Evidence that genetic variants of metabolic detoxication and cell cycle control are not related to gallbladder cancer risk in Chilean women.

BACKGROUND AND AIMS: High consumption of red chili pepper has been shown to be a risk factor for gallbladder cancer (GBC) in Chilean women. However, genetic factors in addition to this and other environmental factors may also be associated with an increased risk of GBC. We aimed to examine the associations of cytochrome P450 1A1 (CYP1A1), glutathione S-transferase class mu (GSTM1), and tumor protein p53 (TP53) polymorphisms with the risk of GBC in Chilean women. METHODS: A hospital-based case-control study of 57 patients with GBC, 119 patients with gallstones, and 70 controls was conducted. The statuses of the polymorphisms CYP1A1 rs4646903, CYP1A1 rs1048943, and TP53 rs1042522 were assayed using Custom Taqman SNP Genotyping Assays and TaqMan SNP Genotyping Assay. GSTM1 deletion polymorphism was detected by allele-specific PCR analysis. RESULTS: No significant differences in the genotypic or allelic frequencies in the CYP1A1, GSTM1, and TP53 polymorphisms were found between the three groups. CONCLUSION: These genetic variants were not related to an increased risk of GBC in Chilean women. Other polymorphisms, such as red-chili-pepper-related polymorphisms, may contribute to the development of GBC in Chilean women.

Frequent epigenetic inactivation of chromosome 3p candidate tumor suppressor genes in gallbladder carcinoma.

Gallbladder carcinoma (GBC) is a highly malignant neoplasm that represents the leading cause of death for cancer in Chilean females. There is limited information about the molecular abnormalities involved in its pathogenesis. We have identified a number of molecular changes in GBC, including frequent allelic losses at chromosome 3p regions. Four distinct 3p sites (3p12, 3p14.2, 3p21.3 and 3p22-24) with frequent and early allelic losses in the sequential pathogenesis of this neoplasm have been detected. We investigated epigenetic and genetic abnormalities in GBC affecting 6 candidate tumor suppressor genes (TSG) located in chromosome 3p, including DUTT1 (3p12), FHIT (3p14.2), BLU, RASSF1A, SEMA3B and hMLH1 (3p21.3). DNA extracted from frozen tissue obtained from 50 surgical resected GBCs was examined for gene promoter methylation using MSP (methylation-specific PCR) technique after bisulfite treatment in all 6 genes. In addition, we performed PCR-based mutation examination using SSCP in FHIT and RASSF1A genes and loss of heterozygosity (LOH) analysis using microdissected tissue in a subset of tumors for the 3p21.3 region with 8 microsatellite markers. A very high frequency of GBC methylation was detected in SEMA3B (46/50, 92%) and FHIT (33/50, 66%), intermediate incidences in BLU (13/50, 26%) and DUTT1 (11/50, 22%) and very low frequencies in RASSF1A (4/50, 8%) and hMLH1 (2/50, 4%). Allelic loss at 3p21.3 was found in nearly half of the GBCs examined. We conclude that epigenetic inactivation by abnormal promoter methylation is a frequent event in chromosome 3p candidate TSGs in GBC pathogenesis, especially affecting genes SEMA3B (3p21.3) and FHIT (3p14.2).

Mitochondrial DNA mutation at the D310 (displacement loop) mononucleotide sequence in the pathogenesis of gallbladder carcinoma.

PURPOSE: Mutations in the mitochondrial DNA (mtDNA) have been observed frequently in human neoplasia, in both coding and noncoding regions. A mononucleotide repeat (poly-C) between 303 and 315 nucleotides (D310) within the regulatory displacement loop has been identified recently as a frequent hot spot of deletion/insertion mutations in tumors. We investigated the frequency and pattern of D310 abnormalities in the pathogenesis of gallbladder carcinoma (GBC). EXPERIMENTAL DESIGN: DNA extracted from neoplastic and nonneoplastic archival gallbladder tissue including 123 tumors, 53 dysplastic areas, and 90 histologically normal epithelia adjacent to GBC, chronic cholecystitis, and 15 normal gallbladders were examined by PCR-based assay for D310 mutations, followed by sequencing in a subset of cases. RESULTS: D310 mutation was a relatively frequent (47 of 123; 38%) abnormality in GBC. A very high frequency of mutations were detected in dysplastic (8 of 14; 57%) and normal-appearing gallbladder epithelia (10 of 22; 46%) accompanying GBC, showing a clonal relationship compared with the corresponding tumors. D310 mutations were also detected in dysplastic (8 of 39; 21%) and normal (17 of 68; 25%) epithelia obtained from chronic cholecystitis. A single case of 15 normal gallbladders showed a D310 abnormality. Overall, deletions (67 of 91; 74%) at D310 were more frequent than insertions. CONCLUSIONS: D310 mutation at the mtDNA displacement loop is a relatively frequent and early event in the sequential pathogenesis of GBC, being detected in normal-appearing epithelium from chronic cholecystitis. Our findings suggest that mtDNA mutations should be additionally investigated in GBC pathogenesis, and D310 mononucleotide abnormalities could be included in a panel of molecular biomarkers for GBC early detection strategy.

