Significance of Serum Pepsinogens as a Biomarker for Gastric Cancer and Atrophic Gastritis Screening: A Systematic Review and Meta-Analysis

Background

Human pepsinogens are considered promising serological biomarkers for the screening of atrophic gastritis (AG) and gastric cancer (GC). However, there has been controversy in the literature with respect to the validity of serum pepsinogen (SPG) for the detection of GC and AG. Consequently, we conducted a systematic review and meta-analysis to assess the diagnostic accuracy of SPG in GC and AG detection.

Methods

We searched PubMed, Embase, and the Chinese National Knowledge Infrastructure (CNKI) for correlative original studies published up to September 30, 2014. The summary sensitivity, specificity, positive diagnostic likelihood ratio (DLR+), negative diagnostic likelihood ratio (DLR-), area under the summary receiver operating characteristic curve (AUC) and diagnostic odds ratio (DOR) were used to evaluate SPG in GC and AG screening based on bivariate random effects models. The inter-study heterogeneity was evaluated by the I² statistics and publication bias was assessed using Begg and Mazumdar’s test. Meta-regression and subgroup analyses were performed to explore study heterogeneity.

Results

In total, 31 studies involving 1,520 GC patients and 2,265 AG patients were included in the meta-analysis. The summary sensitivity, specificity, DLR+, DLR-, AUC and DOR for GC screening using SPG were 0.69 (95% CI: 0.60–0.76), 0.73 (95% CI: 0.62–0.82), 2.57 (95% CI: 1.82–3.62), and 0.43 (95% CI: 0.34–0.54), 0.76 (95% CI: 0.72–0.80) and 6.01 (95% CI: 3.69–9.79), respectively. For AG screening, the summary sensitivity, specificity, DLR+, DLR-, AUC and DOR were 0.69 (95% CI: 0.55–0.80), 0.88 (95% CI: 0.77–0.94), 5.80 (95% CI: 3.06–10.99), and 0.35 (95% CI: 0.24–0.51), 0.85 (95% CI: 0.82–0.88) and 16.50 (95% CI: 8.18–33.28), respectively. In subgroup analysis, the use of combination of concentration of PGI and the ratio of PGI:PGII as measurement of SPG for GC screening yielded sensitivity of 0.70 (95% CI: 0.66–0.75), specificity of 0.79 (95% CI: 0.79–0.80), DOR of 6.92 (95% CI: 4.36–11.00), and AUC of 0.78 (95% CI: 0.72–0.81), while the use of concentration of PGI yielded sensitivity of 0.55 (95% CI: 0.51–0.60), specificity of 0.79 (95% CI: 0.76–0.82), DOR of 6.88 (95% CI: 2.30–20.60), and AUC of 0.77 (95% CI: 0.73–0.92). For AG screening, the use of ratio of PGI:PGII as measurement of SPG yielded sensitivity of 0.69 (95% CI: 0.52–0.83), specificity of 0.84 (95% CI: 0.68–0.93), DOR of 11.51 (95% CI: 6.14–21.56), and AUC of 0.83 (95% CI: 0.80–0.86), the use of combination of concentration of PGI and the ratio of PGI:PGII yield sensitivity of 0.79 (95% CI: 0.72–0.85), specificity of 0.89 (95% CI: 0.85–0.93), DOR of 24.64 (95% CI: 6.95–87.37), and AUC of 0.87 (95% CI: 0.81–0.92), concurrently, the use of concentration of PGI yield sensitivity of 0.46 (95% CI: 0.38–0.54), specificity of 0.93 (95% CI: 0.91–0.95), DOR of 19.86 (95% CI: 0.86–456.91), and AUC of 0.86 (95% CI: 0.52–1.00).

Conclusion

SPG has great potential as a noninvasive, population-based screening tool in GC and AG screening. In addition, given the potential publication bias and high heterogeneity of the included studies, further high quality studies are required in the future.     

