Metastatic Bone Lesions Research Articles

Difficulties in Defining Oligometastatic Prostate Cancer: Implications for Clinical Trial Accrual and Community Practice Adoption of Metastasis-Directed Therapy Approaches

Metastasis-directed therapy is widely utilized for oligometastatic prostate cancer patients, but standard imaging does not always identify metastases definitively and, even with PSMA PET, there may be equivocal findings. Not all clinicians have access to detailed imaging review, particularly outside of academic cancer centers, and PET scan access is also limited. We sought to understand how imaging interpretation impacted recruitment to a clinical trial for oligometastatic prostate cancer. IRB approval was obtained to review medical records from all patients screened for the institutional IRB-approved clinical trial for men with oligometastatic prostate cancer involving androgen deprivation plus stereotactic radiation to all metastatic sites, as well as radium223 (NCT03361735). Clinical trial inclusion required at least one bone metastatic lesion and no more than five total sites of metastasis, including soft tissue sites. Tumor board discussion records were reviewed, along with results from additional radiology studies ordered or confirmatory biopsies performed. Clinical characteristics such as PSA level and Gleason score were studied for association with likelihood of oligometastatic disease confirmation. At the time of data analysis, 18 subjects were deemed eligible and 20 were not eligible. The most common reasons for ineligibility were no confirmed bone metastasis in 16 patients (59%) and too many metastatic sites in 3 (11%). The median PSA of eligible subjects was 3.28 (range 0.4-45.5), whereas the median PSA of those found to be ineligible was 10.45 (range 3.7-26.3) when there were too many metastases identified, and 2.7 (range 0.2-34.5) when metastases were unconfirmed. PET imaging (PSMA or fluciclovine PET) increased the number of metastases, while MRI resulted in downstaging to non-metastatic disease. This research suggests that additional imaging (i.e., at least two independent imaging modalities of a possible metastatic lesion) or tumor board adjudication of imaging findings may be critical to correctly identify patients appropriate for enrollment in oligometastatic protocols. This should be considered as trials of metastasis-directed therapy for oligometastatic prostate cancer accrue and results are translated to broader oncology practice.

Abstract P1-02-05: Endocrine-targeted therapies modify the gut microbiome affecting responsiveness in ER+ breast cancer

Abstract Background: The microbiome consists of the totality of microorganisms (bacteria, fungi, protist, viruses, and phages) that live on and within the body. Studies implicate the gut bacterial microbiome as a risk factor for estrogen receptor-positive (ER+) breast cancer. While diet is the main contributor to the gut microbiome, medications also shift the bacterial microbiome. We currently do not know whether oral endocrine targeting therapies, such as aromatase inhibitors or tamoxifen shift the gut microbiome. Furthermore, we do not know whether gut microbiome populations can influence drug efficacy. Methods: Fecal samples from human donors were placed into ex-vivo colonic bioreactors for stabilization (n=3). Bioreactors were untreated or treated with letrozole or tamoxifen citrate for 48 hours. Samples were collected, DNA isolated, and metagenomic sequencing performed to determine direct drug-bug interactions. C57BL/6 mice were placed on a healthy control (HC; 21% kcal from fat derived from olive oil and fish oil) or a Western diet (45% kcal from fat derived from corn oil, lard, and milkfat) for 6 weeks. Mice within dietary patterns were randomized and administered control, tamoxifen (TAM; 37 ppm tamoxifen citrate), or an aromatase inhibitor (AI; 5 ppm letrozole) for 16 weeks. Metagenomics sequencing were performed on fecal DNA samples at study endpoint. Female BALB/c mice fed a HC or Western diet were injected with bone metastatic 4T1.2ER+ breast cancer cells. Mice were administered tamoxifen citrate, oral probiotics, or a combination of TAM + probiotics for 3-weeks. Tumor volume, tumor weight, and lung weight were recorded at the end of the study. Hindlimbs were analyzed for metastatic lesions. Results: Metagenomic sequencing from the ex-vivo colonic bioreactors treated with aromatase inhibitors or tamoxifen display differential shifts in several β-glucuronidase-expressing and obesity-associated bacterial species suggesting AI and selective estrogen receptor modulators have varying effects in the gut microbiome that may influence estrogen bioavailability and metabolic parameters. C57BL/6 mice on HC or Western diet treated with AI or TAM also display differences in the microbiota and phage populations with TAM elevating Lactobacillus johnsonii and letrozole increasing Lactococcus lactis bacterial proportional abundance. In the tumor-bearing model, combination of oral Lactobacillus probiotics and TAM significantly reduced tumor weight when compared with the tumor weight in control, TAM, or probiotic treated mice fed a Western diet. Combination of probiotics and TAM also prevented the development of ER+ bone metastatic lesions. Conclusions: Our study indicates oral endocrine therapies differentially affect the gut microbiome and these drug-bug interactions are sensitive to dietary-influenced baseline microbiota populations, which may influence drug efficacy and metabolic outcomes. Furthermore, our preclinical studies suggest oral probiotic supplements may enhance tamoxifen efficacy to reduce tumor growth and metastatic development. Further clinical studies are needed on this topic. Citation Format: Alana Arnone, Adam S. Wilson, Akiko Chiba, Bethany Kerr, David R. Soto-Pantoja, Alexandra Thomas, Katherine L. Cook. Endocrine-targeted therapies modify the gut microbiome affecting responsiveness in ER+ breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-02-05.

