Hyperplastic polyposis - Association with colorectal cancer

Hyperplastic polyposis is a loosely defined syndrome initially thought not to confer a clinically important predisposition to colorectal cancer. The aim of the current study was to examine the clinical, histologic, and molecular features of a prospective series of cases meeting a strict definition of the condition. Twelve patients were identified, seven of whom had developed colorectal cancer. Most polyps were hyperplastic, but 11 patients also had polyps containing dysplasia as either serrated adenomas. mixed polyps, or traditional adenomas. The mean percentage of dysplastic polyps in patients with cancer was 35%, and in patients without cancer, 11%(p < 0.05). Microsatellite instability (MSI) was present in 3 of 47 hyperplastic polyps and two of right serrated adenomas. Kras was mutated in 8 of 47 hyperplastic polyps and two of eight serrated adenomas. No polyps showed loss of heterozygosity of chromosomes 5q, 1p, or 18q. Two of seven cancers showed a high level of MSI. It is concluded that hyperplastic polyposis is associated with a high risk of colorectal cancer. Hyperplastic polyps are the dominant type of polyp, but most cases have some dysplastic epithelium. A higher proportion of dysplastic polyps is associated with increased cancer risk. Clonal generic changes are observed in some hyperplastic polyps and serrated adenomas.

Hyperplastic polyps of the colorectum - Innocent or guilty?

Hyperplastic polyps have traditionally been regarded as nonneoplastic polyps lacking malignant potential. The demonstration of genetic alterations within these lesions indicates an underlying neoplastic cause. There is evidence that hyperplastic polyps are heterogeneous. Most are innocuous, but subsets may have malignant potential. Risk factors for neoplastic progression include multiple, large, and proximally located polyps. Aberrant methylation resulting in the silencing of cancer genes may be an important underlying mechanism, particularly in pathways progressing to tumors with DNA microsatellite instability. Lesions intermediate between hyperplastic polyp and cancer include admired polyps and serrated adenomas. Currently, pathologists have different thresholds for diagnosing serrated adenomas, including the distinction from large hyperplastic polyps. Reasons for over looking this pathway in the past may include rapid tumor progression and the fact that proximally located hyperplastic polyps may be flat and not especially numerous. Management of the serrated pathway of colorectal neoplasia may require novel approaches to screening, early detection, and prevention.

Serrated adenoma of the colorectum

An understanding of the pathology and natural history of serrated adenoma of the colorectum has emerged slowly and comparatively recently. In this review, hyperplastic polyps, admixed polyps and serrated adenomas are conceived as a continuum of serrated polyps. Mechanisms underlying the expression of serrated morphology are outlined. The demographic, macroscopic and microscopic features of serrated adenoma are presented but it is stressed that the distinction from other epithelial polyps may not always be straightforward. Molecular studies point to heterogeneity within the serrated pathway and among conditions encompassed by the term serrated polyposis. Management of serrated adenoma is discussed but the need for further research is emphasized. The importance of serrated adenoma as a precancerous lesion has been underestimated. © 2002 Elsevier Science Ltd.

Evolution of colorectal cancer: Change of pace and change of direction

This review compiles evidence for an alternative to the classical adenoma-carcinoma sequence in the evolution of colorectal cancer. It is suggested that between 30 and 50% of colorectal cancers are not initiated by mutation of the tumor suppressor gene APC, but through the epigenetic silencing of genes implicated in the control of differentiation, cell cycle control and DNA repair proficiency. The precursor polyps are often characterized by a serrated architecture, and include hyperplastic polyps, admixed polyps and serrated adenomas. The alternative pathway is heterogeneous and may culminate in cancers showing low or high level DNA microsatellite instability (MSI-L and MSI-H, respectively), and in cancers that are microsatellite stable (MSS). Cancers showing DNA MSI may be characterized by an accelerated evolution. Cancers in hereditary non-polyposis colorectal cancer show features of both classical (adenoma and APC mutation) and alternative pathways (rapid evolution, MSI-H and lack of chromosomal instability). (C) 2001 Blackwell Science Asia Pty Ltd.

