RESUMO O objetivo do presente manuscrito foi fazer uma revisão histórica do desenvolvimento e das mais importantes contribuições em relação à Síndrome de Lynch, desde sua primeira descrição há mais de um século atrás. Em 1895, o reputado patologista Dr. Aldred Scott Warthin ficou intrigado com a história familiar de uma costureira local, chamada Pauline Gross. De acordo com a sua previsão, ela morreria precocemente devido a um câncer, o que realmente aconteceu (do útero). Historicamente, sua família foi designada como Família “G”, caracterizando um grupo reconhecido como a maior e mais longa árvore genealógica relacionada ao câncer familiar jamais estudada. Warthin concluiu que os membros dessa família tinham susceptibilidade genética para câncer, e ainda hoje são considerados a primeira família com Síndrome de Lynch reportada na literatura. Entretanto, naquela época a comunidade médica oncológica não era receptiva à associação entre hereditariedade e câncer, a despeito da descrição de outras famílias com heredogramas similares. Infelizmente, esse fato histórico permaneceu esquecido até que outro investigador inaugurou uma nova era para a melhor compreensão da agregação familiar do câncer. Após diversas descrições dessa mesma agregação de casos de câncer em outras famílias, essa condição inicialmente denominada Síndrome de Câncer Familial foi mudada para o epônimo Síndrome de Lynch. Esse foi um reconhecimento ao extenso e dedicado trabalho desenvolvido pelo Dr. Henry Lynch na descrição de diversas características da doença e seus esforços para estabelecer as recomendações corretas para o seu diagnóstico e tratamento. Embora o futuro anuncie que ainda teremos um longo caminho a percorrer para a completa compreensão da Síndrome de Lynch, as contribuições extraordinárias da intuição de Pauline, da perseverança de Warthin e da consistência do trabalho de Lynch nunca devem ser esquecidas por àqueles que já se beneficiaram, bem como os que ainda irão se beneficiar de todo esse conhecimento. atrás 1895 Dr local Gross previsão útero. útero . útero) Historicamente G, G , “G” estudada literatura Entretanto similares Infelizmente tratamento beneficiaram conhecimento 189 “G 18 1

ABSTRACT The present manuscript aimed to review the historical development and most important contributions regarding Lynch Syndrome since its first description, more than a century ago. In 1895, a reputed pathologist from Michigan University, Dr. Aldred Scott Warthin, got intrigued by the family history of a local seamstress called Pauline Gross. According to her prevision, she would present an early death due to cancer, which actually happened (from the uterus). Historically, her family was designated “Family G”, comprising a group recognized as the longest and most detailed cancer genealogy that has ever been studied. Warthin concluded that its members had genetic susceptibility for cancer, and they are, nowadays, considered the first reported Lynch Syndrome family. At that time, however, the medical cancer community was far less receptive to the association between heredity and cancer, despite the description of other families with similar heredograms. Unfortunately, this historical fact remained somewhat dormant until another investigator inaugurated a new era in the understanding of family cancer clusters. After reports and studies from this family and many others, the condition initially called Cancer Family Syndrome was changed to the eponym Lynch Syndrome. This was a recognition of the extensive and dedicated work developed by Dr. Henry Lynch in describing various characteristics of the disease, and his efforts to establish the correct recommendations for its diagnosis and treatment. Although the future announces there is still far to go for a complete understanding of Lynch Syndrome, the remarkable contributions of Pauline’s intuition, Warthin’s perseverance, and Lynch’s work consistency must never be forgotten by those who already have or will still benefit from this knowledge. ago 1895 University Dr Gross prevision uterus. uterus . uterus) Historically G, G , G” studied are nowadays time however heredograms Unfortunately clusters others disease treatment Paulines s intuition Warthins perseverance Lynchs knowledge 189 18 1

