Genetic and Transcriptional Analysis of 8q24.21 Cluster in Gastric Cancer.

BACKGROUND/AIM: Previous studies from our research group have shown that trisomy 8 and the amplification of the 8q24.21 region is very frequent in gastric cancer (GC). Little is known about the role of most genes located in this region. Thus, the aim of this study was to understand the possible impact of transcriptional alterations and copy number variation (CNV) of four genes located in the 8q24.21 region - FAM49B, FAM84B, GSDMC and miR-5194 - in GC. MATERIALS AND METHODS: Fifty-one to 85 matched pairs of tumoral and adjacent non-tumoral gastric tissues, from patients with primary GC, were used to analyze gene expression and CNV of the selected genes. We also included 29 H. pylori negative and gastritis negative gastric mucosa tissues from individuals without cancer obtained by endoscopy, as control samples. RESULTS: The expression of FAM49B, GSDMC and miR-5194 was higher in both tumoral and adjacent non-tumoral samples compared to the negative control. The expression of FAM84B showed no significant difference between tumoral samples and negative controls. However, the expression of FAM84B in the adjacent non-tumoral samples was higher compared to negative control and tumoral samples. Moreover, the higher expression of GSDMC was associated with T3 and T4 tumors, with tumors on stage III and IV and with advanced tumors. Higher copy numbers of FAM49B and GSDMC were associated with intestinal tumor type and with moderately or well-differentiated tumors. Higher copy number of FAM84B was associated with moderately or well-differentiated tumors. Furthermore, the expression of all four genes was positively correlated. CONCLUSION: All four genes are upregulated in GC and may play an important role in these neoplasms. GSDMC expression was associated with more aggressive tumors.

Differential regulation of LRRC37A2 in gastric cancer by DNA methylation.

Gastric cancer (GC) is one of the leading types of fatal cancer worldwide. Epigenetic manipulation of cancer cells is a useful tool to better understand gene expression regulatory mechanisms and contributes to the discovery of novel biomarkers. Our research group recently reported a list of 83 genes that are potentially modulated by DNA methylation in GC cell lines. Herein, we further explored the regulation of one of these genes, LRRC37A2, in clinical samples. LRRC37A2 expression was evaluated by RT-qPCR, and DNA methylation was studied using next-generation bisulphite sequencing in 36 GC and paired adjacent nonneoplastic tissue samples. We showed that both reduced LRRC37A2 mRNA levels and increased LRRC37A2 exon methylation were associated with undifferentiated and poorly differentiated tumours. Moreover, LRRC37A2 gene expression and methylation levels were inversely correlated at the +45 exon CpG site. We suggest that DNA hypermethylation may contribute to reducing LRRC37A2 expression in undifferentiated and poorly differentiated GC. Therefore, our results show how some genes may be useful to stratify patients who are more likely to benefit from epigenetic therapy.Abbreviations: AR: androgen receptor; 5-AZAdC: 5-aza-2'-deoxycytidine; B2M: beta-2-microglobulin; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GC: gastric cancer; GLM: general linear model; LRRC37A2: leucine-rich repeat containing 37 member A2; SD: standard deviation; TFII-I: general transcription factor II-I; TSS: transcription start site; XBP1: X-box binding protein 1.

Associations between binge eating, depressive symptoms and anxiety and weight regain after Roux-en-Y gastric bypass surgery.

