O objetivo deste estudo foi investigar a qualidade de vida do paciente com estoma intestinal secundário ao câncer cólon-retal na cidade de Aracaju-Se. Trata-se de estudo descritivo-exploratório, na vertente quantitativa, utilizando-se um instrumento contendo três partes, dados sócio-demográficos e clínicos, itens referentes à Escala de Qualidade de Vida de Flanagan (EQVF), e EORTC-QLQ-C-30. A amostra constou de 18 pacientes atendidos no Centro de Oncologia Dr Oswaldo Leite, localizado na cidade de Aracaju – Sergipe no período de janeiro a dezembro de 2005. Os instrumentos mostraram propriedades psicométricas satisfatórias quanto à consistência interna e validade do construto. Quanto às características sócio-demográficas e clínicas, 50% eram do sexo feminino, e 50% masculino. A média de idade foi de 51,3 anos. Quanto à localização do tumor, 38,9% tumor de reto, seguida de cólon-retal 33,3% e cólon 27,8%. 83,3% apresentavam metástase e 16,7% não apresentavam. Em relação ao tipo de estoma, 72,2% tinham colostomia definitiva e 27,8% colostomia provisória. 77,8% dos pacientes apresentaram menos de um ano de estoma e 22,2% mais de um ano de estoma. A análise de qualidade de vida da amostra mostra para EQVF média de 52,3 (DP=1,40) para EQVF Geral. Para EORTC QLQ-C30, a média estado geral de saúde foi de 35,64 (DP=12,39). Foram estatisticamente significativos os resultados obtidos nas escalas: relações com outras pessoas, atividades sociais e desenvolvimento pessoal e realização. Pacientes com menos de um ano de estoma, apresentam maior atividade social,desenvolvimento pessoal e realização do que aqueles com mais de um ano de estoma. Foram estatisticamente significativas as escalas: função física, dor, estado geral de saúde, dificuldades financeiras, dispnéia, fadiga, náusea e vômito, constipação e função emocional. A função física teve como variável estatisticamente significante o estado civil, com maior média entre pessoas casadas, assim como a escala dor, porém com maior média entre as pessoas viúvas. A função física entre as pessoas casadas foi maior. No sintoma dor, a presença desta, foi maior entre o grupo de pessoas viúvas e separadas. Na escala estado geral de saúde, foram estatisticamente significativos o sexo e complicações do estoma, com médias superiores entre aqueles do sexo masculino e com presença de complicações. Na escala dificuldades financeiras, a procedência e as complicações do estoma foram estatisticamente significantes. Com maiores médias entre aqueles da área rural e com presença de complicações do estoma. No sintoma dispnéia, a variável estatisticamente significante foi a presença ou não de metástase, com maior média entre aqueles com metástases. Já os sintomas fadiga, náusea e vômitos e constipação, apresentou como única variável estatisticamente significante o tempo de estoma. Na escala função emocional, a variável complicações do estoma foi estatisticamente significante, havendo maior média entre aqueles com presença de complicações do estoma. A escala relações com outras pessoas foi influenciada pelas variáveis: sexo, tempo de estoma e estado de origem, conforme cálculo de Regressão Linear Múltipla. As escalas função emocional, dispnéia, dificuldade financeira e estado geral de saúde tiveram influência das variáveis sexo, estado civil, estado de procedência, metástase, tempo de estoma e complicações. / The objective of this study was to investigate the quality of life of the patient with secondary intestinal estoma to the cancer colo-retal in the city of Aracaju-Se. This is an description-exploratory study, in the quantitative source, using an instrument contends three parts, given partner-demographic and clinical, itens referring to Scale of Quality of Life of Flanagan (EQVF), and EORTC QLQ-C30. The sample consisted of 18 patients taken care of in the Center of Oncologia Dr Oswaldo Leite located in the city of Aracaju - Sergipe in the period of January to December of 2005. The instruments had shown to satisfactory psicometrics properties such as the internal consistency and validity of construct. About the partner-demographic and clinical characteristics, 50% were of the feminine sex, and 50% masculine. The age average was 51,3 years. About the localization of tumor, 38,9% tumor of rectum, followed 33,3% colo-rectum and colon 27,8%. Metastase were presented by 83,3% and 16.7% didn’t present. In relation to the type of stoma, 72,2% had definitive colostomia and 27,8% provisory colostomia. 77,8% of the patients had presented less than 1 year of stoma and 22,2% more than 1 year of stoma. The analysis of quality of life of the sample shows for average EQVF of 52,3 (DP=1,40) for general EQVF. For EORTC QLQ-C30, the been average general of health was of 35,64 (DP=12,39). The scales had been statisticaly significant: social relations with other people, activities and personal development and accomplishment. Patients with less than one year of stoma, present greater social activity, personal development and accomplishment of that those with more than one year of stoma. The scales had been statistically significant: physical function, pain, general state of health, financial difficulties, dispneia, fatigue, nausea and vomit, constipation and emotional function. The physical function had as changeable statistically significant the civil state, with average greater between married people, as well as the scale pain, however with average greater between the people widowers. The physical function between the married people was bigger. In the symptom pain, the presence of this, it was bigger enters the group of people separate widowers and. In the scale general of health, the sex and complications of stoma had been statisticaly significant, with superior averages between those of the masculine sex and with presence of complications. In the scale financial difficulties, the origin and the complications of stoma they had been statisticaly significant. With average greaters between those of the agricultural area and with presence of complications of stoma. In the dispneia symptom, the statisticaly significant variable was the presence or not of metastase, with average greater it enters those with metastases. Already the symptoms fatigue, nausea and vomits and constipation, the stoma time presented as only statisticaly significant variable. In the scale emotional function, the variable complications of stoma was statisticaly significant, having bigger average between those with presence of complications of stoma. The scale Relations with other people was influenced by the variable: sex, time of stoma and state of origin, as calculation of Multiple Linear Regression. The scales emotional function, dispneia, financial difficulty and general state of health had had influence of the variable sex, civil state, state of origin, metastase, time of stoma and complications.

