The Model of Interstitial Cystitis for Evaluating New Molecular Strategies of Interstitial Regeneration in Humans.

Given the recent evidence in the clinical application of regenerative medicine, mostly on integumentary systems, we focused our interests on recent bladder regeneration approaches based on mesenchymal stem cells (MSCs), platelet-rich plasma (PRP), and hyaluronic acid (HA) in the treatment of interstitial cystitis/bladder pain syndrome (IC/BPS) in humans. IC/BPS is a heterogeneous chronic disease with not-well-understood etiology, characterized by suprapubic pain related to bladder filling and urothelium dysfunction, in which the impairment of immunological processes seems to play an important role. The histopathological features of IC include ulceration of the mucosa, edema, denuded urothelium, and increased detection of mast cells and other inflammatory cells. A deeper understanding of the molecular mechanism underlying this disease is essential for the selection of the right therapeutic approach. In fact, although various therapeutic strategies exist, no efficient therapy for IC/BPS has been discovered yet. This review gives an overview of the clinical and pathological features of IC/BPS, with a particular focus on the molecular pathways involved and a special interest in the ongoing few investigational therapies in IC/BPS, which use new regenerative medicine approaches, and their synergetic combination. Good knowledge of the molecular aspects related to stem cell-, PRP-, and biomaterial-based treatments, as well as the understanding of the molecular mechanism of this pathology, will allow for the selection of the right and best use of regenerative approaches of structures involving connective tissue and epithelia, as well as in other diseases.

New concept in urologic surgery: The total extended genital sparing radical cystectomy in women.

INTRODUCTION AND OBJECTIVES: The aim of the study was to evaluate genital sparing radical cystectomy surgery in female patients from the point of view of both oncologic and functional outcomes (with emphasis on urinary and sexual outcomes) in a single high-volume center for the treatment of muscular invasive bladder cancer. MATERIALS AND METHODS: Between January 2014 and January 2018, 14 female patients underwent radical cystectomy with preservation of genital organs (the entire vagina, uterus, fallopian tubes, ovaries) and orthotopic urinary neobladder (Padua neobladder). Inclusion criteria were recurrent T1G3 tumors; refractory tumors after BCG therapy without associated carcinoma in situ (CIS); T2 or T3a tumors entirely resected at endoscopic transurethral resection of the bladder and not involving urethra/bladder trigone. Exclusion criteria were: T3b or higher bladder cancer, associated CIS and involvement of urethra or bladder trigone. Oncological and histopathological outcomes (Overall Survival - OS, Recurrence Free Survival - RFS), urinary outcomes (day and night incontinence, intermittent catheterization use, Sandvik Score) and sexual outcomes (Female Sexual Function Index 19 FSFI-19) were considered. The average follow-up time was 56 months. RESULTS: Considering oncological outcomes, histologic examination reported urothelial carcinoma in 13/14 patients; 8/13 patients (61.5%) had high grade T1 stage, 3/13 patients (23%) had high grade T2 stage and finally 2/13 patients (15.5%) had high-grade T3 stage. One patient presented with embryonal rhabdomyosarcoma completely excised after surgery (PT2aN0M0). No patient developed local or metastatic recurrence (RFS 100%); OS was 100%. Considering urinary continence outcomes, 12/14 patients retained daytime and nighttime continence (85.5%); 2/14 (14.5%) complained of low stress urinary incontinence daily and nighttime urinary leakage. The Sandvik Score showed complete continence in 7/14 patients (50%); mild degree incontinence in 6/14 patients without use of incontinence devices (43%); moderate degree of incontinence in one patient (7%). The FSFI administered at 1 year from the surgery showed sexual desire in all patients (100%); subjective arousal, achievement of orgasm and sexual satisfaction in 12/14 patients (85.5%); sufficient lubrication in 11/14 patients (78.5%). Only one patient (7%) complained about dyspareunia during sexual intercourse. CONCLUSIONS: Our study aims to demonstrate that genital-sparing radical cystectomy is a safe surgery in terms of oncologic outcomes and, most importantly, that it is beneficial in terms of urinary and sexual function. Indeed, patients' quality of life together with their psychological and emotional health should be put on the same level as oncological safety. However, it is a treatment reserved for selected patients who are strongly motivated to preserve fertility and sexual function and thoroughly informed about the benefits and complications of such a procedure.

Immune-Checkpoint Inhibitors in Advanced Bladder Cancer: Seize the Day.

