Osmar Kenji Yagi

Ectopic expression of homeodomain protein CDX2 in intestinal metaplasia and carcinomas of the stomach.

The roles of CDX2 and CDX1 homeobox genes during gastric carcinogenesis remain poorly defined. We have studied the expression of CDX2/1 in gastric cancers and intestinal metaplasia (IM) of 69 gastric carcinoma patients by immunohistochemistry. CDX2/1 were shown to be ectopically overexpressed in IM in 41 (85%) of 48, and 47 (90%) of 52 cases, respectively. The expression of CDX2/1 was detected in 38 (55%) and 51 (74%) of the 69 gastric carcinomas, respectively. The histological type of the gastric carcinomas was independently associated with CDX2 expression, but not with that of CDX1, with higher CDX2 expression in intestinal type (differentiated type) than in diffuse type (undifferentiated type) gastric carcinomas. Our results thus suggest that CDX2 and CDX1 may play a role during IM formation and gastric carcinogenesis.

Proapoptotic gene BAX is frequently mutated in hereditary nonpolyposis colorectal cancers but not in adenomas

BACKGROUND & AIMS The p53 and BAX genes have been linked to apoptosis. p53 was not frequently found to be mutated in colorectal carcinomas with a microsatellite mutator phenotype, but frame-shift mutations in a tract of eight guanines within BAX were frequently found in these carcinomas. To understand the roles of these genes in hereditary nonpolyposis colorectal cancer (HNPCC) tumorigenesis, we examined whether BAX mutations occur in adenoma and carcinoma specimens from patients with HNPCC and also determined the frequencies of p53 mutations. METHODS Thirteen colorectal adenomas and 24 adenocarcinomas from patients with HNPCC showing a microsatellite instability phenotype were screened by polymerase chain reaction followed by denaturing polyacrylamide gel electrophoresis and direct sequencing. RESULTS Two of the 13 adenomas (15.4%) and 13 of the 24 adenocarcinomas (54.2%) showed mutation patterns and were confirmed to have frame-shift mutations at the BAX repeat site by direct sequencing. For p53, only 1 of the 24 adenocarcinomas (4.2%) showed a missense mutation. CONCLUSIONS In HNPCC colorectal carcinomas, BAX was significantly (P = 0.024) more mutated than in adenomas. p53 was not frequently found to be mutated in these carcinomas. These data suggest that mutations in BAX, rather than mutations in p53, may contribute to the adenoma-carcinoma transition in HNPCC tumorigenesis.

Effect of total parenteral nutrition with different lipid emulsions on human monocyte and neutrophil functions

Parenteral nutrition (TPN) with lipid emulsions is claimed to be associated with impaired monocyte (M) and neutrophil (N) functions. Long-chain triglycerides (LCT) and a mixture containing 50% medium-chain triglycerides (MCT) and 50% LCT, currently used in nutritional therapy with TPN, were evaluated for their ex vivo effects on human N and M chemotaxis, phagocytosis, bacterial killing, and oxidative metabolism by nitroblue tetrazolium reduction test. Cell functions were examined in a randomized, crossover, blind trial in 10 malnourished patients with gastric cancer. Prior to the operation (2 wk), central TPN (40 kcal/kg) with 25% of caloric energy provided as LCT or MCT/LCT emulsion was infused over 48 h. After the crossover period fat-free TPN was given over 48 h. Function tests were done for N and M before and after each lipid emulsion infusion. Every cell function test performed for each patient was controlled by another test done in healthy adult volunteers and the results were compared with the normal range of values previously established for a healthy adult population. All the patients completed the studies without complications. Crossover validity was statistically established. Bacterial killing was the only function reduced in neutrophils after LCT emulsion (% killed bacteria = 79.0 +/- 8.5 versus 67.4 +/- 19.2; P < 0.05), although this function remained within the normal range values in 80% of the patients. In conclusion, the lipid emulsions did not affect any monocyte functions and only moderately decreased neutrophil bacterial killing.

Does the intraoperative peritoneal lavage cytology add prognostic information in patients with potentially curative gastric resection

Peritoneal recurrence is the foremost pattern of failure after potentially curative resection for gastric cancer. Our aim was to evaluate the prognostic value of intraperitoneal free cancer cells (IFCCs) in peritoneal lavage of patients who underwent potentially curative resection for gastric carcinoma. Two hundred twenty patients with gastric cancer stage I, II, or III were prospectively evaluated with peritoneal lavage and cytologic examination. Aspirated fluid from the abdominal cavity was centrifuged and subjected to Papanicolaou staining. The mean age was 60.9 years (range, 21–89 years), and 63.6% were men. IFCCs were detected in 6.8% of the patients; suspicious in 2.7%, and negative in 84.5%. No judgment could be given in 5.9% of the cases. Invasion of the gastric serosa (pT3) was observed in all positive cytology patients. Patients with IFCCs had a mean survival time of 10.5 months, while those with negative IFCC had a mean survival time of 61 months (P = 0.00001). There was no correlation between the presence of IFCCs and tumor size, histology, pN, or tumor site. Our conclusions are that (1) positive cytology indicates a poor prognosis in patients who underwent potentially curative gastric resection and (2) peritoneal lavage cytology improves staging in assessing these patients and may alter their therapeutic approach.

