Glutathione-S-transferase (GST) polymorphisms are associated with relapse after radical prostatectomy.

BACKGROUND: Organ confined prostate cancer (PCa) can be cured by radical retropubic prostatectomy (RRP); however, some tumors will still recur. Current tools fail to identify patients at risk of recurrence. Glutathione-S-transferases (GSTs) are involved in the metabolism of carcinogens, hormones and drugs. Thus, genetic polymorphisms that modify the GST activities may modify the risk of PCa recurrence. METHODS: We retrospectively recruited Argentine PCa patients treated with RRP to study the association between GST polymorphisms and PCa biochemical relapse after RRP. We genotyped germline DNA in 105 patients for: GSTP1 c.313A>G (p.105 Ile>Val, rs1695) by PCR-RFLP; and GSTT1 null and GSTM1 null polymorphisms by multiplex PCR. Kaplan-Meier curves and Cox proportional hazard models were used to evaluate these associations. RESULTS: Patients with GSTP1 c.313GG genotype showed shorter biochemical relapse-free survival (BRFS) (P = 0.003) and higher risk for recurrence in unadjusted (Hazard ratio (HR) = 3.16, 95% confidence interval (95% CI) = 1.41-7.06, P = 0.005) and multivariate models (HR = 3.01, 95% CI = 1.13-8.02, P = 0.028). We did not find significant associations for GSTT1 and GSTM1 genotypes. In addition, we found shorter BRFS (P = 0.010) and increased risk for recurrence for patients having two or more risk alleles when we combined the genotypes of the three GSTs in multivariate models (HR = 3.06, 95% CI = 1.20-7.80, P = 0.019). CONCLUSIONS: Our results give support to the implementation of GSTs genotyping for personalized therapies as a novel alternative for PCa management for patients who undergo RRP. To the best of our knowledge, this is the first study that examined GST polymorphisms in PCa progression in Argentine men. Replication of our findings in larger cohort is warranted.

Punto de corte del indice: antigeno prostatico especifico libre (PSAI)/Antigeno prostatico especifico total (PSAt) / Free prostate specific antigen index (free PSA)/total prostate specific antigen (total PSA) accurate cutoff

Introduccion: El Psat es el marcador mas usado en patologias prostaticas: 10-30 por ciento circula como PSA I y 70-90 por ciento complejado (PSAc). Se ha propuesto que el indice PSAI/PSAt podria variar entre patologias benignas y malignas. Objetivo: El objetivo de este estudio fue establecer el mejor punto de corte para PSAI/PSAt en una poblacion con sospecha clinica-analitica de neoplasia prostatica. Material y metodos: a 136 varones con sospecha clinica-analitica de neoplasia prostatica se les realizo tacto rectal (TR) dosajes sericos de PSAt y PSAI, ecografia transrectal y biopsia. Se calculo sensibilidad y especificidad para diferentes puntos de corte PSAI/PSAt usando como metodo patron el resultado de la biopsia. Resultados: Todos los pacientes presentaron TR no sospechoso: en 47 individuos menores 60 años se detecto PSAt entre 2,50-9,99 ng/ml, 85 pacientes presentaron PSAI/PSAt mayor de 25 por ciento. La especificidad dignostica del indice PSAI/PSAt mostro una disminucion progresiva a medida que se aumento el punto de corte manteniendose los niveles de sensibilidad. Conclusiones: en la poblacion estudiada el indice PSAI/PSAt con mejor especificidad diganostica de CaP fue 15 por ciento en lugar del 25 por ciento empleado previamente(AU)

Punto de corte del indice: antigeno prostatico especifico libre (PSAI)/Antigeno prostatico especifico total (PSAt) / Free prostate specific antigen index (free PSA)/total prostate specific antigen (total PSA) accurate cutoff