Expression of cyclooxygenase enzymes and prostaglandin E2 receptors in inflammatory airway diseases

Dissertação para obtenção do Grau de Mestre em Genética Molecular e Biomedicina

Case Report of Malignant Endometrial Polyps

The aims of this retrospective review were to determine the frequency of malignant endometrial polyps diagnosed with ambulatory hysteroscopy in the Obstetrics/Gynaecology Department of HDE, Lisbon, between January 2001 and December 2005 and to characterize these cases according to risk factors, sonographic and endoscopic findings tumoral histology, and tumor stage.We found seven cases of malignant endometrial polyps in a total of 1333 polyps initially diagnosed: an incidence rate of 0. 53%. These seven patients had a mean age of 68 years (55–82 years), and all were postmenopausal, with five having one risk factor each for endometrial cancer. Metrorrhagia was present in six of the seven patients(85.7%). Ultrasonography was abnormal in all seven patients, with a mean endometrial thickness of 26 mm(range: 12–44 mm). The hysteroscopy images suggested malignancy in all cases. All except one patient had a single polyp. The polyps had volumes between 1.5 and 3 cm; two were removed completely and five were biopsed. The histological subtype was: mixed endometrioid/serous papillary or clear cell (2), adenocarcinoma with squamous differentiation (2), carcinosarcoma (2), and clear cell carcinoma (1). Malignancy inside polyps is rare, but diagnostic hysteroscopy with visual guided biopsies can identify these cases in the earlier stages. The risk factors are not different from those of other endometrial carcinomas, but the histological subtype seems to point to more aggressive cancers.

Office Hysteroscopy After Ultrasonographic Diagnosis of Thickened Endometrium in Postmenopausal Patients

The aim of our study was to access office hysteroscopy results in postmenopausal patients with thickened endometrium. A retrospective descriptive study was carried out on 245 postmenopausal patients submitted to office hysteroscopy after sonographic diagnosis of thickened endometriumin 20 consecutive months.Women were evaluated for age, hormonal therapy, hysteroscopic findings, procedure duration, complications and associated pain, and histological diagnosis. Patients with and without uterine bleeding were considered separately. Symptomatic patients were older and had longer procedure duration. The most frequent hysteroscopic finding was endometrial polyp in both groups. Pain was subjectively assessed in a numeric scale from 0 to 10 and median value was 4. There were no complications reported. Global neoplasia rate was 2.9% for asymptomatic patients and 16.4% for symptomatic ones (p<0.05). Thickened endometrium with postmenopausal metrorrhagia gave patients a significantly higher risk for neoplasia and hyperplasia.

Catalytic core of a membrane-associated eukaryotic polyphosphate polymerase.

Polyphosphate (polyP) occurs ubiquitously in cells, but its functions are poorly understood and its synthesis has only been characterized in bacteria. Using x-ray crystallography, we identified a eukaryotic polyphosphate polymerase within the membrane-integral vacuolar transporter chaperone (VTC) complex. A 2.6 angstrom crystal structure of the catalytic domain grown in the presence of adenosine triphosphate (ATP) reveals polyP winding through a tunnel-shaped pocket. Nucleotide- and phosphate-bound structures suggest that the enzyme functions by metal-assisted cleavage of the ATP gamma-phosphate, which is then in-line transferred to an acceptor phosphate to form polyP chains. Mutational analysis of the transmembrane domain indicates that VTC may integrate cytoplasmic polymer synthesis with polyP membrane translocation. Identification of the polyP-synthesizing enzyme opens the way to determine the functions of polyP in lower eukaryotes.

Contrast ultrasound: a simple-to-use phase-shifting medium offers saline infusion sonography-like images.

