Thesis (Ph. D.)--University of Hong Kong, 2009. / Includes bibliographical references (leaves 143-159). Also available in print.

Background: Metastases to the pancreas are rare, accounting for less then 2 % of all pancreatic malignancies. However, both the benefit of extended tumor resection and the ideal oncological approach have not been established for such cases; therefore, we evaluated patients with metastasis to the pancreas who underwent pancreatic resection. Methods: Between 1994 and 2012, 676 patients underwent pancreatic surgery in our institution. We retrospectively reviewed patients’ medical records according to survival, and surgical and non-surgical complications. Student’s t-test and the log-rank test were used for statistical analysis. Results: Eighteen patients (2.7 %) received resection for pancreatic metastases (12 multivisceral resections and 6 standard resections). The pancreatic metastases originated from renal cell carcinoma (n = 10), malignant melanoma (n = 2), neuroendocrine tumor of the ileum (n = 1), sarcoma (n = 1), colon cancer (n = 1), gallbladder cancer (n = 1), gastrointestinal stromal tumor (n = 1), and non-small cell lung cancer (n = 1). The median time between primary malignancy resection to metastasectomy was 83 months (range, 0–228 months). Minor surgical complications (Grade I-IIIa) occurred in six patients (33.3 %) whereas major surgical complications (Grade IIIb-V) occurred in three patients (16.6 %). No patients died during hospitalization. The median follow-up was 76 months (range, 10–165 months). One-year, 3-year and 5-year survival for standard resection versus multivisceral resection was 83, 50, and 56 % versus 83, 66, and 50, respectively. Twelve patients died after a median of 26 months (range, 5–55 months). Conclusions: A surgical approach with curative intent is justified in select patients suffering from metastases to the pancreas and offers good long-term survival. The resection of pancreatic metastases of different tumor types was associated with favorable morbidity and mortality when compared with resection of the primary pancreatic malignancies. Our findings also demonstrated that multivisceral resection was feasible, with acceptable long term outcomes, even though morbidity rates tended to be higher after multivisceral resection than after standard resection.

published_or_final_version / Surgery / Doctoral / Doctor of Philosophy

Introdução: Os benefícios do emprego do selante de fibrina no reforço de anastomoses pancreatico-jejunais, após ressecção duodenopancreática, visando a redução da incidência de fístula pancreática pós operatória (FPPO), ainda são questionáveis. Objetivo: Avaliar a influência do emprego do selante de fibrina na anastomose pancreatico-jejunal, após duodenopancreatectomia, na incidência de fístula, bem como suas consequências clínicas e os custos hospitalares. Metodologia: Estudo retrospectivo de 62 pacientes consecutivos submetidos a duodenopancreatectomia, divididos em dois grupos: 31 pacientes utilizando o selante de fibrina (GCS) e 31 pacientes sem o emprego de selante (GSS). As variáveis estudadas foram agrupadas em epidemiológicas, clínicas, laboratoriais, com destaque para a incidência de fístula pancreática, classificada segundo a definição do International Study Group on Pancreatic Fistula, suas complicações pós operatórias catalogadas segundo a classificação de Clavien e suas repercussões na assistência e nos seus custos avaliados pelo método de absorção com rateio simples de todas as despesas, exceto a despesa com medicamentos, tratada de forma separada. Resultados: Os grupos foram homogêneos para os parâmetros epidemiológicos, clínicos, e laboratoriais e não foram registradas diferenças significativas na comparação da evolução pós operatória e dos indicadores assistenciais hospitalares. Por outro lado, os custos hospitalares foram mais elevados no GCS, em relação ao GSS (p<0,0001). Conclusão: O emprego do selante de fibrina, no reforço da anastomose pancreatico-jejunal, em pacientes submetidos a duodenopancreatectomias, nas condições estudadas, não melhorou os resultados clínicos e assistenciais e ainda aumentou os custos hospitalares. / Introduction: The benefits of fibrin sealant employment in strengthening pancreatico-jejunal anastomosis after duodenopancreatic resection, reducing the incidence of pancreatic fistula postoperative (PFPO) are still questionable. Objective: To evaluate the influence of the use of fibrin sealant in pancreatico-jejunal anastomosis after pancreaticoduodenectomy in the incidence of fistula and its clinical consequences and hospital costs. Methodology: A retrospective study of 62 consecutive patients who underwent pancreaticoduodenectomy, divided into two groups: 31 patients using fibrin sealant (GCS) and 31 patients without the sealant employment (GSS). The variables were grouped into epidemiological, clinical, laboratory, especially the incidence of pancreatic fistula classified as defined by the International Study Group on Pancreatic Fistula, their postoperative complications cataloged according to Clavien rating and its repercussions on care and its costs assessed by the absorption method with simple apportionment of all expenses except the expenditure on medicines, treated separately. Results: The groups were homogeneous for clinical, epidemiological and laboratory parameters and no significant differences were recorded in the comparison given postoperative progress and hospital assistance indicators. Moreover, hospital costs were higher in GCS, with respect to GSS (p <0.0001). Conclusion: The use of fibrin sealant in pancreatojejunal anastomosis after pancreaticoduodenectomy, in the studied conditions, did not improve the results of care and also increased hospital costs