Abstract WS2-3: Therapy-induced senescence: Friend or foe?

Abstract The stromal compartment plays a pivotal role in tumor progression. This is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKa is frequently expressed in tumor cells and surrounding stromal cells and its expression levels correlate with poor prognosis. Using clinically relevant breast cancer metastasis models, we show that orally administered, small-molecule inhibitors of p38MAPKa or its downstream kinase, MK2, each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. Further we found that this effect is mediated by inhibition of the p38MAPKa pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, we also found that these inhibitors reduced tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity for cancer patients that drastically impacts their quality of life. Mechanistic studies revealed that p38MAPKa’s ability to limit tumor growth within the bone is dependent on CD4 T cells and macrophages. To determine which cell types within the bone contribute to tumor growth and bone loss, we carried out single cell RNA-sequencing of stromal cells located within the bone metastatic lesion and cells outside the lesion. We found numerous differences that could explain how the stromal compartment contributes to tumor progression and bone loss and how inhibition of p38MAPKa or MK2 contribute. These data underscore the vital role stromal-derived factors play in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss. Citation Format: Sheila Stewart. Therapy-induced senescence: Friend or foe? [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr WS2-3.

Near-infrared photoimmunotherapy (NIR-PIT) of bone metastases

The bones are a common site for metastasis arising from solid tumors such as breast and prostate cancer. Chemotherapy, including immunotherapy, is rarely curative. Radiotherapy with pain palliation can temporize bone metastases but is generally considered a short-term solution and retreatment is difficult. Surgery is often necessary, yet recovery times might exceed life expectancy. Therefore, there is a need to develop new approaches to bone metastases that are effective but minimally invasive. Near-infrared photoimmunotherapy (NIR-PIT) uses antibodies labeled with IRDye700DX (IR700) which is activated by NIR light, resulting in rapid cell membrane damage and immunogenic cell death. NIR-PIT using an anti-epidermal growth factor receptor (EGFR) antibody-IR700 conjugate in patients with recurrent head and neck cancer received qualified approval in Japan in 2020 and is now widely used there. However, no bone metastases have yet been treated. In this study, the efficacy of NIR-PIT for bone metastases was investigated using a bone metastases mouse model successfully established by caudal artery injection of a human triple-negative breast cancer cell line, MDAMB468-GFP/luc. The bone metastatic lesions were treated with NIR-PIT using the anti-EGFR antibody, panitumumab-IR700 conjugate. Bioluminescence imaging and histological evaluation showed that EGFR-targeted NIR-PIT has a therapeutic effect on bone metastatic lesions in mice. In addition, micro-CT showed that repeated NIR-PIT led to repair of metastasis-induced bone destruction and restored bone cortex continuity consistent with healing. These data suggest that NIR-PIT has the potential for clinical application in the treatment of bone metastases.

Skeletal standardized uptake values obtained using quantitative SPECT/CT for the detection of bone metastases in patients with lung adenocarcinoma.

To assess the utility of skeletal standardized uptake values (SUVs) obtained using quantitative single-photon emission computed tomography/computed tomography (SPECT/CT) in differentiating bone metastases from benign lesions, particularly in patients with lung adenocarcinoma. Patients with lung adenocarcinoma who had undergone whole-body Tc-99m methyl-diphosphonate (99mTc-MDP) bone scans and received late phase SPECT/CT were retrospectively analyzed in this study. The maximum SUV (SUVmax); Hounsfield units (HUs); and volumes of osteoblastic, osteolytic, mixed, CT-negative metastatic and benign bone lesions, and normal vertebrae were compared. Receiver operating characteristic curves were used to determine the optimal cutoff SUVmax between metastatic and benign lesions as well as the cutoff SUVmax between CT-negative metastatic lesions and normal vertebrae. The linear correlation between SUVmax and HUs of metastatic lesions as well as that between SUVmax and the volume of all bone lesions were investigated. A total of 252 bone metastatic lesions, 140 benign bone lesions, and 199 normal vertebrae from 115 patients with lung adenocarcinoma were studied (48 males, 67 females, median age: 59 years). Metastatic lesions had a significantly higher SUVmax (23.85 ± 14.34) than benign lesions (9.67 ± 7.47) and normal vertebrae (6.19 ± 1.46; P < 0.0001). The SPECT/CT hotspot of patients with bone metastases could be distinguished from benign lesions using a cutoff SUVmax of 11.10, with a sensitivity of 87.70% and a specificity of 80.71%. The SUVmax of osteoblastic (29.16 ± 16.63) and mixed (26.62 ± 14.97) lesions was significantly greater than that of osteolytic (15.79 ± 5.57) and CT-negative (16.51 ± 6.93) lesions (P < 0.0001, P = 0.0003, and 0.002). SUVmax at the cutoff value of 8.135 could distinguish CT-negative bone metastases from normal vertebrae, with a sensitivity of 100.00% and a specificity of 91.96%. SUVmax showed a weak positive linear correlation with HUs in all bone metastases and the volume of all bone lesions. SUVmax of quantitative SPECT/CT is a useful index for distinguishing benign bone lesions from bone metastases in patients with lung adenocarcinoma, particularly in the diagnosis of CT-negative bone metastases, but other factors that may affect SUVmax should be considered.

