Genomics and epidemiology for gastric adenocarcinomas (GE4GAC): a Brazilian initiative to study gastric cancer

Gastric cancer (GC) is the fifth most common type of cancer worldwide with high incidences in Asia, Central, and South American countries. This patchy distribution means that GC studies are neglected by large research centers from developed countries. The need for further understanding of this complex disease, including the local importance of epidemiological factors and the rich ancestral admixture found in Brazil, stimulated the implementation of the GE4GAC project. GE4GAC aims to embrace epidemiological, clinical, molecular and microbiological data from Brazilian controls and patients with malignant and pre-malignant gastric disease. In this letter, we summarize the main goals of the project, including subject and sample accrual and current findings

Encapsulation of cisplatin in long-circulating and pH-sensitive liposomes improves its antitumor effect and reduces acute toxicity.

Cisplatin (CDDP) is one of the most effective and potent anticancer drugs used as first-line chemotherapy against several solid tumors. However, the severe side effects and its tendency to provoke chemoresistance often limit CDDP therapy. To avoid these inconveniences, the present study's research group developed long-circulating and pH-sensitive liposomes containing CDDP (SpHL-CDDP). The present study aimed to evaluate the antitumor effect and toxicity of SpHL-CDDP, as compared with that of free CDDP, and long-circulating and non- pH-sensitive liposomes containing CDDP (NSpHL-CDDP), after their intravenous administration in solid Ehrlich tumor-bearing mice. Antitumor activity was evaluated by analysis of tumor volume and growth inhibition ratio, serum vascular endothelial growth factor (VEGF) levels, and histomorphometric and immunohistochemical studies. Body weight variation and the histological examination of bone marrow and kidneys were used as toxicity indicators. A significant reduction in the tumor volume and a higher tumor growth inhibition ratio was observed after SpHL-CDDP treatment, compared with free CDDP and NSpHL-CDDP treatments. In addition, complete remission of the tumor was detected in 18.2% of the mice treated with SpHL- CDDP (16 mg/kg). As such, the administration of SpHL-CDDP, as compared with free CDDP and NSpHL-CDDP, led to a decrease in the area of necrosis and in the percentage of positive CDC 47 tumor cells. A significant reduction in the VEGF serum level was also observed after SpHL-CDDP treatment, as compared with free-CDDP treatment. SpHL-CDDP administered in a two-fold higher dose than that of free CDDP presented a loss in body weight and changes in the hematopoietic tissue morphology, which proved to be similar to that of free CDDP. No changes could be verified in the renal tissue after any formulations containing CDDP had been administered. These findings showed that SpHL-CDDP allowed for the administration of higher doses of CDDP, significantly improving its antitumor effect.

Acute toxicity study of cisplatin loaded long-circulating and pH-sensitive liposomes administered in mice.

Cisplatin (CDDP) is a very active and cytotoxic agent but causes severe side effects, namely nephrotoxicity, which limits the therapy. The present study aimed to evaluate the acute toxicity of long-circulating and pH-sensitive liposomes containing cisplatin (SpHL-CDDP), as compared to free CDDP, after their intravenous administration in mice. After the administration of free CDDP or SpHL-CDDP at different doses, the body weight was recorded and the LD50 and the maximum tolerated dose (MTD) were calculated. Blood samples were collected for hematological and biochemical analysis. Kidneys, liver, spleen, and bone marrow were removed for histopathological examination. A reduction of body weight of less than 15% could be observed in male and female mice after treatment with free CDDP and SpHL-CDDP at doses of < or = 10 mg/kg and 20 mg/kg, respectively. The LD50 and MTD values obtained after SpHL-CDDP administration were approximately two and three times higher, respectively, than those obtained using free CDDP. Changes in hematological parameters and hematopoietic tissue morphology showed the appearance of toxicity induced by free CDDP. By contrast, the absence of mielotoxicity after SpHL-CDDP treatment could be observed. As regards nephrotoxicity, no alteration in blood urea and creatinine levels, nor morphological change in kidneys, could be observed in mice treated with SpHL-CDDP, as compared to saline-treatment control group. The results showed that SpHL-CDDP at its MTD (20 mg/kg), as compared to the administration of free CDDP at its MTD (7.5 mg/kg), significantly reduced the renal toxicity. Thus, SpHL-CDDP can eliminate CDDP-induced toxicity and is a promising candidate for the intravenous therapy of solid tumors.

Leukocyte-technetium-99m uptake in Crohn's disease: does it show subclinical disease?

