Exosome Analysis in Prostate Cancer: How They Can Improve Biomarkers' Performance.

Exosomes are extracellular nanovesicles (EV), that is, carriers of different biomolecules such as lipids, proteins, nucleic acids. Their composition and the fact that their release dramatically increases in cases of tumorigenesis open up different scenarios on their possible application to research into new biomarkers. The first purpose of the present review was to specifically analyze and compare different methodologies available for the use of exosomes in prostate cancer (PC). The most widely applied methodologies include ultracentrifugation techniques, size-based techniques, immunoaffinity capture-based techniques (mainly ELISA), and precipitation. To optimize the acquisition of exosomes from the reference sample, more techniques can be applied in sequence for a single extraction, thereby determining an increase in labor time and costs. The second purpose was to describe clinical results obtained with the analysis of PSA-expressing exosomes in PC; this provides an incredibly accurate method of discriminating between healthy patients and those with prostate disease. Specifically, the IC-ELISA alone method achieved 98.57% sensitivity and 80.28% specificity in discriminating prostate cancer (PC) from benign prostatic hyperplasia (BPH). An immunocapture-based ELISA assay was performed to quantify and characterize carbonic anhydrase (CA) IX expression in exosomes. The results revealed that CA IX positive exosomes were 25-fold higher in plasma samples from PC patients than in those from healthy controls. The analysis of PC-linked exosomes represents a promising diagnostic model that can effectively distinguish patients with PC from those with non-malignant prostatic disease. However, the use of exosome analysis in clinical practice is currently limited by several issues, including a lack of standardization in the analytical process and high costs, which are still too high for large-scale use.

Prognostic Value of Albumin to Globulin Ratio in Non-Metastatic and Metastatic Prostate Cancer Patients: A Meta-Analysis and Systematic Review.

The aim of our meta-analysis is to analyze data available in the literature regarding a possible prognostic value of the albumin to globulin ratio (AGR) in prostate cancer (PC) patients. We distinguished our analysis in terms of PC staging, histologic aggressiveness, and risk of progression after treatments. A literature search process was performed ("prostatic cancer", "albumin", "globulin", "albumin to globulin ratio") following the PRISMA guidelines. In our meta-analysis, the pooled Event Rate (ER) estimate for each group of interest was calculated using a random effect model. Cases were distinguished in Low and High AGR groups based on an optimal cut-off value defined at ROC analysis. Four clinical trials were enclosed (sample size range from 214 to 6041 cases). The pooled Risk Difference for a non-organ confined PC between High AGR and Low AGR cases was −0.05 (95%CI: −0.12−0.01) with a very low rate of heterogeneity (I2 < 0.15%; p = 0.43) among studies (test of group differences p = 0.21). In non-metastatic PC cases, the pooled Risk Difference for biochemical progression (BCP) between High AGR and Low AGR cases was −0.05 (95%CI: −0.12−0.01) (I2 = 0.01%; p = 0.69) (test of group differences p = 0.12). In metastatic PC cases, AGR showed an independent significant (p < 0.01) predictive value either in terms of progression free survival (PFS) (Odds Ratio (OR): 0.642 (0.430−0.957)) or cancer specific survival (CSS) (OR: 0.412 (0.259−0.654)). Our meta-analysis showed homogeneous results supporting no significant predictive values for AGR in terms of staging, grading and biochemical progression in non-metastatic PC.

How the Analysis of the Pathogenetic Variants of DDR Genes Will Change the Management of Prostate Cancer Patients.

Herein, we analyze answers achieved, open questions, and future perspectives regarding the analysis of the pathogenetic variants (PV) of DNA damage response (and repair) (DDR) genes in prostate cancer (PC) patients. The incidence of PVs in homologous recombination repair (HRR) genes among men with metastatic PC varied between 11% and 33%, which was significantly higher than that in non-metastatic PC, and BRCA2 mutations were more frequent when compared to other DDR genes. The determination of the somatic or germline PVs of BRCA2 was able to define a tailored therapy using PARP inhibitors in metastatic castration-resistant prostate cancer (mCRPC) progression after first-line therapy, with significant improvements in the radiologic progression-free survival (rPFS) and overall survival (OS) rates. We propose testing all metastatic PC patients for somatic and germline HRR mutations. Somatic determination on the primary site or on historic paraffin preparations with a temporal distance of no longer than 5 years should be preferred over metastatic site biopsies. The prognostic use of DDR PVs will also be used in selected high-risk cases with non-metastatic stages to better arrange controls and therapeutic primary options. We anticipate that the use of poly-ADP-ribose polymerase (PARP) inhibitors in hormone-sensitive prostate cancer (HSPC) and in combination with androgen receptor signaling inhibitors (ARSI) will be new strategies.

