Cancers

Research

14 pages, 2619 KiB

Open AccessArticle

The Influence of the Germline HSD3B1 Adrenal-Permissive Allele (c.1100 C) on the Somatic Alteration Landscape, the Transcriptome, and Immune Cell Infiltration in Prostate Cancer

by Samuel Kellen, Allison Makovec, Carly D. Miller, Shayan S. Nazari, Andrew Elliott, Aiden Deacon, Emily John, Nikitha Vobugari, Neeraj Agarwal, Rana R. McKay, Pedro C. Barata, Charles J. Ryan, Nima Sharifi, Justin Hwang and Emmanuel S. Antonarakis

Cancers 2025, 17(), 1270; https://doi.org/10.3390/cancers17081270 - 9 Apr 2025

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Abstract

Background/Objectives: The germline polymorphism in the HSD3B1 gene (c.1100 C) results in adrenal-permissive (CC) or adrenal-restrictive (AA) functions of the protein product by regulating the production of high-affinity ligands that activate androgen signaling. Prior studies have indicated that the CC genotype is [...] Read more.

Background/Objectives: The germline polymorphism in the HSD3B1 gene (c.1100 C) results in adrenal-permissive (CC) or adrenal-restrictive (AA) functions of the protein product by regulating the production of high-affinity ligands that activate androgen signaling. Prior studies have indicated that the CC genotype is associated with worse response to hormonal therapies in prostate cancer (PC) patients. Methods: To characterize the impact of germline HSD3B1 variants on somatic tumor features, we examined 6550 primary and metastatic PCs from the Caris Life Sciences database, in which the genomic and transcriptomic landscapes were acquired via paired whole-exome/whole-transcriptome sequencing. Results: The overall prevalence of the HSD3B1 AA genotype (restrictive–homozygous) was 48.8%, AC (permissive–heterozygous) was 32.8%, and CC (permissive–homozygous) was 14.9%. There was enrichment of the CC genotype in these PC patients as compared to prior reports that examined non-cancerous populations. However, the rates of the CC genotype varied between metastatic site and by race. Compared to the AA genotype, tumors harboring the CC genotype did not demonstrate increased AR alterations, nor higher expression of AR, FOXA1, HOXB13, or AR signaling signatures. We instead found significant changes in immune-associated hallmark pathways, immune cell fractions, and biomarkers that inform the use of immune therapies (TMB-high, MSI-high). Further, the CC and AA genotypes exhibited notable differences in the expression of immunoglobulins, MHC class I/II molecules, and cell surface targets. The differences in expression by HSD3B1 genotype were especially notable in lung and liver metastases. Conclusions: Our study indicates that in prostate cancers, HSD3B1 germline c.1100 allele status may not directly influence tumor-intrinsic genomics but is associated with novel functions beyond androgen signaling. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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19 pages, 3338 KiB

Open AccessArticle

Developing a Predictive Model for Significant Prostate Cancer Detection in Prostatic Biopsies from Seven Clinical Variables: Is Machine Learning Superior to Logistic Regression?

by Juan Morote, Berta Miró, Patricia Hernando, Nahuel Paesano, Natàlia Picola, Jesús Muñoz-Rodriguez, Xavier Ruiz-Plazas, Marta V. Muñoz-Rivero, Ana Celma, Gemma García-de Manuel, Pol Servian, José M. Abascal, Enrique Trilla and Olga Méndez

Cancers 2025, 17(7), 1101; https://doi.org/10.3390/cancers17071101 - 25 Mar 2025

Viewed by 255

Abstract

Objective: This study compares machine learning (ML) and logistic regression (LR) algorithms in developing a predictive model for sPCa using the seven predictive variables from the Barcelona (BCN-MRI) predictive model. Method: A cohort of 5005 men suspected of having PCa who [...] Read more.

Objective: This study compares machine learning (ML) and logistic regression (LR) algorithms in developing a predictive model for sPCa using the seven predictive variables from the Barcelona (BCN-MRI) predictive model. Method: A cohort of 5005 men suspected of having PCa who underwent MRI and targeted and/or systematic biopsies was used for training, testing, and validation. A feedforward neural network (FNN)-based SimpleNet model (GMV) and a logistic regression-based model (BCN) were developed. The models were evaluated for discrimination ability, precision–recall, net benefit, and clinical utility. Both models demonstrated strong predictive performance. Results: The GMV model achieved an area under the curve of 0.88 in training and 0.85 in test cohorts (95% CI: 0.83–0.90), while the BCN model reached 0.85 and 0.84 (95% CI: 0.82–0.87), respectively (p > 0.05). The GMV model exhibited higher recall, making it more suitable for clinical scenarios prioritizing sensitivity, whereas the BCN model demonstrated higher precision and specificity, optimizing the reduction of unnecessary biopsies. Both models provided similar clinical benefit over biopsying all men, reducing unnecessary procedures by 27.5–29% and 27–27.5% of prostate biopsies at 95% sensitivity, respectively (p > 0.05). Conclusions: Our findings suggest that both ML and LR models offer high accuracy in sPCa detection, with ML exhibiting superior recall and LR optimizing specificity. These results highlight the need for model selection based on clinical priorities. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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18 pages, 2354 KiB

