The role of mast cells in glomus tumours: report of a case of an intramuscular glomus tumour with a prominent mastocytic component.
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Adult↗
Biomedical subjects
F J Pardo-Mindán
Publications and source records attributed to F J Pardo-Mindán.
PTEN protein expression correlates with PTEN gene molecular changes but not with VEGF expression in astrocytomas.
PTEN gene (10q23) is a relevant tumor suppressor gene whose protein is a phosphatase involved in the control of angiogenesis of some tumors including astrocytomas. There are no studies correlating molecular changes of PTEN and the immunohistochemical expression of its protein (pPTEN) with the expression of vascular endothelial growth factor (VEGF) in astrocytomas. Fifty-six surgically resected brain gliomas, 10 grade 2, 16 grade 3, and 30 grade 4, were studied by a combined approach, consisting of (1) PCR analysis using four microsatellite markers against the PTEN gene region (10q23), (2) the FISH technique to test chromosome 10 using a pericentromeric probe, and (3) immunohistochemical evaluation of pPTEN and VEGF. Loss of heterozygosity (LOH) of PTEN was observed in 10% of fibrillary grade 2 astrocytomas and all gemistocytic ones. In high-grade tumors, LOH was more frequent in grade 4 than in grade 3 (> or =2 loci deleted, 83% and 56%, respectively). Monosomy for chromosome 10 was observed especially in high-grade tumors (6% of grade 3 and 50% of grade 4) and in 20% of grade 2 tumors, corresponding to gemistocytic astrocytomas. Results with both antibodies against PTEN were concordant: loss of cytoplasmic immunoreactivity was frequently observed according to homogeneous or heterogeneous patterns in 70% and 50% of grades 4 and 3, respectively, but not in grade 2. Immunonegativity of pPTEN was associated with PTEN gene deletion (> or =2 loci deleted) (P = 0.04) but not with monosomy. Cytoplasmic immunoreactivity against VEGF was observed in high-grade and in gemistocytic astrocytomas, but not in conventional grade 2 tumors. Tumor expression of pPTEN was not associated with immunoreactivity against VEGF when the same areas were considered. In conclusion, loss of PTEN expression is frequent in high-grade astrocytomas, but not in grade 2 tumors, and correlates with PTEN deletion and loss of chromosome 10. PTEN immunoreactivity does not correlate with VEGF expression in astrocytomas when similar areas are considered.
Astrocytoma↗
Prognostic impact of P53 status in Ewing sarcoma.
BACKGROUND: Disease stage at the time of diagnosis and response to therapy are the main prognostic factors for patients with Ewing sarcoma or peripheral neuroectodermal tumor (ES/PNET). The primary genetic alteration in ES/PNET, the fusion of the EWS gene with FLI1 or ERG, is diagnostically highly specific for these tumors, and molecular variation in the structure of the EWS-FLI1 fusion gene also is of prognostic significance. In contrast, secondary genetic alterations, such as P53 alterations, are relatively uncommon in ES/PNET, and their prognostic impact has not been extensively studied. METHODS: Prechemotherapy, paraffin embedded, nondecalcified, primary tumor material in a well-characterized series of 55 patients with ES/PNET with defined EWS-FLI1 fusion transcripts (32 patients with type 1 and 23 patients with other types) was studied retrospectively by immunohistochemical techniques for cell cycle regulators and proliferative markers, such as P53, P21(WAF1), and Ki-67, as well as by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) technique for apoptosis. Nuclear P53 expression in > 20% of tumor cells was scored as aberrant overexpression. Histologic response to neoadjuvant chemotherapy was assessed. RESULTS: Aberrant P53 expression (in > 20% of tumor cells) was present in 6 patients (11%) but showed no statistically significant correlation with disease stage, tumor size, proliferation rate (Ki-67), apoptotic rate (TUNEL), or EWS-FLI1 fusion type. By univariate analysis, the P53 > 20% group showed a significantly poorer overall survival among patients with localized disease (n = 43 patients) (P = 0.001) and in the entire study group (P = 0.01). In multivariate Cox analyses of overall survival, P53 > 20% was the strongest negative factor among prognostic factors available at the time of diagnosis (P = 0.001; relative risk [RR] = 9) and when chemotherapy response was included in the analysis (P53 > 20%: P = 0.01; RR = 10). CONCLUSIONS: P53 alteration appears to define a small clinical subset of patients with ES/PNET with a markedly poor outcome. The current observations warrant a systematic prospective study with comprehensive P53 mutation analysis. [See related article on pages 793-9, this issue.]
