Natural history of histologically benign PIRADS 4-5 lesions in multiparametric MRI: Real-life experience in an academic center.

INTRODUCTION: The follow-up findings of patients who underwent prostate biopsy for prostate image reporting and data system (PIRADS) 4 or 5 multiparametric magnetic resonance imaging (mpMRI) findings and had benign histology were retrospectively reviewed. METHODS: There were 190 biopsy-naive patients. Patients with at least 12 months of follow-up between 2012 and 2023 were evaluated. All MRIs were interpreted by two very experienced uroradiologists. Of the patients, 125 had either cognitive or software fusion MR-targeted biopsies with 4 + 8/10 cores. The remaining 65 patients had in-bore biopsies with 4-5 cores. Prostate-specific antigen (PSA) levels below 4 ng/mL were defined as PSA regression following biopsy. PIRADS 1-3 lesions on new MRI images were classified as MRI regression. RESULTS: Median patient age and PSA were 62 (39-82) years and six (0.4-33) ng/mL, respectively, at the initial work-up. During a median follow-up period of 44 months, 37 (19.4%) patients were lost to follow-up. Of the remaining 153 patients, 82 (53.6%) had persistently high PSA. Among them, 72 (87.8%) had repeat mpMRI within 6-24 months which showed regressive findings (PIRADS 1-3) in 53 patients (73.6%) and PIRADS 4-5 index lesion persistence in 19 cases (26.4%). The latter group was recommended to have rebiopsy. Of these 19 patients, 16 underwent MRI-targeted rebiopsy. Prostate cancer was diagnosed in six (37.5%) patients and of these four (25%) were clinically significant (>Grade Group 1). Totally, clinically significant prostate cancer was detected in 4/153 (2.6%) patients followed up. CONCLUSION: Patients should be warned against the relative relaxing effect of a negative biopsy after identification of PIRADS 4-5 index lesion. While PSA decrease was observed in many patients during follow-up, persistent MRI findings were present in nearly a quarter of patients with persistently high PSA. A rebiopsy is warranted in these patients, with significant prostate cancer diagnosed in a quarter of patients with rebiopsy.

The role of PSMA PET/CT in predicting downgrading in patients with Gleason score 4+4 prostate cancer in prostate biopsy.

BACKGROUND: To investigate the predictable parameters associated with downgrading in patients with a Gleason score (GS) 8 (4+4) in prostate biopsy after radical prostatectomy. METHODS: We retrospectively analyzed 62 patients with a GS of 4+4 on prostate biopsy who underwent robotic radical prostatectomy between 2017 and 2022. RESULTS: 38 of 62 (61.2%) were downgraded. In multivariable logistic regression model, Ga-68 prostate-specific membrane antigen (PSMA) positron-emission tomography (PET)/computed tomography (CT) SUV max was independent predictor of downgrading (OR 0.904; p = 0.011) and a Logistic Regression model was constructed using the following formula: Y = 1.465-0.95 (PSMA PET/CT SUV max). The model using this variable correctly predicted the downgrading in 72.6% of patients. The AUC for PSMA PET/CT SUV max was 0.709 the cut off being 8.8. A subgroup analysis was performed in 37 patients who had no other European Association of Urology (EAU) high risk features. 25 out of 37 (67.5%) were downgraded, and 21 of these 25 had organ confined disease. Low PSMA SUV max (<8.1) and percentage of GS 4+4 biopsy cores to cancer bearing cores (45.0%) were independently associated with downgrading to GS 7. CONCLUSION: PSMA PET/CT can be used to predict downgrading in patients with GS 4+4 PCa. Patients with GS 4+4 disease, but no other EAU high risk features, low percentage of GS 4+4 biopsy cores to cancer bearing cores, and a low PSMA PET/CT SUV max are associated with a high likelihood of the cancer reclassification to intermediate risk group.

Quantitative Phosphoproteomics Analysis Uncovers PAK2- and CDK1-Mediated Malignant Signaling Pathways in Clear Cell Renal Cell Carcinoma.