Open AccessArticle

Extracellular Microvesicle MicroRNAs and Imaging Metrics Improve the Detection of Aggressive Prostate Cancer: A Pilot Study

by Kapil K. Avasthi, Jung W. Choi, Tetiana Glushko, Brandon J. Manley, Alice Yu, Jong Y. Park, Joel S. Brown, Julio Pow-Sang, Robert Gantenby, Liang Wang and Yoganand Balagurunathan

Cancers 2025, 17(5), 835; https://doi.org/10.3390/cancers17050835 - 27 Feb 2025

Viewed by 706

Abstract

Background/Objectives: Prostate cancer (PCa) is the most diagnosed cancer in men worldwide. Early diagnosis of the disease provides better treatment options for these patients. Recent studies have demonstrated that plasma-based extracellular vesicle microRNAs (miRNAs) are functionally linked to cancer progression, metastasis, and aggressiveness. [...] Read more.

Background/Objectives: Prostate cancer (PCa) is the most diagnosed cancer in men worldwide. Early diagnosis of the disease provides better treatment options for these patients. Recent studies have demonstrated that plasma-based extracellular vesicle microRNAs (miRNAs) are functionally linked to cancer progression, metastasis, and aggressiveness. The use of magnetic resonance imaging (MRI) as the standard of care provides an overall assessment of prostate disease. Quantitative metrics (radiomics) from the MRI provide a better evaluation of the tumor and have been shown to improve disease detection. Methods: We conducted a study on prostate cancer patients, analyzing baseline blood plasma and MRI data. Exosomes were isolated from blood plasma samples to quantify miRNAs, while MRI scans provided detailed tumor morphology. Radiomics features from MRI and miRNA expression data were integrated to develop predictive models, which were evaluated using ROC curve analysis, highlighting the multivariable model’s effectiveness. Results: Our findings indicate that the univariate feature-based model with the highest Youden’s index achieved average areas under the receiver operating characteristic (ROC) curve of 0.76, 0.82, and 0.84 for miRNA, MR-T2W, and MR-ADC features, respectively, in identifying clinically aggressive (Gleason grade) disease. The multivariable feature-based model yielded an average area under the curve (AUC) of 0.88 and 0.95 using combinations of miRNA markers with imaging features in MR-ADC and MR-T2W, respectively. Conclusions: Our study demonstrates that combining miRNA markers with MRI-based radiomics improves the identification of clinically aggressive prostate cancer. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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17 pages, 2532 KiB

Open AccessArticle

The Homeobox Transcription Factor NKX3.1 Displays an Oncogenic Role in Castration-Resistant Prostate Cancer Cells

by Audris Budreika, John T. Phoenix, Raymond J. Kostlan, Carleen D. Deegan, Marina G. Ferrari, Kristen S. Young, Sean W. Fanning and Steven Kregel

Cancers 2025, 17(2), 306; https://doi.org/10.3390/cancers17020306 - 18 Jan 2025

Viewed by 1454

Abstract

Background/Objectives: Prostate cancer (PCa) is the second leading cause of cancer-related death in men. The increase in incidence rates of more advanced and aggressive forms of the disease year-to-year fuels urgency to find new therapeutic interventions and bolster already established ones. PCa is [...] Read more.

Background/Objectives: Prostate cancer (PCa) is the second leading cause of cancer-related death in men. The increase in incidence rates of more advanced and aggressive forms of the disease year-to-year fuels urgency to find new therapeutic interventions and bolster already established ones. PCa is a uniquely targetable disease in that it is fueled by male hormones (androgens) that drive tumorigenesis via the androgen receptor or AR. Current standard-of-care therapies directly target AR and its aberrant signaling axis but resistance to these therapies commonly arises, and the mechanisms behind the onset of therapy-resistance are still elusive. Research has shown that even with resistant disease, AR remains the main driver of growth and survival of PCa, and AR target genes and cofactors may help mediate resistance to therapy. Here, we focused on a homeobox transcription factor that exhibits a close relationship with AR—NKX3.1. Though NKX3.1 is traditionally thought of as a tumor suppressor, it has been previously reported to promote cancer cell survival by cooperating with AR. The role of NKX3.1 as a tumor suppressor perhaps in early-stage disease also contradicts its profile as a diagnostic biomarker for advanced prostate cancer. Methods: We investigated the physical interaction between NKX3.1 and AR, a modulated NKX3.1 expression in prostate cancer cells via overexpression and knockdown and assayed subsequent viability and downstream target gene expression. Results: We find that the expression of NKX3.1 is maintained in advanced PCa, and it is often elevated because of aberrant AR activity. Transient knockdown experiments across various PCa cell line models reveal NKX3.1 expression is necessary for survival. Similarly, stable overexpression of NKX3.1 in PCa cell lines reveals an androgen insensitive phenotype, suggesting NKX3.1 is sufficient to promote growth in the absence of an AR ligand. Conclusions: Our work provides new insight into NKX3.1’s oncogenic influence on PCa and the molecular interplay of these transcription factors in models of late-stage prostate cancer. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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17 pages, 1777 KiB