OBJECTIVE: To test the ability of a novel phase-shifting medium (PSM) to provide sustained distension of the uterine cavity and produce saline infusion sonography (SIS)-like images in a simplified contrast ultrasound procedure. DESIGN: Prospective pilot feasibility trial of a new diagnostic procedure, contrast ultrasound. SETTING: Clinical reproductive endocrine and infertility unit of regional teaching hospital. PATIENT(S): Twenty-six asymptomatic infertile women (group I) and 27 women presenting with dysfunctional uterine bleeding (DUB) who were scheduled for exploratory surgery (group II). INTERVENTION(S): All women who were temporarily on oral contraceptive first had a regular pelvic ultrasound followed by the intrauterine instillation of up to 3 mL PSM, using a regular insemination catheter, after which all instruments were removed and a regular ultrasound was performed again. RESULT(S): In all 53 women, intrauterine instillation of 1-3 mL PSM resulted in a 3-7 mm uterine distension, sufficient to produce SIS-like images of the uterine cavity that lasted 7-10 min. Contrast ultrasound revealed an endometrial polyp in 3 asymptomatic women of group I. In group II. 12 of 14 women (86%) whose vaginal ultrasound were positive or dubious had positive findings with contrast ultrasound; 9 of 12 patients whose vaginal ultrasounds were negative also had positive contrast ultrasound findings. All the positive and negative findings of contrast ultrasound made in group II were confirmed anatomically (sensitivity and specificity of 100%), whereas the correlation for standard vaginal ultrasound was markedly lower at 57.1% and 85.7%, respectively. Most patients (46 of 53) reported no discomfort during or after the procedure, and 7 women described the procedure as mildly uncomfortable. CONCLUSION(S): Contrast ultrasound, a novel simple diagnostic procedure conducted after intrauterine instillation of 1-3 mL PSM using a simple plastic catheter, delivered SIS-quality images in asymptomatic (group I) and symptomatic (group II) patients while retaining the simplicity of standard ultrasound. We therefore foresee broad application of contrast ultrasound for sensitive and specific assessment for uterine pathologies in the physician's office.