Introdução: Os benefícios do emprego do selante de fibrina no reforço de anastomoses pancreatico-jejunais, após ressecção duodenopancreática, visando a redução da incidência de fístula pancreática pós operatória (FPPO), ainda são questionáveis. Objetivo: Avaliar a influência do emprego do selante de fibrina na anastomose pancreatico-jejunal, após duodenopancreatectomia, na incidência de fístula, bem como suas consequências clínicas e os custos hospitalares. Metodologia: Estudo retrospectivo de 62 pacientes consecutivos submetidos a duodenopancreatectomia, divididos em dois grupos: 31 pacientes utilizando o selante de fibrina (GCS) e 31 pacientes sem o emprego de selante (GSS). As variáveis estudadas foram agrupadas em epidemiológicas, clínicas, laboratoriais, com destaque para a incidência de fístula pancreática, classificada segundo a definição do International Study Group on Pancreatic Fistula, suas complicações pós operatórias catalogadas segundo a classificação de Clavien e suas repercussões na assistência e nos seus custos avaliados pelo método de absorção com rateio simples de todas as despesas, exceto a despesa com medicamentos, tratada de forma separada. Resultados: Os grupos foram homogêneos para os parâmetros epidemiológicos, clínicos, e laboratoriais e não foram registradas diferenças significativas na comparação da evolução pós operatória e dos indicadores assistenciais hospitalares. Por outro lado, os custos hospitalares foram mais elevados no GCS, em relação ao GSS (p<0,0001). Conclusão: O emprego do selante de fibrina, no reforço da anastomose pancreatico-jejunal, em pacientes submetidos a duodenopancreatectomias, nas condições estudadas, não melhorou os resultados clínicos e assistenciais e ainda aumentou os custos hospitalares. / Introduction: The benefits of fibrin sealant employment in strengthening pancreatico-jejunal anastomosis after duodenopancreatic resection, reducing the incidence of pancreatic fistula postoperative (PFPO) are still questionable. Objective: To evaluate the influence of the use of fibrin sealant in pancreatico-jejunal anastomosis after pancreaticoduodenectomy in the incidence of fistula and its clinical consequences and hospital costs. Methodology: A retrospective study of 62 consecutive patients who underwent pancreaticoduodenectomy, divided into two groups: 31 patients using fibrin sealant (GCS) and 31 patients without the sealant employment (GSS). The variables were grouped into epidemiological, clinical, laboratory, especially the incidence of pancreatic fistula classified as defined by the International Study Group on Pancreatic Fistula, their postoperative complications cataloged according to Clavien rating and its repercussions on care and its costs assessed by the absorption method with simple apportionment of all expenses except the expenditure on medicines, treated separately. Results: The groups were homogeneous for clinical, epidemiological and laboratory parameters and no significant differences were recorded in the comparison given postoperative progress and hospital assistance indicators. Moreover, hospital costs were higher in GCS, with respect to GSS (p <0.0001). Conclusion: The use of fibrin sealant in pancreatojejunal anastomosis after pancreaticoduodenectomy, in the studied conditions, did not improve the results of care and also increased hospital costs

