Le syndrome de Lynch est une affection héréditaire autosomique dominante due à des mutations constitutionnelles des gènes du système de réparation de l'ADN (MLH1, MSH2 et MSH6). Depuis 20 ans le réseau français des laboratoires impliqués dans le syndrome de Lynch a identifié un total de 6687 variants. Sept cent sept d'entre eux, essentiellement des variants faux sens, restent encore des variants de signification inconnue (VSI), sans utilité pour le conseil génétique. Le but de notre étude était de développer un algorithme permettant de classer les variants de signification inconnue. Les critères utilisés étaient les données des analyses in silico, phénotypiques (ségrégation, critères d'Amsterdam), l'état de la fonction MMR (MisMatch Repair) dans les cellules tumorales, les tests fonctionnels et d'épissage, ainsi que les données publiées. Cet algorithme a été appliqué à l'ensemble des VSI de la base de données française et nous a permis de caractériser 370 variants . Les données ont été intégrées dans la base de données française UMD des gènes MMR afin d'être disponibles pour la communauté scientifique. Grace aux données collectées par le réseau, nous avons également pu caractériser le phénotype du syndrome de Lynch. Nous avons ainsi confirmé que le cancer du sein ne fait pas partie du spectre du syndrome de Lynch et que les formes de ce syndrome associées à une mutation du gène EPCAM n'entrainent qu'un risque très faible de cancers de l'endomètre, permettant ainsi d'adapter les recommandations de suivi dans cette situation.de l'endomètre, permettant ainsi d'adapter les recommandations de suivi dans cette situation. / Lynch syndrome is a frequent cancer predisposition with an autosomal dominant mode of inheritance and caused by heterozygous germ line mutations in one of the major DNA mismatch repair (MMR) genes (MLH1, MSH2 and MSH6). For 20 years, the French laboratories network involved in Lynch syndrome identified a total of 6687 variations. Among them, 707, mainly missense variations, remained variants of uncertain significance (VUS), thus could not be used for reliable genetic counseling. The aim of our study was to develop an algorithm able to classify VUS, according to the international consensus (IARC). This algorithm was constructed based on criteria usually required for genetic characterization such as in silico analysis, phenotypical data (segregation, Amsterdam criteria's), MMR status in tumor cells, functional assays, splicing analyses and published data. Data were registered in the French database. As a result of this work, we were able to classify 370 variants of the 707 (52,3%). As part of this work, we also analyzed phenotypical data of patients with Lynch syndrome and showed that breast cancer can definitively be excluded from the spectrum of Lynch-related cancers, and that EPCAM mutations, which may lead to Lynch syndrome, are associated with a very low incidence of endometrial cancer and have probably to be considered as an allelic disease with specific clinical recommendations.

<p>Oral 111-Indium-DTPA colonic scintigraphy was used to assess segmental transit in 23 patients with slow transit constipation (STC) and 13 controls. The transit time did not differ between patients and controls in the right colon, whereas the patients had a consistent delay from the transverse colon and distally (<i>P</i><0.05–0.001). Two individual patients had a delay in the right colon.</p><p>Twenty-eight patients underwent a left- (n=26) or a right (n=2) hemicolectomy for STC, after evaluation including colonic scintigraphy. Twenty-three patients (80%) were satisfied with the outcome after a median of 50 months. The median stool frequency increased from one to seven per week (<i>P</i><0.001). The number of patients with bloating, excessive straining and painful defecation decreased (<i>P</i><0.05). The laxative use decreased (<i>P</i><0.01) and faecal continence was unchanged. A blunted rectal sensation correlated to a poor outcome.</p><p>Fifty constipated patients with slow colonic transit and 28 controls were investigated with anorectal manovolumetry. Anal resting pressure was lower (<i>P</i><0.05), and squeeze pressure tended to be lower (<i>P</i>=0.09) in patients. Rectal sensation was not different between groups, although ten patients had a threshold for filling sensation above the 95^th percentile of controls. The rectal compliance was increased in patients (<i>P</i><0.05–0.01).</p><p>Total and segmental colonic transit was assessed with radio-opaque marker study and scintigraphy in 35 constipated patients, and related to normal values. Twenty-seven of 31 female patients had a prolonged total transit time on marker study, and 26 on scintigraphy. Of those 31 patients, 29 had prolonged segmental transit only in one or two segments on marker study. The two methods gave a similar result, except in the descending colon (<i>P</i><0.05). However, the results varied considerably for individual patients.</p><p>In conclusion, patients with STC often benefit from a segmental colonic resection, following assessment including scintigraphy. Anorectal physiology testing may predict surgical results.</p>

