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.

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.

The sialylated Lewis antigens sLe and sLe 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 biosynthesis, structure, function and their role in metastatic progression. We focus on the differential roles of glycoprotein versus glycolipid associated sLe, 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 primes pre-metastatic niche and immune modulation, a new perspective on glycan mediated systemic signaling. We also compile validated tumor specific profiles of sLe across several cancer types, linking structural expression to metastatic phenotypes. Additionally, we discuss emerging strategies targeting sLe pathways from glycosylation inhibitors to selectin blocking therapeutics and the translational challenges and opportunities. Overall, this synthesis shows the importance of sLe and sLe in metastasis and lays the foundation for their use as biomarkers and therapeutic targets in precision oncology.

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 (BED) ≥ 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 & BED ≥ 51 Gy; median OS 43.4 months, 95% CI 22.3 months-Not reached), RPA-II (ECOG < 2 & BED < 51 Gy; median OS 11.9 months, 95% CI 3 months-19.2 months) and RPA-III (ECOG ≥ 2 regardless of BED 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.

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.

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.

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 27 Gy 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. 34.3 min; 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.

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.

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), including female 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, to December 31st, 2023, in 68 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.

Radiation-induced cerebral contrast enhancements (RICE) are frequent after photon and particularly proton radiation therapy (RT) and are associated with a significant risk for neurologic morbidity. While stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT) provide high rates of local control (LC), RICE remains a significant concern that may impact patient outcomes and quality of life. This study aims to assess the incidence, risk factors, and clinical implications of RICE in patients treated with SRS or FSRT for brain metastases (BMs). A retrospective analysis was conducted on 175 patients with 330 BMs treated between October 2015 and November 2023. Median follow-up (FU) was 17 months. The incidence of RICE was determined, and potential predictive factors were evaluated using univariate Cox regression analysis. RICE was identified in 8 patients with 10 lesions (3%). Systemic therapy without immunotherapy (IT) was found to be a significant predictor of RICE (HR = 4.161,  p= 0.027). No significant association was observed between the occurrence of RICE and overall survival (OS), indicating that while RICE is a treatment-related adverse event, it does not appear to significantly influence long-term survival. RICE occurs in a small subset of patients treated with SRS or FSRT. Systemic therapy without IT significantly increases the risk, underscoring the need for careful treatment planning and patient selection. While necrosis does not impact overall survival, its potential effects on neurological function and quality of life warrant continued research into preventive and management strategies.

The abscopal effect (AbE) refers to the regression of non-irradiated tumors following localized radiotherapy (RT), suggesting a systemic immune-mediated response. The combination of RT with immunotherapy (IO) has been proposed to enhance the AbE by overcoming RT-induced immunosuppressive mechanisms, but robust evidence, specifically in non-small cell lung cancer (NSCLC), is lacking. This study aimed to determine the prevalence of the AbE and its association with progression-free survival (PFS) and overall survival (OS) in metastatic lung cancer patients receiving RT and IO.

Fumarate hydratase-deficient renal cell carcinoma (FHdRCC) has been classified under the new category of molecularly defined RCCs according to the WHO classification 2022. Although rare, FHdRCC is an aggressive malignancy with a high metastatic potential and poor prognosis, even at early stages. Due to its low incidence, no standard therapeutic regimen has been established to date. Several phase 2 clinical trials are evaluating combinations of targeted therapies in patients with advanced/metastatic disease. These include immune checkpoint inhibitors (nivolumab, tislelizumab, sintilimab, avelumab), multi-tyrosine kinase inhibitors (cabozantinib, erlotinib, lenvatinib, axitinib, vandetanib), and PARP inhibitors (talazoparib). The most promising combinations are nivolumab/cabozantinib (N = 5, objective response rate (ORR): 100%), lenvatinib/tislelizumab (N = 14, ORR: 93.3%), bevacizumab/erlotinib (N = 43, ORR: 72%), and sintilimab/axitinib (N = 19, ORR: 63.1%). In this review, we will provide a detailed overview of ongoing clinical trials, highlighting the roles of metabolic and epigenetic reprogramming, as well as pro- oncogenic signaling, which together form the backbone for emerging novel targeted treatment strategies. Targeting these specific signaling pathways will shift the therapeutic landscape toward personalized medicine in metastatic FHdRCC.

The abscopal effect (AE) in oncology, where localized radiation therapy (RT) triggers a systemic anti-tumor immune response, holds great promise for revolutionizing cancer treatment. Emerging evidence suggests microRNAs (miRNAs), small non-coding RNAs, are essential in mediating the intricate interactions among the tumor, immune system, and tumor microenvironment underlying the AE. miRNAs, both within the tumor and circulating as exosomal cargo, can regulate gene expression to modulate the tumor microenvironment, enhance antigen presentation, and activate anti-tumor immunity. This miRNA-mediated intercellular communication can influence the radiation response, including tumor radiosensitivity, DNA damage repair, and apoptosis. Targeting specific miRNAs or leveraging miRNA-based therapies may sensitize tumors to radiation-induced immune responses, leading to more robust and durable AEs. Understanding the epigenetic regulation of the AE by miRNAs offers novel strategies to harness this phenomenon for improved cancer outcomes. Exploring the intersection of miRNAs, radiation, and the immune system holds the promise of developing more effective, personalized radiotherapy approaches that can unleash the body's defenses against metastatic disease. Unlocking the power of miRNA-mediated signaling may be the important key to unlocking the full potential of AE in the field of cancer treatment.

We previously identified three molecular subtypes of prostate cancer (PC) bone metastases, MetA-C, with MetB linked to poor prognosis after androgen deprivation therapy (ADT). This study analyzed epithelial and stromal markers using immunohistochemistry, focusing on their relationship to MetA-C subtypes, spatial heterogeneities, and clinical outcomes after ADT. High tumor proliferation and low PSA expression were associated with MetB and poor outcomes after ADT. Most metastases contained tumor epithelial subclones with different morphologies. In the metastasis stroma, blood vessels and fibroblast-like cells expressed smooth muscle actin (SMA), platelet-derived growth factor β, stroma-derived factor 1 (SDF1), periostin (POSTN), and decorin (DCN). Compared to each other, MetB metastases had higher SMA and ERG + endothelial cell densities, while MetA cases showed higher SDF1 and DCN levels. Accordingly, high POSTN and ERG + densities were associated with poor outcomes after ADT, whereas high DCN indicated favorable prognosis. Low levels of AR-positive stromal cells were linked to poor outcomes. Macrophage and T-lymphocyte densities showed no significant associations with metastases subtypes or outcome. Two stroma subtypes were identified: subtype 1 with higher bone content, lower vessel density, MetA-enrichment and better prognosis compared to subtype 2 that exhibited higher tumor proliferation and lower PSA expression. Most metastases contained regions of both stroma subtypes.