Contemporary hepatobiliary surgery practice must accurately assess operative risk in increasingly elderly populations with greater co-morbidity. Current methods fail to identify patients at high risk of postoperative complications. Cardiopulmonary exercise testing (CPET) derived anaerobic threshold (AT) and ventilatory equivalence of carbon dioxide (VE/VCO2) are validated predictors of postoperative outcome in major intra-abdominal surgery and outperform contemporary tools of risk evaluation. Despite evidence of improved in-hospital postoperative survival in large centres offering complex curative hepatobiliary surgery, morbidity remains high and long-term survival in the high-risk subset remains poor. This thesis investigated the role of validated CPET-derived markers in predicting perioperative outcomes for a high-risk hepatobiliary surgery population. It was also utilised to study the impact of malignant obstructive jaundice on peripheral oxygen extraction. In a prospective cohort of high-risk patients undergoing liver resection, an AT of 9.9 ml O2/kg/min predicted in-hospital mortality and long-term survival. Below this threshold, AT was 100% sensitive and 75.9% specific for in-hospital mortality (PPV 19%, NPV 100%). Long-term survival below the threshold of 9.9 was significantly worse when compared to those above (mortality HR 1.81). The VE/VCO2 was the most significant predictor of postoperative complications and a threshold of 34.5 provided 84% specificity and 47% sensitivity (PPV 76%, NPV 60%). Amongst the high-risk pancreaticoduodenectomy patients, VE/VCO2 was the single most predictive marker of in-hospital postoperative mortality with an AUC of 0.850 (p=0.020); a threshold value 41 was 75% sensitive and 94.6% specific (PPV 50%, NPV 98.1%). The VE/VCO2 41 was also the only predictor of poor long-term survival (HR 1.90). Notably, AT, Revised Cardiac Risk Index and Glasgow Prognostic Score did not predict outcome after pancreaticoduodenectomy. Patients with malignant obstructive jaundice, evaluated for peripheral oxygen extraction using CPET, showed lower mean peak oxygen consumption (peak VO2) at 63±17.4% of the predicted value. This was noted in absence of any significant pre-existing cardiopulmonary disease and normal respiratory reserve. Normal patterns of oxygen extraction were seen at rest, during incremental work rate and peak exercise levels. Levels of oxygen partial pressure and saturation exceeded baseline values after exercise signifying normal microcirculatory responses. Thus, aerobic capacity was limited by dysfunction in delivery (cardiac output) rather than oxygen extraction. CPET provides useful prognostic adjuncts for early and long-term outcomes in the high-risk patients undergoing major hepatobiliary surgery. These findings provide useful tools for perioperative optimisation of the high-risk patient and plan appropriate level of postoperative care to address mortality and morbidity after surgery.

Ampullary lesions (ALs) can be treated by endoscopic (EA) or surgical ampullectomy (SA) or pancreaticoduodenectomy (PD). However, EA carries significant risk of incomplete resection while surgical interventions can lead to substantial morbidity. We performed a systematic review and meta-analysis for R0, adverse-events (AEs) and recurrence between EA, SA and PD. Electronic databases were searched from 1990 to 2018. Outcomes were calculated as pooled means using fixed and random-effects models and the Freeman-Tukey-Double-Arcsine-Proportion-model. We identified 59 independent studies. The pooled R0 rate was 76.6% (71.8–81.4%, I2 = 91.38%) for EA, 96.4% (93.6–99.2%, I2 = 37.8%) for SA and 98.9% (98.0–99.7%, I2 = 0%) for PD. AEs were 24.7% (19.8–29.6%, I2 = 86.4%), 28.3% (19.0–37.7%, I2 = 76.8%) and 44.7% (37.9–51.4%, I2 = 0%), respectively. Recurrences were registered in 13.0% (10.2–15.6%, I2 = 91.3%), 9.4% (4.8–14%, I2 = 57.3%) and 14.2% (9.5–18.9%, I2 = 0%). Differences between proportions were significant in R0 for EA compared to SA (p = 0.007) and PD (p = 0.022). AEs were statistically different only between EA and PD (p = 0.049) and recurrence showed no significance for EA/SA or EA/PD. Our data indicate an increased rate of complete resection in surgical interventions accompanied with a higher risk of complications. However, studies showed various sources of bias, limited quality of data and a significant heterogeneity, particularly in EA studies.

