Neovascularization in Outer Membrane of Chronic Subdural Hematoma : A Rationale for Middle Meningeal Artery Embolization.

OBJECTIVE: Chronic subdural hematomas (cSDHs) are generally known to result from traumatic tears of bridging veins. However, the causes of repeat spontaneous cSDHs are still unclear. We investigated the changes in vasculature in the human dura mater and outer membrane (OM) of cSDHs to elucidate the cause of their spontaneous repetition. METHODS: The dura mater was obtained from a normal control participant and a patient with repeat spontaneous cSDHs. The pathological samples from the patient included the dura mater and OM tightly adhered to the inner dura. The samples were analyzed with a particular focus on blood and lymphatic vessels by immunohistochemistry, 3-dimensional imaging using a transparent tissue clearing technique, and electron microscopy. RESULTS: The dural border cell (DBC) layer of the dura mater and OM were histologically indistinguishable. There were 5.9 times more blood vessels per unit volume of tissue in the DBC layer and OM in the patient than in the normal control. The DBC layer and OM contained pathological sinusoidal capillaries not observed in the normal tissue; these capillaries were connected to the middle meningeal arteries via penetrating arteries. In addition, marked lymphangiogenesis in the periosteal and meningeal layers was observed in the patient with cSDHs. CONCLUSION: Neovascularization in the OM seemed to originate from the DBC layer; this is a potential cause of repeat spontaneous cSDHs. Embolization of the meningeal arteries to interrupt the blood supply to pathological capillaries via penetrating arteries may be an effective treatment option.

Verteporfin-mediated on/off photoswitching functions synergistically to treat choroidal vascular diseases.

Choroidal vascular diseases, such as age-related macular degeneration, are the leading cause of vision impairment and are characterized by pathological angiogenesis. Verteporfin-mediated photodynamic therapy is a current strategy that selectively occludes choroidal neovasculature. However, the clinically used large-dose systemic administration increases the risk of systemic adverse events, such as phototoxicity to superficial tissues. In this study, we developed an in situ verteporfin delivery system with a photoswitching synergistic function that disassembles in response to intraocular inflammatory enzymes. Under light-on conditions, verteporfin-mediated photodynamic therapy effectively occurs and this leads to vascular occlusion. Under light-off conditions, non-photoactive verteporfin negatively regulates vascular endothelial growth factor-induced angiogenesis as a yes-associated protein inhibitor. Taken together, our system serves as an intraocular verteporfin reservoir to improve the bioavailability of verteporfin by innovatively exploiting its photochemical and biological functions. This work provides a promising strategy with synergistic antiangiogenic effects for the treatment of choroidal vascular diseases.

Comparative Experimental Study of Dermal Stability: Acellular Dermal Matrix versus Crayopreserved Dermis.

BACKGROUND: Given the potential usefulness of Acellular Dermal Matrices (ADM) for wound healing, we aimed to evaluate the stability, histological characteristics, and effectiveness of ADM compared with cryopreserved dermis (CPD) in rat models. METHODS: This experimental study was conducted in the Department of Surgery, Isfahan University of Medical Sciences, Isfahan, Iran, from January to March 2015. The prepared ADM and CPD were transplanted to the full-thickness skin defects on the back of Sprague-Dawley rats. Forty-five days after grafting, the tissues were harvested for histological examination. These two types of the dermis' quality and stability were compared with consideration of the following factors; inflammation, fibroblasts migration, vascularization, collagen formation, capsule formation, and microabscess formation. RESULTS: From 19 selected rates, nine received CPD, and ten were treated with ADM. After transplantation, the mean (SD) weight of ADM and CPD grafts were 1.74 (0.07) and 1.45 (0.77), respectively (P<0.001). The frequency of inflammation was significantly higher in CPD grafts (P<0.01). Higher grades of collagen organization, fibroblast spreading, and vascularization were more frequent in ADM grafts (P<0.01). The frequency of capsule and microabscesses formation was not significantly different between studied groups. CONCLUSION: ADM have a superior effect than CPD in the wound healing process. Both samples had a similar effect in capsule and microabscesses formation and higher costs of ADM preparation. According to the physicians' decision and evaluation of the process's cost-effectiveness, CPD could be appropriately used as an alternative to ADM.

