Riesgo aumentado de lesiones colónicas preneoplásicas en acromegalia: estudio multicéntrico caso control. Resultados preliminares / Increased risk of pre-cancerous bowel lesions in acromegaly: Multicentre case-control study. Preliminary results

Introducción: El riesgo de desarrollar neoplasias colónicas en pacientes acromegálicos y su relación directa con los niveles elevados de GH/IGF-1 no están bien establecidos y continúan siendo motivo de controversia en la literatura mundial. El objetivo de este trabajo fue evaluar el riesgo de desarrollar lesiones neoplásicas avanzadas (LNA) (adenomas mayores a 1 cm, componente velloso mayor del 75% y/o displasia de alto grado), en pacientes con acromegalia, comparado con un grupo control. Materiales y métodos: Estudio multicéntrico caso-control retrospectivo. Ciento treinta y siete pacientes con acromegalia que realizaron videocolonoscopia (VCC) fueron incluidos inicialmente, aunque solo 69 cumplieron criterios de inclusión. Sesenta y dos controles fueron obtenidos: por cada caso (paciente con acromegalia) 2 «controles¼ fueron seleccionados aleatorizadamente e igualados por edad y sexo. El riesgo se expresó en odds ratio (OR) y su correspondiente intervalo de confianza (IC) del 95%. La significación estadística fue considerada una p < 0,05. Resultados: De los 69 pacientes con VCC completa y datos adecuados para su análisis, 28 presentaron VCC positiva con hallazgos de pólipos (40%) y 41 VCC negativa o normal (60%). Dentro del grupo con VCC positiva, 14 presentaron LNA (20%) y solo un paciente presentó diagnóstico de cáncer colorrectal. Para el análisis caso-control se incluyó a 31 pacientes frente al grupo control (n = 62) que cumplieron con los criterios de inclusión. La presencia de pólipos colónicos, adenomas y LNA en los pacientes con acromegalia fue de 19/31 (61,9%), 14/31 (45,16%) y 10/31 (32,25%), y en el grupo control de 18/62 (29,03%), 11/62 (17,74%) y 4/62 (6,45%), respectivamente. El riesgo de adenomas y LNA fue mayor en el grupo de acromegalia en comparación con el grupo control, siendo ambos resultados estadísticamente significativos: adenomas OR 2,54 (IC 1,22-5,25) p = 0,005, LNA OR: 7,3 (2,4-25), p = 0,00. Conclusión: La acromegalia se asocia a un mayor riesgo de lesiones colónicas preneoplásicas. Este hallazgo justifica el cribado con VCC al diagnóstico en pacientes con acromegalia.

Background: The risk of developing cancerous lesions in the colon of acromegaly patients and their direct relationship with elevated growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels is not well established, and is still controversial in the international literature. The objective of this study was to evaluate the risk of developing advanced neoplastic lesions (ALN: greater than 1 cm adenomas, villous component greater than 75% and/or high grade dysplasia) in patients with acromegaly compared to a control group. Materials and methods: A multicentre, retrospective case-control study was conducted initially on 137 patients with acromegaly (cases) who underwent videocolonoscopy (VCC), although only 69 met inclusion criteria. Sixty-two controls were obtained, and for each case two "controls" were randomly selected and matched by age and gender. Risk was expressed as odds ratio (OR) and its corresponding 95% con"dence interval (CI). P values < .05 were considered statistical significantly. Results: Of the 69 acromegaly patients with a completed VCC and adequate data for their analysis, 28 had a positive VCC with findings of polyps (40%), and 41 VCC negative with no lesions (60%). Within the group with positive VCC, 14 were ALN (20%) and one a colorectal cancer. In the case-control analysis, 31 cases were to be analysed against the control group (n = 62). The presence of colonic polyps, adenomas, and ALN in patients with acromegaly was 19/31 (61.9%), 14/31 (45.16%), and 10/31 (32.25%), respectively, and in the control group, it was 18/62 (29.03%), 11/62 (17.74%), and 4/62 (6.45%), respectively. The risk of adenomas and ALN was higher in the acromegaly group compared to the control group: adenomas OR: 2.54 (95% CI 1.22-5.25) P=.005, ALN OR: 7.3 (2.4-25) P=.00. Conclusion: This preliminary case control study showed an increased risk of pre-cancerous colprectal lesions in patients with acromegaly, supporting the VCC screening at diagnosis.