Introduccion: El Psat es el marcador mas usado en patologias prostaticas: 10-30 por ciento circula como PSA I y 70-90 por ciento complejado (PSAc). Se ha propuesto que el indice PSAI/PSAt podria variar entre patologias benignas y malignas. Objetivo: El objetivo de este estudio fue establecer el mejor punto de corte para PSAI/PSAt en una poblacion con sospecha clinica-analitica de neoplasia prostatica. Material y metodos: a 136 varones con sospecha clinica-analitica de neoplasia prostatica se les realizo tacto rectal (TR) dosajes sericos de PSAt y PSAI, ecografia transrectal y biopsia. Se calculo sensibilidad y especificidad para diferentes puntos de corte PSAI/PSAt usando como metodo patron el resultado de la biopsia. Resultados: Todos los pacientes presentaron TR no sospechoso: en 47 individuos menores 60 años se detecto PSAt entre 2,50-9,99 ng/ml, 85 pacientes presentaron PSAI/PSAt mayor de 25 por ciento. La especificidad dignostica del indice PSAI/PSAt mostro una disminucion progresiva a medida que se aumento el punto de corte manteniendose los niveles de sensibilidad. Conclusiones: en la poblacion estudiada el indice PSAI/PSAt con mejor especificidad diganostica de CaP fue 15 por ciento en lugar del 25 por ciento empleado previamente

Decreased oxidative stress in prehepatic portal hypertensive rat livers following the induction of diabetes.

1. Oxidative stress (OS) is a biological entity indicated as being responsible for several pathologies, including diabetes. Diabetes can also be associated with human cirrhosis. Portal hypertension (PH), a major syndrome in cirrhosis, produces hyperdynamic splanchnic circulation and hyperaemia. The present study was designed to investigate the occurrence of OS in prehepatic PH rat livers following the induction of diabetes. 2. Five groups of rats were used: control, sham operated, chronic diabetes (induced with a single dose of streptozotocin at 60 mg/kg, i.p.), prehepatic PH and chronic diabetic plus prehepatic PH. The occurrence of OS was determined in liver homogenates by measuring hydroperoxide-initiated chemiluminescence and the activity of anti-oxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase). 3. Prehepatic PH produced a significant increase in hydroperoxide-initiated chemiluminescence in the liver compared with control and sham-operated rats, whereas the liver in chronic diabetic rats showed no difference. However, chemiluminescence values decreased almost by 50% in the chronic diabetic plus prehepatic PH group. Concomitantly, the activities of the anti-oxidant enzymes in chronic diabetes, prehepatic PH and chronic diabetic plus prehepatic PH groups were decreased (P < 0.05 vs control and sham-operated groups). 4. Livers from the chronic diabetic group did not show any evidence of the occurrence of OS, whereas the prehepatic PH group showed the occurrence of OS. The association of PH and chronic diabetes resulted in a significant decrease in the occurrence of OS, which could be explained by an anti-oxidant response to an OS.

Reservorio urinario contyinente ortotópico cecoileal con anastomosis uretro-apendicular término-terminal (Técnica original) / Orthotopic continent ceco-ileal urinary diversion with end-to-end urethro-apendicular anastomosis (Original technique)

Introducción: La búsqueda de un reservorio urinario continente ortotópico de fácil realización y con una continencia satisfactoria, nos llevó a desarrollar esta variante técnica. Material y métodos: Se presenta la experiencia en 10 enfermos, estudiados en el período 1997-2000, con diagnóstico de Carcinoma Transicional Infiltrante de vejiga a los que se les realizó cistoprostatectomía radical y se confeccionó reservorio urinario con colon derecho e íleon terminal efectuando la anastomosis entre apéndice y uretra en forma término-terminal. Resultados: Las complicaciones postoperatorias fueron mínimas, incluyendo pérdida transitoria de orina peritalla vesical en un enfermo, y absceso de herida quirúrgica en otro. El volumen promedio obtenido fue de 500 cc., con una continencia efectiva principalmente diurna. El seguimiento de los pacientes no muestra progresión de la enfermedad ni alteraciones del árbol urinario superior. Conclusiones: Esta variante técnica resulta una alternativa interesante para la confección de un reservorio urinario seguro y efectivo. Creemos que con el aumento de la casuística estaremos en condiciones de demostrar los beneficios de nuestra variante técnica y compararla con otras técnicas de difusión universal.

