Extended Versus Limited Pelvic Lymph Node Dissection During Radical Prostatectomy for Intermediate- and High-risk Prostate Cancer: Early Oncological Outcomes from a Randomized Phase 3 Trial.

BACKGROUND: The role of extended pelvic lymph node dissection (EPLND) in the surgical management of prostate cancer (PCa) patients remains controversial, mainly because of a lack of randomized controlled trials (RCTs). OBJECTIVE: To determine whether EPLND has better oncological outcomes than limited PLND (LPLND. DESIGN, SETTING AND PARTICIPANTS: This was a prospective, single-center phase 3 trial in patients with intermediate- or high-risk clinically localized PCa. INTERVENTION: Randomization (1:1) to LPLND (obturator nodes) or EPLND (obturator, external iliac, internal iliac, common iliac, and presacral nodes) bilaterally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was biochemical recurrence-free survival (BRFS). Secondary outcomes were metastasis-free survival (MFS), cancer-specific survival (CSS), and histopathological findings. The trial was designed to show a minimal 15% advantage in 5-yr BRFS by EPLND. RESULTS AND LIMITATIONS: In total, 300 patients were randomized from May 2012 to December 2016 (150 LPLND and 150 EPLND). The median BRFS was 61.4 mo in the LPLND group and not reached in the EPLND group (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.63-1.32; p = 0.6). Median MFS was not reached in either group (HR 0.57, 95% CI 0.17-1.8; p = 0.3). CSS data were not available because no patient died from PCa before the cutoff date. In exploratory subgroup analysis, patients with preoperative biopsy International Society of Urological Pathology (ISUP) grade groups 3-5 who were allocated to EPLND had better BRFS (HR 0.33, 95% CI 0.14-0.74, interaction p = 0.007). The short follow-up and surgeon heterogeneity are limitations to this study. CONCLUSION: This RCT confirms that EPLND provides better pathological staging, while differences in early oncological outcomes were not demonstrated. Our subgroup analysis suggests a potential BCRFS benefit in patients diagnosed with ISUP grade groups 3-5; however, these findings should be considered hypothesis-generating and further RCTs with larger cohorts and longer follow up are necessary to better define the role of EPLND during RP. PATIENT SUMMARY: In this study, we investigated early outcomes in prostate cancer patients undergoing prostatectomy according to the anatomic extent of lymph node resection. We found that extended removal of lymph nodes did not reduce biochemical recurrence of prostate cancer in the expected range.

Oncologic Outcomes in Young Adults With Kidney Cancer Treated During the Targeted Therapy Era.

BACKGROUND: The objective of this study was to determine the outcomes of young adults with kidney cancer treated during the targeted therapy era and evaluate the impact of young age on survival. MATERIALS AND METHODS: We reviewed the records from 445 patients younger than 55 years with kidney cancer at a single institution from 2006 to 2017. Overall survival (OS) and recurrence-free survival were estimated with the Kaplan-Meier method and log-rank test. Cox proportional hazards regression was used to determine the impact of clinical and pathologic variables on all-cause mortality. RESULTS: Overall, 104 (23%) patients 40 years or younger were compared with 341 (77%) patients who were 41 to 55 years old. Younger patients presented with more advanced stages of the disease, including metastasis at diagnosis, positive lymph nodes, venous tumor thrombus and had more non-clear cell tumors (54% vs. 30%; P < .001). Young adults had significantly worse OS at 2 and 5 years (67% vs. 82% and 53% vs. 69%, respectively). Younger patients with metastatic disease received targeted agents less often compared with the older group (64% vs. 75%). There was no difference in recurrence-free survival across patients with localized disease. Independent prognostic factors associated with increased mortality were metastasis at diagnosis, pT2 or greater, and age younger than 40 years (hazard ratio, 1.65; 95% confidence interval, 1.0-2.6; P = .03). CONCLUSION: Patients younger than 40 years with kidney tumors treated during the targeted therapy era have worse OS compared with older adults. Young age is an independent predictor of mortality.

The Moreau Strain of Bacillus Calmette-Guerin (BCG) for High-Risk Non-Muscle Invasive Bladder Cancer: An Alternative during Worldwide BCG Shortage?