Open AccessArticle

Neoadjuvant Accelerated Methotrexate, Vinblastine, Doxorubicin, and Cisplatin Chemotherapy for Muscle-Invasive Urothelial Cancer: Large, Single-Center Analysis of Consecutive Patients’ Data

by Łukasz Kwinta, Kamil Konopka, Krzysztof Okoń, Mateusz Łobacz, Piotr Chłosta, Przemysław Dudek, Anna Buda-Nowak, Paweł Potocki and Piotr J. Wysocki

Cancers 2025, 17(2), 258; https://doi.org/10.3390/cancers17020258 - 14 Jan 2025

Viewed by 738

Abstract

Background/Objectives: Bladder cancer is a significant clinical problem with approximately 500,000 new cases worldwide annually. In approximately 25% of cases, disease is diagnosed at a stage of invasion of the muscle layer of the bladder. The current standard approach in this disease [...] Read more.

Background/Objectives: Bladder cancer is a significant clinical problem with approximately 500,000 new cases worldwide annually. In approximately 25% of cases, disease is diagnosed at a stage of invasion of the muscle layer of the bladder. The current standard approach in this disease is preoperative chemotherapy followed by radical cystectomy. Dose-dense MVAC (ddMVAC), a two-day chemotherapy regimen, is the reference treatment protocol in this setting. The presented study evaluated the effectiveness and safety of accelerated MVAC (aMVAC) chemotherapy—a one-day regimen given before the resection of the bladder due to muscle-invasive disease. Methods: A retrospective analysis included 119 consecutive patients diagnosed with urothelial muscle-invasive bladder cancer (MIBC) who underwent preoperative chemotherapy with the aMVAC regimen. The planned treatment included 4–6 cycles of preoperative chemotherapy. The analysis of the degree of histopathological response to treatment was based on the three-grade TRG (tumor regression grade) classification. Results: A complete pathological response (TRG1) was observed in 44 patients (36.7%), and a major pathologic response (<ypT2) was achieved in 58 patients (48.7%). A reduction in the cisplatin dose was associated with a statistically significant decrease in the chance of achieving complete pathologic responses (46.1% vs. 10%, RR for TRG1 = 0.69, p = 0.00118). Patients who received at least 4 cycles (compared to ≤3 cycles) of neoadjuvant chemotherapy had a significantly higher chance of achieving a pathological response (partial or complete) to treatment (78.1% vs. 52.2%, RR 0.68, p = 0.0374). Administration of at least five cycles of chemotherapy was associated (compared to four cycles) with a significantly higher likelihood of achieving a complete pathological response (63.2% vs. 33.8%, RR = 1.71, p = 0.0221). The vast majority of adverse events were in grades 1 and 2, according to CTCAE version 5.0. Only five patients experienced grade 3–4 toxicities. The most common adverse event was anemia, which occurred in 66.3% of patients. Conclusions: Our real-world data analysis confirms the activity, safety, and feasibility of the aMVAC regimen as neoadjuvant chemotherapy in patients with urothelial MIBC. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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14 pages, 3237 KiB

Open AccessArticle

Surgical Technique and Perioperative Outcomes of the “Sapienza” Urology Residency Program’s Trocar Placement Configuration During Robotic-Assisted Radical Prostatectomy (RARP): A Retrospective, Single-Centre Observational Study Comparing Experienced Attendings vs. Post-Graduate Year I–III Residents as Bedside Assistants

by Valerio Santarelli, Dalila Carino, Roberta Corvino, Stefano Salciccia, Ettore De Berardinis, Wojciech Krajewski, Łukasz Nowak, Jan Łaszkiewicz, Tomasz Szydełko, Rajesh Nair, Muhammad Shamim Khan, Ramesh Thurairaja, Mohamed Gad, Benjamin I. Chung, Alessandro Sciarra and Francesco Del Giudice

Cancers 2025, 17(1), 20; https://doi.org/10.3390/cancers17010020 - 25 Dec 2024

Viewed by 759

Abstract

Background/Objectives: Robot-assisted radical prostatectomy (RARP) for the treatment of prostate cancer (PCa) has been standardized over the last 20 years. At our institution, only n = 3 rob arms are used for RARP. In addition, n = 2, 12 mm lap trocars [...] Read more.

