Prognostic impact of CD133 expression in Endometrial Cancer Patients.

To assess the impact of CD133 expression on the prognosis of endometrioid endometrial carcinoma (EEC). We retrospectively assessed CD133 expression in tissue microarray of 116 surgically treated FIGO I-III EEC. Tumors with ≥10% of CD133-expressing cells were considered CD133-positive (CD133+). On the basis of CD133 expression, clinical and pathological parameters, progression-free survival (PFS) and overall survival (OS) were evaluated. Of the EEC studied 85.2% showed CD133-expressing cells. Only 61% (n = 66) of EEC presented ≥10% of CD133 expressing cells and were considered CD133+. The mean OS for CD133+ tumour patients was 161 months (95% CI, 154-168) as compared with 146 months (95% CI, 123-160) for those with CD133- tumors (p = 0.012). The mean PFS for CD133+ tumour was 159 months (95% CI, 149-168) as compared with 147 months (95% CI, 132-161) in those with a CD133-tumour (p = 0.014). CD133+ tumours were less likely to have vascular invasion (p = 0.010) and more likely to be well differentiated (p = 0.034). C133+ tumours predicted favorable OS and PFS of EEC patients, with a Hazard Ratio 4.731 (95% CI, 1.251-17.89; p = 0.022). CD133+ tumor status correlates with favorable prognosis of EEC. Our findings are in agreement with studies addressing brain and colorectal tumours.

Urine human papillomavirus prevalence in women with high-grade cervical lesions.

OBJECTIVE: To determine the prevalence of human papillomavirus (HPV) in urine samples from women with high-grade cervical lesions. Secondary objectives are to identify the influence of socio-demographic factors and the different genotypes with urinary HPV positivity. STUDY DESIGN: 75 women with a positive biopsy for CIN2+ were included in the study from October 2010 to July 2011. A sample of urine was collected immediately before conization at the outpatient clinic. We analyzed the presence of HPV using a PCR technique. RESULTS: The mean age of the patients was 34.8 years (range 24 to 61). All patients had histological CIN2+, of whom 54.67% had CIN3. The prevalence of HPV in urine test was 58.82% in CIN2 population versus 78.05% in CIN3 patients (p 0.072). 31 different genotypes were found. The most frequent HPV genotype was 16-HPV, which was identified in 58% of women with positive HPV-DNA in urine samples. No demographic characteristics were significantly associated to urinary HPV prevalence. CONCLUSION: Most of the patients with CIN2+ showed positive results for urine HPV test. The prevalence of positive urinary HPV test was higher for patients with CIN3. HPV urine detection could be considered as an acceptable option for high-risk population who skip regular screening programs.

The EMT signaling pathways in endometrial carcinoma

Endometrial cancer (EC) is the most common gynecologic malignancy of the female genital tract and the fourth most common neoplasia in women. In EC, myometrial invasion is considered one of the most important prognostic factors. For this process to occur, epithelial tumor cells need to undergo an epithelial to mesenchymal transition (EMT), either transiently or stably, and to differing degrees. This process has been extensively described in other types of cancer but has been poorly studied in EC. In this review, several features of EMT and the main molecular pathways responsible for triggering this process are investigated in relation to EC. The most common hallmarks of EMT have been found in EC, either at the level of E-cadherin loss or at the induction of its repressors, as well as other molecular alterations consistent with the mesenchymal phenotype-like L1CAM and BMI-1 up-regulation. Pathways including progesterone receptor, TGFβ, ETV5 and microRNAs are deeply related to the EMT process in EC (AU)

Feto-placental morphological effects of prenatal exposure to drugs of abuse.

The aim of the study was to find morphological changes in the feto-placental unit due to prenatal exposure to drugs of abuse. A blind histomorphometric study was performed using 225 placentas. Based on meconium testing, the fetuses were classified as exposed or unexposed to opiates, cocaine, cannabis or alcohol. To establish prenatal tobacco exposure, cotinine in cord blood was analyzed. At the microscopic level a non statistically significant reduction of placental vascularization was observed in cocaine, opiates and alcohol using mothers. In addition, alcohol-consuming mothers did not present with larger placental vessel diameter than controls. Prenatal use of cocaine and tobacco was associated with a decrease in newborn weight and length. Furthermore, tobacco use was associated with a higher rate of previous abortions. In conclusion, placentas from mothers using tobacco, cocaine, opiates or alcohol during pregnancy present vasculature changes that may explain the adverse perinatal outcomes in their newborns.

Oxidative stress in Alzheimer's disease hippocampus: a topographical study.