Adolescent↗
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.
Adolescent↗
Decrease of apoptosis rate in patients with renal transplantation treated with mycophenolate mofetil.
BACKGROUND/AIMS: Mycophenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF prevents acute graft rejection in organ transplants. The aim of this investigation is to study whether MMF has any influence on apoptosis and proliferation rates of cells other than lymphocytes. METHODS: We conducted a retrospective study of renal allograft biopsies taken during the 1st week after transplantation in 25 patients receiving triple therapy with prednisone, ciclosporin and azathioprine 75 mg/day and in 25 patients treated with MMF at a dose of 2 g/day instead of azathioprine, in order to investigate the differences in the proliferation and apoptosis rates of the glomerular, tubular, interstitial and endothelial cells of the kidney. Twelve normal kidneys were used as controls. Conventional histopathological techniques were applied as usual for pathological diagnosis. Proliferative activity was assessed by use of MIB-1 antibody. Sections of formalin-fixed, paraffin-embedded tissue blocks were stained for the presence of apoptotic cells by TUNEL assay. Evaluation of proliferative or apoptotic rates was made by counting the number of positive cells in 10 glomeruli and in 10 transversely cut tubuli in each biopsy. The positive cells in the interstitium were counted in ten high-power fields. Positive cells in the endothelium were scored semiquantitatively from 0 to 3: 0 = none, 1 = isolated cells, 2 = small groups of cells, 3 = most endothelial cells. Mann-Whitney U and chi-square tests were used for intergroup comparisons. RESULTS: All biopsies were normal or had borderline (Banff classification) acute rejection. MIB-1 rates were similar in both groups, without statistical differences (p > 0.05) between them. Significantly lower apoptotic rates were found in the group treated with MMF in tubular epithelium (23.41 +/- 8.86 vs. 57.4 +/- 13.42; p = 0.021), in glomerular (1.25 +/- 0.78 vs. 5.3 +/- 1.66; p = 0.027), and interstitial cells (1.58 +/- 0.6 vs. 5.8 +/- 1.54; p = 0.043). Apoptosis in endothelial cells (p > 0.05) was similar in both groups. CONCLUSION: 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.
Adult↗
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 studies.
Adolescent↗
CD44v6 expression is related to progression in renal epithelial tumours.
AIMS: Expression of CD44 variant isoform including exon 6 has been associated to tumour progression in several carcinomas. However, no studies have been performed to assess the prognostic value of the expression of this marker in renal cell tumours. METHODS AND RESULTS: We studied 58 renal cell tumours. All patients were followed up for at least 3 years after nephrectomy. Tumours were analysed for expression of CD44v6 assessed by two isoform-specific monoclonal antibodies. RT-PCR was performed to detect CD44 variant transcripts in 10 cases in which immunohistochemistry was negative. Twenty-two tumours showed reactivity in at least 1% cells for both antibodies with a strong membrane pattern. RT-PCR did not show CD44v6 transcripts in any of 10 studied tumours. Immunohistochemical staining was more frequent in perivascular areas or in areas of vascular invasion. In fact, CD44v6 expression correlated well with nuclear grade (P = 0.009), stage at diagnosis (P = 0.04) and appearance of metastasis after nephrectomy (P = 0.007). Although univariate survival analysis showed stage (P < 0.001), grade (P = 0.009) and CD44v6 expression (P = 0.04) to be significant predictive factors, only stage remained significant (P = 0.0013) in the multivariate analysis. CONCLUSIONS: CD44v6 expression, assessed immunohistochemically, is related to tumour progression. However, its prognostic value in renal cell tumours is dependent on tumour stage at diagnosis.
Carcinoma↗
Ewing family tumors: potential prognostic value of reverse-transcriptase polymerase chain reaction detection of minimal residual disease in peripheral blood samples.
