Clinical & Experimental Metastasis最新文献

Immune-based combinations have significantly improved the treatment of metastatic renal cell carcinoma (mRCC); however, immunotherapy has reported varying degrees of efficacy across different metastatic sites, with liver and bone metastases traditionally considered more challenging to treat. In MOUSEION-08 study, we aimed to investigate the association between lung, liver, and bone metastases and clinical outcomes such as Overall Survival (OS) and Progression- Free Survival (PFS) in mRCC patients receiving immune-based combinations. The present systematic review and study-level meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). PFS and OS were measured as Hazard Ratios (HRs) and 95% confidence intervals (CIs). The protocol was registered with PROSPERO, Registration number: CRD42024581488. Our search resulted in the identification of 2364 potentially relevant reports, which were subsequently restricted to three. The pooled HRs for OS and PFS in patients with lung metastases receiving immune-based combinations versus sunitinib were 0.61 (95% CI, 0.51-0.72) and 0.47 (95% CI, 0.38-0.59), respectively. In patients with liver metastases, the pooled HRs for OS and PFS were 0.56 (95% CI, 0.42-0.75) and 0.48 (95% CI, 0.34-0.67), while the pooled HRs for OS and PFS in patients with bone metastases were 0.64 (95% CI, 0.49-0.84) and 0.36 (95% CI, 0.27-0.49), respectively. According to our findings, the analyses reported similar HRs for OS and PFS, something that further underlines the role of immune-based combinations in this setting, regardless of metastatic sites, such as lung, liver, and bone metastases. Ongoing research and clinical trials are destined to refine and improve immunotherapeutic strategies for mRCC, aiming to enhance efficacy across all metastatic sites and to define predictive biomarkers.

Patient-derived tumor organoids (PDTOs) models have been widely used to investigate the response of primary cancer tissues to anti-cancer agents. Nonetheless, only few case study tried to establish PDTOs and test treatment response based on bone metastasis (BoM) tissues. Fresh BoM tissues were obtained from lung cancer (LC) patients who underwent spinal metastatic tumor surgery for PDTOs culture. Morphology of LC-BoM-PDTOs were characterized during the process: they were high-efficient in self-assembly and regeneration, forming mature 3D-multicellular structures in 2-3 weeks. To be more specific, organoids of BoM derived from patients with EGFR mutation tended to be follicular conglomeration and resembled "a bunch of grapes", while organoids of BoM derived from patients without driver gene mutation were featured with full sphere and "a ripe sunflower". PDTOs of BoM retained good consistencies of HE morphology and immunohistochemical markers expression with their parental BoM tissues. Down-regulation of receptor activator of nuclear factor kappa-B ligand (RANKL) expression in LC-BoM-PDTOs after in vitro DMAb intervention was associated with earlier clinical ossification efficacy of DMAb on BoM (median time: 5 vs. 8 months, P = 0.049). Accordingly, BoM-PDTOs can be expected to be a preferred model for predicting treatment response of bone metastatic tumors, considering its high-efficient expansion and good biological consistency with parental bone tumor tissues.

Copper promotes tumor growth and metastasis through a variety of mechanisms, most notably as a cofactor within the lysyl oxidase (LOX) family of secreted cuproenzymes. Members of this family, which include LOX and LOX-like enzymes LOXL1-4, catalyze the copper-dependent crosslinking of collagens and elastin within the extracellular matrix (ECM). Elevated LOX expression is associated with higher incidence and worse prognosis in multiple cancers, including colorectal, breast, pancreatic, and head and neck. In this study, we demonstrated that elevated LOX expression correlates with decreased overall survival and shorter median time to first progression in patients with lung cancer. Previous studies have demonstrated that LOX secreted from tumors is critical for pre-metastatic niche formation by promoting ECM remodeling and the recruitment of immune cells and endothelial precursors. Here, we demonstrated that ablation of the LOX gene in Lewis lung carcinoma (LLC) cells diminishes tumor growth and metastasis compared to wild-type LLC cells in a syngeneic mouse model. Although the role of tumor-derived LOX in tumor formation and metastasis is well established, little is known regarding the possible contribution of LOX produced by the parenchymal tissue of metastatic organs. Thus, this report describes our findings that host-derived LOX produced by the lung contributes to the pulmonary metastasis of LLC cells in mice. The suppression of pulmonary lysyl oxidase expression reduces the metastatic potential of Lewis Lung Carcinoma cells in mice, revealing a previously unknown influence of LOX expression in the parenchymal tissue of metastatic target organs on the seeding of tumor cells.

