Osteoblastic Lesions Research Articles

AI-Assisted Detection and Localization of Spinal Metastatic Lesions.

The integration of machine learning and radiomics in medical imaging has significantly advanced diagnostic and prognostic capabilities in healthcare. This study focuses on developing and validating an artificial intelligence (AI) model using U-Net architectures for the accurate detection and segmentation of spinal metastases from computed tomography (CT) images, addressing both osteolytic and osteoblastic lesions. Our methodology employs multiple variations of the U-Net architecture and utilizes two distinct datasets: one consisting of 115 polytrauma patients for vertebra segmentation and another comprising 38 patients with documented spinal metastases for lesion detection. The model demonstrated strong performance in vertebra segmentation, achieving Dice Similarity Coefficient (DSC) values between 0.87 and 0.96. For metastasis segmentation, the model achieved a DSC of 0.71 and an F-beta score of 0.68 for lytic lesions but struggled with sclerotic lesions, obtaining a DSC of 0.61 and an F-beta score of 0.57, reflecting challenges in detecting dense, subtle bone alterations. Despite these limitations, the model successfully identified isolated metastatic lesions beyond the spine, such as in the sternum, indicating potential for broader skeletal metastasis detection. The study concludes that AI-based models can augment radiologists' capabilities by providing reliable second-opinion tools, though further refinements and diverse training data are needed for optimal performance, particularly for sclerotic lesion segmentation. The annotated CT dataset produced and shared in this research serves as a valuable resource for future advancements.

A case of spinal metastasis with osteoblastic lesion: The risk of epidural extension and paralysis.

One patient with metastatic spinal tumors from colorectal cancer experienced malignant spinal cord compression (MSCC). Determining the extent of the lesion using magnetic resonance imaging is essential, even if the lesion is osteoblastic. Therefore, it is important to evaluate the risk of MSCC in patients with metastatic spinal tumors.

A rare case of a solitary osseous metastasis from breast carcinoma presenting with fluid-fluid levels on MRI.

Osseous metastatic disease is commonly encountered in breast carcinoma, which typically presents as either osteolytic, osteoblastic, or mixed lesions on imaging. Osseous metastasis presenting as a multiloculated cystic lesion with fluid-fluid levels resembling that of an aneurysmal bone cyst (ABC) is sparsely described in the literature, and even less so in the case of breast carcinoma. We report an unusual case of fluid-fluid levels in a bone metastasis to the spine in a 66-year-old female with a prior history of breast carcinoma. Magnetic resonance imaging (MRI) demonstrated a cystic lesion with fluid levels resembling that of an ABC. Computed tomography (CT)-guided biopsy revealed the lesion to be a metastasis from breast carcinoma. The management of ABCs and osseous metastases differ drastically. Accurate diagnosis and distinction between these lesions is paramount as the management of metastatic disease can have a significant impact on the quality and length of life. The presentation, differential diagnoses and imaging features of this atypical case are discussed.

Metastatic Prostate Carcinoma in an Early 18th-Century South German Abbot—Interdisciplinary Research Reveals Clues to His Final Disease History

This interdisciplinary investigation of the human remains of Balduin Helm, one of the most important abbots of the Fürstenfeld monastery, provides novel information on this historic individual. This is particularly interesting since Balduin, during the early 18th century, was involved in the renovation of this large Bavarian monastery. Metastatic prostate cancer was found as evidenced by multiple mixed osteolytic–osteoblastic bone lesions in all available vertebral bodies, fragments of both os coxae, and isolated metastases in skull bones. Distribution, radio- and histomorphology, and especially the immunohistochemical detection of prostate-specific antigens in those metastases definitively confirm this diagnosis. Further investigation, especially by stable isotope analysis, showed a balanced high-level diet with considerable contribution from animal protein and significant freshwater fish. These additional findings suggest a significant radiocarbon reservoir effect as an explanation for a “too old” radiocarbon date. Finally, the obviously high-level protein diet may have contributed to the tumorigenesis which caused the death of the abbot at an advanced age.

Multiple Bone Involvement in Low-grade Myofibroblastic Sarcoma Demonstrated on 18F-FDG PET/CT.

A 68-year-old woman with low back pain for 2 months was admitted. T2-weighted fat-saturated imaging revealed hyperintense lesions in multiple lumbar regions, suggesting the possibility of bone metastases. Multiple osteolytic and mixed osteolytic-osteoblastic lesions with significant 18F-fluorodeoxyglucose (18F-FDG) uptake, as well as multiple osteoblastic lesions with mild 18F-FDG uptake, were observed on subsequent 18F-FDG positron emission tomography/computed tomography without an identifiable primary lesion. This patient was pathologically diagnosed with low-grade myofibroblastic sarcoma (LGMS) after biopsy and surgery. Although multiple bone involvement in LGMS is extremely rare, this case suggests that it should be considered in the differential diagnosis of multiple bone metastases.

