Urinary miRNAs Predict Metastasis in Patients With Clinically Localized Clear Cell Renal Cell Carcinoma Treated With Nephrectomy.

PURPOSE: Patients with clear cell renal cell carcinoma (ccRCC) might develop metastasis after surgery with curative intent. We aimed to characterize the expression levels of microRNAs in the urine (UmiRNAs) of patients before and after nephrectomy to determine the impact of UmiRNAs expression in the emergence of metastases. METHODS: We prospectively collected pre- and post-nephrectomy urine samples from 117 patients with clinically localized and locally advanced ccRCC. UmiRNAs were extracted, purified, and measured using RT-PCR. Relative quantifications (RQ) of 137 UmiRNAs were calculated through 2-∆∆ method. The post-surgery/pre-surgery RQs ratio represented the magnitude of the expression levels of the UmiRNAs. The association of UmiRNA expression and the development of distant metastases was tested with Cox regression model. RESULTS: Five UmiRNAs (miR-191-5p, miR-324-3p, miR-186-5p, miR-93-5p, miR-30b-5p) levels were upregulated before nephrectomy (p < .05). This conferred a 2- to 4-fold increased risk of metastasis, with miR-191-5p showing the most significant association with this endpoint (HR = 4.16, 95% CI = 1.38-12.58, p = .011). In a multivariate model stratified with stage and Fuhrman grade, we found that miR-191-5p, miR-324-3p, and miR-186-5p exhibited a strong association with metastasis development in patients with pathological T3 (pT3) tumors. Enrichment analysis with the most differentially expressed UmiRNAs showed that these UmiRNAs targeted genes that regulate cell survival and proliferation. CONCLUSION: Our study indicated UmiR-191-5p, UmiR-324-3p, and UmiR-186-5p are potential markers to predict the development of metastasis, particularly in pT3 patients. PATIENT SUMMARY: We compared changes of UmiRNAs expression detected pre- and postnephrectomy of patients with ccRCC. Our findings suggest that UmiRNA expression likely reflects tumor-specific changes that can be promising to predict the metastasis development, particularly in patients with non-metastatic locally advanced ccRCC. If confirmed, these findings may be useful for surveillance protocols for adjuvant therapy protocols.

Immunotherapy in Penile Squamous Cell Carcinoma: Present or Future? Multi-Target Analysis of Programmed Cell Death Ligand 1 Expression and Microsatellite Instability.

Background: Penile cancer (PC) is an extremely rare malignancy, and the patients at advanced stages have currently limited treatment options with disappointing results. Immune checkpoint inhibitors anti-programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) are currently changing the treatment of several tumors. Furthermore, the microsatellite instability (MSI) and the deficient mismatch repair system (dMMR) proteins represent predictive biomarkers for response to immune checkpoint therapy. Until present, few data have been reported related to PD-L1 expression and MSI in PC. The main aim of our study was the evaluation of PD-L1 expression in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) in immune cells and the analysis of dMMR/MSI status in a large series of PCs. Methods: A series of 72 PC, including 65 usual squamous cell carcinoma (USCC), 1 verrucous, 4 basaloid, 1 warty, and 1 mixed (warty-basaloid), was collected. Immunohistochemistry (IHC) was performed to assess PD-L1 expression using two different anti-PD-L1 antibodies (clone SP263 and SP142 Ventana) and MMR proteins expression using anti-MLH1, anti-PMS2, anti-MSH2, and anti-MSH6 antibodies. PCR analysis was performed for the detection of MSI status. Results: Of the 72 PC cases analyzed by IHC, 45 (62.5%) cases were TC positive and 57 (79%) cases were combined positive score (CPS) using PDL1 SP263. In our cohort, TILs were present in 62 out of 72 cases (86.1%), 47 (75.8%) out of 62 cases showed positivity to PDL1 clone SP142. In our series, 59 cases (82%) had pMMR, 12 cases (16.7%) had lo-paMMR, and only 1 case (1.3%) had MMR. PCR results showed that only one case lo-paMMR was MSI-H, and the case dMMR by IHC not confirmed MSI status. Conclusion: Our findings showed that PD-L1 expression and MSI status represent frequent biological events in this tumor suggesting a rationale for a new frontier in the treatment of patients with PC based on the immune checkpoint inhibitors.

Discrepancy of p16 immunohistochemical expression and HPV RNA in penile cancer. A multiplex in situ hybridization/immunohistochemistry approach study.