O objetivo do presente estudo é avaliar os fatores clínico-patológicos envolvidos na sobrevida dos pacientes portadores de adenocarcinoma pancreático submetidos à ressecção cirúrgica. Foram estudados retrospectivamente 56 pacientes, sendo 32(57,1%) do sexo feminino e 24 (42,8%) do masculino com idade média de 58,1 anos. A duodenopancreatectomia com preservação do piloro foi realizada em 51,8%, seguida da gastroduodenopancreatectomia (41,1%), pancreatectomia total (3,6%) e pancreatectomia corpo-caudal (3,6%). Quatro pacientes eram do estádio IA, sete do IB, 12 do IIA, 29 do IIB e dois do III. A sobrevida média foi de 20,7 meses. Concluiu-se que sexo, tempo de pro-trombina reduzido, ressecção da veia porta, diferenciação tumoral e invasão peri-neural estão associados com a sobrevida / The aim of the present study is to correlate clinical and pathological finding with survival in patients with pancreatic adenocarcinoma treated with surgical resection. Fifty six patients ressected were studied retrospectively. There were 32 females (57,1%) and 24 males (42,8%) with mean age of 58,1 years. Pylorus preserving duodenopancreatectomy were performed in 51,8%, followed by classical duodenopancreatectomy (41,1%), distal pancreatectomy (3,6%) and total pancreatectomy (3,6%). Four patients were stage IA, seven stage IB, 12 stage IIA, 29 stage IIB and two stage III. Mean survival was 20,7 months. It was concluded that sex, pro-trombin time reduction, portal vein resection, tumor differentiation and peri-neural invasion are statistically associated with survival

INTRODUÇÃO: O câncer do pâncreas apresenta taxas anuais de mortalidade e incidência muito semelhantes, sendo uma das principais causas de morte por câncer no mundo. A agressividade do tumor e o retardo no seu diagnóstico são considerados responsáveis pela sua alta letalidade. O tratamento adjuvante convencional aumenta pouco a sobrevida a longo prazo e a terapia-alvo pode ser uma alternativa ao tratamento deste tipo de tumor. OBJETIVO: O objetivo do presente estudo é avaliar a expressão do receptor do fator de crescimento epitelial e seu eventual valor prognóstico em pacientes portadores de adenocarcinoma pancreático submetidos à ressecção cirúrgica. MÉTODO: Foram estudados retrospectivamente 88 pacientes portadores de adenocarcinoma pancreático operados no Serviço de Cirurgia de Vias Biliares e Pâncreas do HC-FMUSP e no Departamento de Cirurgia Abdominal Hospital A.C. Camargo no período de 1990 a 2006. RESULTADOS: Quarenta e sete (53,4%) pacientes do sexo feminino e 41 (46,6%) do masculino com idade mediana de 60 anos. As cirurgias realizadas foram duodenopancreatectomia com preservação do piloro (55,1%), gastroduodenopancreatectomia (34,8%), pancreatectomia corpo-caudal (6,8%) e gastroduodenopancreatectomia total (2,3%). A ressecção venosa portal foi realizada em 12 pacientes (13,5%). O tamanho tumoral médio foi de 3,75cm. Invasão vascular esteve presente em 31% dos casos e neural em 88,5%. A margem de ressecção estava comprometida em 33 pacientes (37,5%). Cinco (5,7%) pacientes eram do estádio IA, 15(17%) do IB, 19(21,6%) do IIA, 47(53,4) do IIB e dois (2,3%) do III.Observou-se diferença na expressão de EGFR na membrana celular entre o tecido tumoral e o tecido não tumoral (p=0,004); entre o tecido metastático linfonodal e o tecido não tumoral (p=0,02) mas não houve diferença quanto à sua expressão quando comparamos o tecido tumoral e o tecido metastático linfonodal (p=0,28). Dentre as variáveis clínicas e patológicas estudadas, observou-se diferença de expressão do EGFR entre os gêneros feminino e masculino (p=0,03), não havendo diferenças entre as outras variáveis. A sobrevida mediana global foi de 22,9 meses. A sobrevida cumulativa global em 1 ano, 3 anos e 5 anos foi de 48%, 20% e 18%, respectivamente. As sobrevidas cumulativas em 1 ano, 3 anos e 5 anos foram 77%, 30% e 8% no grupo sem expressão do EGFR na membrana tumoral versus 46%, 8% e 0% respectivamente no grupo com expressão do EGFR na membrana celular do tumor. Na análise univariada, as seguintes variáveis estiveram associadas a menor sobrevida: sexo masculino, ressecção venosa portal, invasão peri-neural, e vascular, invasão do tecido peri-pancreático, acometimento da margem de ressecção pancreática e expressão positiva de EGFR no tecido tumoral. Na análise multivariada, os fatores associados à sobrevida menor foram: gênero masculino, ressecção venosa portal, invasão vascular e invasão peri-neural. CONCLUSÃO: A expressão do EGFR na membrana celular é significativamente maior no tecido tumoral que no tecido pancreático não tumoral. A expressão do EGFR na membrana celular do tecido tumoral está associada a pior prognóstico (menor sobrevida). / INTRODUCTION: Pancreatic cancer is one of the main cancer related deaths in the world and its incidence is similar to its mortality. Biological aggressiveness and delayed diagnosis are a major concern. Adjuvant treatment has little impact on survival and the expression of potential target molecules has been undertaken in order to increase survival. OBJECTIVE: The aim of the present study is to study the expression of EGFR and its potential prognostic role in tumor, non-tumor and metastatic lymph node tissues of patient with pancreatic adenocarcinoma treated with surgical resection. MATHERIAL AND METHODS: Eighty eight patients with pancreatic adenocarcinoma operated at Serviço de Cirurgia de Vias Biliares e Pâncreas do HC-FMUSP and Departamento de Cirurgia Abdominal do Hospital A.C.Camargo were retrospectively studied between 1990 and 2003. RESULTS: Forty seven females (53,4%) and 41 males (46,6%) with median age of 60 years were studied. Pylorus preserving duodenopancreatectomy was performed in 55%, classical duodenopancreatectomy in 34,8%, distal pancreatectomy in 6,8% and total pancreatectomy in 2,3%. Portal vein resection was performed in 12 patients (13,5%). Mean tumor size was 3,75cm. Vascular and neural invasion were present in 31% and 88,5%, respectively. Positive surgical margin was present in 33 (37,5%) patients. Five (5,7%) patients were stage IA, 15(17%) stages IB, 19(21,6%) stages IIA, 47(53,4%) stages IIB and two (2,3%) stages III. There were difference in the membrane expression of EGFR between tumor and non tumor pancreatic tissue (p=0,004); between metastatic lymph node and non tumor pancreatic tissue (p=0,02); but there were no difference between tumor and metastatic lymph node tissue (p=0,28). Median survival time was 22,9 months. Cumulative one, three and five years survival were 48%, 20% and 18%. Cumulative survival at 1, 3 and 5 years were 77%, 30% and 8% in patients with negative expression of EGFR in tumor membrane and 46%, 8% and 0%, respectively in patients with positive EGFR expression in tumoral membrane. Univariate analysis showed that male gender, portal vein resection, neural, vascular and peri-pancreatic invasion invasion, positive surgical margin and positive membrane EGFR expression in tumoral tissue were correlated with poor survival. Multivariate analysis showed that male gender, portal vein resection, vascular invasion and peri-neural invasion are associated with lower survival after resection. CONCLUSION: EGFR membrane expression is different between tumor tissue and non tumor pancreatic tissue. EGFR membrane expression in tumoral tissue was associated with worst survival.

