Evaluation of the antitumor activity of interleukin-12 in an experimental murine model of colorectal cancer induced by 1,2 dimethyl-hydrazine (DMH).

OBJECTIVE: Interleukin 12 (IL-12) is a cytokine that may enhance the proliferation and cytotoxic activity of T lymphocytes and natural killer (NK) cells. A relationship between extensive intratumoral infiltration of NK cells and longer survival rates in colorectal cancer (CRC) patients was previously noted. Preliminary evidence suggests that the combined administration of IL-12 and IL-2 may produce additive immunomodulatory activity. The purpose of this study was to determine whether the systemic administration of IL-12 (+/- IL-2) may induce an immune response against CRC as induced by 1,2-dimethylhydrazine (DMH). METHODS: Sixty-five 6-week-old Wistar rats were treated with weekly subcutaneous injections of DMH for 26 weeks at a dose of 20 mg/kg of body weight. Once tumoral induction was over, the animals were randomly allocated to one of three groups: I, control; II, intraperitoneal injections of IL-12; III, intraperitoneal injections of IL-12 combined with IL-2. At 30 weeks, all surviving animals were sacrificed. We studied the following parameters in each rat--number of tumors, size of tumors, and total tumoral volume. Tumor samples were studied using the monoclonal antibody CD 57 for the detection of NK cells. The extent of NK infiltration was classified as small, less than 50 NK cells/50 high-power field (HPF); moderate, 50 to 150 NK cells/50 HPF, and extensive, more than 150 NK cells/50 HPF. RESULTS: Thirty-five rats died before completion of the carcinogen exposure, and 30 rats were randomized (10 each group). In group II, 2 animals died during treatment. All rats in groups I and III developed tumors, while in group II two rats (25%) were tumor-free. Moreover, only one rat in group II developed multiple neoplasms, in contrast with group I and group III, where six rats (60%) and seven rats (70%), respectively, had more than one tumor. We found statistically significant differences in the mean number of tumors found in group II when compared to group I (p = 0.028) and group III (p = 0.019). Other parameters measured, such as biggest tumor size and total tumoral volume were found to be lower in group II, although no statistical differences were found between groups. Only 10% of rats in group I showed moderated/extensive NK cell infiltration, vs. 60% of rats in group II (p = 0.077) and 70% in group III (p = 0.02). CONCLUSION: The administration of DMH to rodents provides a reliable and consistent means of inducing CRC that may be suitable for the evaluation of anti-cancer therapies. Our findings suggest that IL-12 is effective against the development of experimental CRC. Its antineoplastic effect could be attributed to the stimulus of this cytokine on the intratumoral infiltration of NK cells.

Estudio de la respuesta antitumoral de la interleucina- 12 en cáncer de colon inducido mediante 1, 2-dimetilhidracina (DMH) / Evaluation of the antitumor activity of interleukin-12 in an experimental murine model of colorectal cancer induced by 1, 2 dimethyl-hydrazine (DMH)

Objetivo: la interleucina (IL-12) es una citocina que estimulala proliferación y la actividad citotóxica de los linfocito T y las célulasnatural killer (NK). En trabajos previos se ha observado unarelación entre la infiltración intratumoral de células NK y una mayorsupervivencia en carcinomas colorrectales (CCR). Existen evidenciasde un efecto aditivo en la actividad inmunomoduladora dela asociación de IL-12 con IL-2. Así, nos hemos propuesto el estudiode la capacidad de respuesta inmune antitumoral, tras la administraciónsistémica de IL-12 sola o combinada con IL-2, en unmodelo experimental de CCR inducidos mediante la administraciónde 1,2-dimetilhidracina (DMH).Método: sesenta y cinco ratas Wistar de 6 semanas a las quese administró en inyección subcutánea una dosis semanal deDMH a razón de 20 mg/kg de peso durante 26 semanas. Finalizadoel periodo de inducción, los animales se distribuyeron aleatoriamenteen tres grupos. I: grupo control. Grupo II, se administróIL-12 recombinante murina. Grupo III: se administró IL-12, combinadacon IL-2. Las ratas se sacrificaron en la semana 30, estudiándoselos siguientes parámetros: número y localización de tumores,tamaño y carga tumoral. Se realizó inmunotinción paracélulas NK con anticuerpo monoclonal CD 57. Se establecierontres grupos según la cuantía del infiltrado: leve, menos 50 células/50 campos de gran aumento (CGA), moderado, entre 50 y150/células/50 CGA y elevado, más de 150 células/50 CGA.Resultados: durante la inducción tumoral fallecieron 35 ratas.Las 30 restantes fueron distribuidas aleatoriamente en 3 gruposde 10. Durante las 2 semanas de tratamiento fallecieron 2 ratas,del grupo II. Todas las ratas de los grupos I y III desarrollaronCCR. En el grupo II, dos animales (25%) no desarrollaron tumor.Sólo una rata del grupo II desarrolló neoplasias múltiples en contrastecon el grupo I en el que esto ocurrió en 6 ratas (60%) y siete(70%) en el grupo III. Se hallaron diferencias estadísticamentesignificativas en el número de tumores desarrollados entre el grupoII respecto al I (p = 0,028) y al grupo III (p = 0,019). El mayortamaño tumoral o el volumen tumoral total fueron menores en elgrupo II pero no se obtuvieron diferencias estadísticamente significativascon los restantes grupos. Un 10% de las ratas del grupo Ipresentó moderada o extensa infiltración, frente al 60% del grupoII (p = 0,077) y al 70% del grupo III (p = 0,02). Entre los grupos IIy III no se encontró ninguna diferencia estadística (p = 1).Conclusión: El modelo usado de inducción tumoral es un modeloútil para el estudio de la eficacia de distintos tratamientos antitumorales.Pensamos que la IL-12 tiene un efecto antineoplásicofrente al desarrollo de tumores experimentales, lo que puede seratribuido, al menos en parte, al estímulo ejercido por esta citocinasobre los infiltrados intratumorales de células NK

