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1.
Clin Otolaryngol ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31646745

RESUMO

OBJECTIVE: To investigate the role of matrix metalloproteinases (MMPs) and their inhibitors (TIMP) in the development of cervical metastases in papillary thyroid cancer Our hypothesis is that level of expression of MMPs and TIMPs is associated with the development of cervical metastases and the pattern of metastatic process in papillary thyroid cancer. DESIGN: This research retrospectively investigates the expression of MMP-1, -2 and -9 as well as TIMP-1 and -2 in papillary thyroid carcinoma tissue. Tissue specimens were immunohistochemically treated with primary monoclonal antibodies against MMP-1, MMP-2 MMP-9, TIMP-1 and TIMP-2. SETTING: Single center study PARTICIPANTS: In total, samples of 159 patients were analyzed. In all patients, total thyroidectomy was performed, whereas 102 patients underwent selective neck dissection of either central (level VI) or lateral neck (level II-V). Subjects were divided into four groups MAIN OUTCOME MEASURES: MMPs and TIMPs expression values ​​were analyzed in each group and groups were compared to each other. RESULTS: Total number of patients was 159, of which 125 were female and 34 male Comparing expression levels of MMPs and TIMPs in metastatic (study groups) and non-metastatic (control group) papillary thyroid carcinomas yielded significant differences in MMP-1 and TIMP-1 expression levels, where the highest expression values were found in the group with metastasis in lateral neck. Expression levels of MMP-2, MMP-9 and TIMP-2 did not differ statistically significantly among the groups. CONCLUSION: Elevated expression of MMP-1 and TIMP-1 in tumor tissue can be considered a predictive factor for the development of metastases.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31127594

RESUMO

Ectopic adrenal cortical neoplasms of the spinal cord are extremely rare. To date only 10 such cases have been described. We present a case of a 46-year-old woman with lower back pain radiating to the right gluteal and posterior femoral regions, without a history of traumatic injury. Magnetic resonance imaging (MRI) of the thoracic and lumbar spine showed an intradural, extramedullary, well-circumscribed, contrast-enhancing lesion located in the T12-L1 region, hypo- to isointense on T2-weighted imaging, and isointense on T1. Complete surgical removal of the lesion, measuring 3 × 2.5 × 1 cm, was performed. The histopathologic findings revealed the lesion was an ectopic adrenal cortical adenoma, with sheets and nests of round and polygonal cells, mostly round regular nuclei, abundant eosinophilic cytoplasm, 1 mitosis per 10 high-power fields, and without necrosis. These tumors have nonspecific MRI features and therefore can be easily confused with other common spinal tumor types such as ependymoma, schwannoma, meningioma, and metastasis. Although rare, ectopic adrenal spinal cord adenomas should be taken into account in the differential diagnosis of spinal canal intradural neoplasms.

3.
PLoS One ; 14(2): e0211577, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30707715

RESUMO

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. Main HNSCC risk factors are tobacco, alcohol, and high-risk human papillomavirus (HPV). HPV+ oropharyngeal squamous cell cancer (OPSCC) usually have different etiology, increasing incidence and often show an improved survival when compared to HPV-negative cases. The objective of the current study was to retrospectively examine the influence of HPV on the survival of OPSCC patients in a non-Western population setting. MATERIALS AND METHODS: We determined the presence of HPV DNA and/or RNA in 99 formalin-fixed paraffin embedded (FFPE) tissue samples of OPSCC patients treated between 2002 and 2015. Patients were compared based on laboratory, demographic, clinical, life style characteristics and survival. RESULTS: HPV RNA was found in 29.3% cases. However, groups based on HPV data (either RNA, DNA or retrospectively collected p16 staining) did not show significant differences. Overall, 5-year survival was 30% with minimal influence of the HPV positivity. CONCLUSIONS: The HPV influence on survival of OPSCC patients is not identical between populations probably due to other factors overshadowing the HPV effect. This should be taken into account when treatment or policy decisions are made in each particular setting.

