Introdução: Pacientes com doença inflamatória intestinal (DII) tem risco aumentado de desenvolvimento de displasias e neoplasias colônicas, a partir de 8 anos de diagnóstico da doença. O desenvolvimento de técnicas que melhorem a acurácia diagnostica destas displasias tem impacto científico, econômico e na prática clínica. Materiais and Métodos: O NBI (narrow band image) tem sido descrito como um método comparável à cromoscopia para a detecção de diversos tipos de cânceres do trato gastrointestinal superior e do sistema respiratório. Neste estudo, as duas técnicas foram comparadas em pacientes com DII de longa data. Resultados: 34 pacientes foram randomizados (18 para a cromoscopia e 16 para o NBI). 66,7% e 68,8% dos pacientes eram do gênero feminino, com média de idade de 48,5 e 49,6 anos, nos grupos cromoscopia e NBI, respectivamente. 61,1% dos pacientes do grupo cromoscopia e 56,2% do grupo NBI tinham doença de Crohn (DC). Nenhuma destas variáveis alcançou diferença estatísticamente significante na comparação entre os grupos: comportamento da DC, localização da retocolite ulcerativa, presença de atividade inflamatória endoscópica e sintomas no momento do exame. O tempo médio gasto para a realização do exame foi de 45,8 minutos no grupo cromoscopia e de 34,1 minutos no grupo NBI. Sobre a presença de displasias, 22,2% dos pacientes no grupo cromoscopia apresentaram lesões displásicas no exame histológico (todas as biopsias foram direcionadas pela presença de lesões), enquanto que, no grupo NBI, nenhuma lesão displásica foi encontrada (qui-quadrado= 4,477; ∑crítico> 3,841, considerando um erro a de 5%). Foram encontrados três lesões adenomatosas e uma lesão displásica tipo DALM (dysplasia-associated lesion or mass), típica da DII. Quando realizada a correção de Yattes, ara amostras pequenas, foi observado ∑ = 2,180 (∑crítico> 3,841, considerando um erro a de 5%). Conclusões: Esses dados mostram diferença estatística entre as técnicas endoscópicas (NBI e cromoscopia). Eles revelam uma forte tendência estatística de superioridade da cromoscopia, comparada ao NBI. / Introduction: Patients with inflammatory bowel disease (IBD) are under increased risk of colonic dysplasia and neoplasia, approximately, 8 years after diagnosis. The development of techniques that improve the diagnostic ability to detect those dysplasias has scientific, economic and practical impact. Materials and Methods: The NBI (narrow band image) has been described as a valuable method comparable to chromoendoscopy for the detection of many cancers of the upper digestive and respiratory systems. The two techniques were compared in this study in patients with IBD after at least 8 years from diagnosis. Results: 34 patients were randomized (18 for chromoendoscopy and 16 for NBI). 66.7% and 68.8% were female, mean age of 48.5 and 49.6 years, in chromoendoscopy and NBI groups, respectively. The mean disease duration was 14.7 (DP 6.5 years 2) and 15.6 years (DP 9.0 years 2) for chromoendoscopy and NBI, respectively. 61.1% of patients in the chromoendoscopy group and 56.2% in the NBI had Crohn\'s disease (CD). None of those epidemiological data, extension and behavior of CD and Ulcerative Colitis, use of medications, endoscopic grade of disease activity and symptoms at the time of the exam disclosed statistical significance. The average time of examination was 45.8 minutes for the chromoendoscopy group, versus 34.1 minutes for the NBI group. Regarding the presence of dysplasia, 22,2% of patients in the chromoendoscopy group showed some dysplastic lesions on histological examination (all biopsies directed to mucosal lesions), while no patients in the NBI group had such lesions (chi-square = 4.477; ∑critical> 3.841, considering an error of 5%). We found three adenomas and one dysplastic lesions of the type DALM (dysplasia-associated lesion or mass), typical of IBD. When we look at correcting by means of the Yates correction test for small samples, we observed ∑ = 2,180 (∑critical > 3.841, considering an error of 5%). Conclusion: Those data have shown statistical difference between the endoscopic techniques (NBI and chromoendoscopy). They revealed a strong statistical tendency of superiority of chromoendoscopy compared to NBI.