BACKGROUND: Weight regain (WR) after bariatric surgery (BS) is frequent. OBJECTIVE: The aim of this study was to evaluate whether the occurrence of psychiatric disorders would be associated with short- and long-term WR after BS. METHODS: Ninety-six patients (77.6% female, age 40.2 ± 10.1 years, BMI of 50 ± 8.2 kg/m2) from the Obesity and Bariatric Surgery Outpatient Clinic of the Universidade Federal São Paulo completed the Questionnaire on Eating and Weight Patterns-Revised, the Beck Depression Inventory and an anxiety inventory to assess the occurrence of binge eating, depressive symptoms (DS) and anxious symptoms (AS) before and after short-term and long-term BS. RESULTS: Twenty-four months after BS, the prevalence of binge eating, depression and anxiety decreased from 100 to 13%, 100 to 15% and 43 to 4%, respectively. The mean WR of 35.2 ± 17.3% of weight loss occurred in nine patients after 24 months and was associated with binge eating (p = 0.002) but not with DS or AS. At long-term follow-up (12 ± 1.5 years), 67% had a mean WR of 50.3 ± 24.9%. The prevalence of binge eating, DS and AS were 48%, 46% and 63%, respectively, in this group, and significant associations were observed between WR and binge eating (p = 0.001), DS (p = 0.029) and AS (p = 0.001). Furthermore, the number of psychiatric disorders was inversely associated with the percentage of weight loss (p < 0.05) and positively associated with WR (p < 0.05). CONCLUSION: Weight regain was associated with the occurrence of binge eating in the short and long term after BS, whereas the occurrence of depressive and anxious symptoms was associated with WR only in the long term. LEVEL III: Evidence obtained from well-designed cohort or case-control analytic studies.

The impact of DNA demethylation on the upregulation of the NRN1 and TNFAIP3 genes associated with advanced gastric cancer.

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Very few therapeutic options are currently available in this neoplasia. The use of 5-Aza-2'-deoxycytidine (5-AZAdC) was approved for the treatment of myelodysplastic syndromes, and this drug can treat solid tumours at low doses. Epigenetic manipulation of GC cell lines is a useful tool to better understand gene expression regulatory mechanisms for clinical applications. Therefore, we compared the gene expression profile of 5-AZAdC-treated and untreated GC cell lines by a microarray assay. Among the genes identified in this analysis, we selected NRN1 and TNFAIP3 to be evaluated for gene expression by RT-qPCR and DNA methylation by bisulfite DNA next-generation sequencing in 43 and 52 pairs of GC and adjacent non-neoplastic tissue samples, respectively. We identified 83 candidate genes modulated by DNA methylation in GC cell lines. Increased expression of NRN1 and TNFAIP3 was associated with advanced tumours (P < 0.05). We showed that increased NRN1 and TNFAIP3 expression seems to be regulated by DNA demethylation in GC samples: inverse correlations between the mRNA and DNA methylation levels in the promoter of NRN1 (P < 0.05) and the intron of TNFAIP3 (P < 0.05) were detected. Reduced NRN1 promoter methylation was associated with III/IV TNM stage tumours (P = 0.03) and the presence of Helicobacter pylori infection (P = 0.02). The identification of demethylated activated genes in GC may be useful in clinical practice, stratifying patients who are less likely to benefit from 5-AZAdC-based therapies. KEY MESSAGES: Higher expression of NRN1 and TNFAIP3 is associated with advanced gastric cancer (GC). NRN1 promoter hypomethylation contributes to gene upregulation in advanced GC. TNFAIP3 intronic-specific CpG site demethylation contributes to gene upregulation in GC. These findings may be useful to stratify GC patients who are less likely to benefit from DNA demethylating-based therapies.

Binge eating disorder is not predictive of alcohol abuse disorders in long-term follow-up period after Roux-en-Y gastric bypass surgery.