BACKGROUND: The high-risk human papillomavirus (HPV) infection represents one of the main etiologic pathways of penile carcinogenesis in approximately 30-50 % of cases. Several techniques for the detection of HPV are currently available including Polymerase chain reaction-based techniques, DNA and RNA in situ hybridization (ISH), p16 immunohistochemistry (IHC). The multiplex HPV RNA ISH/p16 IHC is a novel technique for the simultaneous detection of HPV E6/E7 transcripts and p16INK4a overexpression on the same slide in a single assay. The main aim of this study was to evaluate the discrepancy of p16 IHC expression relatively to HPV RNA ISH in penile cancer tissue. METHODS: We collected a series of 60 PCs. HPV has been analysed through the RNA ISH, p16 IHC and the multiplex HPV RNA ISH/p16 IHC. RESULTS: The multiplex HPV RNA ISH /p16 IHC results in the series were in complete agreement with the previous results obtained through the classic p16 IHC and HPV RNA scope carried out on two different slides. The multiplex HPV RNA ISH /p16 IHC showed that HPV positivity in our series is more frequently in usual squamous cell carcinoma than in special histotypes (19 out of 60 - 15 %- versus 6 out of 60 - 10 %-), in high-grade than in moderate/low grade carcinomas (6 out of 60 - 10 %- versus 4 out of 60 - 6.7 %-). In addition, our data revealed that in 5 out of 20 cases with p16 high intensity expression is not associated with HPV RNA ISH positivity. CONCLUSIONS: Our findings emphasize that the use of p16 as a surrogate of HPV positivity was unsuccessful in approximatively 8 % of cases analysed in our series. Indeed, p16 IHC showed a sensitivity of 100 % and a specificity of 71 %, with a positive predictive value (PPV) of 54 % and a negative predictive value of 100 %; when considering high intensity, p16 IHC showed a sensitivity of 100 %, a specificity of 89 %, with a PPV of 75 % and NPV of 100 %. Since HPV positivity could represent a relevant prognostic and predictive value, the correct characterization offered by this approach appears to be of paramount importance.

Management of Patients with Advanced Prostate Cancer: The Report of the Advanced Prostate Cancer Consensus Conference APCCC 2017.

BACKGROUND: In advanced prostate cancer (APC), successful drug development as well as advances in imaging and molecular characterisation have resulted in multiple areas where there is lack of evidence or low level of evidence. The Advanced Prostate Cancer Consensus Conference (APCCC) 2017 addressed some of these topics. OBJECTIVE: To present the report of APCCC 2017. DESIGN, SETTING, AND PARTICIPANTS: Ten important areas of controversy in APC management were identified: high-risk localised and locally advanced prostate cancer; "oligometastatic" prostate cancer; castration-naïve and castration-resistant prostate cancer; the role of imaging in APC; osteoclast-targeted therapy; molecular characterisation of blood and tissue; genetic counselling/testing; side effects of systemic treatment(s); global access to prostate cancer drugs. A panel of 60 international prostate cancer experts developed the program and the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The panel voted publicly but anonymously on 150 predefined questions, which have been developed following a modified Delphi process. RESULTS AND LIMITATIONS: Voting is based on panellist opinion, and thus is not based on a standard literature review or meta-analysis. The outcomes of the voting had varying degrees of support, as reflected in the wording of this article, as well as in the detailed voting results recorded in Supplementary data. CONCLUSIONS: The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available, including disease extent and location, prior therapies regardless of type, host factors including comorbidities, as well as patient preferences, current and emerging evidence, and logistical and economic constraints. Inclusion of men with APC in clinical trials should be strongly encouraged. Importantly, APCCC 2017 again identified important areas in need of trials specifically designed to address them. PATIENT SUMMARY: The second Advanced Prostate Cancer Consensus Conference APCCC 2017 did provide a forum for discussion and debates on current treatment options for men with advanced prostate cancer. The aim of the conference is to bring the expertise of world experts to care givers around the world who see less patients with prostate cancer. The conference concluded with a discussion and voting of the expert panel on predefined consensus questions, targeting areas of primary clinical relevance. The results of these expert opinion votes are embedded in the clinical context of current treatment of men with advanced prostate cancer and provide a practical guide to clinicians to assist in the discussions with men with prostate cancer as part of a shared and multidisciplinary decision-making process.

Minimally Complex Renal Cysts: Outcomes and Ultrasound Evaluation Compared with Contrast-Enhanced Cross-Sectional Imaging Bosniak Classification.

We correlated contrast-enhanced cross-sectional imaging and outcomes to assess the reproducibility of ultrasonographic criteria for renal minimally complex (MC) cysts. From 2003 to 2015, 143 cysts were described as complex or MC by ultrasound (US). After exclusions, 98 US studies were retrospectively evaluated and compared with computed tomography (CT)/magnetic resonance imaging (MRI). At sonography, 51 were MC cysts and 47 were complexes according to two independent observers. Inter-observer agreement for US was 0.704 and 0.745 for CT/MRI. Of 51 cysts classified as MC by US, 38 were Bosniak I/II and 6 were Bosniak IIF by CT/MRI. In 7, there were no cross-sectional images; however, they were stable for at least 2 y. Of 47 complex cysts, 9 were Bosniak II, 22 Bosniak IIF, 8 Bosniak III and 8 Bosniak IV. No Bosniak III/IV cysts by CT/MRI were classified as MC by US. Our results indicate that US offers reproducible criteria for MC cysts and may be used alone for these lesions.