RESUMO RACIONAL: O status linfonodal é vital para o prognóstico do câncer gástrico (CG), mas o estágio pN convencional pode ser limitado por variações na linfadenectomia e migração do estágio. O N-Ratio, que avalia a proporção entre linfonodos metastáticos e linfonodos ressecados, surge como uma ferramenta prognóstica promissora. OBJETIVOS: Avaliar o valor prognóstico do N-Ratio no CG, particularmente em pacientes com <25 linfonodos ressecados. MÉTODOS: Foram analisados, retrospectivamente, pacientes submetidos à gastrectomia com intenção curativa para CG. As categorias do N-Ratio foram determinadas pelo método da curva ROC, e a área sob a curva (AUC) foi utilizada como medida de desempenho na previsão de recorrência/óbito. RESULTADOS: Foram incluídos no estudo 561 pacientes com CG, 57% tinham status pN+ e 17,5% tinham <25 linfonodos ressecados. O N-Ratio, com média de 0,12, previu a sobrevida com precisão de 74% (AUC=0,74; IC95% 0,70–0,78, p<0,001). As categorias N-Ratio incluíram: N-Ratio 0 (43%); N-Ratio 1 (12,3%); N-Ratio 2 (31,6%); e N-Ratio 3 (13,2%). A sobrevida livre de doença (SLD) variou entre todos os grupos N-Ratio, com o N-Ratio 3 apresentando pior sobrevida do que os casos pN3 (SLD=21,8 vs.11 meses, p=0,022, p<0,05). Nos casos com <25 linfonodos ressecados, a SLD não foi significativamente pior nos grupos N-Ratio 0 (68,8 vs. 81,9%, p=0,061, p>0,05) e N-Ratio 1 (66,2 vs. 50%, p=0,504, p>0,05). A SLD dos casos de N-Ratio 0 com <25 linfonodos foi semelhante aos casos de N-Ratio 1. CONCLUSÕES: O N-Ratio influenciou a sobrevida em pacientes com CG, especialmente na doença linfonodal avançada (N-Ratio 3). Considerando que a proporção N não afeta os casos pN0, a avaliação prognóstica individualizada é essencial para pacientes com <25 linfonodos ressecados. RACIONAL CG , (CG) NRatio, NRatio Ratio, Ratio ressecados promissora OBJETIVOS 25 <2 MÉTODOS analisados retrospectivamente ROC AUC (AUC recorrênciaóbito recorrência óbito recorrência/óbito RESULTADOS 56 57 175 17 5 17,5 012 12 0,12 74 AUC=0,74 AUC074 (AUC=0,74 IC95 IC 070078 70 78 0,70–0,78 p<0,001. p0001 p p<0,001 . 001 p<0,001) incluíram 43% 43 (43%) 12,3% 123 (12,3%) 31,6% 316 31 6 (31,6%) 13,2%. 132 13,2% 13 (13,2%) (SLD SLD=21,8 SLD218 21 8 (SLD=21, vs11 vs 11 vs.1 meses p0022 022 p=0,022 p<0,05. p005 p<0,05 05 p<0,05) 68,8 688 68 (68, 819 81 9 81,9% p0061 061 p=0,061 p>0,05 66,2 662 66 (66, 50 50% p0504 504 p=0,504 p>0,05. CONCLUSÕES 3. 3) pN0 (CG < 17, 01 0,1 7 AUC=0,7 AUC07 (AUC=0,7 IC9 07007 0,70–0,7 p000 p<0,00 00 4 (43% 12,3 (12,3% 31,6 (31,6% 13,2 (13,2% SLD=21, SLD21 (SLD=21 vs1 p002 02 p=0,02 p00 p<0,0 68, (68 81,9 p006 06 p=0,06 p>0,0 66, (66 p050 p=0,50 0, AUC=0, AUC0 (AUC=0, 0700 0,70–0, (43 12, (12,3 31, (31,6 13, (13,2 SLD=21 SLD2 (SLD=2 p=0,0 p0 p<0, (6 81, p>0, p05 p=0,5 AUC=0 (AUC=0 070 0,70–0 (4 (12, (31, (13, SLD=2 (SLD= p=0, p<0 ( p>0 AUC= (AUC= 07 0,70– (12 (31 (13 SLD= p=0 p< p> 0,70 (1 (3 p= 0,7

ABSTRACT BACKGROUND: Lymph node status is vital for gastric cancer (GC) prognosis, but the conventional pN stage may be limited by variations in lymphadenectomy and stage migration. The N-Ratio, which assesses the ratio of metastatic to resected lymph nodes, emerges as a promising prognostic tool. AIMS: To assess N-Ratios prognostic value in GC, particularly in patients with <25 resected lymph nodes. METHODS: Patients who underwent gastrectomy with curative intent for GC were retrospectively evaluated. The N-Ratio categories were determined using the ROC curve method, and the area under the curve (AUC) was used as a measure of performance in predicting recurrence/death. RESULTS: A total of 561 GC patients were included in the study, 57% had pN+ status, and 17.5% had <25 resected lymph nodes. N-Ratio, with a mean of 0.12, predicted survival with 74% accuracy (AUC=0.74; 95%CI 0.70–0.78, p<0.001). N-Ratio categories included: N-Ratio 0 (43%); N-Ratio 1 (12.3%); N-Ratio 2 (31.6%); and N-Ratio 3 (13.2%). Disease-free survival (DFS) varied among all N-Ratio groups, with N-Ratio 3 showing worse survival than pN3 cases (DFS=21.8 vs. 11 months, p=0.022, p<0.05). In cases with <25 resected lymph nodes, DFS was not significantly worse in N-Ratio 0 (68.8 vs. 81.9%, p=0.061, p>0.05) and N-Ratio 1 (66.2 vs. 50%, p=0.504, p>0.05) groups. The DFS of N-Ratio-0 cases with <25 lymph nodes was similar to N-Ratio 1 cases. CONCLUSIONS: N-Ratio influenced survival in GC patients, especially in advanced lymph node disease (N-Ratio 3). Considering that N-Ratio does not impact pN0 cases, individualized prognosis assessment is essential for patients with <25 resected lymph nodes. BACKGROUND (GC migration NRatio, NRatio N Ratio, Ratio tool AIMS NRatios Ratios 25 <2 METHODS evaluated method AUC (AUC recurrencedeath recurrence death recurrence/death RESULTS 56 study 57 175 17 5 17.5 012 12 0.12 74 AUC=0.74 AUC074 (AUC=0.74 95CI CI 95 070078 70 78 0.70–0.78 p<0.001. p0001 p p<0.001 . 001 p<0.001) 43% 43 (43%) 12.3% 123 (12.3%) 31.6% 316 31 6 (31.6%) 13.2%. 132 13.2% 13 (13.2%) Diseasefree Disease free (DFS groups DFS=21.8 DFS218 21 8 (DFS=21. vs months p0022 022 p=0.022 p<0.05. p005 p<0.05 05 p<0.05) 68.8 688 68 (68. 819 81 9 81.9% p0061 061 p=0.061 p>0.05 66.2 662 66 (66. 50 50% p0504 504 p=0.504 NRatio0 N-Ratio- CONCLUSIONS 3. 3) < 17. 01 0.1 7 AUC=0.7 AUC07 (AUC=0.7 07007 0.70–0.7 p000 p<0.00 00 4 (43% 12.3 (12.3% 31.6 (31.6% 13.2 (13.2% DFS=21. DFS21 (DFS=21 p002 02 p=0.02 p00 p<0.0 68. (68 81.9 p006 06 p=0.06 p>0.0 66. (66 p050 p=0.50 0. AUC=0. AUC0 (AUC=0. 0700 0.70–0. (43 12. (12.3 31. (31.6 13. (13.2 DFS=21 DFS2 (DFS=2 p=0.0 p0 p<0. (6 81. p>0. p05 p=0.5 AUC=0 (AUC=0 070 0.70–0 (4 (12. (31. (13. DFS=2 (DFS= p=0. p<0 ( p>0 AUC= (AUC= 07 0.70– (12 (31 (13 DFS= p=0 p< p> 0.70 (1 (3 p= 0.7

