TNF/IL-1/NIK/NF-kappa B transduction pathway: a comparative study in normal and pathological human prostate (benign hyperplasia and carcinoma).

AIMS: Tumour necrosis factor (TNF)-alpha induces death or cell proliferation by activation of nuclear factor (NF)-kappaB, also activated by interleukin (IL)-1 alpha. The aim was to investigate upstream and downstream components of NIK transduction pathway in normal (NP), benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN) and prostatic carcinoma (PC). METHODS AND RESULTS: Immunohistochemistry and Western blotting were performed. In NP, the cytoplasm of epithelial cells was intensely immunoreactive to IL-1 receptor-associated kinase (IRAK), TNF receptor-associated factor (TRAF)-6, NF-kappaB inducing kinase (NIK), I kappa kappa alpha/beta, I kappaB alpha and p-I kappaB; weakly to NF-kappaB-p50; and negative to NF-kappaB-p65. BPH samples were intensely immunoreactive to IRAK, TRAF-6, NIK, I kappa kappa alpha/beta, I kappaB alpha, p-I kappaB; weakly to NF-kappaB-p50 and NF-kappaB-p65. Whereas low-grade PIN showed intermediate results between NP and BPH, results in high-grade PIN were similar to those found in PC (low Gleason). In PC, immunoreactivity was intense for IRAK, TRAF-6, NIK, I kappa kappa alpha/beta (increasing with Gleason), I kappaB alpha, p-I kappaB (decreasing with Gleason); weak for NF-kappaB-p50 and NF-kappaB-p65 (decreasing with Gleason). Nuclear NF-kappaB was observed in PC. CONCLUSIONS: NF-kappaB enhances cell proliferation, but also ATF-2 or Elk-1. Since IL-1 and TNF-alpha are related to inflammation and their immunoexpression increases in PC, inhibition of these cytokines might be a possible target for PC treatment, because they decrease the activity of all transduction pathway members that activate transcription factors such as NF-kappaB, Elk-1 or ATF-2.

The p38 transduction pathway in prostatic neoplasia.

It has been proposed that, among other cellular responses, TNF-alpha induces not only cell death, but also cell proliferation by activation of p38. It has also been reported that IL-1-alpha favours cell proliferation by p38 activation. The aim of the present study was to evaluate upstream (alpha-PAK, MEK-6) and downstream (Elk-1 and ATF-2) components of the p38 transduction pathway in normal prostate, benign prostatic hyperplasia (BPH), and prostate carcinoma (PC). Immunohistochemical and western blot analyses were performed in 20 samples of normal prostate, 47 samples of BPH, and 27 samples of PC. In all normal prostates, immunoreactivity for p-Elk-1 and p-ATF-2 was observed in epithelial cell nuclei, but no expression of alpha-PAK or MEK-6. In BPH, there was expression of alpha-PAK (cytoplasm) and MEK-6 (cytoplasm), while the proportions of lesions that were immunoreactive for p-Elk-1 (nucleus and cytoplasm) and p-ATF-2 (nucleus) decreased. In PC, the percentages of cells that were immunoreactive for alpha-PAK (cytoplasm) or MEK-6 (cytoplasm) rose slightly in comparison with BPH, while the percentages of cells that were immunoreactive for p-Elk-1 (nucleus and cytoplasm) or p-ATF-2 (nucleus and cytoplasm) were much higher than in BPH. It is concluded that overexpression of alpha-PAK, MEK-6, p38, p-Elk-1, and p-ATF-2 in BPH, and more intensely in PC, enhances cell proliferation. In BPH, such proliferation is triggered by IL-1 and in part counteracted by the TNF-alpha/AP-1 pathway, which promotes apoptosis. In PC, proliferation is triggered by IL-1 and TNF-alpha (the TNF-alpha/AP-1 pathway is diverted towards p38 activation). Since in a study of the same patients immunoexpression of IL-1alpha and IL-1RI was previously observed to be increased in PC, inhibition of p38 is a possible target for PC treatment, as this inhibition would both decrease IL-1-induced cell proliferation and increase TNF-alpha-induced cell death.

