Skeletal Metastatic Disease Research Articles

Incidence of exclusive extrapelvic skeletal metastasis in prostate carcinoma on bone scintigraphy.

Bone is one of the common sites of metastasis from prostate carcinoma. Bone scintigraphy (BS) is one of the most sensitive imaging modalities currently used for bone metastatic work-up. Skeletal metastasis in prostate carcinoma commonly involves pelvic bones but rarely involves extrapelvic-extraspinal sites. To retrospectively analyze the BS data to determine the pattern of skeletal metastases in the prostate carcinoma. This retrospective observational study involves patients with biopsy-proven prostate carcinoma referred for BS for staging assessment. Patients with abnormal BS were evaluated for the pattern of skeletal involvement and data were presented in descriptive format in the form of percentages. A total of 150 patients with biopsy-proven prostate cancer who were referred for staging were included in the study. Thirteen of 150 patients (8.67%) had no abnormal uptake on planar images, ruling out metastatic disease. Twenty-four patients (16%) had heterogeneous uptake in the spine with distribution characteristic of degenerative disease and no scan pattern of metastatic disease. Thirty patients (20%) had multifocal uptake involving both pelvic and extra pelvic bones on planar images typical for skeletal metastasis and were considered metastatic. Eighty-three out of 150 patients (55.3%) had increased tracer uptake, which was indeterminate, thus, single photon emission computed tomography-computed tomography (SPECT-CT) was acquired, which showed 51 with metastatic disease, 31 benign lesions, and one indeterminate finding. Seven of 150 patients had exclusive pelvic bone uptake, which was found to be metastatic in 4/7 patients in SPECT-CT. Fifty six out of 150 patients showed exclusive extrapelvic tracer uptake, of which only 3 had vertebral metastatic disease. None of the patients with increased uptake exclusively in the extrapelvic-extraspinal location was metastatic. The incidence of exclusive extrapelvic skeletal metastatic disease in prostate carcinoma is 2% (excluding one patient with indeterminate findings). Further, none of the patients in the current study had exclusive extrapelvic-extraspinal metastasis. Thus, exclusive extrapelvic-extraspinal focal abnormality on planar BS carries a very low probability of metastatic disease and hence, further imaging or SPECT-CT can be safely avoided in such cases.

Abstract PO1-20-11: Delay in Diagnosis of Locally Advanced Breast Cancer during Lactation “Case Report”

Abstract A 38-year-old breastfeeding female with no family history of breast or gynecological cancer presented to her PCP with a 4-month history of galactorrhea and enlarged left-sided breast mass. On physical exam, a 4-inch round complex, nonmobile, non-tender mass in the left breast and bloody-to-pink discharge from the nipple was present on the exam. Diagnostic mammogram and US revealed BIRADS 5, microcalcifications consistent with DCIS, 4-cm mass, with a positive lymph node (LN), and needle core biopsy of both breast and LN, showed DCIS and metastatic carcinoma, respectively. Further workup did not show distant or skeletal metastatic disease. Therefore, a diagnosis was made, and the patient was provided a clinical-stage cT3, cN2, cM0, ER+, PR-, and HER2+. The patient completed neoadjuvant therapy with TCHP and underwent a left lumpectomy with sentinel LN biopsy. Additionally, pathology diagnosis showed scant residual DCIS (10mm) and no metastatic disease in the LN. After that, the patient completed adjuvant radiotherapy and was placed on adjuvant therapy with trastuzumab and pertuzumab. In conclusion, any breast abnormality reported by a pregnant or breastfeeding woman should not be neglected and assumed that it is a regular and physiological change until proven otherwise. Future proposals include guidelines for managing abnormal breast findings during pregnancy. Citation Format: Jesus Flores Banda, Kavitha Donthireddy. Delay in Diagnosis of Locally Advanced Breast Cancer during Lactation “Case Report” [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-11.

Abstract PO1-12-02: Impact of Discontinuation of Denosumab on Bone Health in Breast Cancer Patients