Background/Objectives: Robot-assisted radical prostatectomy (RARP) for the treatment of prostate cancer (PCa) has been standardized over the last 20 years. At our institution, only n = 3 rob arms are used for RARP. In addition, n = 2, 12 mm lap trocars are placed for the bedside assistant symmetrically at the midclavicular lines, which allows for direct pelvic triangulation and greater involvement of the assisting surgeon. The aim of our study was to compare surgical and perioperative outcomes of RARP performed using our alternative trocar placement with no fourth robotic arm in the subgroups of experienced attending surgeons and post-graduate residents as bedside assistants. Residents’ satisfaction was also explored. Methods: RARPs performed within the urology residency program between 2019 and 2024 were retrospectively analyzed. Only rob procedures performed using our 3+2 trocars configuration were included. Intra- and postoperative outcomes, as well as long-term functional outcomes including continence recovery and potency, were assessed, stratified by the level of expertise of the bedside assistant, i.e., an experienced attending or post-graduate Year I–III resident. Satisfaction of residents assigned to the two groups during their robotic rotation was evaluated considering three domains with a score from 1 to 10: insight into surgical procedure, confidence level, and gratification level. Results: Out of n = 281 RARP procedures, the bedside assistant was an attending in 104 cases and a resident in 177. Operative time was found to be slightly longer in cases where the second operator was a resident (attendings vs. residents: 134 ± 40 vs. 152 ± 24; p < 0.001). Postoperative hospitalization time was longer in patients in the resident group (attendings vs. residents: 3.9 ± 1.6 vs. 4.3 ± 1 days; p = 0.025). However, cases where the second operator was a resident had a lower rate of positive surgical margins, with rates of 19.7% in the resident and 43.3% in the attending surgeon cohorts (OR = 0.32; 95% CI 0.18–0.55). This difference remained significant in multivariate analysis. There was no significant difference in postoperative blood transfusion rates (attendings vs. residents: 1.9% vs. 1.2%; p = 0.6). Similarly, long-term functional outcomes in terms of erectile dysfunction and urinary incontinence rates mostly overlapped between groups. The mean score in all three domains evaluating residents’ satisfaction was significantly higher when residents actively participated in the surgical procedure as bedside assistants (p = 0.02, p = 0.004, and p < 0.001, respectively, for insights into surgical procedure, confidence level, and gratification level). Conclusions: These findings provide insight into how an alternative port positioning during RARP could improve the involvement of the bedside assistant, particularly residents, without compromising perioperative outcomes or surgical safety. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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17 pages, 2734 KiB

Open AccessArticle

Isolation of Plasma Extracellular Vesicles for High-Depth Analysis of Proteomic Biomarkers in Metastatic Castration-Resistant Prostate Cancer Patients

by Ali T. Arafa, Megan Ludwig, Onur Tuncer, Lily Kollitz, Ava Gustafson, Ella Boytim, Christine Luo, Barbara Sabal, Daniel Steinberger, Yingchun Zhao, Scott M. Dehm, Zuzan Cayci, Justin Hwang, Peter W. Villalta, Emmanuel S. Antonarakis and Justin M. Drake

Cancers 2024, 16(24), 4261; https://doi.org/10.3390/cancers16244261 - 21 Dec 2024

Viewed by 1387

Abstract

Introduction: Prostate cancer treatment has been revolutionized by targeted therapies, including PARP inhibitors, checkpoint immunotherapies, and PSMA-targeted radiotherapies. Despite such advancements, accurate patient stratification remains a challenge, with current methods relying on genomic markers, tissue staining, and imaging. Extracellular vesicle (EV)-derived proteins [...] Read more.

Introduction: Prostate cancer treatment has been revolutionized by targeted therapies, including PARP inhibitors, checkpoint immunotherapies, and PSMA-targeted radiotherapies. Despite such advancements, accurate patient stratification remains a challenge, with current methods relying on genomic markers, tissue staining, and imaging. Extracellular vesicle (EV)-derived proteins offer a novel non-invasive alternative for biomarker discovery, holding promise for improving treatment precision. However, the characterization of plasma-derived EVs in prostate cancer patients remains largely unexplored. Methods: We conducted proteomic analyses on EVs isolated from plasma in 27 metastatic castration-resistant prostate cancer (mCRPC) patients. EVs were purified using ultracentrifugation and analyzed via mass spectrometry. Proteomic data were correlated with clinical markers such as serum prostate-specific antigen (PSA) and bone lesion counts. Statistical significance was assessed using Mann–Whitney t-tests and Spearman correlation. Results: The median age of patients was 74 (range: 44–94) years. At the time of blood collection, the median PSA level was 70 (range: 0.5–1000) ng/mL. All patients had bone metastasis. A total of 5213 proteins were detected, including EV-related proteins (CD9, CD81, CD63, FLOT1, TSG101) and cancer-related proteins (PSMA, B7-H3, PD-L1). Proteomic profiling of plasma EVs revealed a significant correlation between specific EV-derived proteins and clinical prognostic markers. B7-H3, LAT1, and SLC29A1 showed a strong association with serum PSA levels and number of bone lesions, indicating potential for these proteins to serve as biomarkers of disease burden and therapy response. Conclusions: Our findings demonstrate the potential of EV-based proteomics for identifying biomarkers in mCRPC patients. Proteins such as B7-H3 and LAT1 could guide precision oncology approaches, improving patient stratification. Future research incorporating outcomes data and EV subpopulation analysis is needed to establish clinical relevance. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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16 pages, 3428 KiB