Androgen receptor splice variants drive castration-resistant prostate cancer metastasis by activating distinct transcriptional programs.

One critical mechanism through which prostate cancer (PCa) adapts to treatments targeting androgen receptor (AR) signaling is the emergence of ligand-binding domain-truncated and constitutively active AR splice variants, particularly AR-V7. While AR-V7 has been intensively studied, its ability to activate distinct biological functions compared with the full-length AR (AR-FL), and its role in regulating the metastatic progression of castration-resistant PCa (CRPC), remain unclear. Our study found that, under castrated conditions, AR-V7 strongly induced osteoblastic bone lesions, a response not observed with AR-FL overexpression. Through combined ChIP-seq, ATAC-seq, and RNA-seq analyses, we demonstrated that AR-V7 uniquely accesses the androgen-responsive elements in compact chromatin regions, activating a distinct transcription program. This program was highly enriched for genes involved in epithelial-mesenchymal transition and metastasis. Notably, we discovered that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7. Its protein expression was dramatically upregulated in AR-V7-induced bone lesions. Moreover, we found that Ser81 phosphorylation enhanced AR-V7's pro-metastasis function by selectively altering its specific transcription program. Blocking this phosphorylation with CDK9 inhibitors impaired the AR-V7-mediated metastasis program. Overall, our study has provided molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC.

Abstract 2920: In vitro assays for investigating the effects of cancer therapeutics on bone

Abstract Bone microenvironment is an important factor in regulating bone metastasis. When cancer cells home to bone they secrete factors that stimulate osteoclast activity leading to increased bone resorption. Stimulatory factors released from the resorbed bone matrix in turn promote proliferation of cancer cells and this process, referred as the vicious cycle, often leads to osteolytic lesions in bone when osteoclastic bone resorption exceeds osteoblastic bone formation. The vicious cycle observed in osteolytic disease occurs also in osteoblastic metastases, and in addition cancer cells produce osteoblast-stimulating factors. Cancers with bone metastases often include both osteolytic and osteoblastic lesions. Our aim was to establish in vitro cell culture models to study the effects of cancer therapeutics on osteoblast and osteoclast differentiation and activity. In the osteoclast differentiation assay, human osteoclast precursor cells (Lonza) were cultured on bovine bone slices for 7 days. Denosumab was added in the cultures at day 0, and tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) activity was measured from the culture medium collected at day 7. Osteoclast activity was studied by allowing osteoclasts resorb bone after 7 days’ maturation period for additional 3 days in the presence of odanacatib. The amount of C-terminal cross-linked telopeptides of type I collagen (CTX-I) was measured in the culture medium collected at day 10 to quantitate osteoclast activity. Denosumab and odanacatib showed strong concentration dependent inhibition of osteoclast differentiation and activity, respectively. A mouse osteoblast progenitor cell line KS483 (Pharmatest Services) was used to study differentiation and activity of osteoblasts with test compounds bone morphogenetic protein 2 (BMP-2) and estradiol (E2). In the osteoblast differentiation assay, the activity of cellular alkaline phosphatase (ALP), a marker of osteoblast differentiation, was measured at day 8. In the osteoblast activity assay, the cells were cultured for 13 days. N-terminal propeptide of type I procollagen (PINP) secreted into the culture medium was determined at day 11 to indicate the effects on organic bone formation and calcium deposition was determined at the end of the study as a marker of inorganic bone formation. BMP-2 and E2 stimulated osteoblast differentiation and activity indicated by the increase in ALP activity, PINP and calcium levels. We conclude that these culture systems can be used for studying the effects of cancer therapeutics and identifying new potential compounds affecting the disease process of bone metastases with different mechanisms of action. Citation Format: Jenni H. Mäki-Jouppila, Mervi Ristola, Jukka Rissanen, Katja Fagerlund. In vitro assays for investigating the effects of cancer therapeutics on bone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2920.

