External validation of biochemical recurrence definition to predict oncologic outcomes following focal therapy for localized prostate cancer using high intensity focused ultrasound.

PURPOSE: This is an external validation of several biochemical recurrence definitions based on prostate specific antigen criteria (PSA). The purpose is to predict the need of additional treatment and failure after focal therapy using high intensity focused ultrasound (HIFU) for localized prostate cancer (PCa). MATERIALS AND METHODS: A total of 343 consecutive patients who underwent HIFU with Ablatherm® and Focal One® devices between June 2001 and November 2020 were identified. Treatment failure was defined as clinically significant PCa on postoperative biopsy, the need for salvage radical or systematic treatment, metastasis, or PCa-related death. The biochemical recurrence definitions tested were PSA nadir, time to PSA nadir, percentage of PSA reduction, Huber et al. criteria defined as PSA nadir + 1 ng/mL at 12 months or PSA nadir + 1.5 ng/mL at 24-36 months. Multivariable Cox regression analysis and decision-curve analysis were used to validate and compare criteria. Kaplan-Meier analysis was used to assess criteria associated with the highest accuracy. RESULTS: One hundred seventy-eight patients met the inclusion criteria and were analyzed. Overall, 61 (34%) and 41 (23%) patients had an additional treatment and failure with a median follow-up of 52 months. At multivariable analysis, model including Huber et al. criteria exhibited the highest Harrell's C-index for the prediction of the need of additional treatment (hazard ratio [HR]: 10, p < 0.001, c-index: 84%) and treatment failure (HR: 9.1, p < 0.001, c-index: 82%) as well as higher net benefit. The 60-months need of additional treatment and treatment failure-free survival were 89% and 98% compared to 26% and 49%, respectively, when stratified according to Huber et al. criteria (Log-rank test, p < 0.001). Similar results were found after excluding patient with non-clinically significant PCa at initial biopsy. CONCLUSIONS: We report an external validation of biochemical recurrence definitions predicting the need of additional treatment and failure after focal therapy using HIFU for localized PCa. Huber et al. criteria were identified as the most accurate and could be used to guide clinicians toward further evaluation and salvage treatments.

CAR-T Cell Therapy for Solid Tumors: Are we Still That Far? a Systematic Review of Literature.

This systematic review aims to assess all the prospective studies published to date on the efficacy of CAR-T cell therapy in solid tumors. Databases searched were PubMed and Google Scholar from inception through May 1st 2021. Search query was (Chimeric antigen receptor) or (CAR-T) or (T-CAR). Twenty-nine prospective studies (265 patients) were included. Most published clinical trials are phase I. Clinical benefit was 100% in epithelial ovarian cancer, 70-82% in gastrointestinal tumors, 79% in mesothelioma, 63% in small-cell lung cancer, 24-67% in sarcoma, 50-62% in prostate cancer, and 45-50% in central nervous system tumors. No serious CAR-T cell specific serious toxicities were noted.

Uncovering the role of urinary microbiota in urological tumors: a systematic review of literature.

PURPOSE: Urinary microbiota has been found to play a key role in numerous urological diseases. The aim of this systematic review is to depict the role of urinary microbiota in the pathogenesis, diagnosis, prognosis, and treatment of urological tumors, including bladder cancer (BCa), prostate cancer (PCa) and renal cell carcinoma (RCC). METHODS: A systematic PubMed and Scopus search was undergone from inception through June 2021 for studies investigating urinary microbiota alterations in urological tumors. Study selection followed the PRISMA statement. Phylum, family, genus and species of each bacterium in cancer patients and controls were recorded. RESULTS: Twenty-one studies with 1194 patients (748 cancer patients and 446 controls) were included in our final analysis. Certain bacterial phylum, family, genus, and species were more predominant in each of BCa, PCa and RCC patients compared to controls. Abundance and specificity of urinary microbiota were prognosticators for: (1) recurrence, distinguishing recurrent from non-recurrent BCa, (2) disease stage, distinguishing non-muscle invasive from muscle invasive BCa, and (3) disease grade, distinguishing high- vs. low-grade PCa and BCa. Dietary, environmental and geographic patterns influenced urinary microbiota. Urinary microbiota of benign prostatic hyperplasia was different from PCa. CONCLUSION: Urological cancer patients have an altered urinary microbiota compared to controls. This may predict recurrence, disease stage and disease grade of these tumors. Further prospective studies are needed to depict a potential influence on therapeutic outcomes.

