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1
Macaire, Pauline. "Modélisation par une approche de population de l’effet des facteurs de croissance granulocytaire lors de neutropénies chimio-induites". Thesis, Bourgogne Franche-Comté, 2020. http://www.theses.fr/2020UBFCJ001.
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Les travaux de cette thèse s'appuient sur les résultats d'une étude de cohorte ayant pour objectif principal de définir le schéma optimal d'administration prophylactique des facteurs de croissance granulocytaire (G-CSF) dans le cadre d’un traitement par FOLFIRINOX. Pour ce faire, un modèle pharmacocinétique/pharmacodynamique (PK/PD) a été construit pour décrire l'évolution des polynucléaires neutrophiles (PNN) en fonction du temps dans notre population en tenant compte de l'effet neutropéniant des trois chimiothérapies administrées mais également de l'effet stimulant des G-CSF exogènes sur la prolifération et la maturation des neutrophiles. Sur la base des estimations des paramètres du modèle obtenus, des simulations ont été réalisées afin de déterminer l'incidence et la durée des neutropénies pour chaque schéma prophylactique de G-CSF selon le début, la durée mais également la nature du traitement (formulation pegylée ou non). Pour réaliser ces simulations, la valeur initiale en PNN avant le début du cycle de chimiothérapie a été considérée; en cas de concentration initiale élevée (> 6,5 G/L), l'utilisation d'un traitement prophylactique ne semble pas nécessaire du fait d'un risque de neutropénie limitée. Par ailleurs, pour les patients dont la concentration initiale en PNN se situe en dessous de 6,5 G/L, au vu de nos résultats, une administration unique de peg-G-CSF 24 heures après la fin de la perfusion de 5-FU de 46 heures semble le schéma prophylactique le plus approprié pour réduire l'incidence et la durée des neutropénies induites par le FOLFIRINOX. Néanmoins, contrairement aux idées reçues, l'augmentation de la durée d'injections quotidiennes de G-CSF ou une administration tardive des facteurs de croissance granulocytaire n'est pas forcément profitable pour les patients du fait de l'augmentation de l'incidence des neutropénies sévères par rapport à la non-administration de traitement prophylactiqueThe work of this thesis is based on results of a cohort study whose main objective was to define the optimal schedule of prophylactic administration of granulocyte growth factors (G-CSF) in the context of FOLFIRINOX treatment. For this purpose, a pharmacokinetic/pharmacodynamic (PK/PD) model was built to describe the absolute neutrophil counts (ANC) time course in our population, including the three chemotherapies neutropenic effect, but also the stimulating effect of exogenous G-CSF on the proliferation and maturation of neutrophils. Based on the estimates of the model parameters, simulations were performed to determine the incidence and duration of neutropenia for each prophylactic G-CSF schedule depending on the begining, the duration but also the nature of the treatment (pegylated formulation or not). The pre-therapeutic ANC value was considered; in case of high initial ANC (> 6.5 G/L), the use of prophylactic treatment does not seems necessary due to the limited risk of neutropenia. Furthermore, for patients whose initial ANC is below 6.5 G/L, based on our results, a single administration of peg-G-CSF 24 hours after the end of the 46 hours 5-FU infusion seems to be the most appropriate prophylactic schedule to reduce the incidence and the duration of FOLFIRINOX-induced neutropenia. However, contrary to popular belief, increasing the number of daily G-CSF injections or late administration of G-CSF is not necessarily beneficial for patients due to the increased incidence of severe neutropenia compared to the absence of treatment
2
Väkeväinen, Satu. "Local acetaldehyde production as a pathogenetic factor for upper digestive tract cancers in humans". Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/vakevainen/.
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Vila, Casadesús Maria. "Design of bioinformatic tools for integrative analysis of microRNA-mRNA interactome applied to digestive cancers". Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/663087.
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En esta tesis se han desarrollado e implementado distintas herramientas bioinformáticas que permiten el estudio de las interacciones miRNA-mRNA en contextos celulares específicos. oncretamente se ha creado un paquete de R (miRComb) que calcula las interacciones miRNA-mRNA partiendo de expresión de miRNAs y mRNAs, y predicciones bloinformáticas de bases de datos preexistentes. Las interacciones miRNA-mRNA finales son aquellas que muestran una correlación negativa y han estado predichas por al meno una base de datos. Como valor añadido, el paquete miRComb realiza un resumen en pdf con los resultados básicos del análisis (número de interacciones, número de mRNAs target por miRNA, análisis funcional, etc.), que permite comparar los datos de distintos estudios.
Hemos aplicado esta metodología en el contexto de cánceres digestivos. En un primer estudio hemos utilizado datos públicos de 5 cánceres digestivos (colon, recto, esófago, stómago e hígado) y hemos determinado las interacciones miRNA-mRNA comunes entre ellos y específicas de cada uno.
En un segundo estudio, hemos utilizado la misma metodología para analizar datos de IRNA-mRNA en biopsias de pacientes del Hospital Clínic de Barcelona con cáncer de páncreas. En este estudio hemos descrito interacciones miRNA-mRNA en el contexto de cáncer pancreático y hemos podido validar dos de ellas a nivel experimental.
En resumen, podemos concluir que el paquete miRComb es una herramienta útil para el estudio del interactoma de miRNA-mRNA, y que ha servido para establecer hipótesis biológicas que luego se han podido comprobar en el laboratorio.
4
Perrichet-Pechinez, Anaïs. "Ciblage de l'IL-1beta pour améliorer l'efficacité de la chimio-immunothérapie dans le cancer". Electronic Thesis or Diss., Bourgogne Franche-Comté, 2024. http://www.theses.fr/2024UBFCI014.
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L'IL-1b est connue pour avoir un rôle ambivalent dans le microenvironnement tumoral. Le cancer du poumon et le cancer colorectal figurent parmi les cancers les plus meurtriers, et l'incidence de l'adénocarcinome canalaire pancréatique a considérablement augmenté au cours des 30 dernières années. Ce projet vise à étudier le rôle de l'IL-1b dans les cancers du poumon, du côlon et du pancréas en condition de traitement par chimio-immunothérapie et démontrer comment cette interleukine agit dans le microenvironnement tumoral afin d’identifier des pistes d’amélioration thérapeutique.Dans le cancer du poumon non à petites cellules, l'IL-1b a un rôle antitumoral en présence de chimio-immunothérapie, en participant au recrutement des cellules T CD8+ via la production de CXCL10 par les cellules cancéreuses. En revanche, dans les cancers digestifs tels que ceux du pancréas et du côlon, l'IL-1b joue un rôle pro-tumoral en favorisant l’immunosuppression dans le microenvironnement tumoral, augmentant ainsi la résistance aux traitements.Ainsi, la compréhension du rôle et des interactions spécifiques de l'IL-1b dans différents microenvironnements tumoraux pourrait offrir des perspectives pour développer des stratégies thérapeutiques ciblées et plus efficacesIL-1β is known to have an ambivalent role in the tumor microenvironment. Lung cancer and colorectal cancer are among the deadliest cancers, and the incidence of pancreatic ductal adenocarcinoma has significantly increased over the past 30 years. This project aim to study the role of IL-1β in lung, colon, and pancreatic cancers in a context of chemo-immunotherapy, and investigate how this interleukin functions within the tumor microenvironment, to identify potential therapeutic improvements.In non-small cell lung cancer, IL-1β exhibits an antitumor role in the presence of chemoimmunotherapy by contributing to the recruitment of CD8+ T cells through the production of CXCL10 by cancer cells. Conversely, in digestive cancers such as pancreatic and colon cancers, IL-1β plays a pro-tumoral role by promoting immunosuppression within the tumor microenvironment, thereby increasing resistance to treatments.Thus, understanding the specific roles and interactions of IL-1β in different tumor microenvironments could offer insights for developing more targeted and efficient therapeutic strategies
5
Cui, Yan. "Polymorphism of xeroderma pigmentosum group G and dietary flavonoid intake on the risk of lung and upper aero-digestive tract cancers". Diss., Restricted to subscribing institutions, 2005. http://proquest.umi.com/pqdweb?did=954047411&sid=1&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Gupta, Bhawna. "Life-course approach to behavioural risk factors and quality of life for cancers of the upper aero-digestive tract in an Indian population: a case-control study". Thesis, Griffith University, 2018. http://hdl.handle.net/10072/371971.
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The incidence and mortality rates of cancers of upper aero-digestive tract (UADT)
remain significantly high in India. These cancers, which occur more commonly in later
adulthood, are influenced by social and lifestyle behaviours carried out during
childhood, adolescence and early adult life. Thus, life-course epidemiology attempts to
assess varying health effects of various risk factors, according to timing, duration and
frequency of exposure, which may give important clues to the causes of cancer.
These cancers have serious impacts on quality of life (QoL) as they involve
anatomical structures essential for mastication, speaking, cosmetic appearance and
psychological wellbeing. Moreover, these cancers frequently present late and progress
rapidly. Therefore, there is a need to develop a model for cost-effective screening and
detection of individuals at high-risk of these cancers in the near future as well as early
detection of cancer cases. Thereby, a study was designed with the following hypotheses:
Early age at initiation, frequency and duration of use of tobacco in its all forms,
exposure to second hand tobacco smoke (SHS) at home and drinking alcohol has
a linear dose-response relationship with the incidence of UADT cancers.
There is an association between tobacco, alcohol drinking, diet, oral hygiene and
anthropometry measures with incidence of oral cancers.
Cancer site, staging, gender and age at diagnosis have an impact on QoL.
A risk-factor based screening model for UADT cancers has strong predictive
ability to detect high-risk individuals.
A bi-centre hospital-based frequency matched case-control study was conducted in
Pune, Maharashtra State, India, from June 2014 and May 2015. Cases were
histopathologically confirmed new cases of squamous cell carcinoma of UADT.
Controls were patients diagnosed with a disease other than UADT or any other cancer,
selected from the same hospital during the same period as the cases were recruited. Data
were collected by medical-record abstraction, face-face interviews and by visual
inspection of the oral cavity. A closed-ended questionnaire with a life-course
perspective was used to collect patient‟s self-reported information on sociodemographics,
lifestyle habits (chewing and smoking tobacco, drinking alcohol, SHS, oral hygiene) and QoL. The interviewer recorded anthropometry measures and
number of missing teeth.
Unconditional logistic regression was used to estimate the odds ratios (ORs) and
their corresponding 95% confidence intervals (CIs). A reciever-operater characterstic
curve was plotted against sensitivity and false-positive rate to produce a cut off point for
the presence of UADT cancers. Examination of all QoL domains was done using oneway
analysis of variance and the Bonferroni adjustments for post-hoc comparisons.
Data were analysed by the Statistical Package for Social Sciences version 22.
A total of 480 patients participated in the study. Chewing tobacco emerged as the
strongest predictor for UADT cancers (OR=7.61; 95% CI 4.65-12.45) followed by
smoking and drinking alcohol. Exposure to SHS during childhood (<16 years) rather
than after ≥16 years increased the risk significantly (OR=4.05; 95% CI 2.06-7.95).
There is a linear dose-response relationship between duration, frequency and early age
at initiation for lifestyle risk factors (chewing and smoking tobacco; drinking alcohol)
with incidence of UADT cancers in adulthood. Combined effects of tobacco and alcohol
consumption habits elevated the risk (OR=12.05; 95% CI 4.61-31.49) in comparison to
never users of these habits. Furthermore, the combination of these three lifestyle risk
factors accounted for 86.82% of population attributable risk.
Overall, the most affected QoL domains were anxiety and mood both among cases
and controls. Oropharynx and hypopharynx cancer cases had the worst mean scores
across all QoL domains. Stage IV cancer patients showed the worst QoL. Amongst
UADT cancers in Pune, cancer of the oral cavity was the most common. Chewing
tobacco showed higher odds (OR=8.51; 95% CI 4.90-14.77) for oral cancer risk as
compared to UADT cancers. Poor oral hygiene emerged as significant predictor for oral
cancer risk (OR=6.98; 95% CI 3.72-13.05).
