Defining oligometastatic state in uro-oncological cancers.

PURPOSE OF REVIEW: Oligometastatic tumors illustrate a distinct state between localized and systematic disease and might harbor unique biologic features. Moreover, these tumors represent a different clinical entity, with a potential of long-term disease control or even cure, therefore they receive growing attention in the field of urologic oncology. RECENT FINDINGS: Currently, there is no consensus on the definition of oligometastatic prostate cancer, most experts limit it to a maximum of three to five lesions and involvement of no more than two organs, excluding visceral metastases. Quality data on oligometastatic bladder cancer is scarce, however, a consensus of experts defined it as a maximum of three metastatic lesions, either resectable or suitable for stereotactic therapy, without restrictions to the number of organs involved. As for kidney cancer, a maximum number of five metastases, without limitations to the location are defined as oligometastatic, with an important implication of timing of developing metastases since diagnosis of the primary tumor. SUMMARY: Defining oligometastatic state among urological tumors reflecting their distinct biological and clinical behavior is crucial to establish a sound framework for future clinical trials, and to facilitate guideline and policy formulation for improved patient care. Advancements in molecular imaging are expected to transform the field of oligometastatic urologic tumors in the future.

Adjuvant intravesical therapy in intermediate-risk non-muscle-invasive bladder cancer.

OBJECTIVE: To evaluate the impact of adjuvant therapy on oncological outcomes in patients with intermediate-risk non-muscle-invasive bladder cancer (NMIBC), as due to the poorly-defined and overlapping diagnostic criteria optimal decision-making remains challenging in these patients. PATIENTS AND METHODS: In this multicentre study, patients treated with transurethral resection of bladder tumour for Ta disease were retrospectively analysed. All patients with low- or high-risk NMIBC were excluded from the analysis. Associations between adjuvant therapy administration with recurrence-free survival (RFS) and progression-free survival (PFS) rates were assessed in Cox regression models. RESULTS: A total of 2206 patients with intermediate-risk NMIBC were included in the analysis. Among them, 1427 patients underwent adjuvant therapy, such as bacille Calmette-Guérin (n = 168), or chemotherapeutic agents, such as mitomycin C or epirubicin (n = 1259), in different regimens up to 1 year. The median (interquartile range) follow-up was 73.3 (38.4-106.9) months. The RFS at 1 and 5 years in patients treated with adjuvant therapy and those without were 72.6% vs 69.5% and 50.8% vs 41.3%, respectively. Adjuvant therapy was associated with better RFS (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.70-0.89, P < 0.001), but not with PFS (P = 0.09). In the subgroup of patients aged ≤70 years with primary, single Ta Grade 2 <3 cm tumours (n = 328), adjuvant therapy was not associated with RFS (HR 0.71, 95% CI 0.50-1.02, P = 0.06). While in the subgroup of patients with at least one risk factor including patient age >70 years, tumour multiplicity, recurrent tumour and tumour size ≥3 cm (n = 1878), adjuvant intravesical therapy was associated with improved RFS (HR 0.78, 95% CI 0.68-0.88, P < 0.001). CONCLUSION: In our study, patients with intermediate-risk NMIBC benefit from adjuvant intravesical therapy in terms of RFS. However, in patients without risk factors, adjuvant intravesical therapy did not result in a clear reduction in the recurrence rate.

Estimation of the incidence of urachal cancer: A systematic review and meta-analysis of registry-based studies.

BACKGROUND: Urachal cancer (UrC) is a rare disease with limited availability of representative incidence and clinical data. Although, the prevalence is accounting for less than 1% of bladder tumors, the 5-year survival rate is around only 50% for patients with resectable tumors, and even worse for patients with metastatic disease. Due to the lack of comprehensive prospective studies, our current knowledge of UrC is still limited. OBJECTIVE: The present study aimed to summarize the available registry-based studies with unselected UrC patients to evaluate its incidence and clinicopathological characteristics. MATERIAL AND METHODS: We conducted a systematic literature search of registry-based UrC publications on the 15th of May 2023 in 5 databases, which identified 4,748 publications. After duplicate removal and selection by 2 independent investigators, 6 publications proved to be appropriate for the final meta-analysis. Estimated incidence and clinicopathological parameters were extracted. RESULTS: Estimated incidence ranged between 0.022 and 0.060/ 100.000 person-years, with the highest occurrence in Japan and the lowest in Canada, while the random effect model calculated an overall incidence rate of 0.04 (95%CI: 0.03-0.05) 100.000 person-years. The median age at first diagnosis was 60 years (range: 58-64). The female to male ratio was 2:3. Lymph node or distant metastases were present in 9% and 14% of patients. The predominant tumour type was adenocarcinoma (86%) followed by urothelial carcinoma (12%) and squamous cell carcinoma (2%). The 5-year survival rate was 51.0% with 95%CI: 45.2-57.4. CONCLUSIONS: Our study provides an up-to-date comparison of estimated incidence rates between 6 countries of 3 continents based on rigorously selected registry-based studies. The results suggest low incidence rates for UrC with considerable geographic differences. The present meta-analysis provides unbiased registry-based data on the incidence, clinicopathological parameters and survival of UrC.