Development of a prognostic model in patients with metastatic bone lesions to choose surgical treatment: retrospective study

Choosing surgical management for patients with metastatic bone lesions is one of the essential problems of modern oncology. Surgical interventions are aimed at palliative treatment in most patients with metastatic skeletal lesions. However, curative resections with reconstruction and plasty steps may be considered in selected cases of a solitary metastatic lesion. The life expectancy prognosis based on the histological structure of the tumor is a significant and decisive factor in choosing the appropriate surgery.&#x0D; Aim. To develop a prognostic model for choosing surgical treatment for metastatic bone lesions.&#x0D; Materials and methods. Treatment analysis of 715 patients with a history of surgery for metastatic bone lesions of various localizations is presented. A total of 780 surgical interventions were performed. Surgeries for the complications of bone metastases were mainly performed on the spine (48.5% of all surgeries), followed by long bones with 247 (35%) surgeries, pelvic bones with 81 (11%) interventions, and the chest wall with 40 (5.5%) surgeries.&#x0D; Results. The most unfavorable prognostic factors in patients with metastatic bone lesions are the histological type of the primary tumor of the rapid growth group (risk ratio [RR]=5.11), visceral metastases (RR=3.1), Charlson Comorbidity Index over 10 (RR=3.07) and presence of critical laboratory abnormalities (RR=2.91), as they have the highest rates of impact on survival (over 2.9).&#x0D; Conclusion. The developed 14-point mathematical score of life expectancy prognosis, which includes five oncological and four clinical factors, defines with an accuracy of 91% the risk groups of good (estimated life expectancy over one year), moderate (6 to 12 months), and poor (less than six months) prognosis in patients with metastatic bone lesions.

Risk of leptomeningeal metastasis in children with parameningeal rhabdomyosarcoma with intracranial spread

Introduction. Soft tissue tumors account for up to 8 % of all malignant neoplasms in children. According to the international histological classification, about 150 different morphological variants of soft tissue tumors have been registered, of which 45 % are rhabdomyosarcoma (RMS). Most often, RMS occurs in early childhood – the average age of patients at the time of diagnosis is 5 years. The incidence rate of RMS is 0.9 per 100,000 children. In 25 % cases, the initial diagnosis reveals distant metastasis to the lungs, bones, bone marrow, and 8 % – leptomeningeal metastasis. More than 7 % of patients with localized parameningeal RMS develop leptomeningeal metastasis, according to the Rhabdomyosarcoma Study Group. Purpose of the study – report the incidence, prognosis of leptomeningeal metastasis and treatment outcomes in children with intracranial spread of RMS. Materials and methods. The study included 45 patients aged 1 to 17 years with a diagnosis of RMS of parameningeal localization with intracranial spread, who received special treatment from 2003 to 2020. The study included 6 (20 %) patients in whom the tumor developed in early childhood (up to 3 years). The boys predominated – 25 (55.5 %) in the study. The primary tumor spread to the orbit in 7 (15 %) cases, the skull base in 7 (15 %) cases, the middle ear in 4 (8 %) cases, the nasopharynx in 3 (6 %) cases, and the brain substance was affected in 16 (35 %). Metastases in regional lymph nodes were determined in 7 (15 %) patients. Multiple metastatic lesions of bones and bone marrow – 4 (9 %) cases, leptomeningeal metastases – in 2 (4 %). 45 (100 %) patients received drug treatment according to the protocols approved by the Academic Council of the Research Institute of Pediatric Oncology and Hematology at N. N. Blokhin National Medical Research Centerof Oncology, Ministry of Health of Russia. Radiation therapy was performed in 33 (74 %) patients, while total focal dose of 50 Gy was administered to the primary tumor. Affected lymph nodes of the neck were irradiated in 10 (23 %) patients, total focal dose is 45.0 Gy. Surgical treatment was performed in 15 (34 %) patients. Multicomponent treatment was performed in 15 (34 %) patients. Results. During the observation period from 12 months to 14 years, 21 (49 %) patients are alive. 21 (51 %) patients died from tumor progression, 1 (2 %) died from complications of special treatment. Conclusions. The treatment of this group of patients is one of the urgent problems of pediatric oncology, which is based on polychemotherapy, supplemented by intrathecal administration of anticancer drugs and craniospinal irradiation. The development of new therapies requires a multidisciplinary approach to achieve a significant improvement in the survival of children with leptomeningeal metastases RMS of parameningeal localization.

