Rozprawy doktorskie: „Colorectal neoplasia”

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Pye, G. "Gastrointestinal pH and colorectal neoplasia." Thesis, University of Nottingham, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.381466.

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Kim, Sangmi Sandler Robert Samuel. "Obesity, inflammation and colorectal neoplasia." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,2164.

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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007. Title from electronic title page (viewed Feb. 26, 2009). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Epidemiology, School of Public Health." Discipline: Epidemiology; Department/School: Public Health.

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LaPointe, Lawrence C., and larry lapointe@flinders edu au. "Gene expression biomarkers for colorectal neoplasia." Flinders University. School of Medicine, 2009. http://catalogue.flinders.edu.au./local/adt/public/adt-SFU20091011.090028.

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The aim of this research was to assemble sufficient experimental evidence about candidate gene transcript expression changes between non-neoplastic and neo- plastic colorectal tissues to justify future assay development involving promis- ing leads. To achieve this aim, this thesis explores the hypothesis that gene expression-based biomarkers can be used to accurately discriminate colorectal neoplastic tissues from non-neoplastic controls. This hypothesis was tested by first analysing multiple, large, quality controlled data sets comprising gene expression measurements across colorectal phenotypes to discover potential biomarkers. Candidate biomarkers were then subjected to validation testing using a custom-design oligonucleotide microarray applied to independently derived clinical specimens. A number of novel conclusions are reached based on these data. The most important conclusion is that a defined subset of genes expressed in the colorectal mucosa are reliably differentially ex- pressed in neoplastic tissues. In particular, the apparently high prediction accu- racy achieved for single gene transcripts to discriminate hundreds of neoplastic and non-neoplastic tissues provides compelling evidence that the resulting can- didate genes are worthy of further biomarker research. In addition to addressing the central hypothesis, additional contributions are made to the field of colorectal neoplasia gene expression profiling. These contributions include: The first systematic analysis of gene expression in non-diseased tissues along the colorectum To better understand the range of gene expression in non-diseased tissues, RNA extracts taken from along the longitudinal axis of the large intestine were studied. The development of quality control methodologies for high dimen- sional gene expression data Complex data collection platforms such as oligonucleotide microarrays introduce the potential for unrecognized confound- ing variables. The exploration of quality control parameters across five hundred microarray experiments provided insights about quality control techniques. The design of a custom microrray comprised of oligonucleotide probe- sets hybridising to RNA transcripts differentially expressed in neo- plastic colorectal specimens A custom design oligonucleotide microarray was designed and tested combining the results of multiple biomarker discovery projects. Introduction of a method to filter differentially expressed genes dur- ing discovery that may improve validation efficiencies of biomarker discovery based on gene expression measurements Differential expression discovery research is typically focused only on quantitative changes in transcript concentration between phenotype contrasts. This work introduces a method for generating hypotheses related to transcripts which may be quali- tatively switched-on between phenotypes. Identification of mRNA transcripts which are differentially expressed between colorectal adenomas and colorectal cancer tissues Transcripts differentially expressed between adenomatous and cancerous RNA extracts were discovered and then tested in independent tissues. In conclusion, these results confirm the hypothesis that gene expression profiling can discriminate colorectal neoplasia (including adenomas) from non-neoplastic controls. These results also establish a foundation for an ongoing biomarker development program.

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Bhaskar, P. "Molecular mechanisms of colorectal neoplasia in acromegaly." Thesis, University of Newcastle upon Tyne, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.405070.

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Hubner, Richard Anthony. "Low penetrance polymorphisms and colorectal neoplasia susceptibility." Thesis, Institute of Cancer Research (University Of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.499095.

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Liu, Lin, Karen Messer, John A. Baron, David A. Lieberman, Elizabeth T. Jacobs, Amanda J. Cross, Gwen Murphy, Maria Elena Martinez, and Samir Gupta. "A prognostic model for advanced colorectal neoplasia recurrence." SPRINGER, 2016. http://hdl.handle.net/10150/621531.

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Following colonoscopic polypectomy, US Multisociety Task Force (USMSTF) guidelines stratify patients based on risk of subsequent advanced neoplasia (AN) using number, size, and histology of resected polyps, but have only moderate sensitivity and specificity. We hypothesized that a state-of-the-art statistical prediction model might improve identification of patients at high risk of future AN and address these challenges. Data were pooled from seven prospective studies which had follow-up ascertainment of metachronous AN within 3-5 years of baseline polypectomy (combined n = 8,228). Pooled data were randomly split into training (n = 5,483) and validation (n = 2,745) sets. A prognostic model was developed using best practices. Two risk cut-points were identified in the training data which achieved a 10 percentage point improvement in sensitivity and specificity, respectively, over current USMSTF guidelines. Clinical benefit of USMSTF versus model-based risk stratification was then estimated using validation data. The final model included polyp location, prior polyp history, patient age, and number, size and histology of resected polyps. The first risk cut-point improved sensitivity but with loss of specificity. The second risk cut-point improved specificity without loss of sensitivity (specificity 46.2 % model vs. 42.1 % guidelines, p < 0.001; sensitivity 75.8 % model vs. 74.0 % guidelines, p = 0.64). Estimated AUC was 65 % (95 % CI: 62-69 %). This model-based approach allows flexibility in trading sensitivity and specificity, which can optimize colonoscopy over- versus underuse rates. Only modest improvements in prognostic power are possible using currently available clinical data. Research considering additional factors such as adenoma detection rate for risk prediction appears warranted.

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Parra, del Riego A., Sparks A. Olivares, B. F. Barreda, and Nilton Yhuri Carreazo. "Advanced colorectal neoplasia: The importance of adequate classification." Asociación Mexicana de Gastroenterología, 2016. http://hdl.handle.net/10757/605890.

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Botteri, E. "IMPACT OF LIFESTYLE FACTORS ON SCREENING-DETECTED COLORECTAL NEOPLASIA." Doctoral thesis, Università degli Studi di Milano, 2013. http://hdl.handle.net/2434/215071.

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Background and aims: The detection and removal of precancerous lesions through colorectal cancer (CRC) screening, and the intervention on modifiable risk factors for CRC - such as smoking habits, physical activity, red meat consumption and alcohol intake - represent the two possible ways for reducing CRC incidence and mortality. The aim of this project was to investigate whether lifestyle factors, gender, family history and daily low-dose Aspirin use are important factors in predicting endoscopy findings at a first round screening level and whether they can have a significant impact on the natural history of the disease in screened patients during their follow-up (second round screening level). Patients and methods: Me and my work team identified and selected a study population of 870 men and women of age 50-74 years who underwent a screening colonoscopy at the European Institute of Oncology (IEO) between the years 2007-2009 after a positive Fecal Occult Blood Test (FOBT+). We set up a telephone questionnaire in order to retrieve information on smoking habits, BMI, physical activity, diet, alcohol consumption, family history and usage of low-dose Aspirin at the time of the first colonoscopy. All patients were then interviewed by me by telephone. Ninety-five individuals were not interviewed for various reasons, making the final population size n=775. Patients who could answer the questionnaire were similar to the unreached individuals in terms of outcome of the first colonoscopy. Results: At first colonoscopy, we observed 415 patients presenting with a high-risk neoplasia (i.e. 3 or more adenomas or at least one adenoma bigger than 10 mm / with villous component / with high-grade dysplasia or invasive tumor). At the univariate analysis, gender, family history, physical activity, smoking habits, alcohol intake, fruit and vegetable intake and daily low-dose Aspirin were associated with the prevalence of high-risk neoplasia. Using a “Spike at zero function”, we showed that light drinkers (<5 grams per day) seemed to have a lower risk of high-risk neoplasia compared to non-drinkers. We concluded that a proportion of non-drinkers might avoid alcohol because of some health conditions linked to the endpoint of interest. At a multivariable level, all those factors remained statistically significantly associated with the outcome of interest. We therefore combined the information of lifestyle factors, gender, family history and daily low-dose Aspirin use to obtain a reliable individual risk score (i.e. linear predictor) and build a nomogram. The second colonoscopy visit date was fixed in advanced at the time of first colonoscopy, based on the outcome of the first colonoscopy, following a typical example of Doctor’s care scheme of examinations. After adjusting for the severity of the outcome of the first colonoscopy and for the time from first to second colonoscopy, we obtained a statistically significant association between the linear predictor and the risk of high-risk neoplasia detected at the second colonoscopy. We then applied homogeneous Markov Models to simultaneously model the disease process over time. The effect of the linear predictor on the transitions – from one disease stage to the other – resulted statistically significant. Moreover, as the linear predictor increased, the probability of getting better decreased. In other words, the worse the lifestyle, the lower the probability for the intestinal mucosa to heal. On the other hand, the estimated parameter for the effect of linear predictor on the aggravation transition resulted positive: the worse the lifestyle, the higher the probability to find new high-risk polyps. Conclusions: Lifestyle should be considered in the planning of population CRC screenings, because the identification of different risk groups can lead to more tailored screening policies, and accordingly to more efficient and cost-effective interventions.

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Basso, G. "MOLECULAR HETEROGENEITY AND PROGNOSTIC IMPLICATIONS OF SYNCHRONOUS ADVANCED COLORECTAL NEOPLASIA." Doctoral thesis, Università degli Studi di Milano, 2013. http://hdl.handle.net/2434/222721.

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Introduzione e scopo. In letteratura molte ipotesi sono state formulate sull’insorgenza dei tumori sincroni del colon retto (S-CRC). Infatti, non è ancora del tutto chiaro se questo tipo di malattia sviluppa attraverso un particolare pathway molecolare legato ad una elevata suscettibilità della mucosa colica a divenire neoplastica e se a livello clinico evidenzia una prognosi peggiore. Dal momento che i tumori con instabilità dei microsatelliti (MSI) possono costituire un bias nel valutare la presenza di metilazione e l’andamento clinico dei S-CRC, abbiamo analizzato per neoplasia sincrona e per disease-specific survival (DSS), una ampia casistica di CRC caratterizzata per la mutazione di BRAF e per lo stato dei microsatelliti. Pazienti e Metodi. Nello studio sono stati arruolati 881 pazienti consecutivi, i quali sono stati sottoposti a resezione del cancro del colon e hanno eseguito a livello perioperatorio una colonscopia completa. Per ogni paziente, i dati demografici e clinico-patologici sono stati recuperati e il DSS è stato valutato in modo retrospettivo. Tutti i tumori sono stati sottoposti a screening per MSI, per identificare pazienti con HNPCC, mediante l’analisi di marcatori mononucleotidici come BAT 26 e BAT25. Nei tumori con instabilità dei microsatelliti, il difetto proteico è stato individuato mediante immunoistochimica (IHC) e successivamente sono stati testati per la mutazione germinale del gene corrispondente. Inoltre, tutti i tumori sono stati anche analizzati per la mutazione di BRAF c.1799T> A. Risultati. Il S-CRC è stato associato con lo stadio IV (p = 0.01) e con l’HNPCC (p <0.001), ma solo i casi MSS S-CRC sono più frequentemente metastatici (p = 0.001). La mutazione di BRAF c.1799T> A era associata con gli MSI CRC sporadici (p <0.001), ma non con i S-CRC (p = 0.96). I cancri sincroni non cambiano il miglior DSS dei pazienti con MSI CRC (HR 0.74, 95% CI 0.09-5.75, p = 0.77). Viceversa, i MSS S-CRC (HR 1.82, 95% CI 1.15-2.87, p = 0.01), così come un tumore MSS e la presenza di un adenoma avanzato (sincrono adenoma avanzato) (HR 1.81, 95% CI 1.27-2.58, p = 0.001), e la mutazione di BRAF c.1799T> A (HR 2.16, 95% CI 1.25-3.73, p = 0.01) risultano essere variabili predittori di un aumentato rischio di morte indipendenti dallo stadio di malattia. Conclusioni. I MSS S-CRC evidenziano una prognosi peggiore, e lo stesso vale per la presenza di un sincrono adenoma avanzato. Dallo studio emerge che né la presenza di multiple avanzate neoplasie in tumori MSS né la loro maggiore aggressività sono mediati da un effetto epigenetico. Per cui la sorveglianza e i protocolli terapeutici per i pazienti con un MSS CRC dovrebbero tener conto del peso prognostico dato dalla presenza di neoplasie sincrone avanzate del colon-retto. Background and Aim. It is uncertain whether synchronous colorectal cancers (S-CRC) develop through a preferential carcinogenetic pathway and whether they have a poorer prognosis. Since microsatellite unstable tumors (MSI) might act as a bias when assessing methylation and outcome of S-CRC, we analysed for synchronous neoplasia and for disease-specific survival (DSS) a large series of CRC systematically characterized by BRAF and MS status. Patients and Methods. 881 patients consecutively resected for CRC and perioperatively investigated with complete colonoscopy, were included in the study. For each patient, demographic and clinico-pathological records were retrieved and DSS was retrospectively assessed. All cancers were screened for MSI by BAT 26/BAT25 mononucleotide analysis. MSI tumors had the MMR protein defect identified at immunohistochemistry (IHC) and were tested for germline mutation of the corresponding gene. All tumors were also analysed for BRAF c.1799T>A mutation. Results. S-CRC was associated with stage IV (p=0.01) and with HNPCC (p<0.001), but only MSS S-CRC accounted for the association with metastatic CRC (p=0.001). BRAF mutation was associated with sporadic MSI CRC (p<0.001) but not with S-CRC (p=0.96). S-CRC did not affect DSS in patients with MSI CRC (HR 0.74; 95%CI 0.09-5.75; p=0.77). Conversely, S-CRC (HR 1.82; 95%CI 1.15-2.87;p=0.01), as well as synchronous advanced adenoma (HR 1.81; 95%CI 1.27-2.58; p=0.001), and BRAF c.1799T>A mutation (HR 2.16; 95%CI 1.25-3.73; p=0.01) were stage-independent predictors of death related to MSS CRC. Conclusions. Microsatellite-stable CRC have a worse prognosis if S-CRC, or even a synchronous advanced adenoma, is diagnosed. Neither the occurrence of multiple MSS advanced neoplasia nor their enhanced aggressiveness are mediated by an epigenetic field effect. Surveillance and therapeutic protocols for MSS CRC should take into account the prognostic burden of synchronous advanced colorectal neoplasms.

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Sardo, Christine Louise. "The Biological Role of Fruit Phenolics, Sedentary Behavior, and Inflammation on Colorectal Neoplasia." Diss., The University of Arizona, 2013. http://hdl.handle.net/10150/297045.