Objective: interlukin 12 (IL-12) is a cytokine that may enhancethe proliferation and cytotoxic activity of T lymphocytesand natural killer (NK) cells. A relationship between extensive intratumoralinfiltration of NK cells and longer survival rates in colorectalcancer (CRC) patients was previously noted. Preliminaryevidence suggests that the combined administration of IL-12 andIL-2 may produce additive immunomodulatory activity. The purposeof this study was to determine whether the systemic administrationof IL-12 (+/- IL-2) may induce an immune responseagainst CRC as induced by 1,2-dimethylhydrazine (DMH).Methods: sixty-five 6-week-old Wistar rats were treated withweekly subcutaneous injections of DMH for 26 weeks at a dose of20 mg/kg of body weight. Once tumoral induction was over, theanimals were randomly allocated to one of three groups: I, control;II, intraperitoneal injections of IL-12; III, intraperitoneal injectionsof IL-12 combined with IL-2. At 30 weeks, all surviving animalswere sacrificed. We studied the following parameters in eachrat – number of tumors, size of tumors, and total tumoral volume.Tumor samples were studied using the monoclonal antibodyCD 57 for the detection of NK cells. The extent of NK infiltrationwas classified as small, less than 50 NK cells/50 high-power field(HPF); moderate, 50 to 150 NK cells/50 HPF, and extensive,more than 150 NK cells/50 HPF.Results: thirty-five rats died before completion of the carcinogenexposure, and 30 rats were randomized (10 each group). Ingroup II, 2 animals died during treatment. All rats in groups I andIII developed tumors, while in group II two rats (25%) were tumorfree.Moreover, only one rat in group II developed multiple neoplasms,in contrast with group I and group III, where six rats(60%) and seven rats (70%), respectively, had more than one tumor.We found statistically significant differences in the meannumber of tumors found in group II when compared to group I(p=0.028) and group III (p = 0.019). Other parameters measured,such as biggest tumor size and total tumoral volume were found tobe lower in group II, although no statistical differences were foundbetween groups. Only 10% of rats in group I showed moderated/extensive NK cell infiltration, vs. 60% of rats in group II (p =0.077) and 70% in group III (p = 0.02).Conclusion: The administration of DMH to rodents provides areliable and consistent means of inducing CRC that may be suitablefor the evaluation of anti-cancer therapies. Our findings suggest thatIL-12 is effective against the development of experimental CRC. Itsantineoplastic effect could be attributed to the stimulus of this cytokineon the intratumoral infiltration of NK cells

Los limites del consentimiento informado en la especialidad de aparato digestivo / The limits od informed consent in gastroenterology

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The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma.

