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Purpose we investigated by immunohistochemistry the pepsinogen C (pepC) expression in uveal melanomas and analyzed the possible relationship to clinicopathological parameters and prognostic significance. Methods We studied 22 patients who had undergone enucleation of the eyeball or local tumor resection for uveal melanoma. The specimens were immunostained for pepC on formalin-fixed, paraffin-embedded sections. Sex, age, tumor location, histological type, local invasion, postoperative treatment and metastasis were evaluated. Results Eleven tumors (50%) were positive for pepsinogen C. The percentage of pepC-positive tumors was significantly higher in uveal melanomas with scleral invasion than in those without scleral invasion (pConclusions Our results show that pepsinogen C may be expressed by uveal melanoma and suggest that this protein could be considered as a new, unfavorable prognostic factor in these tumors.

Resumen Objetivo Analizar la expresion tumoral del pepsinogeno C y de la colagenasa-3 en el adenocarcinoma de endometrio y la relacion con las caracteristicas de las pacientes y de sus tumores Sujetos y metodos Analizamos retrospectivamente mediante analisis inmunohistoquimico, utilizando anticuerpos monoclonales, 58 pacientes diagnosticadas y tratadas de adenocarcinoma de endometrio Resultados Se detecto pepsinogeno C en 21 tumores (36%) y colagenasa-3 en 30 (51%). La expresion de estas proteinas se asocio significativamente con la profundidad de la invasion miometrial, de forma que a mayor invasion del miometrio, menor expresion de pepsinogeno C y mayor de colagenasa-3 (p Conclusion Un porcentaje significativo de adenocarcinomas de endometrio expresan pepsinogeno C y colagenasa-3, lo cual refleja un comportamiento biologico diferente, y pueden ser utiles en la prediccion preoperatoria de la invasion miometrial en el cancer de endometrio

Urothelial bladder cancer represents a heterogeneous disease with divergent pathways of tumorigenesis. Tumor invasion and progression are a multifactorial process promoted by microenvironmental changes that include overexpression of matrix metalloproteinases (MMPs). Recent data clearly challenge the classic dogma that MMPs promote metastasis only by modulating the remodeling of extracellular matrix. Indeed, MMPs have also been attributed as an impact on tumor cell behavior in vivo as a consequence of their ability to cleave growth factors, cell surface receptors, cell adhesion molecules, and chemokines/cytokines. Levels of the different MMPs can be measured in several sample types, including tissue, blood (serum and plasma), and urine, and using different methodologies, such as immunohistochemistry, real-time PCR, western and northern blot analyses, enzyme-linked immunosorbent assay, and zymography. Several MMPs have been identified as having potential diagnostic or prognostic utility, whether alone or in combination with cytology. Although MMP inhibitors have shown limited efficacy, advances in the understanding of the complex physiologic and pathologic roles of MMPs might permit the development of new MMP-specific and tumor-specific therapies. In this paper we update the understanding of MMPs based on a systematic PubMed search encompassing papers published up to December 2011.