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Background: Clinical and epidemiologic studies have investigated the effects of diet, physical activity, and inflammation on the risk of colorectal adenoma occurrence and recurrence. Inflammation has been proposed as a mechanism of action for the development of colorectal adenoma and cancer. Research indicates that fruit phenolic exposure may attenuate the inflammatory response and some data suggest that berries are effective in mitigating this process. Inflammatory cytokines such as interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor alpha (TNF-α) are of particular interest due to their role in adenoma development. Epidemiological investigations have studied the association between bioactive fruit phenolic compounds and colorectal neoplasia; however, epidemiological data for the association between consumption of berries, which contain high concentrations of these compounds, and colorectal adenoma recurrence are limited. In addition to a potential role of phenolics in reducing inflammation, physical activity has also been proposed as a mitigator of this process. Numerous studies have investigated the association between physical activity and colorectal neoplasia, yet data on sedentary behavior and colorectal adenoma recurrence are limited. This dissertation was designed to further elucidate the role of fruit phenolics and sedentary behavior on colorectal adenoma recurrence and to specifically highlight the potential role of black raspberries in mitigating the postprandial inflammatory response among overweight and obese individuals. Methods: Ten overweight or obese males (BMI>25 kg/m²), ages 55-72, participated in an open-label, randomized, 14-day, pilot crossover study. Subjects consumed a high- fat, high- calorie (HFHC) meal, with (Group 1) or without (Group 2) a 5 day regimen of 45 g of black raspberry powder in the form of a slurry. The study included a two-day washout period before Group 1 and Group 2 were crossed over. The two-day washout period was based on a pharmacokinetic study conducted with black raspberry powder (1); peak plasma concentrations of ellagic acid and anthocyanin metabolites peaked at 1 to 2 hours following consumption of 45 grams of black raspberry powder and by 12 hours, plasma concentrations of these metabolites were almost fully washed out, with plasma concentrations returning to near baseline levels. Blood samples were obtained prior to consumption of the HFHC breakfast and at 1, 2, 4, 8, and 12 hours afterwards, during two 14-hour clinic visits. The primary study outcomes were changes in areas under the curves (AUCs) of serum biomarkers of TNF-α, CRP, and IL-6. A secondary pooled analysis was conducted among participants from two randomized, double blind, placebo-controlled Phase III clinical trials to investigate the association between berry consumption and colorectal adenoma recurrence, and the association between sedentary behavior and colorectal adenoma recurrence. Analyses included 2,502 subjects who had completed the baseline Arizona Food Frequency Questionnaire to ascertain berry consumption history in the past year and 1,730 men and women who had completed the baseline Arizona Activity Frequency Questionnaire to ascertain sedentary behavior. All subjects had a follow-up colonoscopy during the trial. Logistic regression modeling was employed to estimate the effect of sedentary behavior or berry consumption on colorectal adenoma recurrence. Results: The mean AUC of serum IL-6 was significantly lower (p=0.03) with black raspberry (BRB) feeding (45.5±36.3 pg/mL; mean±SD), compared to high fat, high calorie meal alone (56.7±50.0 pg/mL). No statistically significant differences were observed in the mean AUC of serum TNF-α or CRP. In the pooled analysis, no significant associations were observed between berry consumption and adenoma recurrence in the pooled population or when stratified by sex. In the evaluation of association between sedentary behavior and adenoma recurrence, subjects in the second, third, and fourth quartiles of sedentary behavior experienced higher odds of adenoma recurrence; however, the difference was only statistically significant for the third quartile. Sex-stratified analyses revealed that in men, sedentary activity was statistically significantly associated with 45% higher odds of adenoma recurrence. Compared to the lowest quartile of sedentary activity, the ORs (95% CIs) for the second, third, and fourth quartiles among men were 1.31 (0.93, 1.84), 1.47 (1.04, 2.09), and 1.45 (1.02, 2.06) respectively (P trend=0.03). In contrast, no association with sedentary activity was observed in women. Conclusion: Polyphenol exposure in the form of a black raspberry slurry significantly decreased post-prandial IL-6 in a clinical trial among ten older overweight and obese men. These findings suggest short-term attenuation of an inflammatory maker may not translate to decreased adenoma recurrence, however, long term randomized clinical trials with black raspberries are needed to evaluate this further. However, in an epidemiological analysis, consumption of up to 1 cup per week of whole berries was not associated with lower odds for adenoma recurrence among a pooled population of participants in the Wheat Bran Fiber and Ursodeoxycholic Acid Phase III clinical trials. While the epidemiological results indicated that berry consumption are not associated with the development of early colorectal neoplasia, the effects on later stages of carcinogenesis are unknown. Higher levels of berry consumption may be required in order to reach a cancer inhibitory effect. Finally, results of the physical activity study suggest that sedentary behavior is associated with a higher risk of adenoma recurrence among men, providing evidence of detrimental effects of a sedentary lifestyle early in the carcinogenesis pathway. Efforts to further evaluate these findings in other cohorts or in an intervention trial should be considered.

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Wong, Justin Jong Leong Medical Sciences Faculty of Medicine UNSW. "The role of DNA methylation in the development of colorectal neoplasia." Publisher:University of New South Wales. Medical Sciences, 2008. http://handle.unsw.edu.au/1959.4/43359.

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DNA methylation is increasingly recognised as a significant epigenetic event that may initiate and drive the process of neoplasia in humans. In the colon, DNA methylation of key genes is common in a subset of colorectal cancers. The extent to which DNA methylation at various genes contributes to initiation of colorectal neoplasms is less clear. This study sought to clarify the biological and clinicopathological significance of methylation of various genes in the development of sporadic and familial colorectal neoplasia. Quantitative methylation-specific PCR (qMSP) assays (capable of detecting down to a measureable proportion of 0.1% of the total input DNA) were developed to determine the presence of CpG methylation at a given gene. Methylation of MLH1-C was found in the apparently normal mucosa samples from seven of 104 (7%) of individuals with sporadic colorectal cancer (CRC) showing microsatellite instability (MSI). No methylation of MLH1-C was found in the biological samples of individuals with microsatellite stable (MSS) counterparts (n=131). MLH1-C methylation may be a field defect that predisposes to the development of sporadic colorectal neoplasia, particularly those demonstrating MSI. Methylation of three of five genes within the 3p22 region including AB002340, MLH1, ITGA9, PLCD1 and DLEC1 (regional 3p22 methylation) was found in 83% of sporadic MSI (n=86) and 12% of MSS cancers demonstrating BRAF V600E mutation (n=42). Regional 3p22 correlated strongly with CpG island methylator phenotype (CIMP), and other clinicopathological characteristics typical of CIMP. Thus, regional 3p22 methylation and CIMP may be overlapping phenomena. Regional 3p22 methylation and the BRAF V600E mutation were found in normal colonic mucosa of four individuals with sporadic MSI CRC, and these cases also had multiple synchronous serrated polyps. These molecular aberrancies may predispose some individuals to the development of metachronous serrated neoplasia. Germline epimutations of APC do not contribute towards the development of FAP, AFAP, or hyperplastic polyposis syndromes. However, APC methylation in normal colonic mucosa of these individuals may represent a field defect in the development of futher neoplasms. In conclusion, different patterns of DNA methylation in normal colonic mucosa may represent a field defect important in the development of different subtypes of colorectal neoplasia.

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Ibrahim, A. E. K. "The role of DNA methylation in the progression of colorectal neoplasia." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604918.

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I optimized a microarray method for identifying genome-wide CpG island methylation changes called Microarray-based Methylation Assessment of Single Samples (MMASS). A prospective sample set of matched normal colorectal mucosa, adenoma and adenocarcinoma tissues were collected as well as a retrospective set of primary colorectal carcinomas and where present their metastatic tissues. All cases were assayed for microsatellite instability. Genome-wide methylation patterns were profiled using MMASS and were correlated with their corresponding genome-wide expression changes for a subset of the cases. Differentially methylated and expressed targets were identified during neoplastic progression of CRC. DNA methylation was measured in a set of 10 CpG islands known to be important in CRC, using quantitative pyrosequencing assays, in 261 tissue samples from 138 colectomy specimens removed for CRC and 9 for diverticular disease. Recursive partitioning (RP) was used to identify threshold methylation levels that discriminated normal tissue from neoplastic tissues with 100% sensitivity (95% CI: 93.2-100.0) and 90.5% specificity (95% CI: 69.6-98.8). DNA methyltransferase DNMT3B has been implicated in the progression of colorectal neoplasia. Immunohistochemical analysis of the expression of DNMT3B was positively correlated with methylation of SFRP2 (r = 0.415, p ≤ 0.001) and negatively correlated with methylation of IGF2 DMR0 (r = -0.262, p = 0.014). SFRP2 and IGF2 CpG islands methylation changes are proposed to be potential biomarkers for CRC screening. Faecal DNA can be tested for methylation levels of SFRP2adn IGF2 to identify high risk patients. The UK NHS bowel cancer screening programme is the ideal environment in which to take these findings forward.

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Moorehead, Robert John. "A study of some aspects of the pathogenesis of colorectal neoplasia." Thesis, Queen's University Belfast, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328030.

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Clark, Andrew J. E. "Investigation of mutant DNA in plasma of patients with colorectal neoplasia." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/24459.

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Introduction: Colorectal cancer is a major clinical and public health problem. Early stage colorectal cancer is amenable to surgical intervention with a high cure rate. Screening for the disease has now been rolled out throughout the UK, although current screening modality of faecal occult blood testing (FOBT) is suboptimal. Specific genetic alterations found in primary tumours, including mutations in proto-oncogenes, microsatellite instability and loss of heterozygosity (LOH), have been shown to be detectable in the host plasma. Colorectal cancer is an excellent paradigm in which to investigate the application of assays to detect tumour-related plasma DNA. There is substantial data regarding specific mutations and their frequency in colorectal cancer tissue and adenomas. The ability to detect early stage colorectal neoplasia using DNA plasma assays holds considerable promise as a non-invasive screening modality. Materials and Methods: Assay performance was assessed using colorectal cancer cell lines and archived material from genetic studies. Assays were then applied to a prospective cohort of 124 colorectal neoplasia cases and controls. Plasma DNA was quantified using a sensitive DNA binding fluorescent dye and detection platform. A well-characterised tumour-specific mutation was used as the target for the first assay. This mutation was in a poly A tract of the transforming growth factor beta receptor II (TGFpRII) gene and was assessed using a restriction fragment length polymorphism (RFLP) assay. Microsatellite analysis was performed using 3 polymorphic markers relevant to colorectal neoplasia in matched tumour, normal and plasma DNA samples. A novel assay was developed exploiting real-time fluorescent PCR amplification of single nucleotide polymorphisms in the adenomatous polyposis coli (APC) gene as a means to detect tumour-specific allelic imbalance. Assay performance was determined in spiking experiments, and performance assessed in clinical samples. A further iteration of the assay was developed to quantify tumour specific alleles in plasma by counting individual alleles PCR amplified from plasma DNA of cases and controls. Results: Quantification of total plasma DNA revealed a significant difference between cases and controls (area under the receiver operator curve: 0.7). Despite intensive efforts to overcome the problem, the TGFpRII RFLP assay was affected by technical difficulties when applied to plasma DNA. The required high number of PCR cycles introduced artefact and limited its applicability. Microsatellite analysis demonstrated LOH in matched tumour and plasma samples with maximal sensitivity of 67% but specificity was only 32%. The quantitative PCR assay to detect APC LOH was able to detect 3-5ng of homozygous DNA introduced into 1 ml of heterozygous plasma, and accurately quantified LOH in tumour tissue. However, it was not able to discriminate cases from controls by assessment of plasma DNA. Counting of alleles in plasma DNA from a test case demonstrated matching LOH to that seen in the primary tumour. Allele counting of a further cohort suggested that this approach has a low false positive rate. Discussion: Analysis of plasma DNA is technically challenging due to a low abundance of partially fragmented mutant DNA sequences admixed with normal DNA in plasma with DNAases and PCR inhibitors. However total quantity of plasma DNA was higher in cancer cases compared to controls with good specificity for cancer at high DNA concentrations. Fluorescent microsatellite analysis of plasma DNA demonstrated encouraging overall sensitivity but poor specificity that waslikely at least partly a reflection of low DNA abundance and hence sampling error within aliquots of plasma DNA. A quantitative PCR approach was developed and validated with relevant levels of in vitro sensitivity, and improved discrimination of LOH in some clinical samples. Adaptation of this approach to count alleles individually is labour intensive and expensive but appears to address issues of sampling error due to abundance and hence improves specificity. These data, whilst highlighting some of the technical challenges in the field, demonstrate associations of plasma DNA in colorectal neoplasia that warrant further investigation.

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Khoo, Kong Kheong. "The influence of metabolic phenotypes upon the development of colorectal neoplasia /." Title page, table of contents and conclusions only, 1995. http://web4.library.adelaide.edu.au/theses/09MD/09mdk45.pdf.

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Will, Olivia Constance Claire. "The initiation and progression of neoplasia in inherited and sporadic colorectal cancer." Thesis, Queen Mary, University of London, 2009. http://qmro.qmul.ac.uk/xmlui/handle/123456789/1651.

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This dissertation describes investigations into aspects of neoplastic initiation and progression in the gut, in the context of inherited and sporadic gastrointestinal cancer. In familial adenomatous polyposis, there is marked locoregional variation in polyp density. This work investigated the relationship between gut location and somatic inactivation of APC. It demonstrated that the frequency of APC loss of heterozygosity (LOR) varied along the colon, suggesting a colonic gradient in "just right" signalling. It investigated adenomas of the ileoanal pouch, where small bowel functions as rectum. A longitudinal study revealed the largely indolent natural history of these polyps, while mutational analysis demonstrated that they differed from polyps arising in colon, by usually retaining 2-3 remaining 20-amino-acid repeats. A comparison of pouch and rectal polyps showed differences in their histogenesis. Neoplastic initiation was investigated arising in the context of a f!t' new phenotype of young-onset colorectal cancer, with multiple adenomas and neurological deficit. A novel homozygous mutation involving PMS2 and FSCJV was found. Although neoplastic lesions showed nuclear beta-catenin expression, no mutated wnt pathway genes were identified. No evidence was found that PMS2 or FSCN mutation was causative in other patients with related multiple adenoma or neurological phenotypes. Key stepwise events in the adenoma-carcinoma sequence were investigated in sporadically occurring adenomas with contiguous carcinoma. Laser microdissection allowed crypt-by-crypt analysis of APC, TP53, KRAS2, and LOR at 17p and 18q, in order to establish the presence of cryptal heterogeneity and the inferred order of genetic alterations. Using similar contiguous paired lesions, a further study investigated neoplastic aneuploidy using image cytometry~ genome-wide LOR analysis and individual SNP analysis for LOR 5q, 17p, and 18q. Aneuploidy did not cluster as tetraploidy. The degree of aneuploidy correlated well with the degree of LOR ascertained by genome-wide analysis, with LOR at 17p and 18q (but not 5q), and with nuclear beta-catenin accumulation.