Clear cell Renal Cell Carcinoma (ccRCC) is among the 10 most common cancers in both men and women and causes more than 140,000 deaths worldwide every year. In order to elucidate the underlying molecular mechanisms orchestrated by phosphorylation modifications, we performed a comprehensive quantitative phosphoproteomics characterization of ccRCC tumor and normal adjacent tissues. Here, we identified 16,253 phosphopeptides, of which more than 9000 were singly quantified. Our in-depth analysis revealed 600 phosphopeptides to be significantly differentially regulated between tumor and normal tissues. Moreover, our data revealed that significantly up-regulated phosphoproteins are associated with protein synthesis and cytoskeletal re-organization which suggests proliferative and migratory behavior of renal tumors. This is supported by a mesenchymal profile of ccRCC phosphorylation events. Our rigorous characterization of the renal phosphoproteome also suggests that both epidermal growth factor receptor and vascular endothelial growth factor receptor are important mediators of phospho signaling in RCC pathogenesis. Furthermore, we determined the kinases p21-activated kinase 2, cyclin-dependent kinase 1 and c-Jun N-terminal kinase 1 to be master kinases that are responsible for phosphorylation of many substrates associated with cell proliferation, inflammation and migration. Moreover, high expression of p21-activated kinase 2 is associated with worse survival outcome of ccRCC patients. These master kinases are targetable by inhibitory drugs such as fostamatinib, minocycline, tamoxifen and bosutinib which can serve as novel therapeutic agents for ccRCC treatment.

Can the Briganti 2019 nomogram be modified to predict lymph node metastasis risk in patients with prostate cancer detected with in-bore biopsy?

OBJECTIVES: We aimed to modify the Briganti 2019 nomogram and to test whether it is valid for patients who were diagnosed with prostate cancer through in-bore prostate biopsies. METHODS: Data for 204 patients with positive multiparametric prostate MRI and prostate cancer identified either by mpMRI-cognitive/software fusion or in-bore biopsy and who underwent robot-assisted radical prostatectomy and extended pelvic lymph node dissection between 2012 and 2023 were retrospectively analyzed. The Briganti 2019 nomogram was applied to the mpMRI-cognitive/software fusion biopsy group (142 patients) in the original form, and then, two modifications were tested for the targeted component. Original and modified scores were compared. These modifications were adapted for the in-bore biopsy group (62 patients). The final histopathologic stage was regarded as the gold standard. RESULTS: Nodal metastases were identified in 18/142 (12.6%) of mpMRI-cognitive/software fusion biopsy patients and 8/62 (12.9%) of the in-bore biopsy patients. In the mpMRI-cognitive/software fusion biopsy group, tumor size/core size (%) of targeted biopsy cores and positive core percentage on systematic biopsy were significant parameters for lymph node metastasis based on univariate logistic regression analyses (p < 0.05). With the modifications of these parameters for the in-bore biopsy group, V1 modification of the Briganti 2019 nomogram provided 100% sensitivity and 31.5% specificity (AUC:0.627), while V2 modification provided 75% sensitivity and 46.3% specificity (AUC:0.645). CONCLUSIONS: Briganti 2019 nomogram may be modified by utilizing tumor size/core size (%) for targeted biopsy cores instead of positive core percentage on systematic biopsy or by not taking both parameters into consideration to detect node metastasis risk of patients diagnosed with in-bore biopsies.

The role of the size and number of index lesion in the diagnosis of clinically significant prostate cancer in patients with PI-RADS 4 lesions who underwent in-bore MRI-guided prostate biopsy.

PURPOSE: To evaluate the contribution of the size and number of the sampled lesions to the diagnosis of clinically significant prostate cancer (CSPC) in patients who had PI-RADS 4 lesions. METHODS: In this retrospective study, a total of 159 patients who had PI-RADS 4 lesions and underwent In-bore MRI-Guided prostate biopsy were included. Patients with a lesion classified as Grade Group 2 and above were considered to have CSPC. Univariate and multivariate regression analyses were used to evaluate the factors affecting the diagnosis of prostate cancer (PCa) and CSPC. RESULTS: A great majority (86.8%) of the patients were biopsy-naïve. About three-fourths (71.7%) had PCa, and half (54.1%) had CSPC. When the patients were divided into three groups according to the index lesion size (< 5 mm, 5-10 mm, and > 10 mm), the prevalence of PCa was 64.3, 67.5, and 82.4% and the prevalence of CSPC was 42.9, 51.2, and 64.7%, respectively. In multivariate analysis, age, index lesion size, prostate volume (< 50 ml) and being biopsy-naïve were found significant for PCa, while age and prostate volume (< 50 ml) were significant for CSPC. CONCLUSION: The number of lesions was found to be insignificant in predicting PCa and CSPC. While the size of PI-RADS 4 lesions was significant in predicting PCa, it had no significance in detecting CSPC.