Malformación arteriovenosa de alto flujo en un adulto joven: reporte de caso / High flow arteriovenous malformation in a young adult: case report / Malformação arteriovenosa de alto fluxo em um adulto jovem: relato de caso

Introducción. Las malformaciones arteriovenosas son lesiones relativamente raras e infrecuentes. Se caracterizan por presentar un aumento anormal en el número de vasos sanguíneos como consecuencia de un defecto en el desarrollo vascular. Constituyen un desafío diagnóstico y terapéutico para el médico tratante. Su incidencia es de alrededor el 1.5% de la población general. Dentro de las opciones terapéuticas se incluye la embolización selectiva, la resección quirúrgica o ambas. El objetivo del presente artículo es reportar un caso de una patología poco frecuente y hacer una revisión literaria del tema para arrojar luz sobre su diagnóstico. Reporte de caso. Se presenta el caso de un paciente adulto joven que consulta por presentar una masa en glúteo derecho de 6 años de evolución. Esta es diagnosticada erróneamente como lipoma, por lo que se lleva al paciente a cirugía sin la realización de imágenes diagnósticas previas. En la cirugía, el paciente presenta choque hipovolémico. Posteriormente, se documenta la masa como malformación arteriovenosa profunda. Discusión. Es poco usual la ubicación de dichas malformaciones en los miembros inferiores, como en el paciente del actual caso. El diagnóstico de estas lesiones puede ser clínico, pero requiere del conocimiento o sospecha de esta entidad, ya que pueden ser lesiones clínicamente no visibles, lo que lleva a que pasen inadvertidas o se diagnostiquen de forma errónea. Conclusión. Aunque se trata de una patología poco frecuente, esta puede generar repercusiones clínicas, físicas, psicológicas y estéticas importantes, por lo que es indispensable realizar adecuados métodos por imágenes que permitan establecer su correcto diagnóstico y manejo. Cómo citar. Rodriguez-Londoño NH. Malformación arteriovenosa de alto flujo en un adulto joven. MedUNAB. 2021;24(1): 72-79. doi: https://doi.org/10.29375/01237047.3785

Introduction. Arteriovenous malformations are relative rare and infrequent injuries. Their main characteristic is an abnormal increase in the number of blood vessels as a result of defective vascular development. They represent a diagnostic and therapeutic challenge for the treating physician. Their incidence in the general population is around 1.5%. Some therapeutic options include selective embolization, surgical resection, or both. The purpose of this article is to report a case of an infrequent pathology and to perform a literature review on the topic to shed light on its diagnosis. Case report. The case involves a young adult patient who inquired about the presence of a mass in the right buttock with six years of evolution. It was erroneously diagnosed as a lipoma, as a result of which the patient was taken to surgery without performing preliminary diagnostic images. During surgery, the patient went into hypovolemic shock. Afterwards, the mass was documented as a profound arteriovenous malformation. Discussion. Such malformations are rarely found in the lower limbs, as in this case. These injuries may be clinically diagnosed, but knowledge or suspicion on the existence of this entity is required, because such injuries might not be clinically visible, which implies that they may go unnoticed or be erroneously diagnosed. Conclusion. Even though it is an infrequent pathology, it may have substantial clinical, physical, psychological and aesthetic implications, which implies that it is indispensable to perform adequate imaging-based procedures to enable its adequate diagnosis and management. Cómo citar. Rodriguez-Londoño NH. Malformación arteriovenosa de alto flujo en un adulto joven. MedUNAB. 2021;24(1): 72-79. doi: https://doi.org/10.29375/01237047.3785

