The Immune Landscape and Immunotherapeutic Strategies in Platinum-Refractory Testicular Germ Cell Tumors.

Testicular germ cell tumors (TGCTs) are cancers with very good prognosis, even in the metastatic setting, with high curative potential mainly attributed to the introduction of cisplatin-based chemotherapy. However, approximately 15% of the patients develop platinum-refractory disease and suffer multiple relapses. Therefore, there is an unmet need for novel therapeutic agents with improved efficacy and minimal long-term side effects. Recent advances in the development of immunotherapeutic agents, particularly immune checkpoint inhibitors (ICIs), have offered an opportunity to test their activity in various tumor types, including GCTs. This review aims to analyze the immune microenvironment of these tumors and present the most recently available data from studies that have tested immunotherapeutic agents against GCTs. The majority of the available knowledge derives from case reports or small cohort studies, particularly those involving ICIs of the PD-1/PD-L1 axis alone or in combination with anti-CTLA-4 monoclonal antibodies. Other immunotherapeutic targeted approaches, including antibody-drug conjugates, antibody prodrugs, vaccines, tyrosine kinase inhibitors, chimeric antigen receptor (CAR) T-cell therapy, have biological rationales and have shown preliminary activity or are currently being tested. Growing evidence on these and other approaches will assist in broadening the currently limited treatment armamentarium against platinum-refractory TGCTs.

Co-occurring BRCA2/SPOP Mutations Predict Exceptional Poly (ADP-ribose) Polymerase Inhibitor Sensitivity in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND AND OBJECTIVE: BRCA2 mutations in metastatic castration-resistant prostate cancer (mCRPC) confer sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors. However, additional factors predicting PARP inhibitor efficacy in mCRPC are needed. Preclinical studies support a relationship between speckle-type POZ protein (SPOP) inactivation and PARP inhibitor sensitivity. We hypothesized that SPOP mutations may predict enhanced PARP inhibitor response in BRCA2-altered mCRPC. METHODS: We conducted a multicenter retrospective study involving 13 sites. We identified 131 patients with BRCA2-altered mCRPC treated with PARP inhibitors, 14 of which also carried concurrent SPOP mutations. The primary efficacy endpoint was prostate-specific antigen (PSA) response rate (≥50% PSA decline). The secondary endpoints were biochemical progression-free survival (PSA-PFS), clinical/radiographic progression-free survival (PFS), and overall survival (OS). These were compared by multivariable Cox proportional hazard models adjusting for age, tumor stage, baseline PSA level, Gleason sum, prior therapies, BRCA2 alteration types, and co-occurring mutations. KEY FINDINGS AND LIMITATIONS: Baseline characteristics were similar between groups. PSA responses were observed in 60% (70/117) of patients with BRCA2mut/SPOPwt disease and in 86% (12/14) of patients with BRCA2mut/SPOPmut disease (p = 0.06). The median time on PARP inhibitor treatment was 24.0 mo (95% confidence interval [CI] 19.2 mo to not reached) in this group versus 8.0 mo (95% CI 6.1-10.9 mo) in patients with BRCA2 mutation alone (p = 0.05). In an unadjusted analysis, patients with BRCA2mut/SPOPmut disease experienced longer PSA-PFS (hazard ratio [HR] 0.33 [95% CI 0.15-0.72], p = 0.005) and clinical/radiographic PFS (HR 0.4 [95% CI 0.18-0.86], p = 0.02), and numerically longer OS (HR 0.4 [95% CI 0.15-1.12], p = 0.08). In a multivariable analysis including histology, Gleason sum, prior taxane, prior androgen receptor pathway inhibitor, stage, PSA, BRCA2 alteration characteristics, and other co-mutations, patients with BRCA2mut/SPOPmut disease experienced longer PSA-PFS (HR 0.16 [95% CI 0.05-0.47], adjusted p = 0.001), clinical/radiographic PFS (HR 0.28 [95% CI 0.1-0.81], adjusted p = 0.019), and OS (HR 0.19 [95% CI 0.05-0.69], adjusted p = 0.012). In a separate cohort of patients not treated with a PARP inhibitor, there was no difference in OS between patients with BRCA2mut/SPOPmut versus BRCA2mut/SPOPwt disease (HR 0.97 [95% CI 0.40-2.4], p = 0.94). In a genomic signature analysis, Catalog of Somatic Mutations in Cancer (COSMIC) SBS3 scores predictive of homologous recombination repair (HRR) defects were higher for BRCA2mut/SPOPmut than for BRCA2mut/SPOPwt disease (p = 0.04). This was a retrospective study, and additional prospective validation cohorts are needed. CONCLUSIONS AND CLINICAL IMPLICATIONS: In this retrospective analysis, PARP inhibitors appeared more effective in patients with BRCA2mut/SPOPmut than in patients with BRCA2mut/SPOPwt mCRPC. This may be related to an increase in HRR defects in coaltered disease. PATIENT SUMMARY: In this study, we demonstrate that co-alteration of both BRCA2 and SPOP predicts superior clinical outcomes to treatment with poly (ADP-ribose) polymerase (PARP) inhibitors than BRCA2 alteration without SPOP mutation.