Abstract 5538: Efferocytosis-induced HIF-1α enhances tumor vascularization and promotes osteoblastic bone remodeling in metastatic prostate cancer

Abstract Metastatic prostate cancer (PCA) exhibits a predilection for bone metastasis, initiating a complex interplay with bone cells, leading to dysregulated remodeling and mixed-pathological bone alterations. Human PCA primarily yields osteoblastic bone lesions, linked to bone pain and an adverse prognosis. In this study, we explored the activation of HIF-1α in myeloid phagocytic cells by apoptotic cancer cells in the context of bone metastatic PCA. Our previous findings demonstrated HIF-1α stabilization in bone macrophages engulfing apoptotic PCA cells in vitro. This study extends our understanding to an in vivo setting using mouse prostate cancer cells designed to express inducible caspase 9, triggering apoptosis (and subsequent efferocytosis) when exposed to the dimerizer molecule AP20187 (AP). Our assessment of PCA tumor growth in bone utilized a syngeneic mouse model, introducing a loss-of-function Hif1a mutation into myeloid lineage cells using LysM-Cre mice crossed with Hif1a-floxed mice (Hif1amut (LysM-Cre+/- Hif1aflox)), compared with the LysM-Cre-/- Hif1aflox (WT). In the first model, cancer cells were inoculated into the tibiae of these mice and apoptosis was induced with AP on days 3 and 5 post-inoculation (AP model). Results were compared to a model where apoptosis was not induced after inoculation (No-AP). In the AP model, fractional bone volume (BV/TV) in the medullae was significantly higher in tumor-inoculated tibiae than in non-inoculated (No-tumor) contralateral bone, highlighting the predominance of osteoblastic lesions. Conversely, in the No-AP model, increased BV/TV significance was achieved in WT mice (tumor vs. No-tumor), but not in mutant mice. Trabecular thickness (Tb.Th) was increased in both models in the presence of tumor, regardless of the Hif1a phenotype. Importantly, significant differences in BV/TV and Tb.Th between WT and Hif1amut tumor tibiae were exclusively noted in the context of induced apoptosis. Histological differences between tumors in the AP model were observed by immunofluorescence (IF) staining, which revealed a reduced fractional F4/80+ area in Hif1amut vs. WT tumors, with no differences in TRAP+ (osteoclasts) lining bone surfaces. RNAseq analysis of HIF1amut vs. WT macrophages efferocytosing apoptotic cancer cells showed downregulated processes related to vasculature development and blood vessel morphogenesis (p< 10-5). In correlation, IF analysis with endomucin (EMCN) demonstrated a reduction in stained area (EMCN+) relative to tumor area in Hif1amut tibiae vs. WT, suggesting a role of efferocytosis-induced HIF-1α in tumor vascularization. This study unveils intricacies of metastatic tumor growth in bone and proposes a connection between efferocytosis-induced HIF-1α in myeloid phagocytic cells and the promotion of tumor vascularization, alongside the enhancement of osteoblastic bone remodeling. Citation Format: Gabriel G. Kleer, Maria Molina Sanchez, Veronica Mendoza-Reinoso, Amy J. Koh, John Rubin, Laurie K. McCauley, Hernan Roca. Efferocytosis-induced HIF-1α enhances tumor vascularization and promotes osteoblastic bone remodeling in metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5538.

Abstract 2761: Activating RET mutations promotes osteoblastic bone metastasis by inhibiting osteoclastogenesis and stimulating osteoblast activity via regulation of osteoprotegerin

Abstract Bone metastases (BM) are a source of increased mortality and significant morbidity in patients with medullary thyroid cancer (MTC), with ~50% survival at five years post-diagnosis. MTC causes osteoblastic, osteolytic, or mixed lesions, yet the underlying mechanisms are unknown. The RET proto-oncogene encodes a transmembrane tyrosine kinase receptor and is the driver oncogene in ~60% of MTC cases where a germline or somatic activating mutation results in ligand-independent constitutive activation of the receptor. However, the role of RET mutations in the genesis of bone metastasis lesions is unknown. We show that activating RET mutations promotes an osteoblastic phenotype in mice implanted with patient-derived MTC cells by increasing bone formation and decreasing bone resorption. We found that the radiographic appearance of osteoblastic lesions differed between the types of RET mutations (C634W and M918T). MTC cells with RETC634W mutation showed a four-fold increase in bone mineral density, trabecular bone volume, number, and thickness with a decreased number of osteoblasts compared to the non-tumor-bearing femur. TRAP staining revealed that osteoclast numbers per long bone were reduced in the injected femur compared to the control. In contrast, the MTC-RETM918T mutation showed an increased cortical thickness and porosity with reduced medullary area and increased bone formation rate compared to the non-tumor bearing femur. MTC cells formed tumors with extensive mineralized tissue, composed of bone matrix surrounded by osteoblast-like cells and osteoid. The knockdown of RET in the MTC-RETM918T model significantly reduced cortical thickness and increased the number of osteoclasts per bone surface. We observed increased osteoprotegerin (OPG) expression in MTC-bearing femurs compared to controls, suggesting decreased bone resorption. The factors secreted by MTC cells, including OPG, inhibited osteoclast formation from primary bone marrow cells and Raw264 cells. In addition, RET knockdown by shRNA in MTC cells decreased OPG expression. Moreover, the MTC-conditioned media (CM) increased osteoblast differentiation and mineralization of the primary culture of pre-osteoblasts isolated from calvarial bone, long bones, and MC3T3 cells. The conditioned media of RET-depleted cells inhibits osteoblast differentiation and mineralization. The expression of alkaline phosphatase, osteocalcin, OPG, and osterix increased in pre-osteoblast incubated with MTC-CM. Compared to primary non-metastatic tumors, the OPG expression increases in tissues of sporadic MTC bone metastases harboring RETM918T mutation. These results suggest that MTC with RET-activating mutations induces osteoblastic bone metastasis due to decreased bone resorption and increased bone formation. Citation Format: Rozita Bagheri-Yarmand, Joseph L. Kidd, Gabriel M. Pagnotti, Trupti Trivedi, Leah Guerra, Xinhai Wan, Jian Song, Sue-Hwa Lin, Theresa A Guise. Activating RET mutations promotes osteoblastic bone metastasis by inhibiting osteoclastogenesis and stimulating osteoblast activity via regulation of osteoprotegerin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2761.

