Decrease of apoptosis rate in patients with renal transplantation treated with mycophenolate mofetil

We conclude that treatment with MMF of kidney transplant patients does not affect the proliferative rate of cells of the allograft, but decreases the number of apoptotic cells in tubular epithelium

Biología molecular del carcinoma de tiroides de estirpe folicular. Bases moleculares en la oncogénesis tiroidea

Existen datos que nos permiten afirmar que probablemente, en gran parte de los casos, no existe una solución de continuidad entre las diferentes neoplasias tiroideas de estirpe folicular. Cabe pensar que el proceso evolutivo comienza con una serie de alteraciones moleculares que condicionan la aparición del adenoma folicular (AF). Cambios posteriores propiciarán el desarrollo de un carcinoma folicular (CF). La aparición del carcinoma papilar (CP) tiene probablemente un itinerario similar sin que esté demostrado que tenga su origen en AF. Ulteriores cambios genéticos, tanto en el CP como en el CF encaminarán hacia la indiferenciación celular y con ello el desarrollo del carcinoma indiferenciado (CI). Esta sucesión de alteraciones moleculares condiciona un empeoramiento en el pronóstico de la neoplasia tiroidea. Por ello, las neoplasias tiroideas constituyen un excelente modelo para el estudio de la cronología de los cambios moleculares que condicionan la evolución desde la benignidad a la malignidad. Se ha comprobado que en algunas neoplasias de tiroides existe inestabilidad genética que favorece dichos cambios moleculares. Como fenómeno inicial es frecuente observar alteraciones en los protooncogenes mientras que las mutaciones en los genes supresores de tumor suelen ser un evento tardío. La aparición de agresividad o invasividad de la neoplasia también se puede investigar mediante el estudio de cambios moleculares. La aplicación clínica de dichos hallazgos comienza a ser una realidad, lo que facilitará la precisión diagnóstica y con ello una terapéutica más eficaz.According to current data, it seems probable that there is no interruption in the evolution of different follicular thyroid neoplasm. Probably transforming events responsible for the transition from normal to tumor cells start with molecular changes that determine the appearance of follicular adenoma. Later changes propitiate the development of follicular cancer. It is likely that the generation of papillary carcinoma follows a different pathway without passing through a previous phase of follicular adenoma. Subsequently, genetic changes render the cell prone to a failure to differentiate, culminating in the development of anaplastic cancer. Those incidental molecular changes result in a dramatic worsening in the prognosis of thyroid cancer. Research into thyroid tumors is likely to be instructive in view of the spectrum they span, from benign adenomas to poorly differentiated carcinomas. It has been proven that molecular alterations in thyroid tumor cells are predisposed by genome instability. Usually changes of protooncogenes represent an early event whereas mutations of suppressant genes are usually a late phenomenon. The onset of aggressive or invasive behavior may be studied, and perhaps can be predicted in the future, by molecular changes. The clinical application of the growing understanding of gene alterations involved in thyroidal oncogenesis is becoming a reality. Such knowledge might contribute, in the near future, to greater diagnostic accuracy and effective treatment for thyroid malignancie

Biología molecular del carcinoma de tiroides de estirpe folicular (II). Aplicaciones clínicas

The great advance of molecular medicine over the last few years gives us an attractive vision of the new possibilities in diagnosis and therapeutics of thyroid cancer and helps us to understand its biological behaviour. The clinical application of the growing understanding of gene alterations involved in thyroidal oncogenesis is becoming a reality. Such knowledge might contribute to greater diagnostic accuracy, by helping us characterise malignant or benign cells, predict tumour outcome or state its origin. Likewise it might be useful to know the response to conventional therapies or the future implications of pharmacogenetics. In addition molecular medicine applications ought to be considered in determining the prognosis of spontaneous and familiar carcinomas. Such information can significantly improve current clinical-pathologic prognostic methods

Quiste del cuarto arco branquial en la membrana tirohioidea: un difícil diagnóstico diferencial con el laringocele mixto

We present a case of a 62-year-old female patient with a right latero-cervical mass and an enlarged arytenoepiglottic fold, that caused voice disturbances. Computed tomography of the neck depicted an unilocular and homogeneous well-defined cyst located in the right parapharyngeal space that extended through the thyrohyoid membrane. It was initially diagnosed of mixed laryngocele. During surgical resection, no connexion between the lesion and laryngeal ventricle was detected, so the final diagnosis was branchial cyst. We discuss the pathogenicity and clinical, radiological and histological findings that facilitate differential diagnosis between mixed laryngocele and branchial cysts, mainly those derived from the second and fourth clefts. The radiological and histological findings in both lesions may be similar, so only the communication with the larynx, or its absence, can solve diagnostic doubts, course