Reservorio urinario contyinente ortotópico cecoileal con anastomosis uretro-apendicular término-terminal (Técnica original) / Orthotopic continent ceco-ileal urinary diversion with end-to-end urethro-apendicular anastomosis (Original technique)

Introducción: La búsqueda de un reservorio urinario continente ortotópico de fácil realización y con una continencia satisfactoria, nos llevó a desarrollar esta variante técnica. Material y métodos: Se presenta la experiencia en 10 enfermos, estudiados en el período 1997-2000, con diagnóstico de Carcinoma Transicional Infiltrante de vejiga a los que se les realizó cistoprostatectomía radical y se confeccionó reservorio urinario con colon derecho e íleon terminal efectuando la anastomosis entre apéndice y uretra en forma término-terminal. Resultados: Las complicaciones postoperatorias fueron mínimas, incluyendo pérdida transitoria de orina peritalla vesical en un enfermo, y absceso de herida quirúrgica en otro. El volumen promedio obtenido fue de 500 cc., con una continencia efectiva principalmente diurna. El seguimiento de los pacientes no muestra progresión de la enfermedad ni alteraciones del árbol urinario superior. Conclusiones: Esta variante técnica resulta una alternativa interesante para la confección de un reservorio urinario seguro y efectivo. Creemos que con el aumento de la casuística estaremos en condiciones de demostrar los beneficios de nuestra variante técnica y compararla con otras técnicas de difusión universal.(AU)

Effects of aminoguanidine and meloxicam on nitric oxide and prostaglandin E production induced by lipopolysaccharide in the hypothalamus and anterior pituitary of the rat.

BACKGROUND/OBJECTIVE: Injection of bacterial lipopolysaccharide (LPS) into male rats activates genes that in turn induce many enzymes that participate in the animals' response to LPS. There is induction of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) in many tissues. This induction could result from combination with cell surface LPS receptors that directly induce both genes, or the nitric oxide (NO) released as a result of iNOS induction could induce COX-2. METHODS: To distinguish between these two possibilities, specific inhibitors of iNOS and COX-2 activity, aminoguanidine (AG) and meloxicam (MLX), respectively, were injected either peripherally or intracerebroventricularly (i.c.v.), and their effect on NO and prostaglandin E (PGE) production induced by LPS in the medial basal hypothalamus (MBH) and anterior pituitary gland (AP) were determined. RESULTS: Peripheral injection of AG blocked iNOS-derived NO production in the AP but not in the MBH. When AG was injected i.c.v., iNOS-derived NO production in the MBH was blocked. MLX injected peripherally blocked COX-2-derived PGE(2) production in the MBH and AP, whereas AG injected peripherally or i.c.v. was ineffective. Since AG was only effective in blocking iNOS-derived NO production in the MBH when injected i.c.v., AG apparently does not effectively cross the blood brain barrier, whereas MLX injected peripherally inhibited PGE production, probably by inhibiting COX-2 activity in both the MBH and AP. AG was ineffective in preventing the increase in PGE derived from COX-2 in either the MBH or AP. CONCLUSION: LPS directly induces both enzymes, iNOS and COX-2, in the hypothalamus and AP.

[Functional alterations in central nervous system of prehepatic portal hypertensive rats]. / Cambios funcionales en el sistema nervioso central de ratas hipertensas portales prehepaticas.