INTRODUCTION: Some studies have shown an increase in alcohol use disorders (AUD) after Roux-en-Y gastric bypass surgery (RYGB), but its relationship with binge eating disorder (BED) has not been fully explored. The purpose of this study was to determine the prevalence of AUD and BED after RYGB and also to evaluate if BED is predictive of late postoperative occurrence of AUD or BED. METHODS: Patients (n = 46) submitted to RYGB, in a tertiary outpatient weight management service at a Federal University of Sao Paulo, Brazil, were tested for BED and AUD using the Questionnaire on Eating and Weight Patterns-Revised (QEWP-R) and AUDIT, respectively. BED was tested before surgery, while both disorders were evaluated with a follow-up period of 12 ± 1.6 years after RYGB. RESULTS: No patients reported AUD before RYBP. After a mean period of 12 years from surgery, ten patients (21.7%) were diagnosed with AUD. Before surgery, BED was present in 24 patients (52.2%) and it was detected in seven out of these 24 patients (29.2%) after RYGB. Thirteen new cases of BED (28.2%) were detected after surgery; total of 20 patients (43.5%) with BED. No association was found between pre- and postsurgery BED (p = 0.148). After RYGB, four out of 24 patients (16.6%) with presurgery BED developed AUD, and no association was found between presurgery BED and postsurgery AUD (p = 0.384). Seven out of ten patients (70%) with AUD after RYGB also developed BED, but no statistical significance was found between these two disorders (p = 0.061). CONCLUSION: The presence of BED before RYGB did not predict AUD and BED after RYGB. Nevertheless, factors involved in a possible association between BED and AUD after surgery remain to be determined. LEVEL OF EVIDENCE: Level III, cohort study.

Response to dietary oxalate after bariatric surgery.

BACKGROUND AND OBJECTIVES: Bariatric surgery (BS) may be associated with increased oxalate excretion and a higher risk of nephrolithiasis. This study aimed to investigate urinary abnormalities and responses to an acute oxalate load as an indirect assessment of the intestinal absorption of oxalate in this population. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Twenty-four-hour urine specimens were collected from 61 patients a median of 48 months after BS (post-BS) as well as from 30 morbidly obese (MO) participants; dietary information was obtained through 24-hour food recalls. An oral oxalate load test (OLT), consisting of 2-hour urine samples after overnight fasting and 2, 4, and 6 hours after consuming 375 mg of oxalate (spinach juice), was performed on 21 MO and 22 post-BS patients 12 months after BS. Ten post-BS patients also underwent OLT before surgery (pre-BS). RESULTS: There was a higher percentage of low urinary volume (<1.5 L/d) in post-BS versus MO (P<0.001). Hypocitraturia and hyperoxaluria (P=0.13 and P=0.36, respectively) were more frequent in BS versus MO patients. The OLT showed intragroup (P<0.001 for all periods versus baseline) and intergroup differences (P<0.001 for post-BS versus MO; P=0.03 for post-BS versus pre-BS). The total mean increment in oxaluria after 6 hours of load, expressed as area under the curve, was higher in both post-BS versus MO and in post-BS versus pre-BS participants (P<0.001 for both). CONCLUSIONS: The mean oxaluric response to an oxalate load is markedly elevated in post-bariatric surgery patients, suggesting that increased intestinal absorption of dietary oxalate is a predisposing mechanism for enteric hyperoxaluria.

Relationship between the preoperative body mass index and the resolution of metabolic syndrome following Roux-en-Y gastric bypass.

BACKGROUND: The increased prevalence of overweight and obesity has reached alarming proportions worldwide and has serious health implications, including an association with an increase in metabolic syndrome. Among the methods to control metabolic syndrome, bariatric surgery plays an important role and can provide a significant improvement in the components of metabolic syndrome. OBJECTIVE: The aim of this study was to determine the relationship between the preoperative body mass index (BMI) and the postoperative resolution of metabolic syndrome [using the National Cholesterol Education Program (NCEP ATP III criteria)] in patients undergoing Roux-en-Y gastric bypass (RYGB). METHODS: Retrospective analysis of a consecutive series of cases, stratified by BMI into three groups (group 1, BMI <40 kg/m(2), group 2, BMI 40-49.9 kg/m(2), and group 3, BMI 50 ≥ kg/m(2)) consisting of both sexes between 20 and 60 years of age. The cohort consisted of 149 patients undergoing RYGB. Anthropometric, biochemical, and clinical evaluations were performed preoperatively and then at 30 and 180 days postoperatively. RESULTS: The average age was 40 years, and the patients were predominately female (72%). At the end of the study period, all groups showed a significant reduction in metabolic syndrome compared with preoperative levels. Logistic regression showed a higher percentage of metabolic syndrome in patients in group 3 after 180 days. CONCLUSION: There was significant resolution of metabolic syndrome in all groups, independently of the preoperative BMI. However, in group 3 (BMI ≥ 50 kg/m(2)), 22% of individuals still presented with metabolic syndrome at 180 days postoperatively (P=0.03).

