Methoxide-Enabled Zirconium-Catalyzed Migratory Alkene Hydrosilylation.

A zirconocene dichloride-catalyzed alkene hydrosilylation is reported that can be applied to non-activated and conjugated terminal and internal alkenes. It involves a catalytic Zr-walk process and leads to a selective conversion to the linear product. Lithium methoxide serves as mild catalyst activating agent, which significantly increases the applicability and operational simplicity in comparison to earlier zirconium(II)-based protocols. Supported by additional experiments and calculations, a mechanism via zirconium(IV) intermediates is proposed. Due to the benign nature and ready-availability of the zirconium catalyst, the reaction is an attractive alternative to established alkene hydrosilylation methods.

Reexamining treatment of high-grade T1 bladder cancer according to depth of lamina propria invasion: a prospective trial of 200 patients.

BACKGROUND: Management of high-grade T1 (HGT1) bladder cancer represents a major challenge. We studied a treatment strategy according to substaging by depth of lamina propria invasion. METHODS: In this prospective observational cohort study, patients received initial transurethral resection (TUR), mitomycin-C, and BCG. Subjects with shallower lamina propria invasion (HGT1a) were followed without further surgery, whereas subjects with HGT1b received a second TUR. Association of clinical and histological features with outcomes (primary: progression; secondary: recurrence and cancer-specific survival) was assessed using Cox regression. RESULTS: Median age was 71 years; 89.5% were males, with 89 (44.5%) cases T1a and 111 (55.5%) T1b. At median follow-up of 71 months, disease progression was observed in 31 (15.5%) and in univariate analysis, substaging, carcinoma in situ, tumour size, and tumour pattern predicted progression. On multivariate analysis only substaging, associated carcinoma in situ, and tumour size remained significant for progression. CONCLUSIONS: In HGT1 bladder cancer, the strategy of performing a second TUR only in T1b cases results in a global low progression rate of 15.5%. Tumours deeply invading the lamina propria (HGT1b) showed a three-fold increase in risk of progression. Substaging should be routinely evaluated, with HGT1b cases being thoroughly evaluated for cystectomy. Inclusion in the TNM system should also be carefully considered.

Carcinoma urotelial de vejiga estadio T1: subestadiaje, patrones morfológicos de invasión y su significado pronóstico / Bladder urothelial carcinoma stage T1: substaging, invasion morphological patterns and its prognosis significance

Desde 1990 en que se publicaron las primeras series sobre subestadiaje, han aparecido numerosas publicaciones sobre el subnivel de invasión de los carcinomas de alto grado T1. La invasión profunda conlleva un elevado riesgo de progresión (alrededor del 30-35% de casos progresan) frente a los casos de invasión superficial por encima de la muscularis mucosae, en los que la progresión se encuentra alrededor del 10%, por lo que para la mayoría de autores vale la pena tener en cuenta los subT1, en el manejo del paciente. En esta revisión se presentan las series más exhaustivas que han valorado el subestadiaje y se valoran los diferentes métodos de efectuar esta estadificación teniendo en cuenta la dificultad inherente a las muestras que proceden de resección transuretral (RTU)

Since 1990 when the first series on substaging were published, they have published numerous publications on the invasion sublevel of high degree T1 carcinomas. The deep invasion entails a high risk of progression (around 30-35% of cases progress) as opposed to the cases of superficial invasion over “muscularis mucosae”, in which the progression is around 10%, reason why most authors consider subT1, in patient management. In this revision the more exhaustive series that have evaluated substaging are shown and also the different methods to carry out this staging considering the inherent difficulty to the samples that come from transurethral resection (RTU)

[Bladder urothelial carcinoma stage T1: substaging, invasion morphological patterns and its prognosis significance]. / Carcinoma urotelial de vejiga estadio T1: subestadiaje, patrones morfológicos de invasión y su significado pronóstico.

Since 1990 when the first series on substaging were published, they have published numerous publications on the invasion sublevel of high degree T1 carcinomas. The deep invasion entails a high risk of progression (around 30-35% of cases progress) as opposed to the cases of superficial invasion over "muscularis mucosae", in which the progression is around 10%, reason why most authors consider subT1, in patient management. In this revision the more exhaustive series that have evaluated substaging are shown and also the different methods to carry out this staging considering the inherent difficulty to the samples that come from transurethral resection (RTU).

Urinary retention secondary to presacral myelolipoma; first reported case diagnosed by prostate TUR and requiring a cystectomy.