Characterization of a miRNA Signature with Enhanced Diagnostic and Prognostic Power for Patients with Bladder Carcinoma.

Bladder carcinoma is globally among the most prevalent cancers and is associated with a high mortality rate at advanced stages. Its detection relies on invasive diagnostic methods that are unpleasant for the patient. Non-invasive molecular biomarkers, such as miRNAs, could serve as alternatives for early detection and prognosis of this malignancy. We designed a computational approach that combines transcriptome profiling, survival analyses, and calculation of diagnostic power in order to isolate miRNA signatures with high diagnostic and prognostic utility. Our analysis of TCGA-BLCA data from 429 patients yielded one miRNA signature, consisting of five upregulated and three downregulated miRNAs with cumulative diagnostic power that outperforms current diagnostic methods. The same miRNAs have a strong prognostic significance since their expression is associated with the overall survival of bladder cancer patients. We evaluated the expression of this signature in 19 solid cancer types, supporting its unique diagnostic utility for bladder carcinoma. We provide computational evidence regarding the functional implications of this miRNA signature in cell cycle regulation, demonstrating its abundance in body fluids, including peripheral blood and urine. Our study characterized a novel miRNA signature with the potential to serve as a non-invasive method for bladder cancer diagnosis and prognosis.

Upper Tract Urothelial Carcinoma: A Rare Malignancy with Distinct Immuno-Genomic Features in the Era of Precision-Based Therapies.

Upper tract urothelial carcinoma (UTUC) is a rare malignancy, occurring in 5-10% of patients diagnosed with UC, and involves the renal pelvis, calyces, or ureters. UTUC can be sporadic or hereditary as a clinical manifestation of Lynch syndrome. Therapeutic management of these patients is challenging. Following risk stratification of localized disease, patients with low-grade UTUC may undergo kidney-sparing surgery or radical nephroureterectomy (RNU) and/or chemoablation with mitomycin-c instillation to reduce recurrence. In high-grade disease, RNU followed by adjuvant chemotherapy remains the standard of care. For decades, platinum-based chemotherapy has been the cornerstone of treatment for locally advanced and metastatic disease. The aim of the present review is to summarize recent advances in UTUC's therapeutic management through the lens of its genomic and immune landscape. Accumulating knowledge on the genetic and immune aspects of UTUC tumors has increased our understanding of their underlying biology, supporting a luminal papillary, T-cell depleted contexture and enrichment in fibroblast growth factor receptor (FGFR) expression. These advances have fueled successful clinical testing of several precision-based therapeutic approaches, including immune checkpoint inhibitors (ICIs), the antibody-drug conjugates (ADCs) enfortumab vedotin and sacituzumab govitecan, and agents targeting the FGFR axis such as erdafitinib and other kinase inhibitors, allowing their entry into the therapeutic armamentarium and improving the prognosis of these patients. Not all patients respond to these precision-based targeted therapies; thus, validating and expanding the toolkit of potential biomarkers of response or resistance, including molecular subtypes, FGFR pathway gene alterations, DNA repair gene defects, tumor mutational burden (TMB), circulating tumor DNA (ctDNA), nectin-4, TROP2, and programmed death ligand-1 (PD-L1), are key to maximizing the benefit to these particular subgroups of patients.