Advanced glycation end-products (AGEs) and their receptor (RAGE) are molecules related to oxidative stress demonstrated in aging and in several pathological disorders including Alzheimer's disease (AD). Aging has been considered the main risk factor for AD. Amyloid deposits (Aß-D) and neurofibrillary tangles (NFT) are pathological changes related to AD involving hippocampal regions. Different degrees of AD pathology have been described according to distribution of NFTs in different topographical regions of hippocampus and cerebral cortex. The hippocampus shows a selective vulnerability under several noxes especially those including hypoxia. Hypoxia in the nervous tissue induces oxidative stress. In an attempt to find out more about anatomical distribution of the oxidative stress through hippocampal regions in AD, a collection of brains were studied. Samples from deceased patients who had suffered from AD and from age-matched controls were immunohistochemically studied with AGE and RAGE antibodies according to a topographical division of the hippocampus and brain cortical regions. Results suggest that an oxidative stress pathway starts in the CA3 sector progresses to CA1 and then continues to other hippocampal and cortical areas building a pathoclitic pathway for Alzheimer's disease progression.

MYC gene numerical aberrations in actinic keratosis and cutaneous squamous cell carcinoma.

BACKGROUND: The genetic alterations that drive the transition from actinic keratoses (AKs) to cutaneous squamous cell carcinomas (SCCs) have not been defined precisely. Amplification and/or overexpression of the MYC proto-oncogene have been demonstrated in several human, malignant tumours including head and neck SCCs. OBJECTIVES: To evaluate the presence of MYC genomic aberrations in both AKs and SCCs. METHODS: Skin biopsy specimens corresponding to AKs, SCCs and control samples were included in two paraffin-embedded tissue microarrays. MYC cytogenetic profile was evaluated by fluorescence in situ hybridization (FISH). The results obtained were compared with MYC immunohistochemical expression. RESULTS: Twenty-three AKs and 30 SCCs were evaluated. MYC numerical aberrations were observed in eight of 23 (35%) AKs and 19 of 30 (63%) SCCs (P = 0.05). MYC numerical aberrations were more frequent in moderately to poorly differentiated SCCs (77%) when compared with well-differentiated SCCs (25%; P = 0.027). A significant association between copy number gains of MYC by FISH analysis and MYC protein expression was demonstrated. CONCLUSIONS: MYC gains and amplifications are frequent cytogenetic abnormalities in SCCs and may play a relevant role in promoting SCC undifferentiation and tumoral progression.

Identification of a novel cyclin required for the intrinsic apoptosis pathway in lymphoid cells.

We have identified an early step common to pathways activated by different forms of intrinsic apoptosis stimuli. It requires de novo synthesis of a novel cyclin, cyclin O, that forms active complexes primarily with Cdk2 upon apoptosis induction in lymphoid cells. Cyclin O expression precedes glucocorticoid and gamma-radiation-induced apoptosis in vivo in mouse thymus and spleen, and its overexpression induces caspase-dependent apoptosis in cultured cells. Knocking down the endogenous expression of cyclin O by shRNA leads to the inhibition of glucocorticoid and DNA damage-induced apoptosis due to a failure in the activation of apical caspases while leaving CD95 death receptor-mediated apoptosis intact. Our data demonstrate that apoptosis induction in lymphoid cells is one of the physiological roles of cyclin O and it does not act by perturbing a normal cellular process such as the cell cycle, the DNA damage checkpoints or transcriptional response to glucocorticoids.

Novel molecular profiles of endometrial cancer-new light through old windows.

Endometrial carcinoma (EC) is the most common gynecological malignancy in the western world. A widely accepted dualistic model, which has been established on a morphological basis, differentiates EC into two broad categories: Type I oestrogen-dependent adenocarcinoma with an endometrioid morphology and Type II non-oestrogen-dependent EC with a serous papillary or clear cell morphology. Molecular genetic evidence indicates that endometrial carcinoma, as described in other malignancies, likely develops as the result of a stepwise accumulation of alterations in cellular regulatory pathways, such as oncogene activation and tumor suppressor gene inactivation, which lead to dysfunctional cell growth. These molecular alterations appear to be specific in Type I and Type II cancers. In type I endometrioid endometrial cancer, PTEN gene silencing in conjunction with defects in DNA mismatch repair genes, as evidenced by the microsatellite instability phenotype, or mutations in the K-ras and/or beta-catenin genes, are recognized major alterations, which define the progression of the normal endometrium to hyperplasia, to endometrial intraepithelial neoplasia, and then on to carcinoma. In contrast, Type II cancers show mutations of TP53 and Her-2/neu and seem to arise from a background of atrophic endometrium. Nevertheless, despite the great effort made to establish a molecularly-based histological classification, the following issues must still be clarified: what triggers the tumor cells to invade the myometrium and what causes vascular or lymphatic dissemination, finally culminating in metastasis? RUNX1, a transcription factor, was recently identified as one of the most highly over-expressed genes in a microarray study of invasive endometrial carcinoma. Another candidate gene, which may be associated with an initial switch to myometrial infiltration, is the transcription factor ETV5/ERM. These studies, as well as those conducted for other genes possibly involved in the mitotic checkpoint as a major mechanism of carcinogenesis in non-endometrioid endometrial cancer, could help in understanding the differences in the biology and the clinical outcome among histological types.