Distinct Expression of CDX2 and GATA4/5, Development-Related Genes, in Human Gastric Cancer Cell Lines

CDX2 is a tumor‐suppressor homeobox gene involved in colon carcinogenesis, but its role in gastric cancer is unknown. Although GATA4, −5 and, −6 transcription factors have distinct functions in the regulation of gastrointestinal epithelial cell differentiation, there have been no reports regarding GATA4/5/6 alterations in gastrointestinal carcinomas. By using a semiquantitative reverse transcription–polymerase chain reaction assay, we studied the expression of gut development–related genes CDX2/1 and GATA4/5/6 in 11 human gastric cancer cell lines. The expression of CDX2 appeared to progressively decrease with the transition from well differentiated to poorly differentiated cancer cell lines. CDX1 was below detectable levels in all cell lines. The expression of GATA4 and GATA5 was undetectable in four and six cell lines, respectively, whereas the majority of the cell lines expressed GATA6 abundantly. These results suggest that CDX2 and GATA4/5 may be associated with the carcinogenesis of the stomach. Mol. Carcinog. 28:184–188, 2000.

Genomic structure and alterations of homeobox gene CDX2 in colorectal carcinomas

SummaryExpression of CDX2, a caudal-related homeobox gene, was found to be decreased in colorectal carcinomas. Heterozygous null mutant mice as to Cdx2 develop multiple intestinal adenomatous polyps. To clarify the role of CDX2 in colorectal carcinogenesis, we determined its genomic structure, and searched for mutations of CDX2 in 49 sporadic colorectal carcinomas and ten hereditary non-polyposis colorectal cancers (HNPCC) without microsatellite instability. None of them exhibited a mutation. We further examined 19 HNPCC carcinomas with microsatellite instability for mutations in a (G)7 repeat site within CDX2. One of them (5.3%) exhibited one G insertion. Loss of heterozygosity was observed in 2 of the 20 (10%) informative sporadic carcinomas, and in one of the three (33.3%) informative HNPCC cancers. These data indicate that CDX2 may play only a minor role in colorectal carcinogenesis.

Analyses of the APC and TGF-β type II receptor genes, and microsatellite instability in mucosal colorectal carcinomas

APC and transforming growth factor‐β type II receptor (TGF‐β RII) gene mutations, and microsatcllitc instability have been found in sporadic colorectal carcinomas. To clarify further the early alterations in colorectal carcinogenesis, we investigated these genetic changes in 23 protruding‐ and 24 superficial‐type mucosal colorectal carcinomas. TGF‐β RII gene mutations and microsatellite instability were rarely found in these lesions. Nevertheless, APC was mutated in 16 of the 47 (34.0%) mucosal colorectal carcinomas and was significantly more frequently mutated in protruding‐ (I) and superficial elevated‐type (Ila) (14/32,43.8%) than in other superficial‐type (IIa+IIc, IIb, IIc, and IIc+IIa) (2/ 15,13.3%) mucosal colorectal carcinomas (P<0.04). These results indicate that the APC gene may be involved from the beginning in the tumorigenesis of many early colorectal carcinomas, particularly of the protruding and superficial elevated types. However, there might be a distinct pathway for other superficial‐type colorectal carcinomas, possibly not involving APC as an initial step of tumorigenesis.

Resultados da gastrectomia D2 para o câncer gástrico: dissecção da cadeia linfática ou ressecção linfonodal múltipla?

BACKGROUND: Eastern literature is remarkable for presenting survival rates for surgical treatment of gastric adenocarcinoma superior to those presented in western countries. AIM: To analyze the long-term result after D2 gastrectomy for gastric cancer. METHODS: Two hundred seventy four underwent gastrectomy with D2 lymph node dissection as exclusive treatment. The inclusion criteria were: 1) lymph node removal according to Japanese standardized lymphatic chain dissection; 2) potentially curative surgery described in medical records as D2 or more lymph node dissection; 3) tumoral invasiveness of gastric wall restricted to the organ (T1 - T3); 4) absence of distant metastasis (N0-N2/M0); 5) a minimum of five years follow-up. Clinical pathological data included sex, age, tumor location, Borrmanns macroscopic tumor classification, type of gastrectomy, mortality rates, hystological type, TNM classification and staging according to UICC TNM 1997. RESULTS: Total gastrectomy was performed in 77 cases (28.1%) and subtotal gastrectomy in 197 (71.9%). The tumor was located in the upper third in 28 cases (10.2%), in the middle third in 53 (19.3%), and in the lower third in 182 (66.5%). Among patients that had their Borrmanns classification assigned, five cases (1.8%) were BI, 34 (12.4%) BII, 230 (84.0%) BIII and 16 (5.9%) BIV. Tumors were histologically classified as Lauren intestinal type in 119 cases (43.4%) and as diffuse type in 155 (56.6%). According to UICC TNM 1997 classification, early gastric cancer (T1) was diagnosed in 68 cases (24.8 %); 51 (18.6%) were T2, and 155 (56.6%) were T3. No lymph node involvement (N0) was observed in 129 cases (47.1%), whereas 100 (36.5%) were N1 (1-6 lymph nodes), and 45 (16.4%) were N2 (7-15 lymph nodes).The median number of lymph nodes dissected was 35. The overall long-term (five-year) survival rate, for stages I to IIIb was 70.4%. CONCLUSION: Digestive surgeons must be stimulated in performing D2 gastrectomies to avoid wasting the only treatment to gastric adenocarcinoma that has proven to be efficient up to this days. It must be emphasized that standardized lymph nodes dissection according to tumor location is more important that only the number of removed nodes