Complete Vascular Replacement of the Infrarenal Inferior Vena Cava and Abdominal Aorta during Post-Chemotherapy Retroperitoneal Lymph Node Dissection for a Non-Seminomatous Germ Cell Tumor.

Testicular germ cell tumors (TGCTs) are the leading cause of cancer-related death in males between the ages of 20 and 40. In the advanced stages, the combination of cisplatin-based chemotherapy and surgical excision of the remaining tumor can cure many of these patients. Vascular procedures may be required during retroperitoneal lymph node dissection (RPLND) in order to achieve the complete excision of all residual retroperitoneal masses. Careful assessment of pre-operative imaging and the identification of patients who could benefit from additional procedures are important for minimizing peri- and postoperative complications. We report on a case of a 27-year-old patient with non-seminomatous TGCT, who successfully underwent post-chemotherapy RPLND with additional infrarenal inferior vena cava (IVC) and complete abdominal aorta replacement using synthetic grafts.

The Impact of Enhanced Recovery after Surgery Protocol Implementation on Postoperative Pain Management in the Era of Opioid Crisis: The Postchemotherapy Open RPLND Experience.

AIM: Enhanced Recovery After Surgery (ERAS) protocols have been proven to optimize postoperative outcomes; however, misuse of opioid analgesics can still hinder postoperative recovery due to related side effects and potential complications. INTRODUCTION: To determine if the implementation of ERAS protocol in post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) patients could help with reducing postoperative pain and opioid use. METHODS: A case-control study of consecutive testicular cancer patients with indications for PCRLPND, who were offered Conventional Post-operative Management (CPM) or ERAS protocol. Outcomes of interest included Visual Analogue Scale (VAS)-assessed pain level at postoperative days 3, 7, and 30, and Morphine-Equivalent Doses (MEDs)/postoperative day. Intraoperative parameters and postoperative complications were recorded. Parametric and non-parametric tests were used for statistical analysis. RESULTS: In total, 100 opioid-naïve PC-RPLND patients were studied. CPM and ERAS groups (36 and 64 patients, respectively) had similar demographic and baseline clinical characteristics). ERAS group patients had significantly lower blood loss (p = 0.005), blood transfusion rate (p < 0.001), and duration of the procedure (p < 0.001). Post-operative complications were comparable between groups. Nausea and bowel disorders were numerically but not statistically more frequent in the CPM group. ERAS patients had shorter mean hospital stay (5.3 ± 1.4 vs. 7.4 ± 1.6 days, p < 0.001), lower daily MEDs (4.73 ± 2.63 vs. 7.04 ± 2.29, p < 0.001), and lower VAS scores on post-operative day 7 (3.89 ± 1.07 vs. 4.67 ± 1.17, p = 0.001). Post-operative pain was similar between groups on post-operative days 3 and 30. CONCLUSION: Systematic implementation of ERAS protocol after PC-RPLND improves pain management, optimizes patient recovery, and prevents over-prescription of opioid analgesics.

Granular cell tumors of the urethra.

Granular cell tumors (GCTs) are a rare type of mesenchymal tumors that are histologically derived by Schwann cells and rise within soft tissues such as skin and mucosal surfaces. Differentiation between benign and malignant GCTs is often difficult and relies on their biological behavior and metastatic potential. While there are no standard guidelines for management, upfront surgical resection, whenever feasible, is key as a definitive measure. Systemic therapy is often limited by poor chemosensitivity of these tumors; however, accumulating knowledge of their underlying genomic landscape has opened some opportunities for targeted approaches, for example, the vascular endothelial growth factor tyrosine kinase inhibitor pazopanib, which is already in clinical use for the treatment of many types of advanced soft tissue sarcomas.