Abstract Denosumab (Dmab), an inhibitor of osteoclast activity and proliferation is approved for treatment of women on aromatase inhibitor (AI) therapy for early breast cancer (60 mg Q 6-months) and metastatic disease (120 mg Q 4-weeks) to protect against bone loss and prevention of skeletal-related events (SREs). 60 mg given twice a year has shown fracture reduction, especially in women on aromatase inhibitor therapy, and recent data supports benefits in disease free survival, bone-metastasis free-survival and overall survival with Dmab in early breast cancer. It appears superior in reduction of SREs versus zoledronic acid (ZA) in established skeletal metastatic disease; thus, a preferred choice in the oncology setting. In the osteoporosis setting, withdrawal of Dmab therapy leads to a “rebound” increase of bone resorption, rapid bone loss and potential vertebral fractures. Increased risk of spontaneous and multiple vertebral fractures has been seen in this patient population. To prevent this, after discontinuation of Dmab, the addition of another anti-resorptive such as ZA is initiated. Dmab withdrawal events are uncommonly reported in patients with metastatic skeletal disease due to generally poor prognosis. Dmab given as 120 mg/month in this setting may need to be curtailed for a variety of indications including hypocalcemia, major dental procedures, osteonecrosis of the jaw or atypical femoral fracture. In the oncologic setting, it is unclear if discontinuation of Dmab will lead to rebound bone resorption or increased incidence of fractures. We describe the case is of a 32-year-old woman with a history of T2N3M1, oligometastatic breast cancer (solitary bone metastases at L1, biopsy-proven) that was ER/PR/HER2 positive. She was treated with neoadjuvant trastuzumab, pertuzumab, taxotere and carboplatin followed by bilateral mastectomy, and radiation to chest wall and L1. She received total estrogen blockade initially with GnRH-agonist and exemestane and ultimately bilateral salpingo-oophorectomy plus exemestane. She continues pertuzumab and trastuzumab (80 treatments to date) for the past 5 years and denosumab 120 mg/month for 14 treatments and then every 3 months, 20 total treatments. Development of hip pain (regular runner) and concern for atypical fracture vs metastatic disease led to bone scan and PET/CT. Metastatic disease was ruled out and stress reaction was diagnosed. Dmab therapy was discontinued with monitoring of her metabolic bone turnover. 1 year after her last Dmab injection, bone turnover markers began to increase and ultimately demonstrated a very significant “rebound phenomenon.” Subsequently, a single dose of 120 mg denosumab decreased bone markers to previously low levels which remain low on routine monitoring, table below. In future, ZA will be initiated and continued on a yearly basis. Dmab has replaced ZA in managing bone health in breast cancer patients. Many oncologists use this without the assistance of bone health endocrinologists, who are an integral part of our cancer center. Bone modifying agents are often discontinued without consideration of the negative impact this may have. As this is a major survivorship issue, we document this case with literature review, to raise awareness for oncologists prescribing these medications. Citation Format: Susan Tannenbaum, Alvaro Alvarez Soto, Pamela Taxel. Impact of Discontinuation of Denosumab on Bone Health in Breast Cancer Patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-12-02.

METASTATIC DISEASE OF THE PROXIMAL FEMUR: MANAGEMENT AND OUTCOMES IN A REGIONAL CANCER CENTRE

The burden of metastatic disease presenting with axial skeleton lesions is exponentially rising predominantly due to advances in oncological therapies. A large proportion is these lesions are located in the proximal femora, which given its unique biomechanical architecture is problematic.These patients are frequently comorbid and require prompt and concise decision making regarding their orthopaedic care in line with recent British Orthopaedic Association guidelines.We present data detailing the outcomes for patients with proximal femoral metastatic disease referred and treated over a three year period in an Regional Cancer Centre.We retrospectively reviewed a prospectively maintained database of all patients referred for discussion at MDT with axial skeletal metastatic disease. From this we isolated patients with femoral disease. Demographic data along with primary tumour and metastatic disease site were assessed. Treatment regimens were analysed and compared. Finally predicted and actual mortality data was collated.331 patients were referred over the analysed time period, of which 99 had femoral disease. 66% of patients were managed conservatively with serial monitoring while 34% underwent operative treatment. 65% of those received an intramedullary fixation while 35% had arthroplasty performed. There was a 51:49 split male to female with Prostate, Lung and Breast being the predominant primary tumours. Concurrent spinal metastatic disease was noted in 62% of patients while visceral mets were seen in 37%. Mortality rate was 65% with an average prognosis of 388 days (1.06years) while average mortality was noted within 291 days (0.8 years).Proximal femoral metastatic disease accounts for a large volume of the overall mets burden. There is an overall tendency towards conservative management and of those requiring surgery IM nailing was the treatment of choice. The data would indicate that outcomes for these patients are guarded and on average worse than those predicted.

Evaluating Treatment Response in Breast Cancer: A Case Report on Static Metastatic Disease on Bone Scans

Background: We report a case of a 54-year-old female patient with carcinoma of the left breast with persistent methylene diphosphonate (MDP) uptake in sclerotic osseous lesions. These lesions were finally declared treated osseous metastatic lesions due to non-avidity on the F18 FDG PET-CT scan, normalization of CA-15.3, and resolution of bone pains. To the best of our knowledge, this has not been reported previously. Case presentation: A 54-year-old woman with persistent backache was referred for further evaluation by a Tc99m MDP bone scan. A Tc-99mmMDP bone scan showed wide-spread skeletal metastatic disease. Magnetic resonance imaging (MRI) showed extensive marrow disease involving the spine and iliac bones. A bone marrow biopsy revealed metastatic carcinoma with a tumor phenotype favoring breast primary. On further workup, the patient was diagnosed with invasive ductal carcinoma of the left breast and was treated with cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors along with hormone therapy and bisphosphonates, followed by radiation therapy for bone metastasis. The skeletal metastatic disease remains static on three consecutive Tc99m MDP bone scans, despite the clinical improvement and decreased tumor marker levels. The F18-FDG-FDG-CT scan done for monitoring treatment response revealed multiple non-avid sclerotic osseous lesions, favoring treatment response. The patient was continued with the same treatment, and a follow-up Tc99m MDP bone scan after 6 months revealed no interval change in the reported lesions compared to the initial scan. However, a synergistically performed F18 FDG PET-CT scan again showed multiple non-avid sclerotic osseous lesions suggestive of treated metastasis. Conclusion: This case highlights the importance of 18F-FDG PET-CT in evaluating the treatment response, especially in patients with symptomatic improvement and falling tumor marker levels with static disease on repeated Tc99m MDP bone scans.