Clinical performance of Xpert Bladder Cancer (BC) Monitor, a mRNA-based urine test, in active surveillance (AS) patients with recurrent non-muscle-invasive bladder cancer (NMIBC): results from the Bladder Cancer Italian Active Surveillance (BIAS) project.

PURPOSE: To investigate the clinical performance of a new mRNA-based urine test, aiming to avoid unnecessary follow-up cystoscopy in patients under active surveillance (AS) for recurrent NMIBC. METHODS: This is a prospective cohort study enrolling patients with history of low-grade (LG) NMIBC, who developed a recurrence during the follow-up and underwent AS. Their urinary samples were analyzed by Xpert BC Monitor (Cepheid, Sunnyvale, CA, USA). The primary endpoint was to investigate if Xpert BC Monitor could avoid unnecessary cystoscopy during the follow-up period. Its sensitivity, specificity, PPVs and NPVs were calculated. A cutoff of 0.4 "linear discriminant analysis" (LDA) was optimized for the AS setting. RESULTS: The cohort consisted of 106 patients with a mean age of 72 ± 9.52 and a median follow-up from AS start of 8.8 (range 0-56.5) months. No statistically significant difference was found for the mean age, smoker status, lesion size, and number of lesions with a cutoff of 0.4. Of 106 patients, 22 (20.8%) were deemed to require treatment because of cystoscopic changes in size and/or number of lesions during the follow-up period. Using a cutoff value of < 0.4, 34 (33.7%) cystoscopies could be avoided due to low LDA value, missing 2/22 (9%) failures, none with high-grade (HG) NMIBC. Further research on larger population remains mandatory before its clinical use. CONCLUSION: Xpert BC Monitor seems to be a reliable assay, which might avoid unnecessary cystoscopies without missing HG NMIBC when its cutoff is optimized for the AS setting.

En bloc resection of bladder tumors: indications, techniques, and future directions.

PURPOSE OF REVIEW: En bloc resection of bladder tumor (ERBT) is an innovative new surgical technique, the use of which is becoming increasingly widespread. In this review, we analyze the recent literature and explore new developments, which may impact the future role of en bloc bladder surgery. RECENT FINDINGS: ERBT increases the frequency with which detrusor muscle is present in the specimen (to 95%) and offers a significant improvement in the quality of the resection specimen, thereby helping with T1 substaging. Furthermore, the laser treatment reduces the rate of obturator nerve-related bladder perforation. SUMMARY: ERBT represents a considerable advancement in the surgical management of nonmuscle-invasive bladder cancer. It delivers excellent oncological results and is a well tolerated procedure. VIDEO: In the accompanying video, we shortly report the different modalities and energy sources used for bladder cancer resection. The three strategies are currently employed at the Fundació Puigvert (Barcelona). VIDEO ABSTRACT:.

Intermittent Versus Continuous Androgen Deprivation Therapy for Biochemical Progression After Primary Therapy in Hormone-Sensitive Nonmetastatic Prostate Cancer: Comparative Analysis in Terms of CRPC-M0 Progression.

INTRODUCTION: To analyze whether the use of an intermittent (IAD) versus continuous (CAD) androgen deprivation therapy for the treatment of biochemical progression after primary treatments in prostate cancer can influence the development of nonmetastatic castration resistant prostate cancer (CRPC-M0). PATIENTS: 170 male patients with an histologically confirmed diagnosis of PC, presenting a biochemical progression after primary treatments (82 after radical prostatectomy and 88 after external radiation therapy), nonmetastatic at imaging were considered for continuous (85 cases) or intermittent (85 cases) administration of androgen deprivation therapy. METHODS: we retrospectively collect all data regarding histological diagnosis, primary treatment, imaging for M0-M1 staging, PSA at progression, time to biochemical progression from primary therapy, ADT used, IAD cycles, so to compare in 2 groups (IAD vs. CAD) time for progression from the beginning of ADT treatment and type of progression in terms of CRPC-M0 versus CRPC-M1 cases. RESULTS: no significant (P= .4955) difference in the whole CRPC progression was found between IAD (25.8%) and CAD (30.5%) treatment at a mean of 32.7 ± 7.02 months and 35.6 ± 13.1 months respectively (P= .0738). Mean PSA at CRPC development was significantly higher in the IAD group (5.16 ± 0.68 ng/mL) than in the CAD group (3.1 ± 0.7 ng/mL) (P < .001). In all cases, imaging to detect M status at CRPC development was PET TC scan. At univariate analysis CAD administration significantly increases the RR for CRPC-M0 progression (RR 3.48; 95%CI 1.66-7.29; P = .01) when compared to the IAD administration, and this effect at multivariate analysis remained significant and independent to the other variables (RR 2.34, 95%CI 1.52-5.33; P = .03). CONCLUSIONS: in our population with biochemical progression after primary treatment for PC, the intermittent administration of ADT significantly reduces the risk to develop CRPC-M0 disease when compared to a continuous administration of ADT, whereas no difference between the 2 strategies in terms of CRPC-M1 progression exists.

