Intestinal microbiota in the adenoma progression to colorectal cancer: a cross-sectional study

Background: Colorectal cancer is a major health problem worldwide and many efforts have been done to delineate risk factors and develop screening strategies to reduce its incidence and mortality. Colorectal adenomas have been clearly considered preneoplastic lesions due to their potential malignant transformation via the adenoma-carcinoma sequence. Over the last years, intestinal microbiota has been studied in several diseases and it has been hypothesized that colonic microbiota could influence colorectal cancer pathogenesisObjective: The goal of this study is to analyse whether there is an association between the fecal microbiota profiling and the presence and progression of colorectal adenomas, detected in population undergoing colonoscopy, to better understand the role of intestinal microbiota in colorectal carcinogenesisDesign: A cross-sectional study in the Gastroenterology Department at Hospital Universitari Doctor Josep Trueta in Girona, in a period of time of two yearsParticipants: General population undergoing screening or diagnostic colonoscopy in the Digestive Endoscopy UnitOutcomes: Identification and characterization of intestinal microbiota in stool samples from healthy patients and patients with low and high risk colorectal adenomas

Evaluación de dos estrategias de cribado de cáncer colorrectal: Test inmunológico versus test bioquímico. Cataluña, 2008-2010

Fundamento: El objetivo del estudio fue evaluar el cambio de estrategia de cribado (test inmunológico cuantitativo) en un programa poblacional de detección precoz de cáncer colorrectal (CCR) en Cataluña. Métodos: La cuarta ronda del programa de cribado de CCR en Hospitalet de Llobregat se implementó en 2008-2010. Se ofreció un test bioquímico a 50.227 individuos y uno inmunológico cuantitativo a 12.707 individuos. Se analizaron diferencias en las dos estrategias de cribado respecto a variables de aceptabilidad (entre participación, abandonos y adherencia a la colonoscopia), de precisión diagnóstica (valor predictivo positivo y tasas de detección), de resultados (tamaño y localización de lesiones, estadio de los cánceres detectados) y de recursos (número necesario de colonoscopias e intervalo de tiempo entre el resultado positivo del test y la colonoscopia). Resultados: La participación en el cribado fue superior entre los individuos que utilizaron el test inmunológico (OR: 1,35; IC95%:1,27-1,42). Las tasas de detección fueron superiores para el test inmunológico destacando la de adenomas de alto riesgo (26,7 vs 3,0 ). El valor predictivo positivo para adenomas de alto riesgo fue del 45,0% y del 46,9% en el inmunológico y el guayaco, respectivamente. El número de colonoscopias necesarias para detectar un cáncer fue de casi el doble que en el guayaco (13,6 vs 7,4). Conclusiones: El test inmunológico es una buena estrategia de cribado especialmente sensible para la detección de adenomas de alto riesgo. Sin embargo, requiere realizar un gran número de colonoscopias y por ello se debe disponer de los recursos y medios necesarios.

Adenoma viloso da ampola de Vater

The aim of this paper is to present a case of a 37-year-old female patient with a benign tumor of the Ampulla of Vater and a brief review of the literature. The patient presented with progressive obstructive jaundice and weigth loss due to the presence of two adenomas of the second portion of duodenum. Laboratory tests confirmed the presence of obstruction of the biliary tree. Ultrasound and CT scan of the abdomen revealed bile duct dilatation. ERCP showed a tumor at the site of the Ampulla of Vater. The biopsies revealed tubular adenoma. She was submitted to local resection of the tumors and sphincteroplasty, since the frozen biopsy at the time of surgery showed no malignancy. During the post-operative follow-up she presented recurrence of symptoms. An upper GI endoscopy revealed a tumor at the Ampulla of Vater. She was then submitted to Whipple procedure with an uneventful recovery.

Adenoma viloso com transformação carcinomatosa da ampola de Vater

Villous adenomas of the duodenum and ampulla of Vater are uncommon, but they have been diagnosed more frequently with the increasing use of upper gastrointestinal endoscopy. Differential diagnosis with villous adenocarcinoma may be difficult. The authors present a case of a 47-year-old man with a giant villous adenoma of the duodenum, with intermittent jaundice, that was treated by pancreatoduodenectomy.

