Intravascular hemolysis leads to exaggerated corpus cavernosum relaxation: Implication for priapism in sickle cell disease.

Patients with sickle cell disease (SCD) display priapism. Clinical studies have shown a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD. However, there are no experimental studies that show that intravascular hemolysis promotes alterations in erectile function. Therefore, we aimed to evaluate the corpus cavernosum smooth muscle relaxant function in a murine model that displays intravascular hemolysis induced by phenylhydrazine (PHZ), as well as the role of intravascular hemolysis in increasing the stress oxidative in the penis. Corpus cavernosum strips were dissected free and placed in organ baths. Acetylcholine and electrical field stimulation (EFS)-induced corpus cavernosum relaxations in vitro were obtained. Increased corpus cavernosum relaxant responses to acetylcholine and EFS were observed in the PHZ group. Protein expression of heme oxygenase-1 increased in the corpus cavernosum of the PHZ group, but PDE5 protein expression was not modified. Preincubation with the heme oxygenase inhibitor 1 J completely reversed the increased relaxant responses to acetylcholine and EFS in PHZ mice. Protein expression of NADPH oxidase subunit gp91phox, 3-nitrotyrosine, and 4-hydroxynonenal increased in the corpus cavernosum of the PHZ group, suggesting a state of oxidative stress. Basal cGMP production was lower in the PHZ group. Our results show that intravascular hemolysis promotes increased corpus cavernosum smooth muscle relaxation associated with increased HO-1 expression, as well as increased oxidative stress associated with upregulation of gp91phox expression. Moreover, our study supports clinical studies that point to a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD.

Serum and 24-hour urinary tests cost-effectiveness in stone formers.

OBJECTIVE: To assess the routine serum and 24-hour urine tests proficiency in diagnosing the baseline metabolic abnormality of kidney stone formers. METHODS: This study analyzes the routine serum and 24-hour urine tests proficiency in diagnosing the baseline metabolic abnormality of kidney stone formers. The sensitivity and specificity, false positive, and negative results of the tests are extracted from diagnostic kits used in the laboratories of the target community. To accurately infer the results, a simulation based on 1000 people was used through 22 standard laboratory tests (Additional File 2), including calcium, oxalate, phosphate, uric acid, sulfate, potassium, sodium, citrate, and magnesium in 24-hour urine; and calcium, creatinine, Vit D, uric acid, and intact parathyroid hormone (PTH) in serum. The incremental cost-effectiveness ratio (ICER) was calculated and compared for each diagnostic test versus other diagnostic tests according to the incremental cost required for correct diagnoses of stone causes. RESULTS: Urinary uric acid, citrate, and serum potassium constitute the cost-effectiveness boundary curve in this study. This means that other diagnostic tests are not cost-effective compared to these three tests in terms of indexing at least one item of cost and effectiveness. The ICER index for each correct diagnosis with the urinary uric acid test was $ 1.25 per diagnosis, the most cost-effective test compared to serum potassium and urinary citrate. CONCLUSION: The simplified blood and 24-hour urine metabolic evaluation, including urinary uric acid, citrate, and serum potassium, constitute the cost-effectiveness boundary curve. The most cost-effective test was urinary uric acid measurement.

Robotic approach to vesicourethral anastomotic stenosis and resection of remaining prostate after radical prostatectomy.