Objetivo: La epidemiología de la enfermedad inflamatoria intestinal crónica (EIIC) es una poderosa herramienta de investigación que contribuye a la evaluación de los factores medioambientales que influyen en su etiología. El objetivo de este estudio es conocer distintos aspectos epidemiológicos de la EIIC en nuestro medio. Pacientes y métodos: Estudio epidemiológico descriptivo, poblacional, multicentrico, retrospectivo entre 1954 y 1993 y prospectivo entre 1994 y 1997. Se incluyen 1018 enfermos mayores de 14 años, diagnosticados de EIIC en 5 áreas del Principado de Asturias (España), con un censo de 461.965 habitantes. Resultados: Del total de 1018 identificados [565 CU (55,5%) (incluyendo proctitis), 415 EC (40,8%) y 38 CI (3,7%)], 482 son mujeres (47,2%) y 536 varones (52,8%), con una relación V/M de 1,11. La edad media al diagnóstico es de 39,49 ± 1,08 (IC; 95%: 38,41 - 40,57), [CU: 43,95 ± 1,47; EC: 33,53 ± 1,51; CI: 38,26 ± 5,14]. p = 0,000. La edad media de inicio de síntomas previo al diagnóstico es 37,66 ± 0,97 (CU: 42,84 ± 1,34; EC: 30,68 ± 1,40; CI: 36,74 ± 4,86 (p = 0,000). El diagnóstico de CU ha sido posible con criterios clínicos en el 97,34% (p = ns), criterios endoscópicos en el 96,63% (p = 0,000) y criterios histológicos en el 90,26% (p = 0,000). En la EC: criterios radiológicos 83,61% (p = 0,000). El nivel cultural es superior en la EC: 57,57 (p = 0,0005). Asociación familiar del 8,4%. Extensión: en la CU: proctitis 13,6%, 26,9% colitis distal, 26% colitis izquierda, 6% colitis extensa y el 20% pancolitis; En la EC el 30,3% tienen afectación de íleon terminal, el 16,7% colon, el 41,3% colon e intestino, el 11,7% son intestinales extensas y el 3,7% tienen afectación gastro-duodenal; En la CI destaca un 39,5% de afectación discontinua. La media de cirugías necesarias para el control de la enfermedad es de 0,44 ± 6,11, (26,62% de los enfermos). CU: 0,12 ± 3,33 (9,91%); EC: 0,91 ± 12,9 (50,36%), p = 0,000. Tasa de Mortalidad de 47,15 /1000 habitantes (CU: T = 61,94; EC: T = 26,50; CI: T= 0,004) p = 0,046. RMS: 0,467 (CU: 6,14; EC: 2,63; CI: 100). Conclusiones: Este estudio que abarca una importante población de enfermos, pretende aportar nuestros resultados epidemiológicos a la Enfermedad Inflamatoria Intestinal Crónica. Nuestros resultados no difieren substancialmente de los de otras publicaciones. La colitis ulcerosa y la enfermedad de Crohn así como el sexo, se distribuyen uniformemente. La elevada asociación familiar entre estas enfermedades sugiere un origen genético de la EIIC. La enfermedad de Crohn se expresa con mayor morbilidad reflejada en los requerimientos quirúrgicos, pero sin embargo con menor mortalidad que en la colitis ulcerosa. Aims: The epidemiologic analysis inflammatory bowel disease (IBD) is a powerful research tool to assess the contribution of environmental factors to its etiology. IBD has been reported to have varying frequencies in different parts of the world, and there seem to be significant differences in the disease pattern and clinical course. The aim of the present study was to assess the disease pattern of IBD in Asturias (Spain). Patients and methods: A descriptive epidemiological population based study, retrospective (1954-1993) and prospective (1994-97), was performed to study 1018 patients found, bigger than 14 years, to have IBD, in five areas of Asturias (Spain) (461.965 inhabitants). Results: During the period of time studied, we diagnosed 1018 IBD [565 ulcerative colitis (55.5%), 415 (40.8%) Crohn´s disease and 38 (3.7%) indeterminate colitis], with 482 females (47.2%), 536 males (52.8%), and male/female: 1.11. Age at diagnosis were 39.49 ± 1.08 (95% CI : 38.41 - 40.57); (UC: 43.95 ± 1.47; CD: 33.53 ± 1.51; IC: 38.26 ± 5.14. p = 0.000. Age at onset previously at diagnosis for UC: 42.84 ± 1.34; CD: 30.68 ± 1.40; IC: 36.74 ± 4.86 (p = 0.000). Diagnosis criteria: UC: syntomatic 97.34% (p = ns), endoscopy 96.63% (p = 0.000), pathology 90.26% (p = 0.000). CD: radiology 83.61% (p = 0.000). Study level in CD: 57.57 (p = 0.0005). Family history: 8.4%. The most frequent involvement at diagnosis of UC was proctitis only, in 13.6%, 26.9% rectum and sigmoid, 26% left colitis, 20% pancolitis, and in CD colon only, in 16.7%, 30.3% terminal ileum, 41.3% ileo-colon of the patients. This also helps to explain the differences in severity, need for surgery, and survival noted between community based studies. Conclusions: We highlight the uniformity of distribution of the inflammatory bowel disease in relation to types and sex. The high frequency of familial Crohn's disease suggests a genetic predisposition. Highlighting a bigger morbilidad for the Crohn’s Disease reflected in the surgical requirements, but however with smaller mortality that in ulcerative colitis.