Predictive Value of the Mayo Adhesive Probability (MAP) Score in Laparoscopic Partial Nephrectomies: A Systematic Review from the EAU Section of Uro-Technology (ESUT).

The Mayo Adhesive Probability (MAP) score is a radiographic scoring system that predicts the presence of adherent perinephric fat (APF) during partial nephrectomies (PNs). The purpose of this systematic review is to summarize the current literature on the application of the MAP score for predicting intraoperative difficulties related to APF and complications in laparoscopic PNs. Three databases, PubMed, Scopus and Cochrane, were screened, from inception to 29 October 2023, taking into consideration the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. All the inclusion criteria were met by eight studies. The total operative time was around two hours in most studies, while the warm ischemia time was <30 min in all studies and <20 min in four studies. Positive surgical margins, conversion and transfusion rates ranged from 0% to 6.3%, from 0% to 5.0% and from 0.7% to 7.5%, respectively. Finally, the majority of the complications were classified as Grade I-II, according to the Clavien-Dindo Classification System. The MAP score is a useful tool for predicting not only the presence of APF during laparoscopic PNs but also various intraoperative and postoperative characteristics. It was found to be significantly associated with an increased operative time, estimated blood loss and intraoperative and postoperative complication rates.

Imiquimod Is Effective in Reducing Cervical Intraepithelial Neoplasia: A Systematic Review and Meta-Analysis.

INTRODUCTION: Topical Imiquimod is an immune response modifier approved for the off-label use of vulvar intraepithelial neoplasia. We conducted this systematic review and meta-analysis to investigate the efficacy and safety of Imiquimod in treating cervical intraepithelial neoplasia (CIN) and human papillomavirus (HPV)-positive patients. METHODS: The study was prospectively registered (CRD420222870) and involved a comprehensive systematic search of five medical databases on 10 October 2022. We included articles that assessed the use of Imiquimod in cervical dysplasia and HPV-positive patients. Pooled proportions, risk ratios (RRs), and corresponding 95% confidence intervals (CIs) were calculated using a random effects model to generate summary estimates. Statistical heterogeneity was assessed using I2 tested by the Cochran Q tests. RESULTS: Eight articles reported on 398 patients who received Imiquimod out of 672 patients. Among CIN-2-3 patients, we observed a pooled regression rate of 61% (CI: 0.46-0.75; I2: 77%). When compared, Imiquimod was inferior to conization (RR: 0.62; CI: 0.42-0.92; I2: 64%). The HPV clearance rate in women who completed Imiquimod treatment was 60% (CI: 0.31-0.81; I2: 57%). The majority of side effects reported were mild to moderate in severity. CONCLUSIONS: Our findings indicate that topical Imiquimod is safe and effective in reducing cervical intraepithelial neoplasia and promoting HPV clearance. However, it was found to be inferior compared to conization. Imiquimod could be considered a potential medication for high-grade CIN patients and should be incorporated into guidelines for treating cervical dysplasia.

Magnetic Resonance Imaging in Prostate Cancer Screening: A Systematic Review and Meta-Analysis.