OBJECTIVE: To show a total transabdominal robotic approach to an extensive recalcitrant vesicourethral anastomotic stenosis (VUAS) after open radical prostatectomy (ORP) with end-to-end anastomosis. While there is very little literature on the matter and even fewer videos showing the actual surgical view with a step-by-step explanation in complex cases, VUAS robotic transabdominal surgery provides better view and reach, with potentially better continence results, without the need for pubectomy. METHODS: A 72-year-old male was submitted to a failed ORP for Gleason 3+4 localized cancer 2 years before, where the wrong plane of dissection left behind prostate remnants and the seminal vesicles, which evolved with a complex stenosis and recurrent episodes of acute urinary retention (AUR) that started two weeks after the first catheter removal. Five endoscopic procedures in total were unsuccessful and AUR reoccurred. A vesico-urethral cystography (VUC) and multiparametric prostate and urethral MRI found the seminal vesicles with prostate remnants, two centimeters urethral stenosis from bladder neck to bulbar urethra and periurethral fibrosis with no evidence of residual tumor. PSA was 1.2 and prostate biopsy showed no tumor on prostate remnant. A transabdominal robotic approach was chosen. RESULTS: Prostate residue, bladder neck and periurethral fibrosis were excised, with healthy mucosa found on both ends. End-to-end anastomosis was successful. Drain and catheter were removed on the 1st and 14th post-operative day, respectively, with good urinary stream. A VUC at 30 days showed a patent bladder neck. Incontinence was 3 pads/day after catheter removal and decreased to 1 pad/day after 180 days. CONCLUSION: VUAS may reach 15% (1, 2) and endourologic therapies are first-line choices, however, recalcitrant cases require reconstruction (3-6). The most common approach is perineal, with high incontinence rates, reaching >90% (7, 8). The retropubic alternative has better but also discouraging numbers of up to 58% incontinence rates (9). Though with 100% social continence results, the 2021 European guidelines still could not recommend the robotic procedure as standard of care due to evidence limited to anecdotal reports (10-12).

Validation of Visual Prostate Symptom Score (VPSS) in Brazilian Sample Population.

PURPOSE: The aim of the study was to evaluate the reliability and validity of the Visual Prostate Symptom Score (VPSS), its correlation with the International Prostate Symptom Score (IPSS), and the time required and need for help when completing the instrument. We also aimed to identify variables associated with difficulty completing these instruments. DESIGN: Longitudinal, prospective correlational study. SUBJECTS AND SETTING: The target population was Brazilian men from different cities within the state of São Paulo with lower urinary tract symptoms followed in urological consultation at a university hospital during October 2017. The sample comprised 59 patients with a mean age of 66.53 years. METHODS: Reliability of the VPSS was evaluated using a test-retest approach and its convergent validity with the IPSS. Cronbach α coefficient was also calculated. Both questionnaires were self-administered and, in case of difficulty of comprehension, assistance was provided. RESULTS: Mean completion time of the IPSS was 6.56 minutes and for VPSS was 5.02 minutes. The variables skin color and educational level were associated with the difficulty in completing the IPSS and for comprehending meaning of the VPSS pictograms. Internal consistency evaluated using Cronbach α coefficient was 0.74 for IPSS and 0.15 for VPSS, respectively. Test-retest reliability testing revealed that both instruments had a high intraclass correlation index (>0.75). There was a significant correlation between the health-related quality of life (QoL) scores of the 2 instruments (0.71, P = .0001) and between the total score of each instrument with its corresponding QoL score. CONCLUSION: Although time for response of the VPSS was shorter and it demonstrated good test-retest reliability, it more frequently required help to answer. The VPSS showed low internal consistency and low correlation with the IPSS (except for the QoL item).

Differentially expressed plasmatic microRNAs in Brazilian patients with Coronavirus disease 2019 (COVID-19): preliminary results.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is known that host microRNAs (miRNAs) can be modulated to favor viral infection or to protect the host. Herein, we report preliminary results of a study aiming at identifying differentially expressed plasmatic miRNAs in Brazilian patients with COVID-19. METHODS AND RESULTS: miRNAs were extracted from the plasma of eight patients with COVID-19 (four patients with mild COVID-19 and four patients with severe/critical COVID-19) and four healthy controls. Patients and controls were matched for sex and age. miRNA expression levels were detected using high-throughput sequencing. Differential miRNA expression and enrichment analyses were further evaluated. A total of 18 miRNAs were differentially expressed between patients with COVID-19 and controls. miR-4433b-5p, miR-6780b-3p, miR-6883-3p, miR-320b, miR-7111-3p, miR-4755-3p, miR-320c, and miR-6511a-3p were the most important miRNAs significantly involved in the PI3K/AKT, Wnt/ß-catenin, and STAT3 signaling pathways. Moreover, 42 miRNAs were differentially expressed between severe/critical and mild patients with COVID-19. miR-451a, miR-101-3p, miR-185-5p, miR-30d-5p, miR-25-3p, miR-342-3p, miR-30e-5p, miR-150-5p, miR-15b-5p, and miR-29c-3p were the most important miRNAs significantly involved in the Wnt/ß-catenin, NF-κß, and STAT3 signaling pathways. CONCLUSIONS: If validated by quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) in a larger number of participants, the miRNAs identified in this study might be used as possible biomarkers for the diagnosis and severity of COVID-19.