Open AccessArticle

Development of Traceable Mouse Models of Advanced and Metastatic Bladder Cancer

by Emma Desponds, Konstantina Kioseoglou, Hana Zdimerova, Marco Ongaro, Grégory Verdeil and Marine M. Leblond

Cancers 2024, 16(12), 2245; https://doi.org/10.3390/cancers16122245 - 17 Jun 2024

Viewed by 1606

Abstract

Bladder cancer (BC) is the fourth most common cancer in men, with a poor patient prognosis for advanced disease. The poor survival of patients with muscle-invasive bladder cancer (MIBC) and metastatic status emphasizes the urgent need to develop new therapies. Lacking in the [...] Read more.

Bladder cancer (BC) is the fourth most common cancer in men, with a poor patient prognosis for advanced disease. The poor survival of patients with muscle-invasive bladder cancer (MIBC) and metastatic status emphasizes the urgent need to develop new therapies. Lacking in the field of BC is the availability of relevant advanced BC mouse models, especially metastatic ones, that accurately recapitulate the complexities of human pathology to test and study new therapeutic strategies. Addressing this need, we developed a traceable mouse model of BC that expresses tumor-associated antigens within the context of advanced muscle-invasive BC. This novel system was achieved through the deletion of the tp53 and pten genes, alongside the incorporation of the fusion construct of Firefly luciferase (Luc) and the SIYRYYGL (SIY) T-cell antigen. We validate that the presence of the transgene did not impact on the development of the tumors while allowing us to measure tumor progression by bioluminescence. We show that the transgene did not influence the composition of the immune tumor microenvironment. More importantly, we report that this model was unresponsive to anti-PD-1 treatment, as in the majority of patients with BC. We also develop a new model based on the orthotopic injection of BC clonal cell lines derived from our first model. We demonstrate that this new model invades the muscle layer and has a metastasis development rate of 83%. The advantage of this model is that we can visualize tumor growth and metastasis development in vivo. These mouse models’ characteristics, displaying many similarities with the human pathology, provide a valuable tool for tracking tumor progression, metastasis spread in vivo, and treatment resistance, as well as exploring fundamental and translational aspects of BC biology. This work contributes to the improvement in the landscape of mouse models of advanced BC for testing new therapeutic strategies. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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11 pages, 571 KiB

Open AccessArticle

Low Alanine Aminotransferase as a Marker for Sarcopenia and Frailty, Is Associated with Decreased Survival of Bladder Cancer Patients and Survivors—A Retrospective Data Analysis of 3075 Patients

by Menachem Laufer, Maxim Perelman, Gad Segal, Michal Sarfaty and Edward Itelman

Cancers 2024, 16(1), 174; https://doi.org/10.3390/cancers16010174 - 29 Dec 2023

Cited by 3 | Viewed by 1686

Abstract

Background. Sarcopenia is characterized by the loss of muscle mass and function and is associated with frailty, a syndrome linked to an increased likelihood of falls, fractures, and physical disability. Both frailty and sarcopenia are recognized as markers for shortened survival in a [...] Read more.

Background. Sarcopenia is characterized by the loss of muscle mass and function and is associated with frailty, a syndrome linked to an increased likelihood of falls, fractures, and physical disability. Both frailty and sarcopenia are recognized as markers for shortened survival in a number of medical conditions and in cancer patient populations. Low alanine aminotransferase (ALT) values, representing low muscle mass (sarcopenia), may be associated with increased frailty and subsequently shortened survival in cancer patients. In the current study, we aimed to assess the potential relationship between low ALT and shorter survival in bladder cancer patients and survivors. Patients and Methods. This was a retrospective analysis of bladder cancer patients and survivors, both in and outpatients. We defined patients with sarcopenia as those presenting with ALT < 17 IU/L. Results. A total of 5769 bladder cancer patients’ records were identified. After the exclusion of patients with no available ALT values or ALT levels above the upper normal limit, the final study cohort included 3075 patients (mean age 73.2 ± 12 years), of whom 80% were men and 1362 (53% had ALT ≤ 17 IU/L. The mean ALT value of patients within the low ALT group was 11.44 IU/L, while the mean value in the higher ALT level group was 24.32 IU/L (p < 0.001). Patients in the lower ALT group were older (74.7 vs. 71.4 years; p < 0.001), had lower BMI (25.8 vs. 27; p < 0.001), and their hemoglobin values were lower (11.7 vs. 12.6 g/dL; p < 0.001). In a univariate analysis, low ALT levels were associated with a 45% increase in mortality (95% CI 1.31–1.60, p < 0.001). In a multivariate model controlling for age, kidney function, and hemoglobin, low ALT levels were still associated with 22% increased mortality. Conclusions. Low ALT values, indicative of sarcopenia and frailty, are associated with decreased survival of bladder cancer patients and survivors and could potentially be applied for optimizing individual treatment decisions. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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Review