BACKGROUND: Bacillus Calmette-Guerin (BCG) is the standard of care for adjuvant intravesical instillation therapy for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) after complete transurethral resection. Increasing evidence suggests that there are marked differences in outcomes according to BCG substrains. BCG-Moreau was recently introduced to the European market to cover the issue of BCG shortage, but there are little data regarding the oncologic efficacy. METHODS: We retrospectively analyzed 295 consecutive patients, who received adjuvant intravesical instillation therapy with BCG-Moreau for intermediate- and high-risk NMIBC between October 2007 and April 2013 at a single institution. The end points of this study were time to first recurrence and progression to muscle-invasive disease. RESULTS: Median age was 66 years (interquartile range 59-74, mean 65.9 years). According to the EAU risk group, 76 patients presented with intermediate-risk and 219 patients with high-risk NMIBC. The 5-year recurrence-free survival and progression-free survival rate was 64.8% (95% CI 52.8-74.4) and 81.4% (95% CI 65.2-90.2), respectively. CONCLUSIONS: BCG-Moreau is an effective substrain for adjuvant instillation therapies of NMIBC, and outcomes appear to be comparable to series using other substrains. During worldwide shortage of BCG-TICE, Connaught and RIVM, BCG-Moreau may serve as an equally effective alternative.

Organ-sparing microsurgical resection of incidental testicular tumors plus microdissection for sperm extraction and cryopreservation in azoospermic patients: surgical aspects and technical refinements.

INTRODUCTION: The management of nonpalpable testicular masses is a challenging task, and coexisting infertility can further complicate the treatment decisions. We present our technique for microsurgical organ-sparing resection of incidental nonpalpable testicular nodules combined with microdissection for testicular sperm extraction and tissue cryopreservation in azoospermic patients. TECHNICAL CONSIDERATIONS: Five infertile patients with azoospermia presented with nonpalpable hypoechoic testicular masses that were detected by ultrasonography and underwent organ-sparing surgery. The testis was delivered through an inguinal incision, and the blood circulation was interrupted with a vascular clamp placed on the spermatic cord. Sludged ice was used to prevent warm ischemia, and a temperature probe was used to control the temperature at 12 degrees-15 degrees C. Real-time reflex ultrasonography was used to locate the tumor, and a stereotaxic hook-shaped needle was inserted under ultrasound guidance. The needle was placed adjacent to the tumor to guide the microsurgical resection. The tunica albuginea was incised over the tumor, which was dissected and removed, along with the adjoining parenchymal tissue. Frozen section studies were performed and, if malignancy was confirmed, biopsies of the tumor cavity margins and remaining parenchyma were obtained to ensure the absence of residual tumor. Microdissection was performed for excision of selected enlarged tubules that were processed and cryopreserved. CONCLUSIONS: We present a technique for microsurgical organ-sparing resection of testicular tumor and sperm extraction that can be used in selected infertile patients with azoospermia in whom incidental masses have been diagnosed by ultrasonography. This conservative approach should be especially considered for patients with a solitary testis or bilateral tumors.

Microvascular tumour invasion in renal cell carcinoma: the most important prognostic factor.

OBJECTIVE: To evaluate the role of microvascular invasion (MVI) in the primary lesion for predicting tumour behaviour in patients with renal cell carcinoma (RCC), as reliable clinical prognostic factors would be very valuable. PATIENTS AND METHODS: MVI was assessed in 230 patients with clinically localized RCC (stages T1-4NxM0) who had a radical nephrectomy and/or nephron-sparing surgery. The median (range) follow-up was 48 (3-130) months. The impact of MVI on disease progression and its correlation with clinical and histopathological factors was analysed, including whether patients were symptomatic or not at presentation, Fuhrman nuclear grade, tumour size, pathological stage and lymph node metastasis. Regression analyses and survival curves were used to determine if MVI was associated with the prognosis of RCC. RESULTS: There was MVI in 59 patients (26%); of these, 46% developed disease recurrence. Among the 171 patients with no MVI, only 11 (6%) had tumour recurrence. MVI was associated with tumour diameter, nuclear grade, pathological stage, lymph node metastasis and the presence of sarcomatous elements in the tumour. Multivariate analysis showed that MVI was an independent predictor of disease recurrence and the most important factor related to death. CONCLUSION: MVI is an independent predictor of prognosis in patients with RCC.