Introdução: O tratamento do câncer retal melhorou ao longo das décadas com aprimoramento e surgimento de novas terapêuticas resultando em maior sobrevida. Assim, os resultados e o impacto pós-tratamento sobre a QVRS são cada vez mais considerados e não só a ausência da doença. Objetivo: Avaliar a qualidade de vida imediata e tardia relacionada à saúde em pacientes tratados de câncer retal com intenção curativa. Método: Estudo descritivo-exploratório, com delineamento de coorte prospectivo, de caráter observacional para geração de hipóteses acerca da qualidade de vida de pacientes com câncer de reto. Conduzimos com aplicação de entrevista por questionário específico para dados demográficos; questionário estruturado EORTC QLQ-C30 e EORTC-CR38 para avaliação da QVRS aplicados no início do tratamento, três meses após a cirurgia e 12 meses após. A casuística foi composta de 58 pessoas, totalizando 29 pacientes puderam participar conforme critérios de inclusão e 12 que puderam responder os questionários após 12 meses. Os escores de cada paciente foram comparados - início, após 3 meses de intervenção e 12 meses com ou sem estoma. Os dados foram organizados em planilha Excel e análise dos dados realizada utilizando o software R (R-project) versão 3.1.2. Resultados: Após três meses houve piora da satisfação sexual, Problemas sexuais femininos e Perspectiva futura. Melhoram os Sintomas Gastrointestinais, problemas esfincterianos e perda de peso. Após 12 meses a Perspectiva futura deteriorou, porém houve melhora dos Problemas relacionados ao estoma, Problemas esfincterianos e Imagem Corporal. Conclusão: Apesar de toda complexidade do tratamento multidisciplinar do câncer de reto dentro de um serviço especializado, a qualidade de vida ficou preservada e foi satisfatória na maioria dos quesitos estudados / Introduction: The treatment of rectal cancer has improved over the decades with improvement and emergence of new therapies resulting in greater survival. Thus, the results and post-treatment impact on HRQoL are increasingly considered and not just the absence of the disease. Objective: To evaluate the immediate and late health-related quality of life in patients treated for rectal cancer with curative intent. Method: A descriptive-exploratory study, with a prospective cohort design, with an observational character to generate hypotheses about the quality of life of patients with rectal cancer. We conducted with questionnaire interview application specific to demographic data; structured questionnaire EORTC QLQ-C30 and EORTC-CR38 for the evaluation of HRQoL applied at the beginning of treatment, three months after surgery and 12 months after. The sample consisted of 58 people, totaling 29 patients who could participate according to inclusion criteria and 12 who could answer the questionnaires after 12 months. The scores of each patient were compared - beginning, after 3 months of intervention and 12 months with or without stoma. The data were organized in Excel spreadsheet and data analysis performed using software R (R-project) version 3.1.2. Results: After three months there was worsening of sexual satisfaction, Female sexual problems and Future perspective. Improve Gastrointestinal Symptoms, Sphincter Problems and Weight Loss. After 12 months, the future Perspective deteriorated, but there was improvement of the problems related to the stoma, Sphincter problems and Body Image. Conclusion: Despite the complexity of the multidisciplinary treatment of rectal cancer within a specialized service, the quality of life was preserved and was satisfactory in most of the studied questions