Jump to: Research, Other

21 pages, 1542 KiB

Open AccessReview

Ancestry-Specific DNA Damage Repair Gene Mutations and Prostate Cancer

by Talaibek Borbiev, Kevin Babcock, Kayleigh Sinopole, Gregory T. Chesnut and Gyorgy Petrovics

Cancers 2025, 17(4), 682; https://doi.org/10.3390/cancers17040682 - 18 Feb 2025

Viewed by 2072

Abstract

This review is intended to reflect the currently available literature on both clinically significant germline mutations in DNA damage repair (DDR) genes as well as the importance of ancestral diversity in the pathogenesis of prostate cancer (PCa). The second most prevalent cancer worldwide [...] Read more.

This review is intended to reflect the currently available literature on both clinically significant germline mutations in DNA damage repair (DDR) genes as well as the importance of ancestral diversity in the pathogenesis of prostate cancer (PCa). The second most prevalent cancer worldwide in men is PCa, causing significant morbidity and mortality in its advanced stage. Emerging data highlight the substantial role of germline mutations of DDR genes in PCa pathogenesis, especially in progression to aggressive forms of the disease. Germline genetic testing is recognized as a necessary tool for efficient, individualized patient care. NCCR guidelines recommend inquiring about the family history of PCa and known germline variants and, if indicated, proceeding with germline multigene testing followed by post-test genetic counseling. Depending on the germline mutations in HR repair genes or in MMR genes, specific treatment options may provide clinical benefit. We will discuss specific germline mutations that are involved in PCa progression and prognosis in racially diverse populations. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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14 pages, 1363 KiB

Open AccessReview

Striving for Equity: Examining Health Disparities in Urologic Oncology

by Dhruv Puri, Kshitij Pandit, Noah Choi, Brent S. Rose, Rana R. McKay and Aditya Bagrodia

Cancers 2024, 16(21), 3559; https://doi.org/10.3390/cancers16213559 - 22 Oct 2024

Cited by 2 | Viewed by 1269

Abstract

Health disparities in urologic oncology, particularly in prostate, bladder, kidney, and testicular cancers, significantly impact patient outcomes across different demographic groups. This narrative review aims to investigate the extent and drivers of these disparities, focusing on the influence of race, socioeconomic status, and [...] Read more.

Health disparities in urologic oncology, particularly in prostate, bladder, kidney, and testicular cancers, significantly impact patient outcomes across different demographic groups. This narrative review aims to investigate the extent and drivers of these disparities, focusing on the influence of race, socioeconomic status, and geographic location on diagnosis, treatment, and survival outcomes. We conducted a comprehensive review of the existing literature and analyzed data from national cancer databases to identify patterns of inequity. Our findings reveal that minority populations, individuals with lower socioeconomic status, and those residing in underserved areas are less likely to receive timely and guideline-based care, leading to worse outcomes. This review underscores the urgent need for targeted interventions, including policy reforms, health system restructuring, enhanced community outreach, and increased funding for disparity-focused research, to ensure equitable access to high-quality oncologic care. Addressing these disparities is crucial for improving cancer outcomes and achieving health equity in urologic oncology. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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18 pages, 1058 KiB

Open AccessReview

Developmental Therapeutics in Metastatic Prostate Cancer: New Targets and New Strategies

by Jingsong Zhang and Juskaran S. Chadha

Cancers 2024, 16(17), 3098; https://doi.org/10.3390/cancers16173098 - 6 Sep 2024

Cited by 1 | Viewed by 2753

Abstract

There is an unmet need to develop new treatments for metastatic prostate cancer. With the development of targeted radioligand therapies, bispecific T cell engagers, antibody–drug conjugates and chimeric antigen receptor T cell (CAR T) therapies, tumor-associated cell surface antigens have emerged as new [...] Read more.