A screening model was derived for detection of individuals at high-risk for UADT
cancers. This model has high sensitivity (93.5%), specificity (71.1%), false positive rate (28.8%), false negative rate (6.4%), positive predictive value (74.8%) and negative
predictive value (96.6%). Our research recognises the framework of life-course influences of early exposure to
behavioural risk-factors as independent and combined predictors of UADT cancers. The
significantly compromised QoL in UADT cancer needs to be incorporated as an
outcome measure in an individualized approach to therapeutic and palliative care
planning of these cases to enable a better quality of survival. If validated in other
studies, our proposed screening model can be applicable to many other high-risk UADT
cancer populations with behavioural risk factors similar to our study population.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Dentistry and Oral Health and Menzies Health Institute Queensland
Griffith Health
Full Text
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Chen, Jun 1969. "The association between dietary intake and the risk of cancers of the upper aero-digestive tract : a case-control study in Brazil". Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=29422.
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Cancers of the upper aero-digestive tract (UADT) rank as the fifth most common neoplastic disease worldwide. Two identified risk contributors are consumption of tobacco and alcohol. Among all other potential etiological factors, diet has long been recognized to play an important role in the development of cancers of the UADT. Data from a multi-centre, hospital-based case-control study conducted in Brazil were used to assess the association of dietary intake with the risk of cancers of the UADT. Dietary assessment was made in terms of estimated intake of nutrients, specific foods and food groups. After adjusting for the effects of alcohol and tobacco consumption as well as empirical confounders, protective effects against cancer of the mouth (Odds Ratio (OR) = 0.61, 95% confidence interval (95% CI): 0.4--1.0) and the pharynx (OR = 0.51, 95%CI: 0.3--0.9) were found for consumption of citric fruits. (Abstract shortened by UMI.)
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He, Hua, i 何華. "Anti-tumor mechanisms of cyclooxygenase inhibitors and a c-Jun-N-terminal kinase inhibitor in gastrointestinal cancers". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B30075245.
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Collard, Olivier Conroy Philippe. "Chirurgie des métastases hépatiques dans les cancers colo-rectaux étude rétrospective de 84 patients opérés au Centre Alexis Vautrin et en chirurgie digestive générale, CHU de Nancy de 1985 à 2000 /". [S.l.] : [s.n.], 2002. http://www.scd.uhp-nancy.fr/docnum/SCDMED_T_2002_COLLARD_OLIVIER.pdf.
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Moura, Kelly Cristina Rodrigues de [UNESP]. "Análise da frequencia do polimorfismo rs12979860 C/T no gene IL28B em pacientes acometidos por câncer gástrico". Universidade Estadual Paulista (UNESP), 2015. http://hdl.handle.net/11449/126466.
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000839769.pdf: 1095151 bytes, checksum: 5c5372db38bb52b66a5da5b0b13785b5 (MD5)O câncer gástrico é um dos tipos de câncer mais comum e está associado com uma alta frequência de mortalidade. Embora nas últimas décadas tenha ocorrido um decréscimo na incidência mundial, o prognóstico desta patologia permanece ruim, principalmente quando o diagnóstico é feito em estágios avançados. A etiologia é complexa e multifatorial, onde a combinação de fatores genéticos e ambientais parecem estar envolvidos na carcinogênese e progressão da doença. Desta forma, o objetivo deste estudo foi determinar a frequência do polimorfismo rs12979860 C/T no gene IL28B em amostras de carcinoma gástrico provenientes de dois estados brasileiros, São Paulo e Ceará, associando às características clínicas e epidemiológicas desses pacientes. Os resultados demonstraram que 29,7% dos pacientes apresentam o genótipo CC, enquanto a frequência dos indivíduos heterozigotos e (CT) e homozigotos (TT) foram 56,3% e 9%, respectivamente. Em comparação com dados descritos na literatura e do dBSNP de populações usadas como controle, a frequência do alelo T foi mais alta nos pacientes acometidos por câncer gástrico (tumor difuso: 45,5%, tumor intestinal: 39%, literatura: 11 a 35 e dBSNP: 36%). Ainda neste contexto, encontramos uma significante menor frequência do genótipo CC entre os pacientes acometidos por tumores difusos (22,7%), quando comparados aos indivíduos saudáveis (44 a 51%). Nos casos provenientes da população cearense o alelo C foi significativamente mais elevado no tipo intestinal (67%) quando comparado ao tipo difuso (50%), ressaltando a maior frequência do alelo T nos casos difusos. Analisando-se a frequência do polimorfismo rs12979860 C/T e a genotipagem de Helicobacter pylori foi observada uma forte associação entre o genótipo e a infecção pela bactéria CagA+, onde pacientes portadores da cepa mais patogênica (CagA+) apresentaram frequência maior do genótipo menos protetor (TT), principalmente no...
Gastric cancer is one of the most common types of cancer and is associated with a high mortality rate. Although in recent decades there has been a decrease in the global incidence, prognosis of this condition remains poor, especially when the diagnosis is made in advanced stages. The etiology is complex and multifactorial, where the combination of genetic and environmental factors appear to be involved in carcinogenesis and progression of the disease. Thus, the aim of this study was to determine the frequency of the polymorphism rs12979860 C / T in the IL28B gene in gastric carcinoma samples from two Brazilian states, São Paulo and Ceará, associating the clinical and epidemiological characteristics of these patients. The results showed that 29.7% of patients present with the CC genotype, while the frequency of heterozygotes and (TC) and homozygous (TT) were 56.3% and 9%, respectively. Compared to data reported in the literature and used as control populations of dbSNP, the frequency of the T allele was higher in patients affected by gastric cancer (diffuse tumor: 45.5%, intestinal tumor: 39%, literature: 11-35 and dbSNP: 36%). Also in this context, we found a significant lower frequency of the CC genotype among patients affected by diffuse tumors (22.7%) when compared to healthy subjects (44-51%). In cases from Ceará population the C allele was significantly higher in the intestinal type (67%) compared to the diffuse type (50%), emphasizing the greater frequency of the T allele in diffuse cases. Analyzing the frequency of polymorphism rs12979860 C / T and genotyping of Helicobacter pylori was observed a strong association between genotype and infection with CagA + bacteria, where patients with the most pathogenic strain (CagA +) had a frequency higher than genotype less protective (TT), particularly in diffuse histotype (p = 0.001). In addition, this same allele was significantly associated with the occurrence of metastases in ...
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Moura, Kelly Cristina Rodrigues de. "Análise da frequencia do polimorfismo rs12979860 C/T no gene IL28B em pacientes acometidos por câncer gástrico /". Botucatu, 2015. http://hdl.handle.net/11449/126466.
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Orientador: Adriana Camargo FerrasiBanca: Maria Inês de Campos Moura Pardini
Banca: Juliana Garcia de Oliveira
Resumo: O câncer gástrico é um dos tipos de câncer mais comum e está associado com uma alta frequência de mortalidade. Embora nas últimas décadas tenha ocorrido um decréscimo na incidência mundial, o prognóstico desta patologia permanece ruim, principalmente quando o diagnóstico é feito em estágios avançados. A etiologia é complexa e multifatorial, onde a combinação de fatores genéticos e ambientais parecem estar envolvidos na carcinogênese e progressão da doença. Desta forma, o objetivo deste estudo foi determinar a frequência do polimorfismo rs12979860 C/T no gene IL28B em amostras de carcinoma gástrico provenientes de dois estados brasileiros, São Paulo e Ceará, associando às características clínicas e epidemiológicas desses pacientes. Os resultados demonstraram que 29,7% dos pacientes apresentam o genótipo CC, enquanto a frequência dos indivíduos heterozigotos e (CT) e homozigotos (TT) foram 56,3% e 9%, respectivamente. Em comparação com dados descritos na literatura e do dBSNP de populações usadas como controle, a frequência do alelo T foi mais alta nos pacientes acometidos por câncer gástrico (tumor difuso: 45,5%, tumor intestinal: 39%, literatura: 11 a 35 e dBSNP: 36%). Ainda neste contexto, encontramos uma significante menor frequência do genótipo CC entre os pacientes acometidos por tumores difusos (22,7%), quando comparados aos indivíduos saudáveis (44 a 51%). Nos casos provenientes da população cearense o alelo C foi significativamente mais elevado no tipo intestinal (67%) quando comparado ao tipo difuso (50%), ressaltando a maior frequência do alelo T nos casos difusos. Analisando-se a frequência do polimorfismo rs12979860 C/T e a genotipagem de Helicobacter pylori foi observada uma forte associação entre o genótipo e a infecção pela bactéria CagA+, onde pacientes portadores da cepa mais patogênica (CagA+) apresentaram frequência maior do genótipo menos protetor (TT), principalmente no...
Abstract: Gastric cancer is one of the most common types of cancer and is associated with a high mortality rate. Although in recent decades there has been a decrease in the global incidence, prognosis of this condition remains poor, especially when the diagnosis is made in advanced stages. The etiology is complex and multifactorial, where the combination of genetic and environmental factors appear to be involved in carcinogenesis and progression of the disease. Thus, the aim of this study was to determine the frequency of the polymorphism rs12979860 C / T in the IL28B gene in gastric carcinoma samples from two Brazilian states, São Paulo and Ceará, associating the clinical and epidemiological characteristics of these patients. The results showed that 29.7% of patients present with the CC genotype, while the frequency of heterozygotes and (TC) and homozygous (TT) were 56.3% and 9%, respectively. Compared to data reported in the literature and used as control populations of dbSNP, the frequency of the T allele was higher in patients affected by gastric cancer (diffuse tumor: 45.5%, intestinal tumor: 39%, literature: 11-35 and dbSNP: 36%). Also in this context, we found a significant lower frequency of the CC genotype among patients affected by diffuse tumors (22.7%) when compared to healthy subjects (44-51%). In cases from Ceará population the C allele was significantly higher in the intestinal type (67%) compared to the diffuse type (50%), emphasizing the greater frequency of the T allele in diffuse cases. Analyzing the frequency of polymorphism rs12979860 C / T and genotyping of Helicobacter pylori was observed a strong association between genotype and infection with CagA + bacteria, where patients with the most pathogenic strain (CagA +) had a frequency higher than genotype less protective (TT), particularly in diffuse histotype (p = 0.001). In addition, this same allele was significantly associated with the occurrence of metastases in ...
Mestre
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De, Rosa Antonella. "Oestrogen receptors in oesophageal cancer". Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/52399/.
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Introduction: Oesophageal cancer is more common in men than women. Oestrogen, which mediates its effects via oestrogen receptors (ERs), may be responsible for the gender disparity. This thesis investigates the role of ERs in oesophageal cancer development and explores potential therapeutic possibilities. Methods: ERα and ERβ expression in oesophageal AC cell lines (OE19 and OE33) was knocked down using siRNA, and the effect of knockdown on the expression of proliferation-associated proteins (Ki67, PCNA, E-cadherin, Cyclin D) was assessed. The effect of the SERM, tamoxifen, on oesophageal cancer cell proliferation was investigated using proliferation assays and by evaluating the effect of tamoxifen on proliferation-associated proteins. Finally, a pilot study of tamoxifen in patients with oesophageal cancer was undertaken to assess feasibility of a clinical trial and to determine the short-term biological effect of tamoxifen on proliferation, assessed by a change in the immunohistochemical expression of Ki67 between paired biopsies. Results: ERα and ERβ are expressed at the mRNA (RT-PCR) and protein level (Western Blotting) in the OE19 and OE33 cell lines. ERβ mRNA knock down was achieved in the OE33 cell line (p = < 0.0001). However, reproducible significant ERβ protein knockdown was not demonstrated, and there was no change in the expression of proliferation-associated proteins. Treatment with tamoxifen significantly inhibited OE33 cell proliferation in a dose-dependent manner (p = < 0.0001). Interestingly, treatment with tamoxifen decreased the expression of E-cadherin, but failed to change the expression of the remaining proliferation-associated proteins. Eight patients (6 male with AC and 2 female with SCC) included in the pilot study completed a median on 30 days (range: 28 – 45 days) tamoxifen treatment; the mean Ki67 Labelling Index between paired biopsies increased by 0.625% (ns). Of the two women included, Ki67 expression decreased with tamoxifen treatment. A correlation was demonstrated between a reduction in Ki67 and mean ERβ expression (r= -0.2272, ns). Discussion: ERβ is the dominant ER subtype expressed in oesophageal cancer cell lines and human cancer tissue. Tamoxifen inhibits the proliferation of oesophageal cancer cell lines in-vitro. Further studies to define the role of the ERβ subtype in oesophageal cancer and a clinical trial of tamoxifen in patients with oesophageal cancer is needed.