HPV16/18 genotyping for the triage of HPV positive women in primary cervical cancer screening in Chile.

BACKGROUND: We previously conducted a population-based screening trial of high-risk human papillomavirus (hrHPV) testing and conventional cytology, demonstrating higher sensitivity (92.7 % vs 22.1 % for CIN2+) but lower positive predictive value (10.5 % vs 23.9 %) of hrHPV testing. Here we report the performance of HPV16/18 genotyping to triage the hrHPV positive participants. METHODS: Women aged 25 years and older received hrHPV (Hybrid Capture 2) and Papanicolaou testing; positives by either test underwent colposcopy and directed biopsy, as did a sample of double-negatives. hrHPV positive women were reflex-tested with HPV16/18 genotyping (Digene HPV Genotyping PS Test). RESULTS: Among the 8,265 participants, 10.7 % were hrHPV positive, 1.7 % had ASCUS+ cytology, 1.2 % had CIN2+; 776 (88 %) hrHPV positive women had complete results, of whom 38.8 % were positive for HPV16 (24.0 %), HPV18 (9.7 %) or both (5.1 %). CIN2+ prevalence in HPV16/18 positive women (16.3 %, 95 % CI 12.3-20.9) was twice that of HPV16/18 negative women (8.0 %, 95 % CI 5.7-10.8). HPV16/18 genotyping identified 40.5 % of CIN2, 66.7 % of CIN3 and 75.0 % of cancers. Compared to hrHPV screening alone, HPV16/18 triage significantly reduced the referral rate (10.7 % vs 3.7 %) and the number of colposcopies required to detect one CIN2+ (9 vs 6). When HPV16/18 negative women with baseline ASCUS+ cytology were also colposcopied, an additional 14 % of CIN2+ was identified; referral increased slightly to 4.2 %. CONCLUSIONS: HPV16/18 triage effectively stratified hrHPV positive women by their risk of high-grade lesions. HPV16/18 positive women must be referred immediately; referral could be deferred in HPV16/18 negative women given the slower progression of non-HPV16/18 lesions, however, they will require active follow-up.

Genetic variants involved in gallstone formation and capsaicin metabolism, and the risk of gallbladder cancer in Chilean women.

AIM: To determine the effects of genetic variants associated with gallstone formation and capsaicin (a pungent component of chili pepper) metabolism on the risk of gallbladder cancer (GBC). METHODS: A total of 57 patients with GBC, 119 patients with gallstones, and 70 controls were enrolled in this study. DNA was extracted from their blood or paraffin block sample using standard commercial kits. The statuses of the genetic variants were assayed using Taqman SNP Genotyping Assays or Custom Taqman SNP Genotyping Assays. RESULTS: The non-ancestral T/T genotype of apolipoprotein B rs693 polymorphism was associated with a decreased risk of GBC (OR: 0.14, 95% CI: 0.03-0.63). The T/T genotype of cholesteryl ester transfer protein (CETP) rs708272 polymorphism was associated with an increased risk of GBC (OR: 5.04, 95% CI: 1.43-17.8). CONCLUSION: Genetic variants involved in gallstone formation such as the apolipoprotein B rs693 and CETP rs708272 polymorphisms may be related to the risk of developing GBC in Chilean women.

[Helicobacter pylori infection in symptomatic patients with benign gastroduodenal diseases: analysis of 5.664 cases]. / Infección por Helicobacter pylori en pacientes sintomáticos con patología gastroduodenal benigna: análisis de 5.664 pacientes.