Introdução: Descrita em 1983 e de sólida aplicação clínica, o impacto da microcirurgia endoscópica transanal (TEM) sobre a função anorretal permanece pouco conhecido. Os objetivos do presente estudo foram avaliar o impacto da TEM na função anorretal conforme avaliações clínicas (Wexner score) e funcional (manometria anorretal) antes e após a cirurgia. Método: Prospectivamente, 23 pacientes consecutivos com lesões retais foram operados com o uso do equipamento TEO® (Karl Storz, Tuttlingen, Alemanha). Para todos os pacientes, o valor do escore de Wexner foi obtido antes e após a cirurgia (7, 30 e 90 dias), e a eletromanometria anorretal foi realizada antes da cirurgia e também no pós-operatório (30 e 90 dias). Resultados: Quatorze pacientes eram homens. A idade média foi 53,7 (24-81) anos. A distância média da lesão à linha pectínea foi de 7 (2-15) cm. A histopatologia revelou adenoma em 14 (61%), tumor neuroendócrino em 5 (21,7%), carcinoma invasivo em 3 (13%) e pólipo hiperplásico em 1 (4,3%) caso. A duração média do seguimento pós-operatório foi de 5 (3-7) meses. O escore de Wexner foi significativamente menor aos 30 dias em comparação com 7 dias (Wilcoxon, p = 0,03). A capacidade retal foi significativamente menor aos 30 dias após a cirurgia e recuperada aos 90 dias após a cirurgia (ANOVA, p = 0,04). Conclusões: Após TEM, um impacto modesto na função anorretal pode ser observado. O comprometimento transitório resulta de perda de capacidade retal e não por comprometimento dos esfíncteres anais cessando completamente 90 dias após a cirurgia. Em última análise, não conseguimos detectar um impacto na qualidade de vida após TEM / Background: The impact of transanal endoscopic microsurgery (TEM) on anorectal function remains poorly available, particularly when considering that the technique involves undertaking full- or partial-thickness excision of the rectal wall. Moreover, in spite of wide adoption of TEM, its impact on quality of life remains unknown since most evidence derives from retrospective studies. Objective: The objectives of the present study were to evaluate the impact of TEM on sphincter function determined by clinical (Wexner score), functional (anorectal manometry), and quality of life (FIQL) evaluations conducted before and after surgery. Design: prospective, observational, single-center, 23 consecutive patients with rectal lesions underwent were operated on using the TEO® equipment (Karl Storz, Tuttlingen, Germany). Wexner and FIQL scores were obtained before and after surgery (7 days, 30 days and 90 days postoperatively). Anorectal manometry was obtained before surgery, and postoperatively after 30 and 90 days. Main Outcome Measures: Wexner and FIQL scores; anorectal manometry results. Results: Fourteen patients were men. Mean age was 53.7 (24-81) yrs. Mean distance from the lesion to the dentate line was 7 (2-15) cm. A full- thickness resection was undertaken in 18 (78.3%) cases. Histopathology revealed adenoma in 14 (61%), neuroendocrine tumor in 5 (21.7%), invasive carcinoma in 3 (13%), and hyperplastic polyp in 1 (4.3%) case. Postoperative rectal wound separation occurred in 2 patients and 1 patient developed atrial fibrillation. The mean duration of postoperative follow-up was 5 (3-7) months. Overall, Wexner score significantly declined between postoperative days 7 and 30 (Wilcoxon, p = 0.03). Rectal compliance exhibited significant decline 30 days after surgery and recovery at 90 days after surgery (ANOVA, p = 0.04). It was not possible to measure any difference in the FIQL results before and after surgery. Limitations: small sample size; limited follow-up. Conclusions: Following TEM, a modest impact on anorectal function could be confirmed. Interestingly, anorectal function impairment after surgery was not due to sphincter dysfunction, but resulted from loss of rectal compliance. Ultimately, we could not detect a significant impact on quality of life after TEM