Molecular determinants of invasion in endometrial cancer.

Endometrial carcinoma is the most common gynaecological malignancy in the western world and the most frequent among infiltrating tumours of the female genital tract. Despite the characterisation of molecular events associated with the development of endometrial carcinoma, those associated with the early steps of infiltration and invasion in endometrial cancer are less known. Deep myometrial invasion correlates with more undifferentiated tumours, lymph-vascular invasion, node affectation and decreased global survival. In this review we present an overview of the molecular pathology of myometrial infiltration that defines the initial steps of invasion in endometrial cancer. Down-regulation of E-cadherin as a main player of epithelial to mesenchymal transition, as well as modifications on other molecules involved in cell-cell contacts, render cells with a migratory phenotype. In addition, altered signalling pathways and transcription factors associate with myometrial invasion, histologic grade and metastasis.

Molecular determinants of invasion in endometrial cancer

Endometrial carcinoma is the most common gynaecological malignancy in the western world and the most frequent among infiltrating tumours of the female genital tract. Despite the characterisation of molecular events associated with the development of endometrial carcinoma, those associated with the early steps of infiltration and invasion in endometrial cancer are less known. Deep myometrial invasion correlates with more undifferentiated tumours, lymph-vascular invasion, node affectation and decreased global survival. In this review we present an overview of the molecular pathology of myometrial infiltration that defines the initial steps of invasion in endometrial cancer. Down-regulation of E-cadherin as a main player of epithelial to mesenchymal transition, as well as modifications on other molecules involved in cell-cell contacts, render cells with a migratory phenotype. In addition, altered signalling pathways and transcription factors associate with myometrial invasion, histologic grade and metastasis (AU)

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A study of Ki-67, c-erbB2 and cyclin D-1 expression in CIN-I, CIN-III and squamous cell carcinoma of the cervix.

The histological criteria for cervical intraepithelial neoplastic lesions and their follow-ups have been established, but their reproducibility, specificity and sensibility are not certain. Immunohistochemical markers provide more information on each specific case, in order to facilitate its classification and, eventually, its prognosis. Using immunohistochemical techniques, this study analyzes the prognostic value of three markers (Ki-67, c-erbB2 and Cyclin D1) in cases of low grade squamous intraepithelial neoplasia (CIN-I), high grade squamous intraepithelial neoplasia (CIN-III), and infiltrating squamous cell carcinoma (SCC) taken from a group of cervical samples. In situ hybridization was performed in order to detect high-risk HPV. High risk HPV was demonstrated in 82%, 89% and 100% of the LGSIL, HGSIL and SCC cases, respectively. C-erbB2 expression was detected in 9%, 33% and 50% of the LSIL, HGSIL and SCC cases, respectively. The Ki-67 LI was 25%, 68% and 65.5% in the LGSIL, HGSIL and SCC cases, respectively. Nuclear Cyclin D1 expression was seen in 82%, 11% and 30% of the CIN-I,CIN-III and SCC cases, respectively. We observed that the cytoplasmic cyclin D1 expression increased with the severity of the lesion instead of the nuclear expression decreasing with the progression of the pathology. Nuclear and cytoplasmic Cyclin D1 expression seemed to be related to HPV high risk infection. We concluded that Cyclin D1, cerbB2 and The Ki-67 LI expression changed in relation to the severity of the lesion and that they could be helpful in making a differential diagnosis.

Primitive neuroectodermal tumor of the central nervous system with glial differentiation: a FISH study of an adult case.

Primitive neuroectodermal tumors (PNETs) of the central nervous system (CNS), a rare occurrence in adults, may show glial differentiation and can be misinterpreted as pure astrocytic neoplasms. Few fluorescence in situ hybridization (FISH) studies have been carried out on these tumors; isochromosome 17q was found to be the major chromosomal abnormality. We present the case of an adult in which we performed a FISH study of both the glial and neuronal components. A complex array of FISH changes, not including an isochromosome 17q were identified.