Importance: Prostate magnetic resonance imaging (MRI) is increasingly integrated within the prostate cancer (PCa) early detection pathway. Objective: To systematically evaluate the existing evidence regarding screening pathways incorporating MRI with targeted biopsy and assess their diagnostic value compared with prostate-specific antigen (PSA)-based screening with systematic biopsy strategies. Data Sources: PubMed/MEDLINE, Embase, Cochrane/Central, Scopus, and Web of Science (through May 2023). Study Selection: Randomized clinical trials and prospective cohort studies were eligible if they reported data on the diagnostic utility of prostate MRI in the setting of PCa screening. Data Extraction: Number of screened individuals, biopsy indications, biopsies performed, clinically significant PCa (csPCa) defined as International Society of Urological Pathology (ISUP) grade 2 or higher, and insignificant (ISUP1) PCas detected were extracted. Main Outcomes and Measures: The primary outcome was csPCa detection rate. Secondary outcomes included clinical insignificant PCa detection rate, biopsy indication rates, and the positive predictive value for the detection of csPCa. Data Synthesis: The generalized mixed-effect approach with pooled odds ratios (ORs) and random-effect models was used to compare the MRI-based and PSA-only screening strategies. Separate analyses were performed based on the timing of MRI (primary/sequential after a PSA test) and cutoff (Prostate Imaging Reporting and Data System [PI-RADS] score ≥3 or ≥4) for biopsy indication. Results: Data were synthesized from 80 114 men from 12 studies. Compared with standard PSA-based screening, the MRI pathway (sequential screening, PI-RADS score ≥3 cutoff for biopsy) was associated with higher odds of csPCa when tests results were positive (OR, 4.15; 95% CI, 2.93-5.88; P ≤ .001), decreased odds of biopsies (OR, 0.28; 95% CI, 0.22-0.36; P ≤ .001), and insignificant cancers detected (OR, 0.34; 95% CI, 0.23-0.49; P = .002) without significant differences in the detection of csPCa (OR, 1.02; 95% CI, 0.75-1.37; P = .86). Implementing a PI-RADS score of 4 or greater threshold for biopsy selection was associated with a further reduction in the odds of detecting insignificant PCa (OR, 0.23; 95% CI, 0.05-0.97; P = .048) and biopsies performed (OR, 0.19; 95% CI, 0.09-0.38; P = .01) without differences in csPCa detection (OR, 0.85; 95% CI, 0.49-1.45; P = .22). Conclusion and relevance: The results of this systematic review and meta-analysis suggest that integrating MRI in PCa screening pathways is associated with a reduced number of unnecessary biopsies and overdiagnosis of insignificant PCa while maintaining csPCa detection as compared with PSA-only screening.

Investigating the role of ultrasound-based shear wave elastography in kidney transplanted patients: correlation between non-invasive fibrosis detection, kidney dysfunction and biopsy results-a systematic review and meta-analysis.

INTRODUCTION: Interstitial fibrosis and tubular atrophy are leading causes of renal allograft failure. Shear wave elastography could be a promising noninvasive method for providing information on the state of the kidney, with specific regard to fibrosis but currently available data in the literature are controversial. Our study aimed to analyze the correlation between shear wave elastography and various kidney dysfunction measures. METHODS: This review was registered on PROSPERO (CRD42021283152). We systematically searched three major databases (MEDLINE, Embase, and CENTRAL) for articles concerning renal transplant recipients, shear wave elastography, fibrosis, and kidney dysfunction. Meta-analytical calculations for pooled Pearson and Spearman correlation coefficients (r) were interpreted with 95% confidence intervals (CIs). Heterogeneity was tested with Cochran's Q test. I2 statistic and 95% CI were reported as a measurement of between-study heterogeneity. Study quality was assessed with the QUADAS2 tool. RESULTS: In total, 16 studies were included in our meta-analysis. Results showed a moderate correlation between kidney stiffness and interstitial fibrosis and tubular atrophy, graded according to BANFF classification, on biopsy findings for pooled Pearson (r = 0.48; CI: 0.20, 0.69; I2 = 84%) and Spearman correlations (r = 0.57; CI: 0.35, 0.72; I2 = 74%). When compared to kidney dysfunction parameters, we found a moderate correlation between shear wave elastography and resistive index (r = 0.34 CI: 0.13, 0.51; I2 = 67%) and between shear wave elastography and estimated Glomerular Filtration Rate (eGFR) (r = -0.65; CI: - 0.81, - 0.40; I2 = 73%). All our outcomes had marked heterogeneity. CONCLUSION: Our results showed a moderate correlation between kidney stiffness measured by shear wave elastography and biopsy results. While noninvasive assessment of kidney fibrosis after transplantation is an important clinical goal, there is insufficient evidence to support the use of elastography over the performance of a kidney biopsy.

The Mutographs biorepository: A unique genomic resource to study cancer around the world.