4.
Croat Med J ; 59(5): 213-223, 2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30394013

RESUMO

AIM: To identify the involvement of Secreted Frizzled Related Protein 1 (SFRP1) promoter hypermethylation in different malignancy grades of astrocytoma and assess its association with beta-catenin, lymphoid-enhancer factor 1, and T-cell factor 1. METHODS: Twenty-six astrocytoma samples were collected from 2008-2015. Promoter hypermethylation was evaluated by methylation-specific polymerase-chain-reaction and protein expression by immunohistochemistry and stereological analysis. The staining intensity was scored by comparing immunoreactivity with normal tissue and by using 10% and 50% cut-offs. RESULTS: SFRP1 promoter methylation was found in 32% of astrocytomas. The number of hypermethylated samples increased in higher astrocytoma grades and was the highest in glioblastoma (P=0.042 compared to other astrocytoma grades). There was 45.8% of samples with the lack of or weak expression of SFRP1 protein and 29.2% with strong expression. Samples with methylated promoter expressed significantly less SFRP1 than samples with unmethylated promoter (P=0.031). Beta-catenin expression levels were elevated. Yet, glioblastomas with unmethylated SFRP1 promoter had significantly less beta-catenin (P=0.033). Strong expression of lymphoid-enhancer factor 1 was associated to higher astrocytoma grades (P=0.006). CONCLUSION: SFRP1 gene was epigenetically silenced in glioblastomas when compared to low astrocytoma grades, which may suggest that the lack of its protein is involved in astrocytoma progression.

5.
Brain Pathol ; 2018 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-30246434

RESUMO

Ependymoma with YAP1-MAMLD1 fusion is a rare, recently described supratentorial neoplasm of childhood, with few cases published so far. We report on 15 pediatric patients with ependymomas carrying YAP1-MAMLD1 fusions, with their characteristic histopathology, immunophenotype and molecular/cytogenetic, radiological and clinical features. The YAP1-MAMLD1 fusion was documented by RT-PCR/Sanger sequencing, and tumor genomes were studied by molecular inversion probe (MIP) analysis. Significant copy number alterations were identified by GISTIC (Genomic Identification of Significant Targets in Cancer) analysis. All cases showed similar histopathological features including areas of high cellularity, presence of perivascular pseudo-rosettes, small to medium-sized nuclei with characteristic granular chromatin and strikingly abundant cells with dot-like cytoplasmic expression of epithelial membrane antigen. Eleven cases presented features of anaplasia, corresponding to WHO grade III. MRI showed large supratentorial multinodular tumors with cystic components, heterogeneous contrast enhancement, located in the ventricular or periventricular region. One of two variants of YAP1-MAMLD1 fusions was detected in all cases. The MIP genome profiles showed balanced profiles, with focal alterations of the YAP1 locus at 11q22.1-11q21.2 (7/14), MAMLD1 locus (Xp28) (10/14) and losses of chromosome arm 22q (5/14). Most patients were female (13/15) and younger than 3 years at diagnosis (12/15; median age, 8.2 months). Apart from one patient who died during surgery, all patients are alive without evidence of disease progression after receiving different treatment protocols, three without postoperative further treatment (median follow-up, 4.84 years). In this to date, largest series of ependymomas with YAP1-MAMLD1 fusions we show that they harbor characteristic histopathological, cytogenetic and imaging features, occur mostly in young girls under 3 years and are associated with good outcome. Therefore, this genetically defined neoplasm should be considered a distinct disease entity. The diagnosis should be confirmed by demonstration of the specific fusion. Further studies on large collaborative series are warranted to confirm our findings.

7.
J Allergy Clin Immunol ; 142(4): 1297-1310.e11, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29155098

RESUMO

BACKGROUND: Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ channels is an essential signaling pathway in many cell types. Ca2+ release-activated Ca2+ channels are formed by ORAI1, ORAI2, and ORAI3 proteins and activated by stromal interaction molecule (STIM) 1 and STIM2. Mutations in the ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and nonimmunologic symptoms. OBJECTIVE: We performed molecular and immunologic analysis of patients with CID, anhidrosis, and ectodermal dysplasia of unknown etiology. METHODS: We performed DNA sequencing of the ORAI1 gene, modeling of mutations on ORAI1 crystal structure, analysis of ORAI1 mRNA and protein expression, SOCE measurements, immunologic analysis of peripheral blood lymphocyte populations by using flow cytometry, and histologic and ultrastructural analysis of patient tissues. RESULTS: We identified 3 novel autosomal recessive mutations in ORAI1 in unrelated kindreds with CID, autoimmunity, ectodermal dysplasia with anhidrosis, and muscular dysplasia. The patients were homozygous for p.V181SfsX8, p.L194P, and p.G98R mutations in the ORAI1 gene that suppressed ORAI1 protein expression and SOCE in the patients' lymphocytes and fibroblasts. In addition to impaired T-cell cytokine production, ORAI1 mutations were associated with strongly reduced numbers of invariant natural killer T and regulatory T (Treg) cells and altered composition of γδ T-cell and natural killer cell subsets. CONCLUSION: ORAI1 null mutations are associated with reduced numbers of invariant natural killer T and Treg cells that likely contribute to the patients' immunodeficiency and autoimmunity. ORAI1-deficient patients have dental enamel defects and anhidrosis, representing a new form of anhidrotic ectodermal dysplasia with immunodeficiency that is distinct from previously reported patients with anhidrotic ectodermal dysplasia with immunodeficiency caused by mutations in the nuclear factor κB signaling pathway (IKBKG and NFKBIA).