Abstract 5682: Micro RNA level changes in prostate cancer cells treated with MDMX and MDM2 inhibitors

Abstract INTRODUCTION: Prostate Cancer (PCa) is the most common non-cutaneous cancer and the second leading cause of cancer death among men in the United States. Most of the PCa cases are diagnosed in men between the ages of 65-74. Due to the recent push for frequent prostate screenings, these cancers are being detected early and treated much faster, leading to a 5-year survival of a localized or regional PCa to >99%. However, the 5-year survival of PCa with distant metastasis is significantly reduced to 32%, especially with involvement of osteoblastic bone lesions, lung lesions, and brain lesions. Therefore, there is a clinical need to identify prognostic markers and new targets for developing therapies and effectively treating advanced PCa. Previous studies have shown that levels of MDMX and MDM2, oncogenic inhibitors of p53 tumor suppressor protein, are significantly elevated in PCa cells. Inhibition of MDM2 and MDMX using specific inhibitors has been shown to elevate the levels of p21, p27, and p53 in LNCaP (Lymph Node Carcinoma of the Prostate) cells leading to cell death. Recent studies have demonstrated that micro RNAs (miRNAs) play an important role in supporting the tumor suppressor function of p53 through regulating the balance between p53 and MDM2. In this regard, several miRNAs were found to be significantly altered to modulate the level and intracellular mechanisms of p53 and MDM2 in various cancers. OBJECTIVES: To determine the relative levels of miRNA31, miRNA-34a and miRNA-128 in LNCaP cells that were treated with NSC-207895 (MDMX inhibitor), SJ-172550 (MDMX inhibitor), and RG-7388 (MDM2 inhibitor). METHODS: LNCaP cells were treated with NSC-207895 (20 uM), SJ-172550 (20 uM) or RG-7388 (2 uM) for 24 hrs. After completing the treatments, the miRNAs were extracted from the LNCaP cells using the miRNeasy Tissue/Cells Advanced Kit from Qiagen. We analyzed the levels of miRNA-31, miRNA-34a, and miRNA-128 in the treated samples using qRT-PCR analysis method and compared the levels to the control. During the qRT-PCR analysis the cDNA was amplified using Meridian Biosciences qPCR Master Mix and specific primers for miRNAs from Origene were used according to the manufacturer's protocol. RESULTS: Our experimental results indicate that inhibition of MDMX using NSC-207895 and SJ-172550 can elevate the levels of p21, p27, and p53 leading to cell death. Determination of cell death markers in the past revealed induction of necroptosis following drug treatments. Our current results indicate measurable changes in the levels of miRNA-31 and miRNA-34a following inhibition of MDMX using SJ-172550. We are in the process of determining the possible link between the changes in the levels of miRNAs and cell death. ACKNOWLEDGEMENT: This research was supported by the Royal Dames of Cancer Research, Ft. Lauderdale, Florida. Citation Format: Rojin Fatirkhorani, Ahmed Saleh Alsarrani, Shyam Sundar Jaganathan, Umamaheswari Natarajan, Appu Rathinavelu. Micro RNA level changes in prostate cancer cells treated with MDMX and MDM2 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5682.

Primary Adenosquamous Carcinoma of the Prostate.