Prognostic role of platelet-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio in patients with non-metastatic and metastatic prostate cancer: A meta-analysis and systematic review.

Objective: To analyze data available in the literature regarding a possible prognostic value of the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) in prostate cancer (PCa) patients stratified in non-metastatic and metastatic diseases. Methods: A literature search process was performed following the Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines. In our meta-analysis, the pooled event rate estimated and the pooled hazard ratio were calculated using a random effect model. Results: Forty-two articles were selected for our analysis. The pooled risk difference for non-organ confined PCa between high and low NLR cases was 0.06 (95% confidence interval [CI]: -0.03-0.15) and between high and low PLR cases increased to 0.30 (95% CI: 0.16-0.43). In non-metastatic PCa cases, the pooled hazard ratio for overall mortality between high and low NLR was 1.33 (95% CI: 0.78-1.88) and between high and low PLR was 1.47 (95% CI: 0.91-2.03), whereas in metastatic PCa cases, between high and low NLR was 1.79 (95% CI: 1.44-2.13) and between high and low PLR was 1.05 (95% CI: 0.87-1.24). Conclusion: The prognostic values of NLR and PLR in terms of PCa characteristics and responses after treatment show a high level of heterogeneity of results among studies. These two ratios can represent the inflammatory and immunity status of the patient related to several conditions. A higher predictive value is related to a high NLR in terms of risk for overall mortality in metastatic PCa cases under systemic treatments.

The Current Role of Contrast-Enhanced Ultrasound (CEUS) in the Diagnosis and Staging of Bladder Cancer: A Review of the Available Literature.

Contrast-enhanced ultrasound (CEUS) is an advanced imaging technique that integrates conventional US with the intravenous injection of specific US contrast agents (UCAs), combining the non-invasiveness of US with the higher accuracy of contrast-enhanced imaging. In contrast with magnetic resonance imaging (MRI), computed tomography (CT) and cystoscopy, CEUS has few contraindications, and UCAs are non-nephrotoxic agents that can be safely used in patients with kidney failure. CEUS is a well-established method for the detection of liver lesions and for echocardiography, and its indications are expanding. The updated 2018 WFUMB-EFSUMB guidelines have added the urinary bladder under non-hepatic applications of CEUS. The technique is able to distinguish between benign tissue, such as clots or hematoma, and malignant lesions by perfusing the mass with contrast agent. Thanks to the different perfusion rates of the various layers of the bladder wall, CEUS is also able to predict tumor invasion depth and stage. Despite that, current urological guidelines do not include CEUS as a plausible imaging technique for bladder urothelial carcinoma. The main reason for this omission might be the presence of scarce randomized evidence and the absence of large validated series. In this review, we describe the rationale behind the use of CEUS in bladder cancer and the added value of this imaging technique in the detection and staging of bladder lesions. In addition, we researched the available literature on the topic and then described the results of randomized clinical trials and a meta-analysis investigating the accuracy of CEUS in bladder cancer diagnosis and staging. The reported studies show that CEUS is a highly accurate diagnostic and staging tool for BC, reaching levels of specificity and sensitivity in differentiating between Ta-T1, or low-grade BC, and T2, or high-grade BC, that are comparable to those shown by the reference standard methods. Nonetheless, several limitations were found and are highlighted in this review. The aim of this study is to further validate and promote the use of CEUS as a quick, economic and effective diagnostic tool for this high-impact disease.