Introdução. As malformações arteriovenosas são lesões relativamente raras e infrequentes. São caracterizadas por apresentarem um aumento anormal do número de vasos sanguíneos como consequência de um defeito no desenvolvimento vascular. Constituem um desafio diagnóstico e terapêutico para o médico que trata. Sua incidência gira em torno de 1.5% da população geral. As opções de tratamento incluem embolização seletiva, ressecção cirúrgica ou ambas. O objetivo deste artigo é relatar um caso de patologia pouco frequente e fazer uma revisão bibliográfica sobre o assunto para lançar luz sobre seu diagnóstico. Relato de caso. Apresentamos o caso de um paciente adulto jovem que consultou por apresentar uma massa na nádega direita, de 6 anos de evolução. Isso é diagnosticado erroneamente como um lipoma, então o paciente é levado para cirurgia sem imagens diagnósticas prévias. Na cirurgia, o paciente apresenta um choque hipovolêmico. Posteriormente, a massa é documentada como uma malformação arteriovenosa profunda. Discussão. A localização dessas malformações nos membros inferiores é incomum, como no caso deste paciente. O diagnóstico dessas lesões pode ser clínico, mas requer conhecimento ou suspeita dessa entidade, pois podem ser lesões clinicamente invisíveis, o que as leva a passar despercebidas ou mal diagnosticadas. Conclusão. Embora seja uma patologia pouco frequente, pode gerar importantes repercussões clínicas, físicas, psicológicas e estéticas, pelo que é imprescindível a realização de métodos de imagem adequados para estabelecer seu correto diagnóstico e tratamento. Cómo citar. Rodriguez-Londoño NH. Malformación arteriovenosa de alto flujo en un adulto joven. MedUNAB. 2021;24(1): 72-79. doi: https://doi.org/10.29375/01237047.3785

Implantable anti-angiogenic scaffolds for treatment of neovascular ocular pathologies.

The retinal physiology can accrue oxidative damage and inflammatory insults due to age and metabolic irregularities. Two notable diseases that involve retinal and choroidal neovascularization are proliferative diabetic retinopathy and wet age-related macular degeneration. Currently, these diseases are mainly treated with anti-VEGF drugs (VEGF = vascular endothelial growth factor), generally on a monthly dosage scheme. We discuss recent developments for the treatment of these diseases, including bioactive tissue-engineered materials, which may reduce frequency of dosage and propose a path forward for improving patient outcomes. Graphical abstract Development of materials for long-term intravitreal delivery for management of posterior segment diseases.

Oxidative stress upregulates Wnt signaling in human retinal microvascular endothelial cells through activation of disheveled.

Abnormal retinal neovascularization associated with various retinopathies can result in irreversible vision loss. Although the mechanisms involved in this occurrence is unclear, increasing evidence suggests that aberrant Wnt signaling participates in the pathogenesis of abnormal neovascularization. Because Wnt signaling upregulation can be induced by oxidative stress through the activation of disheveled (DVL), a key molecule in the Wnt signaling pathway, we investigated whether oxidative stress can activate Wnt signaling and induce angiogenic phenotypes in human retinal microvascular endothelial cells (HRMECs). We found that increased Wnt signaling activity, as well as enhanced angiogenic phenotypes, such as tube formation and cell migration, were detected in the hydrogen peroxide-treated HRMECs. Moreover, these effects were effectively suppressed by a small-molecule Wnt inhibitor targeting the PDZ domain of DVL. Therefore, we propose that targeting abnormal Wnt signaling at the DVL level with a small-molecule inhibitor may represent a novel approach in retinal neovascularization treatment and prevention.

Lipid Mediators, M2 Macrophages, and Pathological Neovascularization.

Sasaki and colleagues [1] (JCI Insight 2018;3,e96902) identified the leukocyte inflammatory lipid mediator leukotriene B4 (LTB4)/LTB4 receptor 1 receptor-signaling axis in M2 macrophages as a causal pathway for the vascular endothelial growth factor-dependent pathological neovascularization in a mouse model that mimics wet age-related macular degeneration. This observation provides a novel mechanism by which an eicosanoid lipid mediator drives retinal vascular pathology and suggests a novel therapeutic target for proliferative retinal vascular diseases.