Large-scale biorepositories and databases are essential to generate equitable, effective, and sustainable advances in cancer prevention, early detection, cancer therapy, cancer care, and surveillance. The Mutographs project has created a large genomic dataset and biorepository of over 7,800 cancer cases from 30 countries across five continents with extensive demographic, lifestyle, environmental, and clinical information. Whole-genome sequencing is being finalized for over 4,000 cases, with the primary goal of understanding the causes of cancer at eight anatomic sites. Genomic, exposure, and clinical data will be publicly available through the International Cancer Genome Consortium Accelerating Research in Genomic Oncology platform. The Mutographs sample and metadata biorepository constitutes a legacy resource for new projects and collaborations aiming to increase our current research efforts in cancer genomic epidemiology globally.

PARP inhibitor era in ovarian cancer treatment: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Ovarian cancer is the eighth leading cause of cancer-related death among women, characterized by late diagnosis and a high relapse rate. In randomized controlled trials, we aimed to evaluate the efficacy and safety of PARP inhibitors (PARPi) in treating advanced ovarian cancer. METHODS: This review was registered on PROSPERO (CRD42021283150), included all phase II and phase III randomized controlled trials (RCTs) assessing the effect of PARPi on ovarian cancer until the 13th of April, 2022. The main outcomes were progression- free survival (PFS), overall survival (OS), and adverse events (AEs). Pooled hazard ratios (HRs), and risk ratios (RRs) were calculated with 95% confidence intervals (95% CI). The random-effects model was applied in all analyses. RESULTS: In the meta-analysis, 16 eligible RCTs were included, with a total of 5,815 patients. In recurrent ovarian cancer, PARPi maintenance therapy showed a significant PFS benefit over placebo in the total population (HR 0.34, CI 0.29-0.40), BRCA mutant (HR 0.24, CI 0.18-0.31), germline BRCA mutant (HR 0.23, CI 0.18-0.30), and BRCA wild-type cases (HR 0.50, CI 0.39-0.65). PARPi monotherapy also improved PFS (HR 0.62, CI 0.51-0.76) compared with chemotherapy in BRCAm patients with recurrent ovarian cancer. The use of PARPi maintenance therapy resulted in an improvement in PFS over placebo in newly-diagnosed cancers in the overall population (HR 0.46, CI 0.30-0.71) and the BRCAm population (HR 0.36, CI 0.29-0.44). Although the risk of severe AEs was increased by PARPi therapy compared to placebo in most settings investigated, these side effects were controllable with dose modification, and treatment discontinuation was required in the minority of cases. CONCLUSIONS: PARPis are an effective therapeutic option for newly-diagnosed and recurrent ovarian cancer. Despite a minor increase in the frequency of serious adverse effects, they are generally well tolerated.

Ranking the dietary interventions by their effectiveness in the management of polycystic ovary syndrome: a systematic review and network meta-analysis.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common condition in women, characterised by reproductive and metabolic dysfunction. While dietary approaches have been evaluated as a first-line treatment for patients with PCOS, there is limited evidence to support preference for a specific dietary composition. This systematic review and network meta-analysis was performed with the objective of comparing different dietary interventions in terms of positive impact. Metformin, the currently preferred treatment, was also compared. METHODS: The latest systematic search was performed on the 20th of March, 2023. Eligible randomised controlled trials (RCTs) included patients with PCOS and compared the dietary approach with another intervention or a standard diet. Outcomes were expressed via anthropometric measurements and hormonal, glycemic, and lipid levels. The Bayesian method was used to perform a network meta-analysis and to calculate the surface under the cumulative ranking curve (SUCRA) values in order to rank the dietary interventions. The overall quality of the evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation system. RESULTS: 19 RCTs were identified, comprising data from 727 patients who were variously treated with 10 types of dietary interventions and metformin. The Dietary Approaches to Stop Hypertension (DASH) diet was the most effective in reducing Homeostatic Model Assessment of Insulin Resistance (SUCRA 92.33%), fasting blood glucose (SUCRA 85.92%), fasting insulin level (SUCRA 79.73%) and triglyceride level (SUCRA 82.07%). For body mass index (BMI), the most effective intervention was the low-calorie diet (SUCRA 84.59%). For weight loss, the low-calorie diet with metformin (SUCRA 74.38%) was the most effective intervention. Metformin produced the greatest reductions in low-density lipoprotein cholesterol (SUCRA 78.08%) and total testosterone levels (SUCRA 71.28%). The low-carb diet was the most effective intervention for reducing cholesterol levels (SUCRA 69.68%), while the normal diet (SUCRA 65.69%) ranked first for increasing high-density lipoprotein cholesterol levels. CONCLUSION: Dietary interventions vary in their effects on metabolic parameters in women with PCOS. Based on our results, the DASH diet is the most effective dietary intervention for treating PCOS. Registration PROSPERO ID CRD42021282984.