Background: Rectal hyposensitivity (RH) is associated with functional hindgut disorders. It is hypothesized to involve afferent pathway dysfunction. However, little is known regarding its clinical impact. Aims: To assess whether RH is: • clinically important and associated with specific symptoms; • secondary to afferent neuronal dysfunction; and • primarily a pelvic abnormality. Methods: Epidemiological studies were conducted: (1) a case-controlled study stratified by sensory status, assessing symptoms of constipation and incontinence, health status and quality of life; (2) an observational study exploring RH in faecal incontinence in men; (3) an observational study examining the impact of RH on defaecatory urge. Pathophysiological studies were also conducted: (1) transmission of visceral sensory information was evaluated using rectal evoked potentials;(2) somatic sensory function and visceral efferent function were examined in patients with and without RH. Results: RH is associated with constipation. Patients with RH have more severe symptoms and worse health status and quality of life. Constipated patients report altered defaecatory urge compared to controls, most notably in those with RH. RH is associated with concurrent constipation and evacuatory dysfunction in males with incontinence. Patients with RH have delayed evoked potential latencies, without alteration of cortical activation. A proportion have elevated somatic sensory thresholds although efferent function is similar between groups. Conclusions: 1. In patients with constipation, those with RH have a worse clinical phenotype, with poorer health status and quality of life. Patients with constipation, (particularly those with RH), have alteration of defaecatory urge. 2. RH and constipation may contribute to incontinence in males where sphincter dysfunction is less important. 3. RH is associated with delayed afferent transmission indicating primary afferent pathway dysfunction. In a proportion, reflecting a possible generalised sensory neuropathy. These studies confirm that intact rectal sensation is fundamental to normal hindgut function. Impaired visceral sensation is thus an important therapeutic target.

越來越多證據表明了煙酰胺腺嘌呤核苷酸磷酸（nicotinamide adenine dinucleotide phosphate, NADPH）代謝對腫瘤細胞增殖和生存的重要性。最近一項研究證實了一個p53調節基因，TP53誘導的糖酵解和凋亡調節因數（TP53-inducible glycolysis and apoptosis regulator, TIGAR），在抑制凋亡和誘導NADPH產生方面的作用。抗凋亡蛋白B細胞淋巴瘤2（B-cell lymphoma 2, Bcl-2）之前被報導能夠通過還未確定的機制誘導NADPH的產生。在這篇論文研究中，我們假設Bcl-2與TIGAR耦合從而調節NADPH的產生和細胞生存，並且TIGAR可能成為一個促進細胞生長的新生存因數。這篇論文研究的目的是：1）檢測在NADPH代謝中Bcl-2與TIGAR間的生物聯繫；2）探究在哺乳動物系統中TIGAR調節的分子機制；3）研究TIGAR在體外和體內調節正常及腫瘤細胞生存的作用。 / 這篇論文的第一部分結果顯示在正常小鼠胚胎成纖維細胞（MEFs）和缺少功能性p53的人非小細胞肺癌（NSCLC）細胞中存在Bcl-2/TIGAR/NADPH這樣一個新的信號通路軸，重要抗凋亡蛋白Bcl-2與TIGAR耦合後，以一個特有並持久的方式調節NADPH代謝和細胞生長。用特異的小干擾RNA（siRNA）靶向抑制Bcl-2能夠在NSCLC細胞中抑制TIGAR/NADPH/生長信號軸。用小分子抑制劑ABT-737對Bcl-2進行藥理學抑制也能夠顯示相似的作用，而這個作用能夠通過過表達TIGAR被部分逆轉。而且，敲除TIGAR能夠降低Bcl-2誘導的NADPH產生和細胞生長，表明了TIGAR在介導TIGAR/NADPH/生長信號軸中的關鍵作用。 / 為了第二個目的，我們研究了Bcl-2對TIGAR的機制調節。我們發現過表達Bcl-2不能改變TIGAR的mRNA水平，但是能誘導轉錄後的TIGAR蛋白累積。有趣的是，TIGAR似乎能通過一個正反饋回路誘導Bcl-2的表達，這進一步促進了由Bcl-2誘導的TIGAR表達上調。除了Bcl-2，許多致癌基因或生長調節因數也被證實參與了TIGAR的調節，包括信號轉導和轉錄啟動因數3（signal transducer and activator of transcription 3, STAT3, Bcl-2的上有調節因數），表皮生長因數受體（epidermal growth factor receptor, EGFR）和肝細胞生長因數受體（hepatocyte growth factor receptor, c-Met）。 / 這篇論文的第三部分證實了TIGAR在缺少功能性p53細胞模型中的致癌作用。TIGAR過表達能夠誘導一些癌症的標誌性特徵，包括細胞代謝調節異常，細胞生長增加和凋亡減少。重要的是，TIGAR的過表達在MEFs和缺少功能性p53的NSCLC細胞中直接促成了腫瘤形成，促進了腫瘤的生長。但是功能性p53的存在無論在體外還是體內都能夠消除TIGAR這種生長促進和成瘤的作用。這些發現表明當p53功能消失時TIGAR能成為一個致癌基因，促進腫瘤形成。 / 總的來說，我們發現了在腫瘤中Bcl-2/TIGAR/NADPH這樣一條新的信號通路。Bcl-2通過增加TIGAR蛋白累積的轉錄後機制調節TIGAR。我們也證實了TIGAR受到多種致癌基因或生長調節因數的調節，包括STAT3，EGFR和c-Met。並且，我們闡明了當p53功能消失時TIGAR能成為一個致癌基因，促進細胞轉化和腫瘤形成。 / Emerging evidences reveal the importance of nicotinamide adenine dinucleotide phosphate (NADPH) metabolism for cancer cell proliferation and survival. A recent study demonstrated the role of a p53-regulated gene, TP53-inducible glycolysis and apoptosis regulator (TIGAR), in inhibiting apoptosis and inducing NADPH production. The anti-apoptotic protein B-cell lymphoma 2 (Bcl-2) has previously been reported to induce NADPH generation through undefined mechanism. In this thesis study, we hypothesized that Bcl-2 is coupled to TIGAR for regulation of NADPH production and cell survival, and that TIGAR may serve as a novel survival factor contributing to cell growth. The objectives of the thesis study are: 1) to examine the biologic relationship between Bcl-2 and TIGAR in NADPH metabolism; 2) to investigate the molecular mechanisms of TIGAR regulation in mammalian systems; and 3) to examine the role of TIGAR in regulating normal and cancer cell survival in vitro and in vivo. / Findings in first part of the thesis revealed a novel signaling axis of Bcl-2/TIGAR/NADPH in normal mouse embryonic fibroblasts (MEFs) and human non-small cell lung cancer (NSCLC) cells lacking functional p53, coupling the major anti-apoptotic protein Bcl-2 to TIGAR regulation for NADPH metabolism and cell growth in a specific and sustained manner. Targeting of Bcl-2 by specific siRNA inhibited TIGAR/NADPH/growth axis in NSCLC cells. Pharmacologic inhibition of Bcl-2 by small molecule inhibitor ABT-737 also exhibited similar effects, which was partially reversed by the overexpression of TIGAR. In addition, TIGAR knockdown reduced Bcl-2-induced NADPH production and cell growth, implicating a critical role of TIGAR in mediating Bcl-2/NADPH/growth signaling axis. / For the second objective, we studied the mechanistic regulation of TIGAR by Bcl-2. We found that overexpression of Bcl-2 did not alter TIGAR mRNA expression but induced TIGAR protein accumulation post-transcriptionally. Interestingly, TIGAR seemed to induce Bcl-2 expression via a positive feedback loop, which may further contribute to the upregulation of TIGAR expression induced by Bcl-2. In addition to Bcl-2, a number of oncogene/growth regulators were demonstrated to be involved in TIGAR regulation, including signal transducer and activator of transcription 3 (STAT3, an upstream regulator of Bcl-2), epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (c-Met). / The third part of the thesis demonstrated the oncogenic role of TIGAR in cell models lacking functional p53. TIGAR overexpression induced several hallmark features of cancer including deregulated cell metabolism, increased cell growth and inhibited apoptosis. Strikingly, overexpression of TIGAR directly drove tumor formation and promoted tumor growth in MEFs and NSCLC cells lacking functional p53. The growth stimulatory and tumorigenic activities of TIGAR were abolished in the presence of functional p53 both in vitro and in vivo. These findings revealed TIGAR as an oncogene capable of driving tumorigenesis when p53 function is lost. / In summary, we have identified a novel signaling pathway of Bcl-2/TIGAR/NADPH in cancer. TIGAR is regulated by Bcl-2 via a post-transcriptional mechanism by enhancing TIGAR protein accumulation. We also demonstrated the regulation of TIGAR by multiple oncogene/growth regulators including STAT3, EGFR and c-Met. Furthermore, we have demonstrated TIGAR as an oncogene capable of driving cell transformation and tumorigenesis when p53 function is lost. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Lam, Kai Yee. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2012. / Includes bibliographical references (leaves 158-176). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / Abstract --- p.i / 摘要 --- p.iv / Declaration --- p.vi / Acknowledgements --- p.vii / Publications --- p.viii / Table of Content --- p.ix / List of Illustrations --- p.xii / List of Abbreviations --- p.xv / Chapter Chapter 1: --- Introduction / Chapter 1.1 --- Overview of tumor metabolism --- p.1 / Chapter 1.1.1 --- Glucose metabolism --- p.4 / Chapter 1.1.2 --- Glutamine metabolism --- p.6 / Chapter 1.1.3 --- De novo fatty acid synthesis --- p.7 / Chapter 1.1.4 --- Advantages of metabolic reprogramming in tumor cells --- p.8 / Chapter 1.2 --- Mechanisms regulating metabolic reprogramming in cancers --- p.11 / Chapter 1.2.1 --- Tumor suppressor p53 --- p.11 / Chapter 1.2.2 --- Hypoxia-inducible factor 1 (HIF-1) --- p.13 / Chapter 1.2.3 --- PI3K/Akt/mTOR signaling pathway --- p.15 / Chapter 1.2.4 --- Oncogenic Myc --- p.16 / Chapter 1.2.5 --- Oncogenic Ras --- p.18 / Chapter 1.3 --- TP53-Inducible Glycolysis and Apoptosis Regulator (TIGAR) --- p.22 / Chapter 1.3.1 --- TIGAR and oxidative stress --- p.25 / Chapter 1.3.2 --- TIGAR and carcinogenesis --- p.29 / Chapter 1.3.3 --- TIGAR and other diseases --- p.32 / Chapter 1.4 --- Hypotheses and Aims --- p.36 / Chapter Chapter 2: --- Materials and Methods / Chapter 2.1 --- Materials --- p.38 / Chapter 2.1.1 --- Chemicals and reagents --- p.38 / Chapter 2.1.2 --- Drugs --- p.41 / Chapter 2.1.3 --- Commercial detection kits --- p.41 / Chapter 2.1.4 --- Antibodies --- p.42 / Chapter 2.2 --- Cell culture --- p.43 / Chapter 2.3 --- Plasmids --- p.44 / Chapter 2.4 --- Transfection --- p.46 / Chapter 2.5 --- Retrovirus infection --- p.47 / Chapter 2.6 --- Drug treatment --- p.47 / Chapter 2.7 --- Cell viability assay --- p.48 / Chapter 2.8 --- Trypan blue exclusion assay --- p.49 / Chapter 2.9 --- NADPH assay --- p.49 / Chapter 2.10 --- Cell death detection ELISA --- p.50 / Chapter 2.11 --- Western blotting --- p.50 / Chapter 2.12 --- Reverse TranscriptionPolymerase Chain Reaction (RT-PCR) --- p.51 / Chapter 2.13 --- Cell cycle analysis --- p.52 / Chapter 2.14 --- Transwell migration and matrigel invasion assays --- p.53 / Chapter 2.15 --- In vivo studies --- p.54 / Chapter 2.16 --- Histology and immunohistochemistry --- p.55 / Chapter 2.17 --- Statistical analysis --- p.56 / Chapter Chapter 3: --- Indentification of Novel Bcl-2/TIGAR/NADPH Signaling Axis / Chapter 3.1 --- Introduction --- p.57 / Chapter 3.2 --- Results --- p.60 / Chapter 3.2.1 --- Bcl-2-induced NADPH production and cell growth is associated with TIGAR upregulation in p53-null MEFs --- p.60 / Chapter 3.2.2 --- Identification of Bcl-2/TIGAR/NADPH signaling axis in p53-negative NSCLC cells --- p.63 / Chapter 3.2.3 --- Bcl-2 targeting reduces TIGAR expression and NADPH production in MEFs and NSCLC cells --- p.66 / Chapter 3.2.4 --- Pharmacologic intervention of Bcl-2 alters TIGAR levels in MEFs and NSCLC cells --- p.71 / Chapter 3.2.5 --- Bcl-2 targeting inhibits TIGAR expression, NADPH production and cell growth in Bcl-2-amplified small cell lung cancer (SCLC) cells --- p.76 / Chapter 3.2.6 --- Bcl-2-induced TIGAR expression is highly specific compared to other pro-survival proteins --- p.78 / Chapter 3.2.7 --- Bcl-2/TIGAR/NADPH signaling axis is functionally intact in p53-positive NSCLC cells --- p.80 / Chapter 3.3 --- Discussion --- p.83 / Chapter Chapter 4: --- Mechanisms of TIGAR Regulation / Chapter 4.1 --- Introduction --- p.88 / Chapter 4.2 --- Results --- p.90 / Chapter 4.2.1 --- Bcl-2 regulates TIGAR by post-transcriptional mechanism --- p.90 / Chapter 4.2.2 --- Bcl-2-induced TIGAR expression is associated with upregulation of other pro-survival proteins --- p.94 / Chapter 4.2.3 --- STAT3 activation can serve as a biological signal for TIGAR induction --- p.97 / Chapter 4.2.4 --- Tyrosine kinase receptors contributes to TIGAR regulation --- p.100 / Chapter 4.2.5 --- The existence of TIGAR/Bcl-2 positive feedback loop --- p.102 / Chapter 4.3 --- Discussion --- p.104 / Chapter Chapter 5: --- TIGAR is Oncogenic / Chapter 5.1 --- Introduction --- p.107 / Chapter 5.2 --- Results --- p.109 / Chapter 5.2.1 --- Overexpression of TIGAR alters several hallmark features of cancer --- p.109 / Chapter 5.2.2 --- TIGAR drives tumor formation in vivo --- p.114 / Chapter 5.2.3 --- Tumorigenic activity of TIGAR is functionally counteracted by functional p53 --- p.123 / Chapter 5.3 --- Discussion --- p.134 / Chapter Chapter 6: --- Summary --- p.138 / Chapter Chapter 7: --- Future Prospective --- p.143 / Appendices --- p.148 / References --- p.158

Abstract Rectal prolapse and internal rectal prolapse with symptoms of obstructed defecation and/or faecal incontinence are debilitating conditions. Often, symptoms coexist from other pelvic compartments, reducing quality of life. Robot-assisted surgery with its advanced features may offer better conditions in narrow pelvic space to correct rectal prolapses with rectopexy operation. In this thesis, we compared robot-assisted and laparoscopic techniques during the early learning curve in a ‘matched-pairs’ feasibility study (n = 30, follow-up three months) and in a prospective randomized series (n = 33, follow-up 24 months). The long-term functional