How the Management of Biochemical Recurrence in Prostate Cancer Will Be Modified by the Concept of Anticipation and Incrementation of Therapy.

Biochemical recurrence (BCR) after primary treatments for prostate cancer (PC) is an extremely heterogeneous phase and at least a stratification into low- and high-risk cases for early progression in metastatic disease is necessary. At present, PSA-DT represents the best parameter to define low- and high-risk BCR PC, but real precision medicine is strongly suggested to define tailored management for patients with BCR. Before defining management, it is necessary to exclude the presence of low-volume metastasis associated with PSA progression using new-generation imaging, preferably with PSMA PET/CT. Low-risk BCR cases should be actively observed without early systemic therapies. Early treatment of low-risk BCR with continuous androgen deprivation therapy (ADT) can produce disadvantages such as the development of castration resistance before the appearance of metastases (non-metastatic castration-resistant PC). Patients with high-risk BCR benefit from early systemic therapy. Even with overall survival (OS) as the primary treatment endpoint, metastasis-free survival (MFS) should be used as a surrogate endpoint in clinical trials, especially in long survival stages of the disease. The EMBARK study has greatly influenced the management of high-risk BCR, by introducing the concept of anticipation and intensification through the use of androgen receptor signaling inhibitors (ARSIs) and ADT combination therapy. In high-risk (PSA-DT ≤ 9 months) BCR cases, the combination of enzalutamide with leuprolide significantly improves MFS when compared to leuprolide alone, maintaining an unchanged quality of life in the asymptomatic phase of the disease. The possibility of using ARSIs alone in this early disease setting is suggested by the EMBARK study (arm with enzalutamide alone) with less evidence than with the intensification of the combination therapy. Continued use versus discontinuation of enzalutamide plus leuprolide intensified therapy upon reaching undetectable PSA levels needs to be better defined with further analysis. Real-world analysis must verify the significant results obtained in the context of a phase 3 study.

Regenerative Medicine-Based Treatment of Stress Urinary Incontinence with Mesenchymal Stem Cells: A Systematic Review and Meta-analysis.

OBJECTIVES: The aim of this systematic review and meta-analysis is to analyze clinical trials on the use of autologous stem cell [SC] injection for the treatment of stress urinary incontinence [SUI] in humans. METHODS: We analyzed the effect in terms of UI improvement and continence recovery after treatment. A literature search was performed following the PRISMA guidelines. Entry into the analysis was restricted to data collected from clinical prospective trials on humans, including female and male patients with SUI. We performed a cumulative meta-analysis to explore the trend in the effect size across different groups at follow-up. Available data were compared in terms of Event Rate [ER] for the percentage of pad-free patients. RESULTS: 12 trials were enclosed in the analysis. The sample size of patients with SUI ranged from 5 to 123 cases, mainly female cases. Autologous muscle-derived stem cells [MDSCs] were used in 9 and adipocyte- derived SCs [ADSC] in 3 trials. Considering a random effect model, ER of continence recovery was 0.41 [95%CI 0.29 - 0.54], with similar results between the ADSC [ER, 0.40;95%CI 0.12 - 0.69] and the MDSC group [ER 0.41; 95%CI 0.27-0.55] [I2 84.69%; Q 104.69 - p<0.01] [Test of group differences p=0.96]. CONCLUSION: Autologous MDSC or ADSC injection to treat SUI is demonstrated to be a safe procedure and a 41% mean rate of continence recovery is described. A higher effort should be produced to design better clinical trials, objectively evaluating either modifications inside the urethral sphincter or long-term functional results in terms of pad test and UI questionnaires.

Is It Time to Anticipate the Use of PARP Inhibition in Prostate Cancer Patients?

