Biomedical subjects

Paula Silva

Publications and source records attributed to Paula Silva.

10 recordsLinked to original sources

PubMed2006

Mixed gastric carcinomas show similar chromosomal aberrations in both their diffuse and glandular components.

Gastric cancer is one of the most frequent malignancies in the world. Nonetheless, the knowledge of the molecular events involved in the development of gastric carcinoma is far from complete. One of the hallmarks of gastric cancer is chromosomal instability resulting in abnormal DNA copy number changes throughout the genome. Mixed gastric carcinomas constitute a rare histological entity, containing the two main histological phenotypes (diffuse and intestinal). Very little is known about the underlying mechanisms of phenotypic divergence in these mixed tumours. To the best of our knowledge only E-Cadherin mutations were implicated so far in the divergence of these tumours and nothing is known about the involvement of chromosome copy number changes in the two divergent histological components. In this study, we compared the DNA copy number changes, in the two different components (diffuse and intestinal) of mixed gastric carcinomas by microarray - comparative genomic hybridisation (array CGH). The analysis of 12 mixed gastric carcinomas showed no significant differences in array CGH profiles between the diffuse and intestinal components of mixed carcinomas. This supports the idea that the phenotypic divergence within mixed gastric carcinomas is not caused by DNA chromosomal aberrations.

Chromosome Aberrations↗

PubMed2006

Fascicular ventricular tachycardia: experience with radiofrequency ablation.

Fascicular ventricular tachycardia (VT), the commonest form of idiopathic left VT, occurs more frequently in young males without structural heart disease and usually presents as paroxysmal palpitations. It is subdivided into two more common subtypes, posterior and anterior. A macro-reentrant circuit involving a considerable and variable extent of the left interventricular septum is presumed to be the underlying arrhythmogenic mechanism. A slow conduction zone with particular sensitivity to verapamil participates in the circuit and it seems that diastolic potentials (DP) represent the electrical activity in or near this zone. The fascicles of the left bundle appear to constitute part of the retrograde pathway and Purkinje potentials (PP) are assumed to represent their activation. In the present retrospective study, the authors review twelve cases of fascicular VT (ten posterior and two anterior) evaluated in the electrophysiology laboratory. Although initial induction was obtained in all patients, reproducibility was poor as a consequence of frequent contact inhibition during endocardial mapping of the left ventricle and this meant that ablation was not possible in two cases. Two cases of associated atrioventricular nodal reentrant tachycardia (AVNRT) and a case of associated atrioventricular reentrant tachycardia by a right posterior accessory pathway were documented, which suggest a correlated anatomic substrate. After ablation of the slow nodal pathway in one of the AVNRTs, fascicular VT was no longer inducible. Ablation of the fascicular VT was attempted in nine patients, at the tachycardia exit site (characterized by an early ventricular electrogram fused with a Purkinje potential) in two patients with anterior fascicular VT and in five patients with the posterior subtype, and near the slow conduction pathway (site with simultaneous recording of DP and PP) in the other two patients. The initial success rate with a single procedure was 78%, two of the ablations at the tachycardia exit site failing, with no complications. If we include the success of a repeated case with three-dimensional mapping, the overall success rate was 80%. Ablation of fascicular tachycardia appears to be a good therapeutic option with a good success rate and without significant adverse events. The poor reproducibility as a consequence of contact inhibition during endocardial left ventricular mapping is the principal limiting factor. With the help of currently available mapping systems, we hope that this limitation will disappear, as it is now possible with some devices to acquire accurate information on suitable sites for subsequent radiofrequency application with little or no contact, facilitating the ablation procedure. Ablation at a site with simultaneous recording of DP and PP is considered by most authors to be more effective than that performed at the tachycardia exit site.

Adolescent↗

PubMed2005

Differential Prox-1 and CD 31 expression in mucousae, cutaneous and soft tissue vascular lesions and tumors.