Lactate dehydrogenase: relationship with the diagnostic GLIM criterion for cachexia in patients with advanced cancer

BackgroundAlthough suggestive of dysregulated metabolism, the relationship between serum LDH level, phenotypic/aetiologic diagnostic Global Leadership Initiative on Malnutrition (GLIM) criteria and survival in patients with advanced cancer has yet to examined.MethodsProspectively collected data from patients with advanced cancer, undergoing anti-cancer therapy with palliative intent, across nine sites in the UK and Ireland between 2011–2016, was retrospectively analysed. LDH values were grouped as <250/250–500/>500 Units/L. Relationships were examined using χ2 test for linear-by-linear association and binary logistics regression analysis.ResultsA total of 436 patients met the inclusion criteria. 46% (n = 200) were male and 59% (n = 259) were ≥65 years of age. The median serum LDH was 394 Units/L and 33.5% (n = 146) had an LDH > 500 Units/L. LDH was significantly associated with ECOG-PS (p < 0.001), NLR (p < 0.05), mGPS (p < 0.05) and 3-month survival (p < 0.001). LDH was significantly associated with 3-month survival independent of weight loss (p < 0.01), BMI (p < 0.05), skeletal muscle mass (p < 0.01), metastatic disease (p < 0.05), NLR (p < 0.05) and mGPS (p < 0.01).DiscussionLDH was associated with performance status, systemic inflammation and survival in patients with advanced cancer. LDH measurement may be considered as an aetiologic criteria and become a potential therapeutic target in the treatment of cancer cachexia.

A Retrospective Comparative Study of Sodium Fluoride Na18F-PET/CT and 68Ga-PSMA-11 PET/CT in the Bone Metastases of Prostate Cancer Using a Volumetric 3-D Radiomic Analysis.

Bone is the most common metastatic site in prostate cancer (PCa). 68Ga-PSMA-11 (or gozetotide) and sodium fluoride-18 (Na18F) are rather new radiopharmaceuticals for assessing PCa-associated bone metastases. Gozetotide uptake reflects cell membrane enzyme activity and the sodium fluoride uptake measures bone mineralization in advanced PCa. Here, we aim to characterize this difference and possibly provide a new method for patient selection in targeted therapies. Methods: The study consisted of 14 patients with advanced PCa (M group > 5 lesions), who had had routine PET/CT both with PSMA and NaF over consecutive days, and 12 PCa patients with no skeletal metastases (N). The bone regions in CT were used to coregister the two PET/CT scans. The whole skeleton volume(s) of interest (VOIs) were defined using the CT component of PET (HU > 150); similarly, the sclerotic/dense bone was defined as HU > 600. Additional VOIs were defined for PET, with pathological threshold values for PSMA (SUV > 3.0) and NaF (SUV > 10). Besides the pathological bone volumes measured with each technique (CT, NaF, and PSMA-PET) and their contemporaneous combinations, overlapping VOIs with the CT-based skeletal and sclerotic volumes were also recorded. Additionally, thresholds of 4.0, 6.0, and 10.0 were tested for SUVPSMA. Results: In group M, the skeletal VOI volumes were 8.77 ± 1.80 L, and the sclerotic bone volumes were 1.32 ± 0.50 L; in contrast, in group N, they were 8.73 ± 1.43 L (skeletal) and 1.23 ± 0.28 L (sclerosis). The total enzyme activity for PSMA was 2.21 ± 5.15 in the M group and 0.078 ± 0.053 in the N group (p < 0.0002). The total bone demineralization activity for NaF varied from 4.31 ± 6.17 in the M group and 0.24 ± 0.56 in group N (p < 0.0002). The pathological PSMA volume represented 0.44−132% of the sclerotic bone volume in group M and 0.55−2.3% in group N. The pathological NaF volume in those patients with multiple metastases represented 0.27−68% of the sclerotic bone volume, and in the control group, only 0.00−6.5% of the sclerotic bone volume (p < 0.0003). Conclusions: These results confirm our earlier findings that CT alone does not suit the evaluation of the extent of active skeletal metastases in PCa. PSMA and NaF images give complementary information about the extent of the active skeletal disease, which has a clinical impact and may change its management. The PSMA and NaF absolute volumes could be used for planning targeted therapies. A cut-off value 3.0 for SUVPSMA given here is the best correlation in the presentation of active metastatic skeletal disease.

Venous thromboembolism in musculoskeletal oncology surgery.

Venous thromboembolism (VTE), including both deep venous thrombosis (DVT) and pulmonary embolism (PE), is a major complication of musculoskeletal surgery in general, and the risk is heightened in musculoskeletal oncology surgery. Despite the well-known association between cancer and VTE, the mechanism promoting this pathology is not entirely well understood. It is estimated that nearly all cancer patients will experience from some form of VTE, whether or not clinically relevant, during the course of their disease. Nonetheless, numerous studies have analyzed the occurrence and prevention of VTE in patients with cardiovascular disease or suffering trauma, but very few have specifically examined the safety or efficacy of preventing VTE in cancer patients with metastatic skeletal disease. This review will examine the various types of prophylactic treatment, timing of administration, risk stratification for determining the appropriate course of anticoagulation (AC), and discuss current views on chemical prophylaxes relativity to wound complications and excessive bleeding in orthopedic oncology patients. Overall, careful choice of anticoagulant and timing of administration must be made in order to avoid bleeding complications. A risk stratification system to determine which chemical prophylaxis to administered could be beneficial in both reducing the occurrence of VTE and decreasing associated wound complications or mortality. Further study should be conducted to tailor chemical prophylaxes recommendations to this largely affected population and effectively reduce the occurrence of VTE.