MRI as a screening tool for prostate cancer: current evidence and future challenges.

PURPOSE: Prostate cancer (PCa) screening, which relies on prostate-specific antigen (PSA) testing, is a contentious topic that received negative attention due to the low sensitivity and specificity of PSA to detect clinically significant PCa. In this context, due to the higher sensitivity and specificity of magnetic resonance imaging (MRI), several trials investigate the feasibility of "MRI-only" screening approaches, and question if PSA testing may be replaced within prostate cancer screening programs. METHODS: This narrative review discusses the current literature and the outlook on the potential of MRI-based PCa screening. RESULTS: Several prospective randomized population-based trials are ongoing. Preliminary study results appear to favor the "MRI-only" approach. However, MRI-based PCa screening programs face a variety of obstacles that have yet to be fully addressed. These include the increased cost of MRI, lack of broad availability, differences in MRI acquisition and interpretation protocols, and lack of long-term impact on cancer-specific mortality. Partly, these issues are being addressed by shorter and simpler MRI approaches (5-20 min bi-parametric MRI), novel quality indicators (PI-QUAL) and the implementation of radiomics (deep learning, machine learning). CONCLUSION: Although promising preliminary results were reported, MRI-based PCa screening still lack long-term data on crucial endpoints such as the impact of MRI screening on mortality. Furthermore, the issues of availability, cost-effectiveness, and differences in MRI acquisition and interpretation still need to be addressed.

Postchemotherapy robotic retroperitoneal lymph node dissection for non-seminomatous germ cell tumors in the lateral decubitus position: oncological and functional outcomes.

PURPOSE: Retroperitoneal lymph node dissection (RPLND) is recommended for residual masses following chemotherapy for non-seminomatous germ cell tumors (NSGCT). Recently, aberrant recurrence patterns were reported in patients who underwent robotic RPLND. We aimed to evaluate perioperative safety in addition to functional and early oncological outcomes of postchemotherapy robotic RPLND (pcR-RPLND) for NSGCT. METHODS: A total of 25 patients with NSGCT who underwent a pcR-RPLND between January 2011 and June 2022 were evaluated retrospectively. Descriptive statistics were provided for demographics, clinical characteristics, intraoperative and postoperative parameters. Functional and oncological outcomes were recorded. RESULTS: The median patient age was 28.9 years (IQR 21.5-32.4). The median retroperitoneal tumor size was 2.6 cm (IQR 1.5-3.5). Intraoperative complications occurred in only one case and the open conversion rate was 12%. There were seven cases with postoperative complications (Clavien grade II: 5 and IIIa: 2). Patients were followed for a median of 33.2 months (IQR 14.8-43.0). Antegrade ejaculation was preserved in 85.7% of the patients. Two patients (8%) relapsed and both had out-of-field recurrences at unusual sites (perinephric fat and omentum). Of those, one patient died (4%) of testicular cancer. CONCLUSION: pcR-RPLND is a feasible and technically reproducible procedure with favorable perioperative morbidity, low rate of complications, and acceptable postoperative ejaculatory function. Although the recurrence rate was low (8%), recurrences were observed at unusual sites. Further studies are required to investigate any association between the robotic approach and aberrant recurrence patterns.

Histologically benign PI-RADS 4 and 5 lesions contain cancer-associated epigenetic alterations.