SHDB mutant functional metastatic paraganglioma: The efficacy of Lutetium-177 DOTATE

Abstract Introduction Therapeutic options for metastatic paraganglioma (PGL) are limited, especially in the presence of uncontrolled secondary hypertension (HTN). Early findings from Lutetium-177 (Lu-177) DOTATE show promise for efficacy, although data on HTN control and survival are uncertain. Herein, we presented the successful treatment of a patient with metastatic PGL and uncontrolled HTN with Lu-177 DOTATE. Clinical Case A 16-year-old woman was admitted to the emergency department with severe headache, nausea and vomiting. She also reported stomach and low back pain for three months. The patient's blood pressure was 220/140 mmHg and a sodium nitroprusside infusion was started to treat the hypertensive crisis. On physical examination she had abdominal tenderness. A computer tomography (CT) examination revealed 6 cm mass, multiple metastatic nodular lesions in the lung and liver, as well as lytic lesions in all bones, and metastatic lymph nodes in thorax and abdomen. She is referred to our department for further evaluation HTN. Laboratory examinations revealed that plasma norepinephrine 24926 ng/L (70–480), 24-hour urine norepinephrine 1335 µg/day (20–81), metanephrine 534 µg/day (52–341), 3-metoksitiramine 771 µg/day (0–451), normetanephrine 20456 µg/day (88–444). Other laboratory findings were normal range. MIBG I131 scan which showed pathological uptake of MIBG was demonstrated in the regions described on CT. Genetic panel by next-generation sequencing (NGS) identify germline mutation and she had heterozygous mutations in SHDB (c.725 G&amp;gt;A) and BUB1B (c.1378 C&amp;gt;T). Surgical treatment was performed, and pathological finding reported 6cm mass, Ki-67 labeling index: %2, chromogranin A diffuse positive and there was vascular invasion. It was confirmed to be malignant PGL. 131I-MIBG therapy couldn't be given because of drugs interaction that used by patient. She received 13 cycles chemotherapy (cyclophosphamide, vincristine, dacarbazine) and palliative radiotherapy to metastatic bone lesions. She continued, however, to suffer from low back pain and HTN. Rising plasma and urine catecholamine levels. Therefore, conventional chemotherapy had been discontinued and he was commenced on Lu-DOTATATE therapy. Up to now, she has received 2 cycles at intervals of three months. Her clinical response was excellent with gradual improvement of symptoms and quality of life. Blood pressure is now within normal values without medication. There was significant reduction in the size of overall metastatic disease on Ga-68 DOTATE scanning. Conclusion Lu-177 DOTATE has potential advantages (drug interaction, radiation-safety) compared with 131I-MIBG therapy and chemotherapy. Our case demonstrates significant clinical and biochemical success in patients with metastatic PGL in addition to excellent disease management with low toxicity from PRRT. Lu-177 DOTATATE therapy is an effective and safe modality of treatment for patients with metastatic PGL.

Optimization of staging algorithm for newly detected prostate cancer by using PET/CT with &lt;sup&gt;68&lt;/sup&gt;Ga-PSMA: a retrospective study

INTRODUCTION: Prostate cancer (PC) is the most common malignancy in men worldwide and ranks third in mortality. Improvement of the results of staging of newly detected prostate cancer is rightfully associated with the active use in clinical practice of positron emission tomography combined with computed tomography (PET/CT) with radiotracers based on prostate-specific membrane antigen (PSMA) ligands.OBJECTIVE: The aim of the study was to determine the capabilities of PET/CT with 68Ga-PSMA in evaluating the prevalence of newly diagnosed breast cancer in comparison with traditional imaging techniques (computed tomography, magnetic resonance imaging and bone scan) and to determine the role of this technology in the choice of treatment algorithm.MATERIALS AND METHODS: 120 patients aged 46 to 74 years (median age 62.5 years) with histologically verified prostate cancer underwent PET/CT with 68Ga-PSMA in our center to assess disease prevalence. The selection criteria for the study were: prostate-specific antigen (PSA) level of 5 ng/ml and above, presence of newly detected, histologically verified prostate cancer, no treatment, suspected metastatic lesion of pelvic and skeletal lymph nodes according to CT, MRI and OSG. All patients were divided into groups according to PSA level and Gleason score. Statistics: Statistical processing of the results was performed by methods of variance statistics using Statistica 10.0, GraphPad Prism 9.3.1. Wilcoxon-Mann-Whitney and Friedman tests for ANOVA were used to determine the significance of differences between comparison groups. The chi-square test with Yates correction was used to determine the reliability of intergroup differences for nominal measures (such as the presence of previous recurrences). The level of correlation was assessed using Spearman criterion.RESULTS: PET/CT imaging analysis in addition to MRI, CT, and OSG data showed TNM staging changes in 63 of 120 patients (52.3%) due to the detection of additional foci of metastatic lesions. Change of data about local spread of tumor with increasing of TNM stage due to detection of pathological RFP accumulation in seminal vesicles in 10 of 120 patients (8.3%), without structural changes using conventional imaging methods. In 20 of 64 patients (31.3%), PET/CT revealed lesions of regional lymph nodes (N) that were not visualized by conventional imaging methods due to their small size. Metastatic lesions of distant lymph nodes (M1a) and bones (M1b) undetected by CT, MRI, and OSG were found in 27 (22.5%) and 32 (26.7%) of 120 patients, respectively. At the same time, foci of pathological accumulation of 68Ga-PSMA in the bones without structural changes on CT were detected in 7 and 32 patients (21.8%).DISCUSSION: One of the objectives of this study was to compare the diagnostic capabilities of standard diagnostic imaging techniques, in particular MRI, CT and Bone scan, with the hybrid technology of PET/CT with 68Ga-PSMA to improve the accuracy of PCa staging in order to determine treatment tactics. The results demonstrate minimal superiority of PET/CT with 68Ga-PSMA over MRI in terms of sensitivity (96% and 94%, respectively) in assessing local disease prevalence. Tumor invasion of the seminal vesicles, in most cases, was detected in patients with a Gleason score greater than 8. At the same time there was a tendency for an increase in the level of radiotracer accumulation in the tumor tissue of the seminal vesicles depending on the differentiation group of PCa. Analysis of the histological material obtained after the prostatectomy demonstrated tumorous invasion of the seminal vesicles in 26 (37.1%) out of 70 operated patients. Coincidence of histological examination results with PET/CT data was found in 22 patients, with MRI data — in 20 patients. The sensitivity, specificity, positive predictive value, and negative predictive value of PET/CT were 85%, 92%, 85%, and 92%, while the corresponding values from MRI were as follows: 77%, 88%, 77%, and 88%. Analyzing the levels of 68Ga-PSMA uptake in the tumor tissue, we found that with increasing prostate differentiation group, there was a persistent increase in radiotracer accumulation in the prostate tumor tissue. We also evaluated the interrelation of RFP accumulation with PSA level. The patients with PCa with PSA level ≥10.0 ng/ml demonstrated high accumulation of radiotracer accumulation compared to those with PSA &lt;10.0 ng/ml (p&lt;0.001).CONCLUSIONS: The use of 68Ga-PSMA PET/CT in the staging of newly diagnosed and untreated cancers provides comprehensive information on the local, regional, and distant extent of the disease, and in some cases contributes to a change in TNM stage of the disease in a single study. The use of this method before planned surgical treatment of PCa can significantly reduce the risk of early postoperative relapse, especially in patients with a Gleason score of more than 7 and a PSA level greater than 20 ng/ml.