[Diagnostic efficacy of fine needle aspiration biopsy in patients with thyroid nodular disease. Analysis of 510 cases]. / Eficacia diagnóstica de la punción-aspiración con aguja fina en pacientes con patología nodular tiroidea. Análisis de 510 casos.

INTRODUCTION: The prevalence of palpable thyroid nodules in the general population is 4%-7%. Although most are benign, 5% are carcinomas. This study aimed to assess the efficacy of fine needle aspiration biopsy (FNAB) of thyroid nodules to diagnose malignancy and know the benefit of repeating the FNAB in the same nodule. PATIENTS AND METHODS: A total of 510 patients (431 women and 79 men; mean age [standard deviation]: 47.6 [14.3] years) with surgery due to thyroid nodular condition between 1989 and 2002 and who had at least one FNAB prior to the surgery were studied. RESULTS: The first FNAB was benign in 312 patients (61.2%), malignant in 38 (7.5%), suspicious or indeterminate in 97 (19%) and insufficient in 63 (12.4%). Sensitivity and specificity in the first FNAB for malignancy diagnosis was 76% and 84%, respectively. Successive FNABs had a moderate concordance and significance. However, repeating the puncture did not improve diagnostic performance, since sensitive increased (84%), but specificity worsened (79%) and the area under the ROC curve was similar. In the group with suspicious or indeterminate FNAB, histology was benign in 70% and malignant in 30%. CONCLUSIONS: FNAB sensitivity and specificity for diagnosis of malignancy in thyroid nodules are high. Repetition of puncture on the same nodule does not improve diagnostic performance of the cytology. Among patients with suspicious FNAB, there is a high proportion of malignancy, which makes surgery necessary in these cases.

Eficacia diagnóstica de la punción-aspiración con aguja fina en pacientes con patología nodular tiroidea. Análisis de 510 casos / Diagnostic efficacy of fine needle aspiration biopsy in patients with thyroid nodular disease. Analysis of 510 cases

Introducción. La prevalencia de nódulos tiroideos palpables en la población general es del 4%-7%. Aunque la mayoría son benignos, un 5% son carcinomas. El objetivo de este estudio fue valorar la eficacia de la punción-aspiración con aguja fina (PAAF) de los nódulos tiroideos para diagnosticar malignidad y conocer el rendimiento de repetir la PAAF en el mismo nódulo. Pacientes y métodos. Se estudiaron 510 pacientes (431 mujeres y 79 varones; edad media [desviación estándar]: 47,6 [14,3] años) intervenidos quirúrgicamente por patología nodular tiroidea entre 1989 y 2002 y que tenían, al menos, una PAAF previa a la cirugía. Resultados. La primera PAAF fue benigna en 312 pacientes (61,2%), maligna en 38 (7,5%), sospechosa o indeterminada en 97 (19%) e insuficiente en 63 (12,4%). La sensibilidad y especificidad de la primera PAAF para el diagnóstico de malignidad fue del 76% y 84%, respectivamente. Las PAAF sucesivas tuvieron una concordancia moderada y significativa; sin embargo, la repetición de la punción no mejoró el rendimiento diagnóstico, ya que aumentó la sensibilidad (84%), pero empeoró la especificidad (79%) y el área bajo la curva ROC fue similar. En el grupo con PAAF sospechosa o indeterminada la histología fue benigna en el 70% y maligna en el 30%. Conclusiones. La sensibilidad y especificidad de la PAAF para el diagnóstico de malignidad en los nódulos tiroideos son elevadas. La repetición de la punción sobre el mismo nódulo no mejora el rendimiento diagnóstico de la citología. Entre los pacientes con PAAF sospechosa existe una proporción elevada de malignidad, lo que obliga a la intervención quirúrgica en estos casos