Metastasis-directed therapy (MDT) for oligometastatic breast cancer (≤ 5 metastases) has shown little effect in specific scenarios of randomized trials. Therefore, we aimed to assess outcomes after metastasis-directed stereotactic radiotherapy (SRT) in various clinical scenarios. We conducted an international retrospective cohort study in thirteen centers including breast cancer patients receiving SRT to any metastatic site. Outcomes included local recurrence (LR), progression-free survival (PFS), and overall survival (OS). Cumulative incidence analysis was used for LR, Kaplan-Meier estimates for PFS and OS. Covariables included patient, disease, and SRT characteristics. We performed univariable and multivariable analyses (MVA). Among 444 patients, 751 metastases were treated with SRT. Of these, 73% were intracranial and 27% extracranial lesions. Oligometastatic disease (OMD) was present in 66% of the patients. LR after two years occurred significantly more often in intracranial (25%) versus extracranial lesions (7%). In MVA of patients with OMD treated for intracranial sites, higher performance status was significantly associated with longer PFS. Further, higher performance status, biologic subtype (HR-pos./HER2-pos.), and MDT to all sites were significantly associated with longer OS. In MVA of oligometastatic patients treated for extracranial sites, biologic subtype (HR-neg./HER2-pos.) and synchronous metastasis were associated with significantly longer PFS, whereas higher grading was associated with significantly shorter PFS. Moreover, biologic subtype (HR-neg./HER2-neg.) was associated with significantly shorter OS. In conclusion, the role of MDT for breast cancer may vary per clinical scenario. Patients with OMD treated for intracranial lesions who had MDT to all sites showed superior OS. Our results should be validated prospectively.

Brain metastases (BMs) represent the most prevalent intracranial malignancy within the adult. They are identified in up to 20% of patients with solid tumors and this percentage varies between tumor types and age. Due to the selective permeability of the blood-brain barrier, most anticancer drugs can't reach significant concentrations in the brain, representing a major obstacle to the patients' survival. Furthermore, intra- and inter-patient heterogeneity and the unique brain microenvironment add a layer of complexity to the clinical management of BMs. In the perspective of finding new therapeutic approaches and better understanding the molecular mechanisms involved in brain metastasis, the use of appropriate preclinical models is essential. Here, we review current in vivo, in vitro and ex vivo models for the study of brain metastasis while outlining their advantages and limitations.

Recent studies report excellent local control (LC) and favorable toxicities of stereotactic ablative radiotherapy (SABR) for pulmonary metastasis (PM) from sarcoma. This study compared the LC and survival of SABR and metastasectomy for sarcoma PM. We analyzed the LC rates of 54 PMs treated with SABR between 2008 and 2022. For survival analysis, we compared 14 patients who received SABR as first-line treatment with 61 patients who underwent metastatectomy. For SABR-treated PMs, a median total dose of 55 Gy (range, 48-60) was administered over 3-10 fractions. Median follow-up for LC in SABR-treated PMs was 19.2 months (range, 0.8-124.0), and the 2-year LC rate was 92.2%. No patients experienced toxicities of grade 3 or higher. The median age of the patients in the survival analysis was 73 years (range, 42-83) in the SABR group and 54 years (range, 19-78) in the metastasectomy group (p < 0.001). PMs in the "gray zone" were more common in the SABR group (35.7%) than in the metastasectomy group (8.2%) (p = 0.029). The median follow-up for survival analysis was 44.8 months (interquartile range, 21.5-66.4). The 3-year rates of LC and overall survival were 92.3% and 57.3% in the SABR group and 89.2% and 75.9% in the metastasectomy group (p = 0.807, 0.224), respectively. The out-of-field intrapulmonary failure-free survival and extrapulmonary systemic failure-free survival rates at 3 years were not significantly different (p = 0.673, 0.386). SABR for sarcoma PM demonstrated excellent LC with acceptable toxicity. Survival rates of SABR were comparable to those of metastasectomy.

Mediastinal and hilar lymphadenopathy (MHL) is a common pattern of cancer spread, particularly in lung disease. Recently, there has been interest in the use of SBRT for MHL, especially in the oligometastatic setting. The goal is to improve local control (LC) and to achieve shorter treatment durations to minimize systemic treatment interruptions. The primary endpoint of this study was local control (LC). The secondary endpoints were distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) and predictive factors of response. This is a retrospective study. It analyses a group of patients treated with SBRT for MHL with different primary tumours and histologies. From November 2007 to June 2023, we treated 159 MHL in 128 patients. The primary most represented was lung cancer. A single fraction was used in 16% of cases and multiple fractions in 84% of cases. The medium BED 10 was 75.06 Gy (range: 37-120 Gy). Actuarial LC rates at 1, 2 and 5 years were 80.0%, 78.8% and 75.2%. The actuarial DMFS rates at 1, 2 and 5 years were 43.9%, 34.1% and 14.1%, respectively. Actuarial PFS rates at 1, 2 and 5 years were 37.2%, 23.9% and 8.3%, respectively. Actuarial OS rates at 1, 2 and 5 years were 68.8%, 52.7% and 26.9%, respectively. SBRT may be an option for the treatment of MHL. In addition, achieving a complete response is one of the most important predictors of our endpoints, in addition to tumour burden and volume.

