OBJECTIVE: Metastatic prostate cancer (mPCa) results in high morbidity and mortality. Visceral metastases in particular are associated with a shortened survival. Our aim was to unravel the molecular mechanisms that underly pulmonary spread in mPCa.
METHODS: We performed a comprehensive transcriptomic analysis of PCa lung metastases, followed by functional validation of candidate genes. Digital gene expression analysis utilizing the NanoString technology was performed on mRNA extracted from formalin-fixed, paraffin-embedded (FFPE) tissue from PCa lung metastases. The gene expression data from primary PCa and PCa lung metastases were compared, and several publicly available bioinformatic analysis tools were used to annotate and validate the data.
RESULTS: In PCa lung metastases, 234 genes were considerably up-regulated, and 78 genes were significantly down-regulated when compared to primary PCa. Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) was identified as suitable candidate gene for further functional validation. CEACAM6 as a cell adhesion molecule has been implicated in promoting metastatic disease in several solid tumors, such as colorectal or gastric cancer. We showed that siRNA knockdown of CEACAM6 in PC-3 and LNCaP cells resulted in decreased cell viability and migration as well as enhanced apoptosis. Comprehensive transcriptomic analyses identified several genes of interest that might promote metastatic spread to the lung.
CONCLUSIONS: Functional validation revealed that CEACAM6 might play an important role in fostering metastatic spread to the lung of PCa patients via enhancing proliferation, migration and suppressing apoptosis in PC-3 and LNCaP cells. CEACAM6 might pose an attractive therapeutic target to prevent metastatic disease.

BACKGROUND: Serum bone turnover markers might play a role in the prediction of the development of bone metastases in breast cancer (BC) patients. We conducted a retrospective cohort study to address the association of serum bone turnover markers with oncologic outcomes.
METHODS: We included 80 women with BC, who were operated on at the Department of Gynecology, Obstetrics and Reproductive Medicine, Homburg/Saar, Germany. Serum samples were obtained prior to surgery and were used for estimation of the concentration of tumor and bone turnover markers using enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA).
RESULTS: At baseline, pyridinoline cross-linked carboxy-terminal telopeptide of type-1 collagen (ICTP) concentrations were higher in nodal positive vs. negative tumors (Mann-Whitney test p = 0.04). After a median follow-up of 79.4 months, 17 patients developed metastases, with 9 demonstrating, among other organs, osseous metastases. ICTP demonstrated the best area under the curve in the predection of osseous metastases in our cohort (AUC = 0.740, DeLong Test p = 0.005). Univariable Cox proportional hazard models failed to demonstrate significant associations between serum bone turnover markers and oncologic outcomes (progression-free survival, overall survival).
CONCLUSIONS: Serum bone turnover markers (e.g., ICTP) were able to predict the development of osseous metastases but were not associated with oncologic outcomes. Further investigation and validation are required for the use of such markers in clinical practice.

We sought to identify potential evidence-practice gaps in palliative radiotherapy using quality indicators (QIs), previously developed using a modified Delphi method. Seven QIs were used to assess the quality of radiotherapy for bone metastases (BoM) and brain metastases (BrM). Compliance rate was calculated as the percentage of patients for whom recommended medical care was conducted. Random effects models were used to estimate the pooled compliance rates. Of the 39 invited radiation oncologists, 29 (74%) from 29 centers participated in the survey; 13 (45%) were academic and 16 (55%) were non-academic hospitals. For the QIs, except for BoM-4, the pooled compliance rates were higher than 80%; however, for at least some of the centers, the compliance rate was lower than these pooled rates. For BoM-4 regarding steroid use concurrent with radiotherapy for malignant spinal cord compression, the pooled compliance rate was as low as 32%. For BoM-1 regarding the choice of radiation schedule, the compliance rate was higher in academic hospitals than in non-academic hospitals (P = 0.021). For BrM-3 regarding the initiation of radiotherapy without delay, the compliance rate was lower in academic hospitals than in non-academic hospitals (P = 0.016). In conclusion, overall, compliance rates were high; however, for many QIs, practice remains to be improved in at least some centers. Steroids are infrequently used concurrently with radiotherapy for malignant spinal cord compression.

Bone metastases are a common and debilitating consequence of advanced cancer, often necessitating palliative radiation therapy (RT) for pain relief. Reirradiation (reRT) of bone metastases is often considered after lack of pain relief following an initial course of RT, after a partial but unsatisfying pain response to an initial course of radiotherapy, or after pain recurrence following a complete or partial pain response to an initial course of RT. The NCIC CTG SC.20 trial, a landmark multicenter, randomized, non-blinded, controlled non-inferiority trial, addressed the critical question of optimal dose fractionation for reRT in this patient population. This trial compared the efficacy and toxicity of a single 8 Gy fraction to multiple fractions totaling 20 Gy in 850 patients with painful bone metastases requiring reRT. The primary endpoint was overall pain response at 2 months, with secondary endpoints of quality of life (QoL) measures, functional interference, and toxicity profiles assessed using patient-reported questionnaires and the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30. The intention-to-treat analysis revealed no significant difference in pain response between the two arms, meeting the pre-specified non-inferiority criteria. The per-protocol analysis suggested a potential benefit for a subset of patients receiving multiple fractions, although this was not statistically robust. Acute toxicities were more prevalent in the multiple fractions arm, with implications for patient comfort and healthcare utilization. Importantly, responders to reRT reported significant improvements in functional interference and QoL. The trial\'s findings support the use of a patient-centric approach to palliative RT, highlighting the viability of a single 8 Gy fraction as a less toxic and more convenient treatment option, albeit with consideration for individual patient circumstances. These results have significant implications for clinical practice, potentially reducing healthcare burdens while optimizing patient convenience during palliative care for painful bone metastases.