ABSTRACT Background: This manuscript provides an overview of liver carcinogenesis in murine models of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Objective: A review through MEDLINE and EMBASE was performed to assess articles until August 2022. Methods: Search was conducted of the entire electronic databases and the keywords used was HCC, CCA, carcinogenesis, animal models and liver. Articles exclusion was based on the lack of close relation to the subject. Carcinogenesis models of HCC include HCC induced by senescence in transgenic animals, HCC diet-induced, HCC induced by chemotoxicagents, xenograft, oncogenes, and HCC in transgenic animals inoculated with B and C virus. The models of CCA include the use of dimethylnitrosamine (DMN), diethylnitrosamine (DEN), thioacetamide (TAA), and carbon tetrachloride (CCl4). CCA murine models may also be induced by: CCA cells, genetic manipulation, Smad4, PTEN and p53 knockout, xenograft, and DEN-left median bile duct ligation. Results: In this review, we described different murine models of carcinogenesis that reproduce the key points for HCC and CCA genesis allowing a better understanding of its genetic, physiopathological, and environmental abnormalities. Conclusion: Each model has its advantages, disadvantages, similarities, and differences with the corresponding human disease and should be chosen according to the specificity of the study. Ultimately, those models can also be used for testing new anticancer therapeutic approaches. Background (HCC CCA. . (CCA) Objective 2022 Methods subject dietinduced, dietinduced diet induced, diet-induced chemotoxicagents xenograft oncogenes virus DMN, DMN , (DMN) DEN, DEN (DEN) TAA, TAA (TAA) CCl4. CCl4 CCl (CCl4) cells manipulation Smad4 Smad p p5 knockout DENleft left ligation Results physiopathological abnormalities Conclusion advantages disadvantages similarities study Ultimately approaches (CCA 202 (DMN (DEN (TAA (CCl4 20 (CCl 2

RESUMO Contexto: Este manuscrito fornece uma visão geral da carcinogênese hepática em modelos murinos de carcinoma hepatocelular (CHC) e colangiocarcinoma (CCA). Objetivo: Realizar uma revisão de artigos científicos até agosto de 2022 utilizando as bases de dados MEDLINE e EMBASE. Métodos: A busca foi realizada em todas as bases de dados eletrônicas e as palavras-chave usadas foram CHC, CCA, carcinogenesis, modelos animais e fígado. A exclusão dos artigos baseou-se na falta de estreita relação com o assunto. Os modelos de carcinogênese do CHC incluíram: CHC induzido por senescência em animais transgênicos, CHC induzido por dieta, CHC induzido por agentes quimiotóxicos, xenoenxerto, oncogenes e CHC em animais transgênicos inoculados com vírus B e C. Os modelos de CCA incluíram: o uso de dimetilnitrosamina (DMN), dietilnitrosamina (DEN), tioacetamida (TAA) e tetracloreto de carbono (CCl4). Os modelos murinos de CCA induzidos por incluir: células de CCA, manipulação genética, animais nocaute para Smad4, PTEN e p53, xenoenxerto e ligadura do ducto biliar mediano esquerdo. Resultados: Nesta revisão, descrevemos diferentes modelos murinos de carcinogênese que reproduzem os pontos-chave para a gênese do CHC e do CCA, permitindo uma melhor compreensão de suas anormalidades genéticas, fisiopatológicas e ambientais. Conclusão: Cada modelo tem suas vantagens, desvantagens, semelhanças e diferenças com a doença humana correspondente e deve ser escolhido de acordo com a especificidade do estudo. Em última análise, esses modelos também podem ser utilizados para testar novas abordagens terapêuticas anticancerígenas. Contexto (CHC CCA. . (CCA) Objetivo 202 EMBASE Métodos palavraschave palavras chave carcinogenesis fígado baseouse baseou se assunto incluíram dieta quimiotóxicos C DMN, DMN , (DMN) DEN, DEN (DEN) TAA (TAA CCl4. CCl4 CCl (CCl4) incluir genética Smad4 Smad p53 p esquerdo Resultados pontoschave pontos genéticas ambientais Conclusão vantagens desvantagens estudo análise anticancerígenas (CCA 20 (DMN (DEN (CCl4 p5 2 (CCl

ABSTRACT Objective: To explain the rationale and protocol of the methods and analyses to be used in the LIVER-PAM randomized clinical trial, which seeks to understand whether a higher mean arterial pressure is capable of reducing the incidence of renal dysfunction postoperatively after liver transplantation. Methods: LIVER-PAM is an open-label, randomized, controlled, singlecenter clinical trial. Patients randomized to the intervention group will have a mean arterial pressure of 85 - 90mmHg in the initial 24 hours of postoperative management, while patients in the control group will have a mean arterial pressure of 65 - 70mmHg in the same period. A sample of 174 patients will be required to demonstrate a 20% reduction in the absolute incidence of renal dysfunction, with a power of 80% and an alpha of 0.05. Conclusion: If a 20% reduction in the absolute incidence of renal dysfunction in the postoperative period of liver transplantation is achieved with higher target mean arterial pressure in the first 24 hours, this would represent an inexpensive and simple therapy for improving current outcomes in the management of liver transplant patients. ClinicalTrials.gov Registry:NCT05068713 Objective LIVERPAM LIVER PAM trial Methods openlabel, openlabel open label, label open-label controlled 8 mmHg 2 6 17 20 80 005 0 05 0.05 Conclusion ClinicalTrialsgov ClinicalTrials gov RegistryNCT05068713 RegistryNCT Registry NCT05068713 NCT Registry:NCT0506871 1 00 0.0 RegistryNCT0506871 NCT0506871 Registry:NCT050687 0. RegistryNCT050687 NCT050687 Registry:NCT05068 RegistryNCT05068 NCT05068 Registry:NCT0506 RegistryNCT0506 NCT0506 Registry:NCT050 RegistryNCT050 NCT050 Registry:NCT05 RegistryNCT05 NCT05 Registry:NCT0 RegistryNCT0 NCT0 Registry:NCT