Objetivos: investigar en una población de pacientes de nuestro ámbito clínico con cáncer colorrectal la distribución de sus edades, posibles diferencias en cuanto a los síntomas de presentación, características clínico-biológicas de sus tumores, diferencias en el tratamiento y en el pronóstico. Emplazamiento: Hospital de Jove de Gijón y el Hospital de referencia, Central de Asturias de Oviedo durante el periodo 1975-1999. Material y métodos: se realizó un estudio retrospectivo entre los meses de julio de 2001 a enero de 2002 que incluyo 473 pacientes del ámbito urbano y rural, diagnosticados de cáncer colorrectal. En todos se realizó el diagnóstico histológico de adenocarcinoma colorrectal. Se investigaron las características clásicas de los pacientes y de sus tumores así como su contenido de ADN, fase S, tipo de tratamiento y pronóstico de la enfermedad. Resultados: la edad media de los pacientes fue de 67,5 años (intervalo: 25-90 años). La década de mayor presentación fue la de los 70 años (33,2%) seguida de los 60 (32,6%) y la incidencia más baja correspondió a los

Objetivo: Conocer y comparar la incidencia y prevalencia de la enfermedad inflamatoria intestinal crónica (EIIC) en 5 áreas del Principado de Asturias (España). Pacientes y métodos: Estudio epidemiológico descriptivo, poblacional, multicéntrico, retrospectivo entre 1954 y 1993 y prospectivo entre 1994 y 1997. Se incluyen todos los enfermos mayores de 14 años, diagnosticados de EIIC según un protocolo estándar para el diagnóstico y definición, en 5 áreas del Principado de Asturias, con un censo de 461.965 habitantes. Resultados: En el periodo de tiempo estudiado, han sido diagnosticados 1018 enfermos con EIIC [565 CU (55,5%), 415 EC (40,8%) y 38 CI (3,7%)]; [482 mujeres (47,2%), 536 varones (52,8%)]. En el periodo de 4 años de estudio prospectivo, se identifican 306 EIIC: 176 CU (57,51%), 110 EC (35,94) y 20 CI (6,53%); CU/EC: 1,6. La frecuencia de aparición de los distintos grupos de enfermedad no presenta diferencias significativas, así como tampoco existen diferencias entre ambos sexos. La tasa de incidencia media anual (1954-97) en EIIC es 5,12 (IC 95% = 3,05 - 7,18) (CU: 2,84; EC: 2,08; CI: 0,19; CU/EC 1,36). En el periodo de tiempo de estudio prospectivo, la tasa de incidencia media anual de la EIIC es 16,55 (IC 95% =12,84 - 20,25), (CU: 9,52; EC: 5,95; CI: 1,08; CU/EC: 1,6). La prevalencia, referida a 1997 para la EIIC es de 205,21 (IC 95% = 182,14-227,29), (CU: 109,96; EC: 87,45; CI: 7,79). Se han establecido comparaciones entre las áreas estudiadas, sin encontrar diferencias estadísticamente significativas. Conclusiones: Las tasas brutas de incidencia y de prevalencia de la enfermedad inflamatoria intestinal crónica en nuestro medio son superiores a las históricamente descritas en otras áreas de nuestro país y similares a las publicadas en poblaciones de alta incidencia. No hemos encontrado diferencias significativas entre las cinco áreas que componen el estudio. Aims: To know and to compare Inflammatory Bowel Disease (IBD) Incidence and Prevalence rates in in five areas of Asturias (Spain). We conducted a prospective epidemiologic study of IBD in the Province of Liege (1 million inhabitants). Patient and methods: We conducted a descriptive, populational, collaborative epidemiologic study, retrospective between 1954 and 1993 and prospective between 1994 and 1997. All patients diagnosed according to a standard protocol for case ascertainment and definition of IBD, aged 14 years or more are included, in five areas of Asturias (Spain) (461.965 inhabitants). Results: For the period 1954 to 1997, 1018 IBD have been diagnosed [565 ulcerative colitis (UC) (55.5%), 415 Crohn's disease (CD) (40.8%) and 38 undefined IBD (IC) (3.7%)]; [482 women (47.2%), 536 males (52.8%)]. In the 4 year-prospective period, 306 cases were collected: 176 UC (57.51%), 110 CD (35.94) and 20 IC (6.53%); UC/CD: 1.6. Without appreciable and significant differences between Frequency of illness groups and sexes. IBD incidence rate (per 100,000 per year) (1954-97) is 5.12 ( 95% CI = 3.05 - 7.18) (UC: 2.84; CD: 2.08; IC: 0.19; UC/CD 1.36). In the 4 years- prospective study, IBD incidence rate is 16.55 (95% CI=12.84 - 20.25), (UC: 9.52; CD: 5.95; IC: 1.08; UC/CD: 1.6). IBD prevalence rate in 1997 is 205,21 (95% CI= 182.14-227.29), (UC: 109.96; CD: 87.45; IC: 7.79). Comparisons have settled down among the studied areas, without finding differences statistically significant. Conclusions: Inflammatory Bowel Disease incidence and prevalence rates of in our region are homogeneous between the cities investigated and superior than those historically reported in Spanish studies. These results were similar to those observed in European studies.