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Khreiche, Antoine. "Aspects héréditaires des cancers digestifs familiaux". Montpellier 1, 1998. http://www.theses.fr/1998MON11050.
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Mirams, Gary R. "Subcellular phenomena in colorectal cancer". Thesis, University of Nottingham, 2008. http://eprints.nottingham.ac.uk/10567/.
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The Wnt signalling pathway is involved in stem cell maintenance, differentiation and tissue development, and in so doing plays a key role in controlling the homeostasis of colorectal crypts. In response to an external Wnt stimulus, the intracellular levels of the protein beta-catenin are regulated by the proteins which make up the Wnt signalling pathway. Abnormalities in the Wnt signalling pathway have been implicated in the initiation of colorectal and other cancers. In this thesis we analyse and simplify existing models of the Wnt signalling pathway, formulate models for Wnt's control of the cell cycle in a single cell, and incorporate these into a multiscale model to describe how Wnt may control the patterns of proliferation in a colorectal crypt. A systematic asymptotic analysis of an existing ODE-based model of the Wnt signalling pathway is undertaken, highlighting the operation of different pathway components over three different timescales. Guided by this analysis we derive a simplified model which is shown to retain the essential behaviour of the Wnt pathway, recreating the accumulation and degradation of beta-catenin. We utilise our simple model by coupling it to a model of the cell cycle. Our findings agree well with the observed patterns of proliferation in healthy colon crypts. Furthermore, the model clarifies a mechanism by which common colorectal cancer mutations may cause elevated beta-catenin and Cyclin~D levels, leading to uncontrolled cell proliferation and thereby initiating colorectal cancer. A second model for the influence of the Wnt pathway on the cell cycle is constructed to incorporate the results of a recent set of knockout experiments. This model reproduces the healthy proliferation observed in crypts and additionally recreates the results of knockout experiments by additionally including the influence of Myc and CDK4 on the cell cycle. Analysis of this model leads us to suggest novel drug targets that may reverse the effects of an early mutation in the Wnt pathway. We have helped to build a flexible software environment for cell-based simulations of healthy and cancerous tissues. We discuss the software engineering approach that we have used to develop this environment, and its suitability for scientific computing. We then use this software to perform multiscale simulations with subcellular Wnt signalling models inside individual cells, the cells forming an epithelial crypt tissue. We have used the multiscale model to compare the effect of different subcellular models on crypt dynamics and predicting the distribution of beta-catenin throughout the crypt. We assess the extent to which a common experiment reveals the actual dynamics of a crypt and finally explain some recent mitochondrial-DNA experiments in terms of cell dynamics.
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Saunders, John. "Ex vivo modelling of oesophago-gastric cancer". Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/47574/.
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Introduction The response to neoadjuvant chemotherapy in oesophago-gastric (OG) cancer is only 40%, so over half of the patient’s disease will progress, whilst they also suffer the toxic chemotherapy side-effects. A model to predict chemotherapy response would provide a marked clinical benefit, by enabling personalised treatment of OG cancer. Methods Live chemo-naïve tumour biopsies were obtained following informed consent at staging endoscopy, before patients underwent their routine neoadjuvant chemotherapy. Tumour cells from the endoscopic biopsies were expanded, using an in vitro feeder layer system and supplemented medium. With ethics committee approval and under Home Office guidance, these individual patient cancer cells were engrafted into immuno-compromised mice, where they formed representative tumour xenografts. Primary patient tissue, the corresponding individual patient cancer cells and their matching xenografts were analysed using immunohistochemistry, demonstrating that the in vitro and in vivo cells had retained the characteristics of the original patient’s oesophageal adenocarcinoma. To model the human tumour micro-environment (TME), a three dimensional tumour growth assay (3D-TGA) was developed, whereby the individual patient’s primary tumour cells were grown as 3D cancer cell clusters. This was performed by seeding individual patient’s primary tumour cells within a biological basement membrane extract, rich in extracellular matrix (ECM) components, with and without human mesenchymal stem cells to provide stromal support. The individual patient cancer clusters in the 3D-TGA were subjected to detailed chemotherapeutic assessment, to quantify their chemo-sensitivity to the standard chemotherapy which was administered to the patient in the clinic. This 3D-TGA predicted chemo-sensitivity was then compared with the patient’s actual clinical chemotherapy response, as measured by the histological tumour regression grade, which directly relates to prognosis. In combination with standard platinum-based chemotherapy, the 3D-TGA was assessed as a platform for evaluating new chemotherapeutics: the novel emerging HDAC inhibitor Panobinostat, and the phosphodiesterase type 5 inhibitor Vardenafil, which has recently been shown to be active against cancer stroma, were evaluated. Results Individual patient tumours were grown from primary endoscopic biopsy tissue in over half of samples obtained within a clinically applicable timescale of 2-4 weeks. Incorporating human mesenchymal cells into the 3D-TGA significantly changed the growth and drug resistance profiles (p < 0.005). This 3D-TGA chemo-response in the presence of stroma reflected the clinical chemo-sensitivity, with an accurate correlation between the 3D-TGA predicted chemo-resistance and actual clinical response for the patients evaluated. As well as predicting potential chemo-sensitivity for individual patients, the method allows individual drugs and combinations to be evaluated, trends in chemo-sensitivity between patients to be appraised, and analysis of the effect of the TME on tumour growth and chemotherapy resistance. Combination with Panobinostat enhanced response and proved efficacious in otherwise chemo-resistant tumours. Addition of PDE5i demonstrated an overall significantly enhanced chemotherapeutic response (p=0.003), and consequently provided efficacy in 60% of the otherwise chemo-resistant tumours. Discussion The novel method of growing individual patient OG cancers, using a 3D model with specific components of the tumour micro-environment in particular ECM and mesenchymal cells, provides a clinically-relevant oesophageal cancer model with application for chemo-sensitivity testing. Mesenchymal cells have a significant effect enhancing chemotherapy drug resistance in OG cancer, and this 3D model allowed identification of patients in which stromal targeting using PDE5i provided a significant reduction in chemotherapy drug resistance. In these patients, addition of PDE5i to routine chemotherapy could result in a marked change in the clinical efficacy of their chemotherapy regimen. The 3D model’s chemo-response accurately reflects individual patients’ clinical chemo-sensitivity and so this research has direct clinical application: if this assay proves to be predictive across a wider patient population, then following clinical trials, it could potentially be used to routinely guide individual patient therapy in the clinic, with administration of tailored chemotherapy for individual patient benefit.
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Lafon, Cyril. "Développement d'un applicateur interstitiel ultrasonore pour l'endoscopie digestive". Lyon 1, 1999. http://u556.lyon.inserm.fr/theses/pdf/lafon.pdf.
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JEUNET, ERIC. "Hepatectomies iteratives pour metastases de cancers digestifs". Lyon 1, 1990. http://www.theses.fr/1990LYO1M394.
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Akhlaq, Maham. "Investigation of Cten signalling and regulation in colorectal cancer". Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/32802/.
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Cten (also known as Tensin4) is the fourth member of the Tensin gene family. It lacks the N terminal actin binding domain while retaining the C terminal SH2 and PTB domains. This helps to bind Cten to the intracytoplasmic tail of β1 integrin and puts it at the heart of focal adhesions. It is reported to be a tumour suppressor in kidney and prostate cancer where normal tissues show high expression. However in a number of tumours, including colorectal cancer, Cten has been labelled as an oncogene. Cten which normally is a cytoplasmic protein gives nuclear staining in colorectal metastatic deposits. It increases motility, invasion and colony formation in colorectal cancer cells. In this study we have tried toexplore the mechanism of functional activity and regulation of Cten. We looked at Cten in the nucleus in vitro and identified new downstream binding targets. In addition we investigated the role of the SH2 domain of Cten concentrating on its downstream signalling molecules and binding partners. Furthermore, we explored regulators of Cten. In this study we have forced nuclear localisation of Cten by tagging it with a nuclear localisation sequence (NLS) and found a significant increase in cell motility. In order to investigate the SH2 domain we used site directed mutagenesis to change potentially important amino acids namely Arginine at 474 to Alanine (R474A), which is important for binding tyrosine phosphorylated proteins. Moreover, we displayed that Cten underwent tyrosine phosphorylation and additionally changed three tyrosine residues i.e. Y449F, Y479F and Y530F via site directed mutagenesis. We found R474 and Y479 to be important in regulating cell motility and that known downstream targets such as ILK and FAK are dependent on an intact SH2 domain. Furthermore we have identified Cten to be physically bound to FAK in the cytoplasm and nucleus and new downstream targets identified such as Src and Paxillin. Regarding possible regulators of Cten, we found that Cten might be a possible substrate for calpain. Another regulator considered was CD24 due to its role in movement of integrins into lipid rafts and we found it was a positive regulator of Cten. In conclusion localisation of Cten into the nucleus causes an augmentation of its motility enhancing functions. Cten regulates cell motility via its SH2 domain. Arginine 474 and Tyrosine 479 are important for its function. Cten regulates levels of ILK, FAK, Src and Paxillin through its SH2 domain and binds to FAK in both cytoplasm and nucleus. Calpain and CD24 were found to possible regulators of Cten in colorectal cancer. Future studies are needed to define its role in signalling at focal adhesions and these studies should be validated in other cancer cell models as well to establish Cten as regulator of cell motility in cancer.
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Alsulaiman, Abdullah. "Investigation of the role of CD24 in metastatic colorectal cancer". Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/55401/.
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CD24 is a small (81 amino acids) GPI anchored protein which is involved in promoting cell motility and stemness and may be a part of the metastatic process. It is a heavily glycosylated molecule and contains numerous O-glycosylation sites together with two N-glycosylation sites. N-glycosylation is thought to be important in protein function, and therefore, the aim of this study is to (a) investigate the importance of N-glycosylation in the function of CD24, (b) identify other potentially functional sites in CD24 by deletion mapping, (c) define downstream targets of CD24, and (d) identify the extrinsic signals of which activate CD24. (a) Through site-directed mutagenesis, we changed the glycosylated residues N32 (ACC to CAA) and Q52 (AAT to CAG) in CD24. Mutating each of these sites individually, when compared to pCCD24WT (wild-type CD24), caused a partial reduction in ability to induce cell motility and cell invasion (cell motility p=0.0001 cell invasion p=0.0001) and, unexpectedly, resulted in significantly enhanced cell proliferation (p=0.0001). Mutation of both sites resulted in a near loss of motility induction and retained cell proliferation. (b) We mapped the functional sites of CD24 by deleting seven amino acid segments of the whole of the mature peptide. Apart from the N-glycosylation sites, no other functional domains were identified which altered cell motility or proliferation. (c) Previously, in our lab it has been shown that Cten is downstream motility-inducing target of CD24. We hypothesised that CD24 may signal through the Notch pathway since Notch1 has an important role in maintaining CSCs. Results showed that forced expression of CD24 upregulates Notch1 and Cten whilst knockdown of CD24 causes loss of Notch1 and Cten expression. However, forced expression of CD24 with simultaneous knockdown of Notch1 resulted in failure to induce Cten. (d) CD24 is reported to act as a ligand of P-selectin. We found that stimulating CD24 expressing cell lines induced with P-selectin induced cell motility (p=0.0011) and caused an increased in the protein expression of downstream targets of CD24. Stimulating cell lines expressing CD24 with mutant glycosylation sites resulted in a failure to induce motility or CD24 targets. We conclude, the removal of the N-glycosylation sites in CD24 resulted in a loss of cell migration and invasion, thereby suggesting the importance of these sites in mediating the migration and invasion functions of CD24. Unexpectedly, these mutations also appeared to stimulate cell proliferation, suggesting that wild type CD24 can functionally inhibit cell proliferation. Deletion mapping did not reveal any other functional sites on the mature CD24 suggesting that O-glycosylation is relatively affecting the glycosylation in the biology of CD24. Notch1 was to be an important downstream target of CD24 and a regulator of Cten. The binding of P-selectin with CD24 resulted in increased motility of CD24 which is also dependent on N-glycosylation.