Apoptosis y liquen plano oral: revisión de la literatura / Apoptosis and oral lichen planus: a review of the literature

En los últimos años se han producido grandes avances en el diagnóstico y tratamiento del Liquen Plano Oral (LPO). Sin embargo, sigue siendo una entidad con muchos interrogantes para la estomatología, sobre todo referidos a su proceso de aparición y a su tratamiento. El propósito de este trabajo es realizar una revisión bibliográfica actualizada del LPO y su relación con la apoptosis, tema de gran interés para la investigación científica. La apoptosis por su parte adquiere gran relevancia debido al rol que cumple este mecanismo: regulación en la morfogénesis, homeostasis de las poblaciones celulares y carcinogénesis en relación a la tendencia y potencial capacidad de transformación maligna de algunas variantes de LPO en sus formas atípicas.

In recent years, there have been major advances in the diagnosis and treatment of Oral Lichen Planus (OLP). However, it remains an entity with many questions for stomatology, especially referred to the process of occurrence and treatment. The purpose of this work is to conduct a literature review updated LPO and its relationship with apoptosis, topic of great interest for scientific research. The apoptosis meanwhile acquires great importance because of the role that this mechanism regulating morphogenesis, homeostasis of cell populations and carcinogenesis in relation to the trend and potential ability of malignant transformation of some variants of LPO in their atypical forms.

Análise da expressão de marcadores de morte celular em lesões potencialmente malignas induzidas com 4-NQO e tratadas com terapia fotodinâmica / Analysis of cellular death biomarkers expression in potentially malignant lesions induced with 4-NQO and treated with photodynamic therapy

As lesões potencialmente malignas orais (LPMO) constituem processos com chances de malignização e, portanto, o acompanhamento rigoroso e a retirada das lesões em situações de displasia são mandatórios. A terapia fotodinâmica (PDT) tem sido apontada como uma alternativa promissora e não invasiva para o tratamento dessas lesões. O princípio terapêutico da PDT envolve a geração de altos níveis de estresse oxidativo, pela associação de uma substância fotoativa com a energia eletromagnética e o oxigênio tecidual. É capaz de inviabilizar, através de cascatas de morte ainda pouco esclarecidas, células com alterações metabólicas significativas. A maioria dos trabalhos aponta a necessidade de várias sessões de PDT para erradicar as LPMO, porém o intervalo entre as sessões ainda é discutível. O objetivo deste trabalho foi estabelecer a relação anatomocronológica de marcadores de morte celular (caspase 3, beclin 1 e RIP 1 ) e de proteína de reparo do DNA durante o ciclo celular (PCNA) presentes após a PDT, com o intuito de verificar a cinética morte/proliferação celular e sugerir o intervalo de tempo entre as sessões de PDT mais adequado para a repetição da terapia. Para tanto, LPMOs foram induzidas por intermédio da aplicação tópica de 4-nitroquinolina-1-óxido (4-NQO) na mucosa lingual de ratos e posteriormente tratadas com PDT mediada pela administração tópica do ácido 5-aminolevulínico (5-ALA) e laser comercial (660nm, 90J. cm-2, 1000mW. cm-2). O efeito da PDT foi analisado nos tempos experimentais de 6h, 24h, 48h e 72h após a primeira sessão de PDT, e em 6h e 72h após uma segunda sessão. Nesses períodos, as línguas foram avaliadas clinica e histopatologicamente em relação ao percentual de redução das lesões induzidas e à morfologia do tecido, bem como por meio de análise imuno-histoquímica para PCNA; caspase 3 clivada (presente na apoptose), Beclin 1 (presente na autofagia) e RIP 1 (presente na necroptose).