The increasing diffusion of genetic analysis regarding the pathogenetic variants (PVs) of genes involved in DNA Damage Repair (DDR) mechanisms and the development of Poly ADP ribose polymerase (PARP) inhibitors (PARPis) led to the first valid precision medicine option tailored toward metastatic prostate cancer (mPC). The concept of anticipation in the systemic treatment of mPC was initially adopted for androgen receptor signaling inhibitors (ARSIs) to describe the expansion of their indications, from the setting of the late-stage second-line treatment of metastatic castration-resistant prostate cancer (mCRPC) to first-line therapy in selected cases. There is already mounting evidence in favor of the anticipation of PARPis in the first line of mCRPC therapy, and further evidence in favor of mHSPC is emerging. Many studies have demonstrated the synergism between ARSIs and PARP inhibitors. Recent discoveries regarding the crosstalk between the androgen receptor (AR) and DNA repair mechanisms are disconnecting the use of PARPis from genetic analysis. The new message emerging is that the combination of PARPis with ARSIs may work independently of DDR mutational status. As a matter of fact, most of the recent trials analyzing the combination of PARPis with abiraterone or enzalutamide as a first-line therapy enrolled mCRPC patients irrespective of their mutational status. The PROPEL trial concluded that the advantage of the combination was independent of PV status, despite a higher advantage being reported in the BRCA1/2 mutated subgroup. The MAGNITUDE trial, however, showed a significant advantage only in the DDR mutated subgroup, and the DDR non-mutated cohort was closed for further enrollment. The combination of PARPis with ARSIs represents a significant strategy with a view to the anticipation and intensification of care in mPC. However, it should not nullify the advantages of precision medicine linked to the genetic analysis of DDR genes.

Comparison of Four Validated Nomograms (Memorial Sloan Kettering Cancer Center, Briganti 2012, 2017, and 2019) Predicting Lymph Node Invasion in Patients with High-Risk Prostate Cancer Candidates for Radical Prostatectomy and Extended Pelvic Lymph Node Dissection: Clinical Experience and Review of the Literature.

BACKGROUND: The indication for extended pelvic lymph node dissection (ePLND) at the time of radical prostatectomy (RP) is based on nomograms predicting the risk of lymph node invasion (LNI). However, limited data are available on the comparison of these predictive models in high-risk prostate cancer (PC) patients. Therefore, we compared the accuracy of the most used nomograms (MSKCC, Briganti 2012, 2017, and 2019) in the setting of high-risk PC patients submitted to ePLND. METHODS: 150 patients with high-risk PC disease treated from 2019 to 2022 were included. Before RP + ePLND, we assessed the MSKCC, Briganti 2012, 2017, and 2019 nomograms for each patient, and we compared the prediction of LNI with the final histopathological analysis of the ePLND using pathologic results as a reference. RESULTS: LNI was found in 39 patients (26%), and 71.3% were cT2. The percentage of patients with estimated LNI risk above the cut-off was significantly higher in pN+ cases than in pN0 for all Briganti nomograms. The percentage of patients at risk of LNI, according to Briganti Nomogram (2012, 2017, and 2019), was significantly higher in pN+ cases than in pN0 (p < 0.04), while MSKCC prediction didn't vary significantly between pN0 and pN+ groups (p = 0.2). All nomograms showed high sensitivity (Se > 0.90), low specificity (Sp < 0.20), and similar AUC (range: 0.526-0.573) in predicting pN+. Particularly, 74% of cases patients with MSKCC estimated risk > 7% showed pN0 compared to 71% with Briganti 2012 > 5%, 69% with Briganti 2017 > 7%, and 70% with Briganti 2019 > 7%. CONCLUSIONS: Despite the high-risk disease, in our patients treated with ePLND emerges a still high number of pN0 cases and a similar low specificity of nomograms in predicting LNI.

Can we reduce worldwide neonatal mortality?

Worldwide neonatal mortality rate is still very high in many countries, with a sharp difference between developed and developing countries. The difference of interventions to be implemented for reducing neonatal mortality rate  in developing and developed countries will be discussed.

Non-invasive administration of poractant-α in neonatal respiratory distress syndrome via a supraglottic device in the clinical practice in a second level neonatal unit: comparison of LMA® vs iGel® devices.

Non-invasive pulmonary surfactant (SF) administration for neonatal respiratory distress syndrome (NRDS) is a development of administration of SF. Administration of SF via a supraglottic device (SGD) has been shown to be effective. Here the results of administration of SF in NRDS in infants requiring oxygen and nasal-CPAP (n-CPAP) via two types of SGDs, LMA® vs iGel®, in a second level Neonatal Unit are reported in a retrospective study. Results - Fourteen infants in the LMA®Group were matched with 21 comparable infants in the iGel® Group (g.a. ≥30 wks and b.w. ≥ 1,500 gr) presenting NRDS with fraction of inspired oxygen (FiO2) ≥ 0.25 - 0.6, requiring n-CPAP. All infants presented a significant improvement of PaO2/FiO2 ratio that was seen earlier in the iGel® Group vs the LMA® Group. There was no severe adverse effect during the maneuver with both SGDs. No baby died, No.2 required endotracheal intubation for a second dose of SF as by protocol, and No. 1 was transferred to a higher level of care. Conclusion - Non-invasive SF administration via SGD has been done effectively at a second level Neonatal Unit and very early in the course of the disease therefore limiting transfer of the baby without complications with both SGDs. Improvement in gas exchange was more rapid in the iGel®Group. This result needs confirmation. In our experience iGel® was easier to use than LMA®.