Estudo da prevalência das doenças tireoidianas em pacientes tireoidectomizados no Hospital da Santa Casa de Goiânia

OBJETIVO: O Estado de Goiás deixou de ser oficialmente considerado como região endêmica de bócio em 1995. O objetivo deste estudo é verificar a correspondência entre os diagnósticos das doenças tireoidianas (bócio endêmico, tireoidites e câncer), observados nos laudos anátomo-patológicos e nas observações dos inquéritos epidemiológicos. MÉTODO: Estudo retrospectivo de 1399 pacientes submetidos a tireoidectomias na Santa Casa de Misericórdia de Goiânia de 1993 a 2003, e que resultaram em 1610 diagnósticos anátomo-patológicos. RESULTADOS: Os resultados dos exames anátomo-patológicos dos pacientes revelaram: a) adenoma folicular 155 (9,63%); b) outros adenomas 29 (1,8%); c) bócio adenomatoso 87 (5,4%); d) bócio colóide 981 (60,9%); e) carcinoma folicular 36 (2,24%); f) carcinoma indiferenciado 3 (0,19%); g) carcinoma papilífero 93 (5,78%); h) cistos 9 (0,56%); i) bócio difuso tóxico 75 (4,66%); j) outras tireoidites 12 (0,75%); l) outras neoplasias malignas 6 (0,38%) e m) tireoidite linfocítica 124 (7,71%). CONCLUSÕES: O perfil observado com uma prevalência alta de tireoidite linfocítica e carcinoma papilífero se correlaciona realmente com região não endêmica.

Fatores preditores de malignidade em neoplasias de células de Hurthle

OBJETIVO: neoplasias de células de Hurthle são tumores da glândula tireóide de baixa incidência que apresentam muitas controvérsias quanto à distinção entre carcinomas e adenomas. O objetivo deste estudo foi identificar fatores preditores de malignidade neste tipo específico de neoplasia. MÉTODOS: entre janeiro de 1999 e junho de 2006, 56 casos de neoplasia de células de Hurthle foram diagnosticados em nossa instituição e foram estudados retrospectivamente. RESULTADOS: trinta e sete pacientes apresentaram diagnóstico patológico de adenoma de células de Hurthle (ACH), enquanto 19 casos foram diagnosticados como carcinoma de células de Hurthle (CCH). No grupo de pacientes com adenomas a idade média foi de 47,8 anos, sendo que trinta e cinco (94%) eram do sexo feminino e apenas dois (5,5%) casos do sexo masculino. O tamanho médio dos adenomas foi de 2,1 cm variando de 0,3 a 6,0 cm. Entre os 19 casos de carcinomas a média de idade foi de 51,1 anos, sendo quatorze casos em mulheres (73%) e cinco em homens (26,4%). O tamanho médio dos nódulos neste grupo foi de 3,8 cm, variando de 2,0 cm a 7,5 cm. CONCLUSÃO: Pacientes com neoplasias de células de Hurthle apresentando nódulos maiores que três centímetros, principalmente em homens, apresentam maior risco de malignidade.

Repercussão hepática da carcinogênese colorretal induzida pelo azoximetano

OBJETIVO: Avaliar as repercussões hepáticas da carcinogênese colônica induzida por diferentes doses e tempos de exposição ao azoximetano em ratos Wistar. MÉTODOS: Quarenta e quatro ratos foram distribuídos em quatro grupos. Os animais tinham oito semanas no início do experimento. No grupo 1, receberam 1.0mL de solução salina intraperitonealmente uma vez por semana por duas semanas. No grupo 2, receberam 15 mg/kg de azoximetano intraperitonealmente uma vez por semana por duas semanas. Esses animais foram mortos na 15ª semana do experimento. Os animais do grupo 3 receberam solução salina intraperitonealmente uma vez por semana por duas semanas. Os animais do grupo 4 receberam 20mg/kg de azoximetano intraperitonealmente uma vez por semana por duas semanas. Esses animais foram mortos na 26ª semana do experimento. Os fragmentos de tecido hepático foram corados pela hematoxilina e eosina e avaliadas microscopicamente. RESULTADOS: Grupo 1 e grupo 2 diferiram significantemente em relação a esteatose, mas não houve diferença entre o grupo 3 e o grupo 4. No entanto, no grupo 4 foram observadas lesões pré-neoplásicas (focos de células alteradas, claras, vacuoladas, basofílicas, anfofílicas, tigróides, oncocíticas, pequenas ou acidófilas, espongioses e pelioses) e lesões neoplásicas (colangiomas e adenomas) contendo hepatócitos atípicos de permeio, não identificados no grupo 3. CONCLUSÃO: No modelo de carcinogênese colorretal, lesões hepáticas pré-neoplásicas e neoplásicas aparecem e evoluem na proporção do tempo e dose de exposição ao azoximetano.