Role and regulation of polyphosphate in leishmania parasites

Le protozoaire unicellulaire Leishmania est l'agent responsable de la leishmaniose, une maladie parasitaire humaine qui se manifeste par des lésions de la peau, se résolvant le plus souvent spontanément, jusqu'à des lésions viscérales fatales. Le parasite est transmis de l'insecte à l'hôte mammifère lors d'un repas sanguin de la mouche des sables et y réside respectivement sous formes extra- et intracellulaires. On estime que cette maladie touche environ 12 millions de personnes dans 98 pays. Etant donné que les médicaments disponibles à ce jour sont faiblement efficaces et/ou hautement toxiques, il est indispensable de consolider les connaissances sur le fonctionnement et la survie du parasite pour pouvoir développer de nouvelles stratégies de traitements et de préventions. Tous les organismes vivants, dont Leishmania, contiennent du polyphopshate (polyP). Cette molécule chargée négativement est constituée de trois jusqu'à plusieurs centaines de résidus de phosphates reliées par des liaisons à haute énergie. Le polyP sert donc de source d'énergie et de réservoir de phosphate; dans certaines espèces, il joue aussi un rôle dans l'adaptation au stress et la virulence de pathogènes. Ceci nous a amené à étudier le rôle du polyP dans le parasite Leishmania. L'enzyme responsable de la synthèse de polyP a été identifié récemment dans la levure : il s'agit de la chaperone de transport vacuolaire 4 (Vtc4). Nous avons identifié un homologue de Vtc4 chez les Trypanosomatidae, et avons donc décidé d'examiner sa fonction dans le métabolisme du polyP chez Leishmania. En éliminant l'expression de Vtc4 chez L. major et L. guyanensis, nous avons pu démontrer qu'il est indispensable pour la production de polyP chez Leishmania. De plus, nous avons constaté que ces parasites possèdent des chaînes de polyP allant de trois jusqu'à environ 300 résidus de phosphate. Le taux de polyP dans la cellule est précisément régulé et varie entre un très haut niveau durant la phase proliférative des promastigotes à un niveau bas en phase stationnaire tardive, alors que l'expression de Vtc4p reste stable. Dans les amastigotes intracellulaires, seulement des petites quantités de polyP et de Vtc4p sont détectées. En outre, l'absence de Vc4p et de polyP n'a pas d'effet significatif sur les infections in vivo de souris, ce qui indique que le polyP n'est pas nécessaire au développement de la leishmaniose. Ceci suggère que Vtc4p n 'est pas une bonne cible pour le développement de nouveaux traitements contre Leishmania. "Néanmoins, la présence du polyP favorise fortement la survie du parasite suite à un choc de température (37°C) et aide ainsi à sa persistance intracellulaire pendant les premiers jours d'infection de macrophages. En résumé, nos résultats indiquent que si le polyP a peu d'importance pendant l'infection et le développement de la leishmaniose chez la souris, il est par contre crucial pour l'adaptation à des situations de stress comme l'augmentation de la température. Le fait que le polyP a été conservé dans tous les organismes durant l'évolution suggère toutefois que cette molécule joue un rôle fondamental. Etant donné que l'absence de polyP n'a pas d'effet sur la survie des amastigotes, il pourrait être plus important dans la forme promastigote infectant la mouche des sables. - The unicellular protozoan parasite Leishmania is the causative agent of the human disease leishmaniasis, which can range from self-healing skin lesions to fatal visceral lesions. The parasite is transmitted from the insect vector to the mammalian host when the sand fly takes its blood meal and exists in an extra- and an intracellular form, respectively. The disease is estimated to affect 12 million people in 98 countries and currently available drug treatments are of relatively low potency and/or high toxicity. Thus, investigating parasite survival mechanisms and parasite adaptation to the two host environments contributes to the general understanding of Leishmania propagation and might therefore help to develop future treatments or preventions. All living cells, including Leishmania, contain a negatively charged polymer of a few up to several hundred phosphate residues. These so-called polyphosphates (polyPs) serve as an energy source and phosphate reservoir. In some organisms, polyP is also involved in adaptation to stresses and virulence of pathogens. Therefore we were interested in investigating the importance of polyP in Leishmania parasites. Recently, an eukaryotic enzyme responsible for polyP synthesis has been identified as the vacuolar transporter chaperone 4 (Vtc4) in yeast. We, and others, found a Vtc4 homologue in trypanosomatids and decided to examine its potential function in polyP metabolism. By generating VTC4 knock-out cell lines in L. major and Vtc4 knock-down cell lines in L. guyanensis, we were able to demonstrate that Vtc4p is responsible for the total amount of cellular polyP. We also observed that Leishmania polyP chain length ranges from a few up to around 300 residues and that its level is tightly regulated. PolyP abundance is highest during the logarithmic proliferating phase of promastigotes and decreases in the stationary phase, while Vtc4 protein expression remains stable during both phases. In the intracellular amastigote form, only low amounts of polyP and Vtc4p were detectable. Furthermore, absence of Vtc4p and polyP did not have a significant effect on in vivo mouse infections, indicating that polyP is not necessary for Leishmania disease progression. This suggests that Vtc4p would be a poor drug target against Leishmania infection. However, presence of the polymer strongly supported parasite survival during heat shock (37°C) and thereby promoted intracellular persistence during the first days of macrophage infections. Taken together, we found that polyP has little importance in Leishmania {in vivo) infection but that it plays a crucial role during adaptation to stress, such as heat shock. Given that polyP has been preciously conserved in all organisms during evolution it seems to play a fundamental role. Since absence of polyP does not affect amastigote survival, it might be significant for promastigote existence in the sand fly vector.

Non steroidal anti-inflammatory drugs and COX-2 inhibitors as anti-cancer therapeutics: hypes, hopes and reality.

Non-steroidal anti-inflammatory drugs (NSAIDs) and specific inhibitors of cyclooxygenase (COX)-2, are therapeutic groups widely used for the treatment of pain, inflammation and fever. There is growing experimental and clinical evidence indicating NSAIDs and COX-2 inhibitors also have anti-cancer activity. Epidemiological studies have shown that regular use of Aspirin and other NSAIDs reduces the risk of developing cancer, in particular of the colon. Molecular pathology studies have revealed that COX-2 is expressed by cancer cells and cells of the tumor stroma during tumor progression and in response to chemotherapy or radiotherapy. Experimental studies have demonstrated that COX-2 over expression promotes tumorigenesis, and that NSAIDs and COX-2 inhibitors suppress tumorigenesis and tumor progression. Clinical trials have shown that NSAIDs and COX-2 inhibitors suppress colon polyp formation and malignant progression in patients with familial adenomatous polyposis (FAP) syndrome. Recent advances in the understanding of the cellular and molecular mechanisms of the anti-cancer effects of NSAIDs and COX-2 inhibitors have demonstrated that these drugs target both tumor cells and the tumor vasculature. The therapeutic benefits of COX-2 inhibitors in the treatment of human cancer in combination with chemotherapy or radiotherapy are currently being tested in clinical trials. In this article we will review recent advances in the understanding of the anti-tumor mechanisms of these drugs and discuss their potential application in clinical oncology.