There is an unmet need to develop new treatments for metastatic prostate cancer. With the development of targeted radioligand therapies, bispecific T cell engagers, antibody–drug conjugates and chimeric antigen receptor T cell (CAR T) therapies, tumor-associated cell surface antigens have emerged as new therapeutic targets in metastatic prostate cancer. Ongoing and completed clinical trials targeting prostate-specific membrane antigen (PSMA), six transmembrane epithelial antigens of the prostate 1 (STEAP1), kallikrein-related peptidase 2 (KLK2), prostate stem cell antigen (PSCA), and delta-like protein 3 (DLL3) in metastatic prostate cancer were reviewed. Strategies for sequential or combinational therapy were discussed. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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13 pages, 302 KiB

Open AccessReview

Is There an Opportunity to De-Escalate Treatments in Selected Patients with Metastatic Hormone-Sensitive Prostate Cancer?

by María Antonia Gómez-Aparicio, Fernando López-Campos, David Buchser, Antonio Lazo, Patricia Willisch, Abrahams Ocanto, Paul Sargos, Mohamed Shelan and Felipe Couñago

Cancers 2024, 16(13), 2331; https://doi.org/10.3390/cancers16132331 - 26 Jun 2024

Viewed by 3027

Abstract

The treatment landscape for metastatic hormone-sensitive prostate cancer continues to evolve, with systemic treatment being the mainstay of current treatment. Prognostic and predictive factors such as tumour volume and disease presentation have been studied to assess responses to different treatments. Intensification and de-escalation [...] Read more.

The treatment landscape for metastatic hormone-sensitive prostate cancer continues to evolve, with systemic treatment being the mainstay of current treatment. Prognostic and predictive factors such as tumour volume and disease presentation have been studied to assess responses to different treatments. Intensification and de-escalation strategies arouse great interest, so several trials are being developed to further personalize the therapy in these populations. Is there an optimal sequence and a possible option to de-intensify treatment in selected patients with a favourable profile? This and other goals will be the subject of this review. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

14 pages, 1855 KiB

Open AccessReview

Diagnostic Biomarkers in Renal Cell Tumors According to the Latest WHO Classification: A Focus on Selected New Entities

by Francesca Sanguedolce, Roberta Mazzucchelli, Ugo Giovanni Falagario, Angelo Cormio, Magda Zanelli, Andrea Palicelli, Maurizio Zizzo, Albino Eccher, Matteo Brunelli, Andrea Benedetto Galosi, Giuseppe Carrieri and Luigi Cormio

Cancers 2024, 16(10), 1856; https://doi.org/10.3390/cancers16101856 - 13 May 2024

Cited by 2 | Viewed by 3023

Abstract

The fifth edition of the World Health Organization (WHO) classification for urogenital tumors, released in 2022, introduces some novelties in the chapter on renal epithelial tumors compared to the previous 2016 classification. Significant changes include the recognition of new disease entities and adjustments [...] Read more.

The fifth edition of the World Health Organization (WHO) classification for urogenital tumors, released in 2022, introduces some novelties in the chapter on renal epithelial tumors compared to the previous 2016 classification. Significant changes include the recognition of new disease entities and adjustments in the nomenclature for certain pathologies. Notably, each tumor entity now includes minimum essential and desirable criteria for reliable diagnosis. This classification highlights the importance of biological and molecular characterization alongside traditional cytological and architectural features. In this view, immunophenotyping through immunohistochemistry (IHC) plays a crucial role in bridging morphology and genetics. This article aims to present and discuss the role of key immunohistochemical markers that support the diagnosis of new entities recognized in the WHO classification, focusing on critical topics associated with single markers, in the context of specific tumors, such as the clear cell capillary renal cell tumor (CCPRCT), eosinophilic solid and cystic renal cell carcinoma (ESC-RCC), and so-called “other oncocytic tumors”, namely the eosinophilic vacuolated tumor (EVT) and low-grade oncocytic tumor (LOT). Their distinctive characteristics and immunophenotypic profiles, along with insights regarding diagnostic challenges and the differential diagnosis of these tumors, are provided. This state-of-the-art review offers valuable insights in biomarkers associated with novel renal tumors, as well as a tool to implement diagnostic strategies in routine practice. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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37 pages, 5146 KiB

Open AccessSystematic Review

Application of Geographic Information Systems (GIS) in the Study of Prostate Cancer Disparities: A Systematic Review

by Christiane J. El Khoury

Cancers 2024, 16(15), 2715; https://doi.org/10.3390/cancers16152715 - 30 Jul 2024

Viewed by 1743

Abstract

Introduction: PCa is one of the cancers that exhibits the widest disparity gaps. Geographical place of residence has been shown to be associated with healthcare access/utilization and PCa outcomes. Geographical Information Systems (GIS) are widely being utilized for PCa disparities research, however, [...] Read more.