Prostate cancer accounts for 29% of malignant diagnoses among men in the United States and is the second leading cause of death from cancer. Effective screening methods and improved treatment have decreased the mortality rate significantly. This decreased mortality rate, however, does not apply to all histologic variants. Adenosquamous carcinoma of the prostate is an extremely aggressive neoplasm with no current known curative therapy. It is often diagnosed after chemotherapy, radiation, or androgen deprivation therapy for traditional prostatic adenocarcinomas. Primary carcinomas of the prostate with squamous features include, but are not limited to, pure squamous cell carcinoma and adenocarcinoma mixed with squamous cell carcinoma (SCC). Important distinguishable clinical features of adenosquamous carcinoma include normal prostate-specific antigen (PSA) levels, even with advanced disease and osteolytic versus osteoblastic metastatic lesions in adenocarcinoma. Additional entities to consider in the differential diagnosis are squamous metaplasia of the prostate, secondary involvement of pure SCC, and urothelial carcinoma with squamous differentiation. Here, we present a de novo case of adenosquamous carcinoma in a 48-year-old man who rapidly developed extensive metastatic disease.

Opportunistic screening with multiphase contrast-enhanced dual-layer spectral CT for osteoblastic lesions in prostate cancer compared with bone scintigraphy

Our study aimed to compare bone scintigraphy and dual-layer detector spectral CT (DLCT) with multiphase contrast enhancement for the diagnosis of osteoblastic bone lesions in patients with prostate cancer. The patients with prostate cancer and osteoblastic bone lesions detected on DLCT were divided into positive bone scintigraphy group (pBS) and negative bone scintigraphy group (nBS) based on bone scintigraphy. A total of 106 patients (57 nBS and 49 pBS) was included. The parameters of each lesion were measured from DLCT including Hounsfield unit (HU), 40–140 keV monochromatic HU, effective nuclear numbers (Zeff), and Iodine no water (InW) value in non-contrast phase (N), the arterial phase (A), and venous phase (V). The slope of the spectral curve at 40 and 100 keV, the different values of the parameters between A and N phase (A-N), V and N phase (V-N), and hybrid prediction model with multiparameters were used to differentiate pBS from nBS. Receiver operating characteristic analysis was performed to compare the area under the curve (AUC) for differentiating the pBS group from the nBS group. The value of conventional HU values, slope, and InW in A-N and V-N, and hybrid model were significantly higher in the pBS group than in the nBS group. The hybrid model of all significant parameters had the highest AUC of 0.988, with 95.5% sensitivity and 94.6% specificity. DLCT with arterial contrast enhancement phase has the potential to serve as an opportunistic screening tool for detecting positive osteoblastic bone lesions, corresponding to those identified in bone scintigraphy.

A pictorial view on false positive findings of 68Ga-PSMA-11 PET/CT and their prognostic value in patients with prostate carcinoma after radical prostatectomy and undetectable PSA values.

Recently, gallium-68-prostate-specific membrane antigen-11 (68Ga-PSMA-11) positron emission tomography/computed tomography (PET/CT) has become a key imaging method in prostate carcinoma staging and biochemical progression, with varying sensitivities in different studies (from 40% to 80%). After four years of experience with 68Ga-PSMA-11 PET/CT, we found that it is possible to detect lesions with increased PSMA expression in patients with undetectable prostate specific antigen (PSA) levels after radical prostatectomy. The key questions we wanted to answer were as follows: if those lesions were malignant and could the early detection of those malignant lesions have a role in patient management? We aimed to identify and follow up PSMA-positive findings for a period of 4 years in patients with prostate cancer after radical prostatectomy and undetectable PSA values at the time of the examination. We also explored false-positive lesions in detail. The study included all patients who underwent radical prostatectomy and had undetectable PSA values <0.05ng/mL and who underwent 68Ga-PSMA-11 PET/CT between July 2019 and December 2019. We performed 220 studies and found 40 patients with these characteristics; these patients were included in this study. All of them were followed up until July 2023. Any finding with increased radiopharmaceutical accumulation above the background activity in the respective area was considered a false positive. Prostate-specific membrane antigen accumulation in established lesions was assessed semi-quantitatively by the maximum standardized uptake value (SUVmax) and qualitatively by the four-point visual scale proposed in the E-PSMA recommendations. We found 15/40 (37.5%) patients with PSMA-positive findings. These were predominantly bone changes without a corresponding CT abnormality or discrete cystic or osteoblastic lesions with above-background increased PSMA expression. The mean SUVmax of these non-specific lesions was 3.02 (SD 2.86). After 3.5-4 years of follow-up, biochemical progression was found in only two of the patients.The great sensitivity of the method nowadays is a powerful engine for the development of new therapeutic options. On the other side, the lower specificity due to false positive findings, if misinterpreted, might lead to switching to a higher stage, with the planned radical treatment replaced by palliative treatment. The presence of 68Ga-PSMA-11 PET/CT-positive findings in patients after radical prostatectomy and an undetectable PSA had a low predictive value for future progression. The interpretation of 68Ga-PSMA-11 PET/CT should always include a complex assessment of the clinical setting-the risk group, PSA value and degree of PSMA accumulation in the lesions. In these situations, further clarification of PSMA-positive findings is appropriate before deciding to change treatment.