Early changes in postprandial gallbladder emptying in morbidly obese patients undergoing Roux-en-Y gastric bypass: correlation with the occurrence of biliary sludge and gallstones.

BACKGROUND: Gallstones have been frequently diagnosed after Roux-en-Y gastric bypass (RYGBP). Gallbladder stasis associated with duodenal exclusion may play a role in their pathogenesis. METHODS: Gallbladder emptying was studied before and on the 30th and 31st postoperative days (POD) after RYGBP in 20 morbidly obese patients. Gallbladder volume after fasting and every 15 min during a 2-h period following administration of a standard liquid meal was determined by sonography. On the 31st POD, the meal was administered through the gastrostomy in order to promote its transit through the duodenum. Fasting volume (FV), maximum ejection fraction (Max EF), and residual volume (RV) were determined. Biliary sludge and calculi were investigated after 1 and 6 months, respectively. RESULTS: FV was 39.4 +/- 20.2 ml, 50.1 +/- 22.7 ml, and 47.9 +/- 23.4 ml, respectively, for the preoperative and two postoperative assessments (P = 0.09). RV was 7.6 +/- 8.7 ml, 25.1 +/- 20.0 ml, and 24.6 +/- 20.9 ml; and Max EF was 80.5 +/- 20.9%, 54.3 +/- 21.4%, and 50.5 +/- 29.0%, respectively, for the pre-, postoral, and postgastrostomy infusion measurements. There was only a significant difference between the preoperative value and the two postoperative values (P < 0.001). Biliary sludge was detected in 65% of the patients and 46% of them subsequently developed gallstones. CONCLUSIONS: Gallbladder emptying became significantly compromised after RYGBP. This impairment was unrelated to duodenal exclusion but it was associated with biliary sludge and stone formation.

Incidence of regurgitation after the banded gastric bypass.

BACKGROUND: Frequent regurgitation is a common complication following Roux-en-Y gastric bypass (RYGBP). This study investigated the risk of becoming a chronic regurgitator, by considering silicone ring size and lower esophageal sphincter (LES) function, and their relationship with weight loss. METHODS: 80 morbidly obese patients were randomly selected to undergo surgery using ring length of 62 mm (40 patients, group A) or 77 mm (40 patients, group B), with 6 months' postoperative follow-up. Preoperative esophageal manometry parameters were correlated with occurrence of chronic postoperative regurgitation. Patients were considered to present chronic regurgitation when this occurred on >10 days/month. RESULTS: The groups were homogeneous regarding age, gender, race, weight, BMI (47.8+/-6.1 vs 50.2+/-6.4 kg/m2) and obesity-related diseases. There were 15% more chronic regurgitators in group A than in group B. Chronic regurgitators in group A lost more weight than chronic regurgitators in group B (P=0.026) or non-chronic regurgitators in group A (P=0.016). A greater proportion of chronic regurgitators had LES hypotonia (mean respiratory pressure <14 mmHg) than did non-chronic regurgitators (P=0.008). Logistic regression demonstrated that the chance of being a chronic regurgitator in group A was 4.5 times greater than in group B (P=0.046), and that the chance of a chronic regurgitator having LES hypotonia was seven times greater than of having normal LES pressure (P=0.006). CONCLUSION: Silicone ring size and LES hypotonia are independent prognostic factors for chronic regurgitation following RYGBP. Ring size and chronic regurgitation contribute significantly towards weight loss during the first 6 postoperative months.