O butirato é um importante ácido graxo de cadeia curta proveniente da fermentação bacteriana de vários tipos de fibras no cólon. Diversos estudos têm demonstrado que o butirato desempenha um papel importante na prevenção do câncer e na manutenção da homeostase colônica, por meio da regulação da proliferação celular, diferenciação e apoptose. A acetilação das histonas tem sido proposta como um dos possíveis mecanismos de ação responsável pelo efeito quimiopreventivo do butirato. O objetivo desse trabalho foi avaliar o papel da tributirina (TB), um pró-fármaco do ácido butírico, na fase de pós-iniciação da carcinogênese de cólon induzida por dimetilhidrazina (DMH), enfatizando a expressão das histonas acetiladas (H3K9 e H4K16) e das proteínas pró e anti-apoptóticas da família Bcl-2 (Bak, Bcl-xL). Durante 5 semanas consecutivas, ratos Wistar receberam diariamente TB (200 mg/100 g peso corpóreo; grupo TB) ou maltodextrina (MD; 300 mg/100 g peso corpóreo; grupo MD; controle isocalórico). Focos de Criptas Aberrantes (FCAs) são lesões pré-neoplásicas e biomarcadores da carcinogênese de cólon. Esses foram analisados nos cólons corados com azul de metileno a 0,02%, porém, nenhuma diferença estatística foi encontrada entre os grupos, TB e MD (p>0,05). A mucosa colônica foi utilizada para analisar a expressão de H3K9 e H4K16 por western blot, contudo, não houve diferença significativa entre os grupos TB e MD. A expressão da proteína pró-apoptotica Bak também foi semelhante nos grupos TB e MD; todavia, a expressão da proteína anti-apoptótica Bcl-XL foi menor no cólon distai dos ratos tratados com TB sugerindo participação dessa na indução de apoptose. Portanto, apesar de trabalhos apontarem para os resultados benéficos do butirato, são necessários mais estudos in vivo para o melhor entendimento dos efeitos mediados pelo butirato na carcinogênese de cólon. / Butyrate is an important short-chain fatty acid, product of intestinal bacterial fermentation of mainly dietary fiber. Several studies have shown that butyrate has an important role in the maintenance of colonic homeostasis as regulator of colonocyte proliferation, differentiation and apoptosis. Thus may play a role in cancer prevention. Histone deacetylation has been proposed to be one of the possible mechanisms of action of butyrate mediated effects on colon carcinogenesis. The aim of this study was to evaluate the role of tributyrin (TB), a butyric acid pro-drug, on post-initiation phase of colon carcinogenesis induced by dimethylhydrazine (DMH), emphasizing the expression of acetylated histones (H3K9, H4K16) and BeI-2 family proteins (Bak, Bcl-XL) mediated apoptosis. During 5 consecutive weeks, Wistar rats received daily TB (200 mg/100 9 body weight; TB group) or maltodextrin (MD; 300 mg/100 9 body weight; MD group; isocaloric control). Aberrant Crypt Focus (ACFs) are considered pre-neoplastic cells and biomarker of colon carcinogenesis. ACFs were counted on colons stained with 0,02% methylene blue, under a light microscope. No statistic differences were found for ACF when compared both groups receiving TB or MD (p>0,05). Colonic mucosa scraping was used for analysis of H3K9 and H4K16 by Western Blot. No significant differences were demonstrated between TB and MD groups. Bak expression were similar between TB and MD groups, but Bcl-XL expression seems to be reduced only on distal colon of the TB group, suggesting that TB may induce apoptosis Although most studies point towards beneficial results of butyrate, more in vivo studies are needed to contribute to our current understanding of butyrate-mediated effects on colon carcinogenesis.