Obstructive voiding symptoms may exceptionally be caused by extrinsic compression. We herein present a singular case of a 68-year-old male that presented with urinary retention and underwent prostate trans-urethral resection (TUR) with histology showing benign prostatic hyperplasia admixed with large amounts of myelolipoma tissue. To the best of our knowledge this is the first reported presacral myelolipoma diagnosed at prostate trans-urethral resection (TUR). Computed tomography revealed a 13 x 9 cm presacral mass displacing the rectum. Even though myelolipomas are regarded as benign, this case behaved aggressively since compressive effect evolved to severe constipation and eventually required a cystectomy.

Initial high-grade T1 urothelial cell carcinoma: feasibility and prognostic significance of lamina propria invasion microstaging (T1a/b/c) in BCG-treated and BCG-non-treated patients.

OBJECTIVES: This study aimed to determine the prognostic value of depth of lamina propria invasion in initial high-grade T1 bladder tumors. Secondary aims were to evaluate the prognostic significance of concomitant carcinoma in situ (CIS) and the impact of bacillus Calmette-Guérin (BCG) treatment as well as to assess the feasibility of microstaging by pathologists in a community setting. PATIENTS AND METHODS: Ninety-seven tumors were available for study and were substaged according to invasion superficial to, into or beyond the muscularis mucosae (MM) (T1a, T1b, T1c). Outcomes were compared by chi-square analysis. Recurrence-free and progression-free survival estimates were obtained by Kaplan-Meier analysis. BCG treatment impact and prognostic significance of CIS were also evaluated (Cox regression). RESULTS: T1 subclassification was possible in 87% (85/97) of cases: 38 (39.1%) T1a, 10 (10.3%) T1b, and 37 (38.1%) T1c; in 12 patients (12.4%) substaging was not possible. Mean age was 66.4 years and mean follow-up was 53 months. Recurrence rates were similar for all groups. By contrast, the progression rate for deep lamina propria-invasive tumors, i.e. T1b and T1c, was 34% (16/47) in comparison to 8% (3/38) for T1a (p=0.016). Progression-free intervals were significantly different in patients with (T1b, T1c) or without (T1a) deep lamina propria involvement (p=0.003), regardless of BCG treatment (p=0.02). BCG-treated patients (67 cases) showed a slight trend towards a better outcome, but differences were not significant. CIS was associated with more than 50% of cases that progressed. On multivariate analysis, depth of invasion and CIS remained two independent prognostic factors, increasing the hazards ratio of progression to 4.47 and 3.19 respectively. CONCLUSIONS: The depth of invasion in the TURB specimens is an independent prognostic factor for T1 bladder cancer even in BCG-treated patients. Associated CIS significantly increases the risk of progression in these patients. The percentage of cases that can be substaged according to the depth of lamina propria involvement increases over time with the collaboration between urologists and pathologists. Consequently, we support that routine pathological assessment of the level of MM invasion in patients with stage T1 bladder cancer should be included in the histopathological report.

Renal collecting (Bellini) duct carcinoma displays similar characteristics to upper tract urothelial cell carcinoma.

OBJECTIVES: To describe 3 cases of tumors located in the kidney that may relate collecting (Bellini) duct carcinoma (CDC) to urothelial cell carcinoma (UC). We hypothesized that these distinct tumor types may share a common origin. CDC is a subtype of renal cell carcinoma associated with a highly aggressive course, poor prognosis, and limited response to immunotherapy, behaving similarly to UC. METHODS: We present 2 cases of CDC and 1 case of UC of the renal papilla. We compared the clinical presentation and survival rate, together with the radiologic, histologic, and immunostaining (including p53) findings, with strong emphasis on the similarities. RESULTS: One patient with CDC had a previous history of grade 3, Stage Ta bladder UC. The urothelial carcinoma from the kidney papilla (case 3) presented carcinoma in situ of the adjacent urothelium and displayed mixed characteristics with CDC, namely location, positive staining for Ulex europaeus and pyelonephritic changes. p53 staining showed marked positivity in the tumor of patient 2. Disease progression was rapid, with a median survival of 5.6 months (range 5 to 7). CONCLUSIONS: The results of this study suggest that the broad category of renal cell carcinoma includes a spectrum of lesions. In this range of diseases, CDC might be distinct from conventional renal cell carcinoma but share biologic features with UC, with the consequent implications for management. This association between CDC and UC may reflect the common embryologic origin of collecting duct and urothelial cells, since they derive from progressive branching of the mesonephric (wolffian) duct. Furthermore, the differential cytogenetic expression profiles suggest that the molecular events underlying the development of distal nephron and proximal tubule renal cancers are distinct.

