University of Macau / Institute of Chinese Medical Sciences

El documento digital no refiere asesor / Publicación a texto completo no autorizada por el autor / Determina los resultados del manejo de los pacientes con vólvulo de sigmoides en el Hospital PNP Luis N. Sáenz en el periodo comprendido del 01 de enero del 2004 al 31 de diciembre del 2012, para ello se realizó un estudio, descriptivo, retrospectivo de casos. La muestra seleccionada estuvo comprendida por 397 pacientes, que ingresaron al servicio de cirugía general del Hospital PNP Luis N. Sáenz en el periodo que comprende el estudio. Los instrumentos empleados estuvieron conformados por una ficha de recolección de datos convenientemente elaborada para los fines de estudio. La frecuencia del vólvulo de sigmoides en el Servicio de Cirugía del Hospital PNP Luis N Sáenz en el periodo que corresponde al estudio, es del 10.04%, el grupo etario más frecuente está entre los 60 y 69 años de edad (27.7 %); el 78.3%(311) fueron del sexo masculino y 21.7% (86) del sexo femenino; el antecedente fisiológico más frecuente fue la constipación crónica (46,3%); en el 100% de los pacientes hubo dolor abdominal y no eliminación de heces y flatos; el diagnóstico definitivo se fundamentó, además de la evaluación clínica, en la radiografía simple de abdomen en posición de pie en el 100% de los casos; se operaron 333 pacientes (83.9%); de estos el procedimiento más frecuente fue la sigmoidectomía y anastomosis primaria termino terminal en el 77.6% de los casos. Hubo complicaciones en 53 pacientes operados siendo la más frecuente las bridas y adherencias postoperatorias. La mortalidad fue del 11.3%; siendo la causa más frecuente la sepsis abdominal y shock séptico. Hubo asociación estadísticamente significativa de mortalidad con el tratamiento quirúrgico, con el antecedente fisiológico de constipación, con la corta estancia hospitalaria, con el sexo femenino y con edades mayores de 40 años. (P<0,05). Las limitaciones que se pudieron encontrar están referidas al escaso financiamiento y a la dificultad para acceder ar la recolección de los datos. / Trabajo académico

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Aberrant cell proliferation is a fundamental feature of cancer. It is thus not unexpected that many studies have been devoted to the exploration of tumour cell proliferation as a potential indicator of outcome. Indeed, in most malignancies, high expression of proliferation markers and more accurately, increased expression of proliferation-related genes have been strongly associated with poor outcome. In colorectal cancer (CRC), however, discordant results have been reported and the prognostic significance of cell proliferation has not been demonstrated in this type of cancer. As these results were mostly based on the subjective assessment of a single proliferation marker, this work set out to evaluate the association between the proliferative activity of CRCs and their malignant potential using an objective microarray-based multi-gene proliferation signature. In the first step, a gene proliferation signature (GPS) was derived from analysis of a CRC cell line model. Ten CRC cell lines were harvested under semi- and fully-confluent conditions to obtain RNA from two stages that differed in their proliferative activity. Gene expression profiles of the two growth stages were analyzed on oligonucleotide arrays and a GPS was identified by gene ontology analysis of differentially expressed genes. In the second step, the performance of the signature to classify patients into prognostic groups was examined using two independent cohorts of primary CRC tumours (cohort A: 73 tumours in stages I-IV, cohort B: 55 tumours in stages I-II). Further, the signature was applied to a population of liver metastases to establish its association with the malignant potential of CRC. Finally, the capacity of the signature to detect clinically distinct CRC populations was compared with that of the proliferation marker Ki-67 in a classic immunohistochemical approach. The GPS consisted of 38 mitotic cell cycle genes, which were over-expressed in actively cycling cells relative to growth-inhibited cells in vitro. Intriguingly, a reduced GPS expression was associated with (i) the presence of lymph node or distant metastasis in cohort A, (ii) an increased risk of recurrence, and (iii) shorter overall and recurrence-free survival in both cohorts of primary CRCs (p<0.05). While the association between the GPS and clinical outcome was not independent of the disease stage in cohort A, reduced GPS expression was an independent predictor of outcome in cohort B. Importantly, adjuvant therapy had no impact on this association. Furthermore, GPS expression was reduced in CRC liver metastases, confirming that decreased proliferation is an indicator of the malignant potential in CRC. While reduced proliferation in liver metastases was also observed by Ki-67 immunostaining, the classic proliferation marker was not able to stratify primary CRCs into different prognostic groups. To the best of our knowledge, this study is the first to report an association between the reduced expression of a multi-gene proliferation signature and poor outcome in cancer. This finding contradicts the long-held belief that increased proliferation is an indicator of tumour malignancy. In contrast to many other cancers, reduced proliferation appears to be a significant component of a biological signature associated with malignant potential of CRC tumours. Investigating the reasons why CRC differs from other cancer types may provide insights into important underlying biological mechanisms. If this association can be verified in larger cohorts, the GPS may have important clinical implication for identification of high-risk early stage CRC patients.