Prehepatic Portal Hypertension (PH) leads to morphologic changes in the rat Central Nervous System, including alterations of the blood brain barrier (BBB), and astrogliosis and angiogenesis in CA1 and CA4 hyppocampal fields. The present study investigates functional changes in portal hypertensive rats. Wistar Kyoto rats were used (240 g/bw) and allotted in two groups: GI (n = 8) portal hypertensive rats obtained through a regulated stenosis of the portal vein (Groszmann), and GII (n = 6), sham-operated rats. We have analyzed: BBB integrity with the Trypan Blue diffusion method (TB, Reynolds), protein concentration (PC) in Cerebrospinal Fluid (CSF) and plasma (Bradford method), electroencephalographic activity (EEG), cerebral edema expressed as brain water content (gravidimetric test), and behavior: Animex, righting reflex, pain reflex and Rotarod. TB was positive in GI in peripheral vascular areas in hippocampus, PC in CSF (ug/ml)(mean +/- SED) was GI: 40.6 +/- 6.8 and GII: 16.5 +/- 4.2 (p < 0.005), and the plasma levels were (mg/ml): GI: 108.8 +/- 7.6 and GII: 87.4 +/- 2 (NS). The EEG showed a higher power of the delta band in hypertensive rats (GI: 0.551 +/- 0.033 and GII: 0.342 +/- 0.031, p < 0.008), but water content was not different between GI and GII (water%/per/g/tissue) (GI: 79.21 +/- 0.2, GII: 78.95 +/- 0.18). These results, showing functional changes in the BBB and brain activity without behavioral alterations, suggest the development of a subclinic form of hepatic encephalopathy in our model of PH rats.

Cambios funcionales en el sistema nervioso central de ratas hipertensas portales prehepaticas. / [Functional alterations in central nervous system of prehepatic portal hypertensive rats]

Prehepatic Portal Hypertension (PH) leads to morphologic changes in the rat Central Nervous System, including alterations of the blood brain barrier (BBB), and astrogliosis and angiogenesis in CA1 and CA4 hyppocampal fields. The present study investigates functional changes in portal hypertensive rats. Wistar Kyoto rats were used (240 g/bw) and allotted in two groups: GI (n = 8) portal hypertensive rats obtained through a regulated stenosis of the portal vein (Groszmann), and GII (n = 6), sham-operated rats. We have analyzed: BBB integrity with the Trypan Blue diffusion method (TB, Reynolds), protein concentration (PC) in Cerebrospinal Fluid (CSF) and plasma (Bradford method), electroencephalographic activity (EEG), cerebral edema expressed as brain water content (gravidimetric test), and behavior: Animex, righting reflex, pain reflex and Rotarod. TB was positive in GI in peripheral vascular areas in hippocampus, PC in CSF (ug/ml)(mean +/- SED) was GI: 40.6 +/- 6.8 and GII: 16.5 +/- 4.2 (p < 0.005), and the plasma levels were (mg/ml): GI: 108.8 +/- 7.6 and GII: 87.4 +/- 2 (NS). The EEG showed a higher power of the delta band in hypertensive rats (GI: 0.551 +/- 0.033 and GII: 0.342 +/- 0.031, p < 0.008), but water content was not different between GI and GII (water

/per/g/tissue) (GI: 79.21 +/- 0.2, GII: 78.95 +/- 0.18). These results, showing functional changes in the BBB and brain activity without behavioral alterations, suggest the development of a subclinic form of hepatic encephalopathy in our model of PH rats.

[Does TNF-alpha contribute to liver disease physiopathology?]. / Contribuye el TNF-alpha a la fisiopatología de las hepatopatías?

The aim of the present paper is to establish the possible role of serum TNF in the pathophysiology of three experimental models of liver injury: paracetamol intoxication, cholestasis followed by paracetamol intoxication and cholestasis. We concluded that under our experimental conditions the serum TNF-alpha levels were not responsible for the inflammatory phenomena described in our previous paper as apoptosis.

Contribuye el TNF-alpha a la fisiopatología de las hepatopatías? / [Does TNF-alpha contribute to liver disease physiopathology?]

Theaim of the present paper is to establish the possible role of serum TNF in the pathophysiology of three experimental models of liver injury: paracetamol intoxication, cholestasis followed by paracetamol intoxication and cholestasis. We concluded that under our experimental conditions the serum TNF-alpha levels were not responsible for the inflammatory phenomena described in our previous paper as apoptosis.

[Benzodiazepines metabolism in various models of experimental liver diseases]. / Metabolismo de benzodiacepinas en distintos modelos de hepatopatías experimentales.