UNLABELLED: Infection with Helicobacter pylori (H. pylori) is highly prevalent in Chile, but there are no systematic studies in patients with upper gastrointestinal symptoms. AIM: To determine the prevalence of H. pylori infection, according to age, gender and endoscopic pathology in a large sample of patients. METHODS: We studied 7,893 symptomatic patients submitted to upper gastrointestinal endoscopy between July 1996 and December 2003 in the context of a screening program of gastric cancer in a high risk population. H. pylori infection was determined by rapid urease test (RUT) in antral mucosa. We excluded 158 patients with gastric cancer (2%) and 2,071 patients without RUT. RESULTS: We included 5,664 patients, mean age 50.7 +/- 13.9 years, women 72.1%. Endoscopic diagnoses were normal in 59.3%, erosive esophagitis in 20%, gastric ulcer (GU) in 8.1%, duodenal ulcer (DU) in 6.4%, and erosive gastropathy in 6.2%. RUT was positive in 78% of patients. After adjusting for age and sex and with respect to patients with normal endoscopy, frequency of H. pylori infection was 86.6% in DU (OR 2.1, 95% CI 1.5-2.8, p < 0.001); 81.4% in GU (OR 1.8, 95% CI 1.4-2.4; p < 0.001 ); 79.9% in erosive gastropathy (OR 1.4, 95% CI 1.03-1.8; p = 0.03) and 77.4% in erosive esophagitis (OR 1.1, 95% CI: 0.9-1.3; p = NS). The probability of H. pylori infection decreased significantly with age, more markedly in men with normal endoscopy. CONCLUSIONS: Prevalence of H. pylori infection is very high in symptomatic Chilean patients and even higher in those with gastroduodenal ulcer or erosions, while in patients with erosive esophagitis is similar to those with normal endoscopy. The frequency of infection decreases with age, probably as a consequence of rising frequency of gastric mucosal atrophy.

Polimorfismo genético relacionado al metabolismo de la aflatoxina y el riesgo de cáncer vesicular en mujeres chilenas / Aflatoxin metabolism-related genetic polymorphisms and the risk of gallbladder cancer in Chilean women

Background/aim: High consumption of red chili pepper has been shown to be a risk factor for gallbladder cancer (GBC) in Chilean women with gallstones (GS). GS are the main cause of GBC, but not all patients with gallstones develop GBC. Since red chili pepper is a widely consumed spice among the Chilean population, the development of GBC in Chilean women cannot be completely explained by the presence of GS and red chili pepper consumption alone. Genetic factors in addition to these and other environmental factors may also be associated with an increased risk of GBC. We aimed to study whether genetic polymorphisms involved in aflatoxin metabolism are associated with the risk of GBC in Chilean women, because we detected aflatoxins B1 and B2 in red chili pepper purchased in Santiago, Chile. Methods: We conducted a hospital-based case-control study whose subjects were 57 patients with GBC, 119 patients with GS, and 70 controls. DNA was extracted from subjects’ blood or paraffin block samples using standard commercial kits. The statuses of the genetic polymorphisms of cytochrome P450 (CYP) 1A2 rs762551 and CYP3A4 rs2740574 were assayed using the TaqMan® SNP Genotyping Assay or the Custom TaqMan® SNP Genotyping Assay, respectively. Results: In the assay for the CYP1A2 polymorphism, of the 57 GBC patients, 23 (40.3 percent) had at least one minor allele (A/C or C/C). However, there were no significant differences in the genotypic or allelic frequencies among the three subject groups. In the assay for the CYP3A4 polymorphism, the minor G/G genotype was not detected in the three groups, and there were no significant differences in the genotypic or allelic frequencies among the three groups. Conclusion: These genetic polymorphisms were not related to the risk of GBC in Chilean women. Further studies including a greater number of controls and cases are needed to confirm this preliminary exploratory result.

Introducción/objetivo: El alto consumo de ají rojo ha demostrado ser un factor de riesgo de cáncer vesicular (CV) en mujeres chilenas con cálculos vesiculares. Los cálculos vesiculares son la causa principal de CV, no obstante, no todos los pacientes con cálculos vesiculares desarrollan CV. Debido a que el ají rojo es una especia ampliamente consumida entre la población chilena, el desarrollo de CV en las mujeres chilenas no puede ser explicado en su totalidad sólo por la presencia de cálculos vesiculares y consumo de ají rojo. Factores genéticos además de éstos y otros factores ambientales, también podrían estar relacionados con un aumento del riesgo de CV. Nuestro objetivo es estudiar si los polimorfismos genéticos involucrados en el metabolismo de la aflatoxina están relacionados con el riesgo de CV en mujeres chilenas, porque detectamos aflatoxinas B1 y B2 en ajíes rojos comprados en Santiago de Chile. Métodos: El estudio caso control, incluyó 57 pacientes con CV, 119 pacientes con cálculos vesiculares, y 70 controles. Se extrajo ADN de la sangre de los sujetos o de bloques de parafina, usando kits comerciales estándar. El estado de los polimorfismos genéticos del citocromo P450 (CYP) 1A2 rs762551 y CYP3A4 rs2740574 fueron estudiados usando el ensayo de genotipo SNP TaqMan® o el ensayo de genotipo SNP Custom TaqMan®, respectivamente. Resultados: En el ensayo para el polimorfismo CYP1A2, de los 57 pacientes con CV, 23 (40,3 por ciento) tuvieron al menos un alelo menor (A/C o C/C). No obstante, no hubo diferencias significativas en las frecuencias genotípicas o alélicas entre los tres grupos. En el ensayo para el polimorfismo CYP3A4, el genotipo menor G/G no fue detectado en los tres grupos, y no hubo diferencias significativas en las frecuencias genotípicas o alélicas entre los tres grupos. Conclusión: Estos polimorfismos genéticos no estaban relacionados con el riesgo de CV en mujeres chilenas...