8.
Free Radic Biol Med ; 111: 110-126, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-27993730

RESUMO

Excessive production of reactive oxygen species can induce peroxidation of the polyunsaturated fatty acids thus generating reactive aldehydes like 4-hydroxy-2-nonenal (HNE), denoted as "the second messenger of free radicals". Because HNE has high binding affinity for cysteine, histidine and lysine it forms relatively stable and hardly metabolized protein adducts. By changing structure and function of diverse structural and regulatory proteins, HNE achieves not only cytotoxic, but also regulatory functions in various pathophysiological processes. Numerous animal model studies and clinical trials confirmed HNE as one of the crucial factors in development and progression of many disorders, in particular of cancer, (neuro)degenerative, metabolic and inflammatory diseases. Since HNE has multiple biological effects and is in the living system usually bound to proteins and peptides, many research groups work on development of specific immunochemical methods targeting the HNE-histidine adducts as major bioactive marker of lipid peroxidation, following the research pathway initiated by Hermann Esterbauer, who discovered HNE in 60's. Such immunohistochemical studies did not only prove the high biomedical importance of HNE, but have also given new insights into major diseases of the modern man. Immunohistochemical studies have shown reversibility of formation of the HNE-protein adducts, as well as differential onset of the HNE-mediated lipid peroxidation between age- associated atherosclerosis and photoaging, revealing eventually selective anti-cancer effects of HNE produced by non-malignant cells in vicinity of cancer. This review summarizes some of the HNE-histidine immunohistochemistry findings we believe are of broad biomedical interest and could inspire new studies in the field.


Assuntos
Aldeídos/metabolismo , Peptídeos beta-Amiloides/metabolismo , Doenças Cardiovasculares/metabolismo , Pneumopatias/metabolismo , Neoplasias/metabolismo , Doenças Neurodegenerativas/metabolismo , Proteínas tau/metabolismo , Peptídeos beta-Amiloides/química , Animais , Biomarcadores/metabolismo , Doenças Cardiovasculares/patologia , Ácidos Graxos Insaturados/metabolismo , Humanos , Imuno-Histoquímica , Peroxidação de Lipídeos , Pneumopatias/patologia , Neoplasias/patologia , Doenças Neurodegenerativas/patologia , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Proteínas tau/química
9.
Surg Neurol Int ; 7(Suppl 44): S1158-S1162, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28194305

RESUMO

BACKGROUND: Rosai-Dorfman is a rare disease that usually occurs in young adults. It is characterized with massive painless cervical lymphadenopathy and histiocyte proliferation. Isolated intracranial involvement is extremely rare. Our aim is to present a new rare case of extranodal Rosai-Dorfman disease that involved the right optic nerve in a 4-year-old boy. CASE DESCRIPTION: A 4-year-old boy with right-sided convergent strabismus and amblyopia lasting for 1 year was treated at the Department of pediatric ophthalmology. Initial optical fundus examination was normal. Examination repeated after 1 year noted the atrophy of the optic nerve papilla. Visual evoked potentials of the right eye showed normal findings of prechiasmatic visual pathway with severe dysfunction of the right optic nerve. Magnetic resonance imaging (MRI) of the brain and orbits showed expansive changed and elongated right optic nerve with contrast enhancement, and smaller lesion in the right temporal operculum region visible in T2 and fluid-attenuated inversion recovery sequence. Through small eyebrow "keyhole" osteoplastic frontoorbital craniotomy the fusiform enlarged (to 2 cm) right optic nerve was identified, resected between the eyeball and optic chiasm, and transferred for pathohistological analysis. Early postoperative course had no complications. Histological, immunohistochemical, and ultrastructural analyses revealed extranodal Rosai-Dorfman disease. Right periorbital edema was verified on the 7th postoperative day and regressed to supportive therapy. Control multi slice computed tomography (MSCT) and MRI of endocranium and orbits showed total tumor removal with no signs of complications. CONCLUSION: Although rare, extranodular intracranial Rosai-Dorfman disease should be taken into account in the differential diagnosis of intracranial and intraorbital lesions, especially in the pediatric age group.