Behavior of gastric cancer in Brazilian population

RACIONAL: O câncer gastrico e afeccao predominantemente masculina. Para cada mulher ha dois homens, mas tem ocorrido aumento de casos em mulheres nas ultimas decadas. O Brasil e pobre em dados sobre esse tema. OBJETIVO: Verificar se no Brasil em relacao ao câncer gastrico ocorreu: a) mudanca na relacao entre os sexos; b) aumento no numero de pacientes com mais de 70 anos portadores da doenca; c) alteracao na relacao genero e media de idade nas variadas localizacoes do tumor. METODOS: Prontuarios de pacientes com adenocarcinoma do estomago 1971 e 1998 foram obtidos no Hospital das Clinicas da Universidade de Sao Paulo, Brasil com os seguintes criterios de exclusao: pacientes portadores de doenca nao epitelial; adenocarcinoma de metaplasia intestinal no esofago distal invadindo cardia e pacientes submetidos a resseccao gastrica durante os ultimos cinco anos anteriores ao periodo de estudo. Foram divididos em intervalos de 10 anos e tambem em tres grupos de acordo com suas idades e intervalo de tempo. Foram analisadas inter-relacoes entre sexo e idade, e a localizacao do tumor em relacao a parte anatomica do orgao. RESULTADOS: De 1971 a 1998, 1578 pacientes foram hospitalizados com câncer do estomago. Dentre eles, 1021 foram tratados com resseccao gastrica (64,7%). Houve aumento na proporcao de pacientes com mais de 70 anos e diminuicao entre a faixa de 41 a 70. Nao houve diferenca estatistica entre a idade e as varias localizacoes. Houve diferenca significante favorecendo a localizacao proximal e coto gastrico, ambas mais prevalentes nos homens. CONCLUSOES: a) Ocorreram modificacoes na relacao entre os sexos: maior numero de mulheres e aumento no numero de homens na idade entre 41 e 70; b) demonstrou-se aumento no numero de pacientes com mais de 70 anos; c) houve aumento da prevalencia de tumores na parte proximal do estomago e maior nos homens.

Endoscopy vs surgery in the treatment of early gastric cancer: Systematic review.

AIM To report a systematic review, establishing the available data to an unpublished 2a strength of evidence, better handling clinical practice. METHODS A systematic review was performed using MEDLINE, EMBASE, Cochrane, LILACS, Scopus and CINAHL databases. Information of the selected studies was extracted on characteristics of trial participants, inclusion and exclusion criteria, interventions (mainly, mucosal resection and submucosal dissection vs surgical approach) and outcomes (adverse events, different survival rates, mortality, recurrence and complete resection rates). To ascertain the validity of eligible studies, the risk of bias was measured using the Newcastle-Ottawa Quality Assessment Scale. The analysis of the absolute risk of the outcomes was performed using the software RevMan, by computing risk differences (RD) of dichotomous variables. Data on RD and 95%CIs for each outcome were calculated using the Mantel-Haenszel test and inconsistency was qualified and reported in χ(2) and the Higgins method (I (2)). Sensitivity analysis was performed when heterogeneity was higher than 50%, a subsequent assay was done and other findings were compiled. RESULTS Eleven retrospective cohort studies were selected. The included records involved 2654 patients with early gastric cancer that filled the absolute or expanded indications for endoscopic resection. Three-year survival data were available for six studies (n = 1197). There were no risk differences (RD) after endoscopic and surgical treatment (RD = 0.01, 95%CI: -0.02-0.05, P = 0.51). Five-year survival data (n = 2310) showed no difference between the two groups (RD = 0.01, 95%CI: -0.01-0.03, P = 0.46). Recurrence data were analized in five studies (1331 patients) and there was no difference between the approaches (RD = 0.01, 95%CI: -0.00-0.02, P = 0.09). Adverse event data were identified in eight studies (n = 2439). A significant difference was detected (RD = -0.08, 95%CI: -0.10--0.05, P < 0.05), demonstrating better results with endoscopy. Mortality data were obtained in four studies (n = 1107). There was no difference between the groups (RD = -0.01, 95%CI: -0.02-0.00, P = 0.22). CONCLUSION Three-, 5-year survival, recurrence and mortality are similar for both groups. Considering complication, endoscopy is better and, analyzing complete resection data, it is worse than surgery.