Covid-19 Automated Diagnosis and Risk Assessment through Metabolomics and Machine Learning.

COVID-19 is still placing a heavy health and financial burden worldwide. Impairment in patient screening and risk management plays a fundamental role on how governments and authorities are directing resources, planning reopening, as well as sanitary countermeasures, especially in regions where poverty is a major component in the equation. An efficient diagnostic method must be highly accurate, while having a cost-effective profile. We combined a machine learning-based algorithm with mass spectrometry to create an expeditious platform that discriminate COVID-19 in plasma samples within minutes, while also providing tools for risk assessment, to assist healthcare professionals in patient management and decision-making. A cross-sectional study enrolled 815 patients (442 COVID-19, 350 controls and 23 COVID-19 suspicious) from three Brazilian epicenters from April to July 2020. We were able to elect and identify 19 molecules related to the disease's pathophysiology and several discriminating features to patient's health-related outcomes. The method applied for COVID-19 diagnosis showed specificity >96% and sensitivity >83%, and specificity >80% and sensitivity >85% during risk assessment, both from blinded data. Our method introduced a new approach for COVID-19 screening, providing the indirect detection of infection through metabolites and contextualizing the findings with the disease's pathophysiology. The pairwise analysis of biomarkers brought robustness to the model developed using machine learning algorithms, transforming this screening approach in a tool with great potential for real-world application.

Immunonutrition hope? Oral nutritional supplement on cancer treatment.

OBJECTIVES: To determine the efficacy and safety of antitumoral nutritional supplement (Oncoxin® ), and to describe its mechanism of action. METHODS: Scoping review according to the recommendations of the Joanna Briggs Institute included patients older than 18 years who have any kind of tumour and receive Oncoxin® as a supplement regarding the efficacy in terms of antitumoral properties, quality of life and survival, safety in terms of adverse events, and the mechanism of action. With no limit for language or setting, MEDLINE (Pubmed), EMBASE (Scopus), LILACS and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched from database inception to May 2021. FINDINGS: A promising increment of survival and quality of life in terms of Karnofsky and EORTC scales. Regarding the mechanism of action, studies suggest that it modifies inflammatory mediators' expression, as evidenced by the reduction of COX-2, IL-1ß, IL-6, TNF-α, IL-1ß, IL-12 and IFN-γ. Besides, it promotes an arrest in the progression of cells from G1 into S, along with an increase in p27 and a decrease in cyclin D1 and pRb. It decreases the levels of pro-inflammatory cytokines, it can also decrease cytokines with antitumor activity such as IFN-γ, which should be further explored in larger trials and the long term. INTERPRETATIONS AND IMPLICATIONS: Current literature shows promising complementary effects of oral supplements to the standard treatment of cancer patients in diverse scenarios. It might help patients to deal with toxicities and adverse effects related to cancer treatment and improve their nutritional or clinical profiles.

T cells CD4+/CD8+ local immune modulation by prostate cancer hemi-cryoablation.