BACKGROUND: The detection rate of clinically significant prostate cancer has improved with the use of multiparametric magnetic resonance imaging (mpMRI). Yet, even with MRI-guided biopsy 15%-35% of high-risk lesions (Prostate Imaging-Reporting and Data System [PI-RADS] 4 and 5) are histologically benign. It is unclear if these false positives are due to diagnostic/sampling errors or pathophysiological alterations. To better understand this, we tested histologically benign PI-RAD 4 and 5 lesions for common malignant epigenetic alterations. MATERIALS AND METHODS: MRI-guided in-bore biopsy samples were collected from 45 patients with PI-RADS 4 (n = 31) or 5 (n = 14) lesions. Patients had a median clinical follow-up of 3.8 years. High-risk mpMRI patients were grouped based on their histology into biopsy positive for tumor (BPT; n = 28) or biopsy negative for tumor (BNT; n = 17). From these biopsy samples, DNA methylation of well-known tumor suppressor genes (APC, GSTP1, and RARß2) was quantified. RESULTS: Similar to previous work we observed high rates of promoter methylation at GSTP1 (92.7%), RARß2 (57.3%), and APC (37.8%) in malignant BPT samples but no methylation in benign TURP chips. Interestingly, similar to the malignant samples the BNT biopsies also had increased methylation at the promoter of GSTP1 (78.8%) and RARß2 (34.6%). However, despite these epigenetic alterations none of these BNT patients developed prostate cancer, and those who underwent repeat mpMRI (n = 8) demonstrated either radiological regression or stability. CONCLUSIONS: Histologically benign PI-RADS 4 and 5 lesions harbor prostate cancer-associated epigenetic alterations.

Radical nephroureterectomy for UTUC conferred survival benefits irrespective of age and comorbidities.

PURPOSE: We investigated the effects of age, American Society of Anesthesiologists Physical Status Classification (ASA) grading and Charlson Comorbidity Index (CCI) on the survival outcomes of upper tract urothelial carcinoma (UTUC). METHODS: The CROES-UTUC registry was an international, multicenter study on patients with UTUC. Primary outcomes were overall survival (OS) and disease-free survival (DFS). Kaplan-Meier and multivariate Cox regression analyses were performed by stratifying patients according to their age (≤ 70 and > 70 years old) and ASA grade (I-II and III-V)/CCI (0-1 and ≥ 2). RESULTS: A total of 2352 patients were included in this study. Patients aged ≤ 70 years with ASA grading of I-II (p = 0.002), and patients aged ≤ 70 years with a CCI of 0-1 (p = 0.002) had the best OS. Upon multivariate analysis, both in patients aged ≤ 70 and > 70 years, ASA grading and CCI were not significantly associated with OS. Patients aged ≤ 70 years with ASA grading of III-IV (p = 0.024) had the best DFS. When stratified according to age and CCI, no significant difference in DFS was noted. Upon multivariate analysis, radical nephroureterectomy (RNU) was significantly associated with better DFS in patients aged ≤ 70 and > 70 years; CCI of ≥ 3 was significantly associated with worse DFS in patients ≤ 70 years; ASA grading was not associated with DFS in patients aged ≤ 70 and > 70 years. CONCLUSIONS: A high ASA grading and CCI should not be considered contraindications for RNU. RNU should be considered even in elderly patients when it is deemed feasible and achievable after a geriatric assessment.

Can remote ischemic preconditioning counteract the renal functional deterioration attributable to partial nephrectomy under warm ischemia? Results of an animal study.

BACKGROUND: To investigate if remote ischemic preconditioning (RIPC) can offer any renoprotective value by counteracting the deleterious effect of partial nephrectomy (PN) under warm ischemia on renal function. METHODS: Four groups, each with 5 Wistar albino rats, were constructed; RIPC + PN, PN, RIPC and sham. Right nephrectomy was performed to constitute a solitary kidney model. RIPC denoted sequential clamping/declamping of the femoral artery/vein complex. PN was performed under warm-ischemia following RIPC. Blood samples were collected on multiple occasions until euthanasia on day 7. Immunoassays were conducted to measure the serum and tissues levels of kidney injury markers. Kidneys were examined histologically and morphometric analyzes were performed using digital scanning. RESULTS: IL-33 levels did not differ significantly between the groups. Serum levels of KIM-1, NGAL, and aldose reductase in RIPC + PN, PN and RIPC groups were significantly lower than that of sham group. Tissue biomarker levels were similar across groups. The observed trend in mean necrosis area of PN group was higher than that of RIPC + PN group (p > 0.05). The transitional zone between necrosis and healthy tissue showed a trend towards increasing width in the rats subjected to RIPC before PN vs. those who underwent PN without RIPC (p > 0.05). CONCLUSION: RIPC failed to counteract the renal functional consequences of PN under warm ischemia in a solitary kidney animal model. The supportive but marginal histological findings in favor of RIPC's renoprotective potential were not supplemented with the changes in serum and tissue biomarker levels.