The aim of the present paper is to establish possible disturbances in benzodiazepines glucuronidation in two experimental models of liver injury: paracetamol acute intoxication and cholestasis followed by paracetamol acute intoxication. We concluded that, despite the alterations observed in liver microsomal lipid profile, glucuronidation remained similar to controls in paracetamol intoxicated rats. On the contrary, cholestatic animals followed by paracetamol intoxication showed an increment in the glucuronidation of the utilized substrated.

Metabolismo de benzodiacepinas en distintos modelos de hepatopatías experimentales. / [Benzodiazepines metabolism in various models of experimental liver diseases]

The aim of the present paper is to establish possible disturbances in benzodiazepines glucuronidation in two experimental models of liver injury: paracetamol acute intoxication and cholestasis followed by paracetamol acute intoxication. We concluded that, despite the alterations observed in liver microsomal lipid profile, glucuronidation remained similar to controls in paracetamol intoxicated rats. On the contrary, cholestatic animals followed by paracetamol intoxication showed an increment in the glucuronidation of the utilized substrated.

Prostanoid production in endothelial and Kupffer liver cells from monocrotaline intoxicated rats.

UNLABELLED: A single dose of monocrotaline, a pyrrolizidine alkaloid, was injected into rats in order to produce 25 (Group I) and 45 (Group II) days later a progressive and so called delayed liver injury. The present study investigated the prostanoid production of Kupffer cells and endothelial cells separated from Monocrotaline and saline (Group III) injected rat livers. Kupffer cells: formation of 6 keto Prostaglandin F1 alpha, the major prostacycline metabolite, gradually decreased in Groups I vs II (P < 0.01) and in both Groups I and II vs Controls (P < 0.01). In addition Prostaglandin F2 alpha showed a significant increase in Groups I and II when compared to Group III, (P < 0.001), and Thromboxane B2 was present in both Groups of Monocrotaline treated animals, while it was not detectable in the control Group III. Endothelial cells: 6 keto Prostaglandin F1 alpha decreased in Groups 1 vs II. This differences was significant when compared, and compared to controls (Group III, P < 0.001). Prostaglandin E2 was detected only in Groups I and II. Prostaglandin F2 alpha and Thromboxane B2 could not be detected in any Group. Ultramicroscopy showed morphological cell damage in nonparenchymal cells in Monocrotaline intoxication in Group II, rats sacrificed 45 days after the injection, while it shows normal features in those treated animals sacrificed 25 days after the injection, as well as in control group. CONCLUSION: A single Monocrotaline injection produces, 25 and 45 days later, severe and progressive alterations in the prostanoid production in Kupffer and Endothelial cells, while ultramicroscopic alterations was only observed 45 days after the injection of Monocrotaline. A decreased production of vasodilators and the presence of vasoconstrictor prostanoids that can participate in the production of the circulatory derangements enhancing liver injury and portal hypertension were also observed.

[Correlation between computed axial tomography and ileum obturating lymphadenectomy in localized adenocarcinoma of the prostate]. / Correlación entre tomografía axial computada y linfadenectomía ileoobturatriz en el adenocarcinoma de próstata localizado.

OBJECTIVE: To correlate the findings of CT and ileoobturator lymphadenectomy in patients with localized adenocarcinoma of the prostate. METHODS: 94 patients with adenocarcinoma of the prostate were evaluated. Ileoobturator lymphadenectomy and brachytherapy were performed in 61.1%, radical prostatectomy in 22.5% and lymphadenectomy with prostatic labeling for subsequent external radiation therapy in 5%. Lymph node CT and pathology findings were correlated. RESULTS: Of 92 patients with a normal CT scan, 18 had positive nodes and 19.1% were understaged. Two patients with a CT scan suggestive of metastatic adenopathy had negative pathology findings. Seventy-two of the 92 patients with normal CT scans had negative nodes, accounting for a specificity of 76.6%. CONCLUSION: Pelvic lymph node involvement changes the prognosis of prostate cancer. However, the ability of CT to detect lymph node metastasis is limited. It is therefore not a reliable method and raises the costs of staging unnecessarily.