Histograms of computed tomography values in differential diagnosis of benign and malignant osteogenic lesions.

The use of histogram analysis of computed tomography (CT) values is a potential method for differentiating between benign osteoblastic lesions (BOLs) and malignant osteoblastic lesions (MOLs). To explore the diagnostic efficacy of histogram analysis in accurately distinguishing between BOLs and MOLs based on CT values. A total of 25 BOLs and 25 MOLs, which were confirmed through pathology or imaging follow-up, were included in this study. FireVoxel software was used to process the lesions and obtain various histogram parameters, including mean value, standard deviation, variance, coefficient of variation, skewness, kurtosis, entropy value, and percentiles ranging from 1st to 99th. Statistical tests, such as two independent-sample t-tests and the Mann-Whitney U test with Bonferroni correction, were employed to compare the differences in histogram parameters between BOLs and MOLs. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic efficacy of each parameter. Significant differences were observed in several histogram parameters between BOLs and MOLs, including the mean value, coefficient of variation, skewness, and various percentiles. Notably, the 25th percentile demonstrated the highest diagnostic efficacy, as indicated by the largest area under the curve in the ROC curve analysis. Histogram analysis of CT values provides valuable diagnostic information for accurately differentiating between BOLs and MOLs. Among the different parameters, the 25th percentile parameter proves to be the most effective in this discrimination process.

Aggressive Osteoblastoma of Temporal Bone Causing Facial Palsy in a 9-year-old Child: A Case Report Based on 2020 WHO Classification of Bone Tumors

AbstractAggressive osteoblastoma (AO) is an uncommon bone tumor that represents a borderline lesion between osteoblastoma and osteosarcoma. The vertebral column, the sacrum, the pelvis, and jaw/craniofacial bones are primarily affected. Aggressive osteoblastoma does not metastasize and is treated by surgical resection. The authors report a case of AO in a 9-year-old female patient presenting with 5th and 7th cranial nerve palsy. Prior pathological history included resection of an expansile nodule in the left temporal bone. Conventional radiological examination and computed tomography (CT) of the skull revealed an osteoblastic lesion arising in the petrous portion of the left temporal bone, measuring 5.2 cm in the largest dimension. The patient was subjected to partial surgical resection of the process. Microscopy revealed a primary neoplastic bone composed of numerous epithelioid round osteoblasts disposed in solid sheets and with mild atypia, large eosinophilic cytoplasm, and an eccentric, ovoid nucleus. The process exhibited loose stroma, low mitotic index, osteoid formation, and a few osteoclast-like multinucleated giant cells. The diagnosis of AO was thus established. After 5 months of clinical follow-up, the patient is asymptomatic, without evidence of tumoral growth on CT scans.

Osteoid osteomas of the hands and feet: a series of 71 cases.

Osteoid osteomas typically arise in the long bones of extremities. Patients often report pain relieved by NSAIDS, and radiographic findings are often sufficient for diagnosis. However, when involving the hands/feet, these lesions may go unrecognized or misdiagnosed radiographically due to their small size and prominent reactive changes. The clinicopathologic features of this entity involving the hands and feet are not well-described. Our institutional and consultation archives were searched for all cases of pathologically confirmed osteoid osteomas arising in the hands and feet. Clinical data was obtained and recorded. Seventy-one cases (45 males and 26 females, 7 to 64 years; median 23 years) arose in the hands and feet, representing 12% of institutional and 23% of consultation cases. The clinical impression often included neoplastic and inflammatory etiologies. Radiology studies demonstrated a small lytic lesion in all cases (33/33), the majority of which had a tiny focus of central calcification (26/33). Nearly, all cases demonstrated cortical thickening and/or sclerosis and perilesional edema which almost always had an extent two times greater than the size of the nidus. Histologic examination showed circumscribed osteoblastic lesions with formation of variably mineralized woven bone with single layer of osteoblastic rimming. The most common growth pattern of bone was trabecular (n = 34, 48%) followed by combined trabecular and sheet-like (n = 26, 37%) with only 11 (15%) cases presenting with pure sheet-like growth pattern. The majority (n = 57, 80%) showed intra-trabecular vascular stroma. No case showed significant cytology atypia. Follow up was available for 48 cases (1-432 months), and 4 cases recurred. Osteoid osteomas involving the hands and feet follow a similar age and sex distribution as their non-acral counterparts. These lesions often present with a broad differential diagnosis and may initially be confused with chronic osteomyelitis or a reactive process. While the majority of cases have classic morphologic features on histologic exam, a small subset consists solely of sheet-like sclerotic bone. Awareness that this entity may present in the hands and feet will help pathologists, radiologists, and clinicians accurately diagnose these tumors.