Intravesical instillation with glycosaminoglycan replacement treatment in patients suffering radiation-induced haemorrhagic cystitis: When and which patients can benefit most from it?

INTRODUCTION & OBJECTIVES: Radiation-induced haemorrhagic cystitis (RHC) is a frightening complication occurring after pelvic radiotherapy (PRT) which may significantly affect patients' quality of life. Bladder instillation with glycosaminoglycan replacement therapy (GRT) including hyaluronic acid +/- chondroitin sulphate has been proposed as an emerging alternative to prevent relapses of haematuria. Strong points in favour of using GRT for RHC are the ease of administration, cost, almost absence of side effects and possibility of administration to outpatients. We investigated the effectiveness of GRT in a cohort, single-centre, of patients with past-medical history of PRT attending the outpatient clinic and/or the accident & emergency department (A&E) for RHC. MATERIALS & METHODS: Patients with diagnosis of RHC, either with toxicity grade of 2 or 3, were deemed candidate for GRT as long as no active bleeding was occurring; in the case of non-self-limiting haematuria and/or anaemia for active bleeding, admission in the urology department was prompted for bleeding control prior to GRT instillation. An induction course of 6 weekly instillations was scheduled; if tolerated, patients were given a maintenance course with at least 6 monthly instillations. The primary end-point consisted in assessing the rate of haematuria remission (either partial or complete) defined as no need to readmission in the A&E and/or in the hospital. Secondary end-points included factors related to GRT failure. Univariate and multivariate analysis were undertaken to identify clinical independent variables associated to the events. RESULTS: Fifty-one patients with at least 1-year follow-up from the first GRT were included in the analysis. 88.2, 9.8 and 2% of patients had undergone PRT because affected by prostate, uterus and colorectal cancer, respectively. Median time-to-RHC was 31 months (IQR 21-90). Access to A&E and hospital admission were needed in 47 (92.1%) and 35 (68.6%) of the patients, respectively. Twenty-two (n = 22/35, 62.9%) patients required transurethral fulguration of the bladder, while the remainders could be managed with bladder wash-out. Median number of GRT instillations was 6 (IQR 3-7). Twenty-three (45.1%) patients needed to be readmitted to hospital a second time, receiving bladder wash-out (n = 7/23, 30.4%), transurethral fulguration of the bladder (n = 10/23, 43.5%) and/or cystectomy (n = 6/23, 26.1%). Ten (19.6%) patients received a second induction course of GRT. At the last follow-up, 36 (70.6%) patients did not required further hospital admission. Type of PRT and number of hospital admissions pre-GRT were the only variables statistically associated to the events at both univariate (P = 0.032 and P = 0.045) and multivariate analysis (P = 0.048 and P = 0.049). CONCLUSIONS: GRT should be prompted as soon as possible after diagnosis of the haematuria and settling of active bleeding. Patients who had undergone adjuvant PRT after radical prostatectomy are those at higher risk of GRT failure.

Comparison of Different Invasive Devices for the Treatment of Urinary Incontinence after Radical Prostatectomy.

Purpose: To compare different forms of invasive treatments for postradical prostatectomy (RP) urinary incontinence (UI) in terms of quantitative and qualitative parameters and continence recovery rate. Methods: We distinguished five categories of treatment: A = bulking agents, B = fixed slings, C = adjustable slings, D = circumferential compressor devices (artificial sphincter), and E = noncircumferential compressor devices (ProACT). A literature search was performed following the PRISMA guidelines. We performed a cumulative meta-analysis to explore the trend in the effect sizes across groups at postoperative follow-up. We compared the available treatment arms using standardized mean difference (SMD) and event rate (ER) for questionnaire results, number of pads/day, and percentage of pad-free patients. Evidence synthesis. 36 clinical trials were selected. At baseline, in the different populations, mean number of pad-day varied from 1.1 to 8.8, 24-hour pad weight varied extremely from 17.3 g to 747.0 g, and mean ICIQ-UI-SF questionnaire score varied from 4.8 to 18.6. Considering a random effect model among eligible studies, ER of continence recovery was 0.33 (95% CI -0.12-0.78), 0.63 (95% CI 0.55-0.71), 0.65 (95% CI 0.58-0.72), 0.50 (95% CI 0.34-0.66), and 0.53 (95%CI 0.36-0.70), respectively, in groups A, B, C, D, and E (I 2 85.87%; Q 249.82-P > 0.01) (test of group differences P=0.22). Conclusion: In our analysis, the use of adjustable and fixed slings is associated with the highest whereas the use of bulking agents is associated with the lowest recovery rate of continence after treatment. Results are conditioned by an elevated rate of heterogeneity in part explained with a high variability of consistence in urinary leakage at baseline among populations.