Antibodies targeting Prostate-Specific Membrane Antigen positive prostate cancer: from diagnostic imaging to theranostics.

PURPOSE OF REVIEW: Targeting Prostate-Specific Membrane Antigen (PSMA) has paved the way for personalized medicine in prostate cancer (PCa) patients. This review aims to highlight the role of PSMA targeting antibodies in PCa, for diagnostic and therapeutic purposes. RECENT FINDINGS: PSMA Positron Emission Tomography/Computed Tomography has been a game changer in the diagnosis of PCa in the recent decade. Two anti-PSMA monoclonal antibodies have been studied in PCa: 7E11-C35 (limited use) and J591. J591 antibody was used for diagnostic purposes coupled with different radionuclides. Most importantly, it was combined to numerous therapeutic radionuclides such as Lutetium-177 (177Lu), Yttrium-90 (90Y), Indium-111 (111In), and Actinium-225 (225Ac). It was also conjugated to drugs forming antibody-drug conjugates (e.g. MLN2704 and PSMA-ADC). These compounds were tested in recent phase I/II clinical trials. SUMMARY: PSMA targeting antibodies are very promising for further clinical investigation and continue to be a momentous research area, for both imaging and therapeutic settings. Although some clinical trials resulted in unfavorably safety profiles for some antibodies, they validated PSMA as a crucial immunoconjugate target.

Prognostic role of neutrophil-to-lymphocyte ratio (NLR) in urological tumors: an umbrella review of evidence from systematic reviews and meta-analyses.

BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) has been studied as a biomarker for cancer prognosis, predicting survival in many tumors. The aim of this umbrella review was to combine the results from all systematic reviews and meta-analyses related to the prognostic role of the NLR in patients with urological tumors. METHODS: A PubMed, Scopus, Embase and Cochrane search was undergone from inception through September 2020 for systematic reviews and meta-analyses investigating the prognostic value of NLR in urological tumors, subdivided into prostate cancer, renal cell carcinoma, urothelial bladder and upper tract carcinomas PROSPERO (CRD42020216310). RESULTS: The results have shown, with a high level of evidence, that an elevated NLR predicts worse overall survival (OS), progression-free survival (PFS) and relapse-free survival (RFS) in prostate cancer, worse OS, PFS and RFS in renal cell carcinoma, worse OS, PFS, RFS and cancer-specific survival (CSS) in muscle invasive bladder cancer, worse PFS and RFS in non-muscle invasive bladder cancer, and worse OS, PFS, RFS and CSS in urothelial upper tract carcinoma. CONCLUSION: NLR has a significant prognostic value in urological tumors and should be included in prognostic scores of these cancers.

Urothelial carcinoma in COVID-19: lessons from a pandemic and their impact on clinical practice.

The COVID-19 pandemic has modified the management of urothelial carcinoma (UC). Eighteen months after the onset of the pandemic, a scoping narrative review was able to state that radical cystectomy for UC should not be delayed beyond 10 weeks when neoadjuvant chemotherapy (NAC) was administered and 12 weeks when it was not. NAC should be considered when imminent chemotherapy cannot be performed. Early cystectomy should not be delayed when indicated for patients with high-risk non-MIBC. Patients with non-MIBC should still receive their induction doses of intravesical instillations. Diagnostic cystoscopy should not be deferred in symptomatic patients. Surgical management of upper tract urothelial carcinoma (UTUC) allows for a wider deferral interval.

Laparoscopic transperitoneal pudendal nerve and artery release for pudendal entrapment syndrome.