Usefulness of prostate-specific antigen nadir as predictor of androgen-independent progression of metastatic prostate cancer.

The objective of this study was to analyze the value of the nadir level of prostate-specific antigen (PSA) to predict androgen-independent progression (AIP) in metastatic prostate cancer patients after androgen deprivation therapy. In a group of 185 metastatic prostate cancer patients who received androgen deprivation therapy serum PSA was determined every three months until AIP occurred. Multiple regression analysis was performed to define independent clinical and PSA-related predictors of AIP. AIP was assumed to be present after two consecutive increases in serum PSA after the PSA nadir. Independent predictors of the duration of AIP-free survival (less than 12 months versus more than 12 months) were the extent of bone involvement (six or fewer hot spots versus more than six) with an odds ratio (O.R.) of 3.95, Gleason score (7 or less versus more than 7) with an O.R. of 3.47, and PSA nadir (2 microg/L or less versus more than 2 microg/L) with an O.R. of 14.63. AIP was independently predicted by the extent of bone involvement with an O.R. of 1.72, Gleason score with an O.R. of 1.74, PSA nadir with an O.R. of 3.22, and time to reach the PSA nadir (9 months or less versus more than 9 months) with an O.R. of 2.84. When patients were stratified according to these predictors, those with three good prognostic factors had a median AIP-free survival of 58 months while those with two, one or no good prognostic factors had a median AIP-free survival of 19 months, 12 months and 7 months, respectively. We conclude that the PSA nadir seems to be a good predictor of AIP in patients with metastatic prostate cancer after androgen deprivation therapy. Time to PSA nadir, extent of bone involvement and Gleason score are also independent predictors. The combination of these prognostic factors allows to stratify metastatic prostate cancer patients for the prediction of AIP.

Circuncisión infantil: revisión de la evidencia / Reference to the article "Childhood circumcision: review of the evidence"

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[Congenital renal abnormalities in neonates with fetal vesicoureteral reflux. Detection by 99m-technetium(m)-dimercaptosuccinic acid renal scintigraphy]. / Anomalías renales congénitas en neonatos con reflujo vesicoureteral fetal. Detección con gammagrafía renal-99mTc-DMSA.

BACKGROUND: "Fetal" vesicoureteral reflux (VUR) is characterized by predominance among males, high grade reflux and renal parenchymal abnormalities, indicating an association between sterile VUR and kidney lesions. OBJECTIVES: To determine, using technetium99m-dimercaptosuccinic acid (99mTc-DMSA) renal scan, the incidence of congenital renal abnormalities in infants with sterile VUR detected during the postnatal evaluation of prenatal hydronephrosis or sibling reflux screening and to speculate on the mechanisms of these lesions. METHODS: We retrospectively reviewed the DMSA renal scans of infants with VUR without a history of urinary tract infection (UTI). DMSA differential uptake less than or equal to 40% or cortical defects were considered as renal abnormalities. The findings were correlated with those of postnatal renal ultrasonography. RESULTS: Eighteen patients (15 boys and 3 girls) were included with VUR grade V, IV, III and II in 5, 10, 6 and 6, respectively, of the 36 renal units. DMSA revealed parenchymal abnormalities in 50% (9/18) of the patients and in 33% (9/27) of the renal units with VUR; most of the patients were boys (7 boys, 2 girls) with VUR grade V or IV (6/9; 66%). Postnatal ultrasonography showed low sensitivity (22%) to renal injury. CONCLUSIONS: In infants with sterile VUR, especially boys with high grade VUR, kidney abnormalities can already be present at birth suggesting a pathophysiology of renal injury independent of UTI. Moreover, renal parenchymal defects detected by DMSA renal scan are frequently not identified by postnatal renal ultrasound. Therefore, we recommend DMSA scanning in the initial evaluation of infants with VUR.