Εmerging Biomarkers in the Diagnosis and Treatment of Testicular Tumors.

Testicular germ cell tumors (TGCT) are the leading cause of cancer-related death in young males between the ages of 20-40. Surgical resection and cisplatin-based chemotherapy can achieve a cure for the majority of patients with TGCTs, with survival rates of up to 97% for patients diagnosed at an early stage. The use of serum biomarkers, such as AFP ß-HCG, and LDH, plays a significant role in both diagnosis and evaluation of response to treatment, and despite their low sensitivity and specificity levels, they are an integral part of the current tumor staging system and daily practice. Molecular biomarkers, including micro-RNAs and gene-expression profiles, are currently being developed in TGCTs and could potentially hold a prominent place in the future diagnosis, treatment selection, surveillance, and prognostication of these tumors. This review discusses how current advances in our understanding of the underlying biology of TGCTs have helped biomarker discovery, with a focus on the recognition of key molecular alterations that could serve as potential indicators of disease onset, response to systemic or/and surgical therapies, and overall clinical course.

Prevention, diagnostic evaluation, management and prognostic implications of liver disease in critically ill patients with COVID-19.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, broke out in December 2019 in Wuhan city of China and spread rapidly worldwide. Therefore, by March 2020, the World Health Organization declared the disease a global pandemic. Apart from the respiratory system, various other organs of the human body are also seriously affected by the virus. Liver injury in patients with a severe form of COVID-19 is estimated to be 14.8%-53.0%. Elevated levels of total bilirubin, aspartate aminotransferase and alanine aminotransferase and low levels of serum albumin and prealbumin are the main laboratory findings. Patients with pre-existing chronic liver disease and cirrhosis are much more prone to develop severe liver injury. This literature review presented the recent scientific findings regarding the pathophysiological mechanisms responsible for liver injury in critically ill patients with COVID-19, the various interactions between drugs used to treat the disease and the function of the liver and the specific tests providing the possibility of early diagnosis of severe liver injury in these patients. Moreover, it highlighted the burden that COVID-19 put on health systems worldwide and its effect on transplant programs and the care provided to critically ill patients in general and particularly to those with chronic liver disease.

Differential responses to taxanes and PARP inhibitors in ATM- versus BRCA2-mutated metastatic castrate-resistant prostate cancer.

BACKGROUND: PARP (poly(ADP-ribose) polymerase) inhibitors (PARPi) are now standard of care in metastatic castrate-resistant prostate cancer (mCRPC) patients with select mutations in DNA damage repair (DDR) pathways, but patients with ATM- and BRCA2 mutations may respond differently to PARPi. We hypothesized that differences may also exist in response to taxanes, which may inform treatment sequencing decisions. METHODS: mCRPC patients (N = 158) with deleterious ATM or BRCA2 mutations who received taxanes, PARPi, or both were retrospectively identified from 11 US academic centers. Demographic, treatment, and survival data were collected. Kaplan-Meier analyses were performed and Cox hazard ratios (HR) were calculated for progression-free survival (PFS) as well as overall survival (OS), from time of first taxane or PARPi therapy. RESULTS: Fifty-eight patients with ATM mutations and 100 with BRCA2 mutations were identified. Fourty-four (76%) patients with ATM mutations received taxane only or taxane before PARPi, while 14 (24%) received PARPi only or PARPi before taxane. Patients with ATM mutations had longer PFS when taxane was given first versus PARPi given first (HR: 0.74 [95% confidence interval [CI]: 0.37-1.50]; p = 0.40). Similarly, OS was longer in patients with ATM mutations who received taxane first (HR: 0.56 [CI: 0.20-1.54]; p = 0.26). Among patients with BRCA2 mutations, 51 (51%) received taxane first and 49 (49%) received PARPi first. In contrast, patients with BRCA2 mutations had longer PFS when PARPi was given first versus taxane given first (HR: 0.85 [CI: 0.54-1.35]; p = 0.49). Similarly, OS was longer in patients with BRCA2 mutations who received PARPi first (HR: 0.75 [CI: 0.41-1.37]; p = 0.35). CONCLUSIONS: Our retrospective data suggest differential response between ATM and BRCA2 mutated prostate cancers in terms of response to PARPi and to taxane chemotherapy. When considering the sequence of PARPi versus taxane chemotherapy for mCRPC with DDR mutations, ATM, and BRCA2 mutation status may be helpful in guiding choice of initial therapy.