An aspartic proteinase present in cyst fluid from women with gross cystic breast disease was purified by a procedure involving affinity chromatography on pepstatin-agarose and size-exclusion high performance liquid chromatography. The amino-terminal sequence of the purified breast proteinase was identical to that corresponding to gastric pepsinogen C. Additional data on cleavage specificity, pH optimum, and immunological properties supported the close relationship between both molecules. Northern blot analysis and polymerase chain reaction amplification studies performed on RNAs obtained from normal and pathological breast tissues demonstrated that the protein is produced by mammary carcinomas and cysts, but not by the normal resting mammary gland. Immunohistochemical staining of paraffin-embedded tissue sections confirmed the existence of a subset of tumors that have the ability to synthesize and secrete this pepsin zymogen. On the basis of these results, we suggest that pepsinogen C expression by human mammary epithelium may be involved in the development of breast diseases, being also of potential interest as a biochemical marker of the hormonal imbalance underlying these pathologies.

The protein composition of breast secretions from 99 premenopausal women with benign or malignant breast diseases and from 70 control women without breast pathologies has been studied by using polyacrylamide gel electrophoresis. These fluids have been classified into two types according to their major polypeptide components. Type I fluids are defined by three major distinctive bands at Mr 44,000, 24,000, and 17,000, while those designated Type II present distinctive bands at Mr 80,000, 15,000, and 14,000. Amino acid sequencing and immunoblotting analysis demonstrated that proteins in Type I secretions correspond to Zn-alpha 2-glycoprotein, apolipoprotein D, and gross cystic disease fluid protein-15, while those from Type II fluids have been identified as lactoferrin, lysozyme, and alpha-lactalbumin. Most women (93%) without breast pathology and most patients (88%) with benign diseases had secretions with a Type I polypeptide pattern. By contrast, a large percentage (57%) of secretions from women with breast carcinoma presented a Type II protein pattern. Further studies with a large number of women will be useful for corroborating the potential clinical interest of breast fluid protein analysis.