INTRODUCTION: Pudendal nerve and artery entrapment is an underdiagnosed pathology responsible of several urinary, sexual and anorectal complaints. The aim of our study was to evaluate safety and feasibility of laparoscopic transperitoneal pudendal nerve and artery release in a large retrospective cohort of patients with pudendal nerve entrapment syndrome with both a short and long-term follow-up. Technical details and outcomes are also reported. METHODS: A series of 235 patients with pudendal syndrome underwent laparoscopic transperitoneal pudendal canal release between June 2015 and February 2020. Operative data were recorded prospectively for all patients. A complete history, pain visual analog scale (VAS) for perineodynia, and three scores evaluating the main symptoms (USP, IIEF-5, PAC-SYM) were obtained before and at least 24 months after surgery for 32 patients only. Post-operative complications were also evaluated using Clavien-Dindo classification at regular interval. RESULTS: The mean operating time per side was 33.9 ± 6.8 min and the average hospital stay was 1.9 ± 0.3 days. Blood loss was 20 cc ± 10 cc with no patients needing transfusion. The only significant per-operative complication was hemorrhage (600 ml) in one patient induced by a pudendal artery laceration, successfully treated by laparoscopic suturing. Post-operative complications were noted in 18.7% of patients with no serious Clavien-Dindo complications. Perineodynia VAS dropped from 6.8 ± 0.9 to 2.2 ± 1.8 after surgery (p < 0.001). Mean IIEF-5 scores significantly improved one month after the surgery (15.2 vs 19.3, p = 0.036). Mean USP scores significantly improved for the dysuria domain (4.2 vs 1.6, p = 0.021) but not for stress urinary incontinence (3.9 vs 4.1, p = 0.082) or overactive bladder symptoms (14.1 vs 13.8, p = 0.079). Mean PAC-SYM scores significantly improved after the procedure (1.8 vs 1.1, p < 0.001). CONCLUSION: A complete laparoscopic pudendal nerve and artery release, from the sciatic spine through the Alcock's canal, is a fast and safe surgery with promising functional results. A large prospective trial is needed to validate such an approach.

Cartography-based quality control of prostate cancer care: a necessary ground to targeted focal therapy.

PURPOSE OF REVIEW: We summarize the evidence on accurate target definition, precise imaging, and guiding systems that are a necessary ground to targeted focal therapy. RECENT FINDINGS: Accurate target detection is based on the ability of imaging to locate and characterize precisely the tumor burden and differentiation inside the prostate. There is a clear correlation with the multiparametric MRI (mpMRI) images and the morphologic attributes of the tumor. Limitations stem from the heterogeneity and the multifocality of prostate cancer. Some prostate cancers are MRI-negative tumors. Safety margins should also be elaborated based on the tumor grade and burden. PET prostate specific membrane antigen is another promising technology yielding same results as multiparametric MRI for primary detection of prostate cancer, but PET/MRI imaging is promising. Perfect guiding requires sophisticated software with good quality control to track the needle inside the prostate and to record the position allowing recall when second look biopsy, active surveillance, or targeted focal therapy are required. SUMMARY: The multimodal fusion cartography model proves effective and necessary to fulfill preoperative and postoperative requirements for targeted focal therapy.

Salvage Hemiablation High Intensity Focused Ultrasound for unilateral radio-recurrent prostate cancer.

OBJECTIVE: To report the oncological and functional outcomes of salvage hemiablation high-intensity focused ultrasound (HIFU) in patients with unilateral radio-recurrent prostate cancer. PATIENTS AND METHODS: Patients with biochemical recurrence (BCR) after primary radiation therapy and evidence of unilateral organ confined recurrence based on a complete match between mpMRI and MRI targeted biopsies were included. Patients with distant metastasis were excluded. Patients were followed with serial serum PSA determinations. BCR were defined using the Phoenix criteria. Complications were graded according to the Clavien score. IIEF-5 questionnaire was used to assess erectile dysfunction. Urinary incontinence was reported using physician reported rates. RESULTS: A total of 10 consecutive patients (median age: 71 years, IQR: 69-76) were prospectively enrolled. The median pre-treatment PSA and post-treatment PSA nadir were 3.1ng/mL (IQR: 1.54-8.59) and 1.52ng/mL (IQR: 0.76-2.2), respectively. At a median follow-up of 41.5 (IQR: 18-58) months, 50% of patients experience BCR. BCR free-survival rates at 24 and 36 months were 75% (CI95%: 31-93) and 60% (CI95%: 20-85), respectively. Urinary in continence grade II occurred in two patients and the remaining patients were pad-free. One patient developed de novo erectile dysfunction requiring PDE5I. The erectile function scores decreased from a mean of 10.1 to 8.7. CONCLUSION: Hemiablation HIFU is an alternative to whole gland therapy in patients with unilateral radio- recurrent prostate cancer, which offers limited urinary and rectal morbidity, and preserves functional outcomes. LEVEL OF EVIDENCE: 3.