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Lee, Thomas Jonathan William. "Detection and management of colorectal neoplasia in the NHS bowel cancer screening programme." Thesis, University of Newcastle Upon Tyne, 2012. http://hdl.handle.net/10443/1783.

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Background Screening for colorectal cancer aims to reduce mortality by detecting cancer at an earlier stage. The NHS Bowel Cancer Screening Programme (BCSP) offers faecal occult blood testing (FOBt) followed by colonoscopy for those with a positive FOBt. This thesis examines the detection and management of colorectal neoplasia in the BCSP. Aims and Methods 1. Explore adenoma detection rate (ADR) as a measure of colonoscopic performance and examine which factors influence adenoma detection rate by analysing data gathered from the BCSP. 2. Describe the findings at 12 month surveillance colonoscopy in high risk individuals (according to adenoma surveillance guidelines in the BCSP) and explore factors which may predict findings at surveillance. 3. Describe the management of large sessile colonic polyps (LSCP) in the BCSP and explore factors which influence the choice of treatment modality (surgical or endoscopic) and subsequent outcome. A national study of LSCP management was undertaken. Detection and Management of Colorectal Neoplasia in the NHS Bowel Cancer Screening Programme Results ADR correlated positively with other performance indicators including withdrawal time and caecal intubation rate. The yield of advanced colonic neoplasia (ACN) at surveillance colonoscopy was 6.6%. The presence of right sided or villous lesions at baseline may predict the presence of ACN at surveillance. 121/557 LSCP (21.7%) were managed surgically, 436/557 (78.3%) were managed endoscopically. Increasing size was associated with failure of endoscopic therapy and presence of cancer in the resection specimen. Conclusion ADR is a satisfactory indicator of colonoscopic performance. Measures of the total number of adenomas detected are likely to be more discriminatory indicators of performance. The optimal mean withdrawal time for adenoma detection was 10 minutes. Longer mean withdrawal times were not associated with increasing adenoma detection. 12 month surveillance for high risk individuals is justified by the yield of advanced lesions. Larger or right sided LSCP were more likely to be managed surgically. Safe and effective management of LSCP can be delivered by a national screening programme.

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Basavaraju, Umesh. "Inflammatory biomarkers of colorectal neoplasia and their manipulation by an anti-inflammatory diet." Thesis, University of Aberdeen, 2011. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=182290.

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Colorectal neoplasia (CRN) continues to be a leading cause of morbidity and mortality in the developed world and with westernisation, similar trends are now emerging in the developing world. Although secondary prevention through screening programmes has reduced mortality, uptake remains poor due to the invasive nature of colonoscopy, which also exerts increased costs to the health care system. Primary prevention remains the ultimate aim to reduce the morbidity and mortality associated with CRN. In this regard, chemoprevention strategies through regular use of aspirin and other NSAIDS have showed great promise but the associated significant side-effects of these drugs has prevented their routine clinical application for this purpose. Hence there is an urgent need for the identification of safer alternatives for primary prevention of CRN. In parallel to this search, better understanding of the molecular pathogenesis of CRN to identify biomarkers that aid in stratification of at risk individuals would also help. In this regard, the role of chronic inflammation and the influence of host genetics in the pathogenesis of CRN has been the focus of extensive research in recent years. However there is a lack of studies which have investigated these associations in an exclusively screened population, which confers some advantages for this type of investigation. Firstly, most of the screened subjects are relatively healthy, asymptomatic and with no significant co-morbidities, the factors which could otherwise influence the levels of inflammatory markers. Secondly, the screened population is in the 50 to74 year age group which represents the group with a high prevalence of CRN and hence increasing the possibility of finding associations which would be more relevant and generalisable. Thirdly, the selected controls match the cases in all important respects, apart from having CRN, thus increasing the validity of the findings in this population. The Grampian region was one of the first in the UK to participate in the National Colorectal Cancer Screening Programme and this resource gave the ideal opportunity to conduct research involving an exclusively screened population. Utilising this cohort, the current thesis addressed three important aspects of the association between inflammation and CRN. Firstly the investigation of the association of inflammatory genotype, inflammatory phenotype and CRN risk. Secondly the impact of environmental factors, specifically dietary antiinflammatory salicylic acid intakes on CRN risk. And finally assessing if inflammation, and hence in the long term risk of CRN, could be attenuated through a comprehensive anti-inflammatory dietary supplementation in the form of a randomised dietary intervention clinical trial. The study of the association of polymorphisms in key inflammatory genes (IL1B- 31, IL8-251, IL6-174, TNFα-308, IL10-1082, IL10-592, PTGS2-765, and IL1RN VNTR) and CRN risk showed some significant findings. A novel finding was that the homozygous IL1B-31C*C genotype was associated with statistically significant increased risk of CRN, OR 1.63 (95% CI 1.06-2.50) whilst the IL8-251 A*A genotype increased the propensity of having high risk lesions by two-fold (OR 2.04; 95% CI 1.02-4.07). The study of circulating inflammatory marker levels in subjects in whom the CRN was in-situ showed that increased CRP levels were associated with increased risk of CRN, OR 1.55 (95% CI 1.00-2.39). Increased levels of IL8 were associated with increased risk of having a high risk lesion, OR 2.57 (95% CI 1.03-6.44). In a sub group of subjects, it was observed that levels IL8 and CRP decreased following polypectomy (mean IL8 20.3 pg/ml to 14.9 pg/ml, p=0.05 and mean CRP 5.99 mg/l to 3.82 mg/l, p=0.07) raising an important question regarding the sequence of the inflammation-neoplasia cascade, “Is inflammation the cause or the effect of neoplasia?” The study of the association of dietary salicylic acid (SA) and CRN using the newly constructed SA database showed that high levels of total SA (aspirin and dietary SA) intakes were associated with a 75% and moderate levels with a 67% decreased risk of CRN. But dietary SA on its own showed no significant effect on CRN risk probably because of low intake levels in the current cohort. Applying the SA database to populations with higher dietary SA intake would help to further explore its association with CRN risk. The randomised clinical trial examining the effect of a combined antiinflammatory dietary supplement (curcumin, omega-3 PUFA and polyphenols rich fruit smoothie) on markers of inflammation in subjects who had adenomatous colorectal polyps removed showed that the inflammatory marker levels in the control group who just continued their habitual diet remained stable without any statistically significant changes at 6 weeks compared to the baseline. Whereas following 6 weeks of dietary intervention, there was marginally significant increase in IL8 and IL1B levels. One of the possible mechanisms for increase in pro-inflammatory marker levels in the intervention group was the weight gain seen in the intervention group. In the intervention group, the post-intervention mean weight (86.80kgs) was significantly higher than the pre-intervention mean weight (85.38 kgs). In summary, the findings from these investigations suggest that a proinflammatory genotype (IL1B-31C*C and IL8-251 A*A) and elevated circulating inflammatory marker levels (CRP and IL8) are associated with increased risk of CRN. And along with the findings that regular NSAID use and total dietary SA are associated with decreased risk of CRN, our data point to inflammation as an underlying pathogenetic mechanism in CRN. The pilot clinical trial has demonstrated that a clinical trial with combined dietary supplementation is feasible, but challenging. The anti-inflammatory dietary intervention strategy employed to reduce the inflammatory markers did not achieve the desired effect and hence more research is required to establish the ideal delivery strategy of the anti-inflammatory dietary agents. Once this is established, dietary chemoprevention of CRN as a safe alternative should be a realistic achievable goal in the future.

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Mitrou, Panagiota N. "Genetic polymorphisms in NQ01, mEH and MTHFR, environmental factors and sporadic colorectal neoplasia." Thesis, University of Cambridge, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.615633.

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Egan, Jan Bailey. "Evaluating the Role of VDR Polymorphisms and Beta-catenin Signaling in Colorectal Neoplasia." Diss., The University of Arizona, 2009. http://hdl.handle.net/10150/195709.

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Colorectal cancer is estimated to cause approximately 50,000 deaths each year in the United States. Epidemiological studies have demonstrated an inverse association between sunlight exposure, which stimulates the formation of vitamin D in the skin, and colorectal carcinoma. Laboratory studies report that metabolites of vitamin D, acting through the vitamin D receptor (VDR), regulate cellular proliferation, differentiation and apoptosis. In addition, VDR contains a polymorphic variant, FokI, which results in two different isoforms of VDR. We have demonstrated a differential suppression of β-catenin transcriptional activity by these isoforms in the presence of 1,25(OH)₂D₃ (1,25D). Epidemiological evaluation of metachronous colorectal adenoma formation indicates that VDR includes several single nucleotide polymorphisms (SNPs) which influence the odds of developing colorectal adenoma. In addition, we have found full length Adenomatous Polyposis Coli (APC), a frequently mutated tumor suppressor gene in colorectal cancer, augments both the interaction of VDR and β-catenin as well as the suppression of β-catenin transcriptional activity in the presence of 1,25D. We have also demonstrated in epidemiological studies that the presence of a T-A haplotype in APC codons 486 and 1822, respectively, reduces the odds of any metachronous adenoma by 27% [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.59 – 0.91]. Taken together, these data support not only a protective role for vitamin D acting through the VDR, but also for an important role of heritable polymorphic variation in VDR and APC in carcinogenesis.

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Quirke, P. "The role of flow cytometry in the assessment of the pathobiology of colorectal neoplasia." Thesis, University of Leeds, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.384672.

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Tafner, Edmar. "A colonoscopia com e sem auxílio de métodos de cromoscopia no diagnóstico das lesões planas, deprimidas e elevadas do cólon e reto." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5132/tde-15062011-145410/.

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O câncer colorretal (CCR) é uma das maiores causas de óbito no mundo industrializado, com uma incidência anual de 800.000 casos novos, o que significa 8,5% de todos os novos e 12% das mortes relacionadas a essa doença. No Brasil, excluindo-se os cânceres de pele não melanoma, o CCR é o quarto mais freqüente entre os homens e o terceiro entre as mulheres. O risco de desenvolver CCR é de aproximadamente 5% a 6% na população ocidental. Existem evidências epidemiológicas de redução do CCR em 60% -90% quando a colonoscopia com polipectomia é usada preventivamente A colonoscopia ainda é o melhor método para o diagnóstico precoce do CCR e das lesões precursoras. Contudo existem falhas de detecção não desprezíveis. O objetivo deste estudo foi comparar o resultado do exame detalhado da mucosa do cólon e do reto através da colonoscopia convencional, da cromoendoscopia e do NBI, na detecção de lesões elevadas, deprimidas e planas em pacientes submetidos ao exame sem antecedentes pessoais e ou familiares. Entre janeiro de 2007 e outubro de 2009 foram selecionados 181 pacientes divididos aleatoriamente em três grupos: A: 48 pacientes, controle; B: 29 pacientes, NBI; C: 104 pacientes, cromoscopia difusa. Pode-se observar que dos 181 pacientes examinados 38 (21%) não apresentavam lesões. Os 143 pacientes com lesão, apresentaram um número médio de 2,65 lesões, com mínimo de 1 e máximo de 7 lesões. Nos total dos 181 pacientes e no conjunto dos 143 pacientes com lesões não foi observada diferença estatisticamente significante entre os três grupos A, B e C para a idade, o tempo reto-ceco e o tempo ceco-reto, enquanto que para a altura, peso e conseqüente IMC houve variação estatística. O tamanho médio das 379 lesões encontradas nos 143 pacientes, avaliado pelo seu diâmetro foi de 5,45 ± 2,84 mm, sem variação estatística entre os grupos, entre os hemicólons e entre os hemicólons nos grupos. Os tamanhos das lesões foram reunidos em três intervalos distintos: até 5 mm (76,30%), de 6 a 10 mm (19,50%) e de 11 a 20 mm (4,20%). Do total de 379 lesões, 203 (53,6%) mostraram-se neoplásicas e 176 (46,4%) não neoplásicas. O tamanho médio das 203 lesões neoplásicas foi de 5,96 mm, e das 176 não neoplásicas, 4,87 mm. As lesões neoplásicas mostraram-se maiores que as não neoplásicas, com significância estatística. Nos grupos não houve variação significante entre neoplasia e não neoplasia, mas diferença significante entre o tamanho das neoplasias e não neoplasias. Não houve diferença estatística entre os tamanhos das lesões nos dois hemicólons, mas com diferença significante entre os tamanhos das lesões neoplásicas e não neoplásicas. O mesmo se observa quando os segmentos do cólon são analisados individualmente. Os dois segmentos que apresentaram diferença significante, especificamente, quanto ao tamanho das lesões neoplásicas e não neoplásicos foram o sigmóide e o transverso. Nota-se que todas as lesões subpediculadas e as lesões plano-elevadas com depressão central eram neoplásicas. As lesões planas e neoplásicas são proporcionalmente mais visíveis no hemicólon direito nos grupos B (85,7%) e C (67,9%), sem diferença estatística. As hipóteses diagnósticas das lesões feitas durante o exame colonoscópico foram comparadas com os resultados histopatológicos. Pode-se observar que no grupo A sensibilidade de 82,7%, especificidade de 59%, com taxa de concordância de 72,5 %, considerada regular, no grupo B sensibilidade de 92,3%, especificidade de 61,9%, com concordância de 78,7 %, regular e no C sensibilidade de 88,8%, especificidade de 79,3%, taxa de concordância de 84,2%, considerada boa. Proporcionalmente o grupo C tem maior número de pacientes com três ou mais lesões e três ou mais lesões neoplásicas, mas sem valor estatístico. Conclui-se que não houve diferença estatística entre os 181 pacientes examinados e os 143 pacientes com lesões, quanto aos dados gerais, não houve diferenças significativas quanto ao número relativo, ao tipo e ao tamanho das lesões. As lesões neoplásicas apresentam-se maiores quando comparadas às não-neoplásicas, com significância estatística. A concordância entre a hipótese diagnóstica colonoscópica e a histologia é maior no grupo da cromoscopia Colorectal cancer (CRC) is one of the largest causes of death on the industrialized world. Its annual incidence of 800.000 new cases means 8,5% of all the new ones and 12% of deaths related to this disease. In Brazil, excluding the non-melanoma skin-cancers, CRC is the fourth more frequent among men and the third one among women. The risk for developping CRC is approximately of 5 to 6% on the Western population. There are epidemiological evidences for reducing CRC on 60-90% when colonoscopy with polypectomy is used preventively. Colonoscopy is still the best method both for the early dyagnosis of CRC and precursor lesions. However, there are non-contemptible failures on the detection. This paper purpose was comparing the result of colon and rectum mucous membrane detailed test through conventional colonoscopy, chromoendoscopy and NBI, on the detection of augmented, depressed and flat lesions in patients submitted to it without any personal or familiar antecedents. Between January 2007 and October 2009 181 patients were selected randomically and divided into 3 groups: A: 48 control patients; B: 29 patients, NBI; C: 104 patients, diffuse chromoscopy. It is observed that, from the 181 examined patients, 38 (21%) didnt present lesions. The 143 patients with lesion, presented an average number of 2,65 lesions, with a minimum of 1 and a maximum of 7 lesions. On the total of the 181 patients and on the whole of the 143 patients with lesions it was not observed any statistically significant difference among the three groups A, B and C as for Age, the Rectum-Cecum Time and the Cecum-Rectum Time, while there was a statistical variation for Height, Weight and consequent bmi. The average size of the 379 lesions found on the 143 patients, assessed by its diameter was of 5,45 mm (2.14 in.) + 2,84 mm (1,11 in), without any statistical variation among the groups, among the hemicolons and among the hemicolons in the groups. The size of the lesions were gathered into three distinct intervals: up to 5 mm [1.9 in.] (76,30%), from 6 mm [2.3 in.] to 10 mm [3.9 in] (19,50%) and from 11 to 20 mm [4.3 to 7.8 in] (4,20%). From the total of 379 lesions, 203 (53,6%) revealed themselves neoplastic and 176 (46,4%) non-neoplastic. The average size of the 203 neoplastic lesions was of 5,96 mm (2.34 in.), and of the 176 non-neoplastic ones, 4,87 mm [12,36 in]. Neoplastic lesions have shown larger than the non-neoplastic ones, with a stastistical significance. On the groups there is any significant variation between neoplasia and non-neoplasia, but a significant difference between the neoplasias and non-neoplasias size. There was any statistical difference among the lesion size on both hemicolons, however, a significant difference among the sizes of neoplastic and non-neoplastic ones. The same is observed when colon segments were analyzed individually. The two segments that have presented significant lesions, specifically on what concerns the size of neoplastic and non-neoplastic ones were the Sigmoid and the Transverse. It is observed that all the subpediculated lesions and the flat-augmented ones with a central depression were neoplastics. The flat and neoplastic lesions are proportionally more visible on the right hemicolon at groups B (85,7%) and C (67,9%), without any statistical difference. The diagnostic hypotheses of the lesions grown during the colonoscopic test were compared to the histopathological results. On control group (A) it is observed a 82,7% sensibility, a 59% specificity with a concordance rate of 72,5%, considered regular. On group B it is observed a 92,3% sensibility, a 61,9% specificity, with a regular concordance rate of 78,7%. On group C it is observed a 88,8% sensibility, a 79,3% specificity, a 84,2% concordance rate, considered good. Proportionally group C has a larger number of patients with 3 or more lesions and or more neoplastic lesions, but with no statistical value. On what concerns general data, it is concluded that there wasnt any statistical difference among the 181 patients examined and the 143 ones presenting lesions as for the relative number, the type and size of the lesions. Neoplastic lesions appear to be larger when compared to non-neoplastic ones, with a statistical significance. The concordance between the colonoscopic diagnostic hypothesis and the histology is larger on chromoscopy group