Robot-assisted laparoscopy does not have demonstrable advantages over conventional laparoscopy in endometriosis surgery: a systematic review and meta-analysis.

BACKGROUND: Endometriosis is a chronic condition affecting 6-10% of women of reproductive age, with endometriosis-related pain and infertility being the leading symptoms. Currently, the gold standard treatment approach to surgery is conventional laparoscopy (CL); however, the increasing availability of robot-assisted surgery is projected as a competitor of CL. This study aimed to compare the perioperative outcomes of robot-assisted laparoscopy (RAL) and CL in endometriosis surgery. OBJECTIVES: We aimed to compare the effectiveness and safety of these two procedures. METHODS: A systematic search was conducted in three medical databases. Studies investigating different perioperative outcomes of endometriosis-related surgeries were included. Results are presented as odds ratios (OR) or mean differences (MD) with 95% confidence intervals (CI). RESULTS: Our search yielded 2,014 records, of which 13 were eligible for data extraction. No significant differences were detected between the CL and RAL groups in terms of intraoperative complications (OR = 1.07, CI 0.43-2.63), postoperative complications (OR = 1.3, CI 0.73-2.32), number of conversions to open surgery (OR = 1.34, CI 0.76-2.37), length of hospital stays (MD = 0.12, CI 0.33-0.57), blood loss (MD = 16.73, CI 4.18-37.63) or number of rehospitalizations (OR = 0.95, CI 0.13-6.75). In terms of operative times (MD = 28.09 min, CI 11.59-44.59) and operating room times (MD = 51.39 min, CI 15.07-87.72;), the RAL technique remained inferior. CONCLUSION: RAL does not have statistically demonstrable advantages over CL in terms of perioperative outcomes for endometriosis-related surgery.

Safety and Efficacy of Vaginal Implants in Pelvic Organ Prolapse Surgery: A Meta-analysis of 161 536 Patients.

CONTEXT: Among the many surgical treatments for pelvic organ prolapse (POP), better results can be achieved with the use of vaginal implants. However, owing to perceived complications, vaginal implant surgeries have been restricted or banned in many countries. OBJECTIVE: To assess the real value of vaginal implants in POP surgery and compare the safety and efficacy of operations with and without implants. EVIDENCE ACQUISITION: A systematic search was performed in three medical databases. Randomised controlled trials and observational studies comparing the safety and efficacy of vaginal POP surgery with implants versus native tissue were included. Safety outcomes were defined as different types of complications (functional and non-functional) and reoperations for complications. Efficacy outcomes were parameters of anatomical success and the rate of reoperations due to recurrence. A multivariate meta-analysis framework was used to estimate pooled odds ratios (ORs) with confidence intervals (CIs) with simultaneous control for study correlations and estimation of multiple correlated outcomes. EVIDENCE SYNTHESIS: We included 50 comparative studies in the analysis. Rates of reoperation for complications (OR 2.15, 95% CI 1.20-3.87), vaginal erosion (OR 14.05, 95% CI 9.07-21.77), vaginal bleeding (OR 1.67, 95% CI 1.25-2.23), and de novo stress urinary incontinence (OR 1.44, 95% CI 1.18-1.75) were significantly higher in the implant group. Rates of anatomical success (OR 3.22, 95% CI 2.06-5.0) and reoperation for recurrence (OR 0.55, 95% CI 0.36-0.85) were superior in the implant group. CONCLUSIONS: POP surgeries with vaginal implants are more effective than surgeries without implants, with acceptable complication rates. Therefore, the complete prohibition of implants for POP surgeries should be reconsidered. PATIENT SUMMARY: We compared vaginal surgery with and without implants for repair of pelvic organ prolapse. Despite higher complication rates, vaginal implants provide better long-term results overall than surgery without implants.

Efficacy of immune checkpoint inhibitor therapy for advanced urothelial carcinoma in real-life clinical practice: results of a multicentric, retrospective study.