PURPOSE: Tumors escape from the immune system by decreasing CD8+ and increasing CD4+ T cells' activity, druggable targets. Thermal ablation might activate tumor-specific T cells by raising the presentation of tumor-specific antigens and hindering tumor negative immune regulation. Our aim was to assess T cell infiltrate pre- and post-cryoablation in a prospective observational study. METHODS: A total of 240 sextant prostate biopsies cores (12 cores/patient) were collected from 10 unilateral prostate cancer patients (T1c, PSA density < 0.15 ng/dL, Gleason grade group 1, ≤ 2 cancer biopsy cores, and < 50% cancer core involvement) at diagnosis and 12 months after hemi-cryoablation. Cancer-positive (Diag+) and cancer-negative (Diag-) lobes at diagnosis and the same areas 12 months after hemi-cryoablation (Cryo+ and Cryo-, respectively) were explored by immunohistochemistry for infiltrating CD4+ and CD8+ T cells (in 45 random fields per prostate lobe, 400× magnification). The quantitative analysis of cells/mm2 and CD4+/CD8+ ratio were performed and compared among Diag+, Diag-, Cryo+, and Cryo- using ImageJ software. RESULTS: There was a significant increase in tumor-infiltrating CD8+ T cells/mm2 in the Cryo+ tissue (mean, SD 0.31, 0.30) compared to Diag+ (0.18, 0.15), p = 0.015; confirmed in prostate acini (hot spots), p = 0.029, in which infiltrating CD4+/CD8+ T cells' ratio decreased after hemi-cryoablation, p = 0.006. Infiltrating CD4+ T cells/mm2 presented a trend to decrease in Cryo+ (0.26, 0.27) compared to Diag+ (0.38, 0.32). CONCLUSIONS: This is the first study to show local immune modulation after prostate cancer cryoablation, characterized by decreasing CD4+/CD8+ T cells' ratio, potential for clinical impact by unleashing the T-cell response to cancer. Future studies are necessary to explore different energies and longer follow-up clinical endpoints.

Mutations in CDKN2A and the FGFR3 genes on bladder cancer diagnosis: a systematic review and meta-analysis.

PURPOSE: To determine the association between mutations in CDKN2A and FGFR3 genes and the diagnosis of bladder carcinoma (BCa). METHODS: A systematic search strategy was carried out through MEDLINE, EMBASE, LILACS, CENTRAL and unpublished literature. We included RCTs, cohort, case-control and cross-sectional studies that involved patients > 18-year-old assessing the association between CDKN2A and FGFR3 mutated genes and BCa. The primary outcome was bladder cancer defined by histology of the sample. We assessed the risk of bias with QUADAS2 and performed a meta-analysis with Review Manager v5.3. RESULTS: We found 97 records with the search strategies. After duplicates were removed, six studies were included in meta-analysis. Regarding the association between mutated FGFR3 and bladder cancer, we found an OR 31 95% CI (15-64). However, there was no association for CDKN2A and BCa. CONCLUSION: There is a strong association between FGFR3 mutated gene and the diagnosis of bladder cancer, which has not been observed with CDKN2A. Such a result supports FGFR3 mutated gene as a promissory bladder cancer screening and monitoring biomarker.

Are 10-, 10-12-, or > 12-mm prostate biopsy core quality control cutoffs reasonable?

PURPOSE: To explore the role of prostate biopsy core length on prediction of index tumor clinical significance and localization on radical prostatectomy (RP) and time to recurrence, hypothesizing 10-, 10-12-, or > 12-mm minimum core as potential biopsy quality control. METHODS: Assessed 2424 prostate biopsy cores and corresponding RP of 202 patients submitted to the first set of 12 cores prostate biopsy between 2010 and 2015. Analyzed biopsy core length, age, prostate volume (PV), free and total PSA ratio, PSA density, RP index tumor clinical significance, extension, localization, surgical margins, and cancer control. Prostate biopsy confronted to surgical specimens defined Gleason grade-grouping system (1-5) agreement. RESULTS: Median age was 63.7 years, PSA 10.1 ng/dl, PSA density 28%, and mean follow-up 5 years. Recurrence was identified in 64 (31.7%) patients and predicted by PSA > 10 at time of diagnosis (p = 0.008), seminal vesicle invasion (p = 0.0019), core tumor percentage (p = 0.033), and tumor localization predominantly in the prostate base (p = 0017). The mean core length was longer in index tumor positive cores (p = 0.043) and in tumors classified as clinically insignificant (p = 0.011), without impact on tumor localization (basal vs apical p = 0.592; left vs. right p = 0.320). Biopsy core length categories (≤ 10, 10-12 and > 12 mm) did not significantly impact Gleason grade-grouping agreement or time to recurrence (p > 0.05). Core length was not significantly different in all Gleason grade-groupings 1-5 (p = 0.312). CONCLUSION: Prostate biopsy core length impacts tumor characterization; however, 10 mm minimum core length and even 10-12- and > 12-mm categories failed as a biopsy quality control in our data.