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Silva, Ana Luísa Brás Dos Santos Ribeiro. "Identification of differentially methylated genes as potential biomarkers for the early detection of colorectal neoplasia." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610752.

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Hartley, John Edward. "An evaluation of the use of laparoscopic techniques for the resection of colorectal carcinoma." Thesis, University of Hull, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322452.

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Brauer, Paula Mae. "Familial aggregation of diabetes, hypertension and cardiovascular conditions in a case-control study of colorectal neoplasia." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0023/NQ49836.pdf.

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Aslam, Muhammad Imran. "MicroRNAs are novel biomarkers for the detection of colorectal neoplasia and high risk Dukes' B cancers." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/37943.

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Aims: This study aimed to identify which circulating miRNAs can be used for the early detection of colorectal cancers (CRCs) and to assess the utility of tissue miRNAs combined with common gene mutations, to predict the development of metastasis in patients with Dukes’ B CRCs. Methods: microRNA (miRNA) expression profiling was performed for total RNA extracted from plasma samples (colonoscopy negative controls=11, adenomas=9, carcinomas=12) and formalin-fixed paraffin embedded (FFPE) matched paired cancerous with adjacent normal tissue (n=20, 5 cases from each group of Dukes’ A, Dukes’ B with metastasis during 5 year follow up, Dukes’ B without metastasis during 5 year follow up, and Dukes’ C) using Taqman® MicroRNA Array, Megaplex™ RT and pre-amplification primers Human Pool A v.2.1 and Pool B v.2.0. Discriminatory miRNAs identified from plasma and tissue expression profiles were validated further on cohorts of plasma (n=190) and FFPE tissues (n=72). Three common gene mutations (KRAS, BRAF and PIK3CA) were analysed in DNA extracted from FFPE cancer tissue. miRNA expression analysis was applied to circulating exosomes to quantify CRC-related exosomal miRNAs. Results: Receiver operating characteristics analysis showed miR-135b was associated with an area under the curve value of 0.82 (95% CI: 0.71-0.92), with 80% sensitivity and 84% specificity for the detection of adenomas and carcinomas. miR-135b was also detectable in immunoaffinity-isolated plasma exosomes from patients with CRC. No significant differences were noted for mutation status and the development of metastasis. Expression levels of miR-135b and miR-15b were significantly associated with Dukes’ B cancers tissue and the development of metastasis. Conclusions: miR-135b is a novel diagnostic and prognostic marker. Its expression levels in blood and tissue can be used for the early detection of CRCs and to predict the development of metastasis in Dukes’ B cancers.

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Hibler, Elizabeth Anne. "Genetic and Environmental Factors Influencing Circulating Concentration of Vitamin D Metabolites and Odds of Colorectal Neoplasia." Diss., The University of Arizona, 2011. http://hdl.handle.net/10150/145300.

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Circulating concentrations of vitamin D metabolites are associated with risk for a variety of diseases, including colorectal cancer. It is not known what level of circulating 25(OH)D is optimal for health; however, over-the-counter (OTC) vitamin D supplements are commonly used to improve status, though their effectiveness is unknown. It is also not known if polymorphic variation in genes associated with the vitamin D endocrine system is associated with differences in vitamin D metabolite levels or colorectal neoplasia.METHODS: A double-blind, randomized, placebo-controlled trial examined the effect of 400 IU OTC cholecalciferol on circulating concentrations of 25(OH)D. Associations between polymorphic variation in VDR, RXRA, GC, and CASR and circulating vitamin D metabolites or colorectal neoplasia were examined through analysis of the Ursodeoxycholic Acid (UDCA) and Wheat Bran Fiber (WBF) clinical trial data. A single nucleotide polymorphism (SNP) tagging approach was employed and a total of 42 VDR, 32 RXRA, 35 CASR and 25 GC tagSNPs were analyzed.RESULTS: The net change in serum 25(OH)D in the supplement versus placebo group was 2.3 ng/ml (8.5% change, P = 0.06). Principal components analyses revealed gene-level associations between RXRA and serum 1,25(OH)2D concentrations (p = 0.01) as well as GC and 25(OH)D concentrations (p < 0.01). Seven individual GC polymorphisms were significantly associated with circulating measures of 25(OH)D in addition to CASR polymorphism rs1042636 and proximal colorectal neoplasia (p-value =0.02), following a multiple comparisons adjustment. The CART analysis identified rs17467825 as predictive of continuous measures of 25(OH)D. GC polymorphisms rs1555563, rs7041, and rs222029 were identified as significantly predictive of the 25 ng/ml threshold for insufficiency.CONCLUSION: The results demonstrate that daily 400 IU OTC cholecalciferol is sufficient to maintain baseline concentrations of 25(OH)D in healthy adults, but not to significantly increase levels in all individuals. The results also identified polymorphisms in RXRA, GC, and CASR associated with or that predict vitamin D metabolite levels or colorectal neoplasia risk. The results justify further investigation on the optimal vitamin D supplementation dose for the general population and genetic variation that may be related to circulating concentrations of vitamin D metabolites or colorectal neoplasia.

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Bessa, Caserras Xavier. "Interacció leucòcit-endoteli i mobilització de cèl·lules neoplàsiques en el càncer colorectal." Doctoral thesis, Universitat de Barcelona, 2003. http://hdl.handle.net/10803/2161.

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El procés de disseminació metastàsic en el càncer colorectal és un procés complex multifactorial. La present tesi ha pretès aprofundir en dos aspectes: els mecanismes de defensa immunològic a través de la caracterització dels fenòmens de interacció leucocitària, i el procés de mobilització tumoral a través de la detecció i pronòstic de les cèl·lules neoplàsiques circulants. En la present tesi s'ha confirmat que existeix una deficient interacció dels leucòcits circulants amb l'endoteli dels vasos tumorals respecte a l'endoteli no tumoral, tant de rodament en condicions basals com d'adhesió rere l'administració d'un estímul inflamatori. S'ha demostrat que la molècula implicada en els fenòmens d'adhesió leucocitària es ICAM-1, ja que el seu immunobloqueig reverteix els fenòmens d'adhesió induïts per LPS. S'ha demostrat a través de la tècnica del doble marcatge amb anticossos que la deficient interacció leucòcit-endoteli a nivell tumoral no pot atribuir-se a una menor expressió de les diferents molècules d'adhesió implicades en aquest fenomen. Al intentar avaluar els mecanismes responsables de la deficient interacció leucòcit endoteli es va descartar la participació de l'antigen carcinoembrionari, els productes derivats de la ciclooxigenasa i la sintasa induïble de l'òxid nítric. No obstant es va demostrar que la inhibició no selectiva de la sintasa de l'òxid nítric augmentava de manera dosi-depenent el rodament leucocitari i l'adhesió post-LPS a nivell del teixit tumoral. Efecte similar es va observar al procedir al immunobloqueig del factor transformant B1. Per tant, dels resultats obtinguts, es pot ressaltar que tant l'òxid nítric com el factor de creixement transformant B1 participen, al menys de manera parcial, en els fenòmens d'escapament dels sistemes de immunovigilància a nivell tumoral. La segona part de la tesi doctoral ha confirmat en primer lloc que es possible detectar la existència de cèl·lules neoplàsiques circulants en sang perifèrica de malalts amb càncer colorectal a través de la detecció de RNA missatger de l'antigen carcinoembrionari. Aquesta tècnica s'ha confirmat sensible (detecta una cèl·lula neoplàsica per cada 107 leucòcits) i específica (negativa en els controls sans). Emprat aquesta tècnica s'ha intentat avaluar un dels aspectes més controvertits de la cirurgia laparoscòpica en el càncer colorectal, la disseminació tumoral. Mitjançant estudis de detecció de cèl·lules neoplàsiques circulants en sang perifèrica, portal i en el líquid peritoneal, s'ha descartat el potencial efecte deleteri atribuït a la cirurgia laparoscòpica. No es varen observar diferències significatives entre el grup de cirurgia convencional respecte al grup de cirurgia laparoscòpica, en el número de pacients amb determinacions positives en els tres territoris avaluats rere la resecció quirúrgica . Finalment, es va intentar establir la significació pronòstica de la detecció de cèl·lules neoplàsiques circulants en pacients amb càncer colorectal mitjançant el seu seguiment a llarg termini. Tant en el grup global de pacients amb càncer colorectal com en aquells en els que s'havia realitzat una resecció curativa , la determinació preoperatòria de cèl·lules circulants no s'associava a un pitjor pronòstic a llarg termini (supervivència global i supervivència lliure de malaltia). Tenint en compte que estudis previs havien demostrat que la cirurgia afavoria la mobilització de cèl·lules neoplàsiques en el càncer colorectal, es va valorar la significació pronòstica de la detecció de cèl.lules neoplàsiques a les 24 hores de la cirurgia. Novament, la detecció postoperatòria no s'associava a un pitjor pronòstic a llarg termini.

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Bessa, Caserras Xavier. "Interacció leucòcit-endoteli i mobilització de cèl.lules neoplàsiques en el càncer colorectal." Doctoral thesis, Universitat de Barcelona, 2003. http://hdl.handle.net/10803/2161.

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El procés de disseminació metastàsic en el càncer colorectal és un procés complex multifactorial. La present tesi ha pretès aprofundir en dos aspectes: els mecanismes de defensa immunològic a través de la caracterització dels fenòmens de interacció leucocitària, i el procés de mobilització tumoral a través de la detecció i pronòstic de les cèl·lules neoplàsiques circulants.En la present tesi s'ha confirmat que existeix una deficient interacció dels leucòcits circulants amb l'endoteli dels vasos tumorals respecte a l'endoteli no tumoral, tant de rodament en condicions basals com d'adhesió rere l'administració d'un estímul inflamatori. S'ha demostrat que la molècula implicada en els fenòmens d'adhesió leucocitària es ICAM-1, ja que el seu immunobloqueig reverteix els fenòmens d'adhesió induïts per LPS. S'ha demostrat a través de la tècnica del doble marcatge amb anticossos que la deficient interacció leucòcit-endoteli a nivell tumoral no pot atribuir-se a una menor expressió de les diferents molècules d'adhesió implicades en aquest fenomen. Al intentar avaluar els mecanismes responsables de la deficient interacció leucòcit endoteli es va descartar la participació de l'antigen carcinoembrionari, els productes derivats de la ciclooxigenasa i la sintasa induïble de l'òxid nítric. No obstant es va demostrar que la inhibició no selectiva de la sintasa de l'òxid nítric augmentava de manera dosi-depenent el rodament leucocitari i l'adhesió post-LPS a nivell del teixit tumoral. Efecte similar es va observar al procedir al immunobloqueig del factor transformant B1. Per tant, dels resultats obtinguts, es pot ressaltar que tant l'òxid nítric com el factor de creixement transformant B1 participen, al menys de manera parcial, en els fenòmens d'escapament dels sistemes de immunovigilància a nivell tumoral.La segona part de la tesi doctoral ha confirmat en primer lloc que es possible detectar la existència de cèl·lules neoplàsiques circulants en sang perifèrica de malalts amb càncer colorectal a través de la detecció de RNA missatger de l'antigen carcinoembrionari. Aquesta tècnica s'ha confirmat sensible (detecta una cèl·lula neoplàsica per cada 107 leucòcits) i específica (negativa en els controls sans). Emprat aquesta tècnica s'ha intentat avaluar un dels aspectes més controvertits de la cirurgia laparoscòpica en el càncer colorectal, la disseminació tumoral. Mitjançant estudis de detecció de cèl·lules neoplàsiques circulants en sang perifèrica, portal i en el líquid peritoneal, s'ha descartat el potencial efecte deleteri atribuït a la cirurgia laparoscòpica. No es varen observar diferències significatives entre el grup de cirurgia convencional respecte al grup de cirurgia laparoscòpica, en el número de pacients amb determinacions positives en els tres territoris avaluats rere la resecció quirúrgica . Finalment, es va intentar establir la significació pronòstica de la detecció de cèl·lules neoplàsiques circulants en pacients amb càncer colorectal mitjançant el seu seguiment a llarg termini. Tant en el grup global de pacients amb càncer colorectal com en aquells en els que s'havia realitzat una resecció curativa , la determinació preoperatòria de cèl·lules circulants no s'associava a un pitjor pronòstic a llarg termini (supervivència global i supervivència lliure de malaltia). Tenint en compte que estudis previs havien demostrat que la cirurgia afavoria la mobilització de cèl·lules neoplàsiques en el càncer colorectal, es va valorar la significació pronòstica de la detecció de cèl.lules neoplàsiques a les 24 hores de la cirurgia. Novament, la detecció postoperatòria no s'associava a un pitjor pronòstic a llarg termini.