BACKGROUND: Natural killer (NK) cells have a spontaneous cytotoxic capacity-against tumor cells. These cells represent a small proportion of human colon carcinoma-infiltrating lymphocytes. Their prognostic significance in these tumors has yet to be determined. METHODS: One hundred and fifty-seven patients who each had a colectomy for large bowel adenocarcinoma were studied. No patient received adjuvant therapy. Immunohistochemical stains were performed for NK cells using the monoclonal antibody CD57. The number of NK cells was counted using a MICRON image analyzer. The total area studied for each tumor was 1 cm2. In this area, 50 intratumoral fields of 0.173 mm2 were selected. The degree of NK infiltration was classified as little (< 50 NK cells), moderate (50-150 NK cells), and extensive (> 150 NK cells). The Kaplan-Meier method was used to obtain survival figures. Multivariate analyses were performed using the Cox regression model. RESULTS: At 5 years, patients with little and moderate NK infiltration showed significantly shorter survival rates (overall and disease free survival) than those with extensive infiltration (P < 0.01). Three significant factors affecting survival were selected in a stepwise fashion in increasing order as follows: TNM stage, NK infiltration, and lymphocytic infiltration. Patients with TNM Stage III disease and extensive NK infiltration showed significantly longer survival rates than those with little or moderate infiltration (P < 0.001). In these patients, multivariate analysis using the Cox regression model identified two significant variables: number of involved lymph nodes and NK cells infiltration. CONCLUSIONS: In patients with colorectal carcinoma, an extensive intratumoral infiltration of NK cells is associated with a favorable tumor outcome. Intratumoral infiltration of NK cells can be used as a variable with prognostic value, especially in patients with TNM Stage III disease.

Microparticle immunoenzymatic assay for detection of prostate specific antigen: characterization of the technique and comparative analysis with a monoclonal immunoradiometric assay.

Microparticle immunoenzymatic assay (MEIA) is a new, ultrasensitive technique recently introduced for detection of prostatic specific antigen (PSA). It is easily performed, totally automated, and cheaper and faster than radioimmunometric techniques. In this study, the levels of PSA in 194 males with urologic problems and healthy males, recorded by microparticle monoclonal ultrasensitive enzymoimmunoassay (MEIA) and immunoradiometric assay (IRMA), are comparatively evaluated. Variables recorded were age of patient, size and weight of the prostate, and PSA levels analyzed by the MEIA (MEIA-PSA) and IRMA (ELSA-PSA) techniques. Different determinations of PSA were performed in order to calculate the intra- and interassay variation coefficient for the MEIA-PSA assay. Means of prostatic length, width, and depth, recorded by ultrasonography, were 28.3, 35.8, and 31.4 mm, respectively, with a mean prostatic size of 19 ml and a mean prostatic weight of 23.9 g. Mean IRMA-PSA was 4.53 ng/ml and mean MEIA-PSA was 2.04 ng/ml. The difference between them was 2.49, and the ratio IRMA-PSA:MEIA-PSA was 3.17. Interassay and intraassay variation coefficients for MEIA-PSA were 6.58 and 9.96%, respectively. MEIA-PSA values correlated linearly with the age of the patients (r = 0.65, p = 0.0001), size of the prostate (r = 0.71, p = 0.0001), weight of the prostate (r = 0.71, p = 0.0001), and the value of IRMA-PSA (r = 0.80, p = 0.0001). Paired t tests showed that the values of PSA measured by MEIA and IRMA are statistically different (p = 0.0001), with independence of the level of PSA considered.

[A consensus on Helicobacter pylori and gastroduodenal pathology]. / Consenso sobre Helicobacter pylori y patología gastroduodenal.

The current debate involving Helicobacter pylori (H.p.) and its potential role as an etiological factor for some digestive diseases, as well as the recent discussion through different mass media of this bacterium, including the American N.I.H. Consensus, have lead to the discussion of the H.p. problem, in order to clarify its real importance in acid-related diseases. Thus we want, as gastroenterologists, to give an overview of the current status, so as to facilitate the general practitioner work when confronted with gastrointestinal diseases, particularly related to H.p. Our purpose is to provide a critical and objective view regarding the implications of H.p. infection, and explain when treatment is needed and how this treatment should be accomplished.

[Gastric ulcers caused by post-burning stress: contribution of free radicals]. / Ulceras gástricas de estres postquemadura: contribución de los radicales libres.

The purpose of this study was to analyse the blocking effect of superoxide dismutase (S.O.D.) at doses of 15.000 U.I. per kilogram (body weight), on the release of oxygen-derived free radicals, experimentally caused in the rat by burning 20% of the surface of its body, and its impact over macroscopic and microscopic lesions of the gastric mucosa. We used 48 rats divided into 5 groups. In groups 3 and 5 we provided S.O.D. i.v. immediately after the burn. All the animals had a catheter in their femoral vein for the administration of drugs. Morphologic data showed that 2 hours after the burn S.O.D. did not have any influence on the gastric injury; 5 hours after the burn, the morphologic damage of the gastric mucosa was less severe. The scavenging of the superoxide ion (free radical) by the superoxide dismutase may be responsible of the lower tissular damage of the gastric mucosa. These results confirm that a period of initial ischaemia may be an important etiopathogenic factor in severe lesions of the gastric mucosa after burns.

[AIDS as non-suspected cause of chronic diarrhea and malabsorption]. / El SIDA como causa insospechada de diarrea crónica y malabsorción.