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Asiri, Abdulaziz. "Investigations into the role of Cten signalling in colorectal cancer". Thesis, University of Nottingham, 2018. http://eprints.nottingham.ac.uk/52233/.
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C-terminal tensin-like (Cten, also known as Tensin4) is the member of the tensin gene family. Cten functions as an oncogene in a variety of cancer types and its expression is commonly associated with poor prognosis and metastasis in colorectal cancer (CRC). Although several studies have shown that Cten has a critical role in the regulation of cell motility and invasion in different tumour tissues, the underlying signalling mechanisms have not been fully elucidated. This thesis investigated the biological activity of Cten in four different ways in order to further elucidate the mechanisms of Cten signalling in CRC cells. Potential downstream targets of Cten signalling involved in the regulation of epithelial-to-mesenchymal transition (EMT) induced cell motility i.e. Rho-associated protein kinase1 (ROCK1), Src and Snail were investigated. Cten expression was manipulated in different cell lines using multiple approaches including forced expression, gene knockdown and constitutive depletion (through Crispr/Cas9 gene deletion) to eliminate artefacts of methodology and cell line specific effects. Snail, Src and ROCK1 were identified as novel downstream targets of Cten signalling and additionally, Cten was shown to increase the stabilisation of both Src and Snail proteins. The functional relevance of Cten-Snail, Cten-Src and Cten-ROCK1 signalling was assessed, and the overall findings demonstrated that Cten could promote cell motility and colony formation directly through the positive regulation of the Src/ROCK1/Snail dependent axis. To gain a deeper insight into the mechanisms of Cten’s biological function, mutations, at two important residues (i.e. arginine 474 and tyrosine 479) in the Src homology 2 (SH2) domain of Cten were introduced into one construct (GFP-CtenR474A+Y479F) using site directed mutagenesis. These two residues in the SH2 domain of Cten were found to not only be important for interacting with Src, ROCK1, or Snail signalling, but also for regulating cell motility and colony formation efficiency. Numerous Cten regulatory factors have been identified, however, little is known about how Cten is activated and regulated in cancer cells. The relationship between transforming growth factor beta 1 (TGFβ1) and Cten was investigated and stimulation of cells with TGFβ1 or knockdown of TGFβ1 resulted in changes in Cten expression as well as its downstream targets of ROCK1, Src, Snail, and N-cadherin. Furthermore, this positive interaction between TGFβ1 and Cten was functionally relevant and caused changes in cell motility. and the nuclear translocation of ROCK1, Src, and Snail protein increased by TGFβ1 is probably mediated via upregulation of the Cten signalling pathway The biological function of Cten in the nucleus was further investigated and shown to increase nuclear localisation of Src, ROCK1, and Snail, further promoting the migratory capability and colony formation efficiency in CRC cells. Finally, Cten expression was shown to positively correlate with both ROCK1 and Src expression in a series of primary CRCs. This correlation was consistent with that observed following manipulation of Cten expression in CRC cell lines. In conclusion, this study has revealed a number of novel findings regarding the biological function of Cten signalling in CRC. However, further validation of the findings may enhance the understanding of the role of Cten in the invasion-metastasis cascade in the future.
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Royal, E. L. "Interplay between hypoxia and gastrin in gastrointestinal cancer". Thesis, University of Nottingham, 2009. http://eprints.nottingham.ac.uk/10805/.
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Tumour hypoxia has been linked to increased resistance to both radiotherapy and chemotherapy, especially in solid metastatic GI tumours. Under hypoxic conditions, genes that promote tumour growth and survival are up-regulated, via the transcription factor hypoxia-inducible factor-1 (HIF-1). The digestive hormone gastrin, which is often over-expressed in GI cancers, has also been shown to act as a pro-survival factor, up-regulating processes such as tumour proliferation, angiogenesis and migration, and down-regulating apoptosis. Due to the high level of similarity between the downstream events mediated by the two proteins, the relationship between gastrin and HIF-1 was investigated. HIF-1α nuclear protein expression was inducible under hypoxic conditions, which led to an expected increase in VEGF gene expression, followed by a 12-50 fold increase in hypoxic gastrin mRNA expression. HIF-1α expression and transcriptional activity were not consistently affected by exogenous gastrin. RNA-interference-mediated knockdown of HIF-1α resulted in a 40-60% down-regulation of gastrin gene expression under hypoxic conditions suggesting that HIF-1α is partially responsible for gastrin up-regulation in hypoxia. Potential hypoxia-response elements (HREs) were identified within the gastrin promoter, but were only partially responsive to hypoxic incubation in GI carcinoma cells in luciferase-reporter assays. Other possible mechanisms that may account for the increased gastrin gene expression induced under hypoxic conditions include interactions of gastrin with other transcriptional regulators, either in synergy with or independent from HIF-1, or the sequestration of gastrin within the cell by ‘P’-bodies or RNA-binding proteins. These findings may indicate that the addition of anti-gastrin agents such as CCK-2 receptor antagonists or gastrin immunogens to the treatment regime of patients with solid GI tumours may be clinically beneficial, especially if combined with agents used to reduce radiotherapy and chemotherapy resistance.
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Onyido, Emenike K. "Mechanisms and roles of FLYWCH1 in colorectal cancer". Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/42558/.
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Human colorectal cancer (CRC) is the fourth most common cause of cancer-related death in the UK and worldwide. Defects in conserved signalling pathways play key roles in the development of almost all cancers and, in CRCs, over 80% of tumours show hyper-activation of the canonical Wnt signalling pathway. This pathway, through the transcriptional activity of β-catenin (and its binding partner, TCF4), maintains the stem cell compartment of colon and intestinal-crypts as well as cancer-initiating cells. Whilst the role of β-catenin/TCF4 in the development of both normal and neoplastic colon/intestinal tissues is well documented, the molecular basis of these functionally distinct nuclear-transcriptional programs is still under investigation, hence the functional elucidation of nuclear cofactors that interact with nuclear β-catenin contribute to further unravel the mechanisms involved in the β-catenin-mediated nuclear transcription. In addition to LEF/TCFs, interaction of β-catenin with a plethora of other transcriptional co-activators and/or co-repressors remains vital for gene regulation. To this end, our lab have been dedicated to identifying -catenin/TCF4 interacting partner proteins (CIPs) capable of fine-tuning the Wnt-level in CRC cells. Among other CIPs, my proposed project was focused on FLYWCH1, a totally novel protein with a FLYWCH/Zn-finger DNA-binding domain, called “FLYWCH”. Previous data in our lab demonstrated that FLYWCH1 preferentially binds the nuclear/ un-phosphorylated--catenin whilst -catenin is still bound to TCF4 (Muhammed et al., submitted). Muhammed et al., found that FLYWCH1 is able to modulate transcription of many -catenin target genes including the stem cell marker (Lgr5) and genes that are associated with migration and invasion of CRC cells. They also showed that FLYWCH1 mRNA expression is restricted to a subpopulation of tumour cells in both human CRCs and ApcMin model mouse for intestinal cancer via in-situ hybridization (ISH). However, prior to these almost nothing was known about the FLYWCH1. In my research project it was proposed, to build on these advances in FLYWCH1，Wnt and CRC, and to undertake a cell & molecular research program on the role of the FLYWCH1-transcription regulator in potential suppression of colon cancer via direct regulation of microRNAs. However, commercially available FLYWCH1-antibodies worked endogenously only for immunocytochemistry/immunofluorescent (IF), but not for immunohisto-chemistry (IHC) and Western blotting analysis. Here we provide evidences via FLYWCH1 overexpression and shRNA knockdown in cultured fibroblast (TIG119) and CRC cell lines that FLYWCH1 possess tumour suppressor functions mainly by; i) Inhibition of cell migration via modulating actin cytoskeleton re-modelling and stress fibre formation and by targeting E-cadherin suppressor ZEB1. ii) Inhibiting cancer stemness in-vitro (colonosphere assays), by modulating the Wnt/β-catenin signalling pathway and possibly in a GSK-3β dependent manner. iii) The localization of FLYWCH1 speckled nuclear with splicing factor SC-35 foci, a potential mechanism involved in regulation of miRNA expression. iv) Positively regulating the expression of let-7 miRNA expression via modulating the LIN28A and LIN28B subcellular distribution. We also showed that FLYWCH1 expression is correlated positively with let-7 miRNA expression in primary colorectal cancer samples and matched metastases from patients. While we are currently striving for obtaining substantial knowledge about FLYWCH1 function in-vivo and mechanistic insight into the regulatory circuitry of FLYWCH1/miRNAs, collectively, our data suggest that FLYWCH1 possesses tumour suppressor activity and may exert its influence on cancer cells homeostasis through miRNA regulation.
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Lefaure, Jean-Marc. "Intérêt de l'antigène carcinoembryonnaire, ACE, en cancérologie digestive". Paris 5, 1991. http://www.theses.fr/1991PA05P003.
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GASPAR, LODS MANUELA. "Cancer des voies aero-digestives superieures et douleur". Besançon, 1994. http://www.theses.fr/1994BESA3030.
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Ham, Karom Hersh Abdul. "Investigate tumour heterogeneity and genetic pathways in colorectal cancer". Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/42487/.
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Background: Colorectal cancer is a major global public health problem that has predominantly been considered a genetic disease following a precise series of molecular events. These are characterized by sequential accumulation of genetic and epigenetic alteration in several oncogenes and tumour suppressor genes. Understanding of the genetic mechanisms that explain the initiation and evolution of colorectal cancer are key to improving risk prediction, prognostication and treatment. Aims: The aim of this study was to understand the basic principles of the molecular biology of colorectal cancer based on genomic, transcriptomic, and proteomic profiles analyses. Methods: DNA extracted from 147 formalin fixed paraffin embedded (FFPE) samples from 83 patients with colorectal cancer (first cohort) including (83 primary colorectal cancer (CRC), 22 matched liver metastases, 25 matched biopsies and 17 normal colon tissue) were screened for mutation in 26 genes (Trusight tumour kit) using Targeted Next Generation Sequencing. Additionally, exonuclease domain region of POLE and POLD1 were also screened using High Resolution Melting and Sanger Sequencing methods. These data used to: Investigate mutation profiles of CRCs among 83 primary samples. Investigate the difference between chromosomal instable-CRC (46 primary sample) and chromosomal and microsatellite stable-CRC (35 primary sample). Compare mutations in 26 genes of 25 paired biopsy samples and corresponding resection specimens. Investigate genetic discrepancies between 22 primary colorectal cancers and their respective metastases. Additionally, expression of a panel of six miRNAs (miR-20a, miR-21, miR-29a, miR-31, miR-92a and miR-224) was measured using RT-qPCR and protein expression of 20 genes was measured using Reverse Phase Protein Array (RPPA). In a second cohort including 81 primary CRC and their matched normal samples, expression of the six miRNAs and mRNA of six genes (SMAD4, PTEN, BCL2, TGFBRII, KLF4 and RASA1) targeted by the six miRNAs were measured using RT-qPCR. Additionally, expression of proteins of the targeted six genes was also measured using immunohistochemistry (IHC). Cell-free DNA (cfDNA) extracted from 16 blood samples (third cohort), which were taken from 5 CRC patients at different time points (pre- and post-surgery) were screened for mutations in KRAS, TP53, PTEN, SMAD4, BRAF and PIK3CA genes. Additionally, expression of the six miRNAs was measured using RTqPCR. Results: In the first part; investigating mutation profile of the first cohort 83 CRC showed high frequency of mutation in TP53 (75%), APC (57%) and KRAS (53%). Approximately 93% CRCs have mutation in at least one of APC/TP53/KRAS/BRAF/SMAD4/PIK3CA/PTEN/FBXW7 genes. Moreover, mutations were found in the exonuclease domain regions of POLE in 9.6% and POLD1 in 2.4%. Regarding biopsy vs resection, the mutant allele frequency was 1.03-fold higher in resection specimens than biopsies and there was no mutation in the biopsy specimens that were not seen in the resection specimens. In the second part; Comparison of CIN-CRC vs MACS-CRC, which were included in the first cohort CRCs showed similar mutation frequencies of mutation in all 28 genes except KRAS (41%CIN vs 68%MACS), POLE (15%CIN vs 2%MACS), GNAS (0%CIN vs 11%MACS). Statistically there was a significant difference (each p=0.01) which was lost following multiple testing correction. In the third part; comparison of primary CRC vs matched metastasis showed that a total of 61 non-synonymous somatic variations in 12 genes were found in primary 22 specimens whereas 60 were found in metastasis cases. The mutant allele frequency was 1.01-fold higher in primary than metastasis CRCs. Evaluated expression levels of six miRNAs and protein expression of other 20 genes, did not show any significant differences between primary CRC and matched metastasis. In the fourth part; Expression of the six miRNAs and mRNA and protein of the six targeted genes were tested in the second cohort 81 samples. Statistical analysis revealed significant increase in the expression level of miR-20a (p=0.04), miR-21 (p=0.01) miR-29a (p=0.03) and miR-31 (p=0.01) and decrease in the mRNA expression level of TGFBRII and RASA1 in tumour samples compared to normal tissues. IHC staining showed low expression level of SMAD4 in 51 (63%), PTEN 67 (83%), TGFBRII 65 (80%), RASA1 61 (75%) BCL2 47 (58%) and high expression of KLF4 36 (44%). High miR-21 and miR-224 expression were associated with low expression of TGFBRII. In addition, over expression of both miR-29a and miR-31 inversely correlated with RASA1. In the fifth part; Mutation in the cfDNA was detected in 5 cases. Two of these showed a loss of the mutant signal post-operatively. Whereas the mutant signal was persistent in the rest 3 of the cases for all the samples taken post-operatively. Although miRNAs expression was fluctuated between these time points, paired test showed a non-significant difference when comparing pre- and post-surgical miRNAs level. However, level of the cfmiRNAs is changed by more than 2 folds (upregulated) in the day of surgery compared to normal plasma as follow, miR- 20a in 1/5 (20%), miR-21 in 4/5 (80%), miR-29a in 3/5 (60%), miR-92a in 4/5 (80%) and miR-224 in 2/5 (40%). Conclusion: Investigation profiles of CRCs from both cohorts indicated that, different mutated genes and upregulated miRNAs, which are involved in different signalling pathways, may have roles in CRC carcinogenesis. Significant difference was neither noticed between MACS and CIN group and nor between primary and metastasis tumour. miRNAs from tissues and cfmiRNAs from plasma, can differentiate CRC from healthy group and have potential clinical value in early CRC detection. In addition to the resection specimens, the study found that it is acceptable to use biopsy material for predictive testing and cfNAs can be used for a variety of clinical and investigational applications.