Introduction. The prevalence of palpable thyroid nodules in the general population is 4%-7%. Although most are benign, 5% are carcinomas. This study aimed to assess the efficacy of fine needle aspiration biopsy (FNAB) of thyroid nodules to diagnose malignancy and know the benefit of repeating the FNAB in the same nodule. Patients and methods. A total of 510 patients (431 women and 79 men; mean age [standard deviation]: 47.6 [14.3] years) with surgery due to thyroid nodular condition between 1989 and 2002 and who had at least one FNAB prior to the surgery were studied. Results. The first FNAB was benign in 312 patients (61.2%), malignant in 38 (7.5%), suspicious or indeterminate in 97 (19%) and insufficient in 63 (12.4%). Sensitivity and specificity in the first FNAB for malignancy diagnosis was 76% and 84%, respectively. Successive FNABs had a moderate concordance and significance. However, repeating the puncture did not improve diagnostic performance, since sensitive increased (84%), but specificity worsened (79%) and the area under the ROC curve was similar. In the group with suspicious or indeterminate FNAB, histology was benign in 70% and malignant in 30%. Conclusions. FNAB sensitivity and specificity for diagnosis of malignancy in thyroid nodules are high. Repetition of puncture on the same nodule does not improve diagnostic performance of the cytology. Among patients with suspicious FNAB, there is a high proportion of malignancy, which makes surgery necessary in these cases

Aspiration cytology of 147 adnexal cysts with histologic correlation.

OBJECTIVE: To assess the usefulness of cytology in the diagnosis of 147 histologically established adnexal cysts. STUDY DESIGN: Retrospective, macro-microscopic study based on fluid aspirated from 132 ovarian and 15 extraovarian cysts and projected as a cytohistologic correlation. RESULTS: Typical macroscopic features were identified in 76% of endometriotic cysts, in 53% of mucinous neoplasms and in 67% of dermoid cysts. Cytology helped to identify 67% of nonneoplastic and 56% of neoplastic cysts. The lowest diagnostic sensitivities were observed in functional cysts and benign serous neoplasms (50%), while the highest were shown by endometriotic cysts (76%) and malignant epithelial neoplasms (71%). Inadequate samples were obtained from all types of cysts, even malignant ones (two mucinous cystadenocarcinomas). Diagnostic cytology was useless in extraovarian cysts (33% sensitivity). An adult granulosa cell tumor was erroneously diagnosed as a follicular cyst by cytologic examination. CONCLUSION: Examination of the cyst fluids obtained by aspiration demonstrated low sensitivity, with 43% of inadequate samples obtained from all types of cysts. Malignant cystic neoplasms may be overlooked in inadequate samples. Our study also revealed that specificity in this type of analysis is high in inadequate samples, provided that the technique is carried out correctly.

Changes in renal function in acute experimental pancreatitis in rats: a therapeutic role for somatostatin.

1. The present study was designed to determine the changes in renal function in two models of experimental pancreatitis in rats, in an attempt to assess the possible pathogenic role of reactive oxygen species and to elucidate a possible therapeutic role for somatostatin. 2. Mild pancreatitis was induced by low blockade of the biliary duct and severe pancreatitis was evoked by retrograde infusion of bile salts. Renal function was studied by clearance techniques in rats with pancreatitis, treated or not treated with somatostatin. Plasma and glomerular malonyldialdehyde levels were measured by the thiobarbituric acid method. 3. Renal function did not change in rats with low blockade of the biliary duct, but animals receiving a retrograde infusion of bile salts showed a significant decrease in glomerular filtration rate and renal plasma flow with respect to sham-operated animals. 4. Plasma malonyldialdehyde levels increased significantly in rats treated with bile salts with respect to control animals, whereas no changes were detected in glomerular malonyldialdehyde levels. Thus, the renal dysfunction does not seem to be related to an increased production of reactive oxygen metabolites at the glomerular level. 5. Somatostatin infusion significantly improved renal function in rats with severe pancreatitis (retrograde infusion of bile salts) by increasing glomerular filtration rate, renal plasma flow and filtration fraction. These results support a possible therapeutic role for somatostatin in the renal dysfunction associated with the severe forms of pancreatitis.