Mutational profile of primary clear cell renal cell carcinoma predicts recurrence and potential candidacy for adjuvant immune checkpoint inhibition.

Background: The risk of recurrence after nephrectomy for primary clear cell renal cell carcinoma (ccRCC) is estimated in daily practice solely based on clinical criteria. The aim of this study was to assess the prognostic relevance of common somatic mutations with respect to tumor aggressiveness and outcomes of ccRCC patients after definitive treatment. Methods: Primary tumors from 37 patients with ccRCC who underwent radical nephrectomy were analyzed for presence of somatic mutations using a 15-gene targeted next-generation sequencing (NGS) panel. Associations to histopathologic characteristics and outcomes were investigated in the study cohort (n=37) and validated in The Cancer Genome Atlas (TCGA) ccRCC cohort (n=451). Results: VHL was the most frequently mutated gene (51%), followed by PBRM1 (27%), BAP1 (13%), SETD2 (13%), KDM5C (5%), ATM (5%), MTOR (5%), and PTEN (3%). One-third of patients did not have any somatic mutations within the 15-gene panel. The vast majority of tumors harboring no mutations at all or VHL-only mutations (51%) were more frequently of smaller size (pT1-2) and earlier stage (I/II), whereas presence of any other gene mutations in various combinations with or without VHL was enriched in larger (pT3) and higher stage tumors (III) (p=0.02). No recurrences were noted in patients with unmutated tumors or VHL-only mutations as opposed to three relapses in patients with non- VHL somatic mutations (p=0.06). Presence of somatic mutations in PBRM1, BAP1, SETD2, KDM5C, ATM, MTOR, or PTEN genes in 451 TCGA ccRCC patients was associated with a significantly shorter disease-free survival (DFS) compared to those with unaltered tumors (q=0.01). Conclusions: Preliminary findings from this ongoing study support the prognostic value of non- VHL mutations including PBRM1, BAP1, SETD2, KDM5C, ATM, MTOR, and PTEN in primary ccRCC tumors as surrogates of earlier recurrence and potential selection for adjuvant immune checkpoint inhibition.

Immune-based treatment re-challenge in renal cell carcinoma: A systematic review and meta-analysis.

Introduction: The use of immune checkpoint inhibitors (ICIs) as a front-line treatment for metastatic renal cell carcinoma (RCC) has significantly improved patient' outcome. However, little is known about the efficacy or lack thereof of immunotherapy after prior use of anti-PD1/PD-L1 or/and anti-CTLA monoclonal antibodies. Methods: Electronic databases, including PubMed, EMBASE, Medline, Web of Science, and Cochrane Library, were comprehensively searched from inception to July 2022. Objective response rates (ORR), progression-free survival (PFS), and ≥ grade 3 adverse events (AEs) were assessed in the meta-analysis, along with corresponding 95% confidence intervals (CIs) and publication bias. Results: Ten studies which contained a total of 500 patients were included. The pooled ORR was 19% (95% CI: 10, 31), and PFS was 5.6 months (95% CI: 4.1, 7.8). There were ≥ grade 3 AEs noted in 25% of patients (95% CI: 14, 37). Conclusion: This meta-analysis on different second-line ICI-containing therapies in ICI-pretreated mRCC patients supports a modest efficacy and tolerable toxicity.

Hypoxia-Inducible Factor-2-Altered Urothelial Carcinoma: Clinical and Genomic Features.