The study of lymphatic vessels and lymphatic tumors has been hampered with difficulty due to the overlapping morphological features between blood and lymphatic endothelial cells, as well as to the lack of specific lymphatic endothelial markers. Over the last few years, lymphatic vessels and lymphangiogenesis have received great attention owing to their putative implications in terms of metastatic dissemination and the promise of targets for lymphangiogenic therapy. Prox-1 is a nuclear transcription factor that plays a major role during embryonic lymphangiogenesis and is deemed to be a useful marker for differentiating lymphatic endothelial cells from the other blood vessels endothelial cells. Here, we describe a double-immunostaining strategy for formalin-fixed, paraffin-embedded tissues that aims at evaluating the distribution of Prox-1 and CD 31 - a cytoplasmic pan-endothelial marker - in a series of 28 mucousae, cutaneous and soft tissue vascular lesions and tumors, including hemangiomas, lymphangiomas, lymphangiectasia, and Kaposi's sarcomas. Our results showed that in non-lesional mucousae and skin, Prox-1 decorated exclusively the nuclei of endothelial cells in lymphatic vessels. Prox-1 stained almost all the benign lymphatic vascular lesions/tumors (91%) and was absent or only focally positive in 75% of blood vascular tumors. CD 31 stained endothelial cells of blood vessels of superficial and deep dermal plexuses, lymphatics, and all blood vascular lesions/tumors. Kaposi's sarcomas were all positive for both CD 31 and Prox-1 markers. In conclusion, although Prox-1 expression in vascular lesions/tumors was not entirely restricted to tumors with known lymphatic differentiation, CD 31/Prox-1 double-immunolabeling can be used as an adjunct marker to identify lymphatic vessels in routinely processed formalin-fixed, paraffin-embedded samples.

Adolescent↗

PubMed2004

BRAF mutations are associated with some histological types of papillary thyroid carcinoma.

Mutations in the BRAF gene have recently been detected in a wide range of neoplastic lesions with a particularly high prevalence in melanoma and papillary thyroid carcinoma (PTC). The hot-spot mutation BRAF(V599E) is frequently detected in PTC (36-69%), in contrast to its absence in other benign or malignant thyroid lesions. In order to unravel whether there is any association between the occurrence of the BRAF mutation and the histological pattern of PTC, in this study a previous series of 50 PTCs was extended to 134 cases, including ten cases of PTC-related entities-hyalinizing trabecular tumour (HTT) and mucoepidermoid carcinoma (MEC). Using PCR/SSCP and sequencing, the BRAF(V599E) mutation was detected in 45 of the 124 PTCs (36%). No mutations were detected in any case of HTT and MEC. BRAF(V599E) was present in 75% of Warthin-like PTCs and 53% of conventional PTCs, whereas no BRAF(V599E) mutations were detected in any of the 32 cases of the follicular variant of PTC. BRAF(V599E) was also detected in 6 of 11 cases of the oncocytic variant of PTC that displayed a papillary or mixed follicular-papillary growth pattern and in none of the four oncocytic PTCs with a follicular growth pattern. A distinct mutation in BRAF (codon K600E) was detected in three cases of the follicular variant of PTC. This study has confirmed the high prevalence of BRAF(V599E) in PTC and has shown that the mutation is almost exclusively seen in PTC with a papillary or mixed follicular-papillary growth pattern, regardless of the cytological features of the neoplastic cells. The results support the existence of an oncocytic variant of PTC that should be separated from the oncocytic variant of follicular carcinoma and suggest that the follicular variant of PTC may be genetically different from conventional PTC.

Carcinoma, Papillary↗

PubMed2004

Telomerase expression and proliferative activity suggest a stem cell role for thyroid solid cell nests.

Solid cell nests of the human thyroid gland are composed of main cells and C cells. In order to investigate the putative stem cell nature of the role for solid cell nests, we evaluated the histological features, and the immunohistochemical expression of p63, bcl-2, telomerase catalytic subunit, and two proliferative markers (Ki-67 and minichromosome maintenance protein 2), in a series of 24 cases of solid cell nests. Proliferative indices were determined in (a) solid cell nests, (b) thyroid follicular cells in the vicinity of solid cell nests within a low-power field, and (c) distant thyroid tissue, at a distance of at least three low-power fields from solid cell nests. In 15 cases of solid cell nests (62.5%), mixed follicles were observed; papillary formations were observed in four cases (16.6%), and ciliated cells were observed in the lining of microcysts associated with two cases (8.3%). Salivary gland-type tissue, cartilage islands, adipose and fibrous tissues, and small nerves were also associated with some cases of solid cell nests. We observed that the main cells of the solid cell nests express consistently telomerase, although at lower levels than p63, and show strong cytoplasmic immunoreactivity for bcl-2, which is associated with an increased differentiation potential. We also observed that despite their relative low proliferative index, main cells of the solid cell nests display higher proliferation than follicular cells in the vicinity and follicular cells in more distant thyroid tissue. We conclude that main cells of the solid cell nests apparently harbor the minimal properties of a stem cell phenotype (capacity for both self-renewal, conferred by telomerase activity, and differentiation to one or more than one type of specialized cells, given by the high expression of p63 and bcl-2) and may thus represent a pool of stem cells of the adult thyroid.