In more than 95% of patients, the Ewing family of tumors (ET) has chimeric transcripts caused by fusion of the EWS gene to either FLI1 or ERG. The presence of specific EWS-FLI1 or EWS-ERG transcripts in peripheral blood (PB) samples of patients being treated for ET was prospectively evaluated, and these data were correlated to their clinical status. The authors studied 113 PB samples from 28 patients with ET. Treatment included chemotherapy, radiotherapy, and surgical excision of tumor after induction therapy. PB samples were taken prospectively at least 2 weeks after resection of tumor. Nested reverse-transcriptase polymerase chain reaction (RT-PCR) followed by Southern blot was performed in all samples. Resected tumors were reviewed for the degree of response to chemotherapy and volume. Seventy-seven PB samples from 28 patients had EWS-FLI1/ERG transcripts. In 11 patients, PB samples became negative with treatment, and, in 5 of them, the samples remained negative throughout the study. Samples taken during progression were always positive and, in 4 patients, became positive before progression was clinically evident. All patients with transcripts other than EWS-FLI1 type 1 (n = 3) died from tumor progression. This is a sensitive assay to monitor circulating tumor cells in Ewing tumors. The preliminary data suggest that progression is preceded by positive samples and may be related to specific transcript types.
Adolescent↗
Angiotensin converting enzyme inhibition prevents polyploidization of cardiomyocytes in spontaneously hypertensive rats with left ventricular hypertrophy.
Polyploidization of cardiomyocyte nuclei is a physiological phenomenon that increases in pathological conditions such as myocardial hypertrophy. The purpose of this study was to evaluate the potential benefit of the angiotensin converting enzyme (ACE) inhibitor quinapril in reversing the polyploidization of cardiomyocyte nuclei in spontaneously hypertensive rats (SHR) with established left ventricular hypertrophy (LVH). Sixteen week-old male SHR were treated with oral quinapril (average dose 10 mg/kg per day) for 20 weeks. Sixteen- and 36-week-old untreated SHR and 16- and 36-week-old normotensive Wistar-Kyoto (WKY) rats were used as controls. Nuclear polyploidization was determined by DNA flow cytometry of frozen tissues from the left ventricle, at least 20,000 nuclei being measured in each sample. The rates of tetraploidy in the 16- and 36-week-old SHR groups were 2.8 per cent (range 2.16-3 per cent) and 5.4 per cent (range 4.9-5.9 per cent), respectively. Treated SHR had a similar rate of DNA tetraploidy to the 16- and 36-week-old WKY rat groups: 1.8 per cent (range 1.5-2.3 per cent), 1.55 per cent (range 1.5-1.6 per cent), and 1.5 per cent (range 1.4-1.6 per cent), respectively. The differences in the percentage of tetraploid cardiomyocytes between the SHR untreated groups and the SHR treated group were statistically significant (P < 0.05). Regression of LVH and normalization of blood pressure were observed in treated rats. These results indicate that DNA tetraploidy in the myocardium of SHR increases with hypertrophy and decreases on quinapril treatment. It is suggested that ACE inhibition modifies nuclear processes involved in myocyte growth in arterial hypertension.
Angiotensin-Converting Enzyme Inhibitors↗
[Development of a computer-assisted system to teach pathologic anatomy. Preliminary results].
BACKGROUND: The present study describes the implantation of an interactive teaching system to improve both the active involvement of the student and the learning quality of Pathology. The preliminary results from the evaluation of such system are also reported. METHODS: Two attitude questionnaires (rating scale) were passed to a sample of 36 students of Medicine, randomly elected. These students used for 10 weeks a programme of Pathology (Interpat) assisted by computer. Moreover, the data stored after each session by the control stack of this programme are analyzed. RESULTS: The programme is positively evaluated by the users who consider it as an appropriate mode of learning Pathology. In spite of the scarce experience with computers, students have no difficulty in using this programme. 82% of students consider that they learn more Pathology with Interpat than with the traditional system of magistral classes. 63% of students believe that similar systems must be applied in other curricula. The average time of use of the system by each student has been 11 h 45 min (SD 4 h 55 min). The videodisc is the stack more used. CONCLUSIONS: There is a good acceptance of this methodology by the students, being almost no difficulty in using the programme, despite their low level of computer knowledge. The program is a potent instrument for individualizing the teaching of Pathology. The small size of the sample, accurate for a preliminary study as this is, must be take into account when generalizing the results.