[Correlation between prostate specific antigen and histopathologic findings in ileum-obturator node dissection]. / Correlación entre el antígeno prostático específico y los hallazgos histopatológicos de la linfadenectomía ilioobturatriz.

OBJECTIVE: To determine the correlation between PSA values and the histopathological findings of ileo-obturator node dissection in prostatic cancer. METHODS: We reviewed the data of 51 patients with clinically localized prostatic carcinoma, submitted to ileo-obturator node dissection before definitive treatment of the tumor. The patients were classified into 4 groups according to their previous PSA values: A < 10 ng/ml, B > 10 and < 20 ng/ml, C > 20 and < 50 ng/ml and D < 50 ng/ml. RESULTS: Overall 17.6% of the patients had positive lymph nodes; 9.9% of the patients in group A, 15.4% of the patients in group B, 11.1% of those in group C and 41.7% of those in group D had positive nodes. Using 50 ng/ml as the cut-off point, 10% of those with PSA < 50 ng/ml had positive nodes vs 42.3% of those with PSA > 50 ng/ml, which was statistically significant with the Fischer test. CONCLUSION: Preoperative PSA has a statistically significant correlation with positive nodes, considering 50 ng/ml as the cut-off point. PSA determination in patients that have received no treatment is essential in the diagnosis and evaluation of therapy in prostate cancer.

[Correlation between specific prostatic antigen and findings with total body bone scintigraphy]. / Correlación entre el antígeno prostático específico (P.S.A.) y los hallazgos del centellograma óseo corporal total (COCT).

OBJECTIVES: To analyze the correlation between PSA values, bony symptoms and total body bone scintiscanning in order to determine the utility of the latter technique in patients with adenocarcinoma of the prostate. METHODS: We analyzed the correlation between the PSA values, bony symptoms and total body bone scintiscan findings of 191 patients with adenocarcinoma of the prostate; of these, 129 patients met the criteria for inclusion into the study. RESULTS: Of the 128 patients, 32 (25%) had PSA value < 20 ng/ml, 48 (37.5%) had values ranging from 20-50 ng/ml and 48 (37.5%) had values > 50 ng/ml. The bone scintiscan was positive in only one of the 32 patients with PSA < 20 ng/ml, 45.8% of those with PSA values between 20-50 ng/ml and 70.8% of those with PSA values > 50 ng/ml. All of the patients with PSA < 20 ng/ml and no bony symptoms had a negative bone scintiscan. All patients with PSA > 20 ng/ml and bony symptoms had a positive bone scintiscan. CONCLUSIONS: PSA is a biological marker that can effectively predict the scintiscan findings. The bone scintiscan was negative in 96.9% of the patients with PSA < 20 ng/ml. Total body bone scintiscanning can therefore be obviated in patients with PSA < 20 ng/ml and no bony symptoms, thereby reducing health costs without altering the benefits.

[Treatment of the regional lymph nodes in squamous carcinoma of the penis]. / Tratamiento de los ganglios regionales en el carcinoma escamoso de pene.

OBJECTIVES: We evaluated the management of the regional lymph nodes to determine the appropriate treatment for carcinoma of the penis. METHODS: The records of 36 patients with carcinoma of the penis were reviewed. Lymphadenectomy was performed in 18 patients, 17 were managed conservatively (watchful waiting) and 1 patient had a biopsy and received radiotherapy. RESULTS: Positive nodes were found in 2 of 2 pT4, 2 of 3 pT3, 8 of 13 pT2 and 2 of 12 pT1 patients submitted to lymphadenectomy. Concerning the histological grade, positive nodes were found in all of the 4 G3, 5 of 12 G2 and 3 of 20 G1 patients. The survival rate was 100% for the patients with negative lymph nodes (pNO = 6) or a single positive inguinal lymph node (pN1 = 5). A correlation was found between the T and the histological grade and the likelihood of lymph node invasion. CONCLUSIONS: The T and the histological grade of the primary lesion must be considered when deciding the approach in the management of the lymph nodes as unnecessary lymphadenectomy can be avoided and those at high risk of lymph node invasion can be treated radically and timely.