Expression of Snail protein in tumor-stroma interface.

The product of Snail gene is a repressor of E-cadherin transcription and an inductor of the epithelial-to-mesenchymal transition in several epithelial tumor cell lines. In order to examine Snail expression in animal and human tissues, we have raised a monoclonal antibody (MAb) that reacts with the regulatory domain of this protein. Analysis of murine embryos shows that Snail is expressed in extraembryonic tissues and embryonic mesoderm, in mesenchymal cells of lungs and dermis as well as in cartilage. Little reactivity was detected in adult tissues as Snail was not constitutively expressed in most mesenchymal cells. However, Snail expression was observed in activated fibroblasts involved in wound healing in mice skin. Moreover, Snail was detected in pathological conditions causing hyperstimulation of fibroblasts, such as fibromatosis. Analysis of Snail expression in tumors revealed that it was highly expressed in sarcomas and fibrosarcomas. In epithelial tumors, it presented a more limited distribution, restricted to stromal cells placed in the vicinity of the tumor and to tumoral cells in the same areas. These results demonstrate that Snail is present in activated mesenchymal cells, indicate its relevance in the communication between tumor and stroma and suggest that it can promote the conversion of carcinoma cells to stromal cells.

Molecular pathology of endometrial carcinoma: transcriptional signature in endometrioid tumors.

A dualistic model, which has been established on a morphological basis and that differentiates type I endometrioid from type II non-endometrioid endometrial cancer, is widely accepted. Molecular genetics have provided us with data supporting the dualistic model of endometrial tumorigenesis and with some clues to speculate about the sequence of the molecular alterations defining the tumorigenesis pathways. In type I endometrioid endometrial cancer, PTEN gene silencing, microsatellite instability associated with defects in DNA mismatch repair genes, or mutations in the K-ras gene are the known major alterations defining the progression from normal endometrium to hyperplasia and then on to carcinoma. Recently, cDNA microarray technology for identifying the differences in gene expression patterns between the histological types of endometrial cancer have permitted the identification of differentially expressed genes that could help us to understand differences in the biology and the clinical outcome between histiotypes. Genes involved in the mitotic checkpoint as a major mechanism of carcinogenesis in non-endometrioid endometrial cancer, or altered genes associated with the initial steps of myometrial infiltration in endometrioid endometrial cancer, represent examples of how useful large genetic screenings can be for understanding the tumorigenesis process and the future directions in the molecular pathogenesis of endometrial cancer.

Papel del Helicobacter pylori en el cáncer gástrico tras gastrectomía parcial por úlcera benigna / Role of Helicobacter pylori in stomach cancer after partial gastrectomy for benign ulcer disease

Objetivo: determinar la prevalencia de la infección por Helicobacter pylori en pacientes gastrectomizados por enfermedad no neoplásica, y que han desarrollado posteriormente cáncer gástrico. Material y métodos: estudio retrospectivo con reclutamiento de todos los pacientes con gastrectomía parcial por enfermedad péptica benigna que han sido sometidos a una exploración endoscópica entre 1995-2001. Se ha realizado una comparación de las principales características clínicas e histológicas y de la presencia de Helicobacter pylori en los pacientes con y sin cáncer del remanente gástrico. Resultados: se han estudiado un total de 73 pacientes en este periodo. Se han encontrado 15 pacientes (20,5%) con cáncer en el remanente gástrico, 14 adenocarcinomas (71% tipo intestinal y 29% tipo difuso) y un linfoma. El tiempo transcurrido entre el diagnóstico de cáncer gástrico y la gastrectomía previa ha sido de 32 (14-48) años. Se ha detectado un alto porcentaje de infecciónpor Helicobacter pylori (100% en los pacientes con cáncervs. 81,5% en los pacientes sin cáncer, p < 0,07). No se ha observado relación entre el tipo de reconstrucción gástrica (Billroth I o II) y el porcentaje de infección por Helicobacter pylori. Conclusiones: la infección por Helicobacter pylori es frecuente en pacientes gastrectomizados por patología benigna. Los resultados de este estudio sugieren que la infección por Helicobacter pylori podría jugar un papel en el cáncer gástrico

