Supervivencia según vía de abordaje quirúrgico en pacientes con adenocarcinoma de endometrio tratadas en Navarra en el periodo 2001-2009 / Survival by surgical approach in patients with endometrial adenocarcinoma treated in Navarra in the 2001-2009

Fundamento: El adenocarcinoma de endometrio es la neoplasia ginecológica más frecuente tras el cáncer de mama y representa el 6% de todos los cánceres de la mujer. El tratamiento fundamental de dicha enfermedad es la cirugía. La mayoría de los casos se diagnostican en estadios iniciales y la cirugía será curativa; en otras ocasiones es necesario añadir radioterapia o quimioterapia. El tratamiento clásico del adenocarcinoma de endometrio es la histerectomía con doble anexectomía por vía laparotómica, añadiendo según las características del caso la linfadenectomía pélvica, paraaórtica y omentectomía. Durante los últimos 10-15 años se ha introducido la laparoscopia en el tratamiento quirúrgico del adenocarcinoma de endometrio. El objetivo principal de este trabajo es analizar los casos de adenocarcinoma de endometrio intervenidos quirúrgicamente en el antiguo hospital Virgen de Camino (hoy Complejo Hospitalario de Navarra) durante el periodo 2001-2009. Material y métodos: Se ha recogido una cohorte histórica de 444 pacientes con diagnóstico de adenocarcinoma de endometrio durante el periodo 2001-2009, que recibieron tratamiento quirúrgico, así como su seguimiento durante 4 años. Conclusiones: Los resultados confirman que la vía laparoscópica es una alternativa segura a la laparotomía clásica ya que no afecta a la supervivencia ni al tiempo libre de enfermedad tanto en el adenocarcinoma endometrioide como en el no endometrioide (AU)

Background: Endometrial adenocarcinoma is the most frequent gynaecological neoplasia after breast cancer and represents 6% of cancers in women. The treatment for this disease is surgery. The majority of cases are diagnosed in their initial stages and surgery is curative; on other occasions it is necessary to add radiotherapy and chemotherapy. The classical treatment for endometrial adenocarcinoma is hysterectomy with double adnexectomy by laparotomy, with the addition of pelvic and para-aortic lymphadenectomy and omentectomy according to the characteristics of the case. During the last 10-15 years laparoscopy has been introduced in the surgical treatment of endometrial adenocarcinoma. The main aim of this study is to analyze the cases of endometrial adenocarcinoma treated surgically in the former Virgen de Camino Hospital (nowadays the Hospital Complex of Navarra) during 2001-2009. Methods: Historical cohort of 444 patients with endometrial adenocarcinoma during 2001-2009 who received surgical treatment, followed four years. Conclusions: The results confirm that laparoscopy is a safe alternative to classical laparotomy as it does not affect either survival or time free of disease, in both endometrioid adenocarcinoma and non-endometrioid adenocarcinoma (AU)

Marcadores tumorales procesos ginecológicos benignos / Tumor markers in benign gynecologic diseases

La determinación de marcadores tumorales se emplea como prueba complementaria en el diagnóstico de algunas neoplasias. Cifras muy elevadas se asocian casi invariablemente a neoplasias malignas. Presentamos el caso de una paciente en la que el conjunto de datos analíticos, sobre todo la importante elevación de marcadores tumorales, y exploratorios orientaron hacia un diagnóstico de malignidad que condujo a la realización de cirugía radical. Únicamente el estudio histopatológico diferido de toda la pieza demostró la benignidad del proceso. Tras el tratamiento los niveles de marcadores descendieron hasta su normalización. Se concluye que la presencia de marcadores tumorales muy elevados puede inducir a un diagnóstico erróneo de malignidad en el estudio de las masas ováricas (AU)

Spontaneous and thiazolidinedione-induced B6C3F1 mouse hemangiosarcomas exhibit low ras oncogene mutation frequencies.

