Thesis (doctoral)--Ludwig Maximilians-Universität zu München, 1979.

Thesis (M.Sc.). / Written for the Medical Physics Unit. Title from title page of PDF (viewed 2008/07/30). Includes bibliographical references.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Introdução: A identificação de mecanismos genéticos envolvidos no processo de carcinogênese do câncer colorretal levou ao surgimento de novas estratégias terapêuticas como a terapia gênica. Através do bloqueio ou estímulo de determinados alvos genéticos ou moleculares seria possível interromper o ciclo celular de células transformadas. Uma das estratégias sugeridas foi a utilização de seqüências anti-sense do gene da ciclina G que revelou resultados iniciais clínicos e experimentais promissores em diversas neoplasias, inclusive na colorretal. Assim seria esperado que a expressão da ciclina G estivesse freqüentemente alterada de maneira seletiva nas células do câncer colorretal quando comparado às células normais. Por estas razões, decidiu-se estudar a expressão da ciclina G em pacientes com câncer do reto. Métodos: Dados clínicos, epidemiológicos, anátomo-patológicos e de sobrevivência de 36 pacientes com câncer do reto foram obtidos e correlacionados com os resultados de expressão imunohistoquímica da ciclina G. O tecido neoplásico e normal distante da lesão primária foram submetidos a reação imunohistoquímica com anticorpo monoclonal anti-ciclina G e quantificados através de três métodos: (1) quantitativo, obtido a partir da contagem de células determinando a razão entre o número de células positivas e o número total de células contadas em 10 campos; (2) semi-quantitativo (cruzes), obtido a partir da pontuação em sistema de cruzes conforme a intensidade e quantidade de células positivas em áreas de maior impregnação do corante; (3) semi-quantitativo (escore), obtido a partir da pontuação em sistema de escore (alto ou baixo) conforme a intensidade e quantidade de células positivas em áreas de maior impregnação do corante. O estudo estatístico incluiu teste T de student, Qui-quadrado, exato de Fisher, teste t pareado, Wilcoxon, log-rank e curva ROC sendo considerados significativos quando o valor de p<0,05. Resultados: A expressão da ciclina G foi positiva em 76,5±30% da células contadas, com média de 3,2±1,1 cruzes e escore alto em 32 pacientes no tecido tumoral. No tecido normal dos pacientes a positividade foi de 42,2±27,4%, com média de 1,9±1,1 cruzes e escore alto em 16 casos. Quando comparados os tecidos tumoral e normal de cada paciente, o resultado tumor>normal foi obtido em 28 (77,8%) pacientes (quantitativa), 27 (75%) pacientes (semi-quantitativa/cruzes) e 18 (50%) pacientes (semi-quantitativa/escore). A diferença de expressão entre tecido tumoral e tecido normal maior que 10% apresentou correlação com ausência de metástases sistêmicas enquanto que a diferença maior que 38% apresentou correlação com a ausência de metástases linfonodais (área da curva 0,69 nos dois casos). Houve correlação entre o resultado tumor>normal e a ausência de metástases linfonodais quando o método de quantificação foi semi-quantitativo (cruzes e escore;p=0,02 e 0,04). Não houve correlação entre o resultado tumor>normal e as demais características. Não houve influência do resultado tumor>normal nas curvas de sobrevivência (3 anos). Conclusões: A expressão da ciclina G é maior no tecido neoplásico do câncer colorretal quando comparada ao tecido normal. Apesar disso, a expressão da ciclina G é raramente nula no tecido normal. A expressão de ciclina G tumor>normal esteve associada a ausência de metástases linfonodais quando mensurada através de métodos semi-quantitativos. Apesar disso, a expressão alterada da ciclina G não tem influência sobre sobrevivência precoce em pacientes com câncer do reto. / Introduction: Identification of genetic mechanisms involved in colorectal cancer carcinogenesis led to the development of new treatment strategies such as gene therapy. The aim of this strategy is to interrupt cell-cycle of transformed malignant cells by blocking or stimulating specific gene expression. Utilization of cyclin G antisense constructs has been suggested with clinical and experimental promising results in various neoplasias, including colorectal cancer. In this setting, one would expect that cyclin G would be selectively overexpressed in colorectal cancer cells as opposed to normal tissue. For this reason, we decided to study cyclin G expression in patients with rectal cancer. Methods: Clinical, epidemiological, pathological and survival data from 36 patients with rectal cancer was collected and correlated with Cyclin G