Avaliou-se a atividade quimiopreventiva da tributirina (TB), e da vitamina A (VA) administradas em associação ou não, antes, durante e após a iniciação em ratos submetidos a modelo de carcinogênese de cólon. Ratos Wistar receberam VA [1 mg/100 g de p.c (grupo VA)], tributirina [200 mg/100 g de p.c (grupo TB)] ou associação de VA com TB (grupo VA+TB). Ratos tratados com óleo de milho e maltodextrina serviram como controle (GC). Avaliou-se a presença de focos de criptas aberrantes (FCA) e sua localização nos cólons, além de danos e do padrão de metilação global do DNA na mucosa colônica. No cólon total, distal e proximal, o grupo TB apresentou menor (p<0,05) número de FCA com 4 ou mais criptas/cm2, considerados mais agressivos, em relação ao GC. Quanto aos danos no DNA, os grupos VA, TB e VA+TB apresentaram cometas de comprimentos menores (p<0,05) em comparação ao GC. Não houve diferenças estatisticamente significantes quanto ao padrão de metilação global do DNA. Assim, TB consiste em agente quimiopreventivo promissor da carcinogênese de cólon quando administrada isoladamente, mas não em associação com a VA. 15 / Chemopreventive activities of tributyrin (TB) and vitamin A (VA) were administered in combination or not, before, during and after the initiation in rats subjected to carcinogenesis model of colon. Wistar rats received VA [1 mg/100 g of b.w (group VA)], tributyrin [200 mg/100 g of b.w (TB group)] or association of VA with BD (group VA + TB). Rats treated with corn oil and maltodextrin were used as control (GC). The presence of aberrant foci crypts (ACF) was evaluated and their location in colon tissue was determined. In addition, DNA damages and the global pattern of DNA methylation in colonic cells was measured. In total colon as in distal and proximal portions, the TB group presented lower (p <0.05) number of ACF with 4 or more crypts/cm2 in comparison to the GC group. The number of ACF with 4 or more crypts /cm2 was used as criteria of aggressiveness. In relation to the damage of DNA, the VA, VA + TB and TB groups exhibits smaller nucleoids lengths (p <0.05) compared to the GC group. There were no statistically significant differences on the global pattern of DNA methylation. So TB is promising chemopreventive agent in carcinogenesis of the colon when administered alone, but not in combination with the VA.

O objetivo do estudo foi estudar a expressão de timidilato sintase (TS) como fator preditivo para eficácia de quimioterapia adjuvante com 5-fluorouracil (5-FU) e como fator prognóstico para sobrevida em pacientes portadores de câncer colorretal. Trata-se de estudo retrospectivo em uma série de 114 pacientes com carcinoma colorretal estádios II ou III, distribuídos em dois grupos: 1)cirurgia exclusiva (n=61); 2)cirurgia seguida de quimioterapia com 5-FU (n=53). A expressão de TS foi determinada por imunoistoquímica. Observou-se que a expressão intratumoral de TS foi capaz de selecionar pacientes que se beneficiaram com emprego de quimioterapia adjuvante, mas não se mostrou como variável independente para risco de recidiva ou óbito / The purpose of this study was trying to assess the value of TS expression as a predictive factor in the efficacy of adjuvant chemotherapy in colorectal cancer, as well as its independent prognostic value for survival. It deals with a retrospective study that assesses a series of 114 individuals with high risk colorectal cancer, distributed into two different groups: 1)surgery alone (n=61); 2)surgery and 5-FU-based chemotherapy (n=53). TS expression was determined by immunohistochemistry. We observed that TS expression may select patients that benefit from adjuvant chemotherapy, but it was not shown as an independent variable for the risk of recurrence or death

Infusões prolongadas de 5-fluorouracil são mais seguras e potencialmente mais efetivas no tratamento do câncer de cólon metastático do que infusões rápidas da mesma medicação. No entanto, infusões prolongadas requerem a disponibilidade de um acesso venoso central, bem como de bombas de infusão dispendiosas. O desenvolvimento de fluoropirimidinas orais permitiu que pacientes fossem expostos ao 5-fluorouracil por longo tempo, com maior conveniência. UFT e leucovorin administrados três vezes ao dia demonstraram previamente uma eficácia equivalente, com menor toxicidade, quando comparados a um regime convencional de infusão rápida de 5- fluorouracil e leucovorin. Este estudo com 98 pacientes foi desenhado e conduzido com objetivo de demonstrar equivalência no tempo de progressão com o uso de