The clinical impact of Prostate Imaging-Reporting and Data System classification in patients with haemospermia undergoing multiparametric magnetic resonance imaging of the prostate.

In this study, we evaluated the role of the Prostate Imaging-Reporting and Data System (PI-RADS) classification of multiparametric magnetic resonance imaging (mpMRI) to determine the likelihood of prostate cancer (PCa) in patients with haemospermia. Fifty-one patients presenting with haemospermia between 2018 and 2020 were included in this retrospective study. Forty-two of the patients (82.4%) were over 40 years, and the median prostate-specific antigen (PSA) level was 1.4 ng/ml. Fourteen of the patients (27.5%) had recurrent haemospermia. All patients underwent mpMRI, and assessments were classified according to PI-RADS v2. The mpMRI revealed PI-RADS one to four lesions in 10 (19.6%), 30 (58.8%), 6 (11.8%) and 5 (9.8%) patients respectively. One patient with PI-RADS 3 and five with PI-RADS 4 lesions underwent cognitive fusion prostate biopsy depending on MRI findings, and two patients with PI-RADS 4 lesions were diagnosed with PCa. Patients with haemospermia and risk factors, that is aged over 40 years, a high PSA level or familial history of PCa, need a more thorough evaluation with mpMRI.

Can Extraprostatic Extension Be Predicted by Tumor-Capsule Contact Length in Prostate Cancer? Relationship With International Society of Urological Pathology Grade Groups.

OBJECTIVE. The objective of our study was to evaluate the relationship between the tumor-capsule contact length, defined as tumor contact length (TCL), and extraprostatic extension (EPE) using the MRI-based TCL measurements and the real TCL measurements from pathology and to determine whether the International Society of Urological Pathology (ISUP) grade group of the tumors influenced this relationship. MATERIALS AND METHODS. In this retrospective study, we reviewed prostate multiparametric MRI (mpMRI) studies performed between 2012 and 2018 of 1576 patients and found that 134 patients also underwent radical prostatectomy (RP) after mpMRI. Finally, 86 patients with index lesions in contact with the prostate capsule in RP specimens were enrolled in the study. ROC analysis was used to evaluate the cutoff values of TCLs measured at pathology and TCLs measured on MRI in terms of EPE according to ISUP grade groups. RESULTS. There was no statistically significant cutoff value for pathology-based TCL measurements in individual ISUP grade groups and subgroups. Although not statistically significant, pathology-based TCL cutoff values decreased (from 21.0 to 11.0 mm) as ISUP grade group increased in terms of EPE positivity. When the relationship between MRI-based TCL measurements and EPE was considered, statistically significant cutoff values (range, 14.5-16.6 mm) could be determined in many groups and subgroups with low ISUP grades (sensitivity, 66.7-100%; specificity, 52.8-93.0%; p = 0.006-0.042). However, no statistically significant cutoff value was found for high ISUP grades. CONCLUSION. ISUP grade groups may have an effect on the TCL-EPE relationship. When the MRI-based TCL and EPE relationship is evaluated independent of ISUP grade group, a cutoff value around 15-16 mm may be usable to predict EPE.

Pathologic Outcomes of Candidates for Active Surveillance Undergoing Radical Prostatectomy: Results from a Contemporary Turkish Patient Cohort.

INTRODUCTION: To evaluate the pathological outcomes of Turkish men meeting the criteria for Active Surveillance (AS), who elected to undergo immediate radical prostatectomy (RP). MATERIAL AND METHODS: Retrospective analysis including 1,212 patients with clinically localized prostate cancer (PCa) who met the eligibility criteria for AS. The primary outcomes were pathological upstaging and pathological upgrading. RESULTS: Nine hundred ninety-one patients were eligible for analysis after the central review of the submitted data. The mean prostate-specific antigen (PSA) level was 6.89 (0.51-15) ng/mL and the mean biopsy core number was 12 (8-47). The mean tumor positive core on final biopsy pathology was 1.95 (1-6) (16.6% [2.1-33.3%]). Overall, 30.6% of the men experienced a Gleason sum (GS) upgrade and 13.2% had pathological upstaging. For GS upgrade, the percentage of tumor-positive cores and free-to-total-PSA ratio were significant both in univariate analysis and multivariate logistic regression analysis. Variables predicting pathological upstaging were percentage of tumor-positive cores and PSA density, which were significant in univariate analysis. However, only PSA density was significant in multivariate logistic regression. Although biochemical recurrence-free survival was longer in patients without GS upgrade, it was not statistically significant between patients with and without any GS upgrade (mean 133.7 vs. 148.2 months, p = 0.243). A similar observation was made for patients with or without pathological upstaging (mean 117.1 vs. 148.3 months, p = 0.190). CONCLUSIONS: Upgrading and upstaging at RP are quite common among Turkish men with clinically low-risk PCa, who are candidates for AS, and a great majority of them experienced long-term PSA control.