RESUMO Objetivo: Explicitar o racional e o protocolo de métodos e análises a serem utilizadas no ensaio clínico randomizado LIVER-PAM, que busca entender se um nível mais alto de pressão arterial média é capaz de reduzir a incidência de disfunção renal no pós-operatório de transplante hepático. Métodos: O LIVER-PAM é um estudo clínico randomizado, controlado, unicêntrico e aberto. Pacientes randomizados para o grupo intervenção terão como alvo de pressão arterial média 85 - 90mmHg nas 24 horas iniciais do manejo pós-operatório, enquanto pacientes do grupo controle terão como alvo de pressão arterial média 65 - 70mmHg no mesmo período. Uma amostra de 174 pacientes será necessária para demonstrar redução de 20% na incidência absoluta de disfunção renal, com poder de 80% e alfa de 0,05. Conclusão: Se a redução de 20% da incidência absoluta de disfunção renal no pós-operatório de transplante hepático for obtida com alvos maiores de pressão arterial média nas primeiras 24 horas, o manejo do paciente nesse cenário encontraria uma terapia barata e simples para a melhoria dos desfechos atuais. Registro Cliniclatrials.gov:NCT05068713 Objetivo LIVERPAM, LIVERPAM LIVER PAM, PAM pósoperatório pós operatório Métodos controlado aberto 8 mmHg 2 pósoperatório, operatório, 6 período 17 20 80 005 0 05 0,05 Conclusão atuais Cliniclatrials.govNCT05068713 CliniclatrialsgovNCT05068713 CliniclatrialsgovNCT Cliniclatrials.gov NCT05068713 Cliniclatrials gov NCT Cliniclatrials.gov:NCT0506871 1 00 0,0 govNCT05068713 govNCT Cliniclatrials.govNCT0506871 CliniclatrialsgovNCT0506871 Cliniclatrialsgov NCT0506871 Cliniclatrials.gov:NCT050687 0, govNCT0506871 Cliniclatrials.govNCT050687 CliniclatrialsgovNCT050687 NCT050687 Cliniclatrials.gov:NCT05068 govNCT050687 Cliniclatrials.govNCT05068 CliniclatrialsgovNCT05068 NCT05068 Cliniclatrials.gov:NCT0506 govNCT05068 Cliniclatrials.govNCT0506 CliniclatrialsgovNCT0506 NCT0506 Cliniclatrials.gov:NCT050 govNCT0506 Cliniclatrials.govNCT050 CliniclatrialsgovNCT050 NCT050 Cliniclatrials.gov:NCT05 govNCT050 Cliniclatrials.govNCT05 CliniclatrialsgovNCT05 NCT05 Cliniclatrials.gov:NCT0 govNCT05 Cliniclatrials.govNCT0 CliniclatrialsgovNCT0 NCT0 Cliniclatrials.gov:NCT govNCT0 Cliniclatrials.govNCT

ABSTRACT BACKGROUND: After validation in multiple types of liver disease patients, the MELD score was adopted as a standard by which liver transplant candidates with end-stage liver disease were prioritized for organ allocation in the United States since 2002, and in Brazil, since 2006. AIMS: To analyze the mortality profile of patients on the liver transplant waiting list correlated to MELD score at the moment of transplantation. METHODS: This study used the data from the Secretary of Health of the São Paulo State, Brazil, which listed 22,522 patients, from 2006 (when MELD score was introduced in Brazil) until June 2009. Patients with acute hepatic failure and tumors were included as well. We also considered the mortality of both non-transplanted and transplanted patients as a function of the MELD score at presentation. RESULTS: Our model showed that the best MELD score for patients on the liver transplant waiting list associated to better results after liver transplantation was 26. CONCLUSIONS: We found that the best score for applying to liver transplant waiting list in the State of São Paulo was 26. This is the score that minimizes the mortality in both non-transplanted and liver transplanted patients. BACKGROUND endstage end stage 2002 Brazil AIMS METHODS 22522 22 522 22,52 200 when 2009 well nontransplanted non presentation RESULTS 26 CONCLUSIONS 2252 2 52 22,5 20 225 5 22,

RESUMO RACIONAL: Desde 2002, após validação em múltiplos tipos de hepatopatias, o escore MELD foi adotado como padrão pelo qual os candidatos a transplante de fígado com doença hepática terminal têm sido priorizados para alocação de órgãos nos Estados Unidos, e em 2006 no Brasil. OBJETIVOS: Analisar a mortalidade de pacientes em lista de espera para transplante de fígado correlacionando com o MELD, no momento do transplante. MÉTODOS: Foram utilizados os dados da Secretaria de Saúde do Estado de São Paulo, Brasil, onde foram listados 22.522 pacientes, desde 2006 (quando o escore MELD foi introduzido no Brasil) até junho de 2009. Foram incluídos pacientes com falência hepática e tumores. A mortalidade de pacientes não transplantados e transplantados também foi considerada em função do escore MELD. RESULTADOS: Nosso modelo mostrou que o melhor valor do MELD, em pacientes em lista de espera para transplante e com melhores resultados, foi de 26. Este valor minimiza mortalidade em pacientes não transplantados bem comem pacientes na lista de espera para transplante de fígado. CONCLUSÕES: O escore MELD ótimo para entrar na lista de espera para transplante de fígado, no estado de São Paulo, é em torno de 26. Esse é o valor que minimiza a mortalidade tanto dos pacientes não transplantados em lista de espera, quanto dos submetidos à transplante de fígado. RACIONAL 2002 hepatopatias Unidos 200 Brasil OBJETIVOS MÉTODOS Paulo 22522 22 522 22.52 quando 2009 tumores RESULTADOS resultados 26 CONCLUSÕES 20 2252 2 52 22.5 225 5 22.