UFT e leucovorin administrados duas vezes ao dia, com o uso da mesma combinação administrada três vezes ao dia. Objetivos secundários incluíram análise de toxicidade, resposta objetiva e sobrevida global. O tempo mediano de progressão foi de 3,8 meses, comparado com 3,5 meses observados com o uso da medicação três vezes ao dia e a taxa de resposta foi de 11%, com uma sobrevida mediana de 12,8 meses, sendo comparável aos resultados de 12% e 12,4 meses obtidas com o uso da combinação três vezes ao dia. A incidência de diarréia com graus 3 e 4 foi de 30% no regime de administração duas vezes ao dia, e 21% no de três vezes ao dia. Esses resultados sugerem que o uso de UFT e leucovorin duas vezes ao dia tem eficácia e toxicidade similares àquelas obtidas com o uso da mesma medicação três vezes ao dia. / Prolonged infusions have been shown to be safer and potentially more effective than bolus regimens of 5- fluorouracil as treatment for advanced colorectal cancer. However, infusional 5- fluorouracil requires central venous access and costly infusion pumps. Development of oral fluoropyrimidines has allowed longer exposures to 5-fluorouracil with increased convenience. UFT and leucovorin given thrice daily showed improved safety and no significant difference in survival or response rate compared with bolus 5- fluorouracil and leucovorin. This study with 98 patients was conducted to evaluate whether UFT and leucovorin given twice daily provided comparable time to progression (TTP) to the same combination administered three times a day. Secondary objectives included evaluation of toxicity, overall tumor response rate, and survival. Median time to progression was 3.8 months, compared with 3.5 months observed with the thrice-daily regimen. The twice-daily regimen had a response rate of 11% and median survival of 12.8 months, comparable to the 12% and 12.4 months seen with the thrice-daily regimen. The incidence of grade 3-4 drug-related diarrhea was 30% on the twice-daily and 21% on the thrice-daily schedule. Results suggest that the twice-daily schedule has similar safety and efficacy to the thrice-daily schedule.

The DNA damage response (DDR) pathway is a complicated network of interacting proteins that function to sense and remove DNA damage. Upon exposure to DNA damage, a signaling cascade is generated. The damage is either removed, restoring the original genetic sequence, or apoptosis is activated. In the absence of DDR, cells are unable to effectively process DNA damage. Unprocessed DNA damage can lead to chromosomal changes, gene mutations, and malignant transformation. Thus, the proteins involved in DDR are critical for maintaining genomic stability. One essential DDR protein is the BRCA1 Associated C-terminal Helicase, BACH1. BACH1 was initially identified through its direct association with the BRCT domain of the Breast Cancer Associated Gene, BRCA1. Similar to BRCA1, germline mutations in BACH1were identified in patients with early onset breast cancer. Interestingly, the disease-associated mutations in BACH1 were shown to have altered helicase activity in vitro, providing a direct link between BACH1 helicase activity and disease development. The correlation between BACH1 and cancer predisposition was further confirmed by the identification of BACH1 as the cancer syndrome Fanconi anemia (FA) gene product, FANCJ. Similar to other FA proteins, suppression of FANCJ leads to decreased homologous recombination, enhanced sensitivity to DNA interstrand crosslinking (ICL) agents, and chromosomal instability. In an effort to further understand the function of FANCJ in DDR, FANCJ was shown to directly associate with the mismatch repair (MMR) protein MLH1. This interaction is facilitated by lysines 141 and 142 within the helicase domain of FANCJ. Importantly, the FANCJ/MLH1 interaction is critical for ICL repair. Furthermore, in an attempt to dissect the binding site of FANCJ on MLH1, we discovered an HNPCC associated MLH1 mutation (L607H) that has intact mismatch repair, but lacks FANCJ interaction. In contrast to the MLH1 interaction, the FANCJ/BRCA1 interaction was not required for correcting the cellular defects in FANCJ null cells. Thus, in an effort to understand the functional significance of the FANCJ/BRCA1 interaction, we discovered that FANCJ promotes Pol η dependent translesion synthesis (TLS) bypass when uncoupled from BRCA1. In this thesis, we provide evidence suggesting that FANCJ and MLH1 are functionally linked and that the interaction of these proteins is critical for repair choice.