Abstract IA012: Age related changes in the tumor microenvironment drive tumor progression

Abstract The stromal compartment plays a pivotal role in tumor progression. This is best illustrated in breast cancer bone metastases, where the stromal compartment supports tumor growth, albeit through poorly defined mechanisms. p38MAPKα is frequently expressed in tumor cells and surrounding stromal cells and its expression levels correlate with poor prognosis. Using clinically relevant breast cancer metastasis models, we show that orally administered, small-molecule inhibitors of p38MAPKα or its downstream kinase, MK2, each limited outgrowth of metastatic breast cancer cells in the bone and visceral organs. Further we found that this effect is mediated by inhibition of the p38MAPKα pathway within the stromal compartment. Beyond effectively limiting metastatic tumor growth, we also found that these inhibitors reduced tumor-associated and chemotherapy-induced bone loss, which is a devastating comorbidity for cancer patients that drastically impacts their quality of life. Mechanistic studies revealed that p38MAPKα’s ability to limit tumor growth within the bone is dependent on CD4 T cells and macrophages. To determine which cell types within the bone contribute to tumor growth and bone loss, we carried out single cell RNA-sequencing of stromal cells located within the bone metastatic lesion and cells outside the lesion. We found numerous differences that could explain how the stromal compartment contributes to tumor progression and bone loss and how inhibition of p38MAPKα or MK2 contribute. These data underscore the vital role stromal-derived factors play in tumor progression and identify the p38MAPK-MK2 pathway as a promising therapeutic target for metastatic disease and prevention of tumor-induced bone loss. Citation Format: Sheila A. Stewart. Age related changes in the tumor microenvironment drive tumor progression [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA012.

A Multicompartmental Diffusion Model for Improved Assessment of Whole-Body Diffusion-weighted Imaging Data and Evaluation of Prostate Cancer Bone Metastases

Purpose To develop a multicompartmental signal model for whole-body diffusion-weighted imaging (DWI) and apply it to study the diffusion properties of normal tissue and metastatic prostate cancer bone lesions in vivo. Materials and Methods This prospective study (ClinicalTrials.gov: NCT03440554) included 139 men with prostate cancer (mean age, 70 years ± 9 [SD]). Multicompartmental models with two to four tissue compartments were fit to DWI data from whole-body scans to determine optimal compartmental diffusion coefficients. Bayesian information criterion (BIC) and model-fitting residuals were calculated to quantify model complexity and goodness of fit. Diffusion coefficients for the optimal model (having lowest BIC) were used to compute compartmental signal-contribution maps. The signal intensity ratio (SIR) of bone lesions to normal-appearing bone was measured on these signal-contribution maps and on conventional DWI scans and compared using paired t tests (α = .05). Two-sample t tests (α = .05) were used to compare compartmental signal fractions between lesions and normal-appearing bone. Results Lowest BIC was observed from the four-compartment model, with optimal compartmental diffusion coefficients of 0, 1.1 × 10-3, 2.8 × 10-3, and >3.0 ×10-2 mm2/sec. Fitting residuals from this model were significantly lower than from conventional apparent diffusion coefficient mapping (P < .001). Bone lesion SIR was significantly higher on signal-contribution maps of model compartments 1 and 2 than on conventional DWI scans (P < .008). The fraction of signal from compartments 2, 3, and 4 was also significantly different between metastatic bone lesions and normal-appearing bone tissue (P ≤ .02). Conclusion The four-compartment model best described whole-body diffusion properties. Compartmental signal contributions from this model can be used to examine prostate cancer bone involvement. Keywords: Whole-Body MRI, Diffusion-weighted Imaging, Restriction Spectrum Imaging, Diffusion Signal Model, Bone Metastases, Prostate Cancer Clinical trial registration no. NCT03440554 Supplemental material is available for this article. © RSNA, 2023 See also commentary by Margolis in this issue.