Oral 111-Indium-DTPA colonic scintigraphy was used to assess segmental transit in 23 patients with slow transit constipation (STC) and 13 controls. The transit time did not differ between patients and controls in the right colon, whereas the patients had a consistent delay from the transverse colon and distally (P&lt;0.05–0.001). Two individual patients had a delay in the right colon. Twenty-eight patients underwent a left- (n=26) or a right (n=2) hemicolectomy for STC, after evaluation including colonic scintigraphy. Twenty-three patients (80%) were satisfied with the outcome after a median of 50 months. The median stool frequency increased from one to seven per week (P&lt;0.001). The number of patients with bloating, excessive straining and painful defecation decreased (P&lt;0.05). The laxative use decreased (P&lt;0.01) and faecal continence was unchanged. A blunted rectal sensation correlated to a poor outcome. Fifty constipated patients with slow colonic transit and 28 controls were investigated with anorectal manovolumetry. Anal resting pressure was lower (P&lt;0.05), and squeeze pressure tended to be lower (P=0.09) in patients. Rectal sensation was not different between groups, although ten patients had a threshold for filling sensation above the 95th percentile of controls. The rectal compliance was increased in patients (P&lt;0.05–0.01). Total and segmental colonic transit was assessed with radio-opaque marker study and scintigraphy in 35 constipated patients, and related to normal values. Twenty-seven of 31 female patients had a prolonged total transit time on marker study, and 26 on scintigraphy. Of those 31 patients, 29 had prolonged segmental transit only in one or two segments on marker study. The two methods gave a similar result, except in the descending colon (P&lt;0.05). However, the results varied considerably for individual patients. In conclusion, patients with STC often benefit from a segmental colonic resection, following assessment including scintigraphy. Anorectal physiology testing may predict surgical results.

No description available.

Background: Rectal cancer 5-year survival has increased from 58% of those diagnosed in 1987-1989 to 68% of those diagnosed in 2003-2009. Rectal cancer patients commonly receive one of two surgical treatments: permanent ostomy (a resection of tumor following by a stoma) or anastomosis (a resection followed by a reconnection with or without a prior temporary ostomy). The multifaceted consequences of both types of surgery potentially can affect both long-term psychological well-being and financial concerns of patients and their families. The overall goal of this dissertation is to increase the understanding of the impact of depression on the quality of life of rectal cancer survivors. Methods: The research data were based on a quality of life survey conducted in 2010-2011 among long-term survivors (≥ 5 years post-diagnosis) of rectal cancer. Participants were identified through the Kaiser Permanente (KP) health systems in Northern California and Southwest Washington/Oregon. Data included both the 2010/2011 survey data and KP electronic medical records (EMRs). Results: 1) The 24.7% prevalence of self-reported current depression among long-term rectal survivors was observed with a higher prevalence of 31% among those with permanent ostomies. Although average perceived financial burden level was low in this population of insured cancer survivors, 20% still reported moderate-to-high burden. Perceived financial burden was especially high among those who recalled having depression immediately after surgery and reported depression at the time of survey.2) All self-reported measures showed low sensitivity varying from 26% to 56% and high specificity from 77% to 82.7% against either diagnostic scheme from EMRs. Using either diagnostic scheme, the MCS-12 measure, a Mental Composite Summary (MCS) score from the 12-item Short-Form Health Survey with a cut-off point of≤45.6 for a self-reported depression, performed better as compared to the other two self-reported measures. 3) Approximately one in six rectal cancer survivors experienced depression after their surgery of sufficient severity to result in a depression diagnosis. Among survivors with recurrent depression diagnoses, those with a permanent ostomy reported significantly lower psychological well-being than those with an anastomosis. Conclusions: Depression burden is elevated after receiving surgery and remains a problem long after cancer diagnosis and treatment. Types of rectal cancer surgery received and gender of survivors may complicate the extent of depression burden. Among long-term rectal cancer survivors, having depression is associated with higher perceived financial burden. Chronic or recurrent course of depression may exist in this group of rectal cancer survivors and has significant impact on long-term psychological well-being. Self-reported measures for depression, such as MCS-12 measure with a cutoff point≤45.6, have the potential to be utilized for epidemiological studies when common screening instruments, electronic medical records, or administrative databases are not available. Implications: These findings underline the significance of depression assessments after surgery for this population of rectal cancer survivors and the importance of symptoms monitoring throughout the cancer survivorship continuum. Depressive symptoms should be monitored and managed as early as after cancer diagnosis and surgery to optimize survivors' long-term emotional well-being. In addition, depression screening and treatment as well as discussion of financial issues may have important roles in long-term survivorship care planning, particularly for those with permanent ostomies.