Comparative Prospective and Longitudinal Analysis on the Platelet-to-Lymphocyte, Neutrophil-to-Lymphocyte, and Albumin-to-Globulin Ratio in Patients with Non-Metastatic and Metastatic Prostate Cancer.

PURPOSE: To prospectively evaluate the albumin/globulin ratio (AGR), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR) diagnostic and prognostic predictive value in a stratified population of prostate cancer (PC) cases. METHODS: Population was divided based on the clinical and histologic diagnosis in: Group A: benign prostatic hyperplasia (BPH) cases (494 cases); Group B: all PC cases (525 cases); Group B1: clinically significant PC (426 cases); Group B2: non-metastatic PC (416 cases); Group B3: metastatic PC (109 cases). NLR, PLR, and AGR were obtained at the time of the diagnosis, and only in cases with PC considered for radical prostatectomy, determinations were also repeated 90 days after surgery. For each ratio, cut-off values were determined by receiver operating characteristics curve (ROC) analysis and fixed at 2.5, 120.0, and 1.4, respectively, for NLR, PLR, and AGR. RESULTS: Accuracy in predictive value for an initial diagnosis of clinically significant PC (csPC) was higher using PLR (0.718) when compared to NLR (0.220) and AGR (0.247), but, despite high sensitivity (0.849), very low specificity (0.256) was present. The risk of csPC significantly increased only according to PLR with an OR = 1.646. The percentage of cases with metastatic PC significantly increased according to high NLR and high PLR. Accuracy was 0.916 and 0.813, respectively, for NLR and PLR cut-off, with higher specificity than sensitivity. The risk of a metastatic disease increased 3.2 times for an NLR > 2.5 and 5.2 times for a PLR > 120 and at the multivariate analysis. CONCLUSION: PLR and NLR have a significant predictive value towards the development of metastatic disease but not in relation to variations in aggressiveness or T staging inside the non-metastatic PC. Our results suggest an unlikely introduction of these analyses into clinical practice in support of validated PC risk predictors.

Care to relieve pain-stress in preterm newborns.

BACKGROUND AND AIM OF THE WORK: A variety of non-pharmacological pain-prevention and relief techniques have been studied to evaluate the pain reduction in neonates. The aim of our study was to compare the analgesic effect of sucking a pacifier with the use of eutectic mixture of local anaesthetics (EMLA) during venipuncture in preterm newborns, using physiological and behavioural parameters as indicators of pain. METHODS: We analysed the reaction to invasive procedures in 17 preterm newborns. Our patients underwent repeated vein draws without pain relief, sucking a pacifier, after the application of EMLA; we also evaluated a group of patients approached for care without pricking. For each infant we recorded the average values of the physiological parameters at rest and after pain stimuli, behavioural conditions (crying or grimaces), number and time required for blood draw. RESULTS: The maximum heart rate values, respiratory rate, and the maximum respiratory rate values presented a statistically difference only between subjects that underwent vein draws compared to subjects without pricking (p < 0.01). Moreover, the SpO2 parameter presented a significant increase in the control group compared to the others (p = 0.024). Analysis ofbehavioural parameters shows that crying seems significantly related to the duration and number ofvenipunctures (p = 0.000). CONCLUSIONS: It is clear that pain stress is more closely related to the duration and number of venipuncture than pain relief methods. Our results suggest that limiting the number and duration of vein draws could help to reduce pain stresss in preterm newborns.

How to Predict Outcomes from a Biofeedback and Pelvic Floor Muscle Electric Stimulation Program in Patients with Urinary Incontinence after Radical Prostatectomy.