Abstract A009: Distinct activity of androgen receptor splice variants in promoting prostate cancer metastasis

Abstract Introduction: Constitutively active androgen receptor splice variant 7 (AR-V7) correlates with the adaptation to androgen receptor signaling inhibition treatment in prostate cancer (PCa) patients. Despite intensive studies of AR-V7, it is still unclear how the distinct genomic and epigenomic characteristics of AR-V7-dependent cistrome and transcriptome are distinct from full-length AR (AR-FL) and whether AR-V7 may play a role in promoting the metastatic progression of castration-resistant PCa (CRPC). Experiments: To accurately compare the activity of AR-V7 with AR-FL, we generated lentiviral stable cell lines with inducible overexpression of AR-V7 or AR-FL using AR-V7 negative LNCaP and C4-2 cell lines. We assessed the in vivo impact of AR-V7 or AR-FL expression on PCa metastasis by injecting cells in zebrafish embryos and the tibias of castrated male mice. ChIP-seq analyses of AR-V7, AR-FL, FOXA1, and H3K27ac, ATAC-seq analysis, and RNA-seq analysis were conducted in to characterize the global cistrome and transcriptome activity of AR-V7 in comparison with AR-FL. In addition, we also examined how a posttranslational modification, Ser81 phosphorylation, affects AR-V7 activity by generating an S81A mutant of AR-V7 and using S81-phosphorylation inhibitors. Results: Our in vivo study revealed that overexpressed-AR-V7, but not AR-FL, strongly promotes tumor cell invasion into blood vessels and induces osteoblastic bone lesions. Through integrated ChIP-, ATAC- and RNA-seq analysis, we determined that AR-V7 has a “pioneer factor-like” ability to bind to androgen-responsive elements (AREs) located at compact chromatin regions and activates the enhancers by increasing the chromatin accessibility. This mechanism leads to a unique AR-V7-regulated transcriptional program that is completely independent of AR-FL activity and is highly enriched for genes mediating epithelial-mesenchymal transition and metastatic functions. We then identified a subset of AR-V7-specific targets with significant overexpression in CRPC tumor samples and associated with poor clinical outcomes. In particular, we found that SOX9, a critical metastasis driver gene, was a direct target and downstream effector of AR-V7, and its protein expression was dramatically upregulated at AR-V7-induced bone lesions. Furthermore, we found that the pro-metastasis function of AR-V7 can be enhanced by Ser81 phosphorylation through chromatin-binding-independent mechanisms, and that targeting this phosphorylation by CDK9 inhibitors can block AR-V7-induced SOX9 expression and impair AR-V7-mediated metastasis function. Conclusion: Our study provides novel molecular insights into the role of AR splice variants in driving the metastatic progression of CRPC. In specific, these data have demonstrated the distinctive transcriptional program of AR-V7 from AR-FL, identified critical AR-V7 targets, and determined the function of Ser81 phosphorylation on AR-V7. Our data also suggest a new therapeutic strategy to target AR-V7-induced metastasis cascade in CRPC by using CDK9 inhibitor treatment. Citation Format: Maryam Labaf, Dong Han, Yawei Zhao, Jude Owiredu, Songqi Zhang, Kavita Venkataramani, Jocelyn S. Steinfeld, Wanting Han, Muqing Li, Mingyu Liu, Zifeng Wang, Anna Besschetnova, Susan C. Patalano-Salsman, Jill A. Macoska, Xin Yuan, Steven P. Balk, Stephen R. Plymate, Shuai Gao, Kellee R. Siegfried-Harris, Ruihua Liu, Gabrielle Foxa, Mary M. Stangis, Piotr J. Czernik, Bart Williams, Kourosh Zarringhalam, Xiaohong Li, Changmeng Cai. Distinct activity of androgen receptor splice variants in promoting prostate cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A009.

Diagnosis and Management of Craniofacial Osteomas.