Retinal changes in rabbit after intravitreal injection of sunitinib encapsulated into solid lipid nanoparticles and polymeric nanocapsules / Avaliação das alterações retinais no coelho após injeção intravítrea de sunitinib encapsulado em nanoparticulas lípidas sólidas e nanocapsulas polímeros

ABSTRACT Purpose: We aimed to evaluate the safety of single intravitreal injection of each of two concentrations of 0.1 ml of sunitinib (1 and 10 mg/ml), 0.1 ml of a drug-free dispersion containing solid lipid nanoparticles, and 0.1 ml of a drug-free dispersion containing polymeric nanocapsules for analyzing the possible toxic effects using electrophysiology and histology in albino rabbit retina. Methods: We conducted an experimental controlled study of 20 eyes of albino rabbits. Intravitreal injections of each specific agent were applied to one eye per rabbit in each 5-rabbit group, while the contralateral eyes received no treatment and were used as controls. Results: We noted no electroretinographic changes in the sunitinib (1 and 10 mg/ml) or in solid lipid nanoparticles groups. However, we observed significant abnormalities in ocular morphology and in the electroretinogram in the nanocapsules group. At the histological level, only the nanocapsules group demonstrated abnormal changes, including severe edema and cytoplasmic vacuole formation. Conclusions: While nanocapsules intravitreal injections indicated retinal toxic effects, sunitinib and solid lipid nanoparticles intravitreal injections were not toxic to the retina. Our results suggest that a sunitinib preparation with solid lipid nanoparticles for controlled release may offer a significant therapeutic approach for vasoproliferative ocular disease.

RESUMO Objetivos: O presente estudo teve por objetivo avaliar a segurança da injeção intravítrea de 0,1 ml de sunitinibe em duas concentrações (1 mg/ml e 10 mg/ml), 0,1 ml de dispersão contendo nanopartículas lipídicas sólidas sem droga e 0,1 ml de dispersão contendo nanocápsulas poliméricas livre de drogas analisando os possíveis efeitos tóxicos à retina de coelhos albinos detectados pela eletrofisiologia e histologia por microscopia óptica. Métodos: Um estudo controlado experimental foi rea­lizado com 20 olhos de coelhos albinos. Foram realizadas injeções intravítrea de duas concentrações diferentes de suniti­nibe, uma dispersão contendo nanopartículas lipídicas sólidas e uma dispersão contendo nanocápsulas. O olho contralateral não recebeu tratamento e foi utilizado como controle. Resultados: Não foram observadas alterações eletrorretinográficas nos grupos do sunitinibe (1 mg/ml e 10 mg/ml) e no grupo das nanopartículas lipídicas sólidas. No grupo das nanocápsulas, houve alterações significativas tanto na morfologia, quanto na amplitude e tempo das ondas do eletrorretinograma. Ao estudo histológico, somente o grupo das nanocápsulas apresentou al­terações degenerativas (núcleos tumefeitos) com acentuado edema e formação de vacúolos citoplasmáticos, sugerindo toxidade retiniana. Conclusões: As injeções intravítreas de sunitinibe e nanopartículas lipídicas sólidas não foram tóxicas para a retina. No entanto, nanocápsulas mostraram ser tóxicas para a retina. Sendo assim, a possibilidade de poder combinar o potencial de uma droga que possui a capacidade de inibir duas importantes vias da angiogênese, às vantagens de liberação controlada das nanopartículas lipídicas sólidas, pode ser um importante recurso terapêutico para doenças vasoproliferativas oculares.

Full Functional Knockout of Placental Growth Factor by Knockin with an Inactive Variant Able to Heterodimerize with VEGF-A.

Placental growth factor (PlGF) is a proangiogenic member of the vascular endothelial growth factor (VEGF) family playing a central role in pathological angiogenesis. PlGF-DE is a PlGF variant unable to bind vascular endothelial growth factor receptor 1 (VEGFR-1) but still able to generate heterodimer with VEGF-A. We have generated PlGF-DE knockin mice that are vital and fertile and show unaltered expression of Plgf, Vegf-a, Vegfr-1, and Vegfr-2 compared with wild-type mice. Interestingly, these mutants showed additional and remarkable angiogenesis impairment in tumor growth, hindlimb ischemia, and choroidal neovascularization compared with both PlGF knockout and wild-type mice. These findings provided insights on VEGF-A/PlGF heterodimer function, which was able to rescue neovascularization and vascular leakage in PlGF-DE knockin mice. Collectively, these data show that PlGF-DE knockin mouse could be considered the full functional knockout of PlGF, suggesting a reassessment of the phenotypes of knockout mice for the genes whose products are able to generate heterodimeric proteins.