Introduction: PCa is one of the cancers that exhibits the widest disparity gaps. Geographical place of residence has been shown to be associated with healthcare access/utilization and PCa outcomes. Geographical Information Systems (GIS) are widely being utilized for PCa disparities research, however, inconsistencies in their application exist. This systematic review will summarize GIS application within PCa disparities research, highlight gaps in the literature, and propose alternative approaches. Methods: This paper followed the methods of the Cochrane Collaboration and the criteria set of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Articles published in peer-reviewed journals were searched through the PubMed, Embase, and Web of Science databases until December 2022. The main inclusion criteria were employing a GIS approach and examining a relationship between geographical components and PCa disparities. The main exclusion criteria were studies conducted outside the US and those that were not published in English. Results: A total of 25 articles were included; 23 focused on PCa measures as outcomes: incidence, survival, and mortality, while only 2 examined PCa management. GIS application in PCa disparities research was grouped into three main categories: mapping, processing, and analysis. GIS mapping allowed for the visualization of quantitative, qualitative, and temporal trends of PCa factors. GIS processing was mainly used for geocoding and smoothing of PCa rates. GIS analysis mainly served to evaluate global spatial autocorrelation and distribution of PCa cases, while local cluster identification techniques were mainly employed to identify locations with poorer PCa outcomes, soliciting public health interventions. Discussion: Varied GIS applications and methodologies have been used in researching PCa disparities. Multiple geographical scales were adopted, leading to variations in associations and outcomes. Geocoding quality varied considerably, leading to less robust findings. Limitations in cluster-detection approaches were identified, especially when variations were captured using the Spatial Scan Statistic. GIS approaches utilized in other diseases might be applied within PCa disparities research for more accurate inferences. A novel approach for GIS research in PCa disparities could be focusing more on geospatial disparities in procedure utilization especially when it comes to PCa screening techniques. Conclusions: This systematic review summarized and described the current state and trend of GIS application in PCa disparities research. Although GIS is of crucial importance when it comes to PCa disparities research, future studies should rely on more robust GIS techniques, carefully select the geographical scale studied, and partner with GIS scientists for more accurate inferences. Such interdisciplinary approaches have the potential to bridge the gaps between GIS and cancer prevention and control to further advance cancer equity. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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15 pages, 2877 KiB

Open AccessSystematic Review

Urine-Based Biomarker Test Uromonitor^® in the Detection and Disease Monitoring of Non-Muscle-Invasive Bladder Cancer—A Systematic Review and Meta-Analysis of Diagnostic Test Performance

by Anton P. Kravchuk, Ingmar Wolff, Christian Gilfrich, Ralph M. Wirtz, Paula Soares, Kay-Patrick Braun, Sabine D. Brookman-May, Lisa Kollitsch, Katharina Hauner, Martin Burchardt, Johannes Bründl, Maximilian Burger and Matthias May

Cancers 2024, 16(4), 753; https://doi.org/10.3390/cancers16040753 - 11 Feb 2024

Cited by 3 | Viewed by 2831

Abstract

Optimal urine-based diagnostic tests (UBDT) minimize unnecessary follow-up cystoscopies in patients with non-muscle-invasive bladder-cancer (NMIBC), while accurately detecting high-grade bladder-cancer without false-negative results. Such UBDTs have not been comprehensively described upon a broad, validated dataset, resulting in cautious guideline recommendations. Uromonitor^®, [...] Read more.

Optimal urine-based diagnostic tests (UBDT) minimize unnecessary follow-up cystoscopies in patients with non-muscle-invasive bladder-cancer (NMIBC), while accurately detecting high-grade bladder-cancer without false-negative results. Such UBDTs have not been comprehensively described upon a broad, validated dataset, resulting in cautious guideline recommendations. Uromonitor^®, a urine-based DNA-assay detecting hotspot alterations in TERT, FGFR3, and KRAS, shows promising initial results. However, a systematic review merging all available data is lacking. Studies investigating the diagnostic performance of Uromonitor^® in NMIBC until November 2023 were identified in PubMed, Embase, Web-of-Science, Cochrane, Scopus, and medRxiv databases. Within aggregated analyses, test performance and area under the curve/AUC were calculated. This project fully implemented the PRISMA statement. Four qualifying studies comprised a total of 1190 urinary tests (bladder-cancer prevalence: 14.9%). Based on comprehensive analyses, sensitivity, specificity, positive-predictive value/PPV, negative-predictive value/NPV, and test accuracy of Uromonitor^® were 80.2%, 96.9%, 82.1%, 96.6%, and 94.5%, respectively, with an AUC of 0.886 (95%-CI: 0.851–0.921). In a meta-analysis of two studies comparing test performance with urinary cytology, Uromonitor^® significantly outperformed urinary cytology in sensitivity, PPV, and test accuracy, while no significant differences were observed for specificity and NPV. This systematic review supports the use of Uromonitor^® considering its favorable diagnostic performance. In a cohort of 1000 patients with a bladder-cancer prevalence of ~15%, this UBDT would avert 825 unnecessary cystoscopies (true-negatives) while missing 30 bladder-cancer cases (false-negatives). Due to currently limited aggregated data from only four studies with heterogeneous quality, confirmatory studies are needed. Full article

(This article belongs to the Special Issue New Insights into Urologic Oncology)

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