Objective: to determine the prevalence of Helicobacter pylori infection in patients having undergone gastrectomy for nonneoplastic disease who later developed gastric stump cancer. Material and methods: retrospective study of all patients with partial gastrectomy for non-malignant peptic disease who were submitted to an endoscopic exploration between 1995 and 2001. A comparison was made of major clinical and histological characteristics, and the presence of Helicobacter pylori among patients with and without gastric cancer in the stomach remnant. Results: a total of 73 patients were studied in this period. Fifteen patients (20.5%) had remnant-stump gastric cancer. All but one were adenocarcinomas (71% intestinal and 29% diffuse, respectively). The average time between diagnosis of gastric cancer and previous gastrectomy was 32 (14-48) years. There was a higher detection rate of Helicobacter pylori in patients with cancer in the gastric remnant (100 vs. 81.5%, respectively, p <0.07). No relationship was seen between type of gastric reconstruction (Billroth I or II) and rate of Helicobacter pylori detection. Conclusions: Helicobacter pylori infection is frequent in patients with previous gastrectomy for non-neoplastic disease. The results of the study suggest that Helicobacter pylori infection may play a role in gastric stump cancer

beta-Catenin, Nf-kappaB and FAS protein expression are independent events in head and neck cancer: study of their association with clinical parameters.

In spite of much effort, no good markers have yet been found for predicting prognosis or response to therapy in advanced head and neck squamous cell carcinoma (HNSCCs) patients. beta-catenin, a protein involved in the cytoskeleton, cell-cell adhesion and gene transcription, is a factor associated with tumour progression. Recently, an interaction has been reported between beta-catenin, and NF-kappaB coupled with an inverse association of beta-catenin, and FAS (CD95/APO-1) protein expression in breast and colorectal tumours. To confirm these observations and to test their clinical impact in HNSCCs we have evaluated the expression of beta-catenin, NF-kappaB and FAS proteins. We used tissue microarrays to simultaneously analyse the levels of these proteins immunohistochemically in 118 HNSCCs. Among the 113 tumours evaluable for beta-catenin, increased and decreased levels were detected in 41 (36%) and 62 (55%) of the tumours, respectively. beta-catenin, protein staining was mainly membranous but 10 tumours (9%) showed the clear presence of protein in the cytoplasm, and none in the nucleus. Moreover, 81% of the tumours had decreased FAS protein expression, indicating that loss of FAS protein is a common feature of HNSCCs. Abnormal or nuclear NF-kappaB staining was observed in 24% of the tumours. No association was detected between the expression levels of the proteins evaluated. Regarding clinical associations, tumours from the hypopharynx had significantly lower levels of beta-catenin expression than those from other locations (P<0.05). Moreover, our data revealed that patients whose tumours had low levels of beta-catenin protein expression had decreased survival probability (24.8 months vs. NR, P=0.03) and reduced response to therapy (15.4 vs. 43 months; P=0.01) compared with patients whose tumours had high levels of beta-catenin. Taken together, our observations indicate that beta-catenin, NF-kappaB and FAS expression are independent events during HNSCC development and that levels of beta-catenin protein may identify subsets of advanced HNSCCs patients with different prognosis and response to therapy capabilities.

Adenofibroma papilar del endocérvix / Endocervical papillary adenofibroma

Los pólipos endocervicales son muy frecuentes y no presentan dificultades de tratamiento clínico ni diagnóstico anatomopatológico. Algunas lesiones pueden presentarse como pólipos sin realmente serlo, y plantean problemas de diagnóstico diferencial y manejo clínico. Entre ellos el adenofibroma papilar, que puede presentarse en el endocérvix o en el endometrio, plantea su diagnóstico diferencial con sus variantes malignas, los adenosarcomas, que aunque son benignos pueden recidivar y comportar histerectomía. Los adenofibromas polipoides pueden presentarse en mujeres adultas a cualquier edad, y los pólipos tienden a ser de mayor tamaño que los pólipos convencionales. En el endometrio pueden presentar además una forma difusa. El tratamiento es siempre quirúrgico

Endocervical polyps are very frequent and histologically are conventional polyps. However, some of the cervical polyps can be other lesions that show benign histological features other than conventional polyps, may relapse and can present some diagnostic differential problems for the pathologist. The present case in an endocervical papillary adenofibroma that was excised as a conventional polyp of an asymptomatic woman. The review of the literature is made

Prenatal exposure to arecoline (areca nut alkaloid) and birth outcomes.

The betel nut is commonly used as a drug by Asian populations. A high prevalence of adverse pregnancy outcomes has been reported in women who chewed betel quid during gestation. The hypothesis that chronic exposure of the fetus to arecoline (the principal alkaloid of the areca nut) is the cause was investigated in a clinical observational study on six newborns from Asian mothers who chewed betel nut during pregnancy.