Nódulos benignos da mama: uma revisão dos diagnósticos diferenciais e conduta

Os nódulos mamários benignos são responsáveis por até 80% das massas palpáveis. Seu diagnóstico diferencial é amplo, envolvendo os cistos mamários, os fibroadenomas, os tumores filóides, os papilomas, os lipomas, os hamartomas e os adenomas, entre outros. O fibroadenoma é a neoplasia mamária mais comum em pacientes menores de 35 anos e os cistos são mais freqüentes na perimenopausa. O diagnóstico diferencial entre nódulos sólidos ou císticos poderá ser feito por meio da punção aspirativa com agulha fina ou pela ultra-sonografia, sendo terapêutica para os últimos. Neste artigo serão revisados os aspectos diagnósticos diferenciais entre estes tumores e as novas abordagens terapêuticas.

The prognostic and predictive value of selected biomarkers in colorectal cancer

Tissue-based biomarkers are studied to receive information about the pathologic processes and cancer outcome, and to enable development of patient-tailored treatments. The aim of this study was to investigate the potential prognostic and/or predictive value of selected biomarkers in colorectal cancer (CRC). Group IIA secretory phospholipase A2 (IIA PLA2) expression was assessed in 114 samples presenting different phases of human colorectal carcinogenesis. Securin, Ki-67, CD44 variant 6 (CD44v6), aldehyde dehydrogenase 1 (ALDH1) and β-catenin were studied in a material including 227 rectal carcinoma patients treated with short-course preoperative radiotherapy (RT), long-course preoperative (chemo)RT (CRT) or surgery only. Epidermal growth factor receptor (EGFR) gene copy number (GCN), its heterogeneity in CRC tissue, and association with response to EGFR-targeted antibodies cetuximab and panitumumab were analyzed in a cohort of 76 metastatic CRC. IIA PLA2 expression was decreased in invasive carcinomas compared to adenomas, but did not relate to patient survival. High securin expression after long-course (C)RT and high ALDH1 expression in node-negative rectal cancer were independent adverse prognostic factors, ALDH1 specifically in patients treated with adjuvant chemotherapy. The lack of membranous CD44v6 in the rectal cancer invasive front associated with infiltrative growth pattern and the risk of disease recurrence. Heterogeneous EGFR GCN increase predicted benefit from EGFR-targeted antibodies, also in the chemorefractory patient population. In summary, high securin and ALDH1 protein expression independently relate to poor outcome in subgroups of rectal cancer patients, potentially because of resistance to conventional chemotherapeutics. Heterogeneous increase in EGFR GCN was validated to be a promising predictive factor in the treatment of metastatic CRC.