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Sigglekow, Nicholas David Garvan Institute of Medical Research Faculty of Medicine UNSW. "Mutated in colorectal cancer (MCC): a putative tumour suppressor gene in colorectal cancer." Publisher:University of New South Wales. Garvan Institute of Medical Research, 2009. http://handle.unsw.edu.au/1959.4/43617.

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Colorectal cancer (CRC) remains a significant burden in contemporary society due to an aging population, unhealthy dietary choices and an increasingly sedentary lifestyle. While the underlying defects for many hereditary forms of CRC have been determined, many genetic and epigenetic changes promoting common sporadic CRCs have yet to be identified. The Mutated in Colorectal Cancer (MCC) gene, identified in 1991, was initially thought to be responsible for the hereditary form of CRC, familial adenomatous polyposis, before the discovery of the susceptibility gene Adenomatous Polyposis Coli (APC), which then became the focus of intense research. Recent data, however, suggests that MCC may also be important in the development of CRC. I have investigated the mechanism of MCC gene silencing, the putative structure, and multiple functions of MCC. MCC was frequently silenced by promoter hypermethylation in CRC cell lines and primary tumours. MCC methylation showed strong molecular and clinicopathological associations with hallmarks of the serrated neoplasia pathway. Furthermore, MCC methylation was more frequent in serrated precursor lesions compared with adenomas, thus occurring early during carcinogenesis. MCC is highly conserved in complex multicellular organisms. Re-introduction of MCC in CRC cell lines resulted in partial G1 to S phase, and G2/M phase cell cycle blocks, potentially by upregulating cell cycle inhibitor gene transcription and interfering with the process of mitotic checkpoints and division, respectively. Changes in MCC levels also modulated NF?B pathway signalling, the pathway required for maintaining cell viability and proliferation in colonic epithelial cells. In particular, MCC overexpression suppressed both TNF? and LPS-induced NF?B activation, decreasing both the magnitude and rate of cellular responses. Overexpression also resulted in downregulation of proteins involved in canonical NF?B pathway signalling, while increasing the transcription of non-canonical NF?B genes. Therefore, MCC may direct activation of this pathway to a specific subset of NF?B-regulated genes. These data provide a molecular basis for the role of MCC as a tumour suppressor gene in CRC. MCC may have multiple functions, regulating cell cycle progression and modulating NF?B pathway signalling, either through direct involvement in pathway signalling cascades, or by providing a scaffold on which signalling events can occur.

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Allison, Andrew S. "The insulin-like growth factor type 1 receptor and colorectal neoplasia : modelling the somatic evolution of cancers." Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/26957.

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This thesis examines the temporal expression of the Insulin-like growth factor type 1 receptor gene (IGF-IR) in the evolution of human colon cancer. These studies examine IGF-1R expression in human colo-rectal neoplasia by means of Northern blotting and Immunohistochemistry validated by tissue and reagent controls and by Western blotting. The studies show that in the normal human colon, adult stem cells in the basal crypt region expression high IGF-1R levels which decrease to low levels when these cells migrate to and differentiate in the mid and upper crypt regions. In the aberrant crypt focus, the transformed cells express high IGF-1R levels throughout the crypt axis despite showing varying degrees of differentiation. This pattern of high IGF-R expression occurring de novo in colo-rectal neoplasia continues with the neoplastic progression in polyps and cancers. However, reduced IGF-1R expression is seen in some advanced cancer phenotypes-in epithelial-type cancer cells that show a fully polarised morphology during epithelial-mesenchymal transformation (EMT) and in mesenchymal-type cancer cells that show a loss of cell-basement membrane or cell-cell adhesion during invasion. When these invasive cancer cells regain cell-cell adhesion, they reexpress the IGF-1R. These morphological changes account for the low levels of IGF-1R expression seen in advanced invasive cancers in the current study. These studies provide basic insights into how IGF-1R expression in normal cellular development is disrupted in tumour initiation. Additionally, the studies show how the control of IGF-1R expression might also be involved in later stage cancer progression during EMT and invasion.

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Digby, Jayne. "The relationship between faecal haemoglobin concentration and risk of significant colorectal neoplasia in screening and symptomatic populations." Thesis, University of Dundee, 2016. https://discovery.dundee.ac.uk/en/studentTheses/278e46d6-762b-4a0e-a2cc-3a3cbf475d52.

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Faecal immunochemical tests for haemoglobin (FIT) are replacing traditional guaiac-based faecal occult blood (gFOBT) tests in bowel screening programmes due to their many advantages. An evaluation of using quantitative FIT within the Scottish Bowel Screening Programme (SBSP) has taken place with faecal haemoglobin (Hb) concentration recorded for 38,720 participants. Subsequently, it has been established that faecal Hb concentration is related to severity of colorectal neoplastic disease, with higher median faecal Hb concentration in participants with advanced neoplasia compared to those with less severe outcomes (200.0 v. 166.0 µg Hb/g faeces, p < 0.0001). Those with elevated faecal Hb concentration (60.0 - 79.9 µg Hb/g faeces) at the time of a negative test result (< 80.0 µg Hb/g faeces) were more likely to be later diagnosed with an interval cancer than those with undetectable Hb (adjusted odds ratio = 24.7, 95% CI: 4.9 - 124.6). Follow-up of participants with a negative test result then testing positive in the subsequent screening round allowed calculation of an adjusted odds ratio of 38.0 (95% CI: 20.2 – 71.2) for advanced neoplasia in those with initial faecal Hb concentration 60.0 - 79.9 µg Hb/g faeces compared to those with faecal Hb concentration < 20.0 µg Hb/g faeces. These results give firm support to the role of faecal Hb concentration as a strong predictor of future risk of advanced neoplasia. The use of FIT in symptomatic patients was also evaluated, with results showing that using a cut-off faecal Hb concentration of any detectable Hb would have ruled out colorectal cancer and could have reduced the referral rate by 40%. With introduction of FIT now approved for the SBSP, it is hoped that a risk scoring system can be developed based on age, gender and faecal Hb concentration to better direct colonoscopy resource and reduce the proportion of interval cancers.

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SANTOS, Alex Caetano dos. "Aspectos clínicos e patológicos de pacientes com tumores colorretais diagnosticados durante cirurgia abdominal de urgência." Universidade Federal de Goiás, 2011. http://repositorio.bc.ufg.br/tede/handle/tde/1732.

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Made available in DSpace on 2014-07-29T15:29:11Z (GMT). No. of bitstreams: 1 Dissertacao Alex Caetano dos Santos.pdf: 982242 bytes, checksum: f685e405b1e872acdf53a2790d29d70b (MD5) Previous issue date: 2011-04-25 Context In 85% of the cases, colorectal cancer is diagnosed at an advanced stage during investigation of symptomatic patients. Currently, 10% to 33% of the cases may present emergency situations (obstruction or perforation), requiring immediate surgical treatment, and may result in higher mortality compared with elective surgical procedures. Objective Analyze clinical and pathological features of patients with colorectal cancer diagnosed during emergency abdominal surgery at the Hospital de Urgências de Goiânia. Methods We studied 107 patients operated on between January 2006 and June 2010 presenting with histologically confirmed colorectal malignancy. Results This series consisted of 58 women and 49 men with mean age of 59.81 ± 17.08 years. The most frequent symptoms were: abdominal pain (97.2%), no bowel movements (81.3%), vomiting (76.6%), and anorexia (40.2%). Clinical preoperative diagnosis was divided into five groups: obstructive acute abdomen (n = 68), obstructive acute perforation (n = 21), obstructive acute inflammation (n = 13), abdominal sepsis (n = 3), and severe gastrointestinal bleeding (n = 2). Tumors were located in the rectosigmoid (51.4%), transverse colon (19.6%), ascending colon (12.1%), descending colon (11.2%), and 5.6% of the cases presented association of two colon tumors (synchronic tumors). Histopathological examination revealed the presence of adenocarcinoma in 98.1% of the cases. The surgical treatments were: tumor resection with colostomy (85%), tumor resection with primary anastomosis (10.3%), and colostomy without tumor resection (4.7%). Immediate mortality occurred in 33.4% of the patients. Bivariate analysis of sex, tumor location and stage showed no relation to death (p > 0.05%). Conclusions Colorectal cancer in patients who underwent emergency surgery due to acute abdominal complication was more prevalent in females and elderly individuals with nonspecific colonic complaints. Adenocarcinoma of the rectosigmoid was the most frequent condition. Despite the high mortality rate, surgical treatment of colorectal cancer was indicated due to intestinal occlusion. Contexto Em 85% dos casos, o câncer colorretal é diagnosticado em estádio avançado durante a investigação de pacientes sintomáticos. Atualmente, 10% a 33% dos casos podem apresentar situações emergenciais (obstrução ou perfuração), necessitando de intervenção cirúrgica imediata, podendo resultar em mortalidade operatória maior do que a cirurgia eletiva. Objetivo Analisar os aspectos clínicos e patológicos de pacientes com câncer colorretal operados em urgência, no Hospital de Urgência de Goiânia. Métodos Foram estudados 107 pacientes operados entre janeiro de 2006 e junho de 2010 com diagnóstico histológico de neoplasia maligna colorretal. Resultados A amostra foi constituída de 58 mulheres e 49 homens com idade média de 59,81 ± 17,08 anos. Os sintomas mais frequentes foram: dor abdominal (97,2%), parada de eliminação de gases e fezes (81,3%), vômitos (76,6%) e anorexia (40,2%). Na avaliação pré-operatória foram diagnosticados: abdome agudo obstrutivo (n = 68), abdome agudo perfurativo (n = 21), abdome agudo inflamatório (n = 13), sepse abdominal (n = 3) e hemorragia digestiva grave (n = 2). Os tumores estavam localizados no retossigmoide (51,4%), cólon transverso (19,6%), cólon ascendente (12,1%), cólon descendente (11,2%) e em 5,6% dos casos houve associação de dois tumores no intestino (tumores sincrônicos). Os exames histopatológicos revelaram a presença de adenocarcinoma em 98,1% dos casos. Os tratamentos cirúrgicos adotados foram: ressecção tumoral com colostomia (85%), ressecção tumoral com anastomose primária (10,3%) e colostomia sem ressecção tumoral (4,7%). Houve mortalidade imediata em 33,4% dos casos. Na análise bivariada, as variáveis sexo, localização e estádio tumoral apresentaram p > 0,05% em relação ao óbito. Conclusão O câncer colorretal operado em urgência teve maior prevalência no sexo feminino e nos idosos com queixas inespecíficas. O diagnóstico histopatológico na quase totalidade foi adenocarcinoma localizado no retossigmoide. Embora a mortalidade seja elevada, o tratamento cirúrgico do câncer colorretal deve ser realizado.

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Watson, Mark Alexander. "Inter-individual variation in susceptibility to colorectal neoplasia : the interaction between diet, measures of DNA damage and genetic polymorphisms." Thesis, Imperial College London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404833.

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Banu, Nahida Arjumand. "The role of selective cyclooxygenase-2 inhibitor NS398 in the regulation of cell adhesion and cell migration in colorectal neoplasia." Thesis, University of Bristol, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404309.

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Gruppo, Mario. "Subclinical myopathy and colorectal cancer: identification and role of new muscle damage and regeneration biomarkers." Doctoral thesis, Università degli studi di Padova, 2015. http://hdl.handle.net/11577/3424623.