immunohistochemical expression. Neoplastic and non-adjacent normal tissue were stained with monoclonal anti-Cyclin G antibody and quantified according to 3 different methods: (1) quantitative, obtained from cell count and determined by the ratio between positive counted cells and total number of counted cells observed in 10 microscopic fields; (2) semi-quantitative (crosses), obtained from a scoring system that takes into account both quantity and intensity of most strongly stained areas; (3) semi-quantitative (score), obtained from a scoring system that takes into account both quantity and intensity of most strongly stained areas. Statistical analysis included ROC curves, student\'s T, Chi-square, Fisher\'s exact, log rank, Wilcoxon, and paired t test. Significant differences were considered for p<0.05. Results: In tumor-tissue, positive Cyclin G expression was observed in 76.5±30% of counted cells, with a mean number of 3.2±1.1 crosses and high expression score in 32 patients (89%). In normal tissue, positive cyclin G expression was observed in 42.2±27.4% of counted cells, with a mean of 1.9±1.1 crossed and high expression score in 16 patients. When comparing tumor and normal tissue within each patient, a result of tumor>normal cyclin G expression was observed in 28 (77.8%) patients (quantitative method), 27 (75%) patients (semi-quantitative crosses) and 18(50%) patients (semi-quantitative score). A difference of cyclin G expression between tumor and normal tissue greater than 10% was associated with the absence of metastatic disease. A difference of cyclin G expression between tumor and normal tissue greater than 38% was associated with the absence of lymph node metastases (ROC curve area of 0.69 in both cases). There was significant association between cyclin G expression tumor>normal result and the absence of lymph node metastases when using semi-quantitative quantification methods (p=0.02 for crosses; p=0.04 for score). There was no association between cyclin G expression and other patient\'s characteristics or survival. Conclusion: Cyclin G expression is greater in tumor tissue when compared to normal tissue in patients with rectal cancer. However, cyclin G expression in normal tissue is rarely absent. Tumor>normal cyclin G expression is significantly associated with absence of lymph node metastases when quantified using semiquantitative methods. However, cyclin G expression had no influence in short-term survival.

Introdução: A identificação de mecanismos genéticos envolvidos no processo de carcinogênese do câncer colorretal levou ao surgimento de novas estratégias terapêuticas como a terapia gênica. Através do bloqueio ou estímulo de determinados alvos genéticos ou moleculares seria possível interromper o ciclo celular de células transformadas. Uma das estratégias sugeridas foi a utilização de seqüências anti-sense do gene da ciclina G que revelou resultados iniciais clínicos e experimentais promissores em diversas neoplasias, inclusive na colorretal. Assim seria esperado que a expressão da ciclina G estivesse freqüentemente alterada de maneira seletiva nas células do câncer colorretal quando comparado às células normais. Por estas razões, decidiu-se estudar a expressão da ciclina G em pacientes com câncer do reto. Métodos: Dados clínicos, epidemiológicos, anátomo-patológicos e de sobrevivência de 36 pacientes com câncer do reto foram obtidos e correlacionados com os resultados de expressão imunohistoquímica da ciclina G. O tecido neoplásico e normal distante da lesão primária foram submetidos a reação imunohistoquímica com anticorpo monoclonal anti-ciclina G e quantificados através de três métodos: (1) quantitativo, obtido a partir da contagem de células determinando a razão entre o número de células positivas e o número total de células contadas em 10 campos; (2) semi-quantitativo (cruzes), obtido a partir da pontuação em sistema de cruzes conforme a intensidade e quantidade de células positivas em áreas de maior impregnação do corante; (3) semi-quantitativo (escore), obtido a partir da pontuação em sistema de escore (alto ou baixo) conforme a intensidade e quantidade de células positivas em áreas de maior impregnação do corante. O estudo estatístico incluiu teste T de student, Qui-quadrado, exato de Fisher, teste t pareado, Wilcoxon, log-rank e curva ROC sendo considerados significativos quando o valor de p<0,05. Resultados: A expressão da ciclina G foi positiva em 76,5±30% da células contadas, com média de 3,2±1,1 cruzes e escore alto em 32 pacientes no tecido tumoral. No tecido normal dos pacientes a positividade foi de 42,2±27,4%, com média de 1,9±1,1 cruzes e