177Lu-PSMA-I&T for Treatment of Metastatic Castration-Resistant Prostate Cancer: Prognostic Value of Scintigraphic and Clinical Biomarkers.

The aim of this retrospective analysis was to determine prostate-specific antigen (PSA) response, PSA progression-free survival (PFS), and overall survival (OS) in a large cohort of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with 177Lu-PSMA-I&T and to identify clinical and scintigraphic prognostic factors for outcome. Methods: In total, 301 consecutive mCRPC patients were included in this analysis. Prognostic factors included clinical parameters, routine laboratory parameters, and findings on posttreatment scintigraphy. Scintigraphic tumor uptake of 177Lu-PSMA-I&T was compared with salivary gland uptake and classified as high or low. The longest extent of skeletal metastatic disease was measured, and its changes during therapy were used to define scintigraphic progression, response, and stable disease. A PSA response of at least 50%, PSA PFS, and OS were calculated. Results: In total, 1,138 cycles (median, 3 cycles per patient) of 177Lu-PSMA-I&T using a standard activity of 7.4 GBq were applied intravenously every 4-10 wk (median, 6 wk). Overall, 34% (95% CI, 28%-38%) of patients showed a PSA response of at least 50%, and the median PSA PFS and OS of the total patient cohort were 16.0 wk (95% CI, 12.1-19.9) and 13.8 mo (95% CI, 12.4-15.5), respectively. Patients with high scintigraphic tumor uptake showed a higher PSA response rate of at least 50% (45.7% vs. 10.4%; P < 0.0001) and a significantly reduced risk of PSA progression (median event time, 24.9 vs. 9.0 wk; hazard ratio, 0.3; 95% CI, 0.2-0.5; P < 0.0001). In our data, risk of death was not significantly different between patients with high scintigraphic uptake and those with low scintigraphic uptake (median, 14.4 vs. 12.4 mo; hazard ratio, 0.9; 95% CI, 0.6-1.3; P = 0.6). In a multivariable analysis, the following pretherapeutic prognostic factors for OS were identified: alkaline phosphatase, lactate dehydrogenase, and PSA levels; prior chemotherapy; and the presence of visceral metastases. Scintigraphic response was a strong prognostic factor for PSA response, PSA PFS, and OS after 1 treatment cycle. Conclusion: This retrospective analysis of a large group of consecutive patients corroborates previous clinical experience for 177Lu-PSMA-I&T in mCRPC and establishes previously proposed prognostic factors. The skeletal tumor extent and its changes were identified as new potential biomarkers to predict the outcome of therapy after the first treatment cycle.

Radiomics and Deep Learning for Disease Detection in Musculoskeletal Radiology: An Overview of Novel MRI- and CT-Based Approaches.

Radiomics and machine learning-based methods offer exciting opportunities for improving diagnostic performance and efficiency in musculoskeletal radiology for various tasks, including acute injuries, chronic conditions, spinal abnormalities, and neoplasms. While early radiomics-based methods were often limited to a smaller number of higher-order image feature extractions, applying machine learning-based analytic models, multifactorial correlations, and classifiers now permits big data processing and testing thousands of features to identify relevant markers. A growing number of novel deep learning-based methods describe magnetic resonance imaging- and computed tomography-based algorithms for diagnosing anterior cruciate ligament tears, meniscus tears, articular cartilage defects, rotator cuff tears, fractures, metastatic skeletal disease, and soft tissue tumors. Initial radiomics and deep learning techniques have focused on binary detection tasks, such as determining the presence or absence of a single abnormality and differentiation of benign versus malignant. Newer-generation algorithms aim to include practically relevant multiclass characterization of detected abnormalities, such as typing and malignancy grading of neoplasms. So-called delta-radiomics assess tumor features before and after treatment, with temporal changes of radiomics features serving as surrogate markers for tumor responses to treatment. New approaches also predict treatment success rates, surgical resection completeness, and recurrence risk. Practice-relevant goals for the next generation of algorithms include diagnostic whole-organ and advanced classification capabilities. Important research objectives to fill current knowledge gaps include well-designed research studies to understand how diagnostic performances and suggested efficiency gains of isolated research settings translate into routine daily clinical practice. This article summarizes current radiomics- and machine learning-based magnetic resonance imaging and computed tomography approaches for musculoskeletal disease detection and offers a perspective on future goals and objectives.

Skeletal metastatic disease of the acetabulum: historical and evolving techniques for management.

The skeleton is the third most common organ system to be involved in the spread of metastatic carcinomas. More options for systemic therapies, surgeries and adjuvant treatments are providing longer survival for patients with known metastatic carcinoma to the bone. This means more patients are living with metastatic skeletal disease than ever before. If metastatic disease results in enough bone loss it can cause significant pain and dysfunction for patients. The acetabulum and pelvis are common sites of metastatic disease. The complex anatomy of the bony pelvis and acetabulum, as well as its proximity to important neurovascular and pelvic structures, can make surgical management of acetabular metastatic disease technically difficult. Decision making for patients with symptomatic skeletal metastatic disease is complex, and multidisciplinary teams can be helpful in providing appropriate care for these patients. Systemic chemotherapies, immunotherapies or targeted therapies may not adequately treat large areas of metastatic disease in the hip and pelvis. Radiation therapy is not successful for all patients. Fortunately, there are evolving therapies that are giving patients and providers more options for treatment. This review article will cover some of those new therapies and their outcomes, focusing on newer ablative, minimally invasive and surgical reconstruction techniques for metastatic disease involving the acetabulum. Decision making in the management of a patient's metastatic acetabular disease is still made on a case by case basis. This review article hopefully will remind clinicians of the variety of treatments available to these patients.

