bone Metastasis Cancer Board (BMCB). An anonymous questionnaire survey on problems in bone metastasis treatment and the BMCB was conducted. The respondents were nurses with more than 1 year of clinical experience working in wards where patients with bone metastases were admitted. The number of valid responses was 224. Almost all the nurses felt anxiety about the risk of pathological fracture and paralysis while caring for patients with bone metastases. To reduce this anxiety, about 90% of the nurses supported the suggestion that "patients should be referred to an orthopedic surgeon in advance to obtain opinions on load restrictions". Nurses who had participated in the BMCB had higher expectations regarding treatment, multidisciplinary collaboration, and sharing and accumulating knowledge and experience. To improve treatment and nursing care for patients with bone metastases, it is important to make regular BMCB meetings more functional and to actively consult with specialists.

Comparative Analysis of Stereotactic Radiation Therapy and Conventional Radiation Therapy in Cancer Pain Control: A Systematic Review and Meta-Analysis

AimsApproximately 55% of patients diagnosed with primary or metastatic cancer endure pain directly attributable to the disease. Consequently, it becomes imperative to address pain management through a comparative analysis of stereotactic radiotherapy (SRT) and conventional radiation therapy (CRT), especially in light of the less efficacious improvement achieved solely through pharmacological interventions. Materials and methodsA systematic exploration was undertaken on PubMed, the Cochrane Library, and Elsevier's ScienceDirect databases to identify studies that compare Stereotactic Radiotherapy to Conventional radiation therapy for pain management in individuals with metastatic bone cancer. The analyses were executed utilizing the random-effects model. ResultsA cohort of 1152 participants with metastatic bone cancer was analyzed, demonstrating significantly higher complete pain relief in the Stereotactic Radiotherapy group during both early and late follow-up (RR: 1.61; 95% CI: 1.17, 2.23, p-value: 0.004; I2: 0%). Stereotactic Radiotherapy also showed a non-significant increase in the incidence of partial pain relief (RR: 1.07; 95% CI: 0.85, 1.34, p-value: 0.56; I2: 18%). Furthermore, Stereotactic Radiotherapy was associated with a significantly reduced risk of stationary pain throughout follow-up (RR: 0.61; 95%CI: 0.48, 0.76, p-value: <0.0001; I2: 0. The incidence of progressive pain was non-significantly reduced with Stereotactic Radiotherapy during both early and late follow-up (RR: 0.77; 95% CI: 0.50, 1.17, p-value: 0.22; I2: 0%). Secondary outcomes exhibited a non-significant trend favoring Stereotactic Radiotherapy for dysphagia, esophagitis, pain, and radiodermatitis, while a non-significant increase was observed for nausea, fatigue, and vertebral compression fracture. ConclusionIn summary, stereotactic radiation therapy (SRT) has improved in achieving complete pain relief while exhibiting a decreased probability of delivering stationary pain compared to conventional radiation therapy (CRT). Nevertheless, it is crucial in future research to address a noteworthy limitation, specifically, the risk of vertebral compression fracture.

#40. Bone metastatic cancer derived stem cell factor induces sensory nerve sprouting in vitro and pain behavior in vivo through c-kit receptor activation

#40. Bone metastatic cancer derived stem cell factor induces sensory nerve sprouting in vitro and pain behavior in vivo through c-kit receptor activation

Abstract 2815: Immunotherapy development landscape for bone metastasis - need of predictive preclinical efficacy evaluation for de-risking clinical development

Abstract Most cancer deaths are due to metastases, and bone metastases are challenge especially in breast and prostate cancer, being developed in 70-90% of advanced-stage patients. Bone metastases remain incurable causing high mortality, skeletal-related effects and decreased quality of life. Currently used immunotherapies are ineffective in bone metastases. This creates a need to improve understanding immune microenvironment in bone metastases, namely interactions between tumor, immune and bone cells according to the osteoimmuno-oncology (OIO) concept, and ultimately to develop immunotherapies that primarily target bone metastases. We used 1stOncology database, a cancer drug development resource to identify novel immunotherapies in development for breast and prostate cancer bone metastasis. Twenty-four immunotherapies that included evaluation of effects on bone metastasis were identified. Efficacy of only three of the identified therapies had been evaluated in preclinical bone metastasis models, one reason being that such models have not been commonly available. The use of clinically relevant and predictive preclinical bone metastasis models would significantly de-risk decision making when moving to clinical development in bone metastasizing cancers. To support predictive preclinical evaluation of immunotherapies for bone metastatic cancers, we describe a preclinical bone metastasis technology platform for evaluating efficacy of immunotherapies. The platform utilizes tumors growing in bone microenvironment, mimicking growth of bone metastases in patients, and generates tumor-induced bone effects in a cancer-type specific manner. Syngeneic and/or humanized mouse models with tumor and immune cells of the same species are needed for development of immunotherapies, allowing interactions of tumor and immune cells in the bone metastatic microenvironment to support mode-of-action studies. The platform is clinically predictive, as demonstrated with observed effects that align with clinical findings. As an example, anti-PD-1 antibody had no effects on breast and prostate cancer bone metastases, predicting recent clinical findings that demonstrate lack of efficacy in clinical prostate cancer trials. We conclude that tumor microenvironment in bone metastases has unique characteristics and is understudied as a potential primary cause of lack of efficacy of many immunotherapies, especially in breast and prostate cancer. It is prime time to focus on bone metastases by increasing understanding of the immune landscape in the bone tumor microenvironment according to the OIO concept. The biologically relevant and clinically predictive preclinical bone metastasis technology platform should be routinely used to study the mechanism-of-action and efficacy of therapies before entering clinical development in bone metastasizing cancers. Citation Format: Tiina E. Kähkönen, Jussi M. Halleen, Gary MacRitchie, Ronnie M. Andersson, Jenni Bernoulli. Immunotherapy development landscape for bone metastasis - need of predictive preclinical efficacy evaluation for de-risking clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2815.