Adult↗

PubMed2003

Radiation dose to abdominal organs of the mouse due to 90Y in the urinary bladder.

Radiation dosimetry estimates in mice have proven useful in evaluating therapeutic radiopharmaceuticals. Current models for mice do not take into account the dose to abdominal organs from radioactivity in the urinary bladder. Although the dose from this source is probably low for slowly clearing compounds such as antibodies, it may be considerable for small molecule (90)Y conjugates undergoing rapid renal clearance. To evaluate this possibility, we modeled the mouse bladder as a 6 mm sphere, surrounded by a 0.5 mm thick shell. We then calculated the radiation dose that might be received by the shell and by more distant points, using the point kernel method with the Loevinger analytical point kernel. A Monte Carlo calculation using EGS4 was also performed. Surface dose calculations were compared with in vitro experimental data. LiF TLD dosimeters were placed directly under five separated, flat-bottomed, 6-mm diameter wells containing (90)Y on a 96-well plate. Dose versus distance from the mouse urinary bladder was calculated using kinetic data from imaging studies of a renally cleared (111)In analog compound currently under investigation. From this, it was estimated that whole body administration of 34.8 MBq of the (90)Y analog compound would yield a bladder wall dose estimate of approximately 98 Gy. Structures within 2 mm of the bladder would receive additional estimated doses of at least 15 Gy. This radiation dose approaches that which is known from external beam data to cause fibrosis in mice. Because of the greater size of the human bladder compared with that of the mouse relative to the range of (90)Y beta particles, the radiation exposure from the same residence time in man was estimated to be considerably lower. This highlights a potential practical limitation of extrapolating radiotoxicity findings in the mouse to human subjects.

Abdomen↗

PubMed2003

Design, synthesis, and evaluation of radiolabeled integrin alpha v beta 3 receptor antagonists for tumor imaging and radiotherapy.

The goal of this research is the development of tumor imaging and radiotherapeutic agents based on targeting of the integrin alpha(v)beta(3) (vitronectin receptor). Macrocyclic chelator DOTA has been conjugated to peptidomimetic vitronectin receptor antagonist SH066 to give TA138. TA138 and (89)Y-TA138 retain antagonist properties and high affinity for integrin alpha(v)beta(3) (IC(50) = 12 and 18 nM, respectively), and good selectivity versus integrin alpha(IIb)beta(3) (IC(50) > 10,000 nM). TA138 forms stable complexes with (111)In and (90)Y in > 95% RCP. (111)In-TA138 demonstrates high tumor uptake in the c-neu Oncomouse (Charles River Laboratories [Charles River, Canada]) mammary adenocarcinoma model (9.39% ID/g at 2 hours PI) and low background activity. Blood clearance is rapid and excretion is renal. Tumors are visible as early as 0.5 hours PI. Radiotherapy studies in the c-neu Oncomouse model demonstrated a slowing of tumor growth at a dose of 15 mCi/m(2), and a regression of tumors at a dose of 90 mCi/m(2).

Adenocarcinoma↗

PubMed2003

Novel and classic myoepithelial/stem cell markers in metaplastic carcinomas of the breast.

Metaplastic carcinomas of the breast (MCBs) are unusual neoplasms characterized by an admixture of glandular epithelial components, which frequently exhibit features of squamous differentiation, and mesenchymal malignant components. Regardless of the presence of myoepithelial features in MCB, no consensus concerning their putative histogenesis has yet been achieved. Recently, novel putative myoepithelial markers have been developed, including p63, maspin, and P-cadherin. We assessed the expression of these myoepithelial markers in MCBs and compared their expression with classic myoepithelial markers. Immunohistochemistry using the streptavidin-biotin-peroxidase complex technique with antibodies raised against p63, maspin, P-cadherin, actin (clones CGA7, 1A4 and HHF35), cytokeratin 14 (Ck14), and vimentin was performed on 16 MCBs (7 matrix-producing MCBs, 6 adenosquamous MCBs, and 3 MCBs with heterologous elements). In healthy breast lobules and ducts adjacent to the tumors, myoepithelial cells showed distinctive and consistent immunoreactivity for p63, maspin, P-cadherin, actin, S-100 protein, and Ck14. Matrix-producing MCBs were positive for maspin in all cases, for p63 in 4 of 7 cases, and for P-cadherin in 4 of 7 cases. Adenosquamous MCB showed immunoreactivity for p63, maspin, and P-cadherin in 5 of 6 cases. All novel myoepithelial markers and Ck14 decorated squamous cell islands. MCBs with heterologous elements were positive for p63 in 1 case, for maspin in all 3 cases, and for P-cadherin in 2 cases. All cases showed at least one of the novel myoepithelial markers. Eleven of 16 cases were positive for actin. Eleven of 14 cases reacted with Ck14, and all cases that stained for S-100 protein (9 of 9) and vimentin (13 of 13) were also positive. Based on our findings, the balance of probabilities favors that MCBs may have a basal or myoepithelial cell histogenesis and differentiation.