Foi determinada a porcentagem de células positivas para esses marcadores no epitélio da mucosa lingual. Não houve remissão completa das lesões nas duas sessões de PDT, mas a segunda sessão acarretou diminuição em torno de 50% no tamanho das lesões. O período de 6h após a PDT foi o que exibiu significativa atrofia epitelial, bem como a maior porcentagem de células positivas para todos os marcadores analisados, incluindo o PCNA, em ambas as sessões. Caspase 3, beclin 1 e RIP 1 exibiram significativa diminuição da expressão em 24h. O PCNA exibiu aumento significativo no período 72h, e nos dois períodos do segundo ciclo. Como não houve a presença de necrose, a expressão aumentada de RIP 1 foi associada ao processo de apoptose e autofagia. Concluiu-se que a PDT mediada pelo 5-ALA provocou aumento da expressão de caspase 3, beclin 1 e RIP 1 em LPMO nas primeiras 6h após a terapia. Nesse modelo de PDT, essas proteínas parecem interagir em mecanismos de morte por apoptose e por autofagia, mas não por necrose. Considera- se o intervalo de 24h como o mais adequado para novo ciclo com os presentes parâmetros, sem que se estenda além de 72h.

The potentially malignant oral lesions (PMOL) are processes with great chances for cancer transformation and therefore the close monitoring and removal of lesions in cases of dysplasia are mandatory. Photodynamic therapy (PDT) has been identified as a promising and noninvasive treatment for these injuries. The therapeutic principle of PDT involves the generation of high levels of oxidative stress, by association of a photoactive substance with electromagnetic energy and tissue oxygen. It can kill metabolically changed cells through cascades of death which are still unclear. Most studies indicate the need of several PDT sessions to eradicate PMOL, however the interval between sessions is not consensual. The aim of this study was to establish the anatomical and chronological relationship between cellular death biomarkers (caspase 3, beclin 1 and RIP 1 ) and a DNA repair protein during cell cycle (PCNA) present after PDT, aiming to check the kinetic death/cell proliferation and suggest the time interval between PDT sessions more suitable to repetition of the PDT. For this purpose, PMOLs were induced by 4-nitroquinoline-1-oxide (4-NQO) topical application on the lingual mucosa of rats and further treated with PDT mediated by topical administration of 5-aminolevulinic acid (5-ALA) and a commercial laser (Twin flex-MM Optics São Carlos-Brazil 660nm, 90J.cm-2,1000mW.cm-2).The effect of PDT was analyzed at 6h, 24h, 48h and 72h after the first session, and at 6h and 72h after a second session. In these periods, the tongues have been evaluated clinically and histopathologically regarding the percentage reduction of lesions induced and tissue morphology as well as by immunohistochemical analysis for PCNA, cleaved caspase 3 (present in apoptosis), Beclin 1 (present in autophagy) and RIP (present in necroptosis). The percentage of positive cells for these markers was determined in the epithelium of the tongue mucosa.

There was no complete remission of lesions after two PDT sessions, but the second session resulted in a decrease of around 50% in lesion size. The period of 6 hours after PDT was the one in which significant epithelial atrophy was exhibited, as well as the highest percentage of positive cells for all tested markers, including PCNA in both sessions. Caspase 3, beclin 1 and RIP 1 exhibited a significant decrease of the expression at 24 hours. PCNA showed significant increase in the 72-hour period and after 6h and 72h from the second session. As there was no necrosis, the increased expression of RIP 1 has been linked to apoptosis and autophagy. It was concluded that PDT mediated by 5-ALA promoted incresead expression of caspase 3, beclin 1 and RIP 1 at the PMOLs in the first 6 hours after therapy.