[Appendectomies for suspected acute appendicitis during pregnancy: experience at a Chilean public hospital]. / Apendicectomía en la embarazada: experiencia en un hospital público chileno.

BACKGROUND: Acute appendicitis is the most common non obstetric surgical emergency during pregnancy. AIM: To asses our experience in the diagnosis and management of acute appendicitis occurring during pregnancy. PATIENTS AND METHODS: Data from all pregnant patients who were subjected to an appendectomy for a suspected acute appendicitis from January 1998 to December 2002, were retrospectively analyzed. All pathological, surgical, clinical records and the delivery outcome registry of each patient were reviewed. RESULTS: Among 47,322 deliveries, 46 pregnant women aged 29+/-9 years and with a gestational age of 21+/-7 weeks, were operated because of a presumptive acute appendicitis. Forty (87%) had a histopathologically proven appendicitis; ten (25%) cases had a perforated appendix and 30 (75%) had a non-perforated appendicitis. Five (10.9%) patients had a negative laparotomy and one had a necrotic ovarian tumor. Patients with perforated and non perforated appendices had a similar lapse from the onset of symptoms to operation (69+/-45 and 50+/-34 hours respectively, NS) and a similar white cell count (15,667+/-3,707 and 13,006+/-5,206 cells/mm(3), respectively, NS). Wound infection was the most common surgical complication in 15%. Seven (15%) patients had a premature delivery and there was one fetal death (2.2%). There were no pregnancy complications on negative appendectomy cases. CONCLUSIONS: Acute appendicitis continues to be a challenge in diagnosis and treatment during pregnancy. Maternal and fetal outcome was better than previously reported.

Infección por Helicobacter pylori en pacientes sintomáticos con patología gastroduodenal benigna: análisis de 5.664 pacientes / Helicobacter pylori infection in symptomatic patients with benign gastroduodenal diseases: analysis of 5.664 cases

Infection with Helicobacter pylori (H. pylori) is highly prevalent in Chile, but there are no systematic studies in patients with upper gastrointestinal symptoms. Aim: To determine the prevalence of H. pylori infection, according to age, gender and endoscopic pathology in a large sample of patients. Methods: We studied 7,893 symptomatic patients submitted to upper gastrointestinal endoscopy between July 1996 and December 2003 in the context of a screening program of gastric cancer in a high risk population. H. pylori infection was determined by rapid urease test (RUT) in antral mucosa. We excluded 158 patients with gastric cancer (2 percent) and 2,071 patients without RUT. Results: We included 5,664 patients, mean age 50.7 ± 13.9 years, women 72.1 percent. Endoscopic diagnoses were normal in 59.3 percent, erosive esophagitis in 20 percent, gastric ulcer (GU) in 8.1 percent, duodenal ulcer (DU) in 6.4 percent, and erosive gastropathy in 6.2 percent. RUT was positive in 78 percent of patients. After adjusting for age and sex and with respect to patients with normal endoscopy, frequency of H. pylori infection was 86.6 percent in DU (OR 2.1, 95 percent CI 1.5-2.8, p < 0.001); 81.4 percent in GU (OR 1.8, 95 percent CI 1.4-2.4; p < 0.001 ); 79.9 percent in erosive gastropathy (OR 1.4, 95 percent CI 1.03-1.8; p = 0.03) and 77.4 percent in erosive esophagitis (OR 1.1, 95 percent CI: 0.9-1.3; p = NS). The probability of H. pylori infection decreased significantly with age, more markedly in men with normal endoscopy. Conclusions: Prevalence of H. pylori infection is very high in symptomatic Chilean patients and even higher in those with gastroduodenal ulcer or erosions, while in patients with erosive esophagitis is similar to those with normal endoscopy. The frequency of infection decreases with age, probably as a consequence of rising frequency of gastric mucosal atrophy.

Gota en un lactante / Gout in an infant

Se presenta un caso anátomo-clínico de Gota en un paciente de 1 mes y medio de edad, cuyo diagnóstico, confirmado por la autopsia, no fue sospechado durante su evolución. Son muy pocos los casos publicados a tan corta edad y puede concluirse que se trata de un caso excepcional de interés pediátrico