Actins↗

PubMed2003

Expression of c-met tyrosine kinase receptor is biologically and prognostically relevant for primary cutaneous malignant melanomas.

OBJECTIVES: The c-met tyrosine-kinase receptor and its ligand hepatocyte growth factor are involved in cell survival, proliferation, motility, and invasion. Experimental data have suggested a putative role in melanomagenesis and progression of cutaneous malignant melanoma (CMM). We sought to evaluate c-met expression in a cohort of 62 primary CMM patients diagnosed and primarily treated at the same institution. METHODS: Sixty-two cases of CMM were retrospectively retrieved from the archives of the Department of Pathology, Hospital São João, Porto, Portugal. All classical clinicopathological features were reviewed. Only those patients in whom representative paraffin blocks were available and the diagnosis of primary CMM was confirmed, and who were followed up after the primary diagnosis were included in the study. Immunohistochemistry for c-met was performed in 59 cases, and semiquantitatively and qualitatively (membranous and cytoplasmic, M+C, or cytoplasmic) evaluated. Statistical analysis was performed using chi(2), ANOVA and Kaplan-Meier/log-rank tests. RESULTS: M+C pattern of c-met expression was significantly associated with presence of vertical growth phase (p = 0.0198), thick tumors (p = 0.0006), ulceration (p = 0.0386), high mitotic index (p = 0.0008), lymphatic (p = 0.0086) and vascular (p = 0.0080) invasion, and nodal (p = 0.0422) and combined (nodal and/or visceral) metastases (p = 0.0234). M+C pattern of c-met expression also proved to be a significant prognostic factor for overall survival in univariate analysis (p = 0.0125). CONCLUSIONS: Our findings suggest that the pattern of c-met expression is a relevant prognostic factor for overall survival and is associated with more aggressive behavior of primary CMMs.

Adolescent↗

PubMed2002

Hyaline cell-rich chondroid syringoma: case report and review of the literature.

Hyaline cell-rich chondroid syringoma (HCRCS) is a rare benign cutaneous neoplasm composed of cells with eosinophilic hyaline cytoplasm and plasmacytoid features, the origin of which remains elusive. To the best of our knowledge, only eight cases of this entity have been reported so far, and none of them was submitted to a large panel of myoepithelial markers. We report on a case of a previously healthy 29-year-old male patient who presented with a slowly enlarging flesh-colored nodule on the palmar aspect of the tenar region of his left hand, measuring 2 cm in maximum diameter. The nodule was "shelled-out" and submitted to light microscopy, immunohistochemistry, and ultrastructural examination. Histopathologic analysis disclosed a lobulated neoplasm composed of hyaline cells with plasmacytoid features showing ovoid nuclei, with occasional invaginations, finely granular chromatin, and discrete nucleoli; the cytoplasm was deeply eosinophilic with occasional dot-shaped paranuclear hyaline inclusions. On immunohistochemical evaluation, hyaline cells were strongly and diffusely positive for S-100 protein, vimentin, pan (CAM 5.2) and high molecular weight (34betaE12) cytokeratins; these cells were focally positive for GFAP, maspin, neuron-specific enolase, and cytokeratin 14. Alpha-smooth muscle actin, epithelial membrane antigen, carcinoembryonic antigen, collagen IV, Gp100 (HMB-45), and p63 were negative in neoplastic hyaline cells. Ultrastructural analysis disclosed cells with ovoid nuclei showing occasional invaginations and nuclear pockets; the cytoplasm was rich in meshworks of non-bundling intermediate filaments and a variable amount of rough endoplasmic reticulum cisternae. Based on our findings and those previously reported, hyaline cells of HCRCS might posses an aberrant myoepithelial differentiation. Most importantly, pathologists need to be aware of the histologic and immunohistochemical features of HCRCS to avoid a misdiagnosis of highly malignant neoplams, such as malignant melanoma and extra-skeletal myxoid chondrosarcoma.

Adenoma, Pleomorphic↗