No description available.

Perspektyvinio atsitiktinių imčių tyrimo tikslas – palyginti II–III stadijos rezektabilaus tiesiosios žarnos vėžio chirurginio gydymo rezultatus po priešoperacinės smulkiafrakcijinės spindulinės terapijos ir chemoterapijos ar priešoperacinės stambiafrakcijinės spindulinės terapijos. Darbo uždaviniai: 1. Atlikti sisteminės literatūros apžvalgos metu gautų duomenų matematinę analizę, tikslu palyginti smulkiafrakcijinės spindulinės tarapijos su chemoterapija ir stambiafrakcijinės spindulinės terapijos poveikį ir galimus skirtumus. 2. Nustatyti ir palyginti radikalių operacijų dažnį chST ir tST grupėse. 3. Nustatyti ar chemospindulinis gydymas padidina sfinkterį išsaugančių operacijų dažnį lyginant su stambiafrakcijine spinduline terapija ir atidėtu chirurginiu gydymu. 4. Nustatyti kaip taikytas priešoperacinis gydymas įtakojo artimuosius pooperacinius rezultatus, palyginti komplikacijų dažnį tiriamosiose grupėse. 5. Nustatyti ir palyginti histologinio „pilno pasveikimo“ ir „stadijos sumažėjimo“ (downstaging) dažnį abejose grupėse. 6. Įvertinti priešoperacinio chemospindulinio gydymo ir stambiafrakcijinės spindulinės terapijos įtaką bendram limfmazgių skaičių preparate ir metastatinių limfmazgių skaičių randamų pašalintame tiesiosios žarnos preparate. Grupės: 1. smulkiafrakcijinės spindulinės terapijos (50Gy) ir chemoterapijos 5-Fu/Lv (po 6–7 sav. operacinis gydymas). 2. stambiafrakcijinės spindulinės terapijos (5x5Gy, per 5 dienas, po 6–7 sav. operacija). Įtraukimo... [toliau žr. visą tekstą] / The aim of the randomized controlled trial was to compare the results of two different treatment options for stage II and III resectable rectal cancer: preoperative chemoradiotherapy and short term radiotherapy with delayed surgery (6 weeks). The objectives of the study were as follows: 1. to perform systematic literature review and meta-analysis comparing preoperative chemoradiotherapy with short-term radiotherapy 2. to compare radical resection rates between the groups; 3. to compare sphincter saving procedure rates; 4. to compare morbidity and mortality rates; 5. to evaluate the rates of downstaging and the rates of complete response; 6. to assess the role of preoperative treatment on the number of lymph nodes and the number of metastatic lymph nodes detected in the tumor bearing specimen. Arms 1. chemoradiotherapy arm - radiotherapy 50Gy/25fr, 1.8-2Gy per fraction over 5 weeks with chemotherapy 5-Fu/Lv ( 400mg/m² 5-Fluouracil, 20mg/m² Leucovorine) during first and last week of radiotherapy ( surgery after 6-7 weeks). 2. short-term radiotherapy with delayed surgery arm – radiotherapy 25Gy/5fr, 5Gy per fraction over 5 days (surgery after 6-7 weeks). preoperative short term radiation group 5x5 Gy during 5 days and surgery after 6 weeks Inclusion Criteria: • histologically confirmed stage II and III rectal cancer less than 15 cm from anal verge • less than 80 years old • no other cancer during 5 years period • compensate cardiovascular, pulmonary, hepatic and renal... [to full text]