Pelvic floor muscle training and electrical stimulation as rehabilitation after radical prostatectomy: a randomized controlled trial.

[Purpose] To investigate the effect of electrical stimulation and pelvic floor muscle training on muscle strength, urinary incontinence and erectile function in men with prostate cancer treated by radical prostatectomy. [Subjects and Methods] One hundred twenty-three males were randomized into 3 groups 1 month after RP: (G1, n=40) control; (G2, n=41) guideline: patients were instructed to perform three types of home exercises to strengthen the pelvic floor and (G3, n=42) electrical stimulation: patients in this group were also instructed to perform exercises as group G2, and also received anal electro-stimulation therapy, twice a week for 7 weeks. The primary outcome assessment was based on the measurement of the recovery of pelvic floor muscle strength between groups. Secondary outcomes were: 1 hour Pad Test, ICIQ-SF, IIEF-5 and IPSS. Data were obtained preoperatively and at 1, 3 and 6 months after surgery. [Results] There was no significant difference in the demographic data among groups. Greater urinary leakage and pelvic floor muscle weakness in the first month compared to pre treatment improved after 3 and 6 months postoperative, without difference among groups. [Conclusion] The muscle strength recovery occurs independently of the therapy employed. Pelvic floor exercises or electrical stimulation also did not have an impact on the recovery of urinary continence and erectile function in our study.

Predictors of Nutritional Risk According to NRS-2002 and Calf Circumference in Hospitalized Older Adults with Neoplasms.

OBJECTIVES: To investigate nutritional markers that better predict nutritional risk according to the Nutritional Risk Screening (NRS-2002), to verify agreement between indicators, and to identify the calf circumference cut-off point for diagnosing nutritional risk. METHODS: Cross-sectional study with older patients hospitalized for neoplasms. The nutritional risk was assessed by NRS-2002 and the nutritional status by Subjective Global Assessment (SGA), Mini-Nutritional Assessment (MNA long form), calf circumference (CC), and body mass index (BMI). Statistical analyses included the chi-square and Mann-Whitney tests, Kappa coefficient, univariate and multiple logistic regression analyses to analyze the risk factors, and the receiver operator characteristic (ROC) curve to determine the cut-off point. RESULTS: The NRS-2002 and MNA had good agreement (k = 0.5281), but the NRS-2002 did not agree with the other nutritional indicators. According to regression analysis, the predictors of nutritional risk were the MNA (p = 0.0010, OR = 28.270); BMI (p = 0.0419, OR = 4.681), and age (p = 0.0021, OR = 1.309). The best CC cut-off point for predicting nutritional risk according to the NRS-2002 was ≤32.25 cm. CONCLUSION: Both the NRS-2002 and MNA are useful for the nutritional diagnosis of older adults hospitalized for neoplasms. When the MNA, BMI, and age are used together, they can better predict nutritional risk according to the NRS-2002.

Are we following the guidelines on non-muscle invasive bladder cancer?