[Effect of preoperative radiotherapy in the detection of lymphatic metastasis of rectal cancer]. / Efecto de la radioterapia preoperatoria en la detección de las metástasis ganglionares del cáncer de recto.

The purpose of this study was to assess whether the understaging of rectal tumors seen after preoperative radiotherapy is due to the biological effect of the irradiation or reflect the difficulties of the pathologists in identifying lymph nodes from radiated specimens. To study this question a retrospective non randomized study was undertaken including 31 patients with rectal cancer and oncological resection, 16 after preoperative administration of 36 Gy and 15 without radiotherapy. Metastatic lymph nodes were found in 37% of patients of the radiated group and in 58% of no irradiated group, being de difference between them of 16% with a confidence interval from -15% to 40%. A mean of 13 and 18 lymph nodes were identified in the radiated and non radiated group respectively, being the difference between means of 5 with a confidence interval from -0.6 to 10. A 80% and 57% of the pathological reports in no radiated and radiated group respectively accomplished the criteria of reliability (> 13 lymph modes isolated), being the difference between proportions of 27% with a confidence interval from -3% to 57%. Based on the above stated results no conclusive answer can be addressed to the proposed question; both effects could participate in the downstaging. More studies including more patients are needed to give a reliable answer to the proposed question.

Neurilemoma of the breast in a man. A case report.

A case of neurilemoma of the left breast in an 83-year-old man is presented, including the fine needle aspiration and biopsy diagnosis. A review of the literature did not reveal the existence of such a tumor in a man's breast. The aspirate yielded a cellular smear composed of clusters of spindle-shaped cells showing minimal atypia and Verocay bodies. The final diagnosis was established on the excised mass through histopathologic study.

Cytodiagnosis of gastric ulcer penetration of the liver by examination of endoscopic brushings.

The penetration of a gastric peptic ulcer into the liver was initially diagnosed by the cytologic examination of endoscopic brushings and later confirmed by an endoscopic biopsy of the stomach. One of the smears of the gastric brushing contained sparse groups of liver cells with mild atypia. The endoscopic biopsy specimen included liver parenchyma with signs of peptic hepatitis. The differential diagnostic considerations for a gastric brushing containing hepatoid cells are discussed.

Quantitative and ultrastructural alterations in the lamina propria and Sertoli cells in human cryptorchid testes.

A quantitative and ultrastructural study was performed on biopsies of human cryptorchid testes to investigate lesions in the lamina propria and Sertoli cells. Prepubertal cryptorchid testes (1-9 years of age) were classified into four groups: Type 1, testes with minimal lesions; Type II, testes with a moderate decrease in tubule diameter and spermatogonal number; Type III, testes with Sertoli cell hypoplasia and a marked reduction in tubule diameter and spermatogonal number; and Type IV, testes with Sertoli cell hyperplasia and a variable reduction in spermatogonal number. An increase in thickness of the lamina propria was found in Type II and III testes from 5 years of age onwards. These testes also showed a decrease in both the average number of peritubular cells per cross-sectioned tubule and in the average nuclear volume of these cells. Most of the postpubertal cryptorchid testes from 13- to 18-year-old youths presented a prepubertal pattern suggestive of delayed testicular maturation. Postpubertal testes from 19- to 27-year-old men were classified into three types: Type A testes showed complete spermatogenesis, mature Sertoli cells and no lesions in the lamina propria; Type B testes showed isolated spermatogonia, mature Sertoli cells, and a marked thickening of the lamina propria; and Type C testes showed isolated spermatogonia, hyperplasia of immature Sertoli cells, and a slightly thickened lamina propria. Maturation of the lamina propria was always associated with maturation of the Sertoli cells. Thickening of the lamina propria was associated with peritubular cell alterations consisting of decreases in the nuclear volume (average and total per testis) of peritubular cells and increases in the number of these cells per cross-sectioned tubule. The three types of adult cryptorchid testes appear to be the postpubertal transformation of Type 1 testes (Type A), Type II and Type III testes (Type B), and Type IV testes (Type C).

