Microarray and bioinformatic analysis of conventional ameloblastoma: an observational analysis

Abstract Ameloblastoma is a highly aggressive odontogenic tumor, and its pathogenesis is associated with many participating genes. Objective We aimed to identify and validate new critical genes of conventional ameloblastoma using microarray and bioinformatics analysis. Methodology Gene expression microarray and bioinformatic analysis were performed using CHIP H10KA and DAVID software for enrichment. Protein-protein interactions (PPI) were visualized using STRING-Cytoscape with MCODE plugin, followed by Kaplan-Meier and GEPIA analyses that were used for the candidate's postulation. RT-qPCR and IHC assays were performed to validate the bioinformatic approach. Results 376 upregulated genes were identified. PPI analysis revealed 14 genes that were validated by Kaplan-Meier and GEPIA resulting in PDGFA and IL2RA as candidate genes. The RT-qPCR analysis confirmed their intense expression. Immunohistochemistry analysis showed that PDGFA expression is parenchyma located. Conclusion With bioinformatics methods, we can identify upregulated genes in conventional ameloblastoma, and with RT-qPCR and immunoexpression analysis validate that PDGFA could be a more specific and localized therapeutic target.

Control of Motility in the Internal Anal Sphincter

The internal anal sphincter (IAS) plays an important role in the maintenance of fecal continence since it generates tone and is responsible for > 70% of resting anal pressure. During normal defecation the IAS relaxes. Historically, tone generation in gastrointestinal muscles was attributed to mechanisms arising directly from smooth muscle cells, ie, myogenic activity. However, slow waves are now known to play a fundamental role in regulating gastrointestinal motility and these electrical events are generated by the interstitial cells of Cajal. Recently, interstitial cells of Cajal, as well as slow waves, have also been identified in the IAS making them viable candidates for tone generation. In this review we discuss four different mechanisms that likely contribute to tone generation in the IAS. Three of these involve membrane potential, L-type Ca²⁺ channels and electromechanical coupling (ie, summation of asynchronous phasic activity, partial tetanus, and window current), whereas the fourth involves the regulation of myofilament Ca²⁺ sensitivity. Contractile activity in the IAS is also modulated by sympathetic motor neurons that significantly increase tone and anal pressure, as well as inhibitory motor neurons (particularly nitrergic and vasoactive intestinal peptidergic) that abolish contraction and assist with normal defecation. Alterations in IAS motility are associated with disorders such as fecal incontinence and anal fissures that significantly decrease the quality of life. Understanding in greater detail how tone is regulated in the IAS is important for developing more effective treatment strategies for these debilitating defecation disorders.

Evaluation of the role of platelet derived growth factor in papillary thyroid carcinoma by targeted ultrasound contrast agent / 中华超声影像学杂志

Objective@#To explore the role of targeted ultrasound contrast agent in the evaluation of angiogenesis in papillary thyroid carcinoma (PTC) in nude mice by constructing platelet derived growth factor receptor α (PDGFRα)-targeted ultrasound contrast agents, and to explore the effect of platelet derived growth factor (PDGF) on angiogenesis in PTC.@*Methods@#PDGFRα-targeted ultrasound contrast agents were constructed through biotin-avidin linkage, and blank micro-bubbles were served as control group. After the siRNA-PDGF BCPAP cell line was established, well prepared BCPAP cells or siRNA-PDGF-BCPAP cells were injected subcutaneously into the back of male BABL/C nude mice. The growth of the tumors was observed closely. All tumors of the normal group and the siRNA-PDGF group were examined by PDGFRα-targeted ultrasound contrast agents or blank micro-bubbles, and the dynamic images were analyzed quantitatively by QontraXt software.All mice were sacrificed after ultrasonography. Microvessels density (MVD) in the tumors was counted by CD31 staining and the expressions of vascular endothelial growth factor(VEGF) and PDGF were detected by Western Blot.@*Results@#PTCs in nude mice were enhanced well by PDGFRα-targeted ultrasound contrast agent or blank micro-bubbles. The peak of tumors in siRNA-PDGF group was significantly lower than that in the normal group [(43.085±13.244)% vs (57.428±10.952)%, P=0.004]; MVD of the siRNA-PDGF group was significantly less than that of the normal group [(23.200±6.017)strips/view vs (35.000±8.456)strips/view, P=0.012]. The protein expression of PDGF and VEGF in siRNA-PDGF group were significantly lower than those in the normal group, respectively (0.142±0.058 vs 0.269±0.102, P=0.002; 0.096±0.036 vs 0.158±0.072, P=0.016).@*Conclusions@#PDGF plays an important role in angiogenesis of PTC, it maybe a new ultrasound molecular imaging method for monitoring tumor angiogenesis.