results were assessed in a retrospective multicenter study with cross-sectional questionnaire assessment (n = 508, median follow-up 44 months). In the randomised series, as demonstrated with MR defecography, ventral rectopexy corrects the posterior compartment defects, external and internal rectal prolapses and recto-enteroceles. The operation restores the posterior and middle compartment anatomy and reduces pelvic organ mobility with a minor impact on the anterior compartment. Pelvic floor dysfunction and symptom-specific quality of life is improved after rectopexy; specifically, the colorectal-anal and the pelvic organ prolapse subscales in the questionnaires showed improvement. We found equality between robot-assisted rectopexy and laparoscopic rectopexy in most relevant outcome measures, which does not justify the added cost of the routine use of robots in rectopexy operations. The health-related quality of life and cost-utility analysis in our cohort indicated, however, that in long-term the technique may be cost-effective. The functional results are retained in the long term. The rate of recurrences (7.1%) and complications (10%) are acceptable and mesh-related complications (1.4%) are rare. Denovo symptoms, such as the urge to defecate or urinary incontinence, may arise, while urinary symptoms may be alleviated. In the long-run, patients with external rectal prolapse benefit more than patients with internal rectal prolapse. In part, the results of this thesis support using a multidisciplinary approach in examining patients with posterior pelvic floor dysfunction. Furthermore, the indications for robotic use in rectopexy operations need to be explored in larger patient samples. / Tiivistelmä Rektumprolapsi ja peräsuolen sisäinen tuppeuma eli interni prolapsi aiheuttavat hankalia oireita, kuten ulostusvaikeuksia, ulosteinkontinenssia ja lantion kipua. Elämänlaatua heikentäviä oireita esiintyy usein samanaikaisesti myös muissa lantion osissa. Robottiavusteinen kirurgia tarjoaa paremmat leikkausolosuhteet lantion ahtaassa tilassa tehtävään rektopeksialeikkaukseen ja mahdollisesti edut voivat näkyä leikkaustuloksessa. Tässä väitöskirjassa vertailimme robottiavusteista ja laparoskooppista leikkaustekniikkaa oppimiskäyrän alkuvaiheessa käyttökelpoisuustutkimuksessa kaltaistetussa parivertailuasetelmassa (n = 40, seuranta-aika 3 kk) sekä prospektiivisessa randomoidussa tutkimussarjassa (n = 33, seuranta-aika 24 kk). Monikeskustutkimuksessa (n = 508, seuranta-ajan mediaani 44 kk) selvitimme laajassa aineistossa laparoskooppisen ventraalisen rektopeksian pitkäaikaistuloksia liittämällä aineiston analyysiin poikkileikkauskyselytutkimuksen tulokset. Randomoidussa sarjassa MR-defekografialla todennettiin, että rektopeksialeikkauksen jälkeen peräsuolen sisäinen tuppeuma, rektoseele ja enteroseele korjaantuvat. Rektopeksialeikkaus palauttaa lantion taka- ja keskiosan anatomian, vähentää elinten dynaamista liikkuvuutta ja parantaa lantionpohjan toimintaa sekä oireisiin liittyvää elämänlaatua, erityisesti suolioireiden ja gynekologisten laskeumaoireiden osalta. Robottiavusteinen ja laparoskooppinen tekniikka olivat samanvertaisia perioperatiivisten parametrien, komplikaatioiden, anatomisten ja toiminnallisten tulosten suhteen. Vaikka kustannusvertailussa kalliimpi robottikirurgia voi osoittautua kustannustehokkaaksi pitkäaikaisseurannassa, yhdenvertaiset tulokset eivät oikeuta menetelmää rutiinikäyttöön. Retrospektiivisen tutkimuksen poikkileikkauskyselyn mukaan toiminnalliset tulokset säilyvät pitkäaikaisseurannassa, residiivien (7,1 %) ja komplikaatioiden (10 %) määrä on hyväksyttävä ja verkkoon liittyviä komplikaatioita esiintyy vähän (1,4 %). Leikkauksen jälkeen ilmenee myös uusia oireita, kuten ulostuspakkoa tai virtsankarkailua. Toisaalta virtsankarkailuoire voi korjaantuakin. Pitkäaikaisseurannassa totaalin rektumprolapsin vuoksi leikatut potilaat hyötyvät leikkauksesta enemmän kuin oireisen internin prolapsin vuoksi leikatut. Osa väitöskirjatyön tuloksista tukee moniammatillisen lähestymistavan käyttöä potilaiden arvioinnissa. Jatkossa robottikirurgian käytön indikaatioita rektopeksialeikkauksissa tulisi arvioida isommissa potilasaineistoissa.