<p>Tumorsko pupljenje (TP) u karcinomu je morfolo&scaron;ki fenomen koji predstavlja pojavu pojedinačnih ili malih grupa dediferentovanih tumorskih ćelija koje se na invazivnom frontu karcinoma odvajaju od glavne tumorske mase. Kod metastatskog kolorektalnog karcinoma (KRK) definitivno ne možemo odrediti pravi doprinos TP. Cilj je bio da se ispita terapijski patohistolo&scaron;ki odgovor na primenjeni hemioterapijski režim, prognostički i nezavisni negativni značaj TP , kao i korelacija TP i terapijskog odgovora histolo&scaron;ke regresije kod R0 reseciranih sinhronih i metahronih jetrenih metastaza KRK, koji su primali polihemioterapije po protokolu Folfox 4, sa i bez VEGF inhibitora &ndash; bevacizumaba (AV).&nbsp; Studija je prospektivno &ndash; retrospektivna i obuhvata 77 bolesnika oba pola, uzrasta preko 18 godina, sa patohistolo&scaron;ki verifikovanim jetrenim metastazama KRK, koji su operisani u Institutu za onkologiju Vojvodine u periodu od 1. maja 2007. do 1. juna 2017. godine. Od ukupno 120 bolesnika, njih 77 je ispunjavalo sledeće kriterijume: da je histolo&scaron;ki dokazan metastatski adenokarcinom kolorektuma sa R0 resekcijom i da su preoperativno dobijali HT sa biolo&scaron;kom terapijom ili bez nje. Bolesnike smo podelili u dve grupe: KRK &ndash; sinhrona metastatska bolest i KRK &ndash; metahrona metastatska bolest. Nakon selekcije bolesnika, rađena je mikroskopska analiza rutinskih histolo&scaron;kih i imunohistohemijskih preparata i određivana je gustina TP, histolo&scaron;ka regresija prema mTRG bodovanju komparirala se sa radiolo&scaron;kim odgovorom po RECIST-u. Događaji od interesa u kliničkom toku bolesti jesu progresija nakon hirur&scaron;kog zahvata jetrenih metastaza i ukupno preživljavanje u periodu od 24 meseca. Nema statistički značajne patohistolo&scaron;ke razlike u učestalosti lo&scaron;ijeg terapijskog odgovora (mTRG 3 &ndash; 5) u odnosu na bolji terapijski odgovor (mTRG 1, 2) između bolesnika sa sinhronom i metahronom metastatskom bole&scaron;ću KRK, koji su lečeni hemioterapijskim protokolom Folfox4: 13 (76,5%) vs. 13 (72,2%); p = 0,774. Kod bolesnika sa sinhronim metastazama KRK, lečenih hemioterapijskim protokolom Folfox 4, postoji statistički značajna razlika u učestalosti preživljavanja tokom dve godine, i to kod bolesnika sa malom u odnosu na one sa velikom gustinom TP: 10 (90,9%) vs. 5 (55,6%); p = 0,049. Kod tih bolesnika, lečenih hemioterapijskim protokolom Folfox4/AV, postoji statistički značajna razlika u učestalosti preživljavanja tokom dve godine, i to kod bolesnika sa malom u odnosu na one sa velikom gustinom TP: 9 (100%) vs. 6 (33,3%); p = 0,048. Kod bolesnika sa metahronim metastazama KRK lečenih hemioterapijskim protokolom Folfox4, sa i bez AV, nema statistički značajne razlike u učestalosti preživljavanja tokom dve godine u odnosu na gustinu TP. Kod bolesnika sa sinhronim i metahronim metastazama KRK nema statistički značajne razlike u učestalosti lo&scaron;ijeg histolo&scaron;kog odgovora na terapiju (mTRG 3 &ndash; 5) kod onih sa malom u odnosu na one sa velikom gustinom (TP): (8 (50%) vs. 15 (78,9%); p = 0,072 i TP: 8 (80%) vs. 13 (72,2%); p = 0,649). Kod bolesnika sa sinhronim metastazama KRK lečenih hemioterapijskim protokolom Folfox4, sa i bez AV, postoji statistički značajna razlika u učestalosti preživljavanja tokom dve godine u odnosu na gustinu TP. Takođe, kod tih bolesnika velika gustina TP je nezavistan negativan faktor prognoze u odnosu na date terapijske režime, &scaron;to se vidi u preživljavanju tokom dve godine.