BACKGROUND: In advanced bladder cancer (BCa), platinum-based chemotherapy represents the first-choice treatment. In the last ten years, immune checkpoint inhibitors (ICIs) have changed the therapeutic landscape of many solid tumors. Our review aims to summarize the main findings regarding the clinical use of ICIs in advanced BCa. METHODS: We searched PubMed, Embase, and Cochrane databases, and conference abstracts from international congresses (ASCO, ESMO, ASCO GU) for clinical trials, focusing on ICIs as monotherapy and combinations in metastatic BCa. RESULTS: 18 studies were identified. ICIs targeting PD1 (nivolumab, pembrolizumab), PD-L1 (avelumab, atezolizumab, durvalumab), and CTLA4 (ipilimumab, tremelimumab) were used. Survival outcomes have been improved by second-line ICIs, whereas first-line results are dismal. Avelumab maintenance in patients obtaining disease control with chemotherapy has achieved the highest survival rates. CONCLUSIONS: ICIs improve survival after platinum-based chemotherapy. Avelumab maintenance represents a new practice-changing treatment. The combinations of ICIs and other compounds, such as FGFR-inhibitors, antibody-drug conjugates, and anti-angiogenic drugs, represent promising therapeutic approaches. Biomarkers with predictive roles and sequencing strategies are warranted for best patient selection.

Cancer Vaccines for Genitourinary Tumors: Recent Progresses and Future Possibilities.

BACKGROUND: In the last years, many new treatment options have widened the therapeutic scenario of genitourinary malignancies. Immunotherapy has shown efficacy, especially in the urothelial and renal cell carcinomas, with no particular relevance in prostate cancer. However, despite the use of immune checkpoint inhibitors, there is still high morbidity and mortality among these neoplasms. Cancer vaccines represent another way to activate the immune system. We sought to summarize the most recent advances in vaccine therapy for genitourinary malignancies with this review. METHODS: We searched PubMed, Embase and Cochrane Database for clinical trials conducted in the last ten years, focusing on cancer vaccines in the prostate, urothelial and renal cancer. RESULTS: Various therapeutic vaccines, including DNA-based, RNA-based, peptide-based, dendritic cells, viral vectors and modified tumor cells, have been demonstrated to induce specific immune responses in a variable percentage of patients. However, these responses rarely corresponded to significant survival improvements. CONCLUSIONS: Further preclinical and clinical studies will improve the knowledge about cancer vaccines in genitourinary malignancies to optimize dosage, select targets with a driver role for tumor development and growth, and finally overcome resistance mechanisms. Combination strategies represent possibly more effective and long-lasting treatments.

High Rates of Hidden HCV Infections among Hospitalized Patients Aged 55-85.

BACKGROUND AND AIMS: The WHO has solicited all countries to eliminate HCV by 2030. The Italian government started routine screening for HCV infection in January 2021, initially targeting subjects born between 1969 and 1989. With the aim of achieving micro-elimination, we designed a hospital-wide project focusing on inpatients born from 1935 to 1985 and conducted it in our institution. METHOD: All inpatients aged 35 to 85, admitted from 10 February 2020 to 9 February 2021 for many different diseases and conditions underwent HCV antibody (HCVAb) testing by third-generation ELISA. When positive, reflex HCV RNA testing and genotyping were performed. Clinical history, fibrosis diagnosis, laboratory data and concomitant medications were available for all. RESULTS: The HCV screening rate of inpatients was 100%. In total, 11,748 participants were enrolled, of whom 53.50% were male. The HCVAb positivity rate was 3.03%. The HCVAb rate increased with age and was higher for patients born between 1935 and 1944 (4.81%). The rate of HCV RNA positivity was 0.97%. The vast majority (80.70%) of HCV RNA-positive participants were 55 or older; in about 40% of cases, HCV RNA-positive patients were unaware of their infection. Although 16 patients died after HCV chronic infection diagnosis (two due COVID-19) or HCV treatment prescription (one due to COVID-19), 74.56% of patient HCV diagnoses were linked to HCV treatment, despite their co-morbidities. All patients older than 65 who died had an active HCV infection. CONCLUSION: The present study revealed a rate of active HCV infections among inpatients lower than what has been reported in the past in the general population; this appears to be a result of the widespread use of pangenotypic direct-acting antiviral agents (DAAs). The overall rate of active infection was lower than the rate observed in the 1935-1954 cohort. The high rate of inpatients unaware of HCV infections and the high number of deaths among subjects with an active HCV infection born from 1935 to 1954, suggest that, at least in southern Italy, targeted screening of this birth cohort may be required to reduce the number of undiagnosed cases and hidden infections.