Nephropathic cystinosis is a rare autosomal recessive disease characterised by raised lysosomal levels of cystine in the cells of almost all organs. It is treated by regular oral and topical administration of the aminothiol, cysteamine(Cystagon™), which possesses an offensive taste and smell. The oral form frequently causes emesis,and should be administered every six hours to be maximally effective. The topical eye drop treatment requires hourly application to be most effective.In an attempt to reduce this frequency and improve the treatment, the preparation and evaluation of three alternative cysteamine containing formulations (suppositories, long-acting ophthalmic gels and an inhaler) was undertaken. The physiochemical properties, stability and release profiles of the active (cysteamine or phe conjugate) from the formulations were evaluated. The suppositories released cysteamine over a 20-40 minute period with a T75= 10-13minutes. They were most stable at 4°C. The analysis of the ophthalmic gels demonstrated that a weak gel network was formed at low shear stress, the bioadhesion of the gel was increased with inclusion of a cysteamine derivative (e.g.mean force of 0.067N compared to 0.107N with compound included) and eight-hour, first order release from the gel was observed. There was significant adhesion observed between the ophthalmic gels and bovine corneal tissue. The pulmonary microspheres were spherical and within the optimum size range for deep lung delivery (1-5μm). However, Andersen Cascade Impactor analysis revealed poor deep lung penetration. In conclusion, these results demonstrated that more development work was required to produce a useful pulmonary formulation of cysteamine, however, formulation of an ocular applicable gel or suppository was readily achievable. The suppository preparations may be particularly beneficial for the treatment of infants, whilst the ophthalmic gel preparations could be developed for daily or overnight use. With respect to pulmonary delivery, microspheres in the optimum size range were produced. However, deep lung targeting was prevented by static agglomeration, which requires further investigation.

<p>Endopolyploid cells (hereafter - polyploid cells), which contain whole genome duplications in an otherwise diploid organism, play vital roles in development and physiology of diverse organs such as our heart and liver. Polyploidy is also observed with high frequency in many tumors, and division of such cells frequently creates aneuploidy (chromosomal imbalances), a hallmark of cancer. Despite its frequent occurrence and association with aneuploidy, little is known about the specific role that polyploidy plays in diverse contexts. Using a new model tissue, the Drosophila rectal papilla, we sought to uncover connections between polyploidy and aneuploidy during organ development. Our lab previously discovered that the papillar cells of the Drosophila hindgut undergo developmentally programmed polyploid cell divisions, and that these polyploid cell divisions are highly error-prone. Time-lapse studies of polyploid mitosis revealed that the papillar cells undergo a high percentage of tripolar anaphase, which causes extreme aneuploidy. Despite this massive chromosome imbalance, we found the tripolar daughter cells are viable and support normal organ development and function, suggesting acquiring extra genome sets enables a cell to tolerate the genomic alterations incurred by aneuploidy. We further extended these findings by seeking mechanisms by which the papillar cells tolerated this resultant aneuploidy.</p> / Dissertation