Background: Hypoxia is recognized as a key feature of cancer growth and is involved in various cellular processes, including proliferation, angiogenesis, and immune surveillance. Besides hypoxia-inducible factor 1-alpha (HIF-1α), which is the main mediator of hypoxia effects and can also be activated under normoxic conditions, little is known about its counterpart, HIF-2. This study focused on investigating the clinical and molecular landscape of HIF-2-altered urothelial carcinoma (UC). Methods: Publicly available next-generation sequencing (NGS) data from muscle-invasive UC cell lines and patient tumor samples from the MSK/TCGA 2020 cohort (n = 476) were interrogated for the level of expression (mRNA, protein) and presence of mutations, copy number variations, structural variants in the EPAS1 gene encoding HIF-2, and findings among various clinical (stage, grade, progression-free and overall survival) and molecular (tumor mutational burden, enriched gene expression) parameters were compared between altered and unaltered tumors. Results: 19% (7/37) of UC cell lines and 7% (27/380) of patients with muscle-invasive UC display high EPAS1 mRNA and protein expression or/and EPAS1 alterations. EPAS1-altered tumors are associated with higher stage, grade, and lymph node metastasis as well as with shorter PFS (14 vs. 51 months, q = 0.01) and OS (15 vs. 55 months, q = 0.01). EPAS1 mRNA expression is directly correlated with that of its target-genes, including VEGF, FLT1, KDR, DLL4, CDH5, ANGPT1 (q < 0.001). While there is a slightly higher tumor mutational burden in EPAS1-altered tumors (9.9 vs. 4.9 mut/Mb), they are enriched in and associated with genes promoting immune evasion, including ARID5B, SPINT1, AAK1, CLIC3, SORT1, SASH1, and FGFR3, respectively (q < 0.001). Conclusions: HIF-2-altered UC has an aggressive clinical and a distinct genomic and immunogenomic profile enriched in angiogenesis- and immune evasion-promoting genes.

Current Options for Second-Line Systemic Therapy in Metastatic Renal Cell Carcinoma.

Standard systemic therapy of advanced renal cell carcinoma (RCC) involves targeting angiogenesis, mainly through tyrosine kinase inhibitors (TKI) against the vascular endothelial growth factor receptor (VEGFR) pathway and targeting the immune checkpoints, namely, programmed death-1 (PD-1) or its ligand (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). With current strategies of combining these two approaches in the front-line setting, less is known about optimal selection of therapy upon development of resistance in the second and later lines of treatment for progressive disease. This review discusses currently available therapeutic options in patients who have progressive RCC after prior treatment with double immune check-point inhibitors (ICIs) or ICI-TKI combinations.

The Impact of Androgen Deprivation Therapy on COVID-19 Illness in Men With Prostate Cancer.

BACKGROUND: TMPRSS2, a cell surface protease regulated by androgens and commonly upregulated in prostate cancer (PCa), is a necessary component for SARS-CoV-2 viral entry into respiratory epithelial cells. Previous reports suggested a lower risk of SARS-CoV-2 among PCa patients on androgen deprivation therapy (ADT). However, the impact of ADT on severe COVID-19 illness is poorly understood. METHODS: We performed a multicenter study across 7 US medical centers and evaluated patients with PCa and SARS-CoV-2 detected by polymerase-chain-reaction between March 1, 2020, and May 31, 2020. PCa patients were considered on ADT if they had received appropriate ADT treatment within 6 months of COVID-19 diagnosis. We used multivariable logistic and Cox proportional-hazard regression models for analysis. All statistical tests were 2-sided. RESULTS: We identified 465 PCa patients (median age = 71 years) with a median follow-up of 60 days. Age, body mass index, cardiovascular comorbidity, and PCa clinical disease state adjusted overall survival (hazard ratio [HR] = 1.16, 95% confidence interval [CI] = 0.68 to 1.98, P = .59), hospitalization status (HR = 0.96, 95% CI = 0.52 to 1.77, P = .90), supplemental oxygenation (HR 1.14, 95% CI = 0.66 to 1.99, P = .64), and use of mechanical ventilation (HR = 0.81, 95% CI = 0.25 to 2.66, P = .73) were similar between ADT and non-ADT cohorts. Similarly, the addition of androgen receptor-directed therapy within 30 days of COVID-19 diagnosis to ADT vs ADT alone did not statistically significantly affect overall survival (androgen receptor-directed therapy: HR = 1.27, 95% CI = 0.69 to 2.32, P = .44). CONCLUSIONS: In this retrospective cohort of PCa patients, the use of ADT was not demonstrated to influence severe COVID-19 outcomes, as defined by hospitalization, supplemental oxygen use, or death. Age 70 years and older was statistically significantly associated with a higher risk of developing severe COVID-19 disease.