10.
Onco Targets Ther ; 8: 1285-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26082646

RESUMO

This paper reports a case of sudden bilateral deafness as the first symptom of gastric cancer, an extremely rare and atypical clinical situation. Because common signs of stomach cancer were absent, the patient was first evaluated in the Department of Otolaryngology, University Hospital Center, Zagreb. Only after expanded diagnostic evaluation and rapid progression of the disease in such a case is a malignant tumor suspected. Treatment is mostly ineffective. The unusual presentation of the disease and the rapid course may indicate a hereditary predisposition. Inactivation of tumor suppressor gene DFNA5 was found in 50% of gastric cancers, but of a non-metastasized phenotype. Inactivated DFNA5, otherwise described in hereditary bilateral deafness, perhaps favors the development of deafness in patients with gastric cancer. Our patient had a positive multiple viral antibody titer in serum, inactivated DFNA5 in both gastric cancer tissues and cerebellar metastases, and a metastatic form of the disease. If sudden deafness occurs in elderly patients, the possibility of malignant tumor should be taken into consideration. The link between gastric cancer and the DFNA5 gene is unclear and requires further research.

11.
Appl Immunohistochem Mol Morphol ; 23(10): 696-703, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25611241

RESUMO

BACKGROUND: Oxidative stress is thought to play a major role in etiology of many cancers, including breast cancer. 8-hydroxy-2'deoxyguanosine (8-OHdG) is the most abundant marker of oxidative DNA damage. The aim of this study was to assess the extent of oxidative DNA damage in different breast cancer molecular surrogate subtypes to investigate the prognostic relevance and role of oxidative base lesion (8-OHdG) in the etiology of breast cancer. MATERIALS AND METHODS: 8-OHdG expression was immunohistochemicaly studied on tissue microarrays constructed from 152 patients with invasive breast cancer. Expression was correlated with other prognostic factors, as well as different breast cancer molecular surrogate subtypes such as luminal A, luminal B [human epidermal growth factor receptor 2 (HER2) negative], luminal B (HER2 positive), HER2-enriched ad triple-negative tumors. RESULTS: Triple-negative breast carcinomas (TNBCs) were more frequently 8-OHdG negative compared with non-TNBCs (P=0.036). There was no statistically significant difference between 8-OHdG expression and other breast cancer molecular subtypes.In univariate analysis, there was no significant difference between 8-OHdG expression and breast cancer-specific death, although in multivariate analysis 8-OHdG overexpression was associated with better breast cancer-specific survival (BCSS) (odds ratio=0.04, 95% confidence interval, 0.002-0.62). In Cox regression analysis, patients with moderate and strong 8-OHdG expression had 0.9 times smaller breast cancer death hazard ratio than patients with negative 8-OHdG expression. CONCLUSIONS: Oxidative stress may have less impact in the pathogenesis of TNBCs compared with other surrogate breast cancer molecular subtypes. 8-OHdG may be a promising biomarker in the prediction of prognosis for breast cancer patients.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Dano ao DNA , DNA de Neoplasias/metabolismo , Desoxiguanosina/análogos & derivados , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/classificação , Desoxiguanosina/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Oxirredução , Análise Serial de Tecidos
12.
World J Clin Cases ; 2(5): 151-6, 2014 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-24868516

RESUMO

A 24-year-old female patient with parathyroid carcinoma, the rarest endocrine malignancy, had two pregnancies. In the first pregnancy, she had severe nausea and fatigue. Hypercalcemia and hyperparathyroidism were diagnosed in the postpartum period. Hyperemesis gravidarum masked a diagnosis of hypercalcemia. Neck ultrasound and Tc-99m sestamibi found an enlarged lower right parathyroid gland. The gland was surgically removed, and an initial pathology report described atypical adenoma. Shortly afterward, she became pregnant again. During the second pregnancy, her calcium level was frequently controlled but was always in the normal range. Normocalcemia is explained by the specific physiology of pregnancy accompanied by hemodilution, hypoalbuminemia and maternal hypercalciuria (mediated by increased glomerular filtration). During lactation, calcium levels rose, and a new neck ultrasound showed a solitary mass in the area of prior surgery and an enlarged pretracheal lymph node. Fine needle aspiration of the solitary mass and node showed parathyroid carcinoma cells. The tumor mass was resected en bloc with the contiguous tissues and surrounding lymph nodes (pathology report; parathyroid carcinoma with metastases). Over the next five years, four consecutive surgeries were performed to remove malignant parathyroid tissue, lymph nodes and local metastases. Following the surgical procedures, no hypocalcemia was observed. More serious hypercalcemia recurred; the calcium level was difficult to control with a combination of pamidronate, cinacalcet and loop diuretic. No elements of multiple endocrine neoplasia were present.

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