</p> / <p>Tumor budding (TB) in cancer is a morphological phenomenon representing the appearance of single or small groups of dedifferentiated tumor cells that separate from the main tumor mass on the invasive front of cancer. In metastatic colorectal cancer (MCC), the true contribution of TB cannot be determined. The aim was to investigate the therapeutic pathohistological response to the applied chemotherapy, the prognostic and independent negative significance of TB, as well as the correlation of TB and the therapeutic response of histological regression in R0 resectable synchronous and metachronous liver metastases of MCC receiving polychemotherapy according to the Folfox 4 protocol, with and without VEGF inhibitors - bevacizumab (AV). The research was conducted as a prospective &ndash; retrospective study that included 77 patients of both sex, over 18 years of age, with pathohistologically verified MCC liver metastases, who underwent surgery at the Institute of Oncology of Vojvodina from 1st May 2007 until 1st June 2017. From 120 patients, 77 patients met the following criteria: they had histologically proven metastatic colorectal adenocarcinoma with R0 resection and also received preoperative chemotherapy with or without biological therapy. The patients were divided into two groups: MCC - synchronous metastatic disease and MCC - metachronous metastatic disease. After the patient selection, microscopic analysis of routine histological and immunohistochemical preparations was performed, the density of TB was determined, and the histological regression according to mTRG scoring was compared with a radiologic response according to the RECIST. The events of interest in the clinical course of the disease were the progression of hepatic metastases after surgery and overall survival during 24 months. There is no statistically significant pathohistological difference in the incidence of worse therapeutic response (mTRG 3 - 5) compared to the better therapeutic response (mTRG 1, 2) between patients with synchronous and metachronous MCC who were treated with the Folfox4 chemotherapy protocol: 13 (76.5%) vs. 13 (72.2%); p = 0.774. In patients with synchronous MCC metastases treated with the Folfox 4 chemotherapy protocol, there was a statistically significant difference in the survival rates during two years particularly in patients with low versus high TB density: 10 (90.9%) vs. 5 (55.6%); p = 0.049. In those patients who were treated with the Folfox4 / AV chemotherapy protocol, there was a statistically significant difference in survival rates during two years particularly in patients with low TB density in reference to those with high: 9 (100%) vs. 6 (33.3%); p = 0.048. In patients with metachronous MCC metastases who were treated with the Folfox4 chemotherapy protocol, with and without AV, there was no statistically significant difference in survival rate during two years when referring to the TB density. In patients with synchronous and metachronous metastases, MCC has no statistically significant difference in the incidence of worse histological response to therapy (mTRG 3 - 5) in patients with low TB density versus the ones with high density (TB): (8 (50%) vs. 15 (78.9%); p = 0.072 and TP: 8 (80%) vs. 13 (72.2%); p = 0.649). In patients with synchronous MCC metastases who were treated with the Folfox4 chemotherapy protocol, with and without AV, there is a statistically significant difference in survival rates during a two-year follow up when referring to the TB density. Also, the high density of TB is an independent negative prognostic factor in these patients in reference to the given therapeutic regimens, as seen in the two-year survival rate.</p>

This review summarizes the principles of cancer chemoprevention and discusses the evidence from epidemiologic and experimental studies and preclinical and clinical trials of potential colorectal chemopreventive agents. The putative mechanisms of action of the drugs in chemoprevention and their potential to reduce the incidence and mortality rate of colorectal neoplasms are discussed. The future of colorectal chemoprevention will depend on important new insights into molecular carcinogenesis of colorectal cancer, application of molecular markers as surrogate endpoints, and ultimately on therapeutic targets of prevention in clinical trials.