O objetivo do trabalho foi avaliar a técnica de biópsia retal em equinos e as alterações histopatológicas encontradas na mucosa retal em animais clinicamente saudáveis e em animais com alterações do trato gastrintestinal. Foram utilizados 32 equinos divididos em três grupos: 10 animais clinicamente saudáveis (grupo 1), sete animais com alterações do trato gastrintestinal com diagnóstico estabelecido (grupo 2) e 15 animais com manifestações clínicas inespecíficas do trato gastrintestinal (grupo 3). Os equinos do grupo 1 foram biopsiados duas vezes, a segunda biópsia sendo realizada 48 horas após a primeira. As biópsias retais foram realizadas com os animais em estação, utilizando-se pinça de biópsia tipo jacaré. As amostras de mucosa retal foram coradas por hematoxilina-eosina (HE), azul de alciano com ácido periódico de Schiff a 2,5% e azul de toluidina. No grupo 1, não foram observadas diferenças significativas entre a primeira e a segunda biópsia, mas três equinos apresentaram pequenas alterações que podem ser decorrentes da palpação retal. Na primeira avaliação, sete animais desse grupo apresentaram padrão semelhante, permitindo estabelecer um padrão de normalidade histológica para a mucosa retal: epitélio superficial preservado; criptas uniformes e alinhadas perpendicularmente à superfície com grande número de células caliciformes com mucinas ácidas em maior quantidade; linfócitos intra-epiteliais na superfície do epitélio em número de até 15 linfócitos para cada 100 colonócitos; pequeno número de linfócitos, plasmócitos e eosinófilos infiltrando a lâmina própria e a submucosa. Os outros três equinos deste grupo apresentaram um aumento na intensidade das células inflamatórias (discreto a moderado na intensidade de linfócitos e plasmócitos na lâmina própria e submucosa, e moderado na intensidade dos eosinófilos na submucosa). Os equinos do grupo 2, todos com síndrome cólica, apresentaram as seguintes alterações histopatológicas: proctite linfoplasmocítica simples (4/7) e proctite eosinofílica (1/7). No grupo 3 (12 equinos com diarreia crônica e três com emagrecimento progressivo), apenas um animal apresentou mucosa retal com padrão de normalidade. Nos outros animais foram observadas: proctite linfoplasmocítica simples (6/15), proctite erosiva (3/15), proctite linfoplasmocítica com aumento de neutrófilos (2/15), proctite eosinofílica (2/15), proctite linfoplasmocítica com aumento de neutrófilos e eosinófilos (1/15) e infiltração por linfócitos atípicos/linfoma (1/15). Concluiu-se que: a técnica de biópsia retal avaliada é de fácil execução e segura; embora algumas alterações histológicas possam ser observadas na mucosa retal de equinos clinicamente saudáveis, causadas ou não por palpação retal, há um padrão de normalidade que deve ser usado para a avaliação de equinos com alterações gastrintestinais; apenas em alguns casos as alterações histológicas encontradas na mucosa retal em equinos permitem um diagnóstico definitivo, mas elas podem direcionar o raciocínio diagnóstico em outros, sendo este um importante exame complementar a ser indicado em casos de equinos com alterações gastrintestinais inespecíficas. / The purpose of this study was to asses the rectal biopsy techique in horses and the histopathological changes found in the rectal mucosa in clinically healthy animals and in animals with clinical signs of intestinal disorders. 32 horses were divided into three groups: 10 animals clinically healthy (group 1), seven animals with gastrointestinal disorders with an established diagnosis (group 2) and 15 animals with nonspecific clinical manifestations of the gastrointestinal tract (group 3). The horses in group 1 had two biopsies, the second biopsy was performed 48 hours after the first. Rectal biopsies were performed on the animals station, using alligator biopsy forceps. The samples of rectal mucosa were stained with hematoxylin end eosin (HE), alcian blue PAS pH 2.5% and toluidine blue. In group 1, no significant differences between the first and second biopsy were observed, but three horses showed small changes that may result from rectal palpation. In the first evaluation, seven animals of this group showed a similar pattern, establishing a standard of normality for histological rectal mucosa: Surface epithelial preserved; crypts of uniform length, diameter and perpendicular arrangement to the surface with acid mucins strongly dominated over neutral mucins in the goblet cell population; intraepithelial lymphocytes in the surface of the epithelium with sparse population of approximately 15 cells per stretch of 100 epithelial cells; sparse individual lymphocytes, plasma cells and eosinophils infiltrating the lamina propria and submucosa. The other three horses in this group had an increase in the intensity of inflammatory cells (mild to moderate in intensity of lymphocytes and plasma cells in the lamina propria and submucosa, and moderate intensity of eosinophils in the submucosa). The horses in group 2, all with colic syndrome, showed the following pathological changes: simple lymphocyticplasmacytic proctitis (4/7) and eosinophilic proctitis (1/7). In group 3 (12 horses with chronic diarrhea and three with progressive weight loss), only one animal showed rectal mucosa with normal histology. It was observed in the other animals: simple lymphocytic-plasmacytic proctitis (6/15), erosive proctitis (3/15), lymphocyticplasmacytic proctitis with increased neutrophils (2/15), eosinophilic proctitis (2/15), lymphocytic-plasmacytic proctitis with increased neutrophils and eosinophils (1/15) and atypical lymphocytes infiltration/lymphoma (1/15). It was concluded that: the rectal biopsy technique evaluated is effective and safe; although some histological changes can be observed in the rectal mucosa of clinically healthy horses, whether or not caused by rectal palpation, there is a normal range that should be used to the evaluation of horses with gastrointestinal disorders; only in some cases the histological changes found in the rectal mucosa in horses allow a definitive diagnosis, but they can lead to a diagnostic logic in others, which is an important complementary test to be indicated in cases of horses with nonspecific gastrointestinal disturbances.