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Background Skeletal muscle is the major reservoir of body proteins and it can be affected in conditions associated to altered protein turnover and metabolism such as cancer. Although severe wasting is seen primarily in patients with advanced malignancy, some of them present degree of wasting at the onset of disease. Autophagy has been recently described to play a relevant role in muscle wasting. Materials and Methods We performed morphometric studies and immunohistochemical analyses on intraoperative rectus abdominis muscle biopsies from 50 consecutive weight stable colorectal patients and 25 weight-stable patients operated for non-inflammatory benign diseases with no clinical signs of myopathies. Biochemical and molecular analyses have been performed in order to evaluate protein profile, the presence of autophagy induction and their correlation with clinical outcome. Results In cancer patients, we observed a subclinical myopathy characterized by an abnormal distribution of myonuclei relocated from the periphery inside the myofiber. The percentage of myofibers with abnormally located myonuclei was significantly higher in patients compared to controls. Analyses on serum samples showed that, in the absence of systemic inflammation, in the prevalence of cancer patients the levels of albumin and prealbumin were below the normal range and the mean value was significantly lower compared to that detected in controls. Molecular analyses showed an accumulation of p62, a typical marker of autophagy induction, significantly higher in cancer patients compared to controls. We found an inverse correlation between the number of abnormally nucleated myofibers and the presence of lymph node metastasis. Cancer relapse was correlated with low serum levels of prealbumin and high levels of p62 in myofibers of cancer patients. Conclusions Colorectal cancer patients have a subclinical myopathy characterized by myofibers with internally located myonuclei. In the absence of inflammation, cancer patients show low levels of prealbumin and albumin as markers of altered protein turnover and persistent high levels of p62 in myofibers as expression of autophagy induction with an impairment in physiological autophagic flux. Up to now our data indicate that skeletal muscle fibers show nuclear abnormalities that seems to be associated to a better prognosis, while the presence of an altered protein turnover at an early stage of disease, with an impairment in the physiological autophagic flux, that could be predictive of cancer relapse and onset of cancer cachexia. Introduzione Il muscolo scheletrico rappresenta la principale riserva proteica del corpo e può essere compromesso in varie affezioni metaboliche e di alterato turnover proteico, quale il cancro. Benchè una severa perdita di massa sia generalmente presente in quadri neoplastici avanzati, in alcuni casi può essere già evidente in una fase di malattia iniziale. L’autofagia è stata recentemente descritta come uno dei possibili fattori responsabili del processo catabolico. Materiali e Metodi 50 pazienti sottoposti ad intervento chirurgico per neoplasia colorettale e 25 pazienti operati per patologia benigna non infiammatoria, in assenza di segni clinici di miopatia, sono stati sottoposti a biopsia muscolare su cui sono state eseguite analisi di carattere morfometrico ed istochimico. Sono state, inoltre, eseguite analisi biochimiche e molecolari al fine di valutare l’assetto proteico e lo stato di attivazione del processo autofagico e la loro correlazione con l’outcome clinico dei pazienti. Risultati Nei pazienti neoplastici abbiamo riscontrato la presenza di una miopatia subclinica, caratterizzata dalla presenza di fibre muscolari con un’anomala localizzazione del nucleo cellulare al centro della fibra, significativamente maggiore rispetto ai controlli. L’analisi dell’assetto proteico ha dimostrato valori sierici di albumina e prealbumina significativamente più bassi nei pazienti oncologici, mentre l’analisi molecolare ha documentato elevati livelli di p62 nelle fibre muscolari dei pazienti affetti da carcinoma colorettale, rispetto ai controlli. La valutazione dell’outcome clinico ha dimostrato una correlazione inversa tra la percentuale di miofibre anomale e l’insorgenza di metastasi linfonodali, mentre bassi livelli sierici di prealbumina ed alti livelli di p62 nelle fibre muscolari sono risultati correlati con un aumentato rischio di ripresa di malattia Conclusioni I pazienti affetti da carcinoma colorettale presentano una miopatia subclinica già all’insorgenza della malattia, caratterizzata dalla presenza di fibre con alterata posizione del nucleo nella cellula. In assenza di infiammazione sistemica e tissutale, i pazienti oncologici presentano bassi livelli sierici di albumina e prealbumina, come espressione di un alterato turnover proteico, nonché elevati livelli di p62 nelle fibre muscolari, a dimostrazione dell’attivazione del processo autofagico che risulta tuttavia compromesso. Tali dati suggeriscono, pertanto, un verosimile ruolo protettivo per le anomalie nucleari descritte, mentre un alterato turnover proteico ed una compromissione del normale flusso autofagico, in concomitanza dell’insorgenza della neoplasia, costituiscono un potenziale fattore predittivo negativo in termini di ripresa di malattia ed evoluzione verso uno stato cachettico.

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Hanks, Joanna. "The influence of the MTHFR C677T genotype and folate status on genomic DNA methylation and uracil misincorporation in the colon of subjects without colorectal neoplasia." Thesis, King's College London (University of London), 2017. https://kclpure.kcl.ac.uk/portal/en/theses/the-influence-of-the-mthfr-c677t-genotype-and-folate-status-on-genomic-dna-methylation-and-uracil-misincorporation-in-the-colon-of-subjects-without-colorectal-neoplasia(4175b8e8-1b3d-4dbc-99eb-a3badc61f907).html.

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Background: Colorectal cancer (CRC) is a leading cause of cancer-related mortality in the UK. Folate deficiency and the MTHFR C677T polymorphism may increase colorectal cancer risk by altering normal patterns of DNA methylation and by causing uracil misincorporation into DNA which can in turn induce deletions and double-strand breaks. The methylenetetrahydrofolate reductase (MTHFR) enzyme is pivotal in maintaining the balance between these two critical folate-mediated pathways (DNA methylation and uracil misincorporation) and the commonly occurring MTHFR C667T polymorphism has been associated with a reduction in risk of colorectal cancer under conditions of adequate folate status, but increased risk when folate status is low. Design: In this PhD project, a large cross-sectional study of neoplasia-free volunteers (n=336) recruited at clinically indicated colonoscopy, was designed to investigate the influence of folate status and the MTHFR genotype on genomic DNA methylation and uracil misincorporation in DNA. The relationship between serum and red cell folate, plasma homocysteine and colonic folate concentration was also investigated. A second study, designed as a randomised controlled trial (RCT) in a subset of participants from the cross-sectional study, was conducted to determine whether folate supplementation influences genomic DNA methylation and folate levels in the colon. The relationship between demographic and lifestyle factors was also explored in this small dataset (n=15). Methods: 336 volunteers without colorectal neoplasia were recruited into the cross-sectional study. A health questionnaire was used to collect data on age, weight, height, ethnicity, and smoking, drinking, and nutritional supplement intake. A previously validated food frequency questionnaire was used to collect data on habitual dietary folate intake. Blood samples were taken to determine serum and red cell folate, plasma homocysteine, vitamin B12 and MTHFR C677T genotype, and colonic tissue biopsies were collected to determine colonic tissue folate, genomic DNA methylation and uracil misincorporation in DNA. Additionally, a small number of participants from the cross-sectional study were recruited into a small RCT taking short-term folate supplementation (400g/d) for 12 weeks. Serum and red cell folate, serum vitamin B12, MTHFR C677T genotype, colonic folate and DNA methylation were compared before and after supplementation. Results: The MTHFR C677T genotype did not influence systemic or colonic tissue folate biomarkers, genomic DNA methylation or uracil content in the colonic mucosa. DNA methylation was not influenced by biomarkers of folate status or homocysteine. Uracil content in DNA was positively associated with serum folate and nutritional supplement use after adjustment for age, gender, ethnicity, smoking and systemic folate biomarkers. Colonic tissue folate correlated positively with serum folate and and negatively with smoking. For the 15 subjects who were recruited into the RCT on folic acid supplementation, an increase in serum folate and a non-significant increase in colonic tissue folate was observed in comparison with subjects on placebo. Folate supplementation did not influence genomic DNA methylation, red cell folate plasma homocysteine or serum vitamin B12 levels. Conclusion: The MTHFR C667T genotype and folate status were not associated with DNA methylation or uracil misincorporation into DNA. Uracil misincorporation and colonic tissue folate were both influenced by serum folate, and tissue folate was affected by smoking in this population of neoplasia-free subjects with adequate folate status. Short term supplementation increased serum but conferred no influence on genomic DNA methylation in this population.

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Pinheiro, Rafael Soares Nunes. "Avaliação das margens cirúrgicas e do tipo de borda tumoral nas ressecções hepáticas por metástase de câncer colorretal e seu impacto na mortalidade e recidiva." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/5/5154/tde-09082012-143141/.

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INTRODUÇÃO: Aproximadamente 50% dos pacientes com tumor colorretal apresentam metástase hepática e a hepatectomia é o procedimento terapêutico de escolha. Discutem-se diversos fatores prognósticos, entre eles a margem cirúrgica é um fator sempre recorrente, pois não existe consenso da distância mínima necessária entre o nódulo metastático e a linha de secção hepática. Alguns autores identificaram que a margem cirúrgica maior que 1cm é um fator de melhor prognóstico com maior sobrevida e menor recidiva. Contudo, outros estudos demonstram resultados semelhantes entre pacientes com margens cirúrgicas maiores que 1cm, exíguas e até mesmo microscopicamente acometidas. Essas controvérsias conduzem à idéia de que outros fatores biológicos possam estar envolvidos na fisiopatologia de recorrência. Assim sendo, é de grande importância a avaliação da relação das margens cirúrgicas de ressecções hepáticas de metástases de câncer colorretal com a sobrevida e recidiva da doença. OBJETIVOS: Avaliar as margens cirúrgicas e o tipo de borda tumoral nas ressecções de metástases hepáticas de câncer colorretal e sua correlação com recidiva local e sobrevida. MÉTODOS: Estudo retrospectivo, baseado na revisão dos prontuários de 91 pacientes submetidos à ressecção de metástases hepáticas de neoplasia colorretal, durante o período compreendido entre janeiro de 2000 e dezembro de 2009. Revisão histopatológica prospectiva de todos os casos com aferição da menor margem cirúrgica e classificação das bordas tumorais como expansiva ou infiltrativa. RESULTADOS: Não houve diferença estatística nas taxas de recidiva e no tempo de sobrevivência global entre as margens livres e acometidas, assim como não houve diferença entre as margens subcentimétricas e maiores de 1cm. A sobrevida livre de doença dos pacientes com margens microscopicamente acometidas foi significativamente menor do que os pacientes com margens livres (p=0,002). A análise multivariada identificou o tipo de borda infiltrativa como fator de risco para recidiva (0,05). A sobrevida livre de doença foi significativamente menor nos pacientes com borda infiltrativa em comparação com os tumores com bordas expansivas (p=0,05). CONCLUSÕES: As ressecções de metástase hepática com margens livres de doença, independentemente da distância da margem, não influencia na recidiva tumoral (hepática ou extra-hepática) ou sobrevida do paciente. A borda tumoral do tipo infiltrativa foi fator de risco para recidiva INTRODUCTION: Approximately 50% of patients with colorectal cancer have liver metastases and hepatectomy is the therapeutic procedure of choice. Surgical margin is an ever-recurring discussed prognostic factor, because there is no consensus of the minimum required distance between the metastatic nodule and the liver section line. Some authors reported surgical margin larger than 1 cm as a better prognosis factor ensuring longer survival rates and lower recurrence. However, other studies showed similar outcomes among patients with surgical margins larger than 1 cm, narrow margins and even microscopically affected ones. These controversies led the idea that other biological factors may be involved in the pathophysiology of recurrence. Therefore, it is valuable to assess the relationship between surgical margins of liver resection for colorectal cancer metastases with survival and recurrence. OBJECTIVES: To evaluate the surgical margins size and tumors growth pattern of colorectal liver metastases and its correlation with local recurrence and survival. METHODS: A retrospective study based on review of medical records of 91 patients undergoing resection of colorectal liver metastases during the period between January 2000 and December 2009. In addition, we undertook a detailed pathologic analysis of each pathological specimen with record of the closest surgical margins and tumors growth pattern classification as pushing or infiltrative. RESULTS: There was no statistical difference in recurrence rates and overall survival time between positive or negative margins, as well as no difference between the margins of 1cm width or more with subcentimeter margins. The disease-free survival of patients with microscopically positive margins was significantly lower than patients with negative margins (p = 0.002). Multivariate analysis identified infiltrative tumor growth pattern as a risk factor for recurrence (p=0.05). Disease-free survival was significantly lower in patients with infiltrative growth pattern compared to tumors with expansive margins (p = 0.05). CONCLUSIONS: Colorectal liver metastases resection with negative margins, regardless of width, has no influence on recurrence (hepatic or extrahepatic), neither on patient survival. The infiltrative tumor growth pattern type was a risk factor for recurrence

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Majumdar, Debabrata. "Expression and post-translational modification of intermediate filament proteins in colonic mucosa of patients with ulcerative colitis : role in pathogenesis of colitis associated colorectal neoplasia and dysplasia." Thesis, University of Sheffield, 2016. http://etheses.whiterose.ac.uk/16564/.

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Background: Ulcerative colitis(UC) is a chronic inflammatory disease of the colon associated with increased cancer risk of colitis associated cancer(CAC). Keratins(K) are intermediate filament(IF) proteins, and are key component of the cellular cytoskeleton. K8 null mice develop colitis; a subset of IBD patients have mutation in K8 gene. Keratins play a role in cell-death signalling pathways; epithelial cells lacking K8 and K18 are more sensitive to TNF-mediated apoptosis. Methods: Colonic biopsies obtained from UC patients (and controls) were grouped into eight categories based on risk of cancer and presence of mucosal inflammation: quiescent recent onset (<5 years) UC (ROUC); quiescent long-standing pancolitis (20–40 years) (LSPC); UC with primary sclerosing cholangitis (PSC); active colitis (ACT) and un-inflamed proximal colonic mucosa (INACT) in the same patient; pancolitis with dysplasia-both dysplastic lesions (DT) and distal rectal mucosa (DR). An iTRAQ and western immunoblotting compatible extraction and solubilisation protocol for insoluble IF proteins was developed. Labelled peptides from pooled patient groups were analysed by quantitative proteomics. Results noted were validated by western immunoblotting. Results 52 proteins were identified, 32(61.5%) were matched by 2 or more peptides. Acute inflammation was associated with reduced K8, K18, K19 and vimentin (p < 0.05) compared to controls and un-inflamed mucosa; reduced levels were also seen in DT and DR. LSPC relative to controls or ROUC showed increased levels of IF proteins (K8, K18, K19 and vimentin, p < 0.05). Multiple forms of K8 forms were identified on immunoblotting; in aggressive phenotypes relative K8 phosphorylation (K8pS23) was reduced along with an increase in vimentin:K8 ratio. Acute inflammation reduces K8 levels and phosphorylation; such changes are restored in longstanding quiescent disease LSPC but not in ROUC (despite clinical and endoscopic remission). Conclusion: Alteration in mucosal levels of IF proteins (keratin and vimentin) may play a role in pathogenesis of colitis associated cancers.

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Marques, Carlos Frederico Sparapan. "Tratamento da neoplasia retal pela microcirurgia endoscópica transanal- TEM: fatores de risco para complicações pós-operatórias." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/5/5168/tde-29102014-155628/.