Adrenal incidentaloma

Incidentally discovered adrenal masses, or adrenal incidentalomas, have become a common clinical problem owing to wide application of radiologic imaging techniques. This definition encompasses a heterogeneous spectrum of pathologic entities, including primary adrenocortical and medullary tumors, benign or malignant lesions, hormonally active or inactive lesions, metastases, and infections. Once an adrenal mass is detected, the clinician needs to address two crucial questions: is the mass malignant, and is it hormonally active? This article provides an overview of the diagnostic clinical approach and management of the adrenal incidentaloma. Mass size is the most reliable variable to distinguish benign and malignant adrenal masses. Adrenalectomy should be recommended for masses greater than 4.0 cm because of the increased risk of malignancy. Adrenal scintigraphy has proved useful in discriminating between benign and malignant lesions. Finally, fine-needle aspiration biopsy is an important tool in the evaluation of oncological patients and it may be useful in establishing the presence of metastatic disease. The majority of adrenal incidentalomas are non-hypersecretory cortical adenomas but an endocrine evaluation can lead to the identification of a significant number of cases with subclinical Cushing's syndrome (5-15%), pheochromocytoma (1.5-13%) and aldosteronoma (0-7%). The first step of hormonal screening should include an overnight low dose dexamethasone suppression test, the measure of urinary catecholamines or metanephrines, serum potassium and, in hypertensive patients, upright plasma aldosterone/plasma renin activity ratio. Dehydroepiandrosterone sulfate measurement may show evidence of adrenal androgen excess.

Amplification of 9q34 in childhood adrenocortical tumors: a specific feature unrelated to ethnic origin or living conditions

Adrenocortical tumors (ACT) in children under 15 years of age exhibit some clinical and biological features distinct from ACT in adults. Cell proliferation, hypertrophy and cell death in adrenal cortex during the last months of gestation and the immediate postnatal period seem to be critical for the origin of ACT in children. Studies with large numbers of patients with childhood ACT have indicated a median age at diagnosis of about 4 years. In our institution, the median age was 3 years and 5 months, while the median age for first signs and symptoms was 2 years and 5 months (N = 72). Using the comparative genomic hybridization technique, we have reported a high frequency of 9q34 amplification in adenomas and carcinomas. This finding has been confirmed more recently by investigators in England. The lower socioeconomic status, the distinctive ethnic groups and all the regional differences in Southern Brazil in relation to patients in England indicate that these differences are not important to determine 9q34 amplification. Candidate amplified genes mapped to this locus are currently being investigated and Southern blot results obtained so far have discarded amplification of the abl oncogene. Amplification of 9q34 has not been found to be related to tumor size, staging, or malignant histopathological features, nor does it seem to be responsible for the higher incidence of ACT observed in Southern Brazil, but could be related to an ACT from embryonic origin.

Role of ACTH receptor in adrenocortical tumor formation

Adrenocorticotrophin (ACTH) is the major regulatory hormone of steroid synthesis and secretion by adrenocortical cells. The actions of ACTH are mediated by its specific membrane receptor (ACTH-R). The human ACTH-R gene was recently cloned, allowing systematic determination of its sequence, expression and function in adrenal tumorigenesis. The presence of oncogenic mutations of the ACTH-R gene in adrenocortical tumors has been reported. Direct sequencing of the entire coding region of the ACTH-R gene of sporadic adrenocortical adenomas and carcinomas did not reveal constitutive activating mutations, indicating that this mechanism is not frequent in human adrenocortical tumorigenesis. Recent studies demonstrated allelic loss of the ACTH-R gene in a subset of sporadic adrenocortical tumors using a PstI polymorphism located in the promoter region of the ACTH-R gene. Loss of heterozygosity of the ACTH-R was analyzed in 20 informative patients with a variety of benign and malignant adrenocortical tumors. Three of them showed loss of heterozygosity of the ACTH-R gene. In addition, Northern blot experiments demonstrated reduced expression of ACTH-R mRNA in these three tumors with loss of heterozygosity, suggesting the functional significance of this finding at the transcriptional level. Deletion of the ACTH-R gene seems to be involved in a subset of human adrenocortical tumors, contributing to cellular dedifferentiation.