Role of vascular endothelial growth factor in the pathogenesis of traumatic proliferative vitreoretinopathy / 中华眼底病杂志

Proliferative vitreoretinopathy (PVR) is a common complication and major cause of blindness of ocular trauma.Many cytokines,including vascular endothelial growth factor (VEGF) and plateletderived growth factor (PDGF),participate in the process of the pathogenesis of traumatic PVR.VEGF competitively inhibits binding of PDGF to its receptor (PDGFRα),enables indirect activation of PDGFRα by non-PDGF ligands,resulting in reduced p53 expression,cell proliferation and migration,which is a key point in the pathogenesis of traumatic PVR.

Multiple gene mutation and prognostic factors in gastrointestinal stromal tumors / 中华普通外科杂志

Objective To investigate the status and significance of KIT,PDGFRA and DOG1 gene mutation in gastrointestinal stromal tumors (GIST).Methods 100 GIST patients treated in the First Affiliated Hospital of Guangxi Medical University between May 2002 and May 2013 were analyzed restrospectively.DNA was isolated and amplified for the all exons of KIT,PDGFRA and DOG1.Each PCR product was sequenced to find the position and type of mutation.Results KIT mutations were identified in 75 cases (75％).PDGFRA mutations were found in 16 cases (16％).No DOG1 mutations were found.The overall 5-year survival was 58.8％.Log-rank univariate survival analysis showed that the primary location,tumor size,metastasis,operational mode,type of tumor cells,invasion of the smrounding organs,invasion of the smooth muscle,mitotic counts of the tumor cells,deletions in exon 11 KIT and targeting therapy were significant prognostic factors (all P ＜ 0.05).COX regression model showed that tumor size,metastasis,operational method,invasion of the surrounding organs,mitotic counts of the tumor cehs,deletions in exon 11 KIT and targeting therapy were related to prognosis.Conclusion KIT and PDGFRA mutations are mutually exclusive.The overexpression mechanism of DOG1 is not related to DOG1 gene mutation.The related gene mutations affect the prognosis of GIST.

The Significance of Interstitial Cells in Neurogastroenterology

Smooth muscle layers of the gastrointestinal tract consist of a heterogeneous population of cells that include enteric neurons, several classes of interstitial cells of mesenchymal origin, a variety of immune cells and smooth muscle cells (SMCs). Over the last number of years the complexity of the interactions between these cell types has begun to emerge. For example, interstitial cells, consisting of both interstitial cells of Cajal (ICC) and platelet-derived growth factor receptor alpha-positive (PDGFRalpha+) cells generate pacemaker activity throughout the gastrointestinal (GI) tract and also transduce enteric motor nerve signals and mechanosensitivity to adjacent SMCs. ICC and PDGFRalpha+ cells are electrically coupled to SMCs possibly via gap junctions forming a multicellular functional syncytium termed the SIP syncytium. Cells that make up the SIP syncytium are highly specialized containing unique receptors, ion channels and intracellular signaling pathways that regulate the excitability of GI muscles. The unique role of these cells in coordinating GI motility is evident by the altered motility patterns in animal models where interstitial cell networks are disrupted. Although considerable advances have been made in recent years on our understanding of the roles of these cells within the SIP syncytium, the full physiological functions of these cells and the consequences of their disruption in GI muscles have not been clearly defined. This review gives a synopsis of the history of interstitial cell discovery and highlights recent advances in structural, molecular expression and functional roles of these cells in the GI tract.

The KIT Exon 11 Stop Codon Mutation in Gastrointestinal Stromal Tumors: What Is the Clinical Meaning?

BACKGROUND/AIMS: Gastrointestinal stromal tumors (GISTs) strongly express a receptor tyrosine kinase (RTK, c-KIT-CD117) harboring a KIT mutation that causes constitutive receptor activation leading to the development and growth of tumors; 35% of GISTs without KIT mutations have platelet-derived growth factor receptor alpha (PDGFRA) mutations, and the type of mutation plays an important role in the response to treatment. This study aimed to establish the frequency of stop codon mutations in the RTKs, KIT, and PDGFRA, in GISTs and correlate this molecular alteration with protein expression and treatment responsiveness. METHODS: Seventy-nine GISTs were analyzed for both KIT and PDGFRA mutations. Immunohistochemical expression was studied in tissue microarray blocks. RESULTS: We found three rare KIT mutations in exon 11 that induced a stop codon, two at position 563 and one at position 589, which have never been described before. All three tumors were CD117-, DOG1-, and CD34-positive. Two patients with a KIT stop codon mutation did not respond to imatinib therapy and died shortly after treatment. CONCLUSIONS: The association between stop codon mutations in KIT and patient survival, if confirmed in a larger population, may be useful in choosing effective therapies.