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Al-Masmoum, Hussain. "An investigation of chromosome 20q13 amplification in colorectal cancer". Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/36938/.
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Background: Colorectal cancer (CRC) is the third most prevalent and second most fatal type of cancer in the Western world. 20q amplification has been identified in approximately 50% of CRC cases. 20q amplification and may be associated with liver metastasis. In our lab, a previous array comparative genomic hybridization (aCGH) study of a series of primary CRCs and corresponding liver metastases, found that the 20q13 was frequently amplified in both groups. Several known oncogenes are located at Chromosome 20q (for example SRC, TPX2 and CSE1L) suggesting that 20q amplification may be an important event in the development and metastasis of CRC. Hypothesis and Aim: Although there are many genes located in 20q identified to have role in developing CRC, other genes with potential role in tumour progression have not been studied in CRC. We hypothesized that 20q harbouring genes have a potential role in CRC progression. Therefore, we aimed to (i) study the frequency of 20q amplification in CRC by validating our aCGH data by alternative method and screen larger sample set for 20q amplification. (ii) Protein expression of candidate genes was investigated. Then, candidate genes were evaluated in several cancer related processes including proliferation and cell motility. Materials and Methods: The evaluation of 20q amplification was performed in DNA from FFPE of micro-dissected 20 CRCs and their matched liver metastasis, using comparative quantitative PCR (qPCR) based on 6 genes (PTPN1, CSE1L, ADNP, PREX1, ELMO2 and PTGIS), which are located in the same region. It was found that quantification of two genes was sufficient to evaluate amplification and thus separate series of 103 cases were screened for 20q amplification based on qPCR of two genes (ELMO2 and PTPN1). For studying the functional activity, PTPN1, CD40, PREX1, ELMO2 and PTGIS were studied in CRC cell lines. To evaluate gene function, small interference RNAs (siRNAs) were used to knockdown genes of interest in CRC cell lines. Knockdown was validated by western blot and qPCR and the effect of knockdown was evaluated on cellular functions such as proliferation, cell migration, cell invasion and wound healing. Immunohistochemistry was used to investigate protein expression in primary CRCs. Results: The amplification of 20q in CRC sample was studied by qPCR and aCGH. High concordance was found between the two methods aCGH, and high correlation coefficient between the qPCR results of the genes demonstrated the utility of this method for measuring amplification. In the combined data set, 20q amplification was seen in both primary tumours (51%) and metastases (60%). TP53 mutation was associated with 20q amplification (p =0.010). Then, we investigated the functional activity of 5 genes located on 20q, which might be has a role in CRC progression. (1) PTPN1 has been reported as tumour suppresser and oncogene. Therefore, we studied protein expression and its functional role in CRC cell lines. PTPN1 was overexpressed in 59% of primary tumours. Knockdown of PTPN1 reduced cell motility but did not affect cell proliferation. (2) CD40, previously, has been identified as a tumour suppresser in CRC. However, high CD40 expression was detected 25% of tumours. Functional assays showed CD40 promotes proliferation by altering subG1 phase of the cell cycle. Therefore, CD40 might promote tumour growth by inhibiting apoptosis. (3) PREX1 was expressed in 61% of primary tumours. Functional analysis showed that it promotes both cell proliferation and motility. (4) ELMO2 was expressed in 38% of primary tumours and functional analysis showed it promotes proliferation and cell migrations. (5) Finally, PTGIS is highly expressed in CRC and its expression associated with liver metastasis. However, PTGIS effect on tumour progression has not been studied. PTGIS knockdown had no effect on CRC cell lines growth and motility. Conclusion: Using alternative methods to evaluate the 20q13 amplification, we have confirmed our previous aCGH and found a frequency similar to that reported in the literature. Amplification of 20q appears frequently in primary tumours but it not positively associated with metastasis. Many genes located in 20q have oncogenic effects which would support the hallmarks of cancer. Understanding their role in CRC development could reveal new avenue in understanding cancer biology and treatment.
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Drugeon, Dutin Cécile. "Pratiques en cancérologie digestive : enquête prospective auprès des gastroentérologues du Sud-Ouest". Bordeaux 2, 1997. http://www.theses.fr/1997BOR2M149.
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Barabino, Gabriele. "La chirurgie digestive oncologique aidée par la fluorescence". Thesis, Saint-Etienne, 2015. http://www.theses.fr/2015STET006T/document.
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Dans notre travail de thèse, nous nous sommes attachés à répondre à cette question : peut-t-on améliorer la résécabilité tumorale dans le métastases hépatiques et péritonéales du cancer colorectal? Pour cela nous nous sommes appuyés sur deux éléments : la fluorescence du vert d’indocyanine et sa détection par la caméra NIR. Dans un premier temps, après une mise au point en laboratoire, nous avons appliqué cette technique aux résections hépatiques. Nous avons montré que cette technique a un double intérêt : la détection des lésions tumorales et l’amélioration de la marge de résection oncologique. La question encore ouverte est le pourcentage de cellules cancéreuses ou précancéreuses présentent dans cette couronne fluorescente. Dans un deuxième temps nous avons appliqué cette technique dans la carcinose péritonéale. Il s’agit d’une première étude de faisabilité car nous n’avons retrouvé aucune publication sur ce sujet. Nous avons pu montrer des similitudes avec l’étude sur le foie. La fluorescence de l’ICG permet de détecter des tumeurs du péritoine difficilement visibles à l’œil nu grâce à l’intensité et à la qualité de la fluorescence même. Les perspectives sont centrées sur deux axes: l’agent fluorescent, le vert d’indocyanine, et les caméras NIRIn our work of PhD, we endeavored to answer this question: do we can improve tumor resectability in the liver and peritoneal metastases of colorectal cancer? For this, we relied on two elements: the fluorescence of indocyanine green and its detection by NIR camera. Initially, after formal laboratory development, we applied this technique to liver resections. We have shown that this technique has two advantages: the detection of tumor lesions and improving the margin of oncologic resection. The still open question is the percentage of cancerous or precancerous cells present in the fluorescent ring. Secondly, we applied this technique in peritoneal carcinomatosis. This is a first feasibility study because we did not find any publications on this topic. We could show similarities with the study on the liver. The fluorescence from ICG can detect tumors of the peritoneum hardly visible to the naked eye through the intensity and quality of the fluorescence. The outlook is focused on two areas: the fluorescent agent, indocyanine green, and NIR cameras
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Gamelin, Erick. "Pharmacologie clinique du 5-fluorouracile et de certains sels de platine chez des patients souffrant de cancers du tractus digestif et des voies aéro-digestives supérieures". Bordeaux 2, 1997. http://www.theses.fr/1997BOR28484.
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Gemmill, Elizabeth H. "Minimally invasive gastro-oesophageal surgery for cancer : current evidence and practice". Thesis, University of Nottingham, 2012. http://eprints.nottingham.ac.uk/55424/.
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Background Since its introduction in the early 1990s, minimally invasive gastro-oesophageal surgery for cancer has been growing in popularity. Despite this, published evidence on this type of technique is weak and its role in the management of gastric and oesophageal cancer remains controversial. Aims The aim of this thesis was to test the hypothesis that: minimally invasive gastro- oesophageal cancer surgery has superior outcomes compared to control studies of conventional open surgery; but current studies are methodologically inadequate to confirm this. Methods The first study (chapter 3) is a systematic review of the literature on minimally invasive gastro-oesophageal cancer surgery, outlining the differences between literature published in Eastern and Western countries. The following 3 chapters outline and use a phase II surgical study to obtain data on minimally invasive gastro-oesophageal cancer (MIGOCS.) The MIGOCS group was set up in 2005 amongst UK surgeons. An online database was developed to enable data collection and comprises 5 sections: demographics; pre-operative staging and assessment; surgical intervention; post-operative course; pathology and clinical outcome. The first study is retrospective collecting data up to December 2006; the second study is prospective with data obtained between December 2006- July 2008 from centres around the UK utilising the MIGOCS database. Chapter 7 involves analysis of the learning curve in laparoscopic gastro-oesophageal cancer surgery using CUSUM (continuous surveillance monitoring) assessment. By studying operative time at each centre, improvement or deterioration in quality were detected. Results The systematic review of minimally invasive gastro-oesophageal surgery consists in the majority of case reports, with no randomised controlled trials of oesophagectomies and 4 (low quality) randomised controlled trials of gastrectomies. It demonstrates a mortality and morbidity of 2.3% and 46.2% respectively for oesophagectomies; 0.1% and 12.7% respectively for gastrectomies. Data from this review suggests that the minimally invasive approach is beneficial compared to open surgery in terms of reduced mortality, respiratory complications, blood loss and quicker return to a good quality of life (but not reduced hospital stay as expected.) There are currently 60 MIGOCS member consultant surgeons from over 40 UK centres. The retrospective study obtained data from 7 UK centres with an overall mortality and morbidity of 6.0% and 57% respectively for oesophagectomies and 7.7% and 13% respectively for gastrectomies. The prospective study collected data from 7 UK centres, comprising a total of 258 minimally invasive oesophagectomies and 33 minimally invasive gastrectomies. Overall mortality and morbidity were 2.5% and 56.6% respectively for oesophagectomies and 10.8% and 27.3% respectively for gastrectomies. CUSUM analysis varied considerably between centres. The two larger volume centres however demonstrated an improvement in their operative time with experience, with a possible pateau at around 30 procedures. Conclusions Published data suggests that the minimally invasive approach to gastro-oesophageal cancer has advantages over conventional open surgery. Data collected in this thesis does not overwhelmingly support published evidence, but does demonstrate that this technique is both safe and feasible even during the early part of a surgeon's learning curve. It is the first study to provide an insight into outcomes of this type of surgery in a multicentre setting in the UK; and has made progress towards a randomised controlled trial.