Bone Metastases: State of the Art in Minimally Invasive Interventional Oncology.

Bone is the third most common site involved by cancer metastases, and skeleton-related events such as intractable pain due to direct osseous tumor involvement, pathologic fracture, and neurologic deficits as a consequence of nerve or spinal cord compression often affect patients' functional independence and quality of life unfavorably. The annual medical-economic burden related to bone metastases is a substantial component of the total direct medical cost estimated by the National Institutes of Health. There have been substantial recent advances in percutaneous image-guided minimally invasive musculoskeletal oncologic interventions for the management of patients with osseous metastatic disease. These advances include thermal ablation, cementation with or without osseous reinforcement with implants, osteosynthesis, thermal and chemical neurolyses, and palliative injections, which are progressively incorporated into the management paradigm for such patients. These interventions are performed in conjunction with or are supplemented by adjuvant radiation therapy, systemic therapy, surgery, or analgesic agents to achieve durable pain palliation, local tumor control, or cure, and they provide a robust armamentarium for interventional radiologists to achieve safe and effective treatment in a multidisciplinary setting. In addition, these procedures are shifting the patient management paradigm in modern-era practice. The authors detail the state of the art in minimally invasive percutaneous image-guided musculoskeletal oncologic interventions and the role of radiologists in managing patients with skeletal metastases. ©RSNA, 2021.

123I-Meta-Iodobenzylguanidine Single-Photon Emission Computerized Tomography/Computerized Tomography Scintigraphy in the Management of Neuroblastoma.

Neuroblastoma is the most common pediatric extracranial solid tumor. High-risk neuroblastoma is the most frequent presentation with an overall survival of approximately 50%. 123I-meta-iodobenzylguanidine (123I-mIBG) scintigraphy in the assessment of the primary tumor and its metastases at diagnosis and after chemotherapy is a cornerstone imaging modality. In particular, the bulk of skeletal metastatic disease evaluated with 123I-mIBG at diagnosis and the following chemotherapy has a prognostic value. Currently, single-photon emission computerized tomography/computerised tomography (SPECT/CT) is considered a fundamental part of 123I-mIBG scintigraphy. 123I-mIBG SPECT/CT is a highly specific and sensitive imaging biomarker and it has been the basis of all existing neuroblastoma trials requiring molecular imaging. The introduction of SPECT/CT has shown not only the heterogeneity of the mIBG uptake within the primary tumor but also the presence of completely mIBG nonavid metastatic lesions with mIBG-avid primary neuroblastomas. It is currently possible to semi-quantitatively assess tracer uptake with standardized uptake value, which allows a more precise evaluation of the tracer avidity and can help monitor chemotherapy response. The patchy mIBG uptake has consequences from a theranostic perspective and may partly explain the failure of some neuroblastomas to respond to 131I-mIBG molecular radiotherapy. Various positron emission tomography tracers, targeting different aspects of neuroblastoma cell biology, are being tested as possible alternatives to 123I-mIBG.

Inhibition of STAT3 prevents bone metastatic progression of prostate cancer in vivo.

Prostate cancer (PC) metastasizes to the skeleton forming predominantly sclerotic lesions, and there is currently no cure for bone metastatic disease. The transcription factor signal transducer and activator of transcription 3 (STAT3) is implicated as a metastatic driver, but its potential as therapeutic target in bone metastasis has not been investigated. In this study, we evaluated for the first time a STAT3 inhibitor, Napabucasin, as a therapeutic option for bone metastatic PC. Effects of STAT3 inhibitors, Stattic and Napabucasin, on metastatic potential in PC cells were studied in vitro by assessment of migration capacity, self-renewal potential, and tumorsphere formation. For evaluation of the role of STAT3 in initial skeletal establishment of PC cells as well as in progressed castration-resistant PC (CRPC) in bone, human VCaP prostate cancer cells were inoculated in the tibia of mice which subsequently were treated with the STAT3 inhibitor Napabucasin. Bone specimens were analyzed using computed tomography (CT), immunohistochemistry, and quantitative polymerase chain reaction. The small molecule STAT3 inhibitors Stattic and Napabucasin both effectively impaired metastatic potential of PC cells in vitro. Furthermore, treatment with Napabucasin prevented metastatic establishment in tibial bones in vivo and thereby also the tumor-induced sclerotic bone response seen in vehicle-treated VCaP xenografts. In addition, treatment with Napabucasin of established bone CRPC significantly decreased both tumor burden and tumor-induced trabecular bone volume compared with effects seen in vehicle-treated animals. Anti-mitotic effects were confirmed by decreased Ki67 staining in Napabucasin-treated xenografts compared with vehicle-treated xenografts. Alterations of gene expression in the femoral bone marrow (BM) niche towardthe maintenance of hematopoietic stem cells and the myeloid lineage were demonstrated by quantitative real-time polymerase chain reaction and were further reflected by a substantial increase in the number of erythrocytes in BM of Napabucasin-treated mice. Furthermore, a unique pattern of STAT3 phosphorylation in osteoblasts/stromal cells surrounding the areas of tumor cells was demonstrated immunohistochemically in bone xenograft models using several different PC cell lines. Inhibition of STAT3 activity disrupts the bone metastatic niche and targets both the skeletal establishment of PC and advanced bone metastatic CRPC in mice, suggesting STAT3 as a candidate for molecular targeted therapies of skeletal metastatic disease.