Imatinib atenua a fibrose miocárdica em associação com a inibição da atividade do PDGFRα / Imatinib attenuates myocardial fibrosis in association with inhibition of the PDGFRα activity

FUNDAMENTO: O Imatinib é um inibidor do receptor tirosina-quinase que foi confirmada como exercendo um efeito inibidor sobre a atividade do receptor do PDGF, fator de crescimento plaquetário (PDGFRα e PDGFRβ). OBJETIVO: Investigar o efeito protetor do Imatinib na fibrose miocárdica em acetato de deoxicorticosterona (DOCA)/ratos com hipertensão induzida por sal. MÉTODOS: Sessenta ratos Sprague-Dawley machos, uninefrectomizados foram distribuídos em três grupos: ratos controles (grupo CON): grupo deoxicorticosterona (grupo DOCA); grupo deoxicorticosterona e Imatinib (grupo DOCA IMA). A Pressão Arterial Sistólica (PAS) foi medida quinzenalmente. Foi estudada a porção apical do ventrículo esquerdo. Foram empregados: coloração vermelho sirius, coloração de hematoxilina-eosina, imuno-histoquímica e ensaio de western blot. RESULTADOS: A PAS nos grupos DOCA e IMA+DOCA foi maior que no grupo CON nos dias 14 e 28. Os animais do grupo DOCA apresentaram fibrose intersticial e perivascular grave no dia 28, e as expressões de PI, PIII, tenascina-C e fibronectina foram significativamente maiores que nos grupos DOCA+IMA e CON. Quando comparados com o grupo CON, os grupos DOCA e DOCA+IMA apresentaram resposta inflamatória de tecido miocárdico e infiltração de monócitos/macrófagos de diferentes graus. As expressões proteicas do PDGF-A, PDGF-C e PDGFRα foram significativamente maiores nos grupos DOCA e DOCA+IMA que no grupo CON, mas a expressão proteica do p-PDGFRα no grupo DOCA+IMA foi menor que no DOCA. CONCLUSÃO: O Imatinib pode exercer efeitos inibitórios sobre a fibrose miocárdica em ratos com hipertensão induzida por DOCA/sal, os quais podem ser atribuídos à inibição da atividade do PDGFR-α.

BACKGROUND: Imatinib is a tyrosine kinase receptor inhibitor that has been confirmed to exert inhibitory effect on the platelet derived growth factor PDGF receptor (PDGFRα and PDGFRβ) activity. OBJECTIVE: To investigate the protective effect of imatinib on the myocardial fibrosis in deoxycorticosterone-acetate (DOCA)/salt induced hypertensive rats. METHODS: Sixty male uninephrectomized Sprague-Dawley rats were assigned to three groups: control rats (CON group); deoxycorticosterone group (DOCA group); deoxycorticosterone and imatinib group (DOCA+IMA group). Systolic blood pressure (SBP) was measured biweekly. The apical portion of the left ventricle was studied. Sirius-Red staining, Hematoxylin-Eosin staining, immunohistochemistry and Western blot assay were employed. RESULTS: SBP in the DOCA group and DOCA+IMA group was higher than that in the CON group on day 14 and 28. Animals in the DOCA group showed severe interstitial and perivascular fibrosis on day 28, and the expressions of PI, PIII, tenascin-C and fibronectin were significantly higher than those in the DOCA+IMA group and CON group. When compared with the CON group, myocardial tissue inflammatory response and monocyte/macrophage infiltration of different degrees were observed in the DOCA group and DOCA+IMA group. Protein expressions of PDGF-A, PDGF-C and PDGFRα were signiflcantly higher in the DOCA and DOCA+IMA groups than those in the CON group, but the p-PDGFRα protein expression in the DOCA+IMA group was lower than that in the DOCA group. CONCLUSION: Imatinib can exert inhibitory effects on myocardial fibrosis in DOCA/salt induced hypertensive rats, which may be attributed to the inhibition of PDGFR-α activity.