Polypes et cancers colo-rectaux par sous-localisation: données épidémiologiques genevoises et vaudoises [Colorectal polyps and cancers by sub-site: epidemiologic findings in Geneva and Vaud].

The present study is a comparative analysis of the adenomatous polyps and colorectal cancers, registered during a determined period within the population of the cantons of Geneva and Vaud. The analysis is particularly based on the polyp/cancer ratio by sub-site. Histological type as well as age and sex of the patient are taken into consideration.

Coupled synthesis and translocation restrains polyphosphate to acidocalcisome-like vacuoles and prevents its toxicity.

Eukaryotes contain inorganic polyphosphate (polyP) and acidocalcisomes, which sequester polyP and store amino acids and divalent cations. Why polyP is sequestered in dedicated organelles is not known. We show that polyP produced in the cytosol of yeast becomes toxic. Reconstitution of polyP translocation with purified vacuoles, the acidocalcisomes of yeast, shows that cytosolic polyP cannot be imported, whereas polyP produced by the vacuolar transporter chaperone (VTC) complex, an endogenous vacuolar polyP polymerase, is efficiently imported and does not interfere with growth. PolyP synthesis and import require an electrochemical gradient, probably as a driving force for polyP translocation. VTC exposes its catalytic domain to the cytosol and carries nine vacuolar transmembrane domains. Mutations in the VTC transmembrane regions, which are likely to constitute the translocation channel, block not only polyP translocation but also synthesis. Given that they are far from the cytosolic catalytic domain of VTC, this suggests that the VTC complex obligatorily couples synthesis of polyP to its import in order to avoid toxic intermediates in the cytosol. Sequestration of otherwise toxic polyP might be one reason for the existence of acidocalcisomes in eukaryotes.

Mometasone and desloratadine additive effect on eosinophil survival and cytokine secretion from epithelial cells

Although antihistamines and topical corticosteroids are used in combination to treat allergic rhinitis, their additive effect has not been yet demonstrated. The aim was investigate the antiinflammatory additive effect of mometasone and desloratadine on cytokine and sICAM-1 secretion by epithelial cells, and on eosinophil survival stimulated by human epithelial cells secretions from nasal mucosa and polyps. Methods Epithelial cells obtained from nasal mucosa or polyps were stimulated with 10% fetal bovine serum in presence of mometasone (10-11M-10-5M) with/without desloratadine (10-5M). Cytokine and sICAM-1 concentrations in supernatants were measured by ELISA. Peripheral blood eosinophils were incubated during 4 days with epithelial cell secretions with (10-11M-10-5M) and/or desloratadine (10-5M) and survival assessed by Trypan blue. Results are expressed as percentage (mean ± SEM) compared to control. Results Fetal bovine serum stimulated IL-6, IL-8, GM-CSF and sICAM-1 secretion. In mucosa and polyp epithelial cells, mometasone inhibited this induced secretion while desloratadine inhibited IL-6 and IL-8. The combination of 10-5M desloratadine and 10-9M mometasone reduced IL-6 secretion (48 ± 11%, p < 0.05) greater extent than mometasone alone (68 ± 10%) compared to control (100%). Epithelial cell secretions induced eosinophil survival from day 1 to 4, this effect being inhibited by mometasone. At day 4, the combination of mometasone (10-11M) and desloratadine (10-5M) provoked an increased inhibition of eosinophil survival induced by cell secretions (27 ± 5%, p < 0.01) than mometasone (44 ± 7%) or desloratadine (46 ± 7%) alone. Conclusions These results suggest that the combination of desloratadine and mometasone furoate have a greater antinflammatory effect in an in vitro model of eosinophil inflammation than those drugs administered alone.