Studies conducted in the last few years have suggested a connection between clinical outcomes and the time of immune checkpoint inhibitors (ICIs) infusion. However, few data are available regarding the differences between early and late time-of-day (ToD) administration in metastatic renal cell carcinoma (mRCC) patients receiving immunotherapy and immune-based combinations. In this meta-analysis, we aimed to fully investigate the influence of timing of administration on the efficacy of mRCC immunotherapy, by comparing early ToD versus late ToD dosing in this setting. The present systematic review and meta-analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA). Overall Survival (OS) was measured as Hazard Ratios (HRs) and 95% confidence intervals (CIs). Our search resulted in the identification of 1429 potentially relevant reports, which were subsequently restricted to four following independent evaluation of three authors. The pooled HR for OS in RCC patients receiving early ToD versus late ToD dosing was 0.62 (95% Confidence Interval, 0.50-0.72; p < 0.001). According to our findings, a statistically significant improvement in terms of OS for mRCC patients receiving early ToD administration compared with late ToD dosing was observed, with a reduction of death by 38%. Well-designed, randomized clinical and translational trials are required to clarify this issue and to establish recommendations for personalized treatments according to ToD.

The behaviour of metastases in patients with liver-metastatic colorectal cancer (CRC) is still not adequately considered during treatment planning. However, studies in large cohorts have shown that the disease course in these patients depends on the histopathological growth pattern (HGP) of the liver metastases, with the desmoplastic (or encapsulated) pattern responsible for a favourable outcome and the replacement pattern for an unfavourable course. To increase our knowledge of cancer biology in general as well as to design clinical trials that take into account the diverse behaviour of liver metastases, it is necessary to know the cellular and molecular determinants of these growth patterns. For that purpose, we compared the transcriptome of tumour tissue (prospective cohort; n = 57) sampled very precisely at the transition of metastasis and adjacent liver, between the desmoplastic and replacement HGP. In addition, the mutational profiles for 46 genes related to CRC were extracted from the RNA sequencing reads. First, we show that the genetic constitution of a liver metastasis from colorectal cancer does not determine its HGP. Second, we show clear differences between HGPs regarding the expression of genes belonging to the Molecular Signatures Database hallmark gene sets. Biological themes of the replacement HGP reflect cancer cell proliferation and glucose metabolism, while the desmoplastic HGP is characterized by inflammation and immune response, and angiogenesis. This study supports the view that HGPs are a reflection of the biology of CRC liver metastases and suggests the HGPs are driven epigenetically rather than by specific gene mutations.

Oral squamous cell carcinoma (OSCC) is a prevalent and aggressive malignancy, with metastasis being the leading cause of death in patients. Unfortunately, therapeutic options for metastatic OSCC remain limited. Peptidylarginine deiminases (PADI) are implicated in various tumorigenesis and metastasis processes across multiple cancers. However, the role of PADI2, a type of PADI, in OSCC is not well understood. This study aimed to explore the impact of PADI2 on epithelial-mesenchymal transition (EMT), angiogenesis, and OSCC metastasis. The effect of PADI2 on EMT was evaluated using cell lines by Western blot analysis with shRNA targeting PADI2. In addition, the selective PADI2 inhibitor AFM32a was used to assess the effect of PADI2 on cancer metastasis and angiogenesis in animal models. Our findings indicated that PADI2 expression correlated with EMT changes, and PADI2 knockdown reversed these changes, reducing cell proliferation, cell migration, and invasion. PADI2 inhibition also diminished tube formation in HUVECs and decreased secretion of angiogenesis-related chemokines CCL3, CCL5 and CCL20. In a mouse model, AFM32a markedly reduced lung metastasis and production of CCL3 and CCL5. Our in vitro and in vivo studies suggested inhibiting PADI2 could prevent OSCC metastasis by impeding EMT and angiogenesis via AKT/mTOR signaling pathway. These results highlight PADI2 as a potential therapeutic target for combating OSCC metastasis.