Apolipoprotein D (apo D) is a glycoprotein involved in the human plasma lipid transport system and present at large amounts in cyst fluid from women with gross cystic disease of the breast. Apo D expression in breast carcinomas was examined by immunoperoxidase staining of a series of 163 tumors. A total of 60 (36.8%) tumors were negative for apo D immunostaining, 28 (17.2%) carcinomas were weakly positive, 33 (20.2%) were moderately stained, whereas the remaining 42 (25.8%) tumors were strongly stained with the specific antibodies. No significant correlation was found between apo D content and tumor size, lymph node involvement, or biochemical parameters such as estrogen receptors, cathepsin D, or pS2 protein. However, the finding of a significant association between apo D and menopausal status of patients or differentiation grade of tumors, with apo D values being lower in tumors from premenopausal women or in poorly differentiated carcinomas, suggested a potential value of this glycoprotein as a prognostic factor in breast cancer. Preliminary analysis of relapse-free survival and overall survival in a subgroup of 152 women with a mean follow-up of 42 months confirmed that low apo D values were significantly associated to a shorter relapse-free survival and poorer survival. According to these data, we propose that apo D in combination with other well-established prognostic factors may contribute to more accurately identify subgroups of breast cancer patients with low or high risk for relapse and death.

Cholesterol and apolipoprotein D (apo D) concentrations were measured in cyst fluids and sera from 66 women with gross cystic disease of the breast. Intracystic cholesterol concentrations are about twofold greater than those found in serum, whereas apo D, the major cyst fluid protein, is present in concentrations as much as 1000-fold greater than found in serum. We classified the cyst fluids into two groups by K+/Na+ ratio and albumin concentration and measured intracystic cholesterol and apo D concentrations in each group. Type I cysts had an average content of cholesterol (12.7 mmol/L) moderately lower than that in Type II cysts (17.6 mmol/L). By contrast, the average concentration of apo D in Type I cyst fluids (15.1 g/L) was slightly higher than that in Type II cysts (13.7 g/L). The absence of a correlation between cholesterol concentration and apo D concentration and the results from previous binding analysis suggest that this protein is not involved in the accumulation of cholesterol in breast-cyst fluid.

Collagenase-3 (matrix metalloproteinase 13; MMP-13), a protease originally identified in breast carcinoma, is characterized by a potent degrading activity against a wide spectrum of extracellular matrix proteins. The aims of this study were to localize and identify the MMP-13-expressing cells in invasive human breast carcinoma and to evaluate the role of MMP-13 in transition to invasive lesions by studying ductal carcinoma in situ (DCIS). We found expression of MMP-13 in stromal fibroblast-like cells in all 21 invasive ductal carcinomas studied and in 4 of 9 invasive lobular carcinomas. In most carcinomas, expression of MMP-13 was limited to small stromal foci in the tumor area. Combined in situ hybridization and immunohistochemistry showed coexpression of alpha-smooth muscle actin immunoreactivity and MMP-13 mRNA in myofibroblasts. In contrast, cytokeratin-positive cancer cells, alpha-smooth muscle actin-positive vascular smooth muscle cells, CD68-positive macrophages, and CD31-positive endothelial cells were all MMP-13 mRNA negative. In situ hybridization for MMP-13 in 17 DCIS lesions revealed expression in 10 cases. Immunohistochemical analysis of all DCIS cases identified microinvasion in 8 of the 17 lesions. Seven of the eight lesions with microinvasion were MMP-13 positive. Further analysis showed that MMP-13 expression was often associated with the microinvasive events. This particular expression pattern was unique for MMP-13 among other MMPs analyzed, including MMP-2, -11, and -14. We conclude that MMP-13 is primarily expressed by myofibroblasts in human breast carcinoma and that expression in DCIS lesions often is associated with microinvasive events. On the basis of these data, we propose that MMP-13 may play an essential role during transition of DCIS lesions to invasive ductal carcinomas.