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Prostate Artery Embolization (PAE) is a novel minimally invasive angiographic technique that has been used effectively to treat men with lower urinary tract symptoms (LUTS) from benign prostatic hyperplasia (BPH). However, applications of PAE for men with prostate cancer have been minimally studied. This review serves as an update on the status of PAE in men with prostate cancer, as well as a discussion of emerging indications. Plain Language Summary Prosate artery embolization (PAE) is done by interventional radiologists to help men who have urinary symptoms from an enlarged prostate. This article discusses how PAE is used to help men who have prostate cancer as they consider different treatments and side effects of these treatments

There is emerging evidence that the adaptive anti-tumor activity may be orchestrated by secondary lymphoid organ-like aggregates residing in the tumor microenvironment. Known as tertiary lymphoid structures, these lymphoid aggregates serve as key outposts for lymphocyte recruitment, priming and activation. They have been linked to favorable outcomes in many tumor types, and more recently, have been shown to be effective predictors of response to immune checkpoint blockade. We have previously described a 12-chemokine (12-CK) transcriptional score which recapitulates an overwhelming enrichment for immune-related and inflammation-related genes in colorectal carcinoma. Subsequently, the 12-CK score was found to prognosticate favorable survival in multiple tumors types including melanoma, breast cancer, and bladder cancer. In the current study, we summarize the discovery and validation of the 12-CK score in various tumor types, its relationship to TLSs found within the tumor microenvironment, and explore its potential role as both a prognostic and predictive marker in the treatment of various cancers.

Histological subtypes of bladder cancer are generally associated with more aggressive disease, higher stage at presentation, and worse prognosis compared to conventional urothelial carcinoma. Recent updates in classification systems have further refined the distinction between true histologic subtypes and divergent differentiation, underscoring the complexity of these tumors. Emerging molecular profiling studies have identified subtype-specific genomic alterations, including ERBB2 amplification in micropapillary subtype carcinoma, CDH1 loss in plasmacytoid subtype carcinoma, and TP53 and RB1 co-alterations in neuroendocrine bladder cancer, which may contribute to differences in tumor biology and therapeutic response. Despite these advances, the histological subtypes of bladder cancer remain underrepresented in prospective clinical trials, leading to significant gaps in evidence-based management. Treatment responses vary widely across subtypes, with some demonstrating sensitivity to platinum-based chemotherapy or immunotherapy, while others appear less responsive to conventional approaches. This review summarizes the current understanding of the epidemiology, molecular landscape, and clinical behavior of major bladder cancer subtypes and highlights emerging opportunities for personalized treatment strategies, biomarker-driven therapies, and more inclusive clinical trial design to improve outcomes in this high-risk population.

Background Transcriptomic features of breast cancer locoregional recurrence (LRR) remain poorly understood. We therefore sought to investigate transcriptomic features associated with LRR in newly diagnosed invasive breast tumors from our institutional dataset. Methods Transcriptomic profiling was performed on 632 tumors from consecutive patients treated within our health system for newly diagnosed non-metastatic breast cancer. Univariable Cox models identified genes whose expression was associated with LRR ( q -value < 0.05). Up-regulated (UR) genes were defined as hazard ratio (HR) > 1 and down-regulated (DR) genes were defined as HR < 1. Gene set enrichment analyses were performed for UR and DR gene sets and validated within two external cohorts of ER- tumors. Results With a median follow-up of 7.6 years, we observed 38 LRRs: 28/481 (5.8%) in ER + and 10/151 (6.6%) in ER-. There were 43 UR and 7 DR genes associated with LRR in ER + tumors, while 417 UR and 1150 DR genes were associated with LRR in ER- tumors. UR genes in ER + tumors were enriched for roles in cell proliferation ( q  < 0.05). In contrast, LRR in ER- tumors was most strongly associated with DR genes enriched for MHC-II-mediated antigen presentation and T cell activation ( q  < 0.05). In external cohorts of ER- tumors, 97 significant DR genes ( p  < 0.05) were enriched for 18 pathways, including 5 pathways involved in MHC-II signaling, antigen presentation and T-cell activation. Conclusions Transcriptomic patterns associated with LRR appear distinct between ER + and ER- tumors. In ER + tumors, LRR appears predominantly associated with proliferation, whereas ER- LRR suggests a robust pattern of suppressed antigen presentation via MHC-II.