A Retrospective Comparative Study of Sodium Fluoride (NaF-18)-PET/CT and Fluorocholine (F-18-CH) PET/CT in the Evaluation of Skeletal Metastases in Metastatic Prostate Cancer Using a Volumetric 3-D Radiomics Analysis.

Bone metastases are common in prostate cancer (PCa). Fluorocholine-18 (FCH) and sodium fluoride-18 (NaF) have been used to assess PCa associated skeletal disease in thousands of patients by demonstrating different mechanism of uptake-cell membrane (lipid) synthesis and bone mineralization. Here, this difference is characterized quantitatively in detail. Our study cohort consisted of 12 patients with advanced disease (> 5 lesions) (M) and of five PCa patients with no skeletal disease (N). They had routine PET/CT with FCH and NaF on consecutive days. Skeletal regions in CT were used to co-register the two PET/CT scans. Bone 3-D volume of interest (VOI) was defined on the CT of PET with a threshold of HU > 150, and sclerotic/dense bone as HU > 600, respectively. Additional VOIs were defined on PET uptake with the threshold values on both FCH (SUV > 3.5) and NaF (SUV > 10). The pathologic skeletal volumes for each technique (CT, HU > 600), NaF (SUV > 10) and FCH (SUV > 3.5) were developed and analyzed. The skeletal VOIs varied from 5.03 L to 7.31 L, whereas sclerotic bone VOIs were from 0.88 L to 2.99 L. Total choline kinase (cell membrane synthesis) activity for FCH (TCA) varied from 0.008 to 4.85 [kg] in M group and from 0.0006 to 0.085 [kg] in N group. Total accelerated osteoblastic (bone demineralization) activity for NaF (TBA varied from 0.25 to 13.6 [kg] in M group and varied from 0.000 to 1.09 [kg] in N group. The sclerotic bone volume represented only 1.86 ± 1.71% of the pathologic FCH volume and 4.07 ± 3.21% of the pathologic NaF volume in M group, and only 0.08 ± 0.09% and 0.18 ± 0.19% in N group, respectively. Our results suggest that CT alone cannot be used for the assessment of the extent of active metastatic skeletal disease in PCa. NaF and FCH give complementary information about the activity of the skeletal disease, improving diagnosis and disease staging.

NON-SMALL CELL CARCINOMA OF LUNG WITH METASTASIS TO DELTOID MUSCLE: A RARE AND UNUSUAL PRESENTATION

SESSION TITLE: Medical Student/Resident Lung Cancer Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Lung cancer is the leading cause of cancer-related death worldwide. Major risks factors include tobacco smoking and environmental pollution. Despite its high incidence, the lack of efficacious screening programs for early detection and presence of non-specific symptoms mimicking other respiratory diseases lead to late-stage diagnosis [1]. Lung cancer is known to metastasize to most organs, including brain, bone, liver, adrenal glands, and lymph nodes due to their abundant blood supply [2]. Metastatic spread of lung cancer to skeletal muscle, however, is an extremely rare finding seen in less than 1% of all cases [3]. Skeletal muscle metastases most commonly arise from primary tumors of the gastrointestinal and genitourinary tracts [4], with the muscles most frequently affected being the thigh, iliopsoas, and paraspinous muscles [5]. Multiple hypotheses have been formulated to explain the low prevalence of muscle metastases, which include muscle contractility, tissue pressure, variable blood flow, oxygen free-radical production, cellular and humoral immunity, and hypersensitivity reactions. CASE PRESENTATION: We are reporting a 61-year-old male presenting with left shoulder pain since motor vehicle accident, cough and weight loss. X-ray of shoulder was unremarkable. CT chest showed 10.0 x 7.4 cm mass noted in the left upper lobe concerning for neoplasm. MRI left shoulder showed significant edema involving the deltoid muscle with no drainable fluid. IR US guided deltoid biopsy showed poorly differentiated adenocarcinoma that favored the result of lung mass biopsy as well. DISCUSSION: Skeletal muscle is an extraordinarily rare site of metastasis of lung cancer and usually favors aggressive disease. Non-small cell lung cancer metastasis to skeletal muscle is seen in <1% of cases. Diagnosis is usually obtained by fine needle biopsy of muscle. Adenocarcinoma of the lung with metastatic spread to skeletal muscles described in the literature as more aggressive with median survival of approximately 6 months. The best effective treatment is currently unknown. CONCLUSIONS: Lung cancer is the most common cause of cancer related deaths worldwide, with non-small cell lung cancer (NSCLC) making up 8% of all cases. Skeletal metastatic disease is extremely rare, especially to upper extremities and if present usually affects injured muscle site.Alteration of muscle physiology increases susceptibility to cancer spread. The lactic acid producing activity of tumors has been described as a factor that contributes to the formation of new blood vessels by signaling low perfusion to an area of the body. This neovascularization produces a more hospitable environment for tumor growth. Muscle injury may decrease muscle ability to remove lactic acid. Increased vascular perfusion to injured areas has been associated with increased susceptibility for metastatic disease. Reference #1: Seely S. Possible reasons for the high resistance of muscle to cancer. Med Hypotheses. 1980;6(2):133–137. doi:10.1016/0306-9877(80)90079-1. https://pubmed.ncbi.nlm.nih.gov/7393016-possible-reasons-for-the-high-resistance-of-muscle-to-cancer/ Reference #2: Perisano C, Spinelli MS, Graci C, et al. Soft tissue metastases in lung cancer: a review of the literature. Eur Rev Med Pharmacol Sci. 2012;16(14):1908–1914. https://www.europeanreview.org/article/2667 Reference #3: Surov A, Kohler J, Wienke A, Gufler H, Bach AG, Schramm D, et al. Muscle metastasis: comparison of features of different primary tumors. Cancer imaging 2014;14:21 DISCLOSURES: No relevant relationships by Muhammad Faisal Aslam, source=Web Response No relevant relationships by Ritika Kompella, source=Web Response No relevant relationships by Luis Medina Mora, source=Web Response No relevant relationships by Anastasia Novikov, source=Web Response No relevant relationships by Theo Trandafirescu, source=Web Response No relevant relationships by Salim Yaghi, source=Web Response