Estudo da imunoexpressão do VEGF165 e do VEGF165B em lesões orais de líquen plano e pênfigo vulgar / Study of VEGF165 and VEGF165B immunoexpression in oral lesions of lichen planus and pemphigus vulgaris

O Líquen Plano Oral (LPO) é uma doença mucocutânea mediada imunologicamente, de etiologia desconhecida, relativamente comum, com prevalências, na população mundial, que variam de 0,22 a 5%. O pênfigo vulgar é uma doença autoimue crônica que pode acometer a mucosa oral sendo o mais comum dos tipos de pênfigo. Entretanto, sua ocorrência é rara, com incidência estimada na população geral de um a cinco casos por milhão de pessoas diagnosticadas a cada ano. O VEGF-A é a proteína angiogênica mais potente tanto na angiogênese normal quanto na patológica. O splicing alternativo do éxon 8 do gene do VEGFA dá origem a duas famílias conhecidas de proteínas isofórmicas, uma desempenhando papel angiogênico, VEGFxxxa, e outra um papel antiangiogênico, VEGFxxxb. Este trabalho se propôs a avaliar a expressão imunoistoquímica do VEGF165 (angiogênico), do VEGF165b (antiangiogênico) em 46 casos de LPO reticular, 23 casos de LPO erosivo e 12 casos de PV, usando como controle 11 casos de hiperplasia fibrosa. Todos os espécimes das lesões e os casos controle foram divididos em e zonas para a análise das marcações, em zona superficial (Z1), média (Z2) e profunda (Z3). Os resultados deste experimento foram submetidos a testes estatístico não-paramétricos com nível de significância de 5%. Comparando apenas as lesões para o marcador anti-VEGF165 foram observadas diferenças significativas apenas nas zonas mais profundas entre as lesões de LPO reticular e PV, e entre as lesões de LPO erosivo e PV. Para o marcador anti-VEGF165b diferenças significativas foram observadas nas zonas médias entre as lesões de LPO reticular e PV; e nas zonas profundas entre LPO erosivo e PV e entre LPO reticular e PV. Avaliando o marcador VEGF165b nos espécimes sem categorizá-los por zonas foram observadas diferenças significativas entre as lesões de LPO reticular e PV. Na análise da correlação entre ambos os marcadores em cada lesão foram observadas correlação positiva fraca e significativa nas zonas média e profunda do LPO reticular e na zona superficial do LPO erosivo. Os resultados do presente estudo sugerem a participação do processo angiogênico na patogênese do LPO e na progressão das lesões de líquen plano oral e pênfigo vulgar, porém outros estudos devem ser realizados a fim de que esses achados, principalmente em relação ao pênfigo vulgar seja fundamentado, uma vez que a presente pesquisa é uma das primeiras que avalia a angiogênese na lesão já estabelecida dessa doença (AU).

Oral Lichen Planus is an immunologically mediated mucocutaneous disease of relatively unknown etiology with prevalences in the world population varying from 0.22 to 5%. Pemphigus vulgaris is a chronic autoimmune disease that may affect the oral mucosa being the most common type of pemphigus. However, its occurrence is rare, with an estimated incidence in the general population of one to five cases per million people diagnosed each year. Angiogenesis plays an important role in tumor growth and in the progression of chronic inflammatory diseases. VEGF-A is the most potent angiogenic protein in both normal and pathological angiogenesis. The alternative splicing of exon 8 VEGF-A gene gives rise to two known families of isoform proteins, one playing angiogenic role, VEGFxxxa, and another an antiangiogenic role, VEGFxxxb. The aim of this study was to evaluate the immunohistochemical expression of VEGF165 (angiogenic), VEGF165b (antiangiogenic) in 46 cases of reticular OLP, 23 cases of erosive OLP and 12 cases of PV, using as control 11 cases of fibrous hyperplasia. All specimens of the lesions and the control cases were divided into zones for the analysis of the immunohistochemical stains, in superficial (Z1), medium (Z2) and deep zones (Z3). The results of this experiment were submitted to non-parametric statistical tests with significance level of 5%. For all immunohistochemical stains the comparison between the lesions with the control group (HF) showed significant differences. Comparing only the lesions to the anti-VEGF165 stains, significant differences were observed only in the deeper zones between the reticular LPO lesions X PV; and between erosive LPO lesions X PV. For the anti-VEGF165b stains, significant differences were observed in medium zones between reticular OLP X PV lesions; and in deep zones between erosive LPO X PV and between reticular LPO and PV. And evaluating VEGF165b stains in specimens without categorizing them by zones was observed a significant difference between reticular LPO and PV lesions. In the analysis of the correlation between both markers in each lesion, a weak and significant positive correlation was observed in medium and deep zones of reticular OLP; and a weak positive correlation in superficial zone of erosive LPO. The present study results suggest angiogenic process participation in the pathogenesis and progression of lesions of oral lichen planus and pemphigus vulgaris. However other studies must be carried out in order that this implication, mainly in relation to pemphigus vulgaris be based once this is one of the first studies to evaluate angiogenesis in the already established lesion of this disease (AU).