O objetivo do presente estudo é avaliar os fatores clínico-patológicos envolvidos na sobrevida dos pacientes portadores de adenocarcinoma pancreático submetidos à ressecção cirúrgica. Foram estudados retrospectivamente 56 pacientes, sendo 32(57,1%) do sexo feminino e 24 (42,8%) do masculino com idade média de 58,1 anos. A duodenopancreatectomia com preservação do piloro foi realizada em 51,8%, seguida da gastroduodenopancreatectomia (41,1%), pancreatectomia total (3,6%) e pancreatectomia corpo-caudal (3,6%). Quatro pacientes eram do estádio IA, sete do IB, 12 do IIA, 29 do IIB e dois do III. A sobrevida média foi de 20,7 meses. Concluiu-se que sexo, tempo de pro-trombina reduzido, ressecção da veia porta, diferenciação tumoral e invasão peri-neural estão associados com a sobrevida / The aim of the present study is to correlate clinical and pathological finding with survival in patients with pancreatic adenocarcinoma treated with surgical resection. Fifty six patients ressected were studied retrospectively. There were 32 females (57,1%) and 24 males (42,8%) with mean age of 58,1 years. Pylorus preserving duodenopancreatectomy were performed in 51,8%, followed by classical duodenopancreatectomy (41,1%), distal pancreatectomy (3,6%) and total pancreatectomy (3,6%). Four patients were stage IA, seven stage IB, 12 stage IIA, 29 stage IIB and two stage III. Mean survival was 20,7 months. It was concluded that sex, pro-trombin time reduction, portal vein resection, tumor differentiation and peri-neural invasion are statistically associated with survival