Biodistribution and post-therapy dosimetric analysis of [177Lu]Lu-DOTAZOL in patients with osteoblastic metastases: first results

BackgroundPreclinical biodistribution and dosimetric analysis of [177Lu]Lu-DOTAZOL suggest the bisphosphonate zoledronate as a promising new radiopharmaceutical for therapy of bone metastases. We evaluated biodistribution and normal organ absorbed doses resulting from therapeutic doses of [177Lu]Lu-DOTAZOL in patients with metastatic skeletal disease.MethodFour patients with metastatic skeletal disease (age range, 64–83 years) secondary to metastatic castration-resistant prostate carcinoma or bronchial carcinoma were treated with a mean dose of 5968 ± 64 MBq (161.3 mCi) of [177Lu]Lu-DOTAZOL. Biodistribution was assessed with serial planar whole body scintigraphy at 20 min and 3, 24, and 167 h post injection (p.i.) and blood samples at 20 min and 3, 8, 24, and 167 h p.i. Percent of injected activity in the blood, kidneys, urinary bladder, skeleton, and whole body was determined. Bone marrow self-dose was determined by an indirect blood-based method. Urinary bladder wall residence time was calculated using Cloutier’s dynamic urinary bladder model with a 4-h voiding interval. OLINDA/EXM version 2.0 (Hermes Medical Solutions, Stockholm, Sweden) software was used to determine residence times in source organs by applying biexponential curve fitting and to calculate organ absorbed dose.ResultsQualitative biodistribution analysis revealed early and high uptake of [177Lu]Lu-DOTAZOL in the kidneys with fast clearance showing minimal activity by 24 h p.i. Activity in the skeleton increased gradually over time. Mean residence times were found to be highest in the skeleton followed by the kidneys. Highest mean organ absorbed dose was 3.33 mSv/MBq for osteogenic cells followed by kidneys (0.490 mSv/MBq), red marrow (0.461 mSv/MBq), and urinary bladder wall (0.322 mSv/MBq). The biodistribution and normal organ absorbed doses of [177Lu]Lu-DOTAZOL are consistent with preclinical data.Conclusion[177Lu]Lu-DOTAZOL shows maximum absorbed doses in bone and low kidney doses, making it a promising agent for radionuclide therapy of bone metastasis. Further studies are warranted to evaluate the efficacy and safety of radionuclide therapy with [177Lu]Lu-DOTAZOL in the clinical setting.

Harnessing the versatile role of OPG in bone oncology: counterbalancing RANKL and TRAIL signaling and beyond.

More than 2 decades ago, the discovery of osteoprotegerin (OPG) as inhibitor of the receptor of activator of nuclear factor Kb (RANK) ligand (RANKL) revolutionized our understanding of bone biology and oncology. Besides acting as decoy receptor for RANKL, OPG acts as decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). OPG, RANKL, and TRAIL are ubiquitously expressed, stimulating per se pivotal signaling cascades implicated in cancer. In the context of cancer cell-bone cell interactions, cancer cells skew the OPG/RANKL/RANK (RANKL cognate receptor) balance towards bone destruction and tumor growth through favoring the RANKL/RANK interface, circumventing OPG. Numerous preclinical and clinical studies demonstrate the dual role of OPG in cancer: antitumor and tumor-promoting. OPG potentially conveys an antitumor signal through inhibiting the tumor-promoting RANKL signaling-both the osteoclast-dependent and the osteoclast-independent-and the tumor-promoting TRAIL signaling. On the other hand, the presumed tumor-promoting functions of OPG are: (i) abrogation of TRAIL-induced apoptosis of cancer cells; (ii) abrogation of RANKL-induced antitumor immunity; and (iii) stimulation of oncogenic and prometastatic signaling cascades downstream of the interaction of OPG with diverse proteins. The present review dissects the role of OPG in bone oncology. It presents the available preclinical and clinical data sustaining the dual role of OPG in cancer and focuses on the imbalanced RANKL/RANK/OPG interplay in the landmark "vicious cycle" of skeletal metastatic disease, osteosarcoma, and multiple myeloma. Finally, current challenges and future perspectives in exploiting OPG signaling in bone oncology therapeutics are discussed.