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INTRODUÇÃO: A microcirurgia endoscópica transanal (TEM) é uma técnica minimamente invasiva segura e eficiente para o tratamento de neoplasia retal benigna e maligna precoce. As complicações pós operatórias podem ser graves. Existe controvérsia na literatura a respeito da sua incidência e gravidade. OBJETIVOS: Avaliar os fatores de risco relacionados a incidência e gravidade das complicações pós operatórias e seu comportamento temporal em pacientes com neoplasia retal tratados por TEM. MÉTODOS: Estudo prospectivo das complicações pós-operatórias usando a classificação e graduação de Clavien-Dindo. As características estudadas dos pacientes foram: idade, sexo, risco cirúrgico dado pela Associação Americana de Anestesiologia (ASA), quimiorradioterapia neoadjuvante, altura e tamanho da lesão, margens patológicas, histologia do tumor e tipo de sutura: por TEM ou por afastador anal convencional. RESULTADOS: Dentre os cinquenta e três pacientes tratados, a morbidade geral foi de 50%. Incontinência foi a complicação mais frequente (17,3%). Apenas uma paciente teve incontinência persistente. As taxas de complicações pós-operatórias grau I e grau II (GII) foram ambas 21,1%; para grau III (GIII) e IV também foram ambas: 3,8%. Não houve mortalidade. Dos pacientes que tiveram complicações pós-operatórias, 61,54% tinham lesões abaixo da primeira válvula retal, comparado com 38,46% dos pacientes com lesões acima da primeira válvula (p=0.039). Pacientes submetidos à quimiorradioterapia neoadjuvante tiveram 24 vezes mais chance de apresentarem complicações pós-operatórias GII (p=0,002), e 7,03 vezes mais chance de GIII (p=0,098). Quando a sutura da ferida cirúrgica foi realizada por TEM, houve 16 vezes menos chance de ocorrerem complicações pós-operatórias GIII (p=0,043). 53% das complicações pós-operatórias ocorreram em 10 dias e 95%, em 20 dias. CONCLUSÕES: Complicações pós-operatórias pós TEM são frequentes, aceitáveis e geralmente controladas com medicamentos. Pacientes com lesões mais distais têm mais complicações pós-operatórias. Pacientes que receberam quimiorradioterapia neoadjuvante e submetidos a sutura com afastador de ânus convencional tiveram complicações pós operatórias que requereram intervenção médica - cirúrgica ou endoscópica sobre sedação. O comportamento temporal das complicações é progressivo e inespecífico, a maioria ocorrendo nos primeiros 20 dias INTRODUCTION: Transanal endoscopic microsurgery (TEM) is a safe and efficient minimally invasive treatment for rectal benign and early malignant neoplasia. Postoperative complications may be severe. Controversy exists with regard to incidence and severity. OBJECTIVES: Evaluate risk factors related to incidence and severity of postoperative complications, and time course, in patients with rectal neoplasia treated by TEM. METHODS: Prospective study of postoperative complications using the Clavien-Dindo classification and grading system. Patients\' characteristics included age, sex, ASA score, neoadjuvant chemoradiotherapy (CRT), lesion height and size, pathologic margins, tumor histology, and suture type: through TEM or conventional retractor. RESULTS: Among fifty-three patients treated,overall morbidity rate was 50%. Incontinence was the most frequent complication (17.3%). One patient had persistent incontinence. Grade I and Grade II (GII) postoperative complication rates were both 21.1%, and Grade III (GIII) and IV rates were both 3.8%. There was no mortality. Of the patients with postoperative complications, 61.54% had lesions under the first rectal valve, compared with 38.46% of patients with lesions over the first valve (p=0.039). Patients submitted to CRT had a 24-fold greater chance of presenting GII complications (p=0.002), and a 7.03-fold greater chance of GIII (p=0.098). When the surgical defect was treated using the TEM device to perform the suture, there was a 16-fold less chance of having GIII complications (p=0.043). Fifty-three percent of complications occurred in the first 10 days, and 95% within 20 days. CONCLUSIONS: Postoperative complications after TEM for the treatment of rectal neoplasia are frequent, acceptable, and usually controllable with pharmacologic treatment. Patients with more distal lesions have more postoperative complications. Patients receiving neoadjuvant CRT and submitted to suture with a conventional anal retractor have more postoperative complications that require intervention under sedation. Over time the nature of complications is progressive and nonspecific, with most occurring within the first 20 days

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Jansson, Agneta. "Molecular alterations in colorectal cancer /." Linköping : Univ, 2002. http://www.bibl.liu.se/liupubl/disp/disp2002/med743s.pdf.

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Boetto, Riccardo. "Extreme hepatectomies and non-resectability technical breakthrough for liver neoplasia, focusing on colorectal metastases: experimental pilot study on safety, efficacy, and regeneration patterns with new insight on ALLPS-LT hybrid techniques." Doctoral thesis, Università degli studi di Padova, 2017. http://hdl.handle.net/11577/3426225.

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BACKGROUND New strategies to broaden resectability criteria in hepatobiliary surgery has led to the development of two-stage hepatectomy techniques, multi-step procedures with the aim of promoting effective regeneration of the future liver residue (FLR). The first multicentre international case study was published in 2012 for a new surgical technique defined ALPPS (Associating Liver partition and Portal vein ligation for Staged hepatectomy), which implies in Step1 (laparotomy) ligation of the right portal branch (PVL) with subtotal parenchymal transection (in situ splitting), in order to stimulate rapid FLR hypertrophy for a staged hepatectomy. At the UOC of Hepatobiliary Surgery and Liver Transplantation Unit of Padova University a new surgical technique was introduced that reverses the “classic ALPPS paradigm” based on a Step1 with laparoscopic PVL or portal vein embolization (sequential radiological PVE) and microwave (MWA) thermal ablation on the future transection plane. This method has been identified with the term LAPS (Laparoscopic microwave Ablation and Portal vein occlusion for Staged hepatectomy). MATERIALS AND METHODS Ten patients (M: F = 6: 4, mean age 62.5 years - gamma 29-81) were evaluated, underwent LAPS intervention for primitive or secondary malignant liver disease, upfront unresectable for insufficient preoperative FLR. The intraoperative data, the bio-morphological profile were collected during the first week respectively after both surgical procedures, complications, overall survival and analysis of oncological and postoperative outcomes (median follow-up 17 months, range 4-36). RESULTS Significant increase in FLR from 372.3 cc (range 179-407) to 664 cc (range 491-923) - p = 0.002 – and of the FLR/BW ratio was obtained (0.53% - 0.94%; p = 0.002), with a FLR hypertrophy of 71.5% (range 42.8-132%) and a median daily volume increase of 29.3 cc die (range 16.4 -43.3). All patients considered gained Step2, with effective FLR increase on average in 9.5 days (range 7-11 days). Median duration of Step1 (145 min; range 75-325 min) was significantly lower (p = 0.0005) than Step2 (402.5 min; range 185-630); blood loss was negative (range 0-70 cc) during Step1 so no patient needs transfusion, and 800 cc (range 600-3600) in Step2 (p = 0.0001). The need for postoperative monitoring in intensive care unit was averaged after Step1 and Step2 respectively unnecessary and 2.5 days (range 1-6 days) (p = 0.0057). Total hospitalization was 14 days (range 10-46) with particular feature that 7/10 patients (70%) had interstage home discharge period. The study of postoperative complications using the Dindo-Clavien classification revealed 20 events in 8 patients (80% of patients had at least one complication); analyzing for single Step 4/10 patients (40%) had complications after Step1 while 7/10 (70) patients had complications after Step2; after Step1 and Step2, respectively, 20% and 40% of grade ≥IIIa complications (with a single event IIIb, no grade IV events and no biliary complications). No perioperative mortality event was registered (90-days mortality 0%). Overall Survival (12-months) was 77.8% with a median of 28.2 months. Pathological analysis revealed 8/10 patients (80%) with an oncologically radical resection (R0). CONCLUSIONS LAPS technique was effective in achieving resectability in patients upfront unresectable for FLR insufficiency, although with a remarkable rate of complications, but with comparable data literature ALPPS data. Compared with standard ALPPS data there was sno perioperative mortality rate and 70% of patients had a short interstage discharge. In the broad panorama of two-stage hepatectomy techniques development, LAPS seems to be able to describe one of the new paradigms, enabling by means of minimally-invasive techniques to achieve significant oncological results in selected preoperative unresectable patients. Background La ricerca di nuove strategie per ampliare i criteri resecabilità in chirurgia oncologica epatobiliare, ha condotto allo sviluppo delle tecniche di two-stage hepatectomy, procedure multi-step con l’intento di favorire una rigenerazione efficace del future liver remnant (FLR). Nel 2012 è stata pubblicata la prima casistica internazionale multicentrica relativa ad una nuova tecnica chirurgica definita con l’acronimo ALPPS (Associating Liver Partition and Portal vein ligation for Staged hepatectomy) che sfrutta l’impiego nello uno Step1 (laparotomico) della legatura del ramo portale destro (PVL) in concomitanza di una transezione parenchimale subtotale (in situ splitting), al fine di stimolare una rapida ipertrofia del FLR in vista dello Step2 resettivo. Presso la UOC di Chirurgia Epatobiliare e dei Trapianti Epatici dell’Università di Padova parallelamente all’iniziale impiego della tecnica ALPPS, è stato messo a punto un nuovo modello chirurgico che inverte il paradigma classico ALPPS e prevede uno Step1 in videolaparoscopia con PVL intra-operatoria o embolizzazione portale (PVE) radiologica sequenziale con termoablazione con microonde (MWA) sulla futura trancia di sezione in vista dello Step2. Questa metodica è stata identificata col termine di LAPS (Laparoscopic microwave Ablation and Portal vein occlusion for Staged hepatectomy). Materiali e Metodi Sono stati valutati di 10 pazienti (M:F=6:4; età mediana 62,5 anni - range 29-81), sottoposti a intervento LAPS per patologia epatica maligna primitiva o secondaria, non altrimenti resecabile per insufficiente FLR preoperatorio. Sono stati raccolti i dati intra-operatori, il profilo bioumorale durante la prima settimana rispettivamente dopo entrambi gli Step chirurgici, le complicanze post-operatorie, la sopravvivenza globale e l’analisi dell’outcome oncologico e post-operatorio (follow-up mediano 17 mesi; range 4-36). Risultati In relazione all’analisi volumetrica è stato ottenuto un significativo incremento del FLR da 372.3 cc (range 179-407) a 664 cc (range 491-923) – p=0.002 – e del FLR/BW ratio (mediamente da 0.53% a 0.94%; p=0.002), assistendo a un’ipertrofia del FLR del 71.5% (range 42.8-132%) e a un incremento volumetrico giornaliero mediano di 29.3 cc die (range= 16.4-43.3). Tutti i pazienti considerati hanno avuto accesso allo Step2, ottenendo un’incremento efficace del FLR in media in 9.5 giorni (range 7-11 giorni). La durata mediana dello Step1 (145 min; range 75-325 min) è risultata significativamente inferiore (p=0.0005) a quella dello Step2 (402.5 min; range 185-630). Le perdite ematiche sono risultate mediamente nulle (range 0-70 cc) in corso di Step1 per cui nessun paziente ha necessitato di emotrasfusione, e 800 cc (range 600-3600) in corso di Step2 (p=0.0001). La necessità di monitoraggio post-operatorio in terapia intensiva è risultata mediamente dopo Step1 e Step2 rispettivamente non necessaria e di 2.5 giorni (range=1-6 giorni) (p=0.0057). La degenza totale è risultata mediamente di 14 giorni (range= 10-46) con la particolare caratteristica che 7/10 pazienti (70%) hanno beneficiato di un periodo di dimissione a domicilio interstage. Lo studio delle complicanze post-operatorie utilizzando la Dindo-Clavien Classification ha messo in evidenza 20 eventi in 8 pazienti (80% dei pazienti ha presentato almeno una complicanza); analizzando per singolo Step 4/10 pazienti (40%) hanno presentato complicanze dopo Step1 mentre 7/10 (70%) pazienti hanno presentato complicanze dopo Step2; dopo Step1 e Step2, rispettivamente 20% e 40% di complicanze di grado ≥ IIIa (con un unico evento IIIb, nessun evento di grado IV e nessuna complicanze biliare). Non si è registrato alcun evento di mortalità peri-operatoria (90-days Mortality 0%). La Overall Survival a 12 mesi, indipendentemente dalla patologia di base è risultata 77.8% con una sopravvivenza mediana di 28.2 mesi. Per quanto concerne l’analisi istologica 8/10 pazienti (80%) hanno ottenuto una resezione oncologicamente radicale (R0). Conclusioni La tecnica LAPS è risultata efficace nel raggiungimento della resecabilità in pazienti non operabili upfront per insufficienza del FLR, seppur con un considerevole tasso di complicanze, ma con dati comparabili ai risultati descritti in letteratura. Rispetto ai dati relativi alla tecnica standard ALPPS non si è registrata mortalità peri-operatoria e il 70% dei pazienti ha beneficiato di un breve periodo di dimissione interstage . Nell’ampio panorama dello sviluppo delle tecniche chirurgiche di two-stage hepatectomy la LAPS sembra poter descrivere uno dei nuovi paradigmi, permettendo grazie all’impego di tecniche mini-invasive, di ottenere un significativo risultato oncologico in pazienti selezionati pre-operatoriamente non resecabili.

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Malieno, Paula Braz. "Avaliação sensitiva de doentes com câncer colorretal tratados com oxaliplatina." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-05012017-163025/.