Differentially expressed genes in the prostate cancer cell line LNCaP after exposure to androgen and anti-androgen.

Androgens play an important role in growth and maintenance of prostate cells. The actions of androgens are mediated by the androgen receptor (AR), a transcription factor member of the super-family of nuclear hormone receptors. Androgen regulated genes (ARGs) are potential markers for early diagnosis and treatment of prostate cancer patients. In the present study, we used DDRT-PCR (differential display reverse transcriptase polymerase chain reaction) technique in order to investigate differentially expressed genes in the prostate cancer cell line LNCaP after treatment with dihydrotestosterone and bicalutamide for 6, 24, and 48 hours. Fifty-five differentially expressed fragments were isolated, cloned, and sequenced. Sequencing analysis of these fragments revealed 56 different transcripts that showed homology to transcription factors, cell cycle regulators, metabolic enzymes, and hypothetical proteins. Among the differentially expressed genes, SPA17 and DDEF2 were further validated using quantitative real time RT-PCR (qPCR) in a series of 25 prostate tumor samples. The DDEF2 gene is involved in adhesion and cell migration of monocytes, and the SPA17 gene might be involved in cellular signal transduction. The transcripts of both, SPA17 and DDEF2 genes, showed altered pattern of expression in the group of prostate tumors analyzed by qPCR. The differentially expressed genes identified in this study might provide new insights into the androgen signaling pathways in prostate cells.

Double-barreled wet colostomy is a safe option for simultaneous urinary and fecal diversion. Analysis of 56 procedures from a single institution.

BACKGROUND AND OBJECTIVES: Wide pelvic tumors need urinary and fecal diversion. We set out to assess the efficacy of the double-barreled wet colostomy (DBWC) in patients undergoing simultaneous double diversion. MATERIAL AND METHODS: We reviewed 56 consecutive patients submitted to surgery, divided into two groups: (1) total pelvic exenteration plus DBWC (n = 26); (2) DBWC without simultaneous pelvic resection (n = 30). Pelvic tumor recurrences accounted for most patients (n = 53), whereas the remaining three patients suffered from actinic pelvic complications. RESULTS: Surgical morbidity and mortality rates were 53.8% (14/26) and 11.5% (3/26) in Group 1, and 43.5% (13/30) and 3.3% (1/30) in Group 2, respectively. Only 2 patients out of 51 (3.9%) developed late postoperative urinary tract infection. Regression of the hydronephrosis was observed in 28 out of 33 assessable patients. Median survival in Groups 1 and 2 was 8.36 and 4.14 months, respectively. In the subgroup of patients submitted to curative surgery (n = 24), actuarial cancer-specific survival rate in 2 years was 58.78%. CONCLUSION: DBWC is a safe and efficient alternative for simultaneous urinary and fecal diversion, with low morbidity and mortality rates, improvement of renal insufficiency, and low risk of postoperative urinary tract infection.

The transcripts of SFRP1,CEP63 and EIF4G2 genes are frequently downregulated in transitional cell carcinomas of the bladder.

OBJECTIVE: The aim of the present study was to identify differentially expressed genes that might be associated with the phenotype of superficial and invasive bladder cancer. METHODS: Differential display reverse transcriptase PCR (DDRT-PCR) was used to compare the expression pattern between normal bladder tissue and 4 groups of transitional cell carcinomas of the bladder regarding clinical stage and grade. RESULTS: We were able to identify 72 different transcripts, of which 57 (79%) showed homology to known genes, 12 (17%) to hypothetical proteins and 3 (4%) to human expressed sequence tags. Among the differentially expressed genes, SFRP1,CEP63 and EIF4G2 were further validated by quantitative RT-PCR in a series of 50 transitional cell carcinomas. Overall, the transcripts of these three genes were shown to be downregulated in the bladder tumors analyzed. In accordance with the DDRT-PCR results, the SFRP1 transcripts were shown to be downregulated in 90% (45/50) of the bladder tumors as compared with the normal bladder tissue. Although EIF4G2 and CEP63 transcripts exhibited three different expression patterns, downregulation was found in about 50% of the cases analyzed. In addition, downregulation of both CEP63 and EIF4G2 gene transcription was associated with invasive tumors. CONCLUSION: The use of DDRT-PCR analysis to compare expression patterns among different subgroups of bladder tumors allowed us to identify a significant number of genes implicated in different cellular pathways that, when up- or downregulated, might play a role in the tumorigenic process of the bladder.