AIM: To evaluate inflammatory activity in patients with Crohn's disease (CD) using technetium-99m-hexamethylpropyleneamine oxime (99mTc-HMPAO) granulocyte scintigraphy. METHODS: Twenty patients (7 male and 13 female) with CD and five healthy volunteers were selected for 99mTc-HMPAO granulocyte scintigraphy. The Crohn's Disease Activity Index (CDAI), blood tests and C-reactive protein (CRP) of each patient were performed 7 d before the scintigraphic images. The leukocytes were labeled according to the International Society of Radiolabeled Blood Elements (ISORBE) consensus protocol and the scintigraphic images, including single photon emission computed tomography, were obtained 30 min and 2 h after injection of the radiolabeled leukocytes. RESULTS: The labeling yield of the leukocytes with the lipophilic complex 99mTc-HMPAO was 55.0% +/- 10%. Six of the 20 patients (30%) presented congruent results for the three parameters investigated (CDAI, Scintigraphic Index and CRP). On the other hand, 14 patients (70%) did not show congruent results. There was no significant correlation between the indices analyzed according to the Spearman test (P > 0.05, n = 20). CONCLUSION: The results suggest that 99mTc-HMPAO-labeled leukocyte scintigraphy could be important for determining inflammatory activity in CD even in the absence of clinical symptoms.

Acute toxicity of long-circulating and pH-sensitive liposomes containing cisplatin in mice after intraperitoneal administration.

AIMS: The objective of this work was to evaluate the acute toxicity of long-circulating and pH-sensitive liposomes containing cisplatin (SpHL-CDDP), after their intraperitoneal administration in male and female mice. MAIN METHODS: After single administration of free CDDP (5,10,and 20 mg/kg) or SpHL-CDDP (7,12,30,45 and 80 mg/kg), the body weight was recorded and the LD(50) was calculated. Blood samples were collected for biochemical and hematological analysis. Kidneys, liver, spleen and bone marrow were removed to histopathological examination. KEY FINDINGS: Mice treated with high doses of free CDDP showed a greater loss of body weight and more delayed recovery time than those treated with SpHL-CDDP. The LD(50) values for SpHL-CDDP treatment for male and female mice groups were 2.7 and 3.2 fold higher, respectively, than that obtained for free CDDP. The red and white blood cells counts and quantification of hemoglobin and hematocrit presented no change upon administration of SpHL-CDDP treatment. Free CDDP treatment, however, did lead to an appearance of mild anemia and a reduction in total white blood cell counts. As regards nephrotoxicity, it was observed that free CDDP treatment caused pronounced alterations in the blood urea and creatinine levels of mice. In contrast, these parameters were slightly altered only after SpHL-CDDP treatment at a dose of 30 mg/kg. Microscopic analysis of kidneys from mice treated with SpHL-CDDP showed no morphological alteration. Concerning hepatotoxicity, no histopathological alteration was observed after both treatments. SIGNIFICANCE: These findings reveal that SpHL-CDDP can eliminate CDDP-induced toxicity and is thus a promising candidate for intraperitoneal chemotherapy.

Prevalence of Barrett's esophagus in individuals without typical symptoms of gastroesophageal reflux disease.

BACKGROUND: Barretts esophagus, the major risk factor for esophageal adenocarcinoma, is detected in approximately 10%-14% of individuals submitted to upper endoscopy for the assessment of gastroesophageal reflux disease related symptoms. Prevalence studies of Barretts esophagus in individuals without typical symptoms of gastroesophageal reflux disease have reported rates ranging from 0.6% to 25%. AIM: To determine the prevalence of Barretts in a Brazilian population older than 50 years without typical symptoms of gastroesophageal reflux disease. METHODS: A total of 104 patients (51 men), mean age of 65 years, with an indication for upper endoscopy but without symptoms of heartburn and/or acid regurgitation (determined with a validated questionnaire) were recruited. Subjects submitted to upper endoscopic examination in the last 10 years or using antisecretory medication (proton pump inhibitors) during the last 6 months were not included. Methylene blue chromoscopy was performed during the endoscopic exam to facilitate identification of the metaplastic epithelium. RESULTS: Barretts esophagus was diagnosed endoscopically and confirmed by histology in four patients, all of them males. The metaplastic segment was short (less than 3 cm) and free of dysplasia in all patients. The prevalence of Barretts esophagus was 7.75% in the male population and 3.8% in the general population studied. CONCLUSION: Due to the low prevalence of Barretts esophagus found in the present study, associated with the finding of short-segment Barretts esophagus in all cases diagnosed and the absence of dysplasia in the material analyzed, endoscopic screening for Barretts esophagus in patients above the age of 50 without the classical symptoms of gastroesophageal reflux disease is not indicated for the Brazilian population.