Abstract 6772: A 3D model of breast cancer-bone metastasis to mimic dysregulation of bone remodeling and drug response

Abstract Introduction: Bone metastases are common among advanced stage breast cancer patients and induce dysregulation of bone remodeling. Crosstalk between cancer cells and the bone niche drives the vicious cycle of bone loss and breast cancer growth. To accelerate discovery of targeted therapies, there is a critical need for experimental models that can mimic breast cancer-induced dysregulation of bone remodeling in patients. Mouse models are the current gold standard, but are low throughput, costly, and cannot fully recapitulate human-human cell interactions. To address these limitations, our goal is to engineer a fully human 3D in vitro model of breast cancer-bone metastasis that can mimic dysregulation of bone remodeling and drug responses in patients, and enable screening of potential new drug candidates. Methods: Two human breast cancer cell lines (MDA-MB-231, MCF-7) were chosen given their well characterized clinical features and tendency to invade bone. Our 3D model comprises an outer ring of tissue engineered (TE) bone and a center of breast cancer cells to mimic invasion through the bone marrow/long bone interface. Human mesenchymal stem cells were encapsulated in 3D gelatin microribbon scaffolds and cultured in osteogenic media for 28 days to form TE bone. Human monocyte-derived osteoclasts were seeded onto the bone, and the center was replaced with GFP-labeled breast cancer cells. Denosumab and zoledronic acid were selected as they are standard treatments for reducing bone loss in patients, and were used to treat the model at 30 µg/mL and 2 µg/mL, respectively. Intermittent parathyroid hormone (iPTH) treatment was selected as it showed efficacy in animal models, and was used to treat the model at 10 µg/mL for 6 hours daily. All groups were treated with drugs for 14 days. Bone volume was assessed using microCT. Cancer cell proliferation and invasion into bone was monitored with fluorescence confocal microscopy. Results: MicroCT imaging showed both breast cancer cell lines induced bone loss in the triculture model, compared to the control with no breast cancer cells in the center. Consistent with known clinical features, the more aggressive cell line (MDA-MB-231) induced a greater amount of bone loss than the less aggressive breast cancer cell line (MCF-7). Consistent with clinical findings, both denosumab and zoledronic acid reduced bone loss in our 3D model, and zoledronic acid further reduced breast cancer cell invasion and proliferation. Finally, the 3D model recapitulated the in vivo drug response of iPTH treatment, reducing bone resorption and breast cancer invasion. Conclusions: Here we report a fully human triculture model of breast cancer-bone metastasis that can mimic key clinical features of breast cancer-induced bone resorption and drug response in patients. Such a 3D model could enable screening of drug candidates with reduced time and cost and enable identification of novel druggable targets. Citation Format: Michelle Tai, Eva C. González Díaz, Callan E. Monette, Joy Wu, Fan Yang. A 3D model of breast cancer-bone metastasis to mimic dysregulation of bone remodeling and drug response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6772.

Functional and Rehabilitative Outcomes of Patients Affected by Bone Cancer of the Upper Limb Treated with MUTARS Prosthesis: A Narrative Review.

Megaprostheses are well-known, reliable, and effective reconstruction prostheses used in oncologic surgery for limb salvage in patients affected by primary or metastatic bone tumors. Rehabilitation plays a major role after MUTARS replacement, with the aim of improving function after surgery and maintaining the highest possible quality of life. Only a few studies have been published about the use of megaprostheses for the upper limb. The aim of this narrative review is to describe the results of functional and rehabilitative outcomes of patients affected by bone primary or metastatic bone cancer of the upper limb and surgically treated with MUTARS prostheses. A comprehensive search was conducted on PubMed and Scopus using the following MESH terms: "Mutars", "Megaprosthesis", "bone", "tumors", "metastasis", "upper limb", "rehabilitation", "outcome", "quality of life", and 10 studies were included. The most frequent oncological pathology was found to be metastases of the proximal humerus treated with modular endoprosthesis or modular reverse implants. Outcome measures used were ROM, MSTS, ASES, DASH, Constant-Murley score, Enneking score, VAS, MEP, TESS, and WOSI. Reconstruction of the proximal humerus with the MUTARS system seemed to be a valid treatment option after bone tumor resection. Rehabilitation after MUTARS surgery is very relevant, but currently, functional and rehabilitative outcomes are inadequately represented in the literature. Hence, further studies are needed to define standardized rehabilitation protocols after oncological orthopedic surgery that can be applied routinely in clinical practice.