[Renal and ureteral stones in V.A.C.T.E.R.L. association: endourological management]. / Calcolosi reno-ureterale nella sindrome di V.A.C.T.E.R.L.: risoluzione endourologica.

BACKGROUND: The endourological technique is a safe and effective approach in the treatment of large stones in the pediatric population with congenital malformations. INTRODUCTION: The VACTERL association is a group of congenital malformations that include vertebral defects, anal atresia, cardiac defects, tracheoesophageal fistula with atresia, renal defects, and radial upper limb dysplasia. Renal anomalies are found in approximately 90% of patients. MATERIALS AND METHODS: We present a case of a 7-year-old girl with VACTERL association and cloacal malformations, undergoing multiple surgeries with subsequent Mitrofanoff continent appendico-vesicostomy. She presented at our attention for centimetric left ureteral and inferior pyelo-calyceal stones. She underwent flexible ureteroscopy with laser lithotripsy of both stones. A ureteral catheter and a nephrostomy tube have been left at the end of the procedure. RESULTS: The ureteral catheter was removed in the 2nd post-operative day, the tubes were removed after a nephrostogram in the 8th post-operative day. The patient is stone-free. No complications were observed in the post-operative time. CONCLUSIONS: Endoscopy is the method of choice for the management of pediatric urolithiasis with complex renal calculi, due to its low incidence of major complications and a high stone-free rate.

Long-term follow-up of a neoadjuvant chemohormonal taxane-based phase II trial before radical prostatectomy in patients with non-metastatic high-risk prostate cancer.

OBJECTIVE: To assess the feasibility and activity of a neoadjuvant treatment combining a luteinizing hormone-releasing hormone (LHRH)-analogue, estramustine and docetaxel before radical retropubic prostatectomy (RRP) in patients with high-risk prostate cancer. PATIENTS AND METHODS: High-risk patients were defined as clinical stage > or =T3 and/or a prostate-specific antigen (PSA) level of > or =15 ng/mL, and/or biopsy a Gleason sum of > or =8. Patients received LHRH analogue treatment until the PSA nadir (a stable PSA level for two consecutive determinations) and then, continuing hormone therapy, a combined regimen of estramustine and docetaxel. Patients had RRP within a month of completing the neoadjuvant regimen. All patients were assessed for toxicity and surgical complications. A clinical response was defined as complete (CR, the disappearance of all palpable and radiological abnormalities and a decline in PSA level of > or =90%) or partial (PR, a decline in PSA level of half or more with stable or improved palpable and/or radiological abnormalities). A pathological response was defined as 'complete' (undetectable cancer), 'substantial' (residual cancer in < or =10% of the surgical specimen) or 'minimal' (residual cancer in >10% of the surgical specimen). The biomarkers p53, bcl-2, MIB1, erbB2 and factor VIII were also evaluated. RESULTS: Of 22 patients enrolled between March 1999 and January 2002, 21 (mean age 63 years; mean PSA level 61 ng/mL; median biopsy Gleason sum 8) completed the neoadjuvant therapy. The clinical stage was organ-confined in three patients (15%); five (25%) had pelvic lymphadenopathy on computed tomography. The neoadjuvant treatment was well tolerated, with only one grade 2 toxicity (Eastern Cooperative Oncology Group grading). All PSA values decreased by >90% from baseline after hormonal therapy only, and the mean reduction from before to after chemotherapy was statistically significant (P = 0.001). Three patients (15%) had a CR, 16 (80%) had a PR and one (5%), with sarcomatoid tumour, had progression; 19 had non-nerve-sparing RRP and there were no major complications during or after RRP. The pathological assessment showed that one patient (5%) had no tumour (pT0) and six (32%) had a 'substantial' response. The overall rate of organ-confined disease was 58%, vs a mean 8% predicted likelihood from the Kattan nomogram. Five patients (26%) had positive surgical margins and four (21%) had positive lymph nodes. At a median follow-up of 53 months, eight patients (42%) were disease-free. Organ-confined disease (P = 0.022), residual cancer at pathology in < or =10% of the surgical specimen (P = 0.007) and no seminal vesicle invasion (P = 0.001) correlated with disease-free survival. CONCLUSION: A neoadjuvant chemohormonal regimen before RRP is feasible and active in patients with high-risk prostate cancer. The rate of pathological organ-confined disease was higher than expected and responding patients had an 85% disease-free survival rate at 5 years.

Sexual counseling improved erectile rehabilitation after non-nerve-sparing radical retropubic prostatectomy or cystectomy--results of a randomized prospective study.