Testicular microlithiasis: Systematic review and Clinical guidelines.

INTRODUCTION: There are no clear recommendations on how patients with testicular microlithiasis should be followed up. The aim of our systematic review is to give clinical guidelines based on the evidence in the literature. METHODS: A web search was conducted during February 2018 based on Pubmed data, Embase and Cochrane database. The eligibility of articles was defined using the PICOS method, in concordance with the PRISMA recommendations. RESULTS: Fifty three articles were selected for our final synthesis. Our review highlighted an association between testicular microlithiasis and the already known risk factors of testicular germ cell tumor. The presence of testicular microlithiasis in patients with such risk factors increases more the risk of cancer. In the absence of risk factors, the risk to develop testicular cancer is similar to the risk in general population. CONCLUSION: In patients at risk to develop testicular cancer, observation versus testicular biopsy is debatable. We recommend an individualized approach based on the age of the patient, the presence of concurrent features of testicular dysgenesis syndrome, the fertility of the couple, the desire of paternity and the ultrasound pattern (bilateral and clustered vs. unilateral and limited).

Association between phosphodiesterase type 5 inhibitors and prostate cancer: A systematic review.

INTRODUCTION: We aim to assess the effect of phosphodiesterase type 5 inhibitors (PDE5I) on prostate cancer risk as well on biochemical recurrence after radical prostatectomy. METHOD: We performed a research using the following keywords "Phosphodiesterase type 5 inhibitors" and "Prostate cancer". Only trials examining the effect of PDE5I on prostate cancer risk and recurrence after radical prostatectomy were included. RESULTS: Seventeen preclinical trials and seven clinical trials were included. Preclinical studies demonstrate a pivotal role for PDE5I as a modulator of apoptosis preventing prostate carcinogenesis. The clinical benefit of PDE5I was not demonstrated. PDE5I use was not associated with decreased prostate cancer diagnosis in two retrospective cohort studies. Biochemical recurrence after radical prostatectomy was not lower (nor higher) in patients taking PDE5I in three retrospective case match studies. CONCLUSION: Based on this review, a change in our practice regarding pharmacological reeducation after radical prostatectomy is not justified.

Clinical impact of 68 Ga-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) in patients with prostate cancer with rising prostate-specific antigen after treatment with curative intent: preliminary analysis of a multidisciplinary approach.

OBJECTIVE: To assess the impact of a novel molecular imaging technique, 68 Ga-(HBED-CC)-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT), in the clinical management of patients with prostate cancer with rising prostate-specific antigen (PSA) after treatment with curative intent. PATIENTS AND METHODS: In all, 131 consecutive patients were referred to our centre for a 68 Ga-PSMA PET/CT in the setting of recurring prostate cancer. Of these patients, 11/131(8%) presented with persistent PSA after radical prostatectomy, while 120/131 (92%) were referred for biochemical recurrence after surgery, radiotherapy or both. The images where taken 1 h after injection of 2 MBq/kg of the 68 Ga-(HBED-CC)-PSMA ligand. All examinations were interpreted by two experienced nuclear medicine specialists. Using the results of the examination, a multidisciplinary oncology committee (MOC) reported on the treatment strategy. A positive impact on clinical management was considered if the examination determined a modification in the treatment strategy compared to the MOC decision before PSMA imaging. RESULTS: All patients completed the examination with no adverse reactions. The median (interquartile range) PSA level at the time of the examination was 2.2 (0.72-6.7) ng/mL. Overall, 68 Ga-PSMA PET/CT detected at least one lesion suspicious for prostate cancer in 98/131 (75%) patients. There was an impact on subsequent management in 99/131 patients (76%). The main modifications included continuing surveillance (withholding hormonal therapy), hormonal manipulations, stereotaxic radiotherapy, salvage radiotherapy, salvage node dissection or salvage local treatment (prostatectomy, high-intensity focussed ultrasound). CONCLUSION: Our preliminary experience suggests that performing 68 Ga-PSMA PET/CT in patients with prostate cancer with rising PSA after treatment with curative intent can be clinically useful as it changes the treatment strategy in a significant proportion of patients. However, larger prospective trials are needed to validate our present findings.