Health-Related Quality of Life Assessment in Daily Urologic Practice: A Survey of Greek Urologists.

Purpose: Health-related quality of life (HRQoL) assessment has become an integral part of clinical research across different disciplines. However, the degree of incorporation of QoL standardized questionnaires in daily routine is variable. This survey study examined how HRQoL is perceived and utilized among urologists from the Hellenic Urological Association (HUA) in their daily practice. Methods: A nationwide survey of Greek urologists registered with the HUA was conducted. Participants were asked to complete a questionnaire sent via email. The survey questionnaire consisted of demographic data including sex, age, working position and working environment and 11 Likert-scale questions regarding perception and use of HRQoL in clinical practice. Results: A total of 1000 Greek urologists were contacted, of whom 400 (40%) responded. Participants were predominantly male (94.8%) with a mean age of 43.7 years and a mean working experience of 12.5 years. Most participants considered HRQoL assessment to be important in their clinical practice (95.3%) and valuable in both patient consultation (95.8%) and treatment follow-up (91.8%). Half of urologists (51%) agreed with the statement that there is limited time for HRQoL assessment in daily practice. Validated questionnaires were rated as useful by 75.5% of participants. Overall, only 26.7% of participants stated they have incorporated HRQoL questionnaires in their daily practice. A subgroup analysis of participants showed that experienced physicians (>10 years) were less likely to utilize HRQoL (OR 0.38, p=0.008, 95% CI 0.19-0.77) and experienced difficulty in distinguishing between HRQoL assessment and symptom-rating (OR 0.32, p<0.001, 95% CI 0.17-0.61). Lack of time for HRQoL assessment was a main concern for urologists in-training (OR 0.7, p<0.001, 95% CI 0.57-0.85). Conclusion: HRQoL assessment is well-perceived by Greek urologists, although it has yet to achieve a substantial degree of integration in their daily practice.

Expression of Fibroblast Activation Protein Is Enriched in Neuroendocrine Prostate Cancer and Predicts Worse Survival.

BACKGROUND: Advanced prostate cancer (PC) may accumulate genomic alterations that hallmark lineage plasticity and transdifferentiation to a neuroendocrine (NE) phenotype. Fibroblast activation protein (FAP) is a key player in epithelial-to-mesenchymal transition (EMT). However, its clinical value and role in NE differentiation in advanced PC has not been fully investigated. METHODS: Two hundred and eight patients from a multicenter, prospective cohort of patients with metastatic castration-resistant prostate cancer (CRPC) with available RNA sequencing data were analyzed for tumor FAP mRNA expression, and its association with overall survival (OS) and NE tumor features was investigated. RESULTS: Twenty-one patients (10%) were found to have high FAP mRNA expression. Compared to the rest, this subset had a proportionally higher exposure to taxanes and AR signaling inhibitors (abiraterone or enzalutamide) and was characterized by active NE signaling, evidenced by high NEPC- and low AR-gene expression scores. These patients with high tumor mRNA FAP expression had a more aggressive clinical course and significantly shorter survival (12 months) compared to those without altered FAP expression (28 months, log-rank p = 0.016). CONCLUSIONS: FAP expression may serve as a valuable NE marker indicating a worse prognosis in patients with metastatic CRPC.

Pilot study of the diagnostic utility of 89 Zr-df-IAB2M and 68 Ga-PSMA-11 PET imaging and multiparametric MRI in localized prostate cancer.