We report a case of chronic diarrhoea resulting in malabsorption syndrome in a patient with AIDS. Diarrhoea started two years before AIDS was diagnosed. The absence of risk factors may have delayed the diagnosis.

[A comparative analysis of monoclonal assays for the determination of PSA: radioimmunometric assay (ELSA) vs microparticle immunoenzyme assay (MEIA)]. / Análisis comparativo de dos ensayos monoclonales para la determinación de PSA: ensayo radioinmunométrico (ELSA) vs ensayo inmunoenzimático de micropartículas (MEIA).

Comparative analysis of PSA values measured by MEIA and ELSA techniques in a group of 70 unselected patients. A good correlation was observed between PSA levels determined by ELSA-PSA immunoradiometric techniques and those obtained by MEIA-PSA (r = 0.93, p < 0.00001). However, ELSA-PSA values have been 1.73 +/- 0.1 times higher than those by MEIA-PSA. A mean-paired comparison indicates that PSA mean levels (0.48 +/- 0.07 and 0.29 +/- 0.05 for ELSA and MEIA, respectively) are significantly different and define two groups of nonhomogeneous values (p < 0.0001). The same results are obtained when patients with PSA values higher and lower than 4 ng/ml are analyzed separately. For patients with PSA lower than 1 ng/ml, the difference between mean ELSA-PSA and MEIA-PSA values disappears; 0.74 +/- 0.08 vs 0.62 +/- 0.05, respectively (p > 0.1). In this group, the results from both assays are statistically consistent. When considering the group of patients with PSA < 1 ng/ml, no difference between both techniques becomes apparent, which seems to indicate the absence of differences in sensitivity between both techniques when considering low levels of serum PSA. Nevertheless, it is clear that the results from these techniques can not overlap and are not comparable and so, to all practical effects, it is recommended that follow-up of any particular patient is made always with the same technique and even at the same laboratory.

[Undescended testicle treated with FSH and HCG]. / Tratamiento médico del testículo no descendido con FSH y HCG.

Medical treatment with FSH and HCG was tested during 21 days in 47 cases (76 testis) of undescended testis. The average testis size, as measured by ecography, increased from 0.828 cc to 1.57 cc 48 hours after completing the treatment. Three months later the average testis size was 1.025 cc and 1.24 cc at six months. FSH increased slightly and total testosterone and free testosterone increased significantly. After treatment, 68% of the previously undescended testis descended.

Prevalencia de marcadores sericos del virus de la hepatitis B en el personal femenino de un hospital general / Prevalence of serum markers of hepatitis B virus in female personnel of a general hospital

Hemos determinado los marcadores del virus de la hepatitis B a 209 mujeres del personal de un hospital general: 12 Médicos, 90 ATS, 70 Auxiliares de clínica y de laboratorio y 37 personas de Personal de limpieza y office. La prevalencia fue del 15,31% (32 personas). Cuatro personas (1,91%) presentaron HBs-Ag. La prevalencia fue más baja que las encontradas por otros autores de nuestro país. Las prevalencias más altas se encontraron en el personal de limpieza y office, seguido de los ATS. Por Servicios, las prevalências más altas se encontraron en el personal en contacto con sangre y hemoderivados. No se encontraron marcadores en el personal de la UVI. La prevalencia aumentó y generalmente con la edad y la antigüedad. Asociamos los bajos índices de prevalencia encontrados por nosotros con los elevados porcentajes de personal joven (33,49%) tienen menos de 30 años y con poca antigüedad en el hospital (26,31% con menos de 4 años

Prevalencia de marcadores sericos del virus de la hepatitis B en el personal femenino de un hospital general / Prevalence of serum markers of hepatitis B virus in female personnel of a general hospital

Hemos determinado los marcadores del virus de la hepatitis B a 209 mujeres del personal de un hospital general: 12 Médicos, 90 ATS, 70 Auxiliares de clínica y de laboratorio y 37 personas de Personal de limpieza y office. La prevalencia fue del 15,31% (32 personas). Cuatro personas (1,91%) presentaron HBs-Ag. La prevalencia fue más baja que las encontradas por otros autores de nuestro país. Las prevalencias más altas se encontraron en el personal de limpieza y office, seguido de los ATS. Por Servicios, las prevalÛncias más altas se encontraron en el personal en contacto con sangre y hemoderivados. No se encontraron marcadores en el personal de la UVI. La prevalencia aumentó y generalmente con la edad y la antig³edad. Asociamos los bajos índices de prevalencia encontrados por nosotros con los elevados porcentajes de personal joven (33,49%) tienen menos de 30 años y con poca antig³edad en el hospital (26,31% con menos de 4 años (AU)