Clinical trials revealed significant antitumor activity for immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (mUC). Due to their strict eligibility criteria, clinical trials include selected patient cohorts, and thus do not necessarily represent real-world population outcomes. In this multicentric, retrospective study, we investigated real-world data to assess the effectiveness of pembrolizumab and atezolizumab and to evaluate the prognostic value of routinely available clinicopathological and laboratory parameters. Clinical and follow-up data from mUC patients who received ICIs (01/2017-12/2021) were evaluated. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and duration of response (DOR) were used as endpoints. Patients' (n = 210, n = 76 atezolizumab and 134 pembrolizumab) median OS and PFS were 13.6 and 5.9 months, respectively. Impaired ECOG-PS, the presence of visceral, liver or bone metastases, and hemoglobin levels were independently associated with poor OS and DCR. Furthermore, Bellmunt risk factors and the enhanced Bellmunt-CRP score were shown to be prognostic for OS, PFS and DCR. In conclusion, ICIs are effective treatments for a broad range of mUC patients. Our results confirmed the prognostic value of numerous risk factors and showed that Bellmunt risk scores can further be improved when adding CRP to the model.

Myoinositols Prevent Gestational Diabetes Mellitus and Related Complications: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Although gestational diabetes mellitus (GDM) has several short- and long-term adverse effects on the mother and the offspring, no medicine is generally prescribed to prevent GDM. The present systematic review and meta-analysis aimed to investigate the effect of inositol supplementation in preventing GDM and related outcomes. Systematic search was performed in CENTRAL, MEDLINE, and Embase until 13 September 2023. Eligible randomized controlled trials (RCTs) compared the efficacy of inositols to placebo in pregnant women at high risk for GDM. Our primary outcome was the incidence of GDM, whereas secondary outcomes were oral glucose tolerance test (OGTT) and maternal and fetal complications. (PROSPERO registration number: CRD42021284939). Eight eligible RCTs were identified, including the data of 1795 patients. The incidence of GDM was halved by inositols compared to placebo (RR = 0.42, CI: 0.26-0.67). Fasting, 1-h, and 2-h OGTT glucose levels were significantly decreased by inositols. The stereoisomer myoinositol also reduced the risk of insulin need (RR = 0.29, CI: 0.13-0.68), preeclampsia or gestational hypertension (RR = 0.38, CI: 0.2-0.71), preterm birth (RR = 0.44, CI: 0.22-0.88), and neonatal hypoglycemia (RR = 0.12, CI: 0.03-0.55). Myoinositol decrease the incidence of GDM in pregnancies high-risk for GDM. Moreover, myoinositol supplementation reduces the risk of insulin need, preeclampsia or gestational hypertension, preterm birth, and neonatal hypoglycemia. Based on the present study 2-4 g myoinositol canbe suggested from the first trimester to prevent GDM and related outcomes.

Poly (ADP-ribose) Polymerase Inhibitors Have Comparable Efficacy with Platinum Chemotherapy in Patients with BRCA-positive Metastatic Castration-resistant Prostate Cancer. A Systematic Review and Meta-analysis.

CONTEXT: Testing for mutations in Breast Cancer Gene 1/2 (BRCA) has emerged as a novel decision-making tool for clinicians. Patients with metastatic castration-resistant prostate cancer (mCRPC) harboring pathogenic BRCA mutations can benefit from poly (ADP-ribose) polymerase inhibitor (PARPi) and platinum treatments, whereas the impact of the mutation on sensitivity to cabazitaxel and prostate-specific membrane antigen (PSMA)-ligand therapy is currently unknown. OBJECTIVE: To assess the efficacy of PARPi, platinum, cabazitaxel, and PSMA-ligand therapies in BRCA-positive mCRPC. EVIDENCE ACQUISITION: Databases were queried in February 2022. We performed data synthesis by using both proportional and individual patient data. For prostate-specific antigen (PSA) response rate (≥50% decrease from baseline [PSA50]) evaluation, we pooled event rates with 95% confidence intervals (CIs). Progression-free (PFS) and overall (OS) survival analyses with individual patient data were performed with the mixed-effect Cox proportional hazard model and single-arm random-effect analysis, providing pooled medians. EVIDENCE SYNTHESIS: We included 23 eligible studies with 901 BRCA-positive mCRPC patients. PSA50 response rates for PARPi and platinum were 69% (CI: 53-82%), and 74% (CI: 49-90%), respectively. Analyses of OS data showed no difference between PARPi and platinum treatments (hazard ratio: 0.86; CI: 0.49-1.52; p = 0.6). The single-arm OS and PFS analyses revealed similarities among different PARPis; pooled PFS and OS medians were 9.7 mo (CI: 8.1-12.5) and 17.4 mo (CI: 12.7-20.1), respectively. CONCLUSIONS: Our data revealed that different PARPis were similarly effective in terms of PFS and OS. Moreover, we found that PARPi and platinum therapy were comparable in terms of PSA50 response rate and OS, highlighting that platinum is a valid treatment option for BRCA-positive mCRPC patients. However, prospective interventional studies comparing these agents are essential to provide a higher level of evidence. PATIENT SUMMARY: In this report, we found that different poly (ADP-ribose) polymerase inhibitors had similar efficacy, and platinum was a valid treatment option in BRCA-positive metastatic castration-resistant prostate cancer patients.