Same Session Bilateral Ureteroscopy for Multiple Stones: Results from the CROES URS Global Study.

PURPOSE: This study presents a comparison of the international experience with ipsilateral and bilateral ureteroscopy for multiple, bilateral ureteral and renal stones vs single stone treatment. Patient and treatment characteristics and outcomes were compared. MATERIALS AND METHODS: The CROES (Clinical Research Office of the Endourological Society) Ureteroscopy Global Study includes 114 centers in 32 countries. Patients undergoing bilateral ureteroscopy, ipsilateral ureteroscopy for multiple stones and ureteroscopy for a single stone were examined from January 2010 to October 2012. Intraoperative characteristics and postoperative outcomes were identified for each patient. Inverse probability weighted regression adjustment analyses were done to compare outcomes independent of differences among centers and patient characteristics. RESULTS: The CROES Ureteroscopy Global Study consists of 11,885 patients. A total of 2,153 patients (18.7%) were treated for multiple stones, of whom 1,880 (87.3%) and 273 (12.7%) underwent ipsilateral and bilateral ureteroscopy, respectively. Inverse probability weighted regression adjustment models for bilateral vs ipsilateral ureteroscopy and multiple vs single stone treatments showed that patients with bilateral ureteroscopy and multiple stone treatments had lower stone-free rates, higher re-treatment rates and longer operative times compared to patients who underwent ipsilateral ureteroscopy and single stone treatment. There was no difference in complication rates among bilateral, ipsilateral and single stone ureteroscopy. CONCLUSIONS: This study presents a large series of patients who underwent bilateral and ipsilateral ureteroscopy. Our findings suggest a decrease in stone-free rates, increased re-treatment rates, increased operative times and longer hospital stay in patients treated for multiple stones. The treatment of multiple stones and bilateral ureteroscopy are safe compared to single stone treatment and ipsilateral ureteroscopy, respectively.

Prostate-specific membrane antigen-based imaging in prostate cancer: impact on clinical decision making process.

BACKGROUND: There is an ongoing need for an accurate imaging modality which can be used for staging purposes, metastatic evaluation, predicting biologic aggresiveness and investigating recurrent disease in prostate cancer. Prostate specific membrane antigen, given its favorable molecular characteristics, holds a promise as an ideal target for prostate cancer-specific nuclear imaging. In this study, we evaluated our initial results of PSMA based PET/CT imaging in prostate cancer. METHODS: A total of 22 patients with a median age and serum PSA level of 68 years and 4.15 ng/ml, respectively underwent Ga-68 PSMA PET/CT in our hospital between Februrary and August 2014. Their charts were retrospectively reviewed in order to document the clinical characteristics, the indications for and the results of PSMA based imaging and the impact of Ga-68 PSMA PET/CT findings on disease management. RESULTS: The most common indications were rising PSA after local ± adjuvant treatment followed by staging and metastatic evaluation before definitive or salvage treatment. All except 2 patients had prostatic ± extraprostatic PSMA positive lesions. For those who had a positive result; treatment strategies were tailored accordingly. Above the PSA level of 2 ng/ml, none of the PSMA based nuclear imaging studies revealed negative results. CONCLUSIONS: PSMA based nuclear imaging has significantly impacted our way of handling patients with prostate cancer. Its preliminary performance in different clinical scenarios and ability to detect lesions even in low PSA values seems fairly promising and deserves to be supplemented with further clinical studies.