Orientador: Sandra Aparecida Drigo Linde / Resumo: Introdução: Apesar dos avanços no tratamento, cerca da metade dos pacientes com câncer de reto (CR) desenvolverá metástase à distância. No entanto, as vias biológicas envolvidas na progressão do câncer não são totalmente conhecidas. Neste estudo, investigamos os perfis moleculares e imunológicos em adenocarcinomas de reto relacionados à progressão metastática visando identificar biomarcadores moleculares e/ou alvos terapêuticos. Pacientes e Métodos: O transcritoma de 15 tecidos de CR metastático (M) e não-metastático (NM) pré-tratamento e de duas amostras de tecido de reto normais foi avaliado utilizando a plataforma Clariom D. Os genes foram considerados diferencialmente expressos quando a alteração de expressão era maior que 2 vezes e o valor de p <0,05 e detectados com o pacote limma. As funções moleculares e vias biológicas foram determinadas com a ferramenta Enricher. Os achados foram validados utilizando dados do TCGA e o perfil imunológico determinado com o algorótimo xCell. Resultados: A comparação entre os grupos M e NM revelou 52 genes diferencialmente expressos, sendo 27 regulados positivamente e 25 regulados negativamente. O gene ANLN foi detectado com o maior valor de fold change nos tumores metastáticos. Além disso, expressão aumentada de ANLN foi associada com menor sobrevida em pacientes com CR. A via do fator de crescimento endotelial vascular (VEGF) foi detectada como alterada nos tumores M. Validação dos resultados com dados do TCGA confirmou o gene ANLN co... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Despite advances in treatment, about half of patients with rectal cancer (RC) will develop distant metastasis. However, the biological pathways underpinning the cancer progression are not fully understood. In this study, we sought to identify molecular and immunological profiles in rectal adenocarcinomas related to metastatic progression aiming to identify molecular biomarkers and/or therapeutic targets. Patients and Methods: Transcriptome analysis of 15 pre-treatment metastatic (M) and non-metastatic (NM) rectal cancer tissues and two normal rectal tissue samples was evaluated using Clariom D platform. Genes were considered differentially expressed when presenting 2-fold change and p<0.05 and were obtained with limma package . Molecular function and biological pathways with the Enricher package. Our findings were validated from the TCGA database and the immunological profile was determined using the xCell algorithm. Results: The comparison of M with NM groups revealed 52 differentially expressed genes, being 27 up-regulated and 25 down-regulated. ANLN gene was detected as the top gene upregulated in M tumours. Additionally, ANLN overexpression was associated with shorter survival in RC patients. Vascular endothelial growth factor (VEGF) pathway was detected as altered in M tumours. Cross-study validation with TCGA dataset confirmed ANLN gene as associated with M tumours. Furthermore, KIF14, XRCC2 and GPX3 genes, which have important carcinogenesis functions, we... (Complete abstract click electronic access below) / Mestre

Orientador: Pedro Luiz Toledo de Arruda Lourenção / Resumo: Introdução: A constipação intestinal é uma condição debilitante que afeta mais de 27% da população, representando um problema de saúde pública, além de corresponder a 3% de todas as consultas pediátricas. Existem várias causas congênitas e adquiridas. A Doença de Hirschsprung (DH) é a principal causa congênita de constipação e envolve 90% dos casos congênitos. O diagnóstico de disganglionoses intestinais depende da análise histopatológica de biópsias retais. Nessa revisão sistemática, levantamos todas as series de casos disponíveis na literatura e desenvolvemos uma metanálise de proporções para definer a taxa de resultados conclusivos e as complicações relacionadas aos diferentes tipos de biópsia retal no diagnóstico de disganglionoses intestinais. Métodos: A partir de ampla busca na literatura em múltiplas bases de dados, foi realizada uma revisão sistemática e metanálise de proporção das séries de casos que envolviam biópsias retais em pesquisa de disganglionoses intestinais em crianças. Foram incluídas series de casos que envolvessem mais de 5 biópsias em pacientes menores de 18 anos de idade com suspeita de disganglionose intestinal, que descrevesse ao menos um tipo de biópsia retal. Os estudos deviam especificar a taxa de resultados conclusivos e a taxa de complicações das técnicas de biópsias. A análise de proporção de série de casos foi realizada e os resultados apresentados em gráficos do tipo forest plot. Resultados: Foram selecionados 151 estudos pelos critérios de ... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Intestinal constipation is a debilitating condition that affects up to 27% of the population, representing an important public health problem and corresponding to 3% of all pediatric consultations. There are many different congenital and acquired conditions, but Hirschsprung’s disease (HD) is the main representative entity of congenital disease and is involved in 90% of all cases. The diagnosis of intestinal dysganglionosis depends on the histopathological analysis of rectal biopsies. Here we conducted an updated systematic review of all case series studies available in the literature and performed a pooled analysis of proportions to assess the rate of conclusive results and possible complications of different rectal biopsy techniques in the diagnosis of intestinal dysganglionosis. Methods: A broad literature search using multiple online databases. A systematic literature review and proportional meta-analysis of the available case series studies of rectal biopsies in the diagnosis of intestinal dysganglionosis in children were performed. We included case series with more than 5 rectal biopsies in children under 18 years of age suspected of intestinal dysganglionosis, that described at least one type of rectal biopsy. The studies should have specified the rate of conclusive results and the rate of complications of the biopsy procedures. Proportional meta-analysis of case series studies was performed and forest plot charts were created to summarize the data. Resul... (Complete abstract click electronic access below) / Doutor

Outcomes from surgery are dependent upon technical performance, as demonstrated by the variability that exists in outcomes achieved by different surgeons following surgery for rectal cancer. It is possible to improve such outcomes by focused training and the adoption of specific surgical techniques, such as the total mesorectal excision (TME) training programme in Stockholm which reduced local recurrence rates of cancer by 50%. It is generally accepted that good surgical technique is the enactment of a series of positive surgical actions, and the avoidance of errors. However, the constituents of good surgical technique for rectal cancer have not yet been studied in sufficient detail to identify the specific associations between individual steps and their consequences. In this study the ergonomic principles of human reliability analysis (HRA) were applied to video recordings of rectal cancer surgery. A system of error definition and identification was developed, utilising a bespoke software solution designed for the project. Calculation of optimal camera angles and position was determined in a virtual operating theatre. Analysis of synchronised footage from multiple camera views was performed, through which over 6,000 errors were identified across 14 procedural tasks. The sequences of events contributing to these errors are reported, and a series of error reduction mechanisms formulated for rectal cancer surgery.

Submitted by Silvana Teresinha Dornelles Studzinski (sstudzinski) on 2017-02-08T15:54:08Z No. of bitstreams: 1 Angela Cristina Weissheimer_.pdf: 211763 bytes, checksum: 94a696250d65339dc7adc2dad25d303d (MD5) / Made available in DSpace on 2017-02-08T15:54:08Z (GMT). No. of bitstreams: 1 Angela Cristina Weissheimer_.pdf: 211763 bytes, checksum: 94a696250d65339dc7adc2dad25d303d (MD5) Previous issue date: 2016-11-10 / Nenhuma / Este trabalho tem por objetivo o desenvolvimento de um protocolo de condutas e rotinas de terapia nutricional para pacientes com diagnóstico de câncer cólon retal (CCR) no Hospital do Câncer de Francisco Beltrão, buscando melhorar o atendimento, avaliação e acompanhamento nutricional dos pacientes, atuando de forma preventiva e imediata na intervenção nutricional necessária e de forma individualizada. O emprego deste protocolo volta-se aos profissionais nutricionistas, para ser aplicado especificamente aos pacientes com câncer colorretal. Tal utilização torna indispensável a compreensão dos métodos e técnicas aqui determinados, a rigorosidade do preenchimento de todos os dados e condutas para que esse acompanhamento permita uma avaliação minuciosa da evolução nutricional do paciente. A utilização efetiva do protocolo de padronização de condutas e rotinas de terapia nutricional é o início de um formato diferenciado no atendimento aos pacientes, buscando agilidade, confiança e segurança nas informações prestadas, garantindo à equipe multidisciplinar dados atuais em relação a situação nutricional do paciente para melhor desempenho nas suas respectivas áreas. Sua implantação trará maior individualidade na atenção as necessidades de cada paciente e acompanhamento de forma contínua, buscando atender as necessidades atuais e individuais de cada paciente durante o todo o tratamento, do diagnóstico a alta hospitalar. / This work aims to develop a protocol for conducts and nutritional therapy routines for patients with diagnosis of rectal colon cancer (CCR) in the Francisco Beltrão Cancer Hospital, seeking to improve the care, evaluation and nutritional follow-up of patients, acting in Preventive and immediate way in the necessary nutritional intervention and in an individualized way. The use of this protocol turns to nutritionists, to be applied specifically to patients with colorectal cancer. Such use makes it indispensable to understand the methods and techniques determined here, the accuracy of filling all data and conduct so that this monitoring allows a thorough evaluation of the nutritional evolution of the patient. The effective use of the standardization protocol for nutritional therapy routines and routines is the beginning of a differentiated format in patient care, seeking agility, confidence and security in the information provided, guaranteeing to the multidisciplinary team current data regarding the patient's nutritional status for Performance in their respective areas. Its implementation will bring greater individuality in the attention to the needs of each patient and continuous follow-up, seeking to meet the current and individual needs of each patient during the entire treatment, from diagnosis to hospital discharge.