Utilidad de tinción de tricrómico de Masson en la cuantificación de densidad media vascular en mucosa oral normal, displasia epitelial y carcinoma oral de células escamosas / Utility of Masson's trichrome stain in the quantification of mean vascular density in normal oral mucosa, epithelial dysplasia and oral squamous cell carcinoma

RESUMEN: El objetivo de este estudio fue valuar la utilidad del uso de la tinción de Tricrómico de Masson (TM) en la cuantificación de la densidad media vascular (DMV) en Mucosa Oral Normal (MON), Displasia Epitelial Oral (DEO) y Carcinoma Oral de Células Escamosas (COCE). Estudio descriptivo de serie de casos. Se analizaron 17 muestras de MON, 15 muestras de DEO y 16 de COCE, teñidas con TM. Para determinar su utilidad, se compararon con las mismas muestras analizadas con técnica de inmunohistoquímica contra CD31. La cuantificación de la DMV se realizó en las 3 áreas de mayor vascularización de cada muestra. Se determinó la DMV según diagnóstico mediante la tinción TM e inmunohistoquímica contra CD31, y se calculó la correlación entre ambos. La DMV cuantificada con TM y contra CD31 difiere según el diagnóstico, observándose un aumento de la DMV al malignizarse el diagnóstico. No se encontraron diferencias al comparar la DMV cuantificada con TM y contra CD31. La correlación de la DMV analizado por TM y contra CD31 es significativa y moderada. La cuantificación de vasos sanguíneos es posible mediante la tinción de TM en muestras de MON, DEO y COCE, con una correlación moderada con la inmunohistoquímica contra CD31.

SUMMARY. The objective of this study was to evaluate the utility of Masson's Trichrome (TM) staining in the quantification of the mean vascular density (DMV) in samples of normal oral mucosa (MON), oral epithelial dysplasia (ODE) and oral squamous cell carcinoma (COCE). The design - a descriptive study of case series. We analyzed 17 samples of MON, 15 samples of DEO and 16 samples of COCE, stained with TM. To determine usefulness, we compared and analyzed the same samples, either stained with TM or with immunohistochemical technique against CD31. Quantification of the DMV was performed in the 3 areas of greatest vascularization in each sample. DMV was determined according to diagnosis by TM staining and immunohistochemistry against CD31, and the correlation between the two was then calculated. DMV quantified with TM and against CD31 differs according to the diagnosis, with an increase in DMV upon malignant diagnosis. No differences were found when comparing DMV quantified with TM and against CD31. The correlation of the DMV analyzed by TM and against CD31 is significant and moderate. Quantification of blood vessels is possible by TM staining in samples of MON, DEO and COCE. TM staining is moderately correlated with immunohistochemistry against CD31.

Lymphangiogenesis and angiogenesis in oral cavity and lower lip squamous cell carcinoma / Linfangiogênese e angiogênese em carcinomas de células escamosas de lábio inferior e da cavidade oral