Fatores prognósticos de regurgitação crônica e de perda de peso após bypass gástrico em Y-DE-ROUX com anel de silicone para tratamento de obesidade / Predictive factors of chronicle regurgitation and weight loss after silicon ring ROUX-en-Y gastric bypass for obesity treatment

Introdução: Regurgitação freqüente após bypass gástrico em Y-de-Roux, para tratamento da obesidade mórbida, pode ser decorrente de diâmetro estreito do anel de silicone e, também, de hipotonia do esfíncter esofágico inferior. Objetivos: Medir o risco de se tornar regurgitador crônico depois de cirurgia bariátrica, considerando-se fatores técnicos e fisiológicos, e avaliar a relação entre regurgitação crônica e perda de peso. Métodos: 80 pacientes, obesos mórbidos segundo critério de índice de massa corpórea (IMC), foram selecionados aleatoriamente para serem submetidos a bypass gástrico em Y-de-Roux com anel padrão (62 mm de comprimento - grupo A) ou largo (77 mm - grupo B), e acompanhados durante os primeiros 6 meses de pós-operatório. Parâmetros de manometria esofágica pré-operatória foram relacionados à ocorrência de regurgitação crônica pós-operatória nos dois grupos formados por 40 pacientes cada. Foram considerados regurgitadores crônicos os que apresentavam o evento durante mais de 1° dias por mês. Resultados: Os dois grupos eram homogêneos quanto a idade (38,4 :t 10,9 VS. 39,3 :t 10,5 anos), gênero (1 :4,0 VS. 1 :4,7 na proporção masculino/feminino), raça (90,0 por cento VS. 87,5 por cento de brancos), peso (128,1 :t 21,4 VS. 134,0 :t 25,7 kg), IMC (47,8 :t 6,1 VS. 50,2 :t 6,4 kg/m2) e doenças associadas à obesidade. No grupo B, contudo, haviam mais fumantes (p=o, 043), e os pacientes tinham comprimento de esôfago, sob ação da crura diafragmática, maior (p=0,019) no pré--operatório. Após cirurgia, houve um caso de embolia pulmonar, dois casos de fístula gástrica, e nenhum óbito. O grupo A teve perda do peso em excesso 3,15 por cento :t 1,45 por cento maior que o grupo B (p=o, 033). Observou-se 15 por cento a mais de pacientes regurgitadores crônicos no grupo A quando comparado ao grupo B. Ao todo, regurgitadores crônicos tiveram 4,55 por cento :t 2,08 por cento de perda do peso em excesso a mais que os não- regurgitadores crônicos (p=o, 032). Já os regurgitadores crônicos do grupo A perderam, em média, 9,6 por cento :t 4,2 por cento a mais do peso em excesso quando comparados aos regurgitadores crônicos do grupo B (p=0,026), e 6,1 por cento :t 2,5 por cento a mais do peso em excesso quando comparados aos não-regurgitadores crônicos do grupo A (p=0,016). I Houve maior proporção de regurgitadores crônicos com hipotonia do esfíncter I esofágico inferior (pressão respiratória média <14 mmHg) quando comparados com I não-regurgitadores crônicos (p=o, 008). Em média, não-regurgitadores crônicos apresentaram pressão do componente fásico do esfíncter esofágico inferior, correspondente à ação da crura diafragmática, 14,2 :t 6,6 mmHg maior do que regurgitadores crônicos (p=O,OO1). A regressão logística demonstrou que a chance de ser regurgitador crônico no grupo A é 4,5 vezes maior que no grupo B (p=O,046), e, também, que a chance de ser regurgitador crônico tendo hipotonia do esfíncter esofágico inferior é 7 vezes maior do que tendo pressão normal nesse esfíncter (p=O,OO6). Conclusões: Tamanho do anel de silicone e hipotonia do esfíncter esofágico inferior são fatores prognósticos independentes para regurgitação crônica após bypass gástrico em Y-de-Roux. Tamanho do anel e regurgitação crônica contribuem significantemente para perda de peso, nos primeiros seis meses de pós-operatório.