This work is motivated by the need of providing patients with a decision support system that facilitates the selection of the most appropriate treatment strategy in cancer treatment. Treatment options are currently subject to predetermined clinical pathways and medical expertise, but generally, do not consider the individual patient characteristics or preferences. Although genomic patient data are available, this information is rarely used in the clinical setting for real-life patient care. In the area of personalized medicine, the advancement in the fundamental understanding of cancer biology and clinical oncology can promote the prevention, detection, and treatment of cancer diseases. The objectives of this research are twofold. 1) To develop a patient-centered decision support model that can determine the most appropriate cancer treatment strategy based on subjective medical decision criteria, and patient's characteristics concerning the treatment options available and desired clinical outcomes; and 2) to develop a methodology to organize and analyze gene expression data and validate its accuracy as a predictive model for patient's response to radiation therapy (tumor radiosensitivity). The complexity and dimensionality of the data generated from gene expression microarrays requires advanced computational approaches. The microarray gene expression data processing and prediction model is built in four steps: response variable transformation to emphasize the lower and upper extremes (related to Radiosensitive and Radioresistant cell lines); dimensionality reduction to select candidate gene expression probesets; model development using a Random Forest algorithm; and validation of the model in two clinical cohorts for colorectal and esophagus cancer patients. Subjective human decision-making plays a significant role in defining the treatment strategy. Thus, the decision model developed in this research uses language and mechanisms suitable for human interpretation and understanding through fuzzy sets and degree of membership. This treatment selection strategy is modeled using a fuzzy logic framework to account for the subjectivity associated to the medical strategy and the patient's characteristics and preferences. The decision model considers criteria associated to survival rate, adverse events and efficacy (measured by radiosensitivity) for treatment recommendation. Finally, a sensitive analysis evaluates the impact of introducing radiosensitivity in the decision-making process. The intellectual merit of this research stems from the fact that it advances the science of decision-making by integrating concepts from the fields of artificial intelligence, medicine, biology and biostatistics to develop a decision aid approach that considers conflictive objectives and has a high practical value. The model focuses on criteria relevant to cancer treatment selection but it can be modified and extended to other scenarios beyond the healthcare environment.

<p>The development of new irradiation techniques is presently a very active field of research with increased availability of more sophisticated modalities such as intensity modulated photons (IMRT), protons and light ions. The primary aim of this work is to evaluate if the dose-distributions using IMRT and protons contribute to clinical advantages. A secondary aim is to investigate the potential clinical implication of the increased relative biological effect (RBE) for protons at the end of the Bragg peak. </p><p>The potential benefits are evaluated using physical dose measures and dose-response models for normal tissue complication probability (NTCP) and tumour control probability (TCP). Comparative treatment planning was performed using three locally advanced tumour types, left-sided node positive breast cancer, hypopharyngeal cancer, and rectal cancer. All studies showed that both IMRT and protons could improve the dose distributions compared to 3D-CRT, and significantly improve treatment results with lower NTCPs and, concerning hypopharyngeal cancer, higher TCP. Protons always resulted in smaller volumes receiving intermediate and low radiation doses.</p><p>Using protons or IMRT for left-sided node-positive breast cancer, the advantage is a significantly decreased risk for cardiac mortality (from 6.7% to 1%) and radiation induced pneumonitis (from 28.2% to less than 3%) compared to 3D-CRT. For hypopharyngeal cancer, protons and IMRT provide more selective treatment plans, higher TCP since a simultaneous boost technique is feasible, and better parotid gland sparing for several patients. For locally advanced rectal cancer, the NTCP for small bowel is potentially reduced by approximately 50% using IMRT or protons; protons have an even greater potential if the structure of the small bowel is parallel.</p><p>A variable RBE correction is developed and applied to a clinical proton treatment plan. A significant difference is obtained compared to the commonly accepted RBE correction of 1.1. This indicates that a variable RBE may be of importance in future proton treatment planning.</p><p>This thesis provides support for increased use both IMRT and proton radiotherapy, although stronger for protons. Therefore, investments in proton facilities with capacity for large clinical trials can be supported.</p>