Clinical & Experimental Metastasis最新文献

Metastatic urothelial carcinoma (mUC) may present with metastases at the time of initial diagnosis (synchronous) or develop them during follow-up (metachronous). The impact of the timing of metastasis on the outcome of mUC remains unclear. We aimed to evaluate overall survival (OS) stratified by time to metastasis (TTM) in patients receiving systemic therapy in different lines. Retrospective real-world data from the ARON-2 study were analyzed to compare patient outcomes according to TTM. Cohort 1 included 735 patients receiving first-line platinum-based chemotherapy, Cohort 2 included 1164 patients receiving second-line pembrolizumab, Cohort 3 included 588 patients receiving third-line enfortumab vedotin. TTM (synchronous vs. < 6 months, and ≥ 6 months) significantly influenced overall survival (OS) in Cohort 1 (19.2 vs. 22.3 vs. 27.4 months, p = 0.004) and Cohort 2 (14.6 vs. 15.4 vs. 21.2 months, p = 0.015), but not in Cohort 3. In the multivariable Cox analysis, TTM remained an independent prognostic parameter of poor OS in Cohort 1 (hazard ratio [HR]: 1.14, 95% confidence interval [CI] 1.02-1.27; p = 0.016) and Cohort 2 (HR: 1.12, 95% CI 1.02-1.22; p = 0.014). Our findings suggest that the TTM in mUC significantly influences OS in patients receiving first-line platinum-based chemotherapy and second-line pembrolizumab. The prognostic role of TTM should be considered in the future clinical trial designs.

Diagnosis of brain metastases (BM) has traditionally marked a turning point in treatment goals and prognosis of patients with breast cancer (BC). However, new systemic treatment options have both prevented the development and improved the prognosis of BC patients with BM. Stereotactic radiotherapy techniques (SRT) have widely replaced whole brain radiotherapy (WBRT) in patients with limited BM, yielding impressive survival at modest toxicity rates. However, based on established prognostic scores, many patients will not profit from modern SRT treatment concepts and, therefore, remain candidates for WBRT or best supportive care (BSC). Here, treatment decisions may be challenging. This study aims to describe clinical outcomes and explore potential prognostic factors in a single-center cohort of BC patients treated with WBRT comprising patients across the prognosis continuum reflecting everyday work routine. We retrospectively analyzed 108 patients diagnosed with BM who received WBRT between 2008 and 2020. The cohort included patients with a broad range of prognostic factors (≥ 60 years old, Karnofsky Performance Status [KPS] ≤ 70, >3 BM and a Graded Prognostic Assessment [GPA] score < 1 [anticipated life expectancy of < 4 months]), who were either treated with palliative WBRT alone or in case of focal symptoms attributed to individual location of metastasis with surgery, SRT, or WBRT + focal dose escalation ("boost"). Survival rates were estimated using the Kaplan-Meier method, and factors potentially affecting outcome were statistically assessed by the log-rank test. Uni- and multivariable Cox regression was used in survival analysis to estimate hazard ratios and to evaluate the influence of various variables on survival time. For all statistical procedures SPSS software (v. 26) was used. Median survival after diagnosis of BM was 4 months (95% CI 3-5 months). The most relevant negative prognostic factor within the group of GPA-classifiers was KPS (≤ 70), followed by the number of BM (>3). Metastasectomy displayed significantly improved survival in univariable analysis (log rank p = 0.008; Cox-Regression p = 0.018), but did not elicit as predictive for OS in multivariable analysis (p = 0.47). Furthermore, completion of the prescribed RT series had the strongest impact on OS in both univariable and multivariable Cox regression analyses (p < 0.00001) while delivery of a radiation boost in addition to WBRT exerted no significant benefit (Cox regression p = 0.358). Despite the continuous development of effective treatment strategies for BM, BC patients who are ineligible for innovative treatment modalities show poor survival rates. Following prognostic assessment may help to make treatment decisions. KPS and number of BM may be most important in this context. In our retrospective cohort surgical removal of BM and completion of RT series were associated with improved prognosis, while focal radiation dose escalation in addition to WBRT was not.

Bone disorders frequently manifest as long-term outcomes of breast cancer. Consequently, the relationship between breast cancer and bone metabolism is often studied at advanced stages of the disease. Emerging evidence suggests that bidirectional communication between mammary and bone tissues begins much earlier. In this context, extracellular vesicles (EVs) have been recognized as key mediators of intercellular communication, with emerging evidence supporting their role in breast cancer progression and the regulation of bone metabolism. This review examines bone imbalances occurring throughout the course of breast cancer, the pathophysiological mechanisms behind them, and the role of EVs in their development. From this integrated perspective, we propose the concept of Tumor-Bone Axis, a continuous and dynamic crosstalk between breast cancer and bone cells that supports tumor progression and bone complications. This axis regulates distinct metabolic states governing the activity of breast cancer cells and the balance in bone remodeling, enabling cellular reprogramming events during malignant transformation, immunoediting, tumor growth, and metastasis formation. Additionally, the impact of antineoplastic treatments on this axis may underlie chemoresistance, relapse, or therapy-induced metastasis. While multiple mediators are involved-including cell-to-cell contact, cell migration, osteoimmune interactions, hormones, soluble factors, and nutrients-EVs appear to be critical, especially through their role in exchanging epigenetic regulators of central signaling pathways in these cellular reprogramming events. Understanding the temporal and functional dynamics of the Tumor-Bone Axis and the extracellular vesicular traffic within it could reveal novel diagnostic biomarkers and therapeutic strategies for both breast cancer and its bone-related manifestations.