ABSTRACT BACKGROUND: The main treatment modality for gastric cancer is surgical resection with lymphadenectomy. Despite advances in perioperative care, major surgical complications can occur in up to 20% of cases. To determine the quality of surgical care employed, a new indicator called failure to rescue (FTR) was proposed, which assesses the percentage of patients who die after complications occur. AIMS: To assess the rate of FTR after gastrectomy and factors associated with its occurrence. METHODS: Patients with gastric cancer who underwent gastrectomy with curative intent were retrospectively evaluated. According to the occurrence of postoperative complications, patients were divided into FTR group (grade V complications) and rescued group (grade III/IV complications). RESULTS: Among the 731 patients, 114 had major complications. Of these patients, 76 (66.7%) were successfully treated for the complication (rescued group), while 38 (33.3%) died (FTR group). Patients in the FTR group were older (p=0.008; p<0.05), had lower levels of hemoglobin (p=0.021; p<0.05) and albumin (p=0.002; p<0.05), and a higher frequency of ASA III/IV (p=0.033; p<0.05). There were no differences between the groups regarding surgical and pathological characteristics. Clinical complications had a higher mortality rate (40.0% vs 30.4%), with pulmonary complications (50.2%) and infections (46.2%) being the most lethal. Patients with major complications grade III/IV had worse survival than those without complications. CONCLUSIONS: The FTR rate was 33.3%. Advanced age, worse performance, and nutritional parameters were associated with FTR. BACKGROUND lymphadenectomy 20 cases employed proposed AIMS METHODS evaluated IIIIV III IV . RESULTS 73 11 7 66.7% 667 66 (66.7% group, , group) 3 33.3% 333 33 (33.3% group. p=0.008 p0008 p 0 008 (p=0.008 p<0.05, p005 p<0.05 05 p=0.021 p0021 021 (p=0.021 p=0.002 p0002 002 (p=0.002 p=0.033 p0033 033 (p=0.033 p<0.05. characteristics 40.0% 400 40 (40.0 30.4%, 304 30.4% 30 4 30.4%) 50.2% 502 50 2 (50.2% 46.2% 462 46 (46.2% lethal CONCLUSIONS age performance 1 66.7 6 (66.7 33.3 (33.3 p=0.00 p000 00 (p=0.00 p00 p<0.0 p=0.02 p002 02 (p=0.02 p=0.03 p003 03 (p=0.03 40.0 (40. 30.4 50.2 5 (50.2 46.2 (46.2 66. (66. 33. (33. p=0.0 (p=0.0 p0 p<0. 40. (40 30. 50. (50. 46. (46. (66 (33 p=0. (p=0. p<0 (4 (50 (46 (6 (3 p=0 (p=0 p< ( (5 p= (p= (p

RESUMO RACIONAL: A principal modalidade de tratamento do câncer gástrico (CG) é a ressecção cirúrgica associada a linfadenectomia. Apesar dos avanços no cuidado peri-operatório, as complicações cirúrgicas maiores podem ocorrer em até 20% dos casos. Para determinar a qualidade do atendimento cirúrgico empregado, foi proposto um novo indicador denominado failure to rescue (FTR), que avalia a porcentagem dos pacientes que vão a óbito após a ocorrência de complicações. OBJETIVOS: Avaliar a taxa de FTR após gastrectomia e fatores associados com a sua ocorrência. MÉTODOS: Foram avaliados retrospectivamente os pacientes com CG submetidos à gastrectomia com intenção curativa. De acordo com a ocorrência de complicações pós-operatórias, os pacientes foram divididos em grupo FTR (complicação grau V) e grupo resgatado (complicações grau 3-4). RESULTADOS: Entre os 731 pacientes, 114 tiveram maiores complicações. Desses pacientes, 76 casos (66,7%) obtiveram sucesso no tratamento da complicação (grupo resgatados), enquanto 38 casos (33,3%) foram a óbito (grupo FTR). Os pacientes do grupo FTR apresentaram idade mais avançada (p=0,008, p<0,05), menores níveis de hemoglobina (p=0,021, p<0,05) e de albumina (p=0,002, p<0,05), e maior frequência de ASA III/IV (p=0,033, p<0,05). Não houve diferença entre os grupos quanto às características cirúrgicas e patológicas. As complicações clínicas apresentaram maior taxa de mortalidade (40.0% vs 30,4%), sendo complicações pulmonares (50,2%) e infecções (46,2%) as mais letais. Pacientes com complicações maiores grau III-IV tiveram pior sobrevida comparado aqueles sem complicações. CONCLUSÕES: A taxa de FTR foi de 33,3%. Idade avançada, pior performance, e parâmetros nutricionais associam-se ao FTR. RACIONAL (CG linfadenectomia perioperatório, perioperatório peri operatório, operatório peri-operatório 20 empregado FTR, , (FTR) OBJETIVOS MÉTODOS curativa pósoperatórias, pósoperatórias pós operatórias, operatórias pós-operatórias V 34. 34 3 4 . 3-4) RESULTADOS 73 11 7 66,7% 667 66 (66,7% resgatados, resgatados resgatados) 33,3% 333 33 (33,3% FTR) p=0,008, p0008 p 0 008 (p=0,008 p<0,05, p005 p<0,05 05 p=0,021, p0021 021 (p=0,021 p=0,002, p0002 002 (p=0,002 IIIIV III IV p=0,033, p0033 033 (p=0,033 p<0,05. patológicas 40.0% 400 40 (40.0 30,4%, 304 30,4% 30 30,4%) 50,2% 502 50 2 (50,2% 46,2% 462 46 (46,2% letais CONCLUSÕES performance associamse associam se (FTR 3-4 1 66,7 6 (66,7 33,3 (33,3 p=0,008 p000 00 (p=0,00 p00 p<0,0 p=0,021 p002 02 (p=0,02 p=0,002 p=0,033 p003 03 (p=0,03 40.0 (40. 30,4 50,2 5 (50,2 46,2 (46,2 3- 66, (66, 33, (33, p=0,00 (p=0,0 p0 p<0, p=0,02 p=0,03 40. (40 30, 50, (50, 46, (46, (66 (33 p=0,0 (p=0, p<0 (4 (50 (46 (6 (3 p=0, (p=0 p< ( (5 p=0 (p= p= (p