Thesis (Ph. D.)--University of Rhode Island, 2005. / Typescript. Includes bibliographical references (leaves 83-90).

ABSTRACT THE RELATIONSHIP BETWEEN UNMETABOLIZED FOLIC ACID AND SERUM FOLATE CONCENTRATIONS AND CANCER RISK IN OLDER US ADULTS by Regine L. Baldauff Importance Several studies have reported an increase in serum and unmetabolized folic acid levels since the implementation of folic acid fortification (January 1, 1998). However, the literature published during the post-folic acid fortification period is controversial with regards to the safety and potential risk for cancer in non-target populations. Objective To study the association between unmetabolized folic acid and serum folate and cancer in older US adults. Design, Setting, and Participants This is a cross sectional study using data from National Health and Nutrition Examination Surveys. Among 700 participants with identified unmetabolized folic acid, 147 cases were reported a history of having cancer from 1999-2002. Within the 7,981 subjects who had a recorded value for serum folate from 1999-2008; 1,459 reported a history of all cancer. Among the 4,007 women who had a recorded value for serum folate between 1999-2008; 288 reported a history of breast cancer. Main Outcome Measures Associations of unmetabolized folic acid and serum folate with all cancer and breast cancer was evaluated using a multivariable logistic regression analysis controlling for demographic and dietary intakes. Results Men and women without unmetabolized folic acid were 0.7 times less likely to develop cancer. Those over the age of sixty with the highest concentration of serum folate were 1.4 times more likely to have cancer than participants with lower serum folate concentrations. Women over the age of sixty with the highest concentration of serum folate were 1.8 times more likely to have breast cancer compared to women with lower serum folate concentrations. Conclusions and Relevance The presence of unmetabolized folic acid and high serum folate concentrations were related to an increased prevalence of cancer. Further research is warranted to investigate the cause and effect relationship.

While assessment of folate requirements has been based only on dietary intakes, folate produced by the colonic microflora can exceed amounts consumed in food. Bacterially synthesized folate is absorbed across the rat and piglet colon. In vitro studies suggest, but direct evidence is lacking that folate is absorbed across the intact human colon. If indeed folate is absorbed, the amount synthesized may be susceptible to manipulation by fibre and prebiotics intake. We therefore performed two studies to investigate folate absorption across the colon. To confirm absorption across the intact human colon, in our first study, 684 nmol (320 µg) 13C5-glutamyl-[6S]-5-formyltetrahydrofolate was infused into the cecum of six adults and blood samples were collected. Tandem mass spectrometry confirmed folate absorption across the colon by appearance in plasma of 13C5-[6S]-5-methyltetrahydrofolate, at a rate of 0.6±0.2 nmol/h versus 7±1.2 nmol/h after intravenous injection of 172 nmol 13C5-5-formyltetrahydrofolate. Since bifidobacteria are potent folate producers, in our second study we evaluated the influence of bifidogenic oligosaccharides on colonic folate production and host folate status, using a piglet animal model. Piglets (n=12) were randomly assigned a milk-based formula with 5g/L inulin + 5g/L galactooligosaccharides, or 5g/L maltodextrin (control). After 28 days, the weights of colon contents (178 %) and colon tissue (37.9 %) of piglets fed oligosaccharides were greater than controls (P=0.0003, P=0.0044, respectively). The bacterial load and folate contents in the colons of piglets fed oligosaccharides were greater than controls (P=0.0022, P=0.0218, respectively). Body weights, blood folate status and liver and kidney folate concentrations did not differ. In conclusion, folate is absorbed across the human colon. Supplementation of the piglet diet with 5g/L inulin and 5g/L galactooligosaccharides increased the amounts of microbial folate, and the weights of colon tissue and contents, but folate concentrations in colon contents, blood and organs were not affected.