Pólipos colorrectales no hereditarios / Non hereditary colorectal polyps

Antecedentes: La mayoría de los pólipos colorrectales son pequeños, no neoplásicos, asintomáticos y hallados durante la pesquisa o en forma incidental. Algunos de mayor tamaño pueden causar sangrado u obstrucción, aunque su verdadera importancia radica en que los adenomatosos preceden en más del 90 por ciento, al cáncer colorrectal (CCR), siguiendo en la mayoría de los casos una secuencia adenoma-carcinoma de lenta progresión que involucra múltiples alteraciones en genes supresores y oncogenes. En los últimos años una creciente evidencia demuestra otra vía de carcinogénesis a partir de los pólipos aserrados. Estos son precursores de cánceres colorrectales con inestabilidad microsatélite alta y extensa metilación del ADN, alteraciones genéticas diferentes a las de la vía tradicional que presenta inestabilidad cromosómica. El prolongado lapso de la clásica secuencia adenoma-carcinoma permite la realización de pruebas para la pesquisa de los pólipos adenomatosos y, ante su hallazgo el tratamiento endoscópico, como una forma efectiva de prevenir el CCR. Alrededor del 5 por ciento de los pólipos extirpados endoscópicamente presentan un adenocarcinoma invasor de la submucosa. La pesquisa ha llevado a encontrar más frecuentemente estos pólipos malignos que son por definición carcinomas tempranos T1. La polipectomía endoscópica se considera segura si es completa y el pólipo no tiene factores histológicos de riesgo para presentar metástasis linfáticas y recurrencia local. Sin embargo, hay cierta controversia en la literatura sobre cuáles son estos factores que permiten definir a los pólipos de alto riesgo para un resultado desfavorable con la polipectomía sola y que requieren una resección quirúrgica oncológica. Varios adelantos tecnológicos, algunos surgidos muy recientemente, pueden ayudar en la decisión terapéutica diferenciando las lesiones benignas de las malignas...

Background: Most colorectal polyps are small, non neoplastic, asymptomatic, and are found during screening or incidentally. Some larger polyps may cause bleeding or obstruction, however, their real importance is based on the fact that colorectal cancer (CRC) is preceded in more than 90 per cent by adenomatous polyps, in most cases through a slow progression of the adenoma-carcinoma sequence, involving multiple alterations in suppressor genes and oncogenes. In latest years, accumulative evidence shows that there is another pathway to carcinogenesis, arising in serrated polyps. These polyps are the precursors of CRCs with high microsatellite instability, and extensive DNA metylation, genetic alterations different from those seen in the traditional pathway, which presents chromosomal instability. The long period of time of the classical adenoma-carcinoma sequence allows performance of screcning tests for adenomatous polyps, and their endoscopic treatment when found, as an elective way to CRC prevention. Nearly 5 per cent of polyps removed endoscopically have an adenocarcinoma invading into the submucosa. The screening has lead to find these malignant polyps, early carcinomas T1 by definition, more frequently. Endoscopic polypectomy is considered safe if complete, and the polyp lack histological risk factors for lymphatic metastases and local recurrence. However, there is some controversy in the literature regarding which are these factors that define the high risk polyps for an unfavorable outcome with polypectomy only, and require an oncologic resection. Several technological advances, some very recently aroused, can assist in the therapeutic decision, by differentiating benign from malignant lesions. Others, like transanal endoscopic microsurgery, or laparoscopic technique, have contributed with the advantages of minimally invasive surgery...

Screening and management of precancerous lesions to prevent cervical cancer in low-resource settings.

Cervical cancer is a leading cause of cancer death among women in low-resource settings, but it is completely preventable by screening for and treating precancerous lesions. In this article, the current approaches to screening, confirmation, and treatment of precancerous lesions of the cervix are reviewed from the perspective of low-resource settings. Cervical cytology is compared to visual inspection with acetic acid (VIA) for screening women to detect precancerous lesions. The use of colposcopy to confirm findings in women with positive screening test results and various treatment methods are discussed. With one examination, cytology appears to detect fewer precancerous lesions than VIA, but VIA has a lower specificity and labels proportionately more women falsely positive. When available, colposcopy may be used to obtain directed biopsies from abnormal areas of the cervix to pathologically confirm the findings in women with positive screening tests. Treatment with cryotherapy appears to be a safe, acceptable, and effective procedure for the majority of precancerous lesions. Lesions that are not suitable for cryotherapy because of endocervical canal involvement or large size are amenable to outpatient treatment by loop electrical excision procedure (LEEP). HIV/AIDS and immune system suppression are associated with more rapid CIN progression and HIV-positive women generally have high recurrence rates of CIN after treatment. Women tempora may more readily transmit the virus after cryotherapy and, therefore, they require counseling regarding abstinence and condom use. Highly active antiretroviral therapy (HAART) may cause CIN to regress and may decrease the risk of cervical cancer in HIV-infected women. Cost-effectiveness modeling using South African data shows that use of a single lifetime VIA test and immediate cryotherapy saves costs compared to cytology or to no screening. VIA and cryotherapy are appropriate services for low-resource settings. Colposcopy and LEEP services should be available on a referral basis.