The optimal treatment of metastatic hormone-naive prostate cancer: abiraterone acetate or docetaxel?

AIM: To determine whether abiraterone acetate or docetaxel should be regarded as the current standard of care for metastatic hormone-naive prostate cancer (mHNPC). METHODS & MATERIALS: A network meta-analysis (NMA) using the frequentist approach and generalized pairwise modeling was computed. RESULTS: The results of this NMA favored abiraterone acetate over docetaxel-based regimens (hazard ratio: 0.79; 95% CI: 0.64-0.99) in patients with mHNPC. The results also suggest a reconsideration of the role of prednisone in view of the absence of a survival benefit (hazard ratio: 0.98; 95% CI: 0.59-1.65) with its use. CONCLUSION: Despite the paucity of direct comparative evidence, the results of this NMA favor the use of abiraterone acetate in the first-line treatment of mHNPC.

Network meta-analysis of second-line treatment in metastatic renal cell carcinoma: efficacy and safety.

This paper aims to compare the approved second-line treatment options in metastatic renal cell carcinoma. A network meta-analysis (NMA) using the frequentist approach and generalized pairwise modeling was computed for the approved drugs in this setting. The results of this NMA showed that the combination of lenvatinib and everolimus yielded the lowest hazard ratio (HR) for progression-free survival (HR: 0.4; 95% CI: 0.21-0.75) and overall survival (HR: 0.55; 95% CI: 0.30-1.00). The great efficacy of this combination is limited by the prevalence of grade 3-4 adverse events (70.6%) leading to treatment discontinuation in 17.6%. This NMA is to the best of our knowledge, the first analysis of the approved regimens for the second-line treatment of metastatic renal cell carcinoma.

Critical Analysis of Early Recurrence after Laparoscopic Radical Cystectomy in a Large Cohort by the ESUT.

PURPOSE: We analyze patients with early progression after laparoscopic radical cystectomy in a large cohort by the ESUT (European Association of Urology Section of Uro-Technology). More specifically we focus on patients with favorable pathology (pT2 N0 R0 or less) who experienced an unexpected recurrence and analyze possible causes for such early recurrence, discussing the surgical technique including pneumoperitoneum. MATERIALS AND METHODS: Since 2000 the ESUT has been constructing a large, multicenter, prospective database of patients undergoing laparoscopic radical cystectomy. All procedures were performed via a standard laparoscopic approach without robotic assistance. We specifically analyzed patients with favorable pathological characteristics, in particular pT2 N0 R0 or less, and evaluated those with progression despite these favorable characteristics. Univariate and multivariate logistic regression was performed to evaluate risk factors for early recurrence. RESULTS: A total of 627 patients were available for final analysis with a median followup of 46 months (mean 57). Of these patients 311 had favorable pathological characteristics of pT2 N0 R0 or less. During followup 27 (8.7%) patients experienced disease progression during the first 24 months. Surgical negligence was found in only 1 case. Most of these patients with early recurrence had progression to high tumor volume disseminated metastatic disease. On multivariate logistic regression tumor stage was the only factor significantly associated with early recurrence (p=0.027). CONCLUSIONS: We report early unexpected recurrences after laparoscopic radical cystectomy in nearly 5% of our entire cohort, all in patients with favorable pathological characteristics (pT2 N0 R0 or less). Pneumoperitoneum may have had a role in the development of these relapses. Specifically designed studies are necessary to investigate the possible role of pneumoperitoneum in urothelial cancer recurrence.

Why balls are not put inside the basket? A reflection on testicular cancer clinical trial design.

New concepts of trial design are being developed based on biomarkers, namely basket and umbrella trials. Basket trials appear optimally positioned to evaluate new molecular markers for testicular germ cell tumors, a rare heterogeneous disease with relatively few molecular alterations. However, not uncommonly, the "balls" fall outside the "basket". In this short communication, we discussed the different causes limiting the inclusion of TGCT in basket trials and we proposed a new design for trials suitable for this malignancy.