Aberrant activation of the canonical Wnt signaling pathway accounts for the vast majority of colorectal cancers. The Rac1 GTPase is overexpressed in colon cancer, and its splice variant, Rac1b, is preferentially expressed in colon tumours. Rac1 and Rac1b have both been previously shown to crosstalk with the canonical Wnt signaling pathway in colon cancer; however, the specific means by which this crosstalk occurs were unclear. This study examines the molecular mechanisms of Rac1/1b in the cooperation with canonical Wnt signaling in colon cancer. In a colon cancer cell line with dysregulated Wnt signaling, the constitutively active Rac1 mutant, V12Rac1, was observed to transcriptionally upregulate the expression of a gene set associated with cellular migration. Further, V12Rac1-mediated promotion of cell migration was dependent on its nuclear localization. Previous work in our lab has shown a Rac1-specific activator, Tiam1, is present in the nucleus at the promoter of Wnt target genes upon Wnt3a stimulation; and that exogenous introduction of Tiam1 increased the expression of a Wnt-responsive reporter (TopFlash). Given the importance of nuclear localization of Rac1 in the promotion of tumourigenic processes, we demonstrated that knockdown of endogenous Tiam1 reduced TopFlash expression, proving reverse specificity and strengthening the evidence of a nuclear role for Rac1. Since some functional differences exist between Rac1 and Rac1b, we also examined Rac1b for transcriptional targets following induction, and identified the RhoA effector, ROCK2, which has been previously associated with cell migration. ROCK2 demonstrated a positive correlation with Rac1b transcript expression in primary colon tumours as compared to matched normal tissue specimens. Interestingly, the observed induction in ROCK2 transcript did not translate into a detectable change in protein expression or kinase activity. Like Rac1, Rac1b also promotes cellular motility, which is dependent on nuclear localization. Cell migration can be negatively regulated by E-cadherin. Following Rac1b knockdown in HT29 cells, we show that Rac1b might contribute to motility through upregulation of the E-cadherin-repressor, Slug. Taken together, we provide greater insight into the mechanistic roles of Rac1 and Rac1b in transcriptionally regulating target genes to promote cellular processes, such as cell migration, in colon cancer with dysregulated canonical Wnt signaling.

Glucagon-like peptide-2 (GLP-2) is an intestinotrophic and intestinal anti-inflammatory hormone. Hence, I hypothesized that treatment with degradation-resistant hGly2GLP-2 increases, while blocking endogenous GLP-2 decreases colorectal cancer (CRC) in rodents. In mice, treatment with dextran sodium sulphate (DSS) and azoxymethane (AOM) induced colitis-associated CRC, which was further increased by treatment with hGly2GLP-2 and reduced by blocking endogenous GLP-2 with the antagonist hGLP-23-33. Moreover, while colonic damage score (CDS) was not altered by hGly2GLP-2 or hGLP-23-33 treatment, hGly2GLP-2 increased small intestinal growth and hGLP-23-33 reduced jejunal crypt cell proliferation. In rats fed with of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and high fat (HF) diet for aberrant crypt foci (ACF) induction, treatment with hGly2GLP-2 increased small intestinal growth and ACF occurrence. Moreover, in rats fed with PhIP-HF diet for tumour induction, early treatment with hGly2GLP-2 appears to increase the occurrence of intestinal tumours. Collectively, these findings indicate a pro-carcinogenic role for both exogenous and endogenous GLP-2.

Folate blood levels in North America have dramatically increased over the past decade owing to folic acid (FA) fortification and widespread supplement use. Furthermore, over 50% of newly diagnosed colorectal cancer (CRC) patients use vitamin supplements containing FA while receiving chemotherapy whose mechanisms of action are based on interruption of folate metabolism. This study therefore investigated whether FA supplementation can affect chemosensitivity of human colon cancer cells to 5FU, the cornerstone of CRC treatment, using a xenograft model. FA supplementation was associated with a non-dose dependent decrease in chemosensitivity, where mice receiving 8 mg FA did not respond to 5FU and had greater tumor growth with treatment, compared to 2 (control) or 25 mg FA. Results of this study pose concern given the drastically increased intake of FA, particularly among recently diagnosed CRC patients, and from mandatory fortification. Further studies are warranted to confirm our findings and to elucidate underlying mechanisms.