Hemangiosarcomasare uncommon malignant endothelial cell tumors in humans and experimental animal species. The mechanisms giving rise to these tumors are poorly understood even though the histotypes are comparable between humans and rodents. Activating mutations in cellular ras protooncogenes have been detected in sporadic and chemically induced human and rodent hemangiosarcomas. Ras activation significantly modulates tumor angiogenesis, suggesting that mutations in ras genes might be causally related to vascular tumorigenesis. To more clearly define the role of ras in experimental vascular tumorigenesis, mutations in the Ki- and Ha-ras genes were characterized in 63 hemangiosarcomas that arose unexpectedly in control and treated B6C3F1 mice during a two-year carcinogenicity study of the thiazolidinedione troglitazone. DNA was extracted from paraffin sections of mouse hemangiosarcomas, control liver, or positive control hepatocellular carcinomas with defined mutations in the Ki- or Ha-ras genes. Exons 1 and 2 of the Ki- and Ha-ras genes were independently amplified using primer extension preamplification/locus-specific heminested PCR, and PCR amplicons were directly sequenced to identify mutations in codons 12, 13, or 61. Activating mutations were detected in 3 of 63 hemangiosarcomas: a single G-->A transition in the second position of Ki-ras codon 13 in a tumor from a treated animal and two G-->T transversions in the second position of Ha-ras codon 13, one in a single tumor from a control animal and one in a tumor from a treated animal. These mutations are consistent with endogenous mutagenesis arising from oxidative DNA damage. The low frequency of mutation (<5%) indicates that ras mutations did not contribute significantly to hemangiosarcoma development and suggests that mutational ras activation may not be a necessary step in vascular tumorigenesis in mice.

p53 is not inactivated in B6C3F1 mouse vascular tumors arising spontaneously or associated with long-term administration of the thiazolidinedione troglitazone.

Hemangiomas and hemangiosarcomas are uncommon in rodents and humans and, as such, the mechanisms giving rise to these tumors are poorly understood. Inactivating mutations in the p53 gene have been detected in sporadic and chemically induced human and rodent hemangiosarcomas. Additionally, experimental ablation of p53 function in mice by targeted gene disruption increases the incidence of both spontaneous and carcinogen-induced vascular tumors. These findings implicate p53 disruption in vascular tumor development. In this study, we characterized p53 inactivation immunocytochemically and by gene sequencing in a large number of vascular tumors that developed in B6C3F1 mice during a long-term (2-year) study of the thiazolidinedione troglitazone. For comparative purposes, a murine hemangiosarcoma induced by polyoma middle-T antigen, which transforms endothelial cells via a p53-independent mechanism, five spontaneous human hemangiosarcoma specimens, and species-specific positive control tissues were also evaluated by immunocytochemistry for p53 inactivation. While 20% of the human hemangiosarcomas and all positive control tissues expressed significant levels of nuclear p53, indicating functional inactivation of the protein, none of the 161 mouse vascular tumors studied expressed detectable p53 protein. The absence of inactivating mutations was confirmed in eight of the histologically most malignant mouse hemangiosarcomas by sequencing exons 5 to 8 of the p53 gene. These results demonstrate that p53 inactivation did not play a role in development of the vascular tumors seen in the long-term study of troglitazone, and they indicate that loss of p53 function is not essential for vascular tumor development in mice.

Genetic analysis of multiple loci in microsamples of fixed paraffin-embedded tissue.

Molecular analysis of alterations in genomic DNA is essential for understanding mechanisms by which chemical agents induce or modify tumor development. The assessment of microsatellite polymorphisms, loss of heterozygosity, mutations, and gene rearrangement allows specific comparisons of tumors to premalignant lesions or normal tissue or between similar tumors seen in laboratory species and humans. Utilization of these techniques is frequently limited by minute quantities of available tissue, often restricted to small formalin-fixed tumors or biopsies in paraffin blocks. To address these limitations, we have combined recently developed methodologies for selective recovery, amplification, and analysis of DNA. These techniques provide sufficient materials of high quality for analysis of DNA alterations in microscale amounts of starting material. By combining whole genome amplification through primer extension preamplification with locus-specific heminested PCR, we are able to analyze multiple genetic loci from as little as 1 mm2 of a 3-micron-thick formalin-fixed paraffin section. From 10 to greater than 100 loci can be analyzed per tissue section, and locus-specific PCR products may be further evaluated by a variety of techniques (e.g., SSCP, sequencing). Integrating these methodologies into situations where evaluation of very small tissue samples is necessary provides a powerful approach for elucidating molecular events that may be causally related to chemically induced cellular transformation and tumorigenesis.

Molecular cloning of, and phylogenetic analysis of, an actin in Naegleria fowleri.

We cloned and sequenced an intronless actin gene from the amoebo-flagellate Naegleria fowleri, LEE strain, an opportunistic pathogen of man. Codon usage and third-position-codon nucleotide frequency were significantly different from Acanthamoeba, another amoeba genus which also includes opportunistic pathogens of man. Between the two amoebae, actin peptide sequences were 92.8% similar, while nucleotide sequences were only 70% similar. A phylogenetic reconstruction of actin amino acid sequences, using a distance method, placed Naegleria in a cluster with Plasmodium and Entamoeba.