ABSTRACT INTRODUCTION: Tumors of the lip and oral cavity differ in various aspects; therefore a clarification of the distinctions among these sites may help to better understand the biologic behavior of neoplasms occurring in these locations. OBJECTIVE: Considering that angiogenesis and lymphangiogenesis are two major elements that can influence various aspects of tumor biology, we aimed to compare these factors between squamous cell carcinoma of the lower lip and oral cavity. METHODS: A total of 84 primary squamous cell carcinomas including 45 oral and 39 lower lip tumors were selected and immunohistochemically stained with monoclonal antibody against D2-40 and CD105. Mean microvessel density was assessed in tumoral tissue, while lymphatic vessel density was calculated in both neoplastic tissue and invasion front. Data were statistically analyzed using t-test and p-values of <0.05 were considered significant. RESULTS: We found a mean microvessel density ± standard deviation of 31.94 ± 18.9 in oral cavity and 27.54 ± 20.8 in lower lip squamous cell carcinomas, with no significant difference (p = 0.32). Mean lymphatic vessel density ± standard deviation was 13.05 ± 8.2 and 16.57 ± 10.79 in of oral cavity and lower lip neoplastic tissue, respectively. The corresponding values were 9.94 ± 5.59 and 12.50 ± 7.8 in the invasive front. Significant differences were not observed in either of the lymphatic vessel density variables between the two sites. CONCLUSION: According to our results, it seems that the search for additional factors other than those related to the vasculature should continue, to help clarify the differences in biologic behavior between lower lip and oral cavity squamous cell carcinomas.

Resumo Introdução: Os tumores de lábio e da cavidade oral diferem em vários aspectos; portanto, o conhecimento das diferenças entre eles pode ajudar na melhor compreensão do comportamento biológico das neoplasias que ocorrem nesses locais. Objetivo: Considerando que a angiogênese e a linfangiogênese são dois elementos importantes que podem influenciar diversos aspectos da biologia dos tumores, objetivamos comparar esses fatores entre o carcinoma de células escamosas (CCE) de lábio inferior e da cavidade oral. Método: No total, foram selecionados 84 CCEs primários (45 tumores da cavidade oral e 39 tumores de lábio). Esses tumores foram corados por processo imunohistoquímico com anticorpo monoclonal anti-D2-40 e CD105. Avaliamos a densidade média de microvasos (DMV) no tecido tumoral, enquanto que a densidade vascular linfática (DVL) foi calculada tanto no tecido neoplásico como no front de invasão. Os dados foram estatisticamente analisados com o uso do teste t e valores de p < 0,05 foram considerados significantes. Resultados: Chegamos a uma média para DMV ± DP de 31,94 ± 18,9 para CCEs na cavidade oral e de 27,54 ± 20,8 no lábio inferior, sem diferença significante (p = 0,32). As médias para DVL ± DP foram de 13,05 ± 8,2 e 16,57 ± 10,79 no tecido neoplásico da cavidade oral e lábio inferior, respectivamente. Os valores correspondentes foram 9,94 ± 5,59 e 12,50 ± 7,8 no front invasivo. Não foram observadas diferenças significantes nas duas variáveis DVL entre os dois locais. Conclusão: De acordo com os nossos resultados, a pesquisa por fatores adicionais, além daqueles relacionados à vasculatura, deve ter continuidade, para auxiliar no esclarecimento das diferenças do comportamento biológico entre CCEs no lábio inferior e na cavidade oral.

Expressão imunoistoquímica da endoglina (CD105) e do fator de von Willebrand em carcinoma epidermoide oral e sua relação com parâmetros clinicopatológicos / Immunohistochemical expression of endoglin (CD105) and von Willebrand factor in oral squamous cell carcinoma and its relationship with clinicopathological parameters

CONTEXTO: A angiogênese tem sido associada à progressão de neoplasias malignas e, embora haja estudos acerca de marcadores angiogênicos no carcinoma epidermoide oral (CEO), existem resultados conflitantes na literatura. OBJETIVOS: Avaliar a expressão imunoistoquímica do CD105 e do fator de von Willebrand (FvW) em CEO e sua relação com parâmetros clínicos do tumor. MÉTODOS: A imunoexpressão dos referidos biomarcadores foi analisada em 30 casos de CEO e correlacionada a parâmetros clínicos do tumor (idade e sexo dos pacientes, localização anatômica e estadiamento clínico Tumor, Nodo e Metástase, TNM). RESULTADOS: A imunomarcação com o anticorpo anti-FvW foi mais efetiva que a do CD105 no CEO. No que concerne à localização anatômica, o assoalho bucal e a região retromolar apresentaram diferenças estatisticamente significativas quanto aos índices angiogênicos (p = 0,004), determinados pela técnica de contagem microvascular (MVC). Não houve relação estatisticamente significativa entre o estadiamento clínico TNM e os índices angiogênicos, com os dois biomarcadores. CONCLUSÕES: Com base nos achados deste estudo, sugere-se um envolvimento da neoformação vascular na carcinogênese oral, embora não tenha sido evidenciada associação significativa com o estágio clínico da lesão.