ABSTRACT BACKGROUND: Patients with clinical stage IV gastric cancer may require palliative procedures to manage complications such as obstruction. However, there is no consensus on whether performing palliative gastrectomy compared to gastric bypass brings benefits in terms of survival. AIMS: To compare the overall survival of patients with distal obstructive gastric cancer undergoing palliative surgical treatment, using propensity score matching analysis. METHODS: Patients who underwent palliative bypass surgery (gastrojejunostomy or partitioning) and resection between the years 2009 and 2023 were retrospectively selected. Initial and postoperative clinicopathological variables were collected. RESULTS: 150 patients were initially included. The derived group (n=91) presented more locally invasive disease (p<0.01), greater degree of obstruction (p<0.01), and worse clinical status (p<0.01), while the resected ones (n= 59) presented more distant metastasis (p<0.01). After matching, 35 patients remained in each group. There was no difference in the incidence of postoperative complications, but the derived group had higher 90-day mortality (p<0.01). Overall survival was 16.9 and 4.5 months for the resected and derived groups, respectively (p<0.01). After multivariate analysis, hypoalbuminemia (hazard ratio — HR=2.02, 95% confidence interval — 95%CI 1.17–3.48; p=0.01), absence of adjuvant chemotherapy (HR=5.97; 95%CI 3.03–11.7; p<0.01), and gastric bypass (HR=3,28; 95%CI 1.8–5.95; p<0.01) were associated with worse survival. CONCLUSIONS: Palliative gastrectomy was associated with greater survival and lower postoperative morbidity compared to gastric bypass. This may be due to better local control of the disease, with lower risks of complications and better effectiveness of chemotherapy. BACKGROUND However AIMS treatment analysis METHODS gastrojejunostomy partitioning 200 202 selected collected RESULTS 15 included n=91 n91 n 91 (n=91 p<0.01, p001 p p<0.01 , 0 01 (p<0.01) n= (n 59 p<0.01. . 3 90day day 90 169 16 9 16. 45 4 5 4. groups hazard HR202 HR 2 02 HR=2.02 95 95CI CI 1.17–3.48 117348 1 17 48 p=0.01, p=0.01 p=0.01) HR=5.97 HR597 97 (HR=5.97 3.03–11.7 303117 03 11 7 HR=3,28 HR328 28 (HR=3,28 1.8–5.95 18595 8 CONCLUSIONS 20 n=9 n9 (n=9 p00 p<0.0 (p<0.01 HR20 HR=2.0 1.17–3.4 11734 p=0.0 HR=5.9 HR59 (HR=5.9 3.03–11. 30311 HR=3,2 HR32 (HR=3,2 1.8–5.9 1859 p0 p<0. (p<0.0 HR2 HR=2. 1.17–3. 1173 p=0. HR=5. HR5 (HR=5. 3.03–11 3031 HR=3, HR3 (HR=3, 1.8–5. 185 p<0 (p<0. HR=2 1.17–3 117 p=0 HR=5 (HR=5 3.03–1 303 HR=3 (HR=3 1.8–5 18 p< (p<0 HR= 1.17– p= (HR= 3.03– 30 1.8– (p< 1.17 (HR 3.03 1.8 (p 1.1 3.0 1. 3.

RESUMO RACIONAL: Pacientes com câncer gástrico estádio clínico IV podem necessitar de procedimentos paliativos para o manejo de complicações como a obstrução. Contudo, não há consenso se a realização de gastrectomia paliativa em comparação à derivação gástrica traz benefícios em termos de sobrevida. OBJETIVOS: Comparar a sobrevida global de pacientes com câncer gástrico obstrutivo distal submetidos a tratamento cirúrgico paliativo, empregando a análise com pareamento por escore de propensão. MÉTODOS: Foram selecionados retrospectivamente pacientes submetidos à cirurgia paliativa de derivação (gastrojejunostomia ou partição) e ressecção entre os anos de 2009 e 2023. Variáveis clínico-patológicas iniciais e pós-operatórias foram coletadas. RESULTADOS: Foram inicialmente incluídos 150 pacientes. O grupo derivado (n=91) apresentou mais doença localmente invasiva (p<0,01), maior garu de obstrução (p<0,01) e pior status clínico (p<0,01), enquanto os gastrectomizados (n=59) mais metástase à distância (p<0,01). Após o pareamento, restaram 35 pacientes em cada grupo. Não houve diferença na incidência de complicações pós-operatórias, mas o grupo derivado apresentou maior mortalidade em 90 dias (p<0,01). A sobrevida global foi de 16,9 e 4,5 meses para o grupo ressecado e derivado, respectivamente (p<0,01). Após análise multivariada, hipoalbuminemia (HR=2,02; IC95% 1,17–3,48; p=0,01), ausência de quimioterapia adjuvante (HR=5,97; IC95% 3,03–11,7; p<0,01) e bypass gástrico (HR =3,28; IC95% 1,8–5,95; p<0,01) foram associados a pior sobrevida. CONCLUSÕES: A gastrectomia paliativa esteve associada a maior sobrevida e menor morbidade pós-operatória quando comparada à derivação gástrica. Isto pode se dever a um melhor controle local da doença, com menores riscos de complicações e melhor efetividade da quimioterapia. RACIONAL Contudo OBJETIVOS paliativo propensão MÉTODOS gastrojejunostomia partição 200 2023 clínicopatológicas patológicas pósoperatórias pós operatórias coletadas RESULTADOS 15 n=91 n91 n 91 (n=91 p<0,01, p001 p p<0,01 , 0 01 (p<0,01 n=59 n59 59 (n=59 p<0,01. . 3 pósoperatórias, operatórias, 9 169 16 16, 45 4 5 4, multivariada HR=2,02 HR202 HR 2 02 (HR=2,02 IC95 IC 1,17–3,48 117348 1 17 48 p=0,01, p=0,01 p=0,01) HR=5,97 HR597 97 (HR=5,97 3,03–11,7 303117 03 11 7 =3,28 328 28 1,8–5,95 18595 8 95 CONCLUSÕES pósoperatória operatória 20 202 n=9 n9 (n=9 p00 p<0,0 (p<0,0 n=5 n5 (n=5 HR=2,0 HR20 (HR=2,0 IC9 1,17–3,4 11734 p=0,0 HR=5,9 HR59 (HR=5,9 3,03–11, 30311 =3,2 32 1,8–5,9 1859 n= (n= p0 p<0, (p<0, HR=2, HR2 (HR=2, 1,17–3, 1173 p=0, HR=5, HR5 (HR=5, 3,03–11 3031 =3, 1,8–5, 185 (n p<0 (p<0 HR=2 (HR=2 1,17–3 117 p=0 HR=5 (HR=5 3,03–1 303 =3 1,8–5 18 p< (p< HR= (HR= 1,17– p= 3,03– 30 = 1,8– (p 1,17 3,03 1,8 1,1 3,0 1, 3,