Neoplasias y displasias de vesícula biliar y su relación con litiasis. Estudio clinicopatológico de casos y controles / Neoplasm and dysplasia of the gallbladder and their relation with lithiasis. A case-control clinical-pathological study

Antecedentes. la litiasis es uno de los mayores factores de riesgo para cambios inflamatorios, metaplásicos, displásicos y neoplásicos de vesícula biliar, con frecuencia variable en diferenes poblaciones. Objetivo. determinar la frecuencia de asociación de los principales procesos patológicos y datos clínicos con litiasis vesicular. Material y métodos. estudio transveral, descriptivo de 1,367 piezas de colecistectomía, con (1,096) y sin (271) litiasis fue la siguiente: metaplasia psudopilórica 50 por ciento y 25 por ciento; metaplasia intestinal 16 por ciento y 2 por ciento; displasia de bajo grado 40 por ciento y 17 por ciento; displasia de alto grado 16 por ciento y 2 por ciento; carcinoma in situ 1.5 por ciento y 0 por ciento y carcinoma invasor 2.6 por ciento y 0 por ciento. El 80 por ciento de los casos con litiasis, el 65 por ciento de los casos de carcinoma in situ y el 90 por ciento de los casos de carcinoma invasor correspondieron a mujeres. La edad media de los pacientes con displasia de bajo y alto grado, carcinoma in situ y carcinoma invasor fue de 42, 48, 53 y 61 años, en ese orden. Conclusiones. la frecuencia de procesos inflamatorios agudos, colecititis crónica xantogranulomatosa, adenomiomatosis, metaplasia pseudopilórica e intestinal, pólipos hiperplásicos, displasia de bajo y alto grado, adenomas tubulares, carcinoma in situ y carcinoma invasor fue mayor en vesículas con litiasis que en vesículas sin litiasis (p<.05)

Epidermodisplasia veruciforme de Lewandowsky e Lutz / Epidermodysplasia verruciformis of Lewandowsky and Lutz

FUNDAMENTOS - A epidermodisplasia verruciforme é causada pelo HPV, apresentando alta incidência familiar, concomitância de distúbios imunológicos e possibilidade de transformaçäo carcinomatosa. OBJETIVOS - Foi revista a literatura sobre os HPV, com ênfase para epidermodisplasia verruciforme, correlacionando-a com a nossa casuística na tentativa de contribuir para melhor conhecimento da enfermidade. MÉTODO - Estudaram-se oito pacientes com epidermodisplasia verruciforme por meio de anamnese, observaçäo clínica, exames laboratoriais, genética, histopatologia, imunologia e tratamento. Foram analisados histopatologicamente dois casos de verugas planas, e comparados com a epidermodisplasia verruciforme. RESULTADOS - Os pacientes apresentaram quadro clínico-histopatológico peculiar aos encontrados na epidermodisplasia verruciforme pelo grupo HPV-5 e similares, com nítido acometimento familiar, alteraçoes imunológicas, evoluçäo crônica e resistência às terapêuticas administradas. CONCLUSOES - 1. A epidermodisplasia verruciforme apresentou expressöes clínicas polimorfas, com evoluçäo crônica e progressiva. As lesöes eram geralmente assintomáticas, com distribuiçäo disseminada e simétrica. A área mais acometida foi a face, com palmas, plantas, mucosas e couro cabeludo poupados; 2. Em todos os pacientes estudados, a ezpressäo clínica da doença era distinta da apresentaçäo clínica encontrada em casos de verrugas planas, sendo histologicamente típica de epidermodisplasia verruciforme (grupo HPV5-símile); 3. Foram observadas nos pacientes alteraçoes imunitárias humorais e celulares; e 4. A resistência às terapêuticas foi marcante. Apenas com o uso do etretinato, houve regressäo parcial das lesöes