BACKGROUND: Accurate diagnosis of localized prostate cancer (PCa) is limited by inadequacy of multiparametric (mp) MRI to fully identify and differentiate localized malignant tissue from benign pathologies. Prostate-specific membrane antigen (PSMA) represents an excellent target for molecular imaging. IAB2M, an 85-kD minibody derived from a de-immunized monoclonal antibody directed at the extracellular domain of human PSMA (huJ591), and PSMA-11, a small molecule ligand have been previously tested as probes for visualization of recurrent/metastatic PCa with PET/CT. This pilot, non-randomized trial studied their diagnostic utility in patients (pts) with localized PCa. METHODS: Pts planned for radical prostatectomy (RP) were enrolled and underwent mpMRI and PET/CT imaging with 89 Zr-df-IAB2M and/or 68 Ga-PSMA-PET/CT. Image results were read by a radiologist blinded to clinical information and pathology results, mapped and compared to corresponding histopathology findings from all lesions, both clinically significant and nonsignificant. The detection rates of all three imaging modalities were measured and correlated. RESULTS: 20 pts with median age of 64.5 (46-79) years and PSA level of 7.5 (1.6-36.56) ng/ml were enrolled. 19 pts underwent RP and were imaged pre-operatively with 89 Zr-Df-IAB2M PET/CT and mpMRI. Nine of those were imaged using 68 Ga-PSMA-11 as well. Out of 48 intraprostatic lesions verified on surgical pathology, IAB2M PET/CT was able to detect 36 (75%). A similar proportion of pathologically confirmed, clinically significant lesions (22/29, 76%) was detected. IAB2M PET/CT was also able to identify 14/19 (74%) extraprostatic lesions. The performance of mpMRI was inferior, with 24/48 detectable lesions (50%) and 18/29 clinically significant intraprostatic lesions (62%). Compared to the current standard (mpMRI), IAB2M PET/CT had a sensitivity of 88%, specificity 38%, positive predictive value 58%, and accuracy 63%. In 9 pts who underwent Ga-PSMA-11 as well, the latter yielded a detection rate of 70% (14/20), which was also seen in clinically significant lesions (10/14, 71%). Ga-PSMA-11 PET/CT also detected 4/6 (67%) extraprostatic lesions. CONCLUSIONS: In this pilot study, the performance of 89 Zr-df-IAB2M was superior to mpMRI and similar to 68 Ga-PSMA-11 PET/CT. The higher detection rate of PSMA-PET supports its use as a diagnostic tool with consequent management change implications in men with localized PCa.

Renin-Angiotensin System Single Nucleotide Polymorphisms Are Associated with Bladder Cancer Risk.

The renin-angiotensin system (RAS), besides being a major regulator of blood pressure, is also involved in tumor angiogenesis. Emerging evidence suggests a correlation between the use of pharmacologic RAS inhibitors and a delay in urothelial bladder cancer (BC) progression. However, it is unknown whether RAS gene variants may predispose to the development of BC. This study examined the association of RAS single nucleotide polymorphisms (SNPs) including AT1R rs5186, AT2R rs11091046, REN rs12750834, ANG rs4762, and ANG rs699 with the risk of developing non-invasive BC. Peripheral blood samples from 73 patients with T1 urothelial BC (66 men, seven women) and an equal number of healthy subjects (control group) were collected. The TT genotype of the REN rs12750834 SNP (OR: 2.8 [1.3-6.05], p = 0.008) and to a lesser extent the presence of the T allele (OR: 2.3 [1.2-4.48], p = 0.01) conferred a higher risk of BC. The highest risk for BC within SNP carriers of the RAS system was associated with the presence of the CC genotype (OR: 17.6 [7.5-41.35], p < 0.001) and C allele (OR: 17.7 [8.8-35.9], p < 0.001) of the ANG rs699 SNP. The presence of the AT2R rs11091046 SNP, particularly the AA genotype, was associated with a protective effect against developing BC (OR: 0.268 [0.126-057], p < 0.001). In conclusion, these results support the clinical utility of RAS gene SNPs AT2R rs11091046, REN rs12750834, and ANG rs699 in the genetic cancer risk assessment of patients and families with BC.