Anomalías renales congénitas en neonatos con reflujo vesicoureteral fetal. Detección con gammagrafía renal-99mTc-DMSA / Congenital renal abnormalities in neonates with fetal vesicoureteral reflux. Detection by 99M-technetiumM-Dimercaptosuccinic acid renal scintigraphy

Antecedentes: El reflujo vesicoureteral (RVU) "fetal" se caracteriza por una preponderancia masculina, reflujo de alto grado y anomalías parenquimatosas renales, estableciéndose una asociación entre RVU estéril y lesión renal. Objetivos Determinar, mediante gammagrafía renal con 99m tecnecio ácido dimercapto-succínico (99mTc-DMSA), la incidencia de anomalías renales congénitas en lactantes con RVU detectado posnatalmente por hidronefrosis prenatal o por cribado familiar, y especular sobre los mecanismos de acción de estas lesiones. Métodos: Se han revisado retrospectivamente las gammagrafías renales de lactantes con RVU y sin antecedentes de infección del tracto urinario (ITU), considerando anomalías renales: captación diferencial menor o igual al 40 por ciento o presencia de defectos corticales. Los hallazgos gammagráficos se han correlacionado con los de la ecografía posnatal. Resultados: Dieciocho pacientes cumplieron los criterios de inclusión; 15 niños y 3 niñas con RVU grado V, IV, III y II en 5, 10, 6 y 6 de las 36 unidades renales. La gammagrafía mostró alteraciones parenquimatosas en el 50 por ciento (9/18) de los pacientes y el 33 por ciento (9/27) de las unidades renales refluyentes; la mayoría fueron niños (7 niños, 2 niñas) con RVU de GV o GIV (6/9; 66 por ciento). La sensibilidad de la ecografía posnatal para detectar signos de lesión renal fue baja (22 por ciento). Conclusiones: Lactantes con RVU estéril, especialmente varones con RVU de alto grado, pueden presentar ya al nacimiento anomalías parenquimatosas renales, lo cual sugiere una etiopatogenia congénita de lesión renal independiente de la ITU. Estos defectos identificados por gammagrafía con frecuencia no son detectados en la ecografía posnatal. Por ambos motivos recomendamos la gammagrafía renal DMSA en la evaluación inicial de lactantes con RVU fetal (AU)

Embriología urogenital: bases genéticas y ecografía prenatal / Urogenital embriology, genetic basis and prenatal ecography

Introducción:El 20 por ciento aproximadamente, de las anomalías fetales detectadas por ecografia prenatal afectan al sistema genitourinario. Hasta en un 1 por ciento de los embarazos puede sospecharse una malformación urogenital.Embriogénesís del aparato urogenital:El conducto de Wolff participa de la formación del tramo urinario superior, la vía seminal y el conducto de Müller, actuando como organizador de todos ellos. La vejiga se origina del endodermo en íntima relación con el ano, recto y el tramo genital inferior. Exceptuando el trígono, que se origina en el conducto mesonéfrico, la porción uretral del seno urogenital da origen a la uretra supramontanal en el hombre y a la totalidad de la uretra en la mujer. El sexo gonadal y el desarrollo de los genitales internos dependen de la presencia o ausencia del cromosoma "Y". Su presencia produce la transformación testicular de la gónada primitiva; su ausencia, la diferenciación pasiva de la gónada primitiva en ovario.La testosterona de las células de Leydig estimula localmente la diferenciación del conducto de Wolff en deferente, vesículas seminales, epididimo y eyaculadores. La falta de cromosoma "Y" desarrolla los genitales internos femeninos, aún en ausencia de los ovarios. Los genitales externos en el varón dependen de la presencia sistémica de dihidrotestosterona (DHT). La ausencia de DHT en la mujer determina la formación del clítoris y labios menores.Bases genéticas y moleculares de la embriogénesis:Existen una serie de mediadores moleculares y factores relacionados con la división de la yema ureteral y la nefrogénesis que abarca una compleja interacción entre factores de transcripción, factores de crecimiento locales y composición de la matriz extracelular. El principal mecanismo molecular depende del "Glial ceil line-derived neutrophic factor" (GDNF) que es secretado por el metanefros y estimula el receptor CRET del conducto mesonéfrico. El sistema Renina- Angiotensina (RAS) es importante en el crecimiento y diferenciación renal así como también en la regulación de la tensión arterria. La determinación y la diferenciación sexual son procesos secuenciales que se inician con la fertilización, al establecer el sexo cromosómico y continúan con el desarrollo del sexo gonadal y fenotípico. Aunque están involucrados más de 19 genes, el más importante es el gen SRY (Sex Region Y) que se halla en el brazo corto del cromosoma "Y".Embriogénesis y ecograjia prenatal:En condiciones normales el riñon fetal puede visualizarse a la semana 14, crece durante toda la gestación y especialmente entre la semana 13 y la 24. La nefrogénesis se completa en la semana 36. Los cálices y uréteres no son visibles por ecografía. La vejiga se puede ver a partir de la semana 13 (transvaginal) y 14 (transabdominal). La ecografia tiene una sensibilidad diagnóstica del 78 por ciento para detectar malformaciones urogenitales. En todos los estudios prenatales se debe evaluar: líquido amniótico, localización y características de los riñones, vejiga, sexo fetal y buscar anomalías congénitas asociadas. (AU)

Conservative treatment of phimosis in children using a topical steroid.