Intracellular signaling pathways of muscarinic acetylcholine receptor-mediated detrusor muscle contractions.

Acetylcholine plays an essential role in the regulation of detrusor muscle contractions, and antimuscarinics are widely used in the management of overactive bladder syndrome. However, several adverse effects limit their application and patients' compliance. Thus, this study aimed to further analyze the signal transduction of M2 and M3 receptors in the murine urinary bladder to eventually find more specific therapeutic targets. Experiments were performed on adult male wild-type, M2, M3, M2/M3, or Gαq/11 knockout (KO), and pertussis toxin (PTX)-treated mice. Contraction force and RhoA activity were measured in the urinary bladder smooth muscle (UBSM). Our results indicate that carbamoylcholine (CCh)-induced contractions were associated with increased activity of RhoA and were reduced in the presence of the Rho-associated kinase (ROCK) inhibitor Y-27632 in UBSM. CCh-evoked contractile responses and RhoA activation were markedly reduced in detrusor strips lacking either M2 or M3 receptors and abolished in M2/M3 KO mice. Inhibition of Gαi-coupled signaling by PTX treatment shifted the concentration-response curve of CCh to the right and diminished RhoA activation. CCh-induced contractile responses were markedly decreased in Gαq/11 KO mice; however, RhoA activation was unaffected. In conclusion, cholinergic detrusor contraction and RhoA activation are mediated by both M2 and M3 receptors. Furthermore, whereas both Gαi and Gαq/11 proteins mediate UBSM contraction, the activation at the RhoA-ROCK pathway appears to be linked specifically to Gαi. These findings may aid the identification of more specific therapeutic targets for bladder dysfunctions.NEW & NOTEWORTHY Muscarinic acetylcholine receptors are of utmost importance in physiological regulation of micturition and also in the development of voiding disorders. We demonstrate that the RhoA-Rho-associated kinase (ROCK) pathway plays a crucial role in contractions induced by cholinergic stimulation in detrusor muscle. Activation of RhoA is mediated by both M2 and M3 receptors as well as by Gi but not Gq/11 proteins. The Gi-RhoA-ROCK pathway may provide a novel therapeutic target for overactive voiding disorders.

Routine screening of abnormal vaginal flora during pregnancy reduces the odds of preterm birth: a systematic review and meta-analysis.

Prematurity is the leading cause of perinatal mortality and the morbidity among children under the age of 5. The prevalence of preterm birth is between 5 and 18% worldwide. Approximately 30% of preterm deliveries occur as a consequence of fetal or maternal infections. Bacterial vaginosis can increase the risk of ascending infections. However, there is no recommendation or protocol for screening of abnormal vaginal flora. The aim of this systematic review was to investigate the effectiveness of routine screening of abnormal vaginal flora during pregnancy care. We conducted our systematic search in the following databases: MEDLINE via PubMed, Embase, and Cochrane Library. Studies reporting on pregnant women with no symptoms of bacterial vaginosis were included in our analysis if they provided data on the outcome of their pregnancy. The intervention group went through screening of abnormal vaginal flora in addition to routine pregnancy care. Odds ratio (OR) with 95% confidence intervals (CIs) was used as effect size measure. From each study the total number of patients and number of events was extracted in both the intervention and control arm to calculate OR. Altogether we included 13 trials with 143,534 patients. The screening methods were Gram stain, pH screening, pH self-screening and pH screening combined with Gram stain. Regular screening of vaginal flora compared to no screening significantly reduces the odds of preterm birth before 37 weeks (8.98% vs 9.42%; OR 0.71, CI 0.57-0.87), birthweight under 2500 g (6.53% vs 7.24%; OR 0.64, CI 0.50-0.81), preterm birth before 32 weeks (1.35% vs 2.03%; OR 0.51, CI 0.31-0.85) and birthweight under 1000 g (0.86% vs 2.2%; OR 0.33, CI 0.19-0.57). In conclusion, the routine screening of abnormal vaginal flora might prevent preterm birth, extreme preterm birth, low birthweight deliveries and very low birthweight deliveries. Further research is needed to assess the problem more accurately.