Netrin-1 Role in Nociceptive Neuron Sprouting through Activation of DCC Signaling in a Rat Model of Bone Cancer Pain.

Bone cancer pain (BCP) is a common primary or metastatic bone cancer complication. Netrin-1 plays an essential role in neurite elongation and pain sensitization. This study aimed to determine the role of netrin-1 from the metastatic bone microenvironment in BCP development and identify the associated signaling pathway for the strategy of BCP management. The rat BCP model was established by intratibial implantation of Walker 256 cells. Von Frey filaments measured the mechanical pain threshold. Movement-induced pain was assessed using limb use scores. Expressions of associated molecules in the affected tibias or dorsal root ganglia (DRG) were measured by immunofluorescence, immunohistochemistry, real-time quantitative polymerase chain reaction, or western blotting. Transduction of deleted in colorectal cancer (DCC) signaling was inhibited by intrathecal injection of DCC-siRNA. In BCP rats, the presence of calcitonin gene-related peptide (CGRP)-positive nerve fibers increased in the metastatic bone lesions. The metastatic site showed enrichment of well-differentiated osteoclasts and expressions of netrin-1 and its attractive receptor DCC. Upregulation of DCC and increased phosphorylation levels of focal adhesion kinase (FAK) and Rac family small GTPase 1/Cell division cycle 42 (Rac1/Cdc42) were found in the DRG. Intrathecal administration of DCC-siRNA led to a significant reduction in FAK and Rac1/Cdc42 phosphorylation levels in the DRG, decreased nociceptive nerve innervation, and improved pain behaviors. Netrin-1 may contribute to the activation of the BCP by inducing nociceptive nerve innervation and improving pain behaviors.

Multiple influence of immune cells in the bone metastatic cancer microenvironment on tumors.

Bone is a common organ for solid tumor metastasis. Malignant bone tumor becomes insensitive to systemic therapy after colonization, followed by poor prognosis and high relapse rate. Immune and bone cells in situ constitute a unique immune microenvironment, which plays a crucial role in the context of bone metastasis. This review firstly focuses on lymphatic cells in bone metastatic cancer, including their function in tumor dissemination, invasion, growth and possible cytotoxicity-induced eradication. Subsequently, we examine myeloid cells, namely macrophages, myeloid-derived suppressor cells, dendritic cells, and megakaryocytes, evaluating their interaction with cytotoxic T lymphocytes and contribution to bone metastasis. As important components of skeletal tissue, osteoclasts and osteoblasts derived from bone marrow stromal cells, engaging in 'vicious cycle' accelerate osteolytic bone metastasis. We also explain the concept tumor dormancy and investigate underlying role of immune microenvironment on it. Additionally, a thorough review of emerging treatments for bone metastatic malignancy in clinical research, especially immunotherapy, is presented, indicating current challenges and opportunities in research and development of bone metastasis therapies.

C9orf10/Ossa regulates the bone metastasis of established lung adenocarcinoma cell subline H322L-BO4 in a mouse model.

Lung cancer frequently metastasizes to the bones. An in vivo model is urgently required to identify potential therapeutic targets for the prevention and treatment of lung cancer with bone metastasis. We established a lung adenocarcinoma cell subline (H322L-BO4) that specifically showed metastasis to the leg bones and adrenal glands. This was achieved by repeated isolation of metastatic cells from the leg bones of mice. The cells were intracardially injected into nude mice. Survival was prolonged for mice that received H322L-BO4 cells versus original cells (H322L). H322L-BO4 cells did not exhibit obvious changes in general in vitro properties associated with the metastatic potential (e.g., cell growth, migration, and invasion) compared with H322L cells. However, the phosphorylation of chromosome 9 open reading frame 10/oxidative stress-associated Src activator (C9orf10/Ossa) was increased in H322L-BO4 cells. This result confirmed the increased anchorage independence through C9orf10/Ossa-mediated activation of Src family tyrosine kinase. Reduction of C9orf10/Ossa by shRNA reduced cells' metastasis to the leg bone and prolonged survival in mice. These findings indicate that H322L-BO4 cells can be used to evaluate the effect of candidate therapeutic targets against bone metastatic lung cancer cells. Moreover, C9orf10/Ossa may be a useful target for treatment of lung cancer with bone metastasis.