Efficacy and Safety of Combined Androgen Deprivation Therapy (ADT) and Docetaxel Compared with ADT Alone for Metastatic Hormone-Naive Prostate Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVE: Prostate cancer is the most common nonskin cancer and second most common cause of cancer mortality in older men in the United States (USA) and Western Europe. Androgen-deprivation therapy alone (ADT) remains the first line of treatment in most cases, for metastatic disease. We performed a systematic review and meta-analysis of all randomized controlled trials (RCT) that compared the efficacy and adverse events profile of a chemohormonal therapy (ADT ± docetaxel) for metastatic hormone-naive prostate cancer (mHNPC). METHODS: Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoint was overall survival. Data extracted from the studies were combined by using the hazard ratio (HR) or risk ratio (RR) with their corresponding 95% confidence intervals (95% CI). RESULTS: The final analysis included 3 trials comprising 2,264 patients (mHNPC). Patients who received the chemohormonal therapy had a longer clinical progression-free survival interval (HR = 0.64; 95% CI: 0.55 to 0.75; p<0.00001), and no heterogeneity (Chi2 = 0.64; df = 1 [p = 0.42]; I2 = 0%). The biochemical progression-free survival (bPFS) also was higher in patients treated with ADT plus docetaxel (HR = 0.63; 95% CI: 0.57 to 0.69; p<0.00001), also with no heterogeneity noted (Chi2 = 0.48; df = 2 [p = 0.79]; I2 = 0%). Finally, the combination of ADT with docetaxel showed a superior overall survival (OS) compared with ADT alone (HR = 0.73; 95% CI: 0.64 to 0.84; p<0.0001), with moderate heterogeneity (Chi2 = 3.84; df = 2 [p = 0.15]; I2 = 48%). A random-effects model analysis was performed, and the results remained favorable to the use of ADT plus docetaxel (HR = 0.73; 95% CI: 0.60 to 0.89; p = 0.002). In the final combined analysis of the high-volume disease patients, the use of the combination therapy also favored an increased overall survival (HR = 0.67; 95% CI: 0.54 to 0.83; p = 0.0003). Regarding adverse events and severe toxicity (grade ≥3), the group receiving the combined therapy had higher rates of neutropenia, febrile neutropenia and fatigue. CONCLUSION: The combination of ADT with docetaxel improved the clinical progression-free survival, bPFS and OS of patients with mHNPC. A superior OS was seen especially for patients with metastatic and high-volume disease. This contemporary combination therapy may now be offered as a first-line treatment for selected patients.

Urolitíase no alotransplante renal

Purpose: Urinary lithiasis is an uncommon complication in recipient of kidney allografts. The prevalence varies from 0.02 to 3.4%. The majority of calculi arises de novo in the recipient, however some of them are transferred with the transplanted kidney. The treatment relies on few reports published previously. The aim of the study is to determine the prevalence of lithiasis as well as the treatment in an university hospital. METHODS: We analyzed 953 recipients of renal transplant undertaken in Hospital das Clínicas - FMRP-USP, from February of 1968 to May of 2003. The mean age of patients bearing lithiasis was 47.2 years (range 35 to 63 years). RESULTS: The prevalence of lithiasis was 10/953 (1.0%). Nine patients received kidneys from cadaver donor and 1 from living donor. The diagnosis occurred during the surgery in 2 (20%), within few days after transplantation in 1 (10%) and in the late postoperative period in 7 (70%). Seven patients had no complains, 2 had associated urinary tract infection and 1 a rise in serum creatinine. Of 8 cases with lithiasis in the postoperative period, the stones were localized in the kidney in 6 and in the ureter in 2. Renal calculi were managed as follows: watchful-waiting - 2, extracorporeal lithotrypsy - 2, percutaneous nepholithotrypsy - 1 and open pyelolithomy - 1. One patient with ureteric lithiasis associated ureteral stenosis underwent a pyelo-vesicostomy. The other patient with ureteric lithiasis was treated by retrograde endoscopic ureterolithothrypsy. CONCLUSION: Urinary lithiasis is rare in transplanted kidneys and can be managed as to the general population.