Computer-Assisted Instruction↗
Rhabdomyolysis and acute renal failure in a heart transplant recipient treated with hypolipemiants.
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Acute Kidney Injury↗
[The application of cytofluorometry to solid tumors for measuring DNA and the S phase].
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Cell Transformation, Neoplastic↗
Pathology of renal transplantation.
Renal transplantation is the most appropriate form of treatment for end-stage renal disease in all age groups. We present the experience of two hospitals in the pathology of kidney allograft. Renal biopsy is the most adequate method for the follow-up of these patients, because it permits the differential diagnosis of acute and chronic rejection, transplant glomerulopathy, recurrent and "de novo" glomerulonephritis and immunosuppression nephrotoxicity, mainly by cyclosporine A. We present the pathology features of all these entities, and study the representativity of the biopsy for diagnosis of rejection. The actuarial survival of the graft is 82% and 71% at 1 and 5 years, respectively.
Biopsy↗
Pathology of heart transplant through endomyocardial biopsy.
Cardiac transplantation is most effective method for treatment of patients with end-stage heart disease. We present the experience of our institution with 1,564 biopsies and 11 autopsies of 105 orthotopic heart transplants. This report describes the morphological features and the grading systems of acute rejection. Also, we present the morphological characteristics of other complications of heart transplants such as chronic rejection, "Quilty" effect, interstitial fibrosis, heart hypertrophy, previous biopsy sites, calcification, cytomegalovirus infections, toxoplasmosis, and the appearance of malignancies, mainly, lymphomas. Actuarial survival of patients is 91% and 88% at 1 and 5 years' posttransplant, respectively.
Adolescent↗
Liver changes in patients with hyperthyroidism.
We studied liver changes in the hepatic biopsies of five patients with hyperthyroidism. A characteristic histopathologic picture consisting of mild to moderate intrahepatocytic cholestasis, lobular inflammatory infiltrate with some eosinophils, and Kupffer cell hyperplasia was found in all cases. We discuss the specificity, clinicopathological correlations and the possible pathophysiology of these lesions.
Biopsy↗
Renal siderosis in patients with heart-valve prostheses: clinical implications.
We have studied the clinical and morphological implications of renal siderosis, reviewing the autopsy protocols of 33 patients with valve prostheses in the heart. Seventeen patients had variable amounts of iron in the proximal tubules of the kidney. Renal siderosis was more frequent in women, in patients with longest time of evolution from the surgical procedure, and in patients with two valve prostheses. Histologically three degrees of renal siderosis may be defined: mild and moderate degrees of iron overload do not alter the kidney architecture, but kidneys, with severe siderosis show tubular atrophy and interstitial fibrosis. Episodes of acute renal failure (ARF) were more frequent in patients with more pronounced iron deposits, especially in the premortem stages. We conclude that renal siderosis may damage the proximal tubular epithelium of patients with valve prostheses in the heart; patients with renal overload of iron are more susceptible to episodes of ARF.
Acute Kidney Injury↗
Complications of renal transplant: a morphologic evaluation.
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Biopsy↗
[Cutaneous pigmentation caused by amiodarone. Optical and ultrastructural study].
Thirteen biopsies from 8 patients with amiodarone-induced skin pigmentation were studied. Light microscopy showed that skin pigmentation of these patients was produced by solar elastosis, increase of melanin and accumulation of the properly called amiodarone pigment in the upper dermis. The degree of solar elastosis and the amount of amiodarone pigment was related to total doses of amiodarone. This pigment was negative for fat stains and positive for Masson-Fontana stain, and had neither birrefringency nor autofluorescence. Ultrastructurally, the granules of amiodarone pigment appeared as membrane-bound granules with a fingerprint-like lamellated structure, which others have related to lipofuscin. We conclude, however, that this pigment may be a metabolite of amiodarone, morphologically and histochemically related to melanin.
Adult↗