Differentiation grade of colorectal cancers (CRC) is histologically defined by the proportion of the tumour which retains the glandular architecture of the normal colon. Poorly differentiated CRCs display loss of glandular architecture and canonical markers of colonic differentiation and are associated with increased metastatic capacity and poorer prognosis. It is currently unclear whether poorly differentiated cells within a heterogeneous primary tumour are more likely to establish metastases and if this cellular trait is conserved in the secondary tumours, or whether metastasis is largely stochastic, with most cells in the primary tumour harboring metastatic potential. To explore this, we examined the concordance in histological grade, expression of markers of colonic differentiation, and epithelial to mesenchymal transition (EMT) in 67 matched primary and metastatic CRCs. Tumour differentiation grade was scored categorically, and expression of differentiation and EMT markers were scored as continuous variables. In matched primary-metastatic pairs, tumour grade was concordant in 88% of cases (59/67 pairs), irrespective of the site of metastasis. In tumour pairs with discordant grade (n = 8), tumour grade was higher in the metastatic lesion in 6/8 (75%) cases. Consistent with the histological concordance, expression of the key driver of colonic differentiation (CDX2); colonic lineage-specific markers (VIL1, MUC2, SYN and CHG); and the markers of epithelial-to-mesenchymal transition (E-Cadherin and Vimentin) were highly concordant between matched primary and metastatic lesions. Finally, no staining of the squamous lineage marker Cytokeratin5/6 was observed in either primary or metastatic tumours. Tumour grade assessed histologically or using expression of markers of colonic differentiation or epithelial to mesenchymal transition was largely concordant between primary and metastatic CRC. These findings complement previously reported genomic similarities between primary and metastatic lesions and demonstrate that the histological grade of a primary tumour can in most cases inform the differentiation grade of associated metastatic lesions.

To evaluate outcomes and prognostic factors in patients with resected brain metastases treated with postoperative SRS/SRT, and to develop a novel overall survival (OS) prognostic model. We retrospectively analyzed 70 patients (72 lesions) treated with postoperative SRS/SRT from July 2017 to May 2024. Outcomes included in-field and out-field intracranial progression-free survival (PFS), OS, and incidence of radionecrosis. Prognostic factors were identified using Cox regression. Recursive Partitioning Analysis (RPA) was used to construct an OS model. Median follow-up was 15.1 months. In-field PFS was 96.2% and 90.2%; Out-field PFS was 69.3% and 64.4% at 1 and 2 years respectively. Prior cranial radiotherapy was associated with worse out-field PFS. OS rates were 67.5% at 1 year, 46.7% at 2 years. ECOG performance status, time from surgery to radiotherapy of ≤ 56 days and biologically effective dose using α/ß of 10 (BED₁₀) ≥ 51 Gy were significant OS predictors. Radionecrosis occurred in 7 patients (10%) with median onset at 25.0 months. The novel RPA model stratified patients into 3 groups: RPA-I (ECOG < 2 & BED₁₀ ≥ 51 Gy; median OS 43.4 months, 95% CI 22.3 months-Not reached), RPA-II (ECOG < 2 & BED₁₀ < 51 Gy; median OS 11.9 months, 95% CI 3 months-19.2 months) and RPA-III (ECOG ≥ 2 regardless of BED₁₀ delivered; median OS 4.1 months, 95% CI 1.2 months - 22.0 months) (p < 0.001). RPA-II and RPA-III had higher death risk compared with RPA-I. This model outperformed existing models after bootstrapping validation. Postoperative SRS/SRT is effective for brain metastases. Appropriate patient selection, timely initiation and sufficient radiation dose improve outcomes. Our novel RPA model offers promising prognostic stratification for guiding treatment decisions.

The sialylated Lewis antigens sLe^a and sLe^x are terminal glycans that are crucial for adhesive and signalling functions during cancer metastasis. As high affinity ligands for E-, P-, and L-selectins, these epitopes allow tumor cells to arrest, evade immune cells and extravasate in the vascular microenvironment, mimicking leukocyte trafficking. This review provides a detailed analysis of sLe^a/x biosynthesis, structure, function and their role in metastatic progression. We focus on the differential roles of glycoprotein versus glycolipid associated sLe^a/x, their glycosyltransferase mediated synthesis and the spatial trafficking mechanisms that govern their surface expression. We also highlight the carrier scaffolds and glyco-enzyme hierarchies that present the ligand across different cancers, mucins, integrins and glycosphingolipids. A section is dedicated to how exosome bound sLe^a/x primes pre-metastatic niche and immune modulation, a new perspective on glycan mediated systemic signaling. We also compile validated tumor specific profiles of sLe^a/x across several cancer types, linking structural expression to metastatic phenotypes. Additionally, we discuss emerging strategies targeting sLe^a/x pathways from glycosylation inhibitors to selectin blocking therapeutics and the translational challenges and opportunities. Overall, this synthesis shows the importance of sLe^a and sLe^x in metastasis and lays the foundation for their use as biomarkers and therapeutic targets in precision oncology.