Smooth Muscles Contraction in Gastrointestinal Tract and New Concept of Enteric Neurotransmission: Fibroblast-like Cells / 대한내과학회지

This review provides information regarding an enteric neurotransmission from enteric nerve terminals to smooth muscles. In the gastrointestinal tract, phasic contractions are caused by electrical activity termed slow waves. Slow waves are generated and actively propagated by interstitial cells of Cajal (ICC). The initiation of pacemaker activity in the ICC is caused by release of Ca2+ from inositol 1, 4, 5-trisphosphate (IP3) receptor-operated stores, and the development of unitary currents. Summation of unitary currents causes depolarization and activation of a dihydropyridine-resistant Ca2+ conductance that entrains pacemaker activity in a network of ICC, resulting in the active propagation of slow waves. Slow wave frequency is regulated by a variety of physiological agonists and conditions, and shifts in pacemaker dominance can occur in response to both neural and non-neural inputs. Fibroblast-like cells (FLCs) are also closely associated with nerve varicosities and are labelled robustly with antibodies for platelet-derived growth factor receptor alpha (PDGFRalpha), and expression of this receptor may be a powerful new means of isolating and evaluating the function of FLCs and the possible contribution of these cells in disease. PDGFRalpha+ cells share similar anatomical distributions, and FLCs in colonic smooth muscle functionally express small conductance Ca(2+)-activated K+ channel (SK3). These findings are important to understand purinergic post-junctional responses.

Expression of DOG1, PDGFRA, and p16 in Gastrointestinal Stromal Tumors

BACKGROUND/AIMS: The diagnosis of gastrointestinal stromal tumors (GIST) relies on the demonstration of KIT expression, but KIT expression is absent or reduced in approximately 15% of GIST. METHODS: Eighty-one GISTs were diagnosed between January 1998 and December 2007 at the Department of Pathology at both Chungnam National University Hospital and Eulji University Hospital, Daejeon. Medical history, patient follow-up, and radiographic data were collected if available in the medical records. To determine diagnostic and prognostic markers for GISTs focused on PDGFRA mutation and clinicopathologic features, we analyzed 81 GIST cases for KIT, PDGFRA, DOG1, and p16 expression and for mutation of PDGFRA genes. RESULTS: Among 81 GIST cases, 20 high risk cases (24.7%) were recurred or metastasized. Immunohistochemically, KIT was positive in 76 (93.8%), PDGFRA in 75 (92.7%), and DOG1 in 77 (95.1%). With a cutoff value of 50%, p16 expression was positive in 26 cases were positive (32.1%). A correlation between p16 expression or negative DOG1 expression and recurrence or metastasis was demonstrated (p<0.05). Four cases showed a missense mutation in exon 12 of PDGFRA gene, three of these were of epithelioid GISTs. Two cases showed a silent mutation in exon 18 of PDGFRA. CONCLUSIONS: These results indicate that the expression of DOG1 and PDGFRA is observed in a majority of GIST cases. Expression of p16 and negative DOG1 expression is predictive for development of recurrence and/or metastasis. Even though mutation of the PDGFRA gene is frequently seen in epithelioid GISTs, a clinicopathologic correlation was not demonstrated.

Gastrointestinal Stromal Tumor

Gastrointestinal stromal tumor (GIST) is a relatively rare disease accounted for less than 1% of gastrointestinal tumors. In the past, surgery is the only reliable therapy for the locoregional GISTs. But with the development of the specific target agents such as imatinib or sunitinib, advanced metastatic GIST can be cured now. GISTs are incidentally found by endoscopic ultrasound or laparoscopic surgery for the abdominal mass and positive immunostain for KIT with characteristic histopathology is mandatory for the diagnosis. Mutational analyses for KIT and PDGFRA is helpful in the diagnosis and treatment of GISTs. Because most GISTs are potentially malignant and surgery itself has high recurrence rate, it should be treated at an early stage and chemotherapy should be considered aggressively. The tumor size, mitotic index, and the involved organs are important prognostic factors. In this paper, the pathogenesis of histopathology, clinical diagnosis and treatment of GISTs were reviewed.