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LANGRAND-ESCURE, PHILIPPE. "Role de l'exerese digestive dans la chirurgie du cancer de l'ovaire". Clermont-Ferrand 1, 1989. http://www.theses.fr/1989CLF13077.
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Lasolle, Christophe. "Métastases digestives des cancers bronchiques : à propos de deux cas cliniques". Nancy 1, 1992. http://www.theses.fr/1992NAN1A002.
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Boereboom, Catherine L. "Determining the feasibility and effectiveness of high intensity interval training in preoperative colorectal cancer patients". Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/47342/.
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Colorectal cancer (CRCa) is the 4th most common cancer in the United Kingdom with 41,265 new cases diagnosed in 2014 (Cancer Research UK, 2017). Advancing age is an established risk factor for the development of CRCa (Figure 1.1); between 2012 and 2014 44% of new cancers were diagnosed in patients aged 75 years and over (Cancer Research UK, 2017). Due to our ageing population, national screening programmes and improved diagnostic techniques, a greater number of older people are now being diagnosed with CRCa. However older people are not surviving the disease as well as their younger counterparts. The 5 year survival rate from diagnosis of bowel cancer between 2009 and 2013 was 67.5% for 60-69 year old men and 45.5% for 80-99 year old men. This illustrates an increased burden of this disease in an ageing population (Cancer Research UK, 2017). In general terms, due to improvements in health screening and perioperative care, mortality from CRCa in all populations is decreasing over time. Indeed, the England and Wales age standardised 5 year survival rates for men with CRCa have increased from 24% in the early 1970s to 59% in 2010-11 (Cancer Research UK, 2017). Overall CRCa incidence is increasing over time but this is mirrored by improved survival rates. Age is a significant factor in reduced survival from colorectal cancer and efforts to improve outcomes in elderly CRCa patients should be investigated.
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Tognarelli, Bruno. "Bilan d'extension des cancers digestifs : laparoscopie ou imagerie médicale ?" Montpellier 1, 1992. http://www.theses.fr/1992MON11156.
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Benhamiche, Anne-Marie. "Épidémiologie descriptive des cancers digestifs : incidence, prévalence, tendances chronologiques". Dijon, 2000. http://www.theses.fr/2000DIJOMU05.
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Par leur fréquence et leur gravité, les cancers digestifs posent un réel problème de santé publique. Le Registre Bourguignon des Cancers Digestifs a été crée avec l'idée que la recherche épidémiologique et la recherche en santé publique permettent de concevoir de nouvelles modalités de lutte contre ces cancers. Dans ce contexte, l'objectif de ce travail est de souligner l'intérêt de l'épidémiologie descriptive. Les données collectées localement et dans le cadre du réseau FRANCIM ont modifié nos connaissances sur la fréquence des cancers digestifs qui reposaient auparavant sur les statistiques de mortalité. En France, le cancer colorectal se situe au premier rang des cancers, avec le cancer du sein. Le nombre estimé de nouveaux cas était de 33400 en 1995. L'estimation de l'incidence des cancers digestifs, à la fois sur le plan national et sur le plan régional fournit des données utiles aux décideurs sur la fréquence de ces cancers en France. L'estimation du risque cumulé de cancer colorectal dans les groupes à risque élevé (antécédants familiaux de tumeur colorectale) suggère des recommandations pratiques pour une stratégie de dépistage dans ces groupes. L'étude des tendances évolutives, fondées sur des techniques de modélisation tenant compte de l'âge, de la période de diagnostic et de la cohorte de naissance, permet une meilleure connaissance des variations temporelles et suggère des hypothèses sur le rôle des facteurs environnementaux ou alimentaires dans l'évolution de l'incidence. Au 31 décembre 1995, le nombre estimé de personnes ayant eu un cancer colorectal était de 186000. Ces données sont précieuses pour déterminer les besoins de prise en charge médicale ou de surveillance de ces cancers, concevoir et analyser des enquêtes à visée étiologique, définir ou évaluer une politique de prévention ou de dépistage.
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Lepage, Côme. "Epidémiologie des cancers digestifs rares : incidence, tendances chronologiques, pronostic". Dijon, 2007. http://www.theses.fr/2007DIJOMU01.
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L’objectif principal de ce travail était d’améliorer les connaissances épidémiologiques des tumeurs digestives rares jusqu’alors parcellaires puisque essentiellement basées sur des données hospitalières. Nous avons pu montrer qu’à l’image des autres cancers digestifs, leur incidence est en constante augmentation, et concernant adénocarcinomes de l’oesophage que cette hausse était en passe de devenir préoccupante. Ce travail réunit des données épidémiologiques sur les cancers digestifs rares à partir de bases de population qui pour la plupart étaient inexistantes. Ces données sont précieuses pour estimer la prise en charge médicale ou les besoins de surveillance de ces cancers, pour concevoir et analyser des enquêtes à visée étiologique, définir une politique de prévention et éventuellement de dépistage. Nous avons pu prouver que les données de registres avaient non seulement un intérêt dans l’étude des caractéristiques épidémiologiques des tumeurs digestives rares, mais qu’elles étaient incontournablesImportant changes have occurred in the epidemiology of rare digestive cancers. It is difficult to obtain unbiased data to study the epidemiology of those cancers. Population-based studies recording all cases in a well-defined population represent the only way to assess this disquieting situation. Thus the objective of this study was to examine trends in incidence prognosis and socio economical disparities to improve the epidemiological knowledge of these cancers. The prognosis in the general population is considerably worse than is often reported from small hospital case series. Early diagnosis is difficult: new therapeutic options appear to represent the best approach to improved prognosis. All cancers were characterised by a sharp increase of incidence over the past years, both by period and birth cohort, but the most important rise was for oesophageal adenocarcinoma. Etiological studies still necessary to understand the reasons of such a rise
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Grellet, Pierre. "Les tumeurs du tube digestif dans les Pyrénées Orientales : étude statistique de 1984 à 1990". Montpellier 1, 1992. http://www.theses.fr/1992MON11038.
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Méthy, Nicolas. "Identification et évaluation des critères de substitution en cancérologie digestive". Dijon, 2009. http://www.theses.fr/2009DIJOMU04.
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En cancérologie, le critère de jugement de référence dans les essais cliniques de phase III est la survie globale. Une longue période de suivi est parfois nécessaire à son évaluation. Le recours à un critère de substitution permet alors de réduire la durée des essais. Un critère de substitution doit permettre de prédire l'effet du traitement expérimental sur le critère clinique de référence. Deux approches statistiques sont proposées pour s'assurer de cette relation. La première consiste à estimer la proportion de l'effet traitement expliquée par le critère de substitution. La seconde, dite méta-analytique, consiste à calculer la corrélation entre les effets du traitement sur chacun des deux critères. Peu de critères de substitution sont validés en cancérologie digestive. Une enquête par questionnaires auprès de cliniciens et de méthodologistes a permis de constituer une liste ordonnée de critères candidats à de futures études de validation. Les mieux classés étaient la survie sans maladie et la survie sans progression associée ou non à la qualité de vie. Dans les essais néo-adjuvants du cancer du rectum, les paramètres anatomopathologiques permettent une évaluation précoce de l'effet du traitement. Leur valeur substitutive a été évaluée dans l’essai FFCD 9203. Les analyses n'ont pas permis de valider ces paramètres comme critères de substitution de la survie globale ou du contrôle local. Des analyses poolées avec l'essai EORTC 22921 ont confirmé ces résultats. Les analyses préliminaires avec la technique méta-analytique suggèrent que la survie sans progression pourrait être substitutive de la survie globaleOverall survival is the gold standard endpoint in phase III cancer clinical trials. Its evaluation may require long follow-up. The use of surrogate endpoints allows to reduce trial duration. A surrogate endpoint is expected to predict treatment effect on the clinical endpoint of interest. Two statistical methods have been proposed to evaluate a surrogate endpoint. The first one consists in estimating the proportion of treatment effect explained by the surrogate. The second one is a meta-analytical approach consisting in calculating the correlation between treatment effects on each endpoint. To date, few surrogates have been validated in digestive oncology. A questionnaires survey among clinicians and methodologists allowed to draw up an ordered list of potential surrogates, candidate for statistical evaluations. Best rated endpoints were disease-free survival and progression-free survival in association or not with quality of life. In neo-adjuvant rectal cancer trials, pathological parameters are early indicators of treatment effect. Their surrogacy was evaluated in the FFCD 9203 trial. Single-trial analyses did not validate these parameters as surrogate endpoints for overall survival or local control. Pooled analyses with the EORTC 22921 trial confirmed these results. Preliminary analyses using the meta-analytical technique have suggested that progression-free survival could be surrogate for overall survival
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Faivre-Finn, Corinne. "Amélioration des pratiques de soin et du pronostic du cancer colo-rectal : études de population". Dijon, 2001. http://www.theses.fr/2001DIJOMU10.
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LA PRISE EN CHARGE DU CANCER COLO-RECTAL A BEAUCOUP EVOLUE AU COURS DES 25 DERNIERES ANNEES. TRES PEU DE DONNEES SONT DISPONIBLES CONCERNANT LES AMELIORATIONS THERAPEUTIQUES, L'IMPACT DES ESSAIS THERAPEUTIQUES SUR LES PRATIQUES DE SOIN ET L'EVOLUTION DU PRONOSTIC DE CETTE MALADIE A L'ECHELLE D'UNE POPULATION. CE TRAVAIL EST BASE SUR LES REGISTRES DES TUMEURS DIGESTIVES DE LA COTE-D'OR, DE LA SAONE ET LOIRE ET DU CALVADOS. LE TAUX D'EXERESE EST PASSE DE 66. O % A 80. 1 % ENTRE 1978 A 1993 POUR LE CANCER DU RECTUM ET DE 69. 3 % A 91. 9 % ENTRE 1976 ET 1991 (TAUX STABLE APRES 1991) POUR LE CANCER DU COLON. POUR LES CANCERS DU COLON ET DU RECTUM, LE TAUX DE PATIENTS DIAGNOSTIQUES AUX STADES I ET II A GLOBALEMENT AUGMENTE, CORRESPONDANT A UNE DIMINUTION DU TAUX DE PATIENTS DIAGNOSTIQUE A DES STADES AVANCES. LES AUTRES PROGRES MAJEURS CONCERNANT LE CANCER DU RECTUM SONT L'AUGMENTATION DU TAUX DE CONSERVATION SPHINCTERIENNE ET DU TAUX DE PATIENTS TRAITES AVEC UNE RADIOTHERAPIE ADJUVANTE. CONCERNAT LES CANCERS DU COLON, LE TAUX DE PATIENTS TRAITES AVEC UNE CHIMIOTHERAPIE ADJUVANTE A NETTEMENT AUGMENTE POUR LES STADES III MAIS AUSSI POUR LES STADES II. ENFIN LE TAUX DE MORTALITE POSTOPERATOIRE A DIMINUE SIGNIFICATIVEMENT POUR CES DEUX LOCALISATIONS. L'ENSEMBLE DE CES AMELIORATIONS A CONDUIT A UNE AMELIORATION DES TAUX DE SURVIE RELATIVE A 5 ANS PASSANT DE 35. 4 % (PERIODE 1978-1981) A57. 0 % (PERIODE 1985-1989) POUR LE CANCER DU RECTUM ET DE 33. 0 % A 55. 3 % (PERIODE 1976-1979) A 55. 3 %(sic) (PERIODE 1992-1995) POUR LE CANCER DU COLON. L'ENSEMBLE DE CE TRAVAIL MONTRE QUE MALGRE LES AMELIORATIONS IMPORTANTES QUI ONT EU LIEU LA PRISE EN CHARGE DU CANCER COLORECTAL (sic) DES PROGRES SONT TOUJOURS POSSIBLES, PARTICULIEREMENT CHEZ LES SUJETS AGES DE PLUS DE 75 ANS.
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Constant, Emilie. "Approche multidimensionnelle de l’intimité conjugale et de ses déterminants socio-cognitifs et émotionnels : du couple tout-venant au couple confronté au cancer digestif". Thesis, Lille 3, 2016. http://www.theses.fr/2016LIL30028.