UNASSIGNED: While bone metastases (BMs) are present in a minority of thyroid cancer (TC) patients at the time of initial diagnosis, there has been growing concern regarding their impact on life expectancy and quality of life. The aim of this study was to identify prognostic factors associated with overall survival (OS) and cancer-specific survival (CSS) in these patients and provide therapeutic recommendations based on the findings.
UNASSIGNED: In this retrospective cohort study, we included 82 patients diagnosed as TC with BM received treatment in our department from 2011.03 to 2023.03 (average follow-up duration was 3.02 years). The retrospective study was performed according to the inclusion and exclusion criteria. Kaplan-Meier analysis was used to estimate the OS and CSS, while the univariate and multivariate Cox proportional hazard models were employed to determine prognostic factors associated with OS and CSS. Also, 287 patients\' data were collected from the National Cancer Institute\'s Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015 to confirm the prognostic factors identified in the retrospective study.
UNASSIGNED: The average survival time of the 82 patients was estimated to be 5.818 years (with a 95% confidence interval (CI) of 4.767 to 6.868 years). The cox regression analysis showed that older age (hazard ratio (HR) = 1.045, 95% CI: 1.001-1.092, P = 0.047), larger tumor size (>5cm, HR = 11.087, 95% CI: 3.728 - 32.976, P = 0.000), and the presence of extraosseous metastasis (HR = 3.247, 95% CI: 1.376 - 7.665, P = 0.007) were statistically significant factors associated with worse CSS. The results were furtherly confirmed in 287 SEER-sourced patients (age (HR = 1.020, 95% CI: 1.006 - 1.034, P = 0.006), tumor size (HR = 2.917, 95% CI: 2.044 - 4.161, P = 0.000), and extraosseous metastasis (HR = 3.726, 95% CI: 2.571 - 5.398, P = 0.000)).
UNASSIGNED: These results offer a population-based assessment of prognostic factors for patients with TC and BMs, revealing that age, primary tumor size (>5cm), and presence of extraosseous metastases are independent prognostic factors that correlate with worse survival. Accordingly, treatment for such patients ought to concentrate on systemic integrative therapy instead of surgical intervention.

Introduction: Metastatic castration-resistant prostate cancer (mCRPC) patients face challenges due to limited treatment options. About 50% of patients with mCRPC have a functional loss of phosphatase and tensin homology deleted on chromosome 10 (PTEN), leading to tumor progression, metastasis, and immune suppression. Moreover, elevated IL-23 produced by myeloid-derived suppressor cells (MDSCs) is found in CRPC patients, driving tumor progression. Therefore, a combination strategy based on PTEN restoration and IL-23 inhibition may block CRPC progression and metastasis. Methods: The antitumor effect of restoring PTEN expression combined with the IL-23 inhibitor Apilimod was studied in a mouse model of bone metastasis CRPC and mouse prostate cancer RM-1 cells. To verify the targeting ability of PTEN DNA coated with lipid nanoparticles (LNP@PTEN) in vitro and in vivo. In addition, RT-qPCR and flow cytometry were used to investigate the related mechanisms of the antitumor effect of LNP@PTEN combined with Apilimod. Results: LNPs exhibited significant tumor-targeting and tumor accumulation capabilities both in vitro and in vivo, enhancing PTEN expression and therapeutic efficacy. Additionally, the combination of LNP@PTEN with the IL-23 inhibitor Apilimod demonstrated enhanced inhibition of tumor growth, invasion, and metastasis (particularly secondary organ metastasis) compared to other groups, and extended the survival of mice to 41 days, providing a degree of bone protection. These effects may be attributed to the PTEN function restoration combined with IL-23 inhibition, which help reverse immune suppression in the tumor microenvironment by reducing MDSCs recruitment and increasing the CD8+/CD4+ T cell ratio. Discussion: In summary, these findings highlight the potential of LNPs for delivering gene therapeutic agents. And the combination of LNP@PTEN with Apilimod could achieve anti-tumor effects and improve tumor microenvironment. This combinational strategy opens new avenues for the treatment of mCRPC.