Morphometric and ultrastructural analysis of different pituitary cell populations in undernourished monkeys

Undernutrition elicited by a low-protein diet determines a marked reduction of hypophyseal activity and affects the function of the respective target organs. The objective of the present investigation was to study the ultrastructural and quantitative immunohistochemical changes of the different pituitary cell populations in undernourished monkeys that had been previously shown to have significant changes in craniofacial growth. Twenty Saimiri sciureus boliviensis monkeys of both sexes were used. The animals were born in captivity and were separated into two groups at one year of age, i.e., control and undernourished animals. The monkeys were fed ad libitum a 20% (control group) and a 10% (experimental group) protein diet for two years. Pituitaries were processed for light and electron microscopy. The former was immunolabeled with anti-GH, -PRL, -LH, -FSH, -ACTH, and -TSH sera. Volume density and cell density were measured using an image analyzer. Quantitative immunohistochemistry revealed a decrease in these parameters with regard to somatotrophs, lactotrophs, gonadotrophs and thyrotrophs from undernourished animals compared to control ones. In these populations, the ultrastructural study showed changes suggesting compensatory hyperfunction. On the contrary, no significant changes were found in the morphometric parameters or the ultrastructure of the corticotroph population. We conclude that in undernourished monkeys the somatotroph, lactotroph, gonadotroph, and thyrotroph cell populations showed quantitative immunohistochemical changes that can be correlated with ultrastructural findings.

Lack of mutations of exon 2 of the MEN1 gene in endocrine and nonendocrine sporadic tumors

In addition to the mutations that underlie most cases of the multiple endocrine neoplasia type 1 (MEN1) syndrome, somatic mutations of the MEN1 gene have also been described in sporadic tumors like gastrinomas, insulinomas and bronchial carcinoid neoplasm. We examined exon 2 of this gene, where most of the mutations have been described, in 148 endocrine and nonendocrine sporadic tumors. DNA was obtained by phenol/chloroform extraction and ethanol precipitation from 92 formalin-fixed, paraffin-embedded samples, and from 40 fresh tumor tissue samples. We used 5 pairs of primers to encompass the complete coding sequence of exon 2 of the MEN1 gene that was screened by the polymerase chain reaction-single-stranded conformation polymorphism (PCR-SSCP) technique in 78 sporadic thyroid cancers: 28 follicular adenomas, 35 papillary carcinomas, 14 follicular carcinomas, and 1 anaplastic thyroid carcinoma. We also examined 46 adrenal lesions (3 hyperplasias, 3 adenomas and 35 adrenocortical carcinomas, 2 pheochromocytomas, 2 ganglioneuroblastomas, and 1 lymphoma) and 24 breast cancers (6 noninvasive, 16 infiltrating ductal, and 2 invasive lobular tumors). The PCR product of 5 tumors suspected to present band shifts by SSCP was cloned. Direct sense and antisense sequencing did not identify mutations. These results suggest that the MEN1 gene is not important in breast, thyroid or adrenal sporadic tumorigenesis. Because the frequency of mutations varies significantly among tumor subgroups and allelic deletions are frequently observed at 11q13 in thyroid and adrenal cancers, another tumor suppressor gene residing in this region is likely to be involved in the tumorigenesis of these neoplasms.

Regulation of pituitary hormones and cell proliferation by components of the extracellular matrix

The extracellular matrix is a three-dimensional network of proteins, glycosaminoglycans and other macromolecules. It has a structural support function as well as a role in cell adhesion, migration, proliferation, differentiation, and survival. The extracellular matrix conveys signals through membrane receptors called integrins and plays an important role in pituitary physiology and tumorigenesis. There is a differential expression of extracellular matrix components and integrins during the pituitary development in the embryo and during tumorigenesis in the adult. Different extracellular matrix components regulate adrenocorticotropin at the level of the proopiomelanocortin gene transcription. The extracellular matrix also controls the proliferation of adrenocorticotropin-secreting tumor cells. On the other hand, laminin regulates the production of prolactin. Laminin has a dynamic pattern of expression during prolactinoma development with lower levels in the early pituitary hyperplasia and a strong reduction in fully grown prolactinomas. Therefore, the expression of extracellular matrix components plays a role in pituitary tumorigenesis. On the other hand, the remodeling of the extracellular matrix affects pituitary cell proliferation. Matrix metalloproteinase activity is very high in all types of human pituitary adenomas. Matrix metalloproteinase secreted by pituitary cells can release growth factors from the extracellular matrix that, in turn, control pituitary cell proliferation and hormone secretion. In summary, the differential expression of extracellular matrix components, integrins and matrix metalloproteinase contributes to the control of pituitary hormone production and cell proliferation during tumorigenesis.