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Un sentiment global d’intimité se construit à travers des composantes comportementales ainsi que, des expériences d’intimité qui correspondent à la perception de la réactivité du partenaire. De plus, la manière dont les individus appréhendent leurs relations interpersonnelles ainsi que leurs émotions et celles d’autrui, est susceptible d’influencer la construction de cette intimité. La qualité de l’intimité conjugale se caractériserait par trois dimensions : (1) un sentiment de connexion, (2) une bonne communication et (3) un partage de loisirs avec des amis communs (Article 1). En outre, la construction d’un sentiment d’intimité dans une relation de couple dépendrait du profil d’attachement des individus et de leurs compétences émotionnelles à gérer leurs émotions. Cependant, avoir des compétences élevées pour gérer les émotions des autres serait néfaste pour la qualité de l’intimité perçue (Article 2). Dans une interaction conflictuelle de couple, il existe une relation entre la réactivité perçue vis-à-vis de soi et de son partenaire et les réponses physiologiques des partenaires produites au cours de l'interaction. Plus précisément, la perception des partenaires de la réactivité de l’homme serait associée à des patterns d’activations physiologiques émotionnelles différents selon leur sexe. Aussi, la perception de l’homme envers sa propre réactivité lui permettrait une meilleure régulation émotionnelle (Article 3). Les comportements verbaux et non verbaux exprimés par les partenaires seraient également associés à un degré d’intimité différent selon le sexe (Article 4). Dans un contexte de maladie, ces comportements d’intimité exprimés entre les partenaires lors d’une interaction liée à leur vécu du cancer digestif refléteraient un ajustement émotionnel spécifique selon le rôle social de patient et d’aidant (Article 5). Une discussion intégrative de ces différents éléments empiriques nous amène à proposer des pistes de recherches et d’interventions thérapeutiques dans le domaine du coupleAn overall feeling of intimacy is constructed through behavioral components as well as, experiences of intimacy that correspond to the perception of partner responsiveness. Besides, the way in which people shape their interpersonal relationships and their own emotions and that of others, might influence the construction of this intimacy. The quality of romantic intimacy would be characterized by three dimensions: (1) a feeling of connection, (2) good communication and (3) sharing of leisure time with mutual friends (Article 1). Furthermore, the construction of a feeling of intimacy in couple relationship would depend on the people’s profile of attachment and their emotional competences to deal with their own emotions. However, have high competences to deal with the emotions of others would be harmful for the quality of intimacy perceived (Article 2). In conflictive interaction of couple, there is a relation between the responsiveness perceived toward oneself and one’s partner. In particular, the husbands’ responsiveness perceived by the two partners would be associated with different patterns of physiological emotional arousal, according to their gender (Article 3). Verbal and nonverbal behaviors expressed by the partners would be also associated with a different level of intimacy according to the gender (Article 4). In a context of disease, these intimate behaviors expressed between the partners during an interaction about their life experience of the digestive cancer would reflect a specific emotional adjustment according to their social role of patient and caregiver (Article 5). An integrative discussion of these empirical evidences leads us to propose future research and clinical interventions in the field of couple relationships
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Murphy, Jamie. "The role of PROM-1/CD/AC133 in colorectal cancer". Thesis, Queen Mary, University of London, 2012. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8838.
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Background: Colorectal cancer is the result of dysregulation within classic regulatory pathways in epithelial stem-cell(s): the precursors giving rise to all other intestinal lineages. The resulting cancer stem-cell (CSC) generates tumours utilising its innate properties, e.g. self-renewal and lineage plasticity. CSCs appear to persist within a tumour as a distinct subtype responsible for local recurrence/metastasis. Therefore, therapies targeting colorectal CSCs may lead to improved cancer-specific outcome measures. The PROM-1/CD/AC133 cell surface marker has been associated with colorectal CSCs and its expression is reported as an independent negative prognostic marker. Therefore, this thesis sought to investigate the role of PROM-1/CD/AC133 in colorectal cancer. Methods: Tissue-culture, RT-qPCR, IHC, Western blotting, siRNA, PCR-array and FACS analyses were used to quantify and profile mRNA/protein expression patterns. Results: PROM-1/CD/AC133 was widely expressed in patient-matched colorectal tumour, adjacent normal epithelium, vascular invasion, lymph node metastases with significantly decreased expression in liver metastases. Furthermore, PROM- 1/CD/AC133 expression was not found to enrich colorectal cancer cell line populations for additional stem cell phenotypes (expression of ABCB1/ABCG2/BMIJ Murphy 1/CD44/LGR5/MSI-1). The data confirm the presence of alternative splice variants of PROM-1, and show that transcripts specifying PDZ binding predominate in colorectal cancer cell lines. Concomitantly, siPROM-1 was shown to modulate the expression of several key transcripts in colorectal tumourigenesis as well as regulate signal transduction pathways including the central cancer, colorectal cancer, NF-kB and p53 signalling cascades. Conclusions: PROM-1/CD/AC133 does not identify rare colorectal cancer cells responsible for tumourigenesis. However, it is associated with the regulation of signalling networks associated with cell growth, differentiation and apoptosis suggesting a potential role for this marker in colorectal tumourigenesis. The identification of specific target genes and signalling pathways in this thesis provides a springboard for further investigations into the functional role of this marker in colorectal cancer, with the potential for better treatments for this disease.
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Moka, Nagaishwarya, Manisha Nukavarapu, Jennifer Phemister i Mckinney Jason. "Small cell lung cancer(SCLC) disguised as Dysphagia". Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/asrf/2019/schedule/168.
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Common presenting symptoms of Lung cancer are cough, hemoptysis, chest pain, dyspnea, pleurisy. Dysphagia is a very uncommon presenting feature of Lung cancer. Incidence of Dysphagia in Lung cancer is unclear from Literature. Causes of Dysphagia in case of Lung cancer are Anatomically classified as Oropharyngeal and Esophageal. Causes of oropharyngeal dysphagia are oral candidiasis, oropharyngeal Metastasis of Lung cancer. Causes of esophageal dysphagia are Cervical or Mediastinal Lymphadenopathy, Motor dysfunction because of Brain stem Metastasis, Lambert eaton syndrome, Esophageal candidiasis, Radiation esophagitis. Here by we present an Unusual presentation of an aggressive disease, poorly differentiated SCLC presenting as Mid esophageal dysphagia secondary to extrinsic esophageal compression.
65 year old female with past medical history of Diabetes, Hypertension presented with complaints of worsening sub sternal chest pain radiating to back since last 2 days and progressive dysphagia. Pt underwent Left heart catheterization revealing non obstructive coronary artery disease. Modified Barium swallow showed stasis of contrast in mid esophagus, Endoscopy showed extrinsic compression of the proximal esophagus, normal mucosa. Computerized tomography of chest was done for further evaluation, revealing extensive left cervical, mediastinal, left hilar lymphadenopathy causing extrinsic compression of the esophagus and encasement of the left hilar structures. Further evaluation through Bronchoscopic biopsy of her left upper lobe mass reveals poorly differentiated small cell carcinoma. Staging was performed revealing limited stage disease. Started on concurrent chemotherapy with cisplatin, etoposide and radiation. As SCLC is highly responsive to chemotherapy and radiotherapy sensitive patient got symptomatic relief by the end of first cycle.
SCLC is an aggressive lung cancer. As it is a micro metastatic disease in nature at presentation, it’s management is entirely different from Non SCLC. SCLC being an aggressive disease can cause dysphagia in 1-2% during the disease course. SCLC presenting as dysphagia is almost never reported in the literature. Our patient presented with severe dysphagia, described it as “a tennis ball sitting in her food pipe”. Fortunately she presented to the Emergency room with dysphagia and associated chest pain, we were able to make early diagnosis of SCLC, initiate treatment. Delay in the diagnosis lead to rapid progression of disease and poor prognosis. Through our case we wanted to convey that it is very important to obtain meticulous history, keeping broad differentials, which can help improve prognosis. Because not always the presenting features are from the organ of involvement it could be from the contiguous spread or compression.
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Albasri, Abdulkader. "An investigation of the role of C-terminal tensin-like (Cten) gene in colorectal cancer". Thesis, University of Nottingham, 2011. http://eprints.nottingham.ac.uk/12055/.
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The C-terminal tensin-like (Cten) gene is a member of the tensin family and is localised at the cytoplasmic tail of β-integrin. It is involved in various biological events although the role of in the development of colorectal cancer (CRC) is uncertain. In order to study this, the expression of Cten during the development of CRC was initially evaluated using immunohistochemistry (IHC) on colorectal adenomas and carcinomas. Positive immunoreactivity for Cten was observed in 317/342 (92.6%) of CRC and 19/20 (90%) of colorectal adenoma. High Cten expression was significantly associated with advance Dukes stage (p=0.001), lymph node metastasis (p<0.001), extra-mural vascular invasion (p=0.001) and distant metastases (p=0.008). Survival analysis demonstrated that patients with high Cten expression had significantly shorter disease free survival (DFS) on univariate analysis (p<0.001) a trend towards Cten expression as an independent predictor of DFS on multivariate analysis (p=0.071). To further test the association with metastasis, the role of Cten in metastasis was tested by (a) intrasplenic injection of CRC cells stably transfected with Green Fluorescent Protein (GFP) tagged Cten into nude mice and (b) testing a series of primary CRCs and their metastases by IHC. Compared with control mice (injected with cells transfected with GFP empty vector), mice injected with cells expressing Cten developed larger tumours in the spleen (p=0.03) and liver (p=0.05). Compared with primary tumours, the metastatic deposits had a significantly higher frequency of nuclear localisation of Cten (p=0.002). To further investigate the potential role of Cten in metastasis, in-vitro models were used to investigate Cten function. Ectopic expression of Cten in the HCT116 CRC cell line (which expresses low levels of Cten) caused changes in cell morphology and increased cell motility (both migration and invasion). Conversely, the reciprocal Cten knock-down experiments in SW620 CRC cell line (which expresses high levels of Cten) resulted in inhibition of both cell migration and invasion. Since Cten is in complex with integrins at focal adhesions, its interactiosn with integrin-linked kinase (ILK), focal adhesion kinase (FAK) and CD24 were tested. Cten was shown to regulate ILK, FAK and CD24. Moreover, inhibition of CD24 after forced expression of Cten abrogated the Cten-mediated effects on both cell motility and protein levels of ILK and FAK. The studies were expanded and Cten expression was tested by IHC in another cancer model i.e. breast cancer (BC).Consistent with the data from CRC, increased Cten expression in BC was found to be associated with poor prognostic variables and shorter disease free survival. In conclusion, Cten expression is associated with poor prognosis in CRC and BC. This may be consequent to an ability to enhance metastasis which is related to promotion of cell motility. The activities of Cten are probably consistent across different tumour models.
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Findlay, John Mitchell. "Precision staging and management of Barrett's oesophagus and oesophageal cancer : genomic, imaging and pathological biomarkers". Thesis, University of Nottingham, 2016. http://eprints.nottingham.ac.uk/38037/.