OBJECTIVE: To evaluate the clinical practice of non-muscle invasive bladder cancer (NMIBC) treatment in Brazil in relation to international guidelines: Sociedade Brasileira de Urologia (SBU), European Association of Urology (EAU) and American Urological Association (AUA). METHODS: Cross-sectional study using questionnaires about urological practice on treatment of NMIBC during the 32nd Brazilian Congress of Urology. A total of 650 question forms were answered. RESULTS: There were 73% of complete answers (total of 476 question forms). In total, 246 urologists (51.68%) lived in the southeast region and 310 (65.13%) treat 1 to 3 cases of NMIBC per month. Low risk cancer: Only 35 urologists (7.5%) apply the single intravesical dose of immediate chemotherapy with Mitomicin C recommended by the above guidelines. Adjuvant therapy with BCG 2 to 4 weeks after TUR is used by 167 participants (35.1%) and 271 urologists (56.9%) use only TUR. High risk tumors: 397 urologists (83.4%) use adjuvant therapy, 375 (78.8%) use BCG 2 to 4 weeks after TUR, of which 306 (64.3%) referred the use for at least one year. Intravesical chemotherapy with Mitomicin C (a controversial recommendation) was used by 22 urologists (4.6%). BCG dose raised a lot of discrepancies. Induction doses of 40, 80 and 120mg were referred by 105 (22%), 193 (40.4%) and 54 (11.3%) respectively. Maintenance doses of 40, 80 and 120mg were referred by 190 (48.7%), 144 (37.0%) and 32 (8.2%) urologists, respectively. Schemes of administration were also varied and the one cited by SWOG protocol was the most used: 142 (29.8%). CONCLUSIONS: SBU, EAU and AUA guidelines are partially respected by Brazilian urologists, particularly in low risk tumors. In high risk tumors, concordance rates are comparable to international data. Further studies are necessary to fully understand the reasons of such disagreement.

Safety and feasibility of radiofrequency ablation for treatment of Bosniak IV renal cysts.

PURPOSE: To describe our initial experience with radiofrequency ablation (RFA) of Bosniak IV renal cysts. MATERIALS AND METHODS: From 2010 to 2014, 154 renal tumor cases were treated with percutaneous thermal ablation, of which 10 cases (6.4%) from nine patients were complex renal cysts and were treated with radiofrequency ablation. RESULTS: All complex cysts were classified as Bosniak IV (four women and five men; mean age: 63.6 yrs, range: 33-83 years). One patient had a single kidney. Lesion size ranged from 1.5 to 4.1cm (mean: 2.5cm) and biopsy was performed on four cysts immediately before the procedure, all of which were malignant (two clear cell and two papillary carcinoma). Mean volume reduction of complex cysts was 25% (range: 10-40%). No patients required retreatment with RFA and no immediate or late complications were observed. The follow-up of Bosniak IV cysts had a median of 27 months (interquartile range [IQR], 23 to 38) and no recurrence or significant loss of renal function were observed. CONCLUSIONS: Mid-term follow-up of the cases in our database suggests that image-guided percutaneous RFA can treat Bosniak IV cysts with very low complication rates and satisfactorily maintain renal function.

Urothelial carcinogen resistance driven by stronger Toll-like receptor 2 (TLR2) and Uroplakin III (UP III) defense mechanisms: a new model.

OBJECTIVE: The objective of the study was to illustrate the applicability and significance of the novel Lewis urothelial cancer model compared to the classic Fisher 344. METHODS: Fischer 344 and Lewis females rats, 7 weeks old, were intravesical instilled N-methyl-N-nitrosourea 1.5 mg/kg every other week for a total of four doses. After 15 weeks, animals were sacrificed and bladders analyzed: histopathology (tumor grade and stage), immunohistochemistry (apoptotic and proliferative indices) and blotting (Toll-like receptor 2-TLR2, Uroplakin III-UP III and C-Myc). Control groups received placebo. RESULTS: There were macroscopic neoplastic lesions in 20 % of Lewis strain and 70 % of Fischer 344 strain. Lewis showed hyperplasia in 50 % of animals, normal bladders in 50 %. All Fischer 344 had lesions, 20 % papillary hyperplasia, 30 % dysplasia, 40 % neoplasia and 10 % squamous metaplasia. Proliferative and apoptotic indices were significantly lower in the Lewis strain (p < 0.01). The TLR2 and UP III protein levels were significantly higher in Lewis compared to Fischer 344 strain (70.8 and 46.5 % vs. 49.5 and 16.9 %, respectively). In contrast, C-Myc protein levels were significantly higher in Fischer 344 (22.5 %) compared to Lewis strain (13.7 %). CONCLUSIONS: The innovative Lewis carcinogen resistance urothelial model represents a new strategy for translational research. Preservation of TLR2 and UP III defense mechanisms might drive diverse urothelial phenotypes during carcinogenesis in differently susceptible individuals.