Cell surface expression of the stress response chaperone GRP78 enables tumor targeting by circulating ligands.

We have recently identified glucose-regulated protein-78 (GRP78) as a relevant molecular target expressed in metastatic tumors by fingerprinting the circulating repertoire of antibodies from cancer patients. Here we design and evaluate a ligand-receptor system based on the tumor cell membrane expression of GRP78. We show that GRP78 binding peptide motifs target tumor cells specifically in vivo and in human cancer specimens ex vivo. Moreover, synthetic chimeric peptides composed of GRP78 binding motifs fused to a programmed cell death-inducing sequence can suppress tumor growth in xenograft and isogenic mouse models of prostate and breast cancer. Together, these preclinical data validate GRP78 on the tumor cell surface as a functional molecular target that may prove useful for translation into clinical applications.

Androgen receptor CAG repeat polymorphism in prostate cancer from a Brazilian population.

Shorter CAG repeats in the androgen receptor (AR) gene have been associated with increased prostate cancer risk. Aiming to investigate whether the AR CAG polymorphism is associated with an increased relative risk for prostate cancer in our population, genomic DNA from 133 prostate cancer patients and 279 healthy men controls were examined. We found no association between the AR CAG polymorphism and the relative risk of prostate cancer in white Brazilian individuals with a CAG repeat length

Racial differences in prostate cancer prevalence / Análise da prevalência de câncer de próstata entre as diversas etnias

Objetivo: Analisar descritivamente as diferenças etnicas na prevalência de câncer de próstata no Brasil. Materiais e métodos: Entre 1922 e 1997, 1773 homens foram submetidos a toque retal (TR), dosagem de PSA e questionário padrão (AUA-IPSS). Foram classificados etnicamente em amarelos (45 casos), brancos (1180 casos) e negróides (210 casos). Em 347 homens não foi possível definir a etnia. Os pacientes foram orientados a submeter-se a biópsia de próstata quando o PSA e/ou o TR estivessem alterados. Avaliou-se também o estádio clínico e escore de Gleason na ocasião do diagnóstico, sendo que as etnias foram comparadas quanto à prevalência de câncer. Resultados:Foram feitas 346 biópsias e diagnosticados 51 tumores (14,7 porcento de positividade nas biópsias). Dos tumores, 4 (7,8 porcento) apresentavam PSA normal, 16 (31,4 porcento) PSA entre 4,1 ng/ml e 10 ng/ml e 31 (60,8 porcento), PSA>10 ng/ml. A prevalência de câncer em brancos foi de 2,4 porcento e em negróides de 5,5 porcento (p<0,05). A média de idade para brancos foi de 62,3 ± 0,4 anos e para negróides 62,4 ± 0,7 anos (p>0,05). O PSA mediano para brancos foi 3 ng/ml e para negróides 3,3 ng/ml (p>0,05). Os negróides apresentaram maior prevalência de TR alterado (18,9 porcento versus 11,7 porcento, p<0,05). A instrução mediana de brancos foi 3 e a de negróides 2 (p<0,05). A prevalência de tumores clinicamente localizados foi de 61,3 porcento. Conclusões: A prevalência de câncer de próstata em negróides é maior do que em brancos (5,5 porcento versus 2,4 porcento). O PSA mediano foi similar em ambas etnias. Os negróides apresentaram maior prevalência de toque retal alterado (18,9 porcento versus 11,7 porcento).