OBJECTIVES: The objective of this study was to analyze the pre-operative and intra-operative variables that can condition urinary incontinence (UI) after radical prostatectomy (RP), as well as continence rate recovery during a pelvic floor rehabilitation program. MATERIALS AND METHODS: A total of 72 cases with UI after RP were prospectively examined. All cases were homogeneously treated by the same surgeon, using the same RP technique. A combination of biofeedback (BF) and pelvic floor electric stimulation (PFES) performed by the same clinician and using the same protocol was used. Clinical, pathologic and surgical variables were analyzed in terms of 24 h pad test results (pad weight and pad-free status). RESULTS: Prostate volume (PV) strongly varied from 24 to 127 cc (mean ± SD 46.39 ± 18.65 cc), and the baseline pad weight varied from 10 to 1500 cc (mean ± SD 354.29 ± 404.15 cc). PV strongly and positively correlated with the baseline pad weight (r = 0.4215; p = 0.0269) and inversely with the three-month pad weight (r = - 0.4763; p = 0.0213) and pad-free status (r =- 0.3010; p = 0.0429). The risk of a residual pad weight >10 g after the rehabilitative program significantly increased according to PV (p = 0.001) and the baseline pad weight (p = 0.002 and < 0.0001). In particular, PV > 40 cc and a baseline pad weight >400 g significantly (p = 0.010 and p < 0.0001, respectively) and independently predicted a 5.7 and a 35.4 times increase in the risk of a residual pad weight at the three-month follow-up, respectively. CONCLUSION: This is the first prospective trial whose primary objective is to verify the possible predictors, such as PV, that are able to condition the response to a pelvic floor rehabilitation program for UI after RP.

Prospective Evaluation of 68Ga-labeled Prostate-specific Membrane Antigen Ligand Positron Emission Tomography/Computed Tomography in Primary Prostate Cancer Diagnosis.

BACKGROUND: Positron emission tomography (PET)/computed tomography (CT) with 68Ga-labeled prostate-specific membrane antigen ligand (68Ga-PSMA) may represent the most promising alternative to multiparametric magnetic resonance imaging (mpMRI) for prostate cancer (PCa) diagnosis. OBJECTIVE: To test the diagnostic performance of 68Ga-PSMA PET/CT in this clinical context. DESIGN, SETTING, AND PARTICIPANTS: From January 2017 to December 2018 we prospectively enrolled 97 patients with persistently elevated prostate-specific antigen and/or Prostate Health Index score, negative digital rectal examination, and previous negative biopsy. We also included patients with either negative mpMRI or contraindications to or positive mpMRI but previous negative biopsy. INTERVENTION: Patients underwent 68Ga-PSMA PET/CT with additional pelvic reconstruction. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint of the study was the diagnostic performance of 68Ga-PSMA PET/CT in detecting malignant lesions and clinically significant PCa (Gleason score [GS] ≥7). RESULTS AND LIMITATIONS: 68Ga-PSMA PET/transrectal ultrasound fusion biopsy was performed in 64 of 97 patients (66%) for 114 regions of interest (ROIs). Forty patients (41%) had already undergone mpMRI with either a negative result for PCa (n = 15; 22 ROIs) or a positive mpMRI result but a previous negative biopsy. According to pathology, 23 patients (36%) had evidence of PCa: eight (16 ROIs) with GS 6, 13 (21 ROIs) with GS 7 (3 + 4 or 4 + 3), one (2 ROIs) with GS 8, and one (2 ROIs) with GS 10. Clinically significant PCa was identified in four patients with previous negative mpMRI (25%). PET/CT demonstrated PCa in seven patients (14 ROIs) with previous positive mpMRI and negative biopsy. The median maximum standardized uptake value (SUVmax) and median SUV ratio were significantly higher for PCa lesions than for benign lesions (p < 0.001). Optimal cutoff points obtained for SUVmax (>5.4) and SUV ratio (>2.2) could identify clinically significant PCa with accuracy of 81% and 90%, respectively. CONCLUSIONS: In our cohort of patients with high suspicion of cancer,68Ga-PSMA PET/CT was capable of detecting malignancy and accurately identifying clinically relevant PCa. PATIENT SUMMARY: Positron emission tomography/computed tomography with a 68Ga-labeled ligand for prostate-specific membrane antigen is capable of detecting prostate cancer in patients with a high suspicion of cancer and a previous negative biopsy.