GnRH agonist leuprolide acetate does not confer any protection against ovarian damage induced by chemotherapy and radiation in vitro.

STUDY QUESTION: Is there any in vitro evidence for or against ovarian protection by co-administration of a GnRH agonist with chemotherapy in human? SUMMARY ANSWER: The co-administration of GnRH agonist leuprolide acetate with cytotoxic chemotherapy agents does not preserve ovarian reserve in vitro. WHAT IS KNOWN ALREADY: Randomized controlled trials of the co-administration of gonadotrophin-releasing hormone (GnRH) agonists with adjuvant chemotherapy to preserve ovarian function have shown contradictory results. This fact, together with the lack of a proven molecular mechanism of action for ovarian protection with GnRH agonist (GnRHa) places this approach as a fertility preservation strategy under scrutiny. We therefore aimed in this study to provide in vitro evidence for or against the role of GnRHa in the prevention of chemotherapy-induced damage in human ovary. STUDY DESIGN, SETTINGS, SIZE AND DURATION: This translational research study of ex vivo and in vitro models of human ovary and granulosa cells was conducted in a university hospital between 2013 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian cortical pieces (n = 15, age 14-37) and mitotic non-luteinized (COV434 and HGrC1) and non-mitotic luteinized human granulosa cells (HLGC) expressing GnRH receptor were used for the experiments. The samples were treated with cyclophosphamide, cisplatin, paclitaxel, 5-FU, or TAC combination regimen (docetaxel, adriamycin and cyclophosphamide) with and without GnRHa leuprolide acetate for 24 h. DNA damage, apoptosis, follicle reserve, hormone markers of ovarian function and reserve (estradiol (E2), progesterone (P) and anti-mullerian hormone (AMH)) and the expression of anti-apoptotic genes (bcl-2, bcl-xL, bcl-2L2, Mcl-1, BIRC-2 and XIAP) were compared among control, chemotherapy and chemotherapy + GnRHa groups. MAIN RESULTS AND THE ROLE OF CHANCE: The greatest magnitude of cytotoxicity was observed in the samples treated with cyclophosphamide, cisplatin and TAC regimen. Exposure to these drugs resulted in DNA damage, apoptosis and massive follicle loss along with a concurrent decline in the steroidogenic activity of the samples. GnRHa co-administered with chemotherapy agents stimulated its receptors and raised intracellular cAMP levels. But it neither activated anti-apoptotic pathways nor prevented follicle loss, DNA damage and apoptosis induced by these drugs. LIMITATIONS, REASONS FOR CAUTION: Our findings do not conclusively rule out the possibility that GnRHa may offer protection, if any, through some other mechanisms in vivo. WIDER IMPLICATIONS OF THE FINDINGS: GnRH agonist treatment with chemotherapy does not prevent or ameliorate ovarian damage and follicle loss in vitro. These data can be useful when consulting a young patient who may wish to receive GnRH treatment with chemotherapy to protect her ovaries from chemotherapy-induced damage.

Determining the origin of synchronous multifocal bladder cancer by exome sequencing.

BACKGROUND: Synchronous multifocal tumours are commonly observed in urothelial carcinomas of the bladder. The origin of these physically independent tumours has been proposed to occur by either intraluminal migration (clonal) or spontaneous transformation of multiple cells by carcinogens (field effect). It is unclear which model is correct, with several studies supporting both hypotheses. A potential cause of this uncertainty may be the small number of genetic mutations previously used to quantify the relationship between these tumours. METHODS: To better understand the genetic lineage of these tumours we conducted exome sequencing of synchronous multifocal pTa urothelial bladder cancers at a high depth, using multiple samples from three patients. RESULTS: Phylogenetic analysis of high confidence single nucleotide variants (SNV) demonstrated that the sequenced multifocal bladder cancers arose from a clonal origin in all three patients (bootstrap value 100 %). Interestingly, in two patients the most common type of tumour-associated SNVs were cytosine mutations of TpC* dinucleotides (Fisher's exact test p < 10(-41)), likely caused by APOBEC-mediated deamination. Incorporating these results into our clonal model, we found that TpC* type mutations occurred 2-5× more often among SNVs on the ancestral branches than in the more recent private branches (p < 10(-4)) suggesting that TpC* mutations largely occurred early in the development of the tumour. CONCLUSIONS: These results demonstrate that synchronous multifocal bladder cancers frequently arise from a clonal origin. Our data also suggests that APOBEC-mediated mutations occur early in the development of the tumour and may be a driver of tumourigenesis in non-muscle invasive urothelial bladder cancer.