Objectives Stereotactic body radiotherapy (SBRT) is widely used for localized prostate cancer and implementation of MR-guided radiotherapy has the advantage of tighter margins and improved sparing of organs at risk. Here we evaluate outcomes and time required to treat using non-adaptive MR-guided SBRT (MRgSBRT) for localized prostate cancer at our institution. Methods From 9/2019 to 11/2021 we conducted a retrospective review of 80 consecutive patients who were treated with MRgSBRT to the prostate. Patients included low (LR) (5%), favorable intermediate (FIR) (40%), unfavorable intermediate (UIR) (49%), and high risk (HR) (6%). Short-term androgen deprivation therapy was used in 32% of patients. Target volumes included prostate gland and proximal seminal vesicles with an isotropic 3 mm margin. Treatment was prescribed to 36.25 Gy in 5 fractions every other day with urethral sparing. Hydrogel spacer was used in 18% of patients. Time on the linac was recorded as beam on time (BOT) plus total treatment time (TTT) including gating. Analyzed outcomes included PSA response and patient reported outcomes scored by the American Urological Association (AUA) questionnaire and toxicity per CTCAE v5. General linear regression model was used to analyze factors affecting PSA and AUA in longitudinal follow up, and chi-square test was used to assess factors affecting toxicity. Results Median follow up was 19.3 months (3.8 – 36.6). Median BOT was 4.6 min (2.6 – 7.2) with a median TTT of 11 min (7.6 – 15.8). Pre-treatment vs post-RT median PSA was 6.36 (2.20 – 19.6) vs 0.85 (0.19 – 3.6), respectively (P < 0.001). PSA decrease differed significantly when patients were stratified by risk category, favoring LR/FIR vs UIF/HR group (P = 0.019). Four (5%) patients experienced a biochemical failure (BCF), with a median time to BCF of 20.4 months (7.9 – 34.5). Median biochemical failure free survival (BCFFS) was not reached, with 2-yr and 4-yr BCFFS of 97.1% and 72.1%, respectively. Patients with LR/FIR disease had 100% 2-yr and 4-yr BCFFS, whereas patients with UIF/HR had 95% and 41% 2-yr and 4-yr BCFFS (P = 0.05). Mean pre-treatment AUA was 7.3 (1 - 25) vs 11.3 (1 - 26) at first follow-up; however, AUA normalized to baseline over time. Urethral Dmax ≥35 Gy trended to lower AUA score at all follow-ups (P = 0.07). Forty-one (51%) patients reported grade 1-2 genitourinary toxicities at the 1 month follow up. Grade 3 toxicity (proctitis) was noted in 1 patient. There was no decrease in any grade rectal toxicity with use of hydrogel spacer (3 vs 6, P = 0.2). No grade ≥4 toxicities was observed. Conclusions MRgSBRT has the potential for treatment adaptation but this comes at the cost of increased resource utilization. Our experience with non-adaptive MRgSBRT of the prostate highlights its short treatment times as well as efficacy with good PSA control and low toxicity profile.

Pathway-level survival analysis offers the opportunity to examine molecular pathways and immune signatures that influence patient outcomes. However, available survival analysis algorithms are limited in pathway-level function and lack a streamlined analytical process. Here we present a comprehensive pathway-level survival analysis suite, PATH-SURVEYOR, which includes a Shiny user interface with extensive features for systematic exploration of pathways and covariates in a Cox proportional-hazard model. Moreover, our framework offers an integrative strategy for performing Hazard Ratio ranked Gene Set Enrichment Analysis and pathway clustering. As an example, we applied our tool in a combined cohort of melanoma patients treated with checkpoint inhibition (ICI) and identified several immune populations and biomarkers predictive of ICI efficacy. We also analyzed gene expression data of pediatric acute myeloid leukemia (AML) and performed an inverse association of drug targets with the patient’s clinical endpoint. Our analysis derived several drug targets in high-risk KMT2A-fusion-positive patients, which were then validated in AML cell lines in the Genomics of Drug Sensitivity database. Altogether, the tool offers a comprehensive suite for pathway-level survival analysis and a user interface for exploring drug targets, molecular features, and immune populations at different resolutions.