Oximetria do estômago: estudo comparativo entre vagotomia gástrica proximal e seromiotomia da curvatura gástrica menor anterior com vagotomia troncular posterior na úlcera duodenal crônica / Oximetry of stomach: comparative study between proximal gastric vagotomy and anterior lesser curve seromyotomy with posterior truncal vagotomy in chronic duodenal ulcer

Retardo do esvaziamento gástrico de alimentos sólidos ocorre mais intensamente depois de vagotomia gástrica proximal (VGP) que após seromiotomia da curvatura gástrica menor anterior com vagotomia troncular posterior (SMAVTP), podendo estar relacionado à hipóxia da parede gástrica e, principalmente, do marcapasso gástrico. OBJETIVO: Determinar a repercussäo da desvascularizaçäo cirúrgica da curvatura menor e do fundo gástrico no estômago como um todo e, particularmente, na regiäo do marcapasso. MÉTODOS: Mediu-se a saturaçäo de oxigênio da hemoglobina (SpO2) intra-operatória, por oximetria de pulso, da parede gástrica anterior em 20 portadores de úlcera duodenal crônica, alocados casualmente em dois grupos de 10 pacientes para tratamento cirúrgico por VGP ou SMAVTP. RESULTADOS: As mediçöes, obtidas antes de fundoplicatura parcial, mostraram que o fundo gástrico e a curvatura menor proximal tiveram reduçäo significante da SpO2 quando comparados ao corpo gástrico (p < 0,05); que a SpO2, na regiäo do marcapasso gástrico, näo sofreu alteraçäo estatisticamente significante; que a associaçäo entre ligadura dos vasos gástricos curtos e VGP ou SMAVTP reduziu significantemente a SpO2 (p < 0,05); e que a técnica da VGP resultou em SpO2 significantemente menor que a SMAVTP (p < 0,05). CONCLUSÄO: A VGP, quando associada à ligadura dos vasos gástricos curtos, produz alteraçöes isquêmicas agudas da parede gástrica, na regiäo da curvatura menor proximal e do fundo gástrico, mais intensas que a SMAVTP. A regiäo do marcapasso gástrico näo sofre hipóxia imediatamente após os procedimentos operatórios

[Oximetry of stomach: comparative study between proximal gastric vagotomy and anterior lesser curve seromyotomy with posterior truncal vagotomy in chronic duodenal ulcer]. / Oximetria do estômago: estudo comparativo entre vagotomia gástrica proximal e seromiotomia da curvatura gástrica menor anterior com vagotomia troncular posterior na úlcera duodenal crônica.

UNLABELLED: Delayed gastric emptying of solid food is greater after proximal gastric vagotomy (PGV) than after anterior lesser curve seromyotomy with posterior truncal vagotomy (ASPTV) and may be due to the hypoxia in the gastric wall and mainly in the gastric pacemaker. PURPOSE: To verify if operative devascularization of the lesser curve and the gastric fundus could affect the entire stomach and particularly the pacemaker area. METHODS: Measures of intraoperative oxyhemoglobin saturation (SpO2) were taken by pulse oximetry on the anterior gastric wall in 20 patients with chronic duodenal ulcer, randomly allocated in two groups of 10 individuals for surgical treatment, by PGV or ASPTV. RESULTS: Measurements, before partial fundoplication, showed that the area of the proximal lesser curve and the gastric fundus had a significant decrease in the SpO2 when compared to the gastric corpus (p < 0,05); the SpO2 was not reduced significantly by the procedures on the pacemaker area; the ligature of short gastric vessels, in association with PGV or ASPTV, reduced significantly the SpO2 (p < 0,05); and, PGV resulted in a SpO2 significantly lower than in ASPTV (p < 0,05). CONCLUSION: When PGV is associated with the ligature of the short gastric vessels, it causes acute ischemic changes in the proximal lesser gastric curve and in the fundus more intensively than ASPTV. The gastric pacemaker area does not present hypoxia immediately after operative procedures.