Toward the biochemical assessment of myocardial fibrosis in hypertensive patients

The serum concentrations of amino-terminal procollagen type III and carboxy-terminal procollagen type I-derived peptides, which have been proposed as useful markers of the tissue synthesis of collagen types III and type I, respectively, were abnormally increased in patients with essential hypertension and became normal after angiotensin-converting enzyme (ACE) inhibition. An association was found between baseline serum concentrations of these peptides and left ventricular hypertrophy, diastolic dysfunction, and ventricular arrhythmias in hypertensive patients. On the other hand, increased serum concentration of the carboxy-terminal procollagen type I-derived peptide was found in spontaneously hypertensive rats compared with normotensive Wistar-Kyoto control rats. An association was found between the serum concentration of this peptide and the extent of myocardial fibrosis and the hydroxyproline concentration in the left ventricle of spontaneously hypertensive rats. It is proposed that procollagen-derived peptides in serum may be markers of exaggerated collagen tissue synthesis involved in hypertensive myocardial fibrosis

Pathological and virological findings in patients with persistent hypertransaminasaemia of unknown aetiology

BACKGROUND: The histopathological spectrum and role of hepatitis viruses in cases of hypertransaminasaemia of unknown aetiology have not been correctly analysed in a sufficiently large number of patients. METHODS: We studied 1075 consecutive patients referred for liver biopsy because of elevation of alanine aminotransferase (ALT) levels for more than six months. From this population we selected those cases in whom the aetiology could not be defined from clinical, biochemical, and serological data obtained before biopsy. In these patients liver biopsies were reviewed, and hepatitis B virus (HBV)-DNA and hepatitis C virus (HCV)-RNA were assayed in serum by polymerase chain reaction (PCR). Serum hepatitis G virus (HGV)-RNA was determined by PCR in 74 patients. RESULTS: Of 1075 patients studied, the cause of the increased serum ALT levels remained elusive after appropriate testing in 109 patients (10.1%). Liver biopsies from these patients showed non-specific changes in 32.7% of cases, non-alcoholic steatohepatitis (NASH) in 15.8%, and chronic hepatitis or cirrhosis in 51.5%. HBV-DNA and/or HCV-RNA was detected more frequently in cryptogenic liver disease than in healthy blood donors (26.7% v 3.4%; p<0.001). HGV-RNA was found in only one patient. The proportion of cases with detectable HBV-DNA or HCV-RNA was 14.3% in patients with non-specific changes or NASH, 30.7% in patients with chronic hepatitis, and 61.5% in patients with cirrhosis. Cirrhosis was found more frequently in patients with positive HBV-DNA and/or HCV-RNA in serum than in those who tested negatively (p=0.005). CONCLUSIONS: In our series, patients in whom biochemical and serological data did not determine the aetiology of the disease represented 10% of all cases referred for liver biopsy for persistent elevation of serum transaminases. Approximately 50% of patients had chronic hepatitis or cirrhosis and the remainder had NASH or non-specific changes. Occult viral infections were found in a high proportion of cases in the first group and in a low percentage of patients in the second

Molecular features in a biphenotypic small cell sarcoma with neuroectodermal and muscle differentiation

We report a case of a 13-year-old girl with soft tissue sarcoma of the hand, which showed muscle and neuroectodermal immunophenotypes. Molecular studies were performed on RNA collected from fine-needle aspiration (FNA) cytology and peripheral blood samples by nested reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blot analysis. This biphenotypic tumor showed simultaneous expression of EWS-FLI1 and PAX3-FKHR transcripts, specific of Ewing family tumors and alveolar rhabdomyosarcoma, respectively. Although childhood sarcomas with simultaneous muscle and neural differentiation have been described to have EWS-FLI1 transcripts, there are no reports of tumors with both transcripts. Cytological specimens are a good source of RNA for molecular studie

Association of EWS-FLI1 Type 1 Fusion with Lower Proliferative Rate in Ewing’s Sarcoma