Laminin, type IV collagen, and fibronectin in normal and cryptorchid human testes. An immunohistochemical study.

An immunohistochemical study of laminin, type IV collagen, and fibronectin was carried out in the testes of normal men and in the cryptorchid and contralateral scrotal testes of cryptorchid men from 2 to 40 years of age. The integrated optical density (IOD) per unit area of the lamina propria was measured in the immunostained sections. Fibronectin was found throughout the thickness of the lamina propria of the seminiferous tubules and in the interstitial connective tissue. No differences between normal and cryptorchid testes were found. Laminin was observed in the innermost part of the lamina propria of the seminiferous tubules and surrounding the endothelium of blood capillaries from infancy. No differences were found between normal and cryptorchid testes in the prepubertal period. In adult cryptorchid testes, laminin formed more numerous and deeper invaginations towards the seminiferous epithelium than in normal adult testes. Type IV collagen appeared throughout the thickness of the lamina propria of normal testes as well as in the wall of interstitial blood vessels. From infancy, the lamina propria of seminiferous tubules, but not blood vessel walls, showed lesser immunostaining for type IV collagen and a lower IOD of this component than did control tests from men of the same age. No differences between unilateral and bilateral cryptorchidism were found. The contralateral scrotal testes of cryptorchid males showed intermediate immunostaining for type IV collagen between that of normal control testes and that of cryptorchid testes. These findings suggest that the lamina propria of seminiferous tubules is lesioned at an early age in both cryptorchid and contralateral scrotal testes of cryptorchid men.

Anatomic findings in acute papillary muscle necrosis.

To investigate the consequences of acute papillary muscle necrosis of the left ventricle, 25 cases from a total of 133 autopsies of acute myocardial infarction were studied. Cardiac hypertrophy was found in 84%. The anterior papillary muscle was involved in four cases, the posterior in 13, and both muscles in eight. Left ventricular subendocardial infarction was found in 32% of cases. The size of left ventricular necrosis ranged from 11% to 75% of the left ventricular mass. Associated right ventricular infarction was observed in 68%. There were 19 cases of cardiogenic shock, four cases of pulmonary edema, and two cases of sudden death. We conclude that papillary muscle necrosis is usually associated with cardiac hypertrophy, posterior necrosis of both ventricles, and subendocardial infarction. Acute mitral regurgitation is probably an important contributing factor to clinical impairment and death, mostly in cases of small necrosis.

Acute right ventricular infarction secondary to massive pulmonary embolism.

Isolated right ventricular infarction has been found in cases of right ventricular hypertrophy, but there are no reports on right ventricular infarction secondary to massive pulmonary embolism. Six autopsied patients with massive pulmonary embolism and pure right ventricular infarction, suspected to be secondary to the embolism, were selected from a population of 216 autopsies. Pulmonary embolism was the suspected diagnosis in five cases due to typical clinical, electrocardiographic and haemodynamic data. Right ventricular infarction was a post-mortem finding, not previously diagnosed. In every case the thickness of the right ventricular myocardium was normal. The necrosis of the right ventricle was transmural in four cases and subendocardial in two and the entire right ventricular wall (anterolateral as well as posterior) was involved. No mural thrombi were present and in no case did the necrosis involve the left ventricle. In one case the coronary arteries were normal, in the other five significant lesions of the right or left coronary arteries were observed. These lesions may have been, in part, responsible for the necrosis of the right ventricle when the massive pulmonary embolism was added. We conclude that right ventricular infarction may be secondary to pulmonary hypertension in the setting of massive pulmonary embolism, even in the absence of right ventricular hypertrophy and with normal or stenotic coronary arteries.