Eosinofilia reacional, leucemia eosinofílica crônica e síndrome hipereosinofílica idiopática / Reactive eosinophilia, chronic eosinophilic leukemia and idiopathic hypereosinophilic syndrome

A eosinofilia é freqüente na prática clínica, principalmente quando os valores estão entre 500 e 1000 eosinófilos/uL e indica a presença de doença parasitária, alérgica ou reação a medicamentos. Afora essas situações, a eosinofilia pode ser devida a doenças do tecido conjuntivo, infecções e, mais raramente, a doença hematológica maligna ou a tumores sólidos. Os critérios estabelecidos na década de 70 para a definição para a definição da síndrome hipereosinofílica idiopática se tornaram insuficientes para caracterizar todas as entidades albergadas sob o termo eosinofilia e, hoje, melhor compreendidas graças aos avanços na biologia celular e molecular, que proporcionaram a caracterização de doenças distintas e que envolvem células das linhagens mieloide e linfoide. Nesse contexto, as eosinofilias sanguíneas são categorizadas como reacionais, clonais e idiopáticas (SHE). O advento de terapia antitirosinoquinase (a exemplo do mesilato de imatinibe), eficaz para os casos com o rearranjo gênico FIP1L1/PDGFR, também abriu novas perspectivas para o controle ideal da leucemia eosinofílica crônica. Daí a importância do diagnóstico preciso e rápido para a indicação terapêutica ideal, antes que se instalem as complicações orgânicas, em especial cardíacas, que são irreversíveis. O presente manuscrito objetiva rever as situações de eosinofilia sanguínea e oferecer uma atualização da investigação diagnóstica e terapêutica.

Mild eosinophilia with values of less than 1000 eosinophils/µL is commonly seen in the clinical practice and can be secondary to parasitic, inflammatory or allergic diseases or to drug reactions. Additionally, eosinophilia may be due to connective tissue disorders, infections and occasionally to hematopoietic malignancies or solid tumors. The criteria established in the 1970s, for the definition of idiopathic hypereosinophilic syndrome is today unsatisfactory to characterize all conditions described as eosinophilia. Now these conditions are better understood due to the evolution of cellular and molecular biology. This knowledge has helped to characterize distinct disorders involving myeloid and lymphoid lineages. Hence, eosinophilia is categorized as reactive, clonal or idiopathic. With the introduction of anti-tyrosine kinase (imatinib mesylate) therapy, which is effective for the FIP1L1/PDGFRa rearrangement, there is a possibility to control or cure chronic eosinophilic leukemia. For this reason, precise and fast diagnosis is necessary for ideal therapeutic decisions before organic lesions that are irreversible, such as heart injury, become established. The aim of this manuscript is to review eosinophilia and offer an update on diagnostic and therapeutic investigations.

An Approach to Diagnosing Gastrointestinal Stromal Tumors Using Immunohistochemistry of c-kit and PDGFRA with Molecular Analysis

BACKGROUND: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the gastrointestinal tract. Recently, many methods for the diagnosis of GIST have been developed including molecular diagnosis. METHODS: We selected 90 cases of GIST that had presented at Kyungpook National University Hospital between 1998 and 2007. Tissue microarrays were made using core areas of tumor tissues. Immunohistochemical staining for c-kit, protein kinase C-theta, and platelet-derived growth factor receptor alpha (PDGFRA) was done. Direct sequencing of hot spot exonal areas for c-kit and PDGFRA were done using extracted DNAs of all 90 paraffin block tissues. RESULTS: Among the 90 cases, 83.3% (75/90) were c-kit positive, 16.6% (15/90) were c-kit negative, 93.3% (84/90) were PDGFRA positive, and 6.6% (6/90) cases were PDGFRA negative. Fifteen cases of c-kit negative GIST included 1 case of PDGFRA negative and 5 cases of PDGFRA negative GIST were ckit positive. The one case in which both c-kit and PDGFRA were negative, showed a c-kit mutation in exon 11. CONCLUSIONS: Combined immunohistochemical staining of c-kit, discovered on GIST 1 (DOG1) and PDGFRA is helpful for the diagnosis of GIST. When all staining tests are negative for immunoreactivity, c-kit mutation analysis for exon 11, 9 should be done. Genotyping of kit and PDGFRA do not need to be examined initially, if it is only for the diagnosis of GIST.