The Ewing's sarcoma (ES) family of tumors, including peripheral neuroectodermal tumor (PNET), is defined genetically by specific chromosomal translocations resulting in fusion of the EWS gene with a member of the ETS family of transcription factors, either FLI1 (90-95%) or ERG (5-10%). A second level of molecular genetic heterogeneity stems from the variation in the location of the translocation breakpoints, resulting in the inclusion of different combinations of exons from EWS and FLI1 (or ERG) in the fusion products. The most common type of EWS-FLI1 fusion transcript, type 1, is associated with a favorable prognosis and appears to encode a functionally weaker transactivator, compared to other fusion types. We sought to determine whether the observed covariation of structure, function, and clinical course correlates with tumor cell kinetic parameters such as proliferative rate and apoptosis, and with expression of the receptor for insulin-like growth factor I (IGF-1R). In a group of 86 ES/PNET with defined EWS-ETS fusions (45 EWS-FLI1 type 1, 27 EWS-FLI1 non-type 1, 14 EWS-ERG), we assessed proliferation rate by immunostaining for Ki-67 using MIB1 antibody (n = 85), apoptosis by TUNEL assay (n = 66), and IGF-1R expression by immunostaining with antibody 1H7 (n = 78). Ki-67 proliferative index was lower in tumors with EWS-FLI1 type 1 than those with non-type 1 EWS-FLI1, whether analyzed as a continuous (P = 0.049) or categorical (P = 0.047) variable. Logistic regression analysis suggests that this association was secondary to the association of type 1 EWS-FLI1 and lower IGF-1R expression (P = 0.04). Comparing EWS-FLI1 to EWS-ERG cases, Ki-67 proliferative index was higher in the latter (P = 0.01, Mann-Whitney test; P = 0.02, Fisher's exact test), but there was no significant difference in IGF-1R. TUNEL results showed no significant differences between groups. Our results suggest that clinical and functional differences between alternative forms of EWS-FLI1 are paralleled by differences in proliferative rate, possibly mediated by differential regulation of the IGF-1R pathway

Metástasis ganglionares de osteosarcomas

En este artículo presentamos dos pa cientes con osteosarcoma osteoblástico de tercio distal de fémur que cursaron con afectación ganglionar loco - regional. En el primer caso, el paciente presentó dos metástasis ganglionares en re gión inguinal y pél vica dos años después del diagnóstico del tumor pri mario. Actualmente tres meses después de la linfadenectomía se encuentra libre de enfermedad. En el segundo caso, durante el estudio de extensión del tu mor primario, se observaron imá genes nodulares de alta densidad en zona inguinal derecha, que corres pondieron a metástasis del tumor primari

Imatinib inhibits proliferation of Ewing tumor cells mediated by the stem cell factor/KIT receptor pathway, and sensitizes cells to vincristine and doxorubicin-induced apoptosis

Purpose and Experimental Design: The stem cell factor/ KIT receptor loop may represent a novel target for molecular- based therapies of Ewing tumor. We analyzed the in vitro impact of KIT blockade by imatinib in Ewing tumor cell lines. Results: KIT expression was detected in 4 of 4 Ewing tumor cell lines and in 49 of 110 patient samples (44.5%) by immunohistochemistry and/or Western blot analysis. KIT expression was stronger in Ewing tumors showing EWSFLI1 nontype 1 fusions. Despite absence of c-kit mutations, constitutive and ligand-inducible phosphorylation of KIT was found in all tumor cell lines, indicating an active receptor. Treatment with KIT tyrosine kinase inhibitor imatinib (0.5–20 M) induced down-regulation of KIT phosphorylation and dose response inhibition of cell proliferation (IC50, 12–15 M). However, imatinib administered alone at doses close to IC50 for growth inhibition (10 M) did not induce a significant increase in apoptosis. We then analyzed if blockade of KIT loop through imatinib (10 M) was able to increase the antitumor in vitro effect of doxorubicin (DXR)and vincristine (VCR), drugs usually used in Ewing tumor treatment. Addition of imatinib decreased in 15–20 and 15–36% of the proliferative rate of Ewing tumor cells exposed to DXR and VCR, respectively, and increased in 15 and 30% of the apoptotic rate of Ewing tumor cells exposed to the same drugs. Conclusions: Inhibition of Ewing tumor cell proliferation by imatinib is mediated through blockade of KIT receptor signaling. Inhibition of KIT increases sensitivity of these cells to DXR and VCR. This study supports a potential role for imatinib in the treatment of Ewing tumor