A Retrospective Analysis of Denosumab for the Treatment of Bone Metastases in Chinese Patients With Breast Cancer.

Denosumab entered the Chinese market for the first time in 2020. Since it is a short period of time, there is a lack of data on its effectiveness and safety in Chinese people. The objective of this study was to evaluate the effectiveness and safety of denosumab in delaying skeletal-related events (SREs) in patients with breast cancer metastatic to bone. The study retrospectively analyzed data from breast cancer patients with bone metastases (BM) who were treated with denosumab in the First Affiliated Hospital of Nanjing Medical University from September 2020 to January 2022. The primary endpoint was SRE incidence at 1 year after receiving denosumab treatment. The secondary endpoints included time to first on-study SRE and safety. Descriptive analysis was utilized to display clinicopathological features. The Kaplan-Meier method was used to estimate the median time to first on-study SRE in total population and subgroups. Logistic regression analysis and χ2 test were employed to determine the potential factors influencing the occurrence of SREs. Fifty breast cancer patients with BM were enrolled in our study, and 54.0% of the patients had 5 or more metastatic bone lesions. After a median follow-up of 17.00 months, 24% of the patients developed SREs at 1 year after receiving denosumab treatment, and the median time to first on-study SREs was not reached. Five or more metastatic bone lesions were an independent risk factor for SRE occurrence (odds ratio = 6.06, 95% CI: 1.09-33.54, P = .039). The adverse events (AEs) associated with denosumab mainly included hypocalcemia (68.0%), periodontitis (28.0%), and myalgia (14.0%). Only 3 cases of grade III/IV AEs were reported, and no serious AEs occurred. Denosumab was effective and well tolerated in Chinese breast cancer patients with BM.

Metastatic bone lesions: molecular mechanisms as new avenues of therapeutic influence. Literature review

Metastatic bone lesions: molecular mechanisms as new avenues of therapeutic influence. Literature review

Multiple myeloma with disseminated sclerotic lesions mimicking metastatic bone lesions; a rare case series

Background: Lesions characterized by myeloma are lytic lesions surrounded by sclerosis. Diffuse or wide-length sclerotic bone lesions associated with myeloma are infrequent. Case presentation: Two men, 70 and 72 years old, were referred from oncology to hematology for diffuse, large-length sclerotic bone lesions. Their findings were interpreted as having bone metastasis of primary cancer in orthopedics, internal medicine, and oncology due to diffuse sclerotic bone lesions found incidentally during the examinations performed for another reason. The probable causes (prostate, lung, and gastrointestinal cancer) of metastasis were investigated, and they were referred to hematology after a nearly 2-month examination period. Conclusion: The remarkable extensive sclerotic bone lesions may mask the myeloma and may not be considered in the differential diagnosis. However, these cases had the typical clinical findings and laboratory results of MM, except for bone disease. Therefore, we aimed to highlight this issue.

Guidelines for Evaluating Treatment Response Based on Bone Scan for Metastatic Castration-Resistant Prostate Cancer: Prostate Cancer Clinical Trial Working Group 3 Recommendations

In prostate cancer, the bone is the most common site of metastasis, and it is essential to evaluate metastatic bone lesions to assess the tumor burden and treatment response. Castration-resistant prostate cancer refers to the state wherein the cancer continues to progress despite a significant reduction of the sex hormone level and is associated with frequent distant metastasis. The Prostate Cancer Working Group 3 (PCWG3) released guidelines that aimed to standardize the assessment of treatment effects in castration-resistant prostate cancer using bone scintigraphy. However, these guidelines can be challenging to comprehend and implement in practical settings. The purpose of this review was to provide an overview of a specific image acquisition method and treatment response assessment for bone scintigraphy-based evaluation of bone lesions in metastatic castration-resistant prostate cancer, in accordance with the PCWG3 guidelines.

Additively manufactured Bi-functionalized bioceramics for reconstruction of bone tumor defects.