Evaluation of the influence of protein p53 in penile carcinoma / Avaliaçäo da influência da proteína p53 no câncer de pênis

Introduçäo: A expressäo da proteína p53 e a sua influência no comportamento biológico do carcinoma epidermóide do pênis (CEP) foram estudadas em relaçäo aos seguintes parâmetros: grau histológico, estadio clinicopatológico, e fatores prognósticos, tais como curva de sobrevida e risco de morte pelo tumor. Material e métodos: De 1979 a 1995, 55 pacientes com CEP tratados cirurgicamente foram estudados retrospectivamente. A presença da proteína p53 foi verificada nos espécimes cirúrgicos do tumor primário e de suas metástases mais respresentativos pela análise imunohistoquímica. A intensidade da expressäo da p53 foi determinada pelo número de núcleos corados nas células tumorais, classificando-a em 4 grupos: grupo 1 - até 25 por cento; grupo 2 - de 26 a 50 por cento; grupo 3 - de 51 a 75 por cento; grupo 4 - mais de 75 por cento de núcleos corados. A relaçäo entre a expressäo da p53 nas células tumorais e os parâmetros estudados foi analisada. Resultados: Taxas elevadas de expressäo da p53 correlacionaram-se com graus menores de diferenciaçäo celular (p=0,053). Doze pacientes faleceram em decorrência do tumor durante este estudo. Nossos dados mostram que quanto maior a expressäo da p53 no tumor, pior é o prognóstico (p=0,025). Näo houve relaçäo significativa entre a presença da p53 e o estadio clinicopatológico do tumor. Conclusäo: Nossos dados mostram que existe expressäo significativa da p53 no CEP. Quanto maior a expressäo da p53, pior o prognóstico para o paciente e maior a agressividade biológica do tumor. O tumor se torna mais agressivo de acordo com a intensidade da proteína no núcleo das células tumorais.

Treatment of patients with superficial bladder cancer stratified by risk groups treated with lyophilized Moreau-Rio de Janeiro BCG strain.

INTRODUCTION: The Moreau-Rio de Janeiro BCG strain is considered the most effective to stimulate immunologic activity in mice. The objective of this prospective study was to evaluate BCG results for patients with superficial bladder cancer stratified by risk groups. MATERIAL AND METHODS: From April 1988 to May 2000, 100 patients were treated by transurethral resection for bladder tumor, followed by intravesical instillation of 40 mg BCG, with induction and maintenance cycles. Fisher exact test and Chi-square test, with 95% significance, were used to evaluate possible associations among variables. The Kaplan-Meier method was used to evaluate the disease-free interval and patients' survival, while log-rank test was used to compare the curves among the groups. RESULTS: The median follow-up was 69.3 months and varied from 10 to 153 months. Overall recurrence and progression rates were 55% and 13%, respectively. The medium time to recurrence was 9.4 months and to progression was 24.4 months. The cancer specific survive was 90%. Univariate analysis revealed that tumor recurrence was significantly associated with weekly BCG failure (p=0.011), multifocality (p=0.001), number of recurrences after primary therapy (p=0.001) and the need to Mitomycin C instillation (p=0.001). However, no variable was significantly associated with recurrence in multivariate analysis. There were significant associations, in univariate analysis, between disease progression and the following variables: tumor grade, weekly and 15-days BCG failure, both as first line and second line therapy, recurrence and need of Mitomycin C therapy. Independent variables to progression were 6.7 relative risk to weekly BCG failure, tumor grade and 15-days BCG (p= 0.08; CI=0.79-56.7), 2.4 (p= 0.11; CI=0.80-7.15) and 1.5 (p=0.23; CI=1.05-2.13), respectively. Patient stratification by risk groups were able to predict progression (p=0.045), but not recurrence (p=0.311). Disease progression rates were 3.2%, 12.2% e 25%, in low, intermediate and high risk groups, respectively. The BCG administration was well tolerated, and 21 patients (21%) didn't present any side effects. CONCLUSIONS: Intravesical instillation of BCG was overall well tolerated. Adjuvant BCG didn't decrease significantly recurrence rates, and 16% of the patients underwent alternative therapy with intravesical Mitomycin to prevent new recurrences. The risk group classification was able to select patients with high risk to progression. Tumor grade, BCG failure as first and second line therapies, were predictive factors of poor prognosis. BCG of Moreau-Rio de Janeiro strain was well tolerated, similar to other strains used in literature.