Comparative proteome and serum analysis identified FSCN1 as a marker of abiraterone resistance in castration-resistant prostate cancer.

BACKGROUND: Abiraterone (Abi) is an androgen receptor signaling inhibitor that significantly improves patients' life expectancy in metastatic prostate cancer (PCa). Despite its beneficial effects, many patients have baseline or acquired resistance against Abi. The aim of this study was to identify predictive serum biomarkers for Abi treatment. METHODS: We performed a comparative proteome analysis on three Abi sensitive (LNCaPabl, LAPC4, DuCaP) and resistant (LNCaPabl-Abi, LAPC4-Abi, DuCaP-Abi) PCa cell lines using liquid chromatography tandem mass spectrometry (LC-MS/MS) technique. Two bioinformatic selection workflows were applied to select the most promising candidate serum markers. Serum levels of selected proteins were assessed in samples of 100 Abi-treated patients with metastatic castration-resistant disease (mCRPC) using ELISA. Moreover, FSCN1 serum concentrations were measured in samples of 69 Docetaxel (Doc) treated mCRPC patients. RESULTS: Our proteome analysis identified 68 significantly, at least two-fold upregulated proteins in Abi resistant cells. Using two filtering workflows four proteins (AMACR, KLK2, FSCN1 and CTAG1A) were selected for ELISA analyses. We found high baseline FSCN1 serum levels to be significantly associated with poor survival in Abi-treated mCRPC patients. Moreover, the multivariable analysis revealed that higher ECOG status (>1) and high baseline FSCN1 serum levels (>10.22 ng/ml by ROC cut-off) were independently associated with worse survival in Abi-treated patients (p < 0.001 and p = 0.021, respectively). In contrast, no association was found between serum FSCN1 concentrations and overall survival in Doc-treated patients. CONCLUSIONS: Our analysis identified baseline FSCN1 serum levels to be independently associated with poor survival of Abi-treated, but not Doc-treated mCRPC patients, suggesting a therapy specific prognostic value for FSCN1.

[Current therapeutic and familial implications of the genetic background of prostate cancer]. / A prosztatarák genetikai hátterének aktuális terápiás és familiáris vonatkozásai.

Genetic testing for prostate cancer (PC) is becoming more widely used in the clinical routine, primarily due to the introduction of PARP inhibitors targeting genetically affected patients in their BRCA1/2 and other homologous recombination repair (HRR) genes. Simultaneously, the number of available therapies that are specifically targeting genetically defined PC subgroups is steadily increasing. As a result, the selection of treatment for PC patients is likely to require testing of multiple genes to enable more specific treatment sequences that consider the genetic characteristics of the tumor. Some of the mutations discovered by genetic testing may be hereditary, necessitating the use of germline testing from normal tissue, which is only permitted within the framework of clinical counseling. This change in PC care requires the collaboration by multiple specialists, including experts in molecular pathology, bioinformatics, biology, and genetic counseling. In this review, we aim to provide an overview on the currently relevant genetic alterations in PC for therapeutic purposes and their implications for familial testing.

Comprehensive Analysis of the Prognostic Value of Circulating MMP-7 Levels in Urothelial Carcinoma: A Combined Cohort Analysis, Systematic Review, and Meta-Analysis.

Lymph node (LN) status is the most significant prognostic factor for invasive urothelial bladder cancer (UBC); however, the optimal extent of LN dissection (LND) is debated. We assessed circulating matrix metalloproteinase-7 (MMP-7) as a prognostic factor and decision-making marker for the extent of LND. Preoperative serum MMP-7 levels were determined in two independent UBC cohorts (n = 188; n = 68) and in one control cohort (n = 97) by using the ELISA method. A systematic review and meta-analysis on the prognostic role of circulating pretreatment MMP-7 levels were performed. Serum MMP-7 levels were higher in patients compared to controls (p < 0.001) with the highest levels in LN-positive cases. Half of LN-positive UBC patients had low MMP-7 levels, whereas the survival of LN-negative patients with high serum MMP-7 findings was poor. MMP-7 levels were independently associated with poor survival in both cohorts (p = 0.006, p < 0.001). Accordingly, our systematic review of six eligible publications revealed a 2.5-fold higher mortality risk in patients with high MMP-7 levels. In conclusion, preoperative MMP-7 level is a validated and independent prognostic factor in urothelial cancer. It cannot be used to decide between regional or extended LND but may be useful in identifying LN-negative high-risk patients with potentially undetected metastases.