Bone tissue exhibits critical factors for metastatic cancer cells and represents an extremely pleasant spot for further growth of tumors. The number of metastatic bone lesions and primary tumors that arise directly from cells comprised in the bone milieu is constantly increasing. Bioceramics have recently received significant attention in bone tissue engineering and local drug delivery applications. Additionally, additive manufacturing of bioceramics offers unprecedented advantages including the possibilities to fill irregular voids after the resection and fabricate patient-specific implants. Herein, we investigated the recent advances in additively manufactured bioceramics and ceramic-based composites that were used in the local bone tumor treatment and reconstruction of bone tumor defects. Furthermore, it has been extensively explained how to bi-functionalize ceramics-based biomaterials and what current limitations impede their clinical application. We have also discussed the importance of further development into ceramic-based biomaterials and molecular biology of bone tumors to: (1) discover new potential therapeutic targets to enhance conventional therapies, (2) local delivering of bio-molecular agents in a customized and "smart" way, and (3) accomplish a complete elimination of tumor cells in order to prevent tumor recurrence formation. We emphasized that by developing the research focus on the introduction of novel 3D-printed bioceramics with unique properties such as stimuli responsiveness, it will be possible to fabricate smart bioceramics that promote bone regeneration while minimizing the side-effects and effectively eradicate bone tumors while promoting bone regeneration. In fact, by combining all these therapeutic strategies and additive manufacturing, it is likely to provide personalized tumor-targeting therapies for cancer patients in the foreseeable future. STATEMENT OF SIGNIFICANCE: To increase the survival rates of cancer patients, different strategies such as surgery, reconstruction, chemotherapy, radiotherapy, etc have proven to be essential. Nonetheless, these therapeutic protocols have reached a plateau in their effectiveness due to limitations including drug resistance, tumor recurrence after surgery, toxic side-effects, and impaired bone regeneration following tumor resection. Hence, novel approaches to specifically and locally attack cancer cells, while also regenerating the damaged bony tissue, have being developed in the past years. This review sheds light to the novel approaches that enhance local bone tumor therapy and reconstruction procedures by combining additive manufacturing of ceramic biomaterials and other polymers, bioactive molecules, nanoparticles to affect bone tumor functions, metabolism, and microenvironment.

Transarterial Embolization of Bone Metastases

Embolization of bone metastases is most commonly performed for hypervascular tumors prior to surgical resection. When employed in this fashion embolization can significantly decrease perioperative hemorrhage and improve surgical outcomes. In addition, embolization of bone metastases may lead to local tumor control and decreased tumoral associate bone pain. Careful techniques and choice of embolic material are required when performing embolization of bone lesions to ensure low procedural complications and high rates of clinical success.4 The indications, technical considerations, and complications associated with embolization of metastatic hypervascular bone lesions will be discussed in this review with subsequent case examples.

Long-term oncological results of patients with primary and metastatic tumors of the musculoskeletal system who underwent arthroplasty

Introduction. Primary malignant tumors of the skeletal system mostly develop in young and middle-aged people. Morbidity in this age group amounts to between 75 and 80 % of overall morbidity. Due to low survival caused by patient death in the first 5 years mostly because of metastases of primary malignant tumors, the main focus of treatment was on prolongation of life, study and development of new methods of conservative therapy. Therefore, until the early 1970 amputation surgery was the generally accepted standard of surgical intervention. Positive oncological results required revision of the surgical concept of treatment in this patient group. This problem was solved through active development of oncological endoprosthesis started in the second half of the 1970s and led to shaping of orthopedic oncology into a separate oncological specialty. The study objective is to study long-term oncological results of treatment of patients with primary and metastatic tumors of the locomotor system after oncological endoprosthesis.Materials and methods. The study included 1292 patients with primary sarcomas of the bones, soft tissues and patients with metastatic and benign bone tumors who underwent 1200 bone resections/extirpations of varying scale with endoprosthetic replacement between January of 1992 and January of 2020. In the total group of patients who underwent endoprosthesis, the number of men and women was approximately the same: 677 (52.4 %) and 615 (47.6 %), respectively. At the time of surgery, age of the patients in the total group varied between 10 and 81 years. Mean patient age was 34.7 years. Most commonly, endoprosthetic replacement was performed in patients between the ages of 21 and 30 years (in 29 % of cases). Oncological endoprosthesic replacement was performed in 814 (67.8 %) patients with primary malignant tumors, 143 (11.9 %) patients with metastatic lesions in long bones, and 243 (20.3 %) patients with benign neoplasms. Mean follow-up period after endoprosthesis of different bone segments was 82.8 months (between 0 and 335.7 months).Results. In 27 years of observations, total frequency of recurrences after endoprosthesis for various tumor locations (type V complication per the International Society of Limb Salvage system (2013) (ISOLS 2013)) was 8.8 % (86/979); among them recurrence in the bone (type VA complication) was observed in 1.7 % (17/979) of cases, recurrence in the soft tissues (type VB complication) in 7.0 % (69/979) of cases. Primary endoprosthetic replacement due to recurrence after previous surgical treatment leads to 2.2-time increase in the risk of development of this complication. The obtained results show that repeat recurrence significantly increases the risk of recurrence in soft tissues and does not affect the risk of recurrence in the bone. The most recurrences developed in patients with non-differentiated pleomorphic sarcoma (15.4 % of cases), chondrosarcoma (15.0 % of cases) and parosteal osteosarcoma (14.3 % of cases). Frequency of recurrences in patients with giant cell bone tumors and aneurysmal bone cysts was 4.0 and 3.8 %, respectively. In cases of tumor recurrence after endoprosthesis, limb amputation was the most common treatment: 33.7 % (28/83) of cases. In this study, recurrence mostly developed after femur resection with knee joint endoprosthesis: in 45.8 % (38/83) of cases. Frequency of oncological complications in patients with bone sarcomas who underwent endoprosthetic replacement was 31.9 % (283/886). In the total patient group in 27 years of observations, in 25.3 % (224/886) of patients disease progression in the form of metastases was observed. Local tumor recurrence was accompanied by metastases in 6.7 % (59/886) of cases.Conclusion. Decreased risk of development of local recurrences depends on the effectiveness of complex approach to therapy in this disease group. Changes in surgical endoprosthesis techniques in tumors of varying differentiation levels allowed to achieve significant radicalness of treatment. Progression risk for bone sarcomas, level of response to specialized therapy and, as a result, patient’s prognosis depend on the presence of epigenetic, genetic, molecular and chromosomal abnormalities.