OBJETIVO: A litíase urinária é uma complicação incomum no alotransplante renal, a incidência varia de 0,02 a 3,4%. A maioria dos cálculos forma-se após o transplante, porém alguns podem ser transferidos junto com o enxerto para o hospedeiro. O tratamento desta complicação está baseado em alguns casos descritos na literatura. O objetivo deste trabalho é o de relatar a incidência da litíase renal no paciente com transplante renal, assim como a conduta adotada no HCFMRPUSP. MÉTODOS: Foram analisados 953 pacientes submetidos a transplante renal no HCFMRPUSP, de fevereiro 1968 a maio de 2003. A idade média foi de 47,2 anos (35 a 63 anos). Em 09 pacientes, o rim foi proveniente de doador cadáver e apenas 01 doador vivo. RESULTADOS:Foram diagnosticados 10 casos de litíase (1,05%). Em 02 pacientes (20%) o cálculo foi diagnosticado no intraoperatório, em 01 (10%) no peri-operatório (5º. dia), os 07 restantes (70%) no pós-operatório tardio. Em 04 pacientes (57%) não havia sintomatologia específica, 02 (29%) apresentaram ITU, em 03 (43%) ocorreu elevação da creatinina sérica. De 8 pacientes com litíase no pós-operatorio, em 06 os cálculos estavam localizados no rim e 02 no ureter. Dos pacientes com cálculos renais, 02 foram observados, 02 submetidos a LECO, 01 a nefrolitripsia percutânea, 01 à pielolitotomia. Em 01 paciente com cálculo ureteral foi realizada pielovesicostomia (cálculo + estenose), no outro paciente foi feita a ureterorrenoscopia retrógrada. CONCLUSÃO: A urolitíase é complicação rara no transplante renal, a conduta terapêutica no pós-operatório tardio é semelhante à da população geral.

Incontinência urinária no idoso

The prevalence of urinary incontinence in the elderly varies from 8 to 34% according to the criteria or method of investigation. The etiology or main associated factors are: aging tissular degeneration that compromise the lower urinary tract and pelvic floor, changes of peripheric and central nervous system, hormonal alterations such as menopause, nocturnal polyuria, benign prostate hyperplasia, concomitant diseases and side effects of medical drugs. The incontinence may be transitory or permanent. Besides a criterious medical history for a better characterization of the urinary loss, a search for associated or concomitant causes and the miccional diary, one oftenly may rely on specialized exams such as urodynamics. A specific diagnosis is of utmost value for correct management that may require only conservative measures based on changes of behaviour or counceiling, drugs prescription, or invasive methods including surgical procedures.

A prevalência da incontinência urinária no idoso varia de 8 a 34% segundo o critério ou método de avaliação. A principais causas são: alterações teciduais da senilidade que comprometem o trato urinário inferior e o assoalho pélvico, do sistema nervoso central e periférico, alterações hormonais como a menopausa, poliúria noturna, alterações psicológicas, hiperplasia prostática benigna, doenças concomitantes e efeitos colaterais de medicamentos. A incontinência pode ser transitória ou permanente. Além da anamnese cuidadosa para caracterização das perdas urinárias, a busca de causas associadas ou concomitantes e o diário miccional, recorre-se com freqüência a exames especializados como a urodinâmica. O diagnóstico preciso é importante para o manejo adequado que pode requerer apenas medidas conservadoras baseadas em orientações e mudanças de hábitos, como o uso de medicamentos, ou então métodos invasivos que incluem procedimentos cirúrgicos específicos.

Performance of PSA and of PSA density in the diagnosis of prostate carcinoma

OBJECTIVE: The aim of the study was to investigate the influence of the prostate volume and PSA density on the performance of total PSA to diagnosis of prostate carcinoma. METHODS: We analyzed 217 patients (PSA 0-10ng/ml) submitted to transrectal sextant prostate biopsy. Criteria for biopsy indication was PSA >2ng/ml and/or digital rectal exam suspicious of prostate cancer. RESULTS: Fifty five patients had prostate neoplasia (25.3%) and in 8/55 (25.3%) the serum PSA was under 4ng/ml. The sensitivity and specificity of the test were respectively 98.2% / 16.6% at a cut-off point of 2.5ng/ml and 85.4% / 38.8% at cut-off of 4ng/ml. The corresponding values for prostates >40ml or 40ml were: 96.2% / 8.1% and 100% / 27.2% at the cut-off point of 2.5ng/ml, and 92.5% / 20% and 78.5% / 62.3% at a cut-off level of 4ng/ml. For prostates 40ml a PSA cut-off point of 4ng/ml leads to a misdiagnosis in 21.4% of the malignant tumors. The median PSAD of benign prostates are different according to prostate volume (.40ml or 40ml). PSAD at cut-off of 0.08 increases the PSA specificity at both PSA cut-off points. CONCLUSIONS: Prostate volume affects the sensitivity and specificity of PSA and the median values of PSAD. PSAD of 0.08 increases the PSA specificity specially at a cut-off point of 2.5ng/ml in prostates smaller than 40ml.