BACKGROUND: Angiogenesis has been linked with progression of malignant neoplasms and although studies have been conducted investigating angiogenic markers in oral squamous cell carcinoma (OSCC), contradictory results are reported in the literature. OBJECTIVES: To evaluate immunohistochemical expression of CD105 and von Willebrand factor (vWF) in OSCC and their relationships with clinical parameters of the tumors. METHODS: Immunoexpression of these biomarkers was analyzed in 30 cases of OSCC and correlated with clinical parameters of the tumors (age and sex of patients, anatomic site and Tumor, Node and Metastasis clinical staging [TNM]). RESULTS: In OSCC specimens, immunostaining was more effective using the anti-vWF antibody than using the anti-CD105 antibody. Angiogenic indices, determined by microvascular count (MVC) technique, were different for the floor of the mouth and the retromolar region, with statistical significance (p = 0.004). There were no statistically significant relationships between results for the two biomarkers and TNM clinical staging or angiogenic indices. CONCLUSIONS: The findings of this study suggest that vascular remodeling is involved in oral carcinogenesis, although there was no evidence of a significant association with clinical stage of lesions.

Lymphangiogenesis and angiogenesis in oral cavity and lower lip squamous cell carcinoma.

INTRODUCTION: Tumors of the lip and oral cavity differ in various aspects; therefore a clarification of the distinctions among these sites may help to better understand the biologic behavior of neoplasms occurring in these locations. OBJECTIVE: Considering that angiogenesis and lymphangiogenesis are two major elements that can influence various aspects of tumor biology, we aimed to compare these factors between squamous cell carcinoma of the lower lip and oral cavity. METHODS: A total of 84 primary squamous cell carcinomas including 45 oral and 39 lower lip tumors were selected and immunohistochemically stained with monoclonal antibody against D2-40 and CD105. Mean microvessel density was assessed in tumoral tissue, while lymphatic vessel density was calculated in both neoplastic tissue and invasion front. Data were statistically analyzed using t-test and p-values of <0.05 were considered significant. RESULTS: We found a mean microvessel density±standard deviation of 31.94±18.9 in oral cavity and 27.54±20.8 in lower lip squamous cell carcinomas, with no significant difference (p=0.32). Mean lymphatic vessel density±standard deviation was 13.05±8.2 and 16.57±10.79 in of oral cavity and lower lip neoplastic tissue, respectively. The corresponding values were 9.94±5.59 and 12.50±7.8 in the invasive front. Significant differences were not observed in either of the lymphatic vessel density variables between the two sites. CONCLUSION: According to our results, it seems that the search for additional factors other than those related to the vasculature should continue, to help clarify the differences in biologic behavior between lower lip and oral cavity squamous cell carcinomas.

Antiangiogenic cancer drug using the zebrafish model.

The process of de novo vessel formation, called angiogenesis, is essential for tumor progression and spreading. Targeting of molecular pathways involved in such tumor angiogenetic processes by using specific drugs or inhibitors is important for developing new anticancer therapies. Drug discovery remains to be the main focus for biomedical research and represents the essence of antiangiogenesis cancer research. To pursue these molecular and pharmacological goals, researchers need to use animal models that facilitate the elucidation of tumor angiogenesis mechanisms and the testing of antiangiogenic therapies. The past few years have seen the zebrafish system emerge as a valid model organism to study developmental angiogenesis and, more recently, as an alternative vertebrate model for cancer research. In this review, we will discuss why the zebrafish model system has the advantage of being a vertebrate model equipped with easy and powerful transgenesis as well as imaging tools to investigate not only physiological angiogenesis but also tumor angiogenesis. We will also highlight the potential of zebrafish for identifying antitumor angiogenesis drugs to block tumor development and progression. We foresee the zebrafish model as an important system that can possibly complement well-established mouse models in cancer research to generate novel insights into the molecular mechanism of the tumor angiogenesis.