Osteoid osteomas are benign bony overgrowths that can occur in any region of the body. However, they have a predilection to occur in the craniofacial region. Because of the rarity of this entity, there is a lack of literature detailing the management and prognosis of craniofacial osteoid osteomas. Craniofacial osteomas have a predilection to involve the paranasal sinuses, but can also be found within the jaw, skull base, and facial bones. Because of their slow-growing nature, craniofacial osteomas are often incidentally discovered on routine imaging or after they compress nearby structures or distort nearby anatomy. Osteoid osteomas of the face can be treated with resection via various approaches. Recent advancements describe minimally invasive endoscopic techniques and adjuvant therapy with radiofrequency ablation guided by cone biopsy computed tomography. Osteoid osteomas have an excellent prognosis with complete resection. They demonstrate a low incidence of recurrence when compared with other osteoblastic lesions of the craniofacial structures. Craniofacial osteoid osteomas remain a developing topic within the field of craniofacial surgery. Their removal may be trending toward minimally invasive techniques. However, all treatment modalities appear to result in improved cosmetic outcomes and low recurrence rates.

The link between bone-derived factors osteocalcin, fibroblast growth factor 23, sclerostin, lipocalin 2 and tumor bone metastasis.

The skeleton is the third most common site of metastatic disease, which causes serious bone complications and short-term prognosis in cancer patients. Prostate and breast cancers are responsible for the majority of bone metastasis, resulting in osteolytic or osteoblastic lesions. The crosstalk between bone cells and their interactions with tumor cells are important in the development of lesions. Recently, both preclinical and clinical studies documented the clinical relevance of bone-derived factors, including osteocalcin (OC) and its undercarboxylated form (ucOC), fibroblast growth factor 23 (FGF23), sclerostin (SCL), and lipocalin 2 (LCN2) as prognostic tumor biomarkers and potential therapeutic targets in bone metastasis. Both OC and ucOC could be useful targets for the prevention of bone metastasis in breast cancer. Moreover, elevated OC level may be a metastatic marker of prostate cancer. FGF23 is particularly important for those forms of cancer that primarily affect bone and/or are characterized by bone metastasis. In other tumor entities, increased FGF23 level is enigmatic. SCL plays a significant role in the pathogenesis of both osteolytic and osteoblastic lesions, as its levels are high in metastatic breast and prostate cancers. Elevated expression levels of LCN2 have been found in aggressive subtypes of cancer. However, its role in anti-metastasis varies significantly between different cancer types. Anyway, all aforementioned bone-derived factors can be used as promising tumor biomarkers. As metastatic bone disease is generally not curable, targeting bone factors represents a new trend in the prevention of bone metastasis and patient care.

Procoxacin bidirectionally inhibits osteoblastic and osteoclastic activity in bone and suppresses bone metastasis of prostate cancer

BackgroundBone is the most common site of metastasis of prostate cancer (PCa). PCa invasion leads to a disruption of osteogenic-osteolytic balance and causes abnormal bone formation. The interaction between PCa and bone stromal cells, especially osteoblasts (OB), is considered essential for the disease progression. However, drugs that effectively block the cancer-bone interaction and regulate the osteogenic-osteolytic balance remain undiscovered.MethodsA reporter gene system was constructed to screen compounds that could inhibit PCa-induced OB activation from 631 compounds. Then, the pharmacological effects of a candidate drug, Procoxacin (Pro), on OBs, osteoclasts (OCs) and cancer-bone interaction were studied in cellular models. Intratibial inoculation, micro-CT and histological analysis were used to explore the effect of Pro on osteogenic and osteolytic metastatic lesions. Bioinformatic analysis and experiments including qPCR, western blotting and ELISA assay were used to identify the effector molecules of Pro in the cancer-bone microenvironment. Virtual screening, molecular docking, surface plasmon resonance assay and RNA knockdown were utilized to identify the drug target of Pro. Experiments including co-IP, western blotting and immunofluorescence were performed to reveal the role of Pro binding to its target. Intracardiac inoculation metastasis model and survival analysis were used to investigate the therapeutic effect of Pro on metastatic cancer.ResultsLuciferase reporter gene consisted of Runx2 binding sequence, OSE2, and Alp promotor could sensitively reflect the intensity of PCa-OB interaction. Pro best matched the screening criteria among 631 compounds in drug screening. Further study demonstrated that Pro effectively inhibited the PCa-induced osteoblastic changes without killing OBs or PCa cells and directly killed OCs or suppressed osteoclastic functions at very low concentrations. Mechanism study revealed that Pro broke the feedback loop of TGF-β/C-Raf/MAPK pathway by sandwiching into 14–3-3ζ/C-Raf complex and prevented its disassociation. Pro treatment alleviated both osteogenic and osteolytic lesions in PCa-involved bones and reduced the number of metastases of PCa in vivo.ConclusionsIn summary, our study provides a drug screening strategy based on the cancer-host microenvironment and demonstrates that Pro effectively inhibits both osteoblastic and osteoclastic lesions in PCa-involved bones, which makes it a promising therapeutic agent for PCa bone metastasis.Graphical