RESUMO Relatamos o caso de um homem de 68 anos, com cirrose hepática de etiologia alcoólica, diagnosticado com carcinoma hepatocelular (CHC) não elegível para transplante hepático. Após imunoterapia com atezolizumabe associado ao bevacizumabe, ele foi submetido a um transplante hepático (TH) de doador vivo com sucesso, não mostrando evidencia de doença ou lesão no enxerto, mantendo-se clínica e radiologicamente estável 14 meses após a cirurgia. Esse é um relato de sucesso da combinação atezolizumabe mais bevacizumabe sendo usados como ponte para o TH em um paciente com CHC, mostrando um achado importante na terapia dos pacientes com tumores irresecáveis ao diagnóstico. 6 anos alcoólica CHC (CHC (TH enxerto mantendose mantendo se 1 cirurgia diagnóstico

ABSTRACT We report the case of a 68-year-old male with alcohol-related cirrhosis, diagnosed with hepatocellular carcinoma (HCC) not eligible for liver transplant. After immunotherapy with atezolizumab associated with bevacizumab, he underwent a successful living donor liver transplantation (LT), not showing disease evidence or graft injury, maintaining clinically and radiologically stable 14 months after surgery. This is a successful report of combined atezolizumab plus bevacizumab being used as a bridge to LT in a patient with HCC, showing an important finding in therapy in patients with unresectable tumors at diagnosis. 68yearold yearold 68 year old alcoholrelated alcohol related cirrhosis HCC (HCC transplant LT, , (LT) injury 1 surgery diagnosis 6 (LT

Abstract Objectives: To evaluate results of patients undergoing liver resection in a single center over the past two decades with a particular look at Colorectal Liver Metastasis (CRLM) and Hepatocellular Carcinoma (HCC). Method: Patients were divided into two eras, from 2000 to 2010 (Era 1) and 2011 to 2020 (Era 2). The most frequent diagnosis was CRLM and HCC, with 738 (52.4%) and 227 (16.1%) cases respectively. An evaluation of all liver resection cases and a subgroup analysis of both CRLM and HCC were performed. Preoperative and per operative variables and long-term outcomes were evaluated. Results: 1409 liver resections were performed. In Era 2 the authors observed higher BMI, more: minimally invasive surgeries, Pringle maneuvers, and minor liver resections; and less transfusion, less ICU necessity, and shorter length of hospital stay. Severe complications were observed in 14.7% of patients, and 90-day mortality was 4.2%. Morbidity and mortality between eras were not different. From 738 CRLM resections, in Era 2 there were significantly more patients submitted to neoadjuvant chemotherapy, bilateral metastases, and smaller sizes with significantly less transfusion, the necessity of ICU, and shorter length of hospital stay. More pedicle clamping, minimally invasive surgeries, and minor resections were also observed. From 227 HCC resections, in Era 2 significantly more minimally invasive surgeries, fewer transfusions, less necessity of ICU, and shorter length of hospital stay were observed. OS was not different between eras for CRLM and HCC. Conclusions: Surgical resection in a multidisciplinary environment remains the cornerstone for the curative treatment of primary and metastatic liver tumors.

Abstract Introduction: The increase in the incidence of pancreatic and biliary cancers has attracted the search for methods of early detection of diseases and biomarkers. The authors propose to analyze new findings on the association between microbiota and Pancreatic Ductal Adenocarcinoma (PDAC) or Cholangiocarcinoma (CCA). Methods: This systematic review was carried out according to the items of Preferred Reports for Systematic Reviews and Protocol Meta-Analysis (PRISMA-P). This study was registered by the Prospective Register of Systematic Reviews (PROSPERO), identification code CRD42020192748 before the review was carried out. Articles were selected from the PUBMED, EMBASE, and Cochrane databases. Results: Most studies (86.67%) used 16s rRNA as a sequencing method. The main comorbidities found were diabetes mellitus, systemic arterial hypertension, and dyslipidemia. Many studies were limited by the small number of participants, but the biases were mostly low. There was very little concordance about the composition of the microbiome of different sites, for both case and control groups when compared to other studies’ results. Bile sample analysis was the one with a greater agreement between studies, as three out of four studies found Escherichia in cases of CCA. Conclusion: There was great disagreement in the characterization of both the microbiota of cases and control groups. Studies are still scarce, making it difficult to adequately assess the data in this regard. It was not possible to specify any marker or to associate any genus of microbiota bacteria with PDAC or CCA.

