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. < 6months, and ≥ 6months) significantly influenced overall survival (OS) in Cohort 1 (19.2 vs. 22.3 vs. 27.4months, p = 0.004) and Cohort 2 (14.6 vs. 15.4 vs. 21.2months, 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.

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 15.1months. In-field PFS was 96.2% and 90.2%; Out-field PFS was 69.3% and 64.4% at 1 and 2years respectively. Prior cranial radiotherapy was associated with worse out-field PFS. OS rates were 67.5% at 1year, 46.7% at 2years. ECOG performance status, time from surgery to radiotherapy of ≤ 56days and biologically effective dose using α/ß of 10 (BED10) ≥ 51Gy were significant OS predictors. Radionecrosis occurred in 7 patients (10%) with median onset at 25.0months. The novel RPA model stratified patients into 3 groups: RPA-I (ECOG < 2 & BED10 ≥ 51Gy; median OS 43.4months, 95% CI 22.3months-Not reached), RPA-II (ECOG < 2 & BED10 < 51Gy; median OS 11.9months, 95% CI 3months-19.2months) and RPA-III (ECOG ≥ 2 regardless of BED10 delivered; median OS 4.1months, 95% CI 1.2months - 22.0months) (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 sLea and sLex 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 sLea/x biosynthesis, structure, function and their role in metastatic progression. We focus on the differential roles of glycoprotein versus glycolipid associated sLea/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 sLea/x primes pre-metastatic niche and immune modulation, a new perspective on glycan mediated systemic signaling. We also compile validated tumor specific profiles of sLea/x across several cancer types, linking structural expression to metastatic phenotypes. Additionally, we discuss emerging strategies targeting sLea/x pathways from glycosylation inhibitors to selectin blocking therapeutics and the translational challenges and opportunities. Overall, this synthesis shows the importance of sLea and sLex in metastasis and lays the foundation for their use as biomarkers and therapeutic targets in precision oncology.

This study aims to compare the dosimetric performance of GammaKnife ICON and CyberKnife S7 radiosurgery systems in the treatment of single brain metastases using a fractionated stereotactic schedule. Fifteen patients with single brain metastases were retrospectively and consecutively included. For each patient, treatment plans were generated using both GammaKnife ICON and CyberKnife S7 systems, delivering a total dose of 27Gy in three fractions. Dosimetric parameters including Paddick Conformity Index (PCI), Gradient Index (GI), Heterogeneity Index (HI), beam-on time (BOT), and doses to organs at risk (OARs) were compared across modalities and stratified by target volume. GammaKnife plans showed significantly higher PCI (0.862 vs. 0.825; p < 0.05) and lower HI (1.94 vs. 2.09; p < 0.05), indicating superior dose conformity and acceptable heterogeneity. GI was lower for GammaKnife, though not statistically significant. BOT was significantly shorter for GammaKnife (14.2 vs. 34.3min; p < 0.05). Brainstem doses were significantly lower in GammaKnife plans, especially for lesions close to critical structures. Volume-based subgroup analysis confirmed that GammaKnife consistently delivered more conformal and steep dose distributions across all tumor sizes. GammaKnife ICON demonstrates dosimetric superiority in conformity, gradient sharpness, and treatment efficiency. These advantages may translate into improved clinical outcomes, such as enhanced local control, reduced toxicity, and increased patient comfort through shorter treatment sessions and better motion management. Gamma Knife, CyberKnife, Brain Metastasis, Radiosurgery.

Recent years have seen the development and advent of novel combinatorial strategies based on immunotherapy, and immune checkpoint inhibitor (ICI) - based treatment has established itself as a mainstay in the treatment of metastatic urothelial carcinoma (UC). Herein, we aimed to validate the prognostic value of a previously developed score, the Prognostic Immunotherapy Score (PIS), includingfemale sex, Eastern Cooperative Oncology Group Performance Status (ECOG-PS) and liver metastases, in patients treated with pembrolizumab for advanced UC from the ARON-2 dataset. We retrospectively analyzed clinical data from Metastatic UC patients diagnosed at age ≥ 18 years. Patients progressing or recurring after platinum-based therapy were included, and treated with pembrolizumab from January 1st, 2016, toDecember 31st, 2023,in68 oncological centers from 21 Countries. The Kaplan-Meier analysis was used to calculate the median follow-up. Cox proportional hazard models were used to compare the multivariable effects on patients' survival and to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). A survival receiver operating characteristic (ROC) analysis was exploited in relation to OS and PFS in patients stratified by the presence of 0, 1 or ≥ 2 risk factors and OS with 0, 1 or ≥ 2 risk factors in patients stratified by age, tumor histology, site and time to metastatic disease. The comparison between subgroups was performed with the Fisher exact test. We included 1040 patients from the ARON-2 dataset. We further stratified patients based on the three previously published risk factors: female sex, ECOG-PS = 2 and liver metastases; 526 patients (51%) had 0 risk factors, 408 patients (39%) had 1 factor and 106 patients (10%) had ≥ 2 risk factors. At univariate and multivariate analyses, bone metastases, synchronous metastatic disease and our PIS model based on female sex, liver metastasis, and poor performance status were significantly associated with both OS and PFS. Our findings validate the PIS as a practical scoring model using sex, ECOG-PS, and liver metastasis to stratify survival outcomes in advanced urothelial carcinoma treated with pembrolizumab, supporting more personalized treatment decisions.

Significant variability exists in the use of corticosteroids for treating adverse radiation effects (ARE) after stereotactic radiosurgery (SRS) of brain metastasis (BM). Here, we determine the diagnostic utility of a quadrant-based, visual assessment of magnetic resonance (MR) FLAIR as an imaging biomarker for steroid-dependent ARE. FLAIR was assessed at four axial levels along the rostral-caudal axis of the cerebrum, defined by standard landmarks of superior temporal line, third ventricle, temporal horn, and fourth ventricle. Each axial level was divided into four quadrants, defined by 12, 3, 6, and 9 on a clock face. New, post-SRS FLAIR hyperintensity extending beyond any quadrant was defined as FEQ+. FEQ+ was then correlated with corticosteroid treatment instituted within a month of the MRI. To establish intra- and inter-rater reliability of FEQ, MR images from 20 patients (10 FEQ+ and 10 FEQ-) were assessed by three clinicians (a radiation oncologist and two neurosurgeons) for FEQ positivity. These results showed an > 85% intra- and inter-rater reliability (Cohen's Kappa and Fleiss' Kappa of 0.970 and 0.785, respectively, both p < 0.001). We tested the hypothesis that FEQ+ is associated with corticosteroid use post-SRS in an initial cohort of 40 patients. The sensitivity, specificity, positive predictive value, and negative predictive value of FEQ for corticosteroid treatment were 75.0%, 96.4%, 75.0%, and 90.0%, respectively. To validate these findings, we examined the association of FEQ and corticosteroid use in an independent cohort of 214 SRS-treated BM patients. The sensitivity, specificity, positive predictive value, and negative predictive value of FEQ for corticosteroid treatment in this validation cohort were 94.6%, 74.0%, 43.2%, and 98.5%, respectively. We conclude that FEQ is an imaging marker with high intra- and inter-rater reliability, with a high negative predictive value (90.0-98.5%) for steroid treatment in SRS-treated BM patients. These results lay the foundation for future studies of FEQ for research and clinical applications.