OBJECTIVES: From 1997 through 1998, we conducted a prospective study to evaluate the long-term outcome of using topical steroids in the treatment of childhood phimosis. METHODS: Both the parents and their children were instructed to apply 0.05% betamethasone cream topically twice a day for 1 month and to retract the prepuce after the fifth day of treatment. Results were evaluated at the end of the treatment and 6 months later. RESULTS: One hundred thirty-seven boys were evaluated. The median age was 5.4 years. At initial presentation, 61 boys had a phimotic but retractable prepuce, 37 had a nonretractable phimotic ring, and 39 had a pinpoint opening. Patients with a history of previous forcible foreskin retractions were considered to have secondary phimosis. By 6 months following treatment, 90% (124 children) had an easily retractable prepuce without a phimotic ring. No differences were seen in the response rate between those with primary and secondary phimosis. In all cases, the treatment was well tolerated without local or systemic side effects. All the patients with persistent or recurrent phimosis were found to be noncompliant with the suggested daily foreskin care. CONCLUSIONS: Topical steroid for the treatment of phimosis is a safe, simple, and inexpensive procedure that avoids surgery and its associated risks. It is effective both in primary and in secondary phimosis. We emphasize the importance of proper and regular foreskin care and hypothesize on the mechanism of action of the steroids.

Controlled release of therapeutic agents: slow delivery and cell encapsulation.

Some of the most promising systems for the controlled release of bioactive agents, i.e., peptides or hormones, involve the encapsulation or entrapment of hormones or peptides in biocompatible polymeric devices that enable their continuous release over prolonged periods. In urology, two major pathologic conditions, androgen deficiency and prostate cancer, currently benefit from treatments based on controlled delivery. Leuprolide acetate depot (Lupron-depot) was one of the first controlled-delivery systems used for the treatment of prostate cancer. Clinical studies indicate that patients with prostate cancer who undergo therapy with leuprolide acetate depot can benefit from this treatment. Currently available androgen-replacement therapies include the oral administration of testosterone tablets or capsules, depot injections, sublingual treatment, and skin patches. However, side effects such as metabolic inactivation of testosterone on oral administration; fluctuations in levels of the hormone; and burning, rash, and skin necrosis during the use of skin patches may occur. These side effects may be avoided through the application of encapsulated Leydig cells, which produce testosterone. Studies in our laboratory have shown that Leydig cells encapsulated in alginate/poly-L-lysine/alginate microspheres are capable of secreting testosterone in culture and in vivo. Microencapsulated Leydig cells delivered intraperitoneally into castrated rats maintained a testosterone level of 0.51 ng/ml for more than 3 months without any human chorionic gonadotropin stimulation. Similar studies are also being conducted in our laboratory on encapsulation of ovarian cells for the secretion of progesterone and estrogen in culture and in vivo using microencapsulation techniques.

Heparin-binding EGF-like growth factor is up-regulated in the obstructed kidney in a cell- and region-specific manner and acts to inhibit apoptosis.

The expression of certain growth factors in the epidermal growth factor (EGF) family is altered in response to renal injury. Recent studies have demonstrated that heparin binding EGF-like growth factor (HB-EGF) expression may be cytoprotective in response to apoptotic signals. The purpose of this study was to investigate the potential role of HB-EGF in the upper urinary tract following unilateral ureteral obstruction. We present evidence that: i) ureteral obstruction induced cell-specific but transient activation of HB-EGF gene expression; ii) HB-EGF expression in renal epithelial cells increased under conditions where mechanical deformation, such as that caused by hydronephrotic distension, induces apoptosis, but HB-EGF expression did not increase in renal pelvis smooth muscle cells under identical conditions; and iii) enforced expression of HB-EGF served to protect renal epithelial cells from stretch-induced apoptosis. These results suggest a potential mechanism by which the kidney protects itself from apoptosis triggered by urinary tract obstruction.