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A avaliação sensitiva de pacientes tratados com oxaliplatina tem se tornado objeto de estudo, pelo fato deste medicamento causar como efeito colateral, uma neuropatia periférica com características sensitivas, imediatamente após início da infusão. Sintomas que causam restrições nas atividades de vida diárias e na qualidade de vida do paciente durante o tratamento. Para uma melhor compreensão do mecanismo das alterações sensitivas, atualmente tem se utilizado o teste quantitativo da sensibilidade (TQS), que através da mensuração quantitativa dos limiares de detecção aos estímulos quente, frio e de vibração, nos concede um perfil para melhor relacionar com as possibilidades de manejo ou tratamento. Neste estudo propomos uma análise da através do TQS e de instrumentos que quantificam e qualificam a neuropatia, a dor neuropática e suas características. Objetivos: Descrever de forma prospectiva as alterações de sensibilidade exteroceptiva somática causadas pelo uso da oxaliplatina em doentes com câncer colorretal. Métodos: Foram incluídos 110 doentes (média 55 anos) com câncer colorretal que realizaram tratamento antineoplásico com oxaliplatina por seis meses, e foram avaliados por mais seis após a quimioterapia. Os pacientes realizaram avaliação sensitiva com TQS e responderam questionário sócio demográfico e questionários específicos para dor e neuropatia na visita basal (VB), ao término da quimioterapia (VT) e novamente após 6 meses de seguimento (VS). Resultados: Os questionários de dor e neuropatia mostraram seu início e as suas características, na qual foi evidente a dor com características neuropáticas na visita término do tratamento em 21,7% dos participantes manifestada pela dormência, choque elétrico, alfinetadas e agulhadas e a sensibilidade ao frio. As principais alterações demonstradas pelo TQS foram: nos limiares de detecção mecânica; aumento dos limiares dolorosos térmicos; diminuição da hiperalgesia mecânica; diminuição do limiar de detecção vibratória na mão e aumento no pé. O TQS indicou alterações entre os participantes do estudo e o grupo de voluntários saudáveis em algum momento das avaliações. Conclusão: Os pacientes com câncer colorretal submetidos ao tratamento com oxaliplatina cursam com dor com características neuropáticas que interferem em suas atividades diárias. O TQS caracterizou as principais alterações relacionadas ao início do tratamento, término do tratamento e durante o seguimento. As comparações com voluntários saudáveis sugerem que a presença da neoplasia e outras comorbidades são capazes de causarem alterações no TQS Sensory evaluation of patients treated with oxaliplatin has become an object of study, because this medication cause as a side effect, peripheral neuropathy with sensory characteristics, immediately after start of infusion. Symptoms that cause restrictions in daily activities and in the patient\'s quality of life during treatment. For a better understanding of the mechanism of sensory changes, currently it has used quantitative sensitivity testing (QST). That by the quantitative measurement of thresholds to warm stimuli, cold and vibration, gives us a profile to better relate to the possibilities of management or treatment. In this study we propose an analysis by QST and tools to quantify and qualify neuropathy, neuropathic pain and its features. Objectives: To describe prospectively the somatic exteroceptive sensitivity changes caused by the use of oxaliplatin in patients with colorectal cancer. Methods: We included 110 patients (mean 55 years) with colorectal cancer who underwent anticancer treatment with oxaliplatin for six months and were evaluated for six after chemotherapy. Patients underwent sensory evaluation with QST and answered sociodemographic questionnaire and specific questionnaires for pain and neuropathy at baseline, at the end of chemotherapy (visit six months) and again after 6 months of follow-up (visit twelve months). The instruments used were reduced McGill Pain Questionnaire (MPQ), Inventory symptoms of neuropathic pain (ISDN), Brief Pain Inventory (BPI-Brief Pain Inventory) Questionnaire neuropathic pain 4 (DN4), hospital scale of anxiety and depression (HADS). Results: The pain questionnaires and neuropathy showed its beginning and its characteristics, which was evident pain with neuropathic characteristics in the end visit of treatment in 21.7% of participants manifested by numbness, electric shock, pins and needles and sensitivity to cold. The main changes demonstrated by QST were in mechanical thresholds; painful increase in thermal thresholds; reduction in mechanical hyperalgesia; reduction of vibration detection limit for the hand and foot increases. The QST indicated changes between the study participants and the group of healthy volunteers at some point of the evaluations. Conclusion: Patients with colorectal cancer undergoing treatment with oxaliplatin occur with pain with neuropathic characteristics that interfere with their daily activities. QST characterized the major changes related to the start of treatment, end of treatment and during follow-up. Comparisons with healthy volunteers suggest that the presence of neoplasia and other comorbid conditions are capable of causing changes in the QST

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Dahl, Kjell. "Human colorectal cancer : experimental staging and therapeutics /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-154-8/.

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Gudzuhn, Andrej. "Virulenzfaktoren von E.coli aus gewaschenen Kolonbiopsien von Patienten mit kolorektalen Neoplasien." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2004. http://dx.doi.org/10.18452/15059.

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Hintergrund: Die Pathogenese nicht-familiärer kolorektaler Neoplasien ist heute noch nicht bekannt. Die Besonderheiten der Epidemiologie der Erkrankung sprechen für die Beteiligung von Umweltfaktoren, wie sozioökonomischer Faktoren, der Ernährung oder der bakteriellen Flora des Darmes. Eine intrazelluläre, von E.coli dominierte Flora wurde in Kolonbiopsien dieser Patienten beschrieben. Methoden: Es wurden Virulenzfaktoren von Escherichia coli untersucht, die aus gewaschenen koloskopischen Biopsien von 43 Patienten mit kolorektalen Adenomen und Karzinomen isoliert worden waren. 100 Stämme wurden mittels PCR auf Gene für folgende Virulenzfaktoren untersucht: s-Fimbrien (sfa), pyelonephritisassoziierter Pilus (pap), Hämolysin A (hlyA), hitzestabiles und -labiles Toxin (ST, LT, EAST), Intimin (eae), Verotoxin (stx), Invasionsplasmid (ipa), cytolethal distending toxin (cdt) und cytotoxic necrotizing factor 1 (cnf1). Für die Kontrollgruppe wurden E.coli aus Biopsien von 55 Patienten mit chronisch-entzündlichen Darmerkrankungen (CED) und unspezifischer Kolitis, von 16 Patienten mit Colon irritabile (IBS) und aus Stuhlproben von 29 gesunden Probanden isoliert und untersucht. Ergebnisse: Bei 69% der Patienten mit kolorektalen Karzinomen und bei 58% der Patienten mit kolorektalen Adenomen wurde mindestens einer der Virulenzfaktoren gefunden, dagegen nur bei 25 bis 39% der IBS- und CED- Patienten sowie der gesunden Probanden (p Background: Pathogenesis of non-hereditary colorectal neoplasia is poorly understood. The differences in regional incidence indicate an influence of environmental factors, as socio-economic conditions, nutrition and intestinal flora. An intracellular flora with a predominance of Escherichia coli in colon biopsies has been described in these patients. Methods: We studied virulence factors of Escherichia coli isolated from washed colonoscopic biopsies of 43 patients with colorectal carcinoma and adenoma. 100 strains of E.coli were isolated and used for detection of a broad range of virulence genes by PCR encoding: s-fimbriae (sfa), pyelonephritis-associated pili (pap), hemolysin A (hlyA), heatstable and heatlable toxins (ST, LT, EAST), verotoxin (stx), invasionplasmidantigen (ipaH), intimin (eae), cytolethal distending toxin (cdt) and cytotoxic necrotizing factor 1 (cnf1). E.coli from biopsies of 55 patients with inflammatory bowel disease (IBD) and non-specific colitis, of 16 patients with irritable bowel syndrom (IBS) and from stool samples of 29 healthy individuals were isolated and examined as controls. Results: The prevalence of virulent strains bearing at least one of the tested genes was 69% in colorectal carcinoma and 58% in colorectal adenoma, but only 25 to 39% of IBD and IBS patients and healthy individuals (p

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Habermann, Jens Karsten. "Colorectal cancer : genome, transcriptome, and proteome dynamics /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-411-2/.

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Fontana, Rafael. "Resultados do tratamento cirúrgico e de estudo dos fatores prognósticos de sobrevida em pacientes com metástases hepáticas sincrônicas do câncer de cólon e reto." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5154/tde-13062011-150536/.

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O câncer colorretal (CCR) é a neoplasia mais prevalente no mundo e, cerca de 60% apresentarão metástases hepáticas, representando uma importante causa de mortalidade. Aproximadamente 35% dos pacientes apresentam metástases hepáticas no momento do diagnóstico do tumor primário ou desenvolverão metástases durante o primeiro ano após o tratamento da neoplasia colorretal, conhecidas como metástases sincrônicas. Inúmeros trabalhos têm demonstrado que as metástases sincrônicas representam importante fator prognóstico negativo na evolução destes pacientes, representando um grupo de pacientes que necessita uma abordagem multidisciplinar mais agressiva. O objetivo deste trabalho foi de avaliar os resultados do tratamento cirúrgico das metástases sincrônicas de CCR e determinar os possíveis fatores que pudessem interferir no prognóstico de sobrevida livre de doença e sobrevida atuarial. Entre maio de 1996 e dezembro de 2007, 59 pacientes submetidos à ressecção hepática por metástases sincrônicas foram avaliados retrospectivamente através de análise uni e multivariada. A mortalidade pós-operatória foi de 3,38%, e a morbidade pós-operatória de 30,50%. A sobrevida estimada em 5 anos foi de 38,45% e a sobrevida livre de doença no mesmo período foi de 23,96. O valor do antígeno carcinoembrionário igual ou superior a 50 ng/ml e o número de metástases hepáticas maior que três lesões representaram fatores prognósticos limitados da sobrevida livre de doença, porém sem interferir na sobrevida atual. Pacientes com metástases no fígado e com doença extra-hepática, selecionados para a ressecção, não apresentaram sobrevida livre de doença acima de 20 meses, porém sem impacto na sobrevida a longo prazo. Nenhum dos fatores prognósticos estudados interferiu na sobrevida atual tardia. Entretanto,não foi observada sobrevivência além de 40 meses em pacientes com mais de três metástases hepáticas. A ressecção de metástases sincrônicas de câncer colorretal pode propiciar sobrevida tardia em mais de um terço dos pacientes. O valor do CEA e do número de metástases representaram fatores prognósticos limitantes da sobrevida livre de doença Colorectal cancer is the world´s most prevalent digestive neoplasia and about 60% of the patients will present liver metastases, representing an important cause of mortality. About 35% of the patients present hepatic metastases at the diagnosis of the colorectal tumor or will develop metastases during the first year after the treatment of the primary tumor, known as synchronous metastases. Innumerable studies have shown that synchronous metastases represent a negative prognostic factor in the evolution of these patients, representing a group of patients that need an aggressive multidisciplinary approach. The purpose of this study was to evaluate results of the surgical treatment of colorectal cancer synchronous metastases and to determine possible factors that might interfere in the prognosis of disease-free and actuarial survival. Between May 1996 and December 2007, 59 patients submitted to liver resection for synchronous metastases were retrospectively evaluated through univariate and multivariate analysis. Postoperative morbidity and mortality were 30.5% and 3.38%, respectively. Cumulative survival estimated in 5 years was 38.45% and disease-free survival in the same period was 23.96%. Levels of carcino-embrionary antigen (CEA) higher than 50 ng/ml and the number of hepatic metastases higher than three lesions represented negative prognostic factors limiting disease-free survival; however, with no impact on cumulative survival. Patients with liver metastases and extrahepatic disease selected for resection didnt present a disease-free survival above 20 months, yet without impact in global survival. None of the prognostic factors studied interfered in long term actuarial survival, however survival beyond 40 months in patients with more than three hepatic metastases was not observed. Resection of synchronous metastases of colorectal cancer may provide late survival in more than one third of the patients. CEA values and the number of metastases represented prognostic factors with negative impact on disease-free survival

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An, Zhengwen. "Integrin-interacting proteins in human cancer progression." Stockholm, 2010. http://diss.kib.ki.se/2010/978-91-7409-877-8/.

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Araujo, Raphael Leonardo Cunha de. "Análise comparativa da sobrevida entre pacientes submetidos à cirurgia exclusiva ou associada à quimioterapia para o tratamento de metástases hepáticas de câncer colorretal: revisão sistemática e meta-análise." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/5/5168/tde-01042015-112159/.

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Introdução: A ressecão hepática é considerada um tratamento potencialmente curativo para metástases hepáticas de câncer colorretal (MHCCR), mas os benefícios a longo prazo oferecidos pela complementação do tratamento com quimioterapia sistêmica não foram completamente comprovados. Existe ganho já bem estabelecido para sobrevida livre de doença com o uso de quimioterapia perioperatória, mas não existe ganho de sobrevida global demonstrado em ensaios clínicos randomizados (ECR). Objetivo: Comparar sobrevida global e livre de doença em pacientes com MHCCR submetidos apenas ao tratamento cirúrgico com intenção curativa com aqueles que além da cirurgia também receberam tratamento complementar com quimioterapia sistêmica, independentemente do regime utilizado. Métodos: Construção de revisão sistemática com meta-análise avaliando estudos publicados entre 1991 e 2013 e que compararam o tratamento cirúrgico isolado ao associado à quimioterapia sistêmica para o tratamento de MHCCR ressecáveis. Os ECR foram avaliados através da ferramenta Cochrane para detecção de viéses, e os estudos observacionais comparativos (EOC) de boa qualidade foram incluídos no processo meta-analítico após terem sido selecionados seguindo a metodologia MINORS (índice metodológico para análise de ensaios clinicos não randomizados). Sobrevidas global e livre de doença foram comparadas utilizando modelos fixos e randômicos de efeitos de tratamento e razão de riscos (RR). Resultados: Na avaliação de sobrevida global foram incluídos 5 estudos (3 ECR e 2 EOC), compreendendo 2475 pacientes, com 1024 pacientes recebendo quimioterapia complementar e apresentando ganho relativo de sobrevida global de 23 % quando comparados com cirurgia isolada (RR 0.77, 95% IC. 0.67 - 0.88, p < 0.001). Quatro estudos reportaram sobrevida livre de doença e foram incluídos nesta análise (3 ECR e 1 EOC) totalizando 1592 pacientes e nestes, o uso de quimioterapia (702 pacientes) também reduziu o risco de recidiva em 29% (RR 0.71, 95% IC 0.61 - 0.83, p < 0.001). Conclusões: Esta revisão sistemática com meta-análise demonstrou que o uso de quimioterapia para pacientes submetidos à hepatectomia com intenção curativa como tratamento de MHCCR é uma estratégia terapêutica que propicia ganho de sobrevida global e livre de doença Introduction: Hepatic resection is considered a potentially curative treatment for patients with colorectal liver metastases (CRLM). The benefits of the use systemic chemotherapy in these patients have not been proven. It is likely to improve recurrence free-survival (RFS); however, no differences in overall survival (OS) have been demonstrated yet. Objective: Comparison between surgery plus systemic chemotherapy, regardless of the timing of administration, with surgery alone looking for long term outcomes in patients with CRLM who underwent curative-intent liver resection. Methods: Systematic review and meta-analysis of studies published from January 1991 to December 2013 that compared surgery alone and surgery plus chemotherapy for patients with CRLM who underwent curative-intent liver resection. Randomized clinical trials (RCT\'s) were evaluated by Cochrane risk of bias tool. Selection of high-quality observational comparative studies (OCS) was based on a validated tool (Methodological Index for Nonrandomized Studies - MINORS). RFS and OS were compared using fixed and random effects model and Hazard Ratio (HR). Results: Concerning OS, 5 studies (3 RCT and 2 OCS), comprising 2475 patients were analyzed and chemotherapy (750 patients) relatively improved OS rates in 23% when compared to surgery alone (HR of 0.77, 95% C.I. 0.67 - 0.88, p < 0.001). Four studies described RFS (3 RCT and 1 OCS), totalizing 1592 patients, and chemotherapy (702 patients) also decreased the risk of recurrence in 29% (HR 0.71, 95% C.I 0.61 - 0.83, p < 0.001). Conclusion: This systematic review and meta-analysis has demonstrated that the use of chemotherapy for patients with CRLM who underwent curative-intent resection is a worthwhile strategy to improve both RFS and OS

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Williams, Alistair Robert William. "Expression of oncogenes in human colorectal neoplasms." Thesis, University of Edinburgh, 1988. http://hdl.handle.net/1842/19415.

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