escore alto em 16 casos. Quando comparados os tecidos tumoral e normal de cada paciente, o resultado tumor>normal foi obtido em 28 (77,8%) pacientes (quantitativa), 27 (75%) pacientes (semi-quantitativa/cruzes) e 18 (50%) pacientes (semi-quantitativa/escore). A diferença de expressão entre tecido tumoral e tecido normal maior que 10% apresentou correlação com ausência de metástases sistêmicas enquanto que a diferença maior que 38% apresentou correlação com a ausência de metástases linfonodais (área da curva 0,69 nos dois casos). Houve correlação entre o resultado tumor>normal e a ausência de metástases linfonodais quando o método de quantificação foi semi-quantitativo (cruzes e escore;p=0,02 e 0,04). Não houve correlação entre o resultado tumor>normal e as demais características. Não houve influência do resultado tumor>normal nas curvas de sobrevivência (3 anos). Conclusões: A expressão da ciclina G é maior no tecido neoplásico do câncer colorretal quando comparada ao tecido normal. Apesar disso, a expressão da ciclina G é raramente nula no tecido normal. A expressão de ciclina G tumor>normal esteve associada a ausência de metástases linfonodais quando mensurada através de métodos semi-quantitativos. Apesar disso, a expressão alterada da ciclina G não tem influência sobre sobrevivência precoce em pacientes com câncer do reto. / Introduction: Identification of genetic mechanisms involved in colorectal cancer carcinogenesis led to the development of new treatment strategies such as gene therapy. The aim of this strategy is to interrupt cell-cycle of transformed malignant cells by blocking or stimulating specific gene expression. Utilization of cyclin G antisense constructs has been suggested with clinical and experimental promising results in various neoplasias, including colorectal cancer. In this setting, one would expect that cyclin G would be selectively overexpressed in colorectal cancer cells as opposed to normal tissue. For this reason, we decided to study cyclin G expression in patients with rectal cancer. Methods: Clinical, epidemiological, pathological and survival data from 36 patients with rectal cancer was collected and correlated with Cyclin G immunohistochemical expression. Neoplastic and non-adjacent normal tissue were stained with monoclonal anti-Cyclin G antibody and quantified according to 3 different methods: (1) quantitative, obtained from cell count and determined by the ratio between positive counted cells and total number of counted cells observed in 10 microscopic fields; (2) semi-quantitative (crosses), obtained from a scoring system that takes into account both quantity and intensity of most strongly stained areas; (3) semi-quantitative (score), obtained from a scoring system that takes into account both quantity and intensity of most strongly stained areas. Statistical analysis included ROC curves, student\'s T, Chi-square, Fisher\'s exact, log rank, Wilcoxon, and paired t test. Significant differences were considered for p<0.05. Results: In tumor-tissue, positive Cyclin G expression was observed in 76.5±30% of counted cells, with a mean number of 3.2±1.1 crosses and high expression score in 32 patients (89%). In normal tissue, positive cyclin G expression was observed in 42.2±27.4% of counted cells, with a mean of 1.9±1.1 crossed and high expression score in 16 patients. When comparing tumor and normal tissue within each patient, a result of tumor>normal cyclin G expression was observed in 28 (77.8%) patients (quantitative method), 27 (75%) patients (semi-quantitative crosses) and 18(50%) patients (semi-quantitative score). A difference of cyclin G expression between tumor and normal tissue greater than 10% was associated with the absence of metastatic disease. A difference of cyclin G expression between tumor and normal tissue greater than 38% was associated with the absence of lymph node metastases (ROC curve area of 0.69 in both cases). There was significant association between cyclin G expression tumor>normal result and the absence of lymph node metastases when using semi-quantitative quantification methods (p=0.02 for crosses; p=0.04 for score). There was no association between cyclin G expression and other patient\'s characteristics or survival. Conclusion: Cyclin G expression is greater in tumor tissue when compared to normal tissue in patients with rectal cancer. However, cyclin G expression in normal tissue is rarely absent. Tumor>normal cyclin G expression is significantly associated with absence of lymph node metastases when quantified using semiquantitative methods. However, cyclin G expression had no influence in short-term survival.