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Barrett’s oesophagus and oesophageal cancer represent two of the most important and challenging oesophageal disease processes globally, combining increasing incidences with high morbidity treatments, often with poor clinical outcomes. A major contributory factor is that disease susceptibility, progression and response to therapy are largely unpredictable, due to inherent biological complexity and variability. At present, just staging groups are used routinely as thresholds for guiding the use of therapies such as ablation, resection, and oncological therapies. However, these represent blunt tools that do not necessarily reflect patients’ experiences, or appropriately select from the range of treatments available. The aim of this thesis was to explore the potential of genomic, imaging, and pathological biomarkers in guiding more tailored and personalised therapy. The first half of this thesis explores the role of genomic markers. The first results chapter describes the identification of new loci and gene pathways associated with susceptibility to Barrett’s oesophagus, dysplasia and oesophageal adenocarcinoma, by further replication and analysis of a genome-wide association study. In addition, all reported genomic markers of these endpoints were identified and criticised by systematic review, and synthesised by meta-analysis. Validation of these was then attempted, and lessons for markers and future research drawn. The second results chapter describes a similar appraisal and synthesis of genomic markers of oesophageal cancer prognosis, response to therapy, and stage. The third describes the first next generation sequencing study performed in oesophageal adenocarcinoma (and indeed any gastrointestinal cancer as far as the author is aware), before and after neoadjuvant chemotherapy. Using whole exome sequencing a new model of genomic tumour response was developed, and the implications for biomarkers explored. The second half of this thesis follows a large cohort of patients with oesophageal cancer, from nearly 1000 undergoing staging, to more than 300 undergoing neoadjuvant chemotherapy, restaging and resection. In the fourth results chapter, the first application of decision theory to cancer staging identified the potential for routine imaging data to personalise and optimise oesophageal cancer staging. In the following chapter, positron emission tomography-computed tomography was found to be more sensitive for identifying disease progression during neoadjuvant chemotherapy than computed tomography alone. Two factors were identified that could stratify risk of progression to incurable disease, including that encountered at surgery. These included 18F-FDG avid nodes, with new concepts of metabolic nodal stage and response developed in conjunction with predictive models. Thereafter, a number of conventional and experimental metrics of metabolic tumour response were compared and refined as predictors of pathological response. Existing metrics of metabolic tumour response were found to be suboptimal, and these new concepts and classifications of metabolic nodal stage and response were found to have independent utility for clinical practice. Again, predictive models were generated. Finally, the prognostic utilities of these markers were explored. Metabolic tumour response was found to be an imperfect surrogate of pathological response. However, metabolic nodal response demonstrated independent utility in identifying patients at high risk of early recurrence and death, both when used before surgery and afterwards. Indeed, a number of analyses demonstrated the additive utility of considering the primary tumour and nodal metastases as separate entities. Finally, prognostic models were generated, and a simple risk score was generated, using the four independent prognostic markers identified to stratify prognosis.
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TOUILLON, ANVARI NASSIME. "Incidence des cancers digestifs en saone-et-loire (1982-1992)". Dijon, 1994. http://www.theses.fr/1994DIJOM108.
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Ducreux, Michel. "Tumeurs neuroendocrines : nouvelles approches diagnostiques et thérapeutiques, facteurs pronostiques". Dijon, 2000. http://www.theses.fr/2000DIJOMU16.
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Les tumeurs neuroendocrines (tne) sont des tumeurs rares dont le point de depart est le plus souvent digestif. Les objectifs de ce travail ont ete de definir la place des nouveaux examens, l'efficacite des nouvelles therapeutiques permettant d'ameliorer la strategie diagnostique et therapeutique de ces tumeurs. Apres une premiere etude demontrant le peu d'interet de la recherche de catecholamines urinaires, une seconde etude a montre que la chromogranine a etait plus sensible et avait une meilleure valeur predictive positive que l'enolase neurone-specifique. Enfin une grande etude de screening menee chez 130 patients consecutifs a determine les recherches hormonales qu'il fallait effectuer en fonction du siege de la tumeur. Bilan limite en cas de tne du grele ou de l'appendice, bilan plus exhaustif en cas de tne pancreatique. Apres la demonstration d'une equi-efficacite du lanreotide par rapport a l'octreotide dans le traitement du syndrome carcinoidien, une etude de phase ii a evalue l'effet anti-tumoral de ce nouvel analogue de la somatostatine. Quarante-six patients ont ainsi ete traites par le lanreotide administre tous les 15 jours.
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VOLPATTO, SILVIO. "Robotic technology and endoluminal surgery in digestive surgery". Doctoral thesis, Politecnico di Torino, 2018. http://hdl.handle.net/11583/2709912.
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BACKGROUND. Colorectal cancer (CRC) is the third most common cancer in males and second in females, and the fourth most common cause of cancer death worldwide. The implementation of screening programs has allowed to the identification of an increasing number of early-stage neoplastic lesions. Presently, superficial colorectal neoplasms (including precancerous lesions and early cancer) can be resected in the colon by Endoscopic Mucosal Resection (EMR) and Endoscopic Submucosal Dissection (ESD), while in the rectum by Transanal Endoscopic Microsurgery (TEM). They are the preferred choices inside of the minimally invasive panorama regarding the CRC treatment. TEM technique offers more advantages than EMR and ESD, but it can’t overcome the recto-sigmoid junction. Many authors, research institutes and biomedical industries have proposed different solutions for microsurgery dissection of early lesions in the colon, but all these proposals have in common the development of platforms expressly designed for this use, with significant purchasing and management costs. The aim of our research project is to develop a robotic platform that allows to treat lesions throughout the colon limiting the costs of management and purchasing. This new robotic platform, developed in collaboration with Scuola Superiore Sant’Anna in Pisa, is called RED (Robot for Endoscopic Dissection). At the tip of a standard endoscope a hood (RED) is placed. RED is equipped by two extractable teleoperated robotic arms (i.e., diathermic hook and gripper); their motion is provided by onboard miniaturized commercial motors and a dedicated external platform. The endoscopist holds the endoscope near the lesion, while the operator drives the robotic arms through a remote control.
MATERIALS AND METHODS. Several preliminary studies have been conducted in the following order. A first test was conducted for identification of force value for lifting and pulling maneuvers using a modified TEM instrument. A CAD study was conducted to determine the maximum size that the hood must have in order to overcome the critical angle represented by the splenic flexure. Several tests were conducted to determine the degrees of freedom of each robotic arm, starting with the CAD drawing to make subsequently the mock-ups of each configuration. Finally, a 3D mock-up was produced that was assembled on an endoscope to perform the in vitro test to evaluate the workspace and field of view using a pelvic trainer for TEM.
RESULTS. The first test shown that the minimum force that the gripper will have to develop with the push-pull is 1.5N. The CAD study shown that the maximum dimensions the hood must have to overcome splenic flexure are: maximum diameter 28mm, maximum length 57mm. After several configurations was been tested, the final prototype features are: gripper arm with pitch sliding and open/close of the tip and diathermic hook arm with pitch, roll and sliding. There will be 6 such distributed motors: 3 external motors for the gripper arm that will operate through cables contained in a sheath adherent to colonscope and 3 embedded motors for diathermic hook arm (one integrated on the hood for the sliding degree of motion and the other two inside of the arm). The in-vitro test has been carried out to evaluate the workspace and they proved that the operating field vision is not obstructed by the hood and the working range is sufficiently wide to perform a dissection.
CONCLUSION. Tests conducted up to this point have allowed us to identify the overall layout of the RED: dimensions, degrees of freedom, number and distribution of motors needed for the operation of robotic arms; moreover, it is proved that the device, once assembled, maintained the visual and operational field characteristics necessary to perform an accurate dissection. The next step will be to realize a RED steel final prototype and in-vivo tests will be carry out to replicate an endoscopic dissection into the colon.
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Maxwell-Armstrong, Charles Alan. "Studies using the anti-idiotypic monoclonal antibody 105AD7 in patients with advanced and primary colorectal cancer". Thesis, University of Nottingham, 1998. http://eprints.nottingham.ac.uk/14137/.
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Introduction. The anti-idiotypic monoclonal antibody 10SAD7 mimics the tumour associated antigen 791T/ gp72, present on approximately 80% of colorectal cancer cells. A Phase I study using 10SAD7 in 13 patients with advanced colorectal cancer has shown that it is nontoxic, and conferred a survival advantage on patients who received it [Denton GWL 1994]. Aim. There were two aims of this work. The first was to assess whether. the survival advantage seen in the Phase I study was reproducible in a Phase II study. The second was to immunise patients with primary colorectal cancer, in a non-randomised adjuvant study, and explore further the immune responses generated. Materials and Methods. Patients with advanced colorectal cancer were recruited to a randomised, double-blind, placebo controlled survival study. The first patient was recruited to this Phase II study in April 1994, and the last in October 1996. Four trial centres were used- Nottingham, Hull, Leeds, and Newcastle. Eligible patients had a life expectancy of 3 months, and none had received radiotherapy or chemotherapy in the preceding 1 and 3 months, respectively. Patients attended on 3 occasions, 6 weeks apart, receiving 10µg of 10SAD7/alum i.d. followed by 100µg i.m. Venous blood was assayed for blood count and differential, liver function, urea and electrolytes, and CEA. Chest X-rays and CT scans were performed at trial entry and week 12 where possible. Dates of death were recorded following consultation with General Practitioner or referring clinician. In addition, patients with primary colorectal cancer were recruited to a non-randomised adjuvant study, whereby they received 10SAD7 before surgery. Venous blood samples were taken between immunisation and operation, and assayed for lymphocyte subsets. Samples taken from resection specimens were analysed immunohistochemically. Fresh tumours were in addition disaggregated, and separated TIL labelled with a panel of monoclonal antibodies, and analysed by flow cytometry. Control tumours were similarly labelled. All analysis was performed blind. Results. 162 patients were randomised to the Phase II study, between April 1994 and October 1996. 85 received 105AD7 and 77 placebo. The mean ages and sex-ratios of the two groups were comparable, as was the time from diagnosis of advanced disease to trial entry (172v179 days). Median survival from date on study was 124 and 184 days, in 105AD7 and placebo arms, respectively (p=O.38). Survival from date of diagnosis of advanced disease was 456 and 486 days (p=O.82). Chemotherapy and radiotherapy all prolonged survival in a multivariate analysis. Only one serious adverse event was seen in the 105AD7 arm, and this was felt unlikely to be attributable to the vaccine. Twenty-four patients were recruited to the adjuvant study. Immunohistochemical analysis of tumour sections from 16 patients showed increased infiltration of CD4 and CD8 expressing lymphocytes, relative to a well matched control group (p
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Segara, Davendra St Vincents Hospital Clinical School UNSW. "Studies of retinoic acid signalling in pancreatic cancer". Awarded by:University of New South Wales. St Vincents Hospital Clinical School, 2006. http://handle.unsw.edu.au/1959.4/26269.
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Pancreatic cancer (PC) is the fourth leading cause of cancer death in Western societies. Despite significant progress in understanding the molecular pathology of PC and its precursor lesion: pancreatic intraepithelial neoplasia (PanIN), there remain no molecules with proven clinical utility. Affymetrix Genechipfi oligonucleotide microarrays were used to interrogate mRNA expression of PC and normal pancreas to identify molecular pathways dysregulated in PC. Analysis of these data identified altered expression of numerous components of the S100 Calcium Binding Protein Family, Retinoic Acid signalling pathway and the HOX transcriptional network in PC compared to normal pancreas. These pathways were assessed using immunohistochemistry (IHC) and in-situ hybridisation (ISH) in a cohort of patients with PC. Increased protein expression, of S100A2, S100A6 and S100P was observed in 43%, 60% and 48% of PC respectively. Expression of S100A2 was associated with a poor outcome (p = 0.009), whilst increased expression of S100A6 (p = 0.0008) and S100P (p = 0.0005) were associated with an improved outcome. Additionally, S100A2 expression was identified as an independent marker of outcome in resected tumours. Aberrant expression of retinoic acid signalling components was demonstrated in PC cell lines using semi-quantitative RT-PCR. ISH demonstrated expression of Retinoic Acid Induced 3 (RAI3), an orphan G protein coupled receptor normally expressed in the fetal lung, in 68% of PC, and this co-segregated with an improved overall survival (p = 0.026).Ectopic protein expression of HOXB2, a transcription factor normally expressed in the developing hindbrain and modulated by retinoic acid, was observed in 15% of early PanIN lesions and 38% of PC specimens. Expression of HOXB2 was associated with non-resectable tumours and was an independent predictor of poor survival in resected tumours. Suppression of HOXB2 protein expression using small interfering RNA, resulted in epithelioid trans-differentiation in the Panc-1 PC cell line, however no alteration in proliferation rates were observed compared to controls. This thesis has shown that transcript profiling and tissue validation has identified potential markers of early diagnosis and outcome in PC. Furthermore, pathways and molecules previously thought to be associated with normal human development have been implicated to play a role in the development and progression of PC. Further analyses of these markers will determine any potential role in future diagnostic and therapeutic strategies.
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Badoual, Cécile. "Rôle pronostique des lymphocytes T CD4+CD25+ intratumoraux et analyse des mécanismes de production du CD25 soluble dans les tumeurs des voies aéro-digestives supérieures". Paris 6, 2005. http://www.theses.fr/2005PA066467.
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