Infectious complications of transrectal prostate biopsy in patients receiving targeted antibiotic prophylaxis after urethral and rectal swab versus standard prophylaxis: A prospective comparative study.

Background: To evaluate the role of targeted antibiotic prophylaxis (TAP) after rectal and urethral swab cultures compared to empiric antibiotic prophylaxis (EAP) for the prevention of infectious complications after transrectal ultrasound-guided prostate biopsy (TRUS-Bx). Methods: We conducted a prospective comparative study on 141 patients who underwent TRUS-Bx and were allocated in two groups. The first group (n = 71) received EAP with ciprofloxacin and the second (n = 70) received TAP according to rectal and urethral cultures. Post-biopsy infectious complications rates were compared between the two groups. Fluoroquinolone resistance (FQ-R) in the urethral and rectal swabs was recorded. Baseline characteristics were analyzed to assess their relationship with infectious complications and antibiotic resistance. Results: A total of 8 infectious complications were observed, 7 of them in the EAP group (9.85%) and 1 in the TAP group (1.4%). There was a statistically significant difference in febrile UTIs between the two groups (6 vs 0, P = 0.028). FQ-R rate was 4.3% and 12.9% for rectal and urethral samples, respectively. Recent antibiotic exposure was associated with higher post-biopsy infection rates for EAP group and FQ-R rates for TAP group. Conclusion: Combination of rectal and urethral swab cultures for TAP was able to detect FQ-R bacteria carriers and was associated with fewer infectious complications compared to EAP.

Randomized, placebo-controlled, double-blinded study of prophylactic cranberries use in women with recurrent uncomplicated cystitis.

BACKGROUND: Τhe adherence of p-fimbriated Escherichia coli (E. coli) to urothelial cells leading to recurrent urinary tract infections (rUTIs) may be prevented by proanthocyanidins (PACs) contained in American cranberries. PURPOSE: The purpose of this clinical trial was to assess the clinical utility of prophylactic use of high-dose PACs daily in women with a history of rUTIs. MATERIALS AND METHODS: 172 adult women with a history of rUTIs, defined as ≥ 2 within a 6-month period or ≥ 3 within a 12-month period were enrolled and randomized in two groups to receive either Cysticlean™ 240 mg or placebo for a 12-month period. Urine samples, vaginal and rectal swabs were collected at initial and quarterly study visits. The primary study endpoints were the number of urinary tract infections (UTIs) and changes in Quality of Life (QoL), assessed by the 36-Item Short Form Survey (SF-36) questionnaire. RESULTS: 160 adult women of median age 40 years old (range 19-82) were finally analyzed in this randomized, placebo-controlled, double-blinded clinical trial. In response to intervention, the number of UTIs was significantly lower (Incidence rate ratio IRR 0.49, p < 0.001) and QoL was slightly improved. The numbers of E. coli isolates detected in vaginal (IRR 0.71, p value < 0.001) and in rectal swabs (IRR 0.87, p value < 0.001) were also significantly decreased. No adverse events were reported. CONCLUSION: The daily use of Cysticlean™ 240 mg was associated with a reduction of UTIs and a prolongation of UTI-free survival compared to placebo treatment, supporting its use as prophylaxis in this patient population. TRIAL REGISTRATION: Clinicaltrials.gov, identifier NCT03032003.

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.

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.

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.

Clear-cell renal cell carcinoma single urinary bladder metastasis: a case report and review of the literature.

Renal cell carcinoma (RCC) is the most frequent solid lesion accounting for ~90% of all kidney malignancies. Clear-cell RCC (ccRCC) represents the most frequent subtype. Urinary bladder is a rare metastatic site either synchronous or metachronous. Hereby, we report the case of an 85-year-old male patient with a single urinary bladder metastasis due to ccRCC and we present a review of the literature.

Mixed epithelial and stromal tumor-adult cystic nephroma of the kidney: a case report with immunohistochemical analysis.

The mixed epithelial and stromal tumor family of kidney contain neoplasms with biphasic epithelial and stromal component. According to the 2016 World Health Organization Classification, they encompasses a spectrum of tumors ranging from predominantly cystic tumors (adult cystic nephroma) to tumors that are variably solid (Mixed epithelial and stromal tumor-MESTs). We present the case of a 20-year-old woman with an adult cystic nephroma which was verified by immunohistochemical examination.

The use of an artificial neural network in the evaluation of the extracorporeal shockwave lithotripsy as a treatment of choice for urinary lithiasis.

Objective: Artificial neural networks (ANNs) are widely applied in medicine, since they substantially increase the sensitivity and specificity of the diagnosis, classification, and the prognosis of a medical condition. In this study, we constructed an ANN to evaluate several parameters of extracorporeal shockwave lithotripsy (ESWL), such as the outcome and safety of the procedure. Methods: Patients with urinary lithiasis suitable for ESWL treatment were enrolled. An ANN was designed using MATLAB. Medical data were collected from all patients and 12 nodes were used as inputs. Conventional statistical analysis was also performed. Results: Finally, 716 patients were included in our study. Univariate analysis revealed that diabetes and hydronephrosis were positively correlated with ESWL complications. Regarding efficacy, univariate analysis revealed that stone location, stone size, the number and density of shockwaves delivered, and the presence of a stent in the ureter were independent factors of the ESWL outcome. This was further confirmed when adjusted for sex and age in a multivariate analysis. The performance of the ANN at the end of the training state reached 98.72%. The four basic ratios (sensitivity, specificity, positive predictive value, and negative predictive value) were calculated for both training and evaluation data sets. The performance of the ANN at the end of the evaluation state was 81.43%. Conclusion: Our ANN achieved high score in predicting the outcome and the side effects of the ESWL treatment for urinary stones.

Poorly differentiated muscle-invasive giant cell tumor of the bladder leads to unfavorable clinical outcome.

Urothelial carcinoma of the urinary bladder is a common clinical entity. Recently, researchers focused on the emerging clinical significance of histologic variants, because they may need special therapy and their prognosis differs. Hereby, we describe a case of a giant cell osteoclast-like urothelial carcinoma of the urinary bladder.

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.