Improving testicular blood flow with electroacupuncture-like percutaneous nerve stimulation in an experimental rat model of testicular torsion.

INTRODUCTION: The purpose of this study was to determine the blood-flow-enhancing effect of electroacupuncture (EA) in an experimental rat model of testicular torsion. METHODS: At the first stage, 3D color Doppler ultrasound (3D-CDUS) scans were made to detect baseline perfusion of each testicle in 12 male albino Wistar rats. Then, the left testicles of all rats were twisted 180° clockwise, and 3D-CDUS recordings were repeated. In the next step, 10-Hz EA was applied for 5 min over the T13 and L4 dermatome territories in the study group of six rats. In the control group of six rats, acupuncture needles were inserted in the same manner, but EA was not applied. Baseline, posttorsion, and postintervention (EA and manual needling) 3D-CDUS perfusion recordings were interpreted as volumetric data, and group comparisons were performed. RESULTS: After EA, we observed statistically significant perfusion improvements in both the ipsilateral torsed and contralateral nontorsed testicles. In the control group, testicular perfusion did not show a significant change after manual needling. CONCLUSION: EA can improve testicular blood flow bilaterally in a rat model of unilateral testicular torsion at 180°.

Do we need to clamp the renal hilum liberally during the initial phase of the learning curve of robot-assisted nephron-sparing surgery?

OBJECTIVE: We aimed to compare the results of our initial robot-assisted nephron-sparing surgeries (RANSS) performed with or without hilar clamping. MATERIAL AND METHOD: Charts of the initial RANSSs (n = 44), which were performed by a single surgeon, were retrospectively reviewed. R.E.N.A.L. nephrometry system, modified Clavien classification, and M.D.R.D. equation were used to record tumoral complexity, complications, and estimated glomerular filtration rate (eGFR), respectively. Outcomes of the clamped (group 1, n = 14) versus off-clamp (group 2, n = 30) RANSSs were compared. RESULTS: The difference between the two groups was insignificant regarding mean patient age, mean tumor size, and mean R.E.N.A.L. nephrometry score. Mean operative time, mean estimated blood loss amount, and mean length of hospitalization were similar between groups. A total of 4 patients in each group suffered 11 Clavien grade ≥ 2 complications early postoperatively. Open conversion rates were similar. The difference between the 2 groups in terms of the mean postoperative change in eGFR was insignificant. We did not encounter any local recurrence after a mean follow-up of 18.9 months. CONCLUSIONS: Creating warm-ischemic conditions during RANSS should not be a liberal decision, even in the initial phases of the learning curve for a highly experienced open surgeon.

De-Escalation of Therapy for Prostate Cancer.

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men with around 1.4 million new cases every year. In patients with localized disease, management options include active surveillance (AS), radical prostatectomy (RP; with or without pelvic lymph node dissection), or radiotherapy to the prostate (with or without pelvic irradiation) with or without hormonotherapy. In advanced disease, treatment options include systemic treatment(s) and/or treatment to primary tumour and/or metastasis-directed therapies (MDTs). Specifically, in advanced stage, the current trend is earlier intensification of treatment such as dual or triple combination systemic treatments or adding treatment to primary and MDT to systemic treatment. However, earlier treatment intensification comes with the cost of increased morbidity and mortality resulting from drug-/treatment-related side effects. The main goal is and should be to provide the best possible care and oncologic outcomes with minimum possible side effects. This chapter will explore emerging possibilities to de-escalate treatment in PCa driven by enhanced insights into disease biology and the natural course of PCa such as AS in intermediate-risk disease or salvage versus adjuvant radiotherapy in post-RP patients. Considerations arising from advancements in PCa imaging and technological advancements in surgical and radiation therapy techniques including omitting pelvic lymph node dissection in the era of prostate-specific membrane antigen positron emitting tomography, the potential of MDT to delay/omit systemic treatment in metachronous oligorecurrence, and the efficacy of hypofractionation schemes compared with conventional fractionated radiotherapy will be discussed.