ABSTRACT Introduction: Portal hypertension still represents an important health problem worldwide. In the search for knowledge regarding this syndrome, experimental studies with animal models have proven to be useful to point the direction to be taken in future randomized clinical trials. Purpose: To validate the experimental model of portal hypertension and esophagogastric varices in a medium-sized animal. Methods: This study included five minipigs br1. Midline laparotomy with dissection of the portal vein and production of a calibrated stenosis of this vein was performed. Measurement of pressure in the portal venous and digestive endoscopic were performed before and five weeks after the production of a stenosis. Results: All animals were 8 months old, average weight of 17 ± 2.5 kg. The mean pressure of the portal vein immediately before the partial ligation of the portal vein was 8.9 + 1.6 mm Hg, with 26.6 + 5.4 mm Hg in the second measurement five weeks later (p < 0.05). No gastroesophageal varices or hypertensive portal gastropathy were seen at endoscopy procedures in our sample at any time in the study. Conclusion: Portal vein ligation in minipigs has been validated in the production of portal hypertension, but not in the formation of esophageal varices.

ABSTRACT Ischemia-reperfusion injury is a pathophysiological event occuring after abdominal organ transplantation, and has a significant influence on prognosis and survival of the graft. It is involved in delaying the primary function or non-functioning of the graft. The objective of this study was to provide information on heat shock protein mechanisms in ischemia-reperfusion injuries in abdominal organ transplantations, and to indicate the possible factors involved that may influence the graft outcome. Several classes of heat shock proteins are part of the ischemia and reperfusion process, both as inflammatory agonists and in protecting the process. Studies involving heat shock proteins enhance knowledge on ischemia-reperfusion injury mitigation processes and the mechanisms involved in the survival of abdominal grafts, and open space to support therapeutic future clinical studies, minimizing ischemia and reperfusion injuries in abdominal organ transplantations. Expression of heat shock proteins is associated with inflammatory manifestations and ischemia-reperfusion injuries in abdominal organ transplantations and may influence graft outcomes.

RESUMO - RACIONAL: O câncer colorretal é a terceira neoplasia mais frequente e metade dos pacientes desenvolvem metástase hepática. O melhor fator prognóstico na metástase hepática de câncer colorretal (MHCCR) é a possibilidade de ressecção com margens livres, porém a maioria permanece irressecável. O racional em realizar transplante hepático (TH) em pacientes portadores de MHCCR está na ampliação do número de pacientes ressecáveis através de uma hepatectomia total. OBJETIVO: Apresentar protocolo brasileiro para realização de transplante hepático em pacientes com MHCCR irressecável. MÉTODO: O protocolo foi realizado por duas instituições com grande volume de ressecções e transplantes hepáticos no Brasil, baseado no trabalho realizado pela Universidade de Oslo. A elaboração foi dividida em 4 etapas. RESULTADO: É apresentada proposta de protocolo para esta doença a ser validada na aplicação clínica. CONCLUSÃO: Foi possível elaborar protocolo de transplante hepático para MHCCR irressecável a fim de uniformizar o tratamento e melhor avaliar os resultados cirúrgicos.

ABSTRACT - BACKGROUND: Colorectal cancer (CRC) is the third most common neoplasm, and half of the patients with CRC develop liver metastasis. The best prognostic factor for colorectal liver metastasis (CRLM) is the possibility of performing a resection with free margins; however, most of them remain unresectable. The justification for performing liver transplantation (LT) in patients with CRLM regards an increase in the number of resectable patients by performing total hepatectomy. AIM: The aim of this study was to provide a Brazilian protocol for LT in patients with unresectable CRLM. METHOD: The protocol was carried out by two Brazilian institutions, which perform a large volume of resections and LTs, based on the study carried out at the University of Oslo. The elaboration of the protocol was conducted in four stages. RESULT: A protocol proposal for this disease is presented, which needs to be validated for clinical use. CONCLUSION: The development of an LT protocol for unresectable CRLM aims to standardize the treatment and to enable a better evaluation of surgical results.

RESUMO Racional: O colangiocarcinoma hilar representa mais da metade de todos os casos de colangiocarcinoma; tem prognóstico reservado e sobrevida global mediana de 12- 24 meses após o diagnóstico. A proposta de realizar transplante hepático surgiu para ampliar a possibilidade de margens livres através de hepatectomia total nos portadores de tumoresirressecáveis com melhor prognóstico. Objetivo: Apresentar protocolo brasileiro para realização de transplante hepático em pacientes com colangiocarcinoma hilar. Método: O protocolo foi realizado por duas instituições com grande volume de ressecções e transplantes hepáticos no Brasil, baseado no trabalho realizado pela MayoClinic. A elaboração foi dividida em quatro etapas. Resultado: É apresentada proposta de protocolo para esta doença a ser validada na aplicação clínica. Conclusão: Foi possível elaborar protocolo de transplante hepático para colangiocarcinoma a fim de uniformizar o tratamento e melhor avaliar os resultados cirúrgicos.

ABSTRACT Background: Hilar cholangiocarcinoma represents more than half of all cholangiocarcinoma cases, having poor prognosis and presenting a median overall survival after diagnosis of 12-24 months. In patients who have unresectable tumors with a better prognosis, the proposal to perform liver transplantation emerged for expanding the possibility of free margins by performing total hepatectomy. Aim: To provide a Brazilian protocol for liver transplantation in patients with hilar cholangiocarcinoma. Method: The protocol was carried out by two Brazilian institutions which perform a large volume of resections and liver transplantations, based on the study carried out at the Mayo Clinic. The elaboration of the protocol was conducted in four stages. Result: A protocol proposal for this disease is presented, which needs to be validated for clinical use. Conclusion: The development of a liver transplantation protocol for cholangiocarcinoma aims not only to standardize the treatment, but also enable a better assessment of the surgical results in the future.