Spinal Radiofrequency Ablation Combined with Cement Augmentation for Painful Spinal Vertebral Metastasis: A Single-Center Prospective Study

Background: The spine is the most common site of skeletal metastatic disease. Vertebral body metastases (VBM) can cause crippling pain, fractures, and spinal cord compression. Radiofrequency ablation (RFA) is a minimally invasive technique that has proven to be a safe method of targeted tissue destruction. Studies have shown that RFA combined with cement vertebral augmentation is safe and effective and has been associated with significant improvements in pain and quality of life. Objectives: The purpose of this study was continued evaluation of the safety and efficacy of this technique. Study Design: Prospective cohort. Setting: A single academic medical center. Methods: Patients undergoing RFA with cement vertebral augmentation for a painful thoracic or lumbar VBM were eligible for inclusion. Additional inclusion criteria included pain concordant with a metastatic lesion on cross-sectional imaging, aged 18 years or older, and considered candidates for spinal tumor ablation by the operating physician. Patients with vertebral metastatic disease in the cervical spine or patients with spinal cord compression from posterior tumor extension were excluded. Ablation within each VBM was performed using a bipolar radiofrequency probe with an extensible electrode and available articulation, permitting vertebral body navigation percutaneously. Patients were evaluated at baseline, 3 days, one week, one month, and 3 months using the Numeric Rating Scale (NRS-11) and Functional Assessment of Cancer Therapy-General 7 (FACT-G7) to assess pain and quality-of-life, respectively. A one-sample t test was performed, and 95% confidence intervals were calculated to assess changes in average NRS-11 and FACT-G7 scores. Results: A total of 30 patients met inclusion criteria and underwent RFA of one or more VBM. Patients with 13 different primary cancers types underwent treatment. Patients received RFA to either one (n = 26; 87%) or 2 vertebral body levels (n = 4; 13%). Of the 34 levels, 13 were thoracic vertebra (38%) and 21 were lumbar vertebra (62%). Average NRS-11 scores decreased from a baseline of 5.77 to 4.65 (3 days; P = 0.16), 3.33 (one week; P &lt; 0.01), 2.64 (one month; P &lt; 0.01), and 2.61 (3 months; P &lt; 0.01). FACT-G7 increased from a baseline average of 13.0 to 14.7 (3 days; P = 0.13), 14.69 (one week; P = 0.15), 14.04 (one month; P = 0.35), and 15.11 (3 months; P = 0.07). No major adverse events were reported. Limitations: A heterogeneous patient population, small sample size, and potential confounders of concurrent variable adjuvant therapies were limitations. Additionally, most patients received both cement augmentation and targeted RFA, making it difficult to distinguish independent analgesic benefits of the therapies. Conclusions: This study demonstrates that minimally invasive targeted RFA with cement augmentation of spinal metastatic lesions is an effective treatment for patients with VBM. Key words: Cancer, cancer pain, spinal metastasis, radiofrequency ablation, tumor ablation, cement augmentation

Preliminary results of biodistribution and dosimetric analysis of [68Ga]Ga-DOTAZOL: a new zoledronate-based bisphosphonate for PET/CT diagnosis of bone diseases.

Pre-clinical studies with gallium-68 zoledronate ([68Ga]Ga-DOTAZOL) have proposed it to be a potent bisphosphonate for PET/CT diagnosis of bone diseases and diagnostic counterpart to [177Lu]Lu-DOTAZOL and [225Ac]Ac-DOTAZOL. This study aims to be the first human biodistribution and dosimetric analysis of [68Ga]Ga-DOTAZOL. Five metastatic skeletal disease patients (mean age: 72 years, M: F; 4:1) were injected with 150-190MBq (4.05-5.14mCi) of [68Ga]Ga-DOTAZOL i.v. Biodistribution of [68Ga]Ga-DOTAZOL was studied with PET/CT initial dynamic imaging for 30min; list mode over abdomen (reconstructed as six images of 300s) followed by static (skull to mid-thigh) imaging at 45min and 2.5h with Siemens Biograph 2 PET/CT camera. Also, blood samples (8 time points) and urine samples (2 time points) were collected over a period of 2.5h. Total activity (MBq) in source organs was determined using interview fusion software (MEDISO Medical Imaging Systems, Budapest, Hungary). A blood-based method for bone marrow self-dose determination and a trapezoidal method for urinary bladder contents residence time calculation were used. OLINDA/EXM version 2.0 software (Hermes Medical Solutions, Stockholm, Sweden) was used to generate residence times for source organs, organ absorbed doses and effective doses. High uptake in skeleton as target organ, kidneys and urinary bladder as organs of excretion and faint uptake in liver, spleen and salivary glands were seen. Qualitative and quantitative analysis supported fast blood clearance, high bone to soft tissue and lesion to normal bone uptake with [68Ga]Ga-DOTAZOL. Urinary bladder with the highest absorbed dose of 0.368mSv/MBq presented the critical organ, followed by osteogenic cells, kidneys and red marrow receiving doses of 0.040, 0.031 and 0.027mSv/MBq, respectively. The mean effective dose was found to be 0.0174mSv/MBq which results in an effective dose of 2.61mSv from 150MBq. Biodistribution of [68Ga]Ga-DOTAZOL was comparable to [18F]NaF, [99mTc]Tc-MDP and [68Ga]Ga-PSMA-617. With proper hydration and diuresis to reduce urinary bladder and kidney absorbed doses, it has clear advantages over [18F]NaF owing to its onsite, low-cost production and theranostic potential of personalized dosimetry for treatment with [177Lu]Lu-DOTAZOL and [225Ac]Ac-DOTAZOL.