BackgroundTo determine whether combining brachytherapy with immunotherapy is safe in prostate cancer (PCa) and provides synergistic effects, we performed a Phase I/II trial on the feasibility, safety, and benefit of concurrent delivery of anti-PD-1 (nivolumab) with high-dose-rate (HDR) brachytherapy and androgen deprivation therapy (ADT) in patients with Grade Group 5 (GG5) PCa.MethodsEligible patients were aged 18 years or older with diagnosis of GG5 PCa. Patients received ADT, nivolumab every two weeks for four cycles, with two cycles prior to first HDR, and two more cycles prior to second HDR, followed by external beam radiotherapy. The primary endpoint was to determine safety and feasibility. This Phase I/II trial is registered with ClinicalTrials.gov (NCT03543189).ResultsBetween September 2018 and June 2019, six patients were enrolled for the Phase I safety lead-in with a minimum observation period of 3 months after nivolumab administration. Overall, nivolumab was well tolerated in combination with ADT and HDR treatment. One patient experienced a grade 3 dose-limiting toxicity (elevated Alanine aminotransferase and Aspartate aminotransferase) after the second cycle of nivolumab. Three patients (50%) demonstrated early response with no residual tumor detected in ≥4 of 6 cores on biopsy post-nivolumab (4 cycles) and 1-month post–HDR. Increase in CD8+ and FOXP3+/CD4+ T cells in tissues, and CD4+ effector T cells in peripheral blood were observed in early responders.ConclusionCombination of nivolumab with ADT and HDR is well tolerated and associated with evidence of increased immune infiltration and antitumor activity.

Background: Prostate cancer is a heterogeneous disease with variable clinical outcomes. If localized, the patient may be cured. However, prostate cancer is lethal if recurrence/progression to metastatic castrate resistant disease occurs. Thus, there is an unmet need to further understand the molecular underpinnings of this progression. Epidemiologic studies show that increased risk of developing and dying from prostate cancer has been associated with elevated serum IGF-1 levels, hyperinsulinemia and metabolic syndrome. Alterations in insulin pathway genes, such as PTEN, FOXO, and PIK3CA, are mutated in up to 32%, 15%, and 11% of localized prostate tumors, respectively. We aimed to further characterize expression of insulin pathway genes in localized prostate cancers in an effort to (1) provide insights into potential mechanisms of progression to metastatic disease and (2) try to further enrich for those prostate tumors that portend worse survival outcomes. Methods: Using the multi-institutional Oncology Research Information Exchange Network (ORIEN) database, gene expression data was analyzed from localized prostate cancer tumors. The raw counts were first normalized, and 176 genes related to the insulin receptor and its downstream pathways were then subset and used for clustering using the non-negative matrix factorization (NMF). The NMF cluster analysis was performed in an attempt to separate gene expression into two groups. Gene Set Enrichment Analysis (GSEA) was then performed between the two groups that had been separated by cluster analysis to determine homology between other GSEA sets. Kaplan–Meier curves were used to assess median overall survival. Cox analysis was performed to generate the adjusted KM curve. Mediation analysis was conducted to determine the relationship between cluster status, TN stage, and survival. Results: Cluster analysis revealed two distinct groups of insulin gene expression, cluster 1 (n = 96) and cluster 2 (n = 337). Compared with cluster 2, cluster 1 consisted of decreased expression of PTEN (p < 0.001) and PIK3R1 (p < 0.001), along with increases in the expression of AKT1 (p < 0.001), IRS1/2 (p < 0.001), FASN (p < 0.001), IGFBP2 (p < 0.001), and MTOR (p < 0.001). GSEA analysis revealed changes in lipid metabolism and WNT secretion pathways in cluster 1. Cluster 2 GSEA showed pathway changes related to DNA damage repair and testosterone. Patient characteristics between clusters differed significantly in the T and N stages of tumor but not in other ways. In unadjusted analysis, median overall survival was estimated at 117 months and 232 months for cluster 1 and cluster 2, respectively (p < 0.05). The proportion of patients who went on to develop metastases (p < 0.05) or need chemotherapy (p < 0.05) was increased in cluster 1 compared to cluster 2. Repeat survival analysis adjusted for confounders (T stage, N stage, age at diagnosis, pathologic grade) showed no difference in survival between clusters. Mediation analysis showed that the contribution of cluster status to survival was independent of T or N stage. Conclusions: A subset of localized prostate cancer patients demonstrated linked insulin pathway changes that are consistent with prior studies describing a pattern of insulin dysregulation. Though the group characterized by insulin dysregulation initially showed worse survival outcomes, this difference disappeared when controlling for confounders. Though baseline differences in tumor stage seemed to most readily explain the difference in survival between clusters, mediation analysis showed that the effect of cluster status on survival was independent of tumor stage. This suggests that other confounders, such as pathologic grade or baseline age, may explain the survival difference.