Laparoscopic surgery for colorectal cancer was first reported in 1991. However, early experiences with laparoscopic colectomy were unfavorable, with higher than expected rates of port-site recurrence and concerns about compromised long-term oncologic outcomes. These concerns have been resolved by the results of several large-scale European and American multicenter randomized controlled trials (RCTs) that reported no difference in oncologic clearance and survival between laparoscopic and open colectomy for colon cancer. / The role of laparoscopic surgery for rectal cancer, on the other hand, still remains controversial. Because laparoscopic surgery for rectal cancer is technically more difficult and has a higher morbidity rate than laparoscopic colectomy for colon cancer, most of the published large-scale multicenter RCTs comparing laparoscopic and open colorectal cancer did not include patients with rectal cancer. To date, good-quality data comparing laparoscopic and open surgery for rectal cancer are still scarce in the literature. The main objective of this thesis is to provide additional evidence to justify the role of laparoscopic surgery for rectal cancer. / To be justified, laparoscopic surgery for rectal cancer should have equal or better clinical outcomes than open surgery and improve quality of life. Furthermore, oncologic clearance as well as long-term survival should not be adversely affected by the laparoscopic approach. / In this thesis, a series of RCTs and comparative studies with long-term follow-up were conducted to address the above issues. Our results demonstrate that laparoscopic surgery for rectal cancer is associated with earlier postoperative recovery, better preservation of urosexual function and quality of life, and less late morbidity when compared with open surgery. Oncologic clearance in terms of resection margins and number of lymph nodes harvested are comparable between the laparoscopic and open groups. Most importantly, laparoscopic surgery does not adversely affect disease control or jeopardize long-term survival of rectal cancer patients. The benefits of the laparoscopic over the open approach remain the same regardless of the types of rectal cancer surgery (laparoscopic-assisted anterior resection, total mesorectal excision, or abdominoperineal resection) or the location of the tumor. It is therefore concluded that laparoscopic surgery for rectal cancer is safe and justified. Based on our results, we believe that laparoscopic surgery can be regarded as an acceptable alternative to open surgery for treating curable rectal cancer. / Ng, Siu Man Simon. / Thesis (M.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 323-366). / Dedication --- p.1 / Declaration of Originality --- p.2 / Abstract --- p.3 / Table of Contents --- p.5 / List of Tables --- p.8 / List of Figures --- p.10 / List of Abbreviations --- p.13 / PRÉCIS TO THE THESIS --- p.15 / Chapter PART I --- BACKGROUND --- p.37 / Chapter Chapter 1 --- Management of Colorectal Cancer: From Open to Laparoscopic Surgery --- p.38 / Chapter 1.1 --- Introduction to Colorectal Cancer --- p.39 / Chapter 1.2 --- A Brief History of Laparoscopic Surgery --- p.51 / Chapter 1.3 --- Laparoscopic Colorectal Surgery: The Beginning --- p.58 / Chapter 1.4 --- Evidence for the Safety and Efficacy of Laparoscopic Surgery for Colon Cancer --- p.62 / Chapter Chapter 2 --- Laparoscopic Surgery for Rectal Cancer: A Critical Appraisal of Published Literature --- p.71 / Chapter 2.1 --- Introduction --- p.72 / Chapter 2.2 --- Evidence from Single-Center Trials --- p.76 / Chapter 2.3 --- Evidence from Multicenter Trials --- p.82 / Chapter 2.4 --- Ongoing Trials --- p.89 / Chapter 2.5 --- Discussion --- p.92 / Chapter Chapter 3 --- Laparoscopic Surgery for Rectosigmoid and Rectal Cancer: Experience at The Prince of Wales Hospital, Hong Kong --- p.97 / Chapter 3.1 --- The Beginning of Laparoscopic Era in Hong Kong --- p.98 / Chapter 3.2 --- Early Experience of Laparoscopic Colorectal Surgery --- p.102 / Chapter 3.3 --- Nonrandomized Comparative Studies --- p.105 / Chapter 3.4 --- The Hong Kong Trial --- p.110 / Chapter PART II --- HYPOTHESES AND CLINICAL STUDIES --- p.116 / Chapter Chapter 4 --- Research Hypotheses and Objectives --- p.117 / Chapter 4.1 --- Research Hypotheses --- p.118 / Chapter 4.2 --- Research Plan and Objectives --- p.120 / Chapter Chapter 5 --- Laparoscopic-Assisted Versus Open Anterior Resection for Upper Rectal Cancer: Short-Term Outcomes --- p.122 / Chapter 5.1 --- Abstract --- p.123 / Chapter 5.2 --- Introduction --- p.125 / Chapter 5.3 --- Patients and Methods --- p.128 / Chapter 5.4 --- Results --- p.133 / Chapter 5.5 --- Discussion --- p.144 / Chapter 5.6 --- Conclusions --- p.148 / Chapter Chapter 6 --- Laparoscopic-Assisted Versus Open Anterior Resection for Upper Rectal Cancer: Long-Term Morbidity and Oncologic Outcomes --- p.149 / Chapter 6.1 --- Abstract --- p.150 / Chapter 6.2 --- Introduction --- p.152 / Chapter 6.3 --- Patients and Methods --- p.154 / Chapter 6.4 --- Results --- p.158 / Chapter 6.5 --- Discussion --- p.173 / Chapter 6.6 --- Conclusions --- p.179 / Chapter Chapter 7 --- Laparoscopic-Assisted Versus Open Abdominoperineal Resection for Low Rectal Cancer --- p.180 / Chapter 7.1 --- Abstract --- p.181 / Chapter 7.2 --- Introduction --- p.183 / Chapter 7.3 --- Patients and Methods --- p.185 / Chapter 7.4 --- Results --- p.190 / Chapter 7.5 --- Discussion --- p.201 / Chapter 7.6 --- Conclusions --- p.207 / Chapter Chapter 8 --- Laparoscopic-Assisted Versus Open Total Mesorectal Excision with Anal Sphincter Preservation for Mid and Low Rectal Cancer --- p.208 / Chapter 8.1 --- Abstract --- p.209 / Chapter 8.2 --- Introduction --- p.211 / Chapter 8.3 --- Patients and Methods --- p.214 / Chapter 8.4 --- Results --- p.221 / Chapter 8.5 --- Discussion --- p.238 / Chapter 8.6 --- Conclusions --- p.246 / Chapter Chapter 9 --- Long-Term Oncologic Outcomes of Laparoscopic Versus Open Surgery for Rectal Cancer: A Pooled Analysis of Three Randomized Controlled Trials --- p.247 / Chapter 9.1 --- Abstract --- p.248 / Chapter 9.2 --- Introduction --- p.250 / Chapter 9.3 --- Patients and Methods --- p.254 / Chapter 9.4 --- Results --- p.258 / Chapter 9.5 --- Discussion --- p.272 / Chapter 9.6 --- Conclusions --- p.280 / Chapter Chapter 10 --- Prospective Comparison of Quality of Life Outcomes After Curative Laparoscopic Versus Open Sphincter-Preserving Resection for Rectal Cancer --- p.281 / Chapter 10.1 --- Abstract --- p.282 / Chapter 10.2 --- Introduction --- p.284 / Chapter 10.3 --- Patients and Methods --- p.287 / Chapter 10.4 --- Results --- p.292 / Chapter 10.5 --- Discussion --- p.308 / Chapter Chapter 11 --- Conclusions --- p.314 / Chapter 11.1 --- Conclusions --- p.315 / REFERENCES --- p.322 / LIST OF PUBLICATIONS RELATED TO THE THESIS --- p.367 / ACKNOWLEDGEMENTS --- p.373

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 5 uppsatser.

Diss. (sammanfattning) Uppsala : Uppsala universitet, 2006. / Härtill 4 uppsatser.