Prevalence of Barrett's esophagus in individuals without typical symptoms of gastroesophageal reflux disease

BACKGROUND: Barrett’s esophagus, the major risk factor for esophageal adenocarcinoma, is detected in approximately 10 percent-14 percent of individuals submitted to upper endoscopy for the assessment of gastroesophageal reflux disease related symptoms. Prevalence studies of Barrett’s esophagus in individuals without typical symptoms of gastroesophageal reflux disease have reported rates ranging from 0.6 percent to 25 percent. AIM: To determine the prevalence of Barrett’s in a Brazilian population older than 50 years without typical symptoms of gastroesophageal reflux disease. METHODS: A total of 104 patients (51 men), mean age of 65 years, with an indication for upper endoscopy but without symptoms of heartburn and/or acid regurgitation (determined with a validated questionnaire) were recruited. Subjects submitted to upper endoscopic examination in the last 10 years or using antisecretory medication (proton pump inhibitors) during the last 6 months were not included. Methylene blue chromoscopy was performed during the endoscopic exam to facilitate identification of the metaplastic epithelium. RESULTS: Barrett’s esophagus was diagnosed endoscopically and confirmed by histology in four patients, all of them males. The metaplastic segment was short (less than 3 cm) and free of dysplasia in all patients. The prevalence of Barrett’s esophagus was 7.75 percent in the male population and 3.8 percent in the general population studied. CONCLUSION: Due to the low prevalence of Barrett’s esophagus found in the present study, associated with the finding of short-segment Barrett’s esophagus in all cases diagnosed and the absence of dysplasia in the material analyzed, endoscopic screening for Barrett’s esophagus in patients above the age of 50 without the classical symptoms of gastroesophageal reflux disease is not indicated for the Brazilian population.

RACIONAL: O esôfago de Barrett, principal fator de risco para o adenocarcinoma do esôfago, é uma complicação da doença por refluxo gastroesofágico de longa duração, sendo detectado em, aproximadamente, 10 por cento-14 por cento dos indivíduos submetidos a endoscopia digestiva alta para avaliação de sintomas relacionados à doença por refluxo gastroesofágico. Estudos de prevalência do esôfago de Barrett em indivíduos sem sintomas típicos de doença por refluxo gastroesofágico mostram taxas oscilando entre 0,6 por cento e 25 por cento. OBJETIVO: Determinar a prevalência do esôfago de Barrett em indivíduos maiores de 50 anos sem os sintomas clássicos da doença por refluxo gastroesofágico. MÉTODOS: Foram recrutados 104 pacientes (51 homens e 53 mulheres), idade média 65 anos, com indicação de se submeterem a endoscopia digestiva alta, porém sem sintomas de pirose e/ou regurgitação ácida (certificados através de questionário validado). Foram excluídos indivíduos com exame endoscópico prévio nos últimos 10 anos ou que fizeram uso de medicação anti-secretora nos últimos 6 meses. Durante o exame endoscópico foi realizada cromoscopia com azul de metileno, para facilitar a identificação do epitélio metaplásico. RESULTADOS: O esôfago de Barrett foi diagnosticado por endoscopia e confirmado pela histologia em quatro pacientes, todos do sexo masculino. Os segmentos metaplásicos eram curtos (inferior a 3 cm) e livre de displasia em todos os pacientes. A prevalência encontrada foi de 7,75 por cento na população masculina e 3,8 por cento na população geral avaliada. CONCLUSÃO: Diante da baixa prevalência do esôfago de Barrett encontrada no presente estudo, associada ao achado de segmento curto de Barrett em todos os casos diagnosticados e ausência de displasia no material analisado, rastreamento endoscópico para o esôfago de Barrett em pacientes acima de 50 anos sem os sintomas clássicos da doença por refluxo gastroesofágico não se justificaria na população...

The presence of Helicobacter pylori in postmenopausal women is not a factor to the decrease of bone mineral density.