Muscle invasive bladder cancer (MIBC) is an aggressive disease with a high risk of metastasis. Bladder preservation with trimodality therapy (TMT) is an option for well-selected patients or poor cystectomy candidates. Cone beam computed tomography (CBCT)-guided online adaptive radiotherapy (oART) shows promise in improving the dose to treatment targets while better sparing organs at risk (OARs). The following series presents two cases in which the capabilities of a CBCT-guided oART platform were leveraged to meet clinical challenges. The first case describes a patient with synchronous MIBC and high-risk prostate cancer with challenging target-OAR interfaces. The second recounts the case of a patient with a history of low dose rate (LDR) brachytherapy to the prostate who was later diagnosed with MIBC and successfully treated with CBCT-guided oART with reduced high-dose volume bladder targeting. To date, both patients report minimal side effects and are without disease recurrence. These cases illustrate how CBCT-guided online adaptive systems may efficiently aid radiation oncologists in treating patients with more complex clinical scenarios who desire bladder-sparing therapy.

Background: The use of stereotactic body radiation therapy (SBRT) is widely utilized for treatment of localized prostate cancer. Magnetic-resonance-guided radiotherapy (MRgRT) was introduced in 2014 and has recently been implemented in SBRT for prostate cancer as it provides an opportunity for smaller margins and adaptive daily planning. Currently, the only publications of MRgRT for prostate SBRT describe European clinical experiences which utilized adaptive planning. However, adaptive planning adds significantly to the time required for daily treatment. Objectives: Since prostate SBRT has demonstrated acceptable toxicity for several years, we did not consider daily adaptation critical to the process of prostate SBRT. After Institutional Review Board approval, we analyzed and now report our experience using MRgRT without adaptation. Methods: Between 25 September 2019 and 21 December 2020, 35 consecutive patients were treated with MRgRT prostate SBRT at our center. Patients treated with MRgRT included favorable intermediate risk (43%) and unfavorable intermediate risk (54%), and only one patient had low-risk prostate cancer. Nine patients (25%) received adjuvant leuprolide for a median of 4.5 months (range 4–6 m). Our clinical pathway allows for a maximum prostate gland volume of 60 cc; median prostate volume of this cohort was 35.0 cc (range 17–58.4 cc). Median pre-treatment PSA was 6.30 (range 2.55–16.77). Each patient was treated with 36.25 Gy delivered in five fractions over 2 weeks with urethral sparing to a maximal dose of 35 Gy. Target volumes included the prostate gland and proximal seminal vesicles with a 3 mm margin. Results: Median follow-up as of 26 May 2021 was 11.97 months (range 4.37–19.80). First follow-up data are available for all patients, with a median of 1.10 month from completion of treatment (0.63–3.40). The median PSA at first visit was 2.75 (range 0.02–9.00) with a median AUA symptom score of 9 (range 1–24). Second follow-up data are available for 34 patients at a median of 4.45 months (range 2.57–8.90). At second follow-up, the median PSA was 1.60 (range 0.02–5.40) with a median AUA symptom score of 6 (range 1–33). Seventeen patients had third follow-up data with a median of 9.77 months (range 4.70–12.33) after SBRT. The median PSA was 1.13 (range 0.02–4.73) with an AUA score of 9 (2–22) at the third follow-up. We observed a statistically significant decrease in PSA between pre-treatment and at first follow-up (p < 0.005). The most common toxicity was grade 2 urethritis, managed in all cases by tamsulosin. One patient developed grade 2 tenesmus relieved by topical steroids. No cases of grade ≥ 3 toxicity were seen in our patient population. Conclusions: By avoiding the extra time required for plan adaptation, MRgRT without daily adaptation allows for successful prostate SBRT with manageable toxicity. We continue to reserve our limited adaptive treatment slots for preoperative pancreatic and ultra-central lung SBRT patients, which require time-intensive respiratory gating and adaptive planning.