KIT/PDGFRA Expression and Mutation in Testicular Seminoma and Ovarian Dysgerminoma

BACKGROUND: KIT and PDGFRA are tyrosine kinase receptors. Stem cell factor/KIT-mediated signaling plays a role in normal spermatogenesis, and the alteration of KIT is important in the pathogenesis of seminomas/dysgerminomas (SD). METHODS: To determine the role of expression and mutation of the KIT and PDGFRA genes, we analyzed 16 seminoma cases, 4 spermatocytic seminoma (SS) cases and 8 dysgerminoma cases for KIT and PDGFRA expression and mutation of KIT (exons 9, 11, 13, and 17) and PDGFRA (exons 12 and 18) using PCR-SSCP methods. RESULTS: KIT was immunohistochemically positive in all 24 SD cases, and one of four (25%) SS cases. PDGFRA was immunohistochemically evident in 16 of the 24 (66.6%) SD cases, and two of the four (50%) SS cases. KIT expression was significantly reduced in SS compared with seminoma (p=0.0035). Four cases (14.3%) displayed mutation in KIT exon 17 or PDGFRA exon 12. Distant metastasis was present in three cases (10.7%), one of which had a nonsense mutation in KIT. CONCLUSIONS: These results indicate that KIT is expressed in the majority of SD cases, but not in most SS cases. However, there was no significant correlation between the clinicopathologic features and mutation or expression of KIT and PDGFRA.

Protein expression of VEGF, IGF-1 and FGF in retroocular connective tissues and clinical correlation in Graves' ophthalmopathy / Expressão protéica de VEGF, IGF-1 e FGF no tecido conjuntivo retro-ocular e correlação clínica na oftalmopatia de Graves

PURPOSE: To investigate the immunohistochemical expression (IGF-1, EGFr, EGF, c-erbB-2/HER-2/neu, PDGF-A, PDGF-B, FGF and VEGF) in patients with Graves' ophthalmopathy. METHODS: Twenty-four samples (Graves' ophthalmopathy patients) underwent lateral rectus muscle and surrounding fibrous and adipose tissue biopsy. The control group was obtained by strabismus surgery. Correlation between clinical- ophthalmologic, endocrinological, ultrasonographic findings, and immunohistochemical expression was performed. RESULTS: IGF-1: There were 7 positive cases (29.2 percent). There was a direct relation with higher CAS (clinical activity score) in all of them and if only CAS equal or higher than 5 was considered, this was 54.5 percent. FGF: There was expression in 5 cases (20.8 percent) with a direct relation in all those with higher CAS (>5) (45.4 percent). VEGF: There were two positive cases (8.3 percent) for VEGF in endothelial cells, in these cases the patients also presented CAS higher than 5. There was no expressions of all growth factors in the control group. CONCLUSIONS: All patients, except one, with positive expression of FGF, IGF-1 and VEGF showed CAS greater than 5, suggesting in this way an important role of these growth factors in the pathogenesis and severity of Graves' ophthalmopathy. However, statistical analysis revealed only significant association between IGF-1 and male sex (P=0.034). Low ultrasound reflectivity and endocrine status may not correlate directly with disease activity or with immunoexpression of growth factors and c-erbB-2/HER-2/neu.

OBJETIVO: Investigar a expressão imuno-histoquímica de IGF-1, EGFr, EGF, c-erbB-2/HER-2/neu, PDGF-A, PDGF-B, FGF e VEGF na oftalmopatia de Graves. MÉTODOS: Vinte e dois pacientes (oftalmopatia de Graves) foram submetidos à biópsia do músculo reto lateral e tecido fibroso e adiposo adjacente. O grupo controle foi de pacientes de cirurgia de estrabismo. Foi feita correlação entre achados clínico-oftalmológicos, endocrinológicos, ultra-sonográficos e da expressão imuno-histoquímica dos fatores de crescimento. RESULTADOS: IGF-1: Houve 7 casos positivos (29,2 por cento). Houve correlação direta com o CAS (clinical activity score) elevado em todos os casos e em que consideramos CAS apenas acima de 5, em 54,5 por cento. FGF: Houve expressão em 5 casos (20,8 por cento) com relação direta com CAS elevado em todos os casos e em que consideramos CAS maior que 5 (45,4 por cento). VEGF: Houve dois casos positivos (8,3 por cento) para VEGF nas células endoteliais e estes casos também apresentavam CAS maior que 5. A imunorreatividade foi negativa em todo grupo controle. CONCLUSÃO: Todos os pacientes, com exceção de um, com expressão positiva para FGF, IGF-1 e VEGF mostraram CAS maior que 5, sugerindo importante papel destes fatores de crescimento na patogênese e gravidade da oftalmopatia de Graves. Entretanto, a análise estatística demonstrou associação significativa entre IGF-1 e o sexo masculino (P=0,034). Baixa refletividade ao ultra-som e condição endócrina não estiveram correlacionadas.