BACKGROUND: Osteoporosis affects approximately 30% of postmenopausal women. Gastrectomy, pernicious anemia, and more recently Helicobacter pylori infection, have all been implicated in the pathogenesis of osteoporosis. A reduced parietal cell mass is a common feature in these conditions. AIM: To study a possible relationship between chronic gastritis, parietal cell density of the oxyntic mucosa and bone mineral density in postmenopausal women, as chronic gastritis, Helicobacter pylori infection and osteoporosis are frequently observed in the elderly. METHODS: Fifty postmenopausal women (61.7 +/- 7 years) were submitted to gastroduodenal endoscopy and bone densitometry by dual energy X-ray absorptiometry. Glandular atrophy was evaluated objectively by the determination of parietal cell density. Helicobacter pylori infection was evaluated by histology, urease test and breath test with 13C. RESULTS: Thirty-two patients (64%) presented chronic multifocal gastritis, and 20 of them (40%) showed signs of gastric mucosa atrophy. Lumbar spine osteoporosis was found in 18 patients (36%). The parietal cell density in patients with and without osteoporosis was 948 +/- 188 and 804 +/- 203 cells/mm(2), respectively. Ten osteoporotic patients (55%) and 24 non-osteoporotic patients (75%) were infected by Helicobacter pylori. CONCLUSION: Postmenopausal women with osteoporosis presented a well-preserved parietal cell density in comparison with their counterparts without osteoporosis. Helicobacter pylori infection was not different between the two groups. We concluded that neither atrophic chronic gastritis nor Helicobacter pylori seem to be a reliable risk factor to osteoporosis in postmenopausal women.

The presence of Helicobacter Pylori in postmenopausal women is not a factor to the decrease of bone mineral density

BACKGROUND: Osteoporosis affects approximately 30 percent of postmenopausal women. Gastrectomy, pernicious anemia, and more recently Helicobacter pylori infection, have all been implicated in the pathogenesis of osteoporosis. A reduced parietal cell mass is a common feature in these conditions. AIM: To study a possible relationship between chronic gastritis, parietal cell density of the oxyntic mucosa and bone mineral density in postmenopausal women, as chronic gastritis, Helicobacter pylori infection and osteoporosis are frequently observed in the elderly. METHODS: Fifty postmenopausal women (61.7 ± 7 years) were submitted to gastroduodenal endoscopy and bone densitometry by dual energy X-ray absorptiometry. Glandular atrophy was evaluated objectively by the determination of parietal cell density. Helicobacter pylori infection was evaluated by histology, urease test and breath test with 13C. RESULTS: Thirty-two patients (64 percent) presented chronic multifocal gastritis, and 20 of them (40 percent) showed signs of gastric mucosa atrophy. Lumbar spine osteoporosis was found in 18 patients (36 percent). The parietal cell density in patients with and without osteoporosis was 948 ± 188 and 804 ± 203 cells/mm², respectively. Ten osteoporotic patients (55 percent) and 24 non-osteoporotic patients (75 percent) were infected by Helicobacter pylori. CONCLUSION: Postmenopausal women with osteoporosis presented a well-preserved parietal cell density in comparison with their counterparts without osteoporosis. Helicobacter pylori infection was not different between the two groups. We concluded that neither atrophic chronic gastritis nor Helicobacter pylori seem to be a reliable risk factor to osteoporosis in postmenopausal women.

RACIONAL: A osteoporose afeta aproximadamente 30 por cento das mulheres na pós-menopausa. Gastrectomia, anemia perniciosa e mais recentemente, a infecção pelo H. pylori, têm sido implicados na patogênese da osteoporose. A diminuição da massa de células parietais constitui aspecto comum a estas condições. OBJETIVOS: Estudar possível relação entre gastrite crônica, densidade de células parietais da mucosa oxíntica e a densidade mineral óssea em mulheres na pós-menopausa. MÉTODOS: Cinqüenta mulheres na pós-menopausa (média de idade 61.7 ± 7 anos) foram submetidas a endoscopia digestiva alta e a densitometria óssea pela absorciometria com raio-X de dupla energia. A atrofia glandular foi avaliada, histologicamente e pela determinação da densidade das células parietais na mucosa do corpo gástrico. A infecção pelo H. pylori foi avaliada através da histologia, teste da urease e teste respiratório com C13. RESULTADOS: Trinta e dois pacientes (64 por cento) apresentaram gastrite crônica e 20 (40 por cento) deles apresentaram sinais de atrofia de mucosa gástrica através da análise histopatológica rotineira. Osteoporose da coluna lombar foi encontrada em 18 (36 por cento) pacientes. A densidade de células parietais em pacientes com e sem osteoporose foi 948 ± 188 e 804 ± 2003 células/mm², respectivamente. Dez pacientes (55 por cento) com osteoporose e 24 por cento (75 por cento) pacientes sem osteoporose estavam infectados pelo H. pylori. CONCLUSÃO:Mulheres na pós-menopausa com osteoporose apresentaram mucosa gástrica e população de células parietais mais conservadas em relação àquelas sem osteoporose. A infecção pelo H.pylori não foi estatisticamente diferente entre mulheres com e sem osteoporose, indicando que a infecção por esta bactéria, com ou sem atrofia da mucosa gástrica, não se constitui em fator de risco para osteoporose em mulheres na pós-menopausa.