AIM: The efficacy of prostaglandin E1 (PGE1)-intracavernous injection (ICI) therapy for erectile dysfunction (ED) after non-nerve-sparing (NNS) radical pelvic surgery depends on patient compliance. The purpose of this study was to verify the utility of sexual counseling in ICI in terms of treatment efficacy, compliance, and dropout rate. METHODS: In this prospective randomized study, 57 patients with ED after NNS radical prostatectomy or cystectomy were divided: 29 patients (group SC+) were treated with sexual counseling and PGE1-ICI therapy; the others 28 (group SC-) were treated with only ICI. At the start of the study all patients were administered the International Index of Erectile Function (IIEF) questionnaire and ICI training test; follow-up (at 3, 6, 9, 12, 18 months) was achieved by home Sildenafil test and ambulatory IIEF test; sexual counseling was provided only to group SC+. RESULTS: The mean IIEF score at the end of study was 26.5 (SC+) vs. 24.3 (SC-) (P < 0.05); eight patients (SC+, 27.5%) became responders to home Sildenafil vs. five (SC-, 17.8%) (P < 0.05); no dropout cases occurred (SC+) vs. eight (SC-, 28.5%) (P < 0.05). Moreover, we recorded best IIEF scores in group SC+ in sexual satisfaction (P < 0.05), sexual desire (P < 0.05), orgasmic function, and general satisfaction. Mean PGE1 doses were better in group SC+ (P < 0.05). ICI-oriented sexual counseling was utilized to motivate couples, to improve sexual intercourses, to correct mistakes in ICI administration. At the end of follow-up 21 patients (SC+) declared themselves satisfied vs. 12 (SC-). CONCLUSIONS: ICI-oriented sexual counseling in ICI increased the efficacy of treatment, the compliance, and Sildenafil responders rate, decreased the dropout rate.

Lymphatic and vascular embolizations are independent predictive variables of inguinal lymph node involvement in patients with squamous cell carcinoma of the penis: Gruppo Uro-Oncologico del Nord Est (Northeast Uro-Oncological Group) Penile Cancer data base data.

BACKGROUND: The objective of the current study was to identify independent clinical and pathologic variables that were predictive of lymph node involvement in patients with squamous cell carcinoma of the penis in a multicenter series with the intent to select patients who were suitable to undergo immediate inguinal lymphadenectomy. METHODS: Data were analyzed from 175 patients who underwent surgery for penile carcinoma in 11 urologic centers participating in the Gruppo Uro-Oncologico del Nord-Est (Northeast Uro-Oncological Group) Penile Cancer Data Base. Pathologically positive lymph nodes were defined as the presence of histologically confirmed lymph node metastasis in patients who underwent either immediate or delayed inguinal and/or pelvic lymphadenectomy. Patients who had clinically positive lymph nodes with cytologically positive fine-needle aspiration results and who had not undergone lymphadenectomy were censored. RESULTS: Overall, lymph-node involvement was observed in 71 of 175 patients (40.6%) included in the analyses. After analyzing the whole group of patients, the following variables were identified as independent predictors of pathologic lymph node metastasis: clinical lymph node status, pathologic stage of the primary tumor, venous and lymphatic embolizations, and histologic grade. In the subgroup of patients with clinically negative lymph nodes, tumor thickness, histologic grade, lymphatic and venous embolizations, infiltration of both corpus spongiosum and urethra, and pathologic stage of the primary tumor (according to the 1997 TNM classification system) were predictive of lymph node involvement on univariate analysis. The generated logistic regression model showed that venous and/or lymphatic embolizations and infiltration of the corpus spongiosum and/or urethra were independent predictors of pathologic lymph node metastasis in patients with clinically negative lymph nodes. CONCLUSIONS: Venous and/or lymphatic embolizations played relevant roles as predictors of pathologic lymph node involvement in patients with penile neoplasia and should be considered important parameters in determining which patients with clinically negative lymph nodes should undergo immediate lymphadenectomy.

Predictive medicine in non-malignant urological disorders.

The potential of disease prediction in non-malignant disorders should not be undervalued. Such disorders present several characteristics which make them suitable for disease prediction: they can be wide-spread, strongly affect the patients' quality of life, lead to a heavy burden on social health expenses and have a protracted clinical course. Moreover, people who present a high risk for non-malignant disease can be successfully introduced to long-term preventive measures such as lifestyle modifications, dietary changes and improvement in hygienic conditions. There is a growing demand for developing predictive medical strategies in urology. While urological cancers are the main focus of interest, we analyse the potentialities and challenges of predictive medicine in non-malignant urological disorders, with particular attention to benign prostate hyperplasia and urolithiasis.