Patients with advanced NSCLC have heterogenous responses to immune checkpoint inhibitors (ICIs) with or without chemotherapy. In NSCLC, the impact of the distribution of metastatic sites and the response to systemic therapy combinations remain poorly understood. In a retrospective cohort study of patients with unresectable stage III/IV NSCLC who received first-line systemic therapy, we sought to assess the association between the site of metastases with patterns of response and progression. Data regarding demographics, tumour characteristics (including site, size, and volume of metastases), treatment, and outcomes were examined at two cancer care centres. The endpoints included organ site-specific response rate, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Two-hundred and eighty-five patients were included in the analysis. In a multivariate analysis, patients with bone metastases had a reduced ORR, PFS, and OS. Primary resistance was also more likely in patients with bone metastases. Patients with bone or liver metastases had a shorter OS when receiving ICIs with or without chemotherapy, but not with chemotherapy alone, suggesting an immunological basis for therapeutic resistance. A directed assessment of the tumour microenvironment in these locations and a deeper understanding of the drivers of organ-specific resistance to immunotherapy are critical to optimise novel combination therapies and sequencing in these patients.

Background: Non-seminomatous germ cell tumors (NSGCTs) represent a rare yet the most prevalent malignancy among young men. Bone metastases (BMs) are exceedingly uncommon in this neoplasm, and available data regarding the initial disease presentation, survival outcomes, and prognostic significance of BMs are limited. Methods: We conducted a retrospective analysis of 40 NSGCT patients with BMs treated between 2001 and 2021 in our tertiary care center. The cohort was stratified into synchronous (n = 29) and metachronous (n = 11) groups based on the presence of BM at diagnosis or only at relapse, respectively. We assessed overall survival (OS), progression-free survival (PFS), disease presentation, and treatments. Results: After a median follow-up of 93 months, the 5-year PFS and OS rates were 37.6% and 53.9% in the synchronous group and 18.2% and 36.4% in the metachronous group, respectively. At the initial diagnosis, most patients were classified into the IGCCCG poor prognostic group (n = 34, 85%). BMs were mostly asymptomatic (n = 23, 57.5%), involved the spine (n = 37, 92.5%), and could become visible only after disease response (n = 4, 10%). A pathological examination of resected bone lesions after first-line treatment revealed necrosis (n = 5, 71.4%), teratoma, or seminoma (both n = 1, 14.3%). At first relapse, eight patients in the synchronous group did not experience bone recurrence, while eight patients experienced recurrence at the initial affected bone site. Conclusions: In NSGCT patients, BMs often present asymptomatically and may initially be unnoticed. However, these patients may have a poorer prognosis compared to those in the IGCCCG poor prognostic group. Further studies including control groups are needed to assess the independent prognostic significance of BMs.

Stereotactic body radiotherapy is a highly effective form of radiation therapy for palliation of bone metastases, but it can also lead to rare but severe side effects, such as myonecrosis. According to the literature, the incidence of myonecrosis after stereotactic body radiotherapy is low and mostly dose dependent. It is crucial to consider the potential impact of immunotherapy and other systemic therapies in the assessment. The course of radiation myonecrosis can vary, and corticosteroids or vascular endothelial growth factor inhibitors may potentially play a role in its treatment. Herein, we report two patients presenting with myonecrosis after stereotactic body radiotherapy for bone metastasis.

BACKGROUND: The identification of objective pain biomarkers can contribute to an improved understanding of pain, as well as its prognosis and better management. Hence, it has the potential to improve the quality of life of patients with cancer. Artificial intelligence can aid in the extraction of objective pain biomarkers for patients with cancer with bone metastases (BMs).
OBJECTIVE: This study aimed to develop and evaluate a scalable natural language processing (NLP)- and radiomics-based machine learning pipeline to differentiate between painless and painful BM lesions in simulation computed tomography (CT) images using imaging features (biomarkers) extracted from lesion center point-based regions of interest (ROIs).
METHODS: Patients treated at our comprehensive cancer center who received palliative radiotherapy for thoracic spine BM between January 2016 and September 2019 were included in this retrospective study. Physician-reported pain scores were extracted automatically from radiation oncology consultation notes using an NLP pipeline. BM center points were manually pinpointed on CT images by radiation oncologists. Nested ROIs with various diameters were automatically delineated around these expert-identified BM center points, and radiomics features were extracted from each ROI. Synthetic Minority Oversampling Technique resampling, the Least Absolute Shrinkage And Selection Operator feature selection method, and various machine learning classifiers were evaluated using precision, recall, F1-score, and area under the receiver operating characteristic curve.
RESULTS: Radiation therapy consultation notes and simulation CT images of 176 patients (mean age 66, SD 14 years; 95 males) with thoracic spine BM were included in this study. After BM center point identification, 107 radiomics features were extracted from each spherical ROI using pyradiomics. Data were divided into 70% and 30% training and hold-out test sets, respectively. In the test set, the accuracy, sensitivity, specificity, and area under the receiver operating characteristic curve of our best performing model (neural network classifier on an ensemble ROI) were 0.82 (132/163), 0.59 (16/27), 0.85 (116/136), and 0.83, respectively.
CONCLUSIONS: Our NLP- and radiomics-based machine learning pipeline was successful in differentiating between painful and painless BM lesions. It is intrinsically scalable by using NLP to extract pain scores from clinical notes and by requiring only center points to identify BM lesions in CT images.