PP122 Magnetic Resonance-guided High-intensity Focused Ultrasound For Non-surgical Treatment Of Prostate Cancer, Uterine Fibroids, Adenomyosis And Pain In Bone Metastases

IntroductionMagnetic resonance imaging guided high-intensity focused ultrasound (MR-HIFU) is a non-invasive technique with a low risk of complications for the patient and few side effects. Integration with MRI allows monitoring of the temperature regime of thermal doses, which protects important structures from overheating, and at the same time directing a high thermal dose to the target tissue.MR-HIFU in the treatment of uterine fibroids, prostate cancer and the treatment of pain in bone metastases is compared with both traditional methods of treatment (uterine artery embolization, hysterectomy, prostatectomy, etc.).MethodsTo assess the clinical effectiveness and safety of non-invasive MR-HIFU, a literature search was performed in the MEDLINE database using the following keywords:“MRgFUS” “MR-HIFU”. The following filters were used: (i) article type: meta-analysis, systematic review, guidance; (ii) date of publication: no later than 5 years (from 2016).ResultsAccording to the search terms, 104 publications were submitted to MEDLINE for keywords. After using filters, 57 publications were identified to familiarize themselves with research abstracts. The analysis included six publications according to PICO criteria.The use of non-invasive MR-HIFU therapy for the treatment of uterine fibroids, prostate cancer and various forms of metastatic bone lesions does not have convincing evidence of advantages over standard treatment methods (surgical resection, embolization, etc.) and may be used only as an alternative technique or in addition to standard therapy.ConclusionsDespite some advantages of the MR-HIFU technology, it is experimental and should only be used as an alternative to surgical treatment. Convincing evidence of the efficacy of MR-HIFU treatment in meta-analyses, systematic reviews, and randomized controlled trials has not yet been published.

ODP085 Denosumab Induced Severe Hypophosphatemia

Abstract Introduction Denosumab is a receptor activator of nuclear factor kappa-B (RANK) ligand inhibitor used for treatment of osteoporosis and bone metastases in patients with solid tumors. Denosumab induced hypophosphatemia has been reported in less than 1% of patients, and in most cases described as mild to moderate in severity. We present a case of severe hypophosphatemia after denosumab treatment for diffuse bone metastases due to prostate cancer. Case report A 78-year-old male patient with history of diffuse bone metastases due to prostate cancer, schizophrenia on treatment and intermittent alcohol use, presented to the hospital with suicidal ideation and worsening fatigue. Patient was found to have a phosphorus levels of &amp;lt;1. 0 mg/dL (2.5-4.6 mg/dL), corrected calcium of 8.2 mg/dL (8.4-10.5 mg/dl), vitamin D 25 OH of 36.34 ng/mL (30-100 ng/mL), magnesium of 2.3 mg/dL (1.7-2.5 mg/dL), parathyroid hormone (iPTH) level of 379 pg/mL (10-65pg/mL) and serum creatinine of 1.1 mg/dL (0.5-1.2 mg/dL). Urinary studies showed 24 hour urinary phosphate 1282 mg/24h (360-1600 mg/24h), urine creatinine 1570 mg/24h (500-2150 mg/24h). There was no evidence of acidosis, chronic kidney disease, preexisting osteomalacia or vitamin D deficiency. The patient had no recent alcohol consumption and his alcohol level was undetectable. After reviewing the outside medical records it was noted that the patient had received denosumab 120 mg, 11 days prior to the hospital admission, as part of the management of bone metastases due to prostate cancer. The patient's baseline phosphorus prior to denosumab was in the low normal range. The severe hypophosphatemia and secondary hyperparathyroidism were attributed to denosumab administration. Patient was initially treated with intravenous phosphate and then transitioned to oral phosphate along with elemental calcium and calcitriol during the course of his hospitalization. Patient's phosphorus improved to 2.3 mg/dL by the time of discharge. Discussion In patients treated with denosumab, the primary concern is potential post-treatment hypocalcemia, however, our case brings attention to severe hypophosphatemia as a serious side effect to treatment with denosumab. Multiple specialties are involved in the treatment of osteoporosis and metastatic bone lesions, and each should be aware that denosumab can lead to lower serum phosphate levels due to its effects on bone resorption and reduction of proximal tubular reabsorption of the phosphate resulting in clinical symptoms of muscle weakness, bone pain, fractures and even stupor, coma and death. We therefore conclude that monitoring phosphate levels should be part of the pre- and post-treatment evaluation in patients who are candidates for treatment with denosumab, particularly high-dose denosumab. Presentation: No date and time listed