胃癌与萎缩性胃炎的血清拉曼光谱数据分析

利用激光诱导拉曼光谱技术,测定了萎缩性胃炎患者、胃癌患者血清的拉曼光谱。采用主成分分析法和判别分析法对拉曼光谱数据进行了分析和处理,得到辨别胃癌和萎缩性胃炎的准确率为92％。     

Gene Polymorphisms of Micrornas in Helicobacter pylori-Induced High Risk Atrophic Gastritis and Gastric Cancer

Background and aims

MicroRNAs (miRNAs) are known for their function as translational regulators of tumor suppressor or oncogenes. Single nucleotide polymorphisms (SNPs) in miRNAs related genes have been shown to affect the regulatory capacity of miRNAs and were linked with gastric cancer (GC) and premalignant gastric conditions. The purpose of this study was to evaluate potential associations between miRNA-related gene polymorphisms (miR-27a, miR-146a, miR-196a-2, miR-492 and miR-608) and the presence of GC or high risk atrophic gastritis (HRAG) in European population.

Methods

Gene polymorphisms were analyzed in 995 subjects (controls: n = 351; GC: n = 363; HRAG: n = 281) of European descent. MiR-27a T>C (rs895819), miR-146a G>C (rs2910164), miR-196a-2 C>T (rs11614913), miR-492 G>C (rs2289030) and miR-608 C>G (rs4919510) SNPs were genotyped by RT-PCR.

Results

Overall, SNPs of miRNAs were not associated with the presence of GC or HRAG. We observed a tendency for miR-196a-2 CT genotype to be associated with higher risk of GC when compared to CC genotype, however, the difference did not reach the adjusted P-value (odds ratio (OR) - 1.46, 95% confidence interval (CI) 1.03-2.07, P = 0.032). MiR-608 GG genotype was more frequent in GC when compared to controls (OR −2.34, 95% CI 1.08–5.04), but significance remained marginal (P = 0.029). A similar tendency was observed in a recessive model for miR-608, where CC + CG vs GG genotype comparison showed a tendency for increased risk of GC with OR of 2.44 (95% CI 1.14–5.22, P = 0.021). The genotypes and alleles of miR-27a, miR-146a, miR-196a-2, miR-492 and miR-608 SNPs had similar distribution between histological subtypes of GC and were not linked with the presence of diffuse or intestinal-type GC.

Conclusions

Gene polymorphisms of miR-27a, miR-146a, miR-196a-2, miR-492, miR-492a and miR-608 were not associated with the presence of HRAG, GC or different histological subtypes of GC in European subjects.     

Serum Gastrin and the Antral Mucosa in Atrophic Gastritis

The gastric antral mucosa was studied histologically in 22 patients with atrophic gastritis, of whom 11 had high levels and 11 had normal levels of serum gastrin. The antrum was graded histologically from normal to grade 3 gastritis. All patients with hypergastrinaemia (nine seropositive and two seronegative for parietal cell antibody) had either a normal antrum or minimal (grade 1) antral gastritis. In contrast all but one patient without raised serum gastrin (nine seronegative and two seropositive for parietal cell antibody) had severe (grades 2-3) antral gastritis. Thus circulating gastrin levels observed in patients with gastritis and achlorhydria can be directly related to the presence or absence of antral mucosal damage.Comparison of the histological appearances of the antral mucosa with serum gastrin and parietal cell antibody status has provided a basis for the separation of two distinctive forms of atrophic gastritis.     

High-risk Population for Gastric Cancer Development Based on Serum Pepsinogen Status and Lifestyle Factors

Background: Gastric atrophy is a major risk factor for non-cardiac gastric cancer. Serum pepsinogen status could identify people at high-risk for gastric cancer development during our previous cohort study. However, lifestyle-related factors may additionally affect this risk.
Materials and methods: A total of 6983 Japanese were followed up by annual endoscopy in the previous study, and 43 cases of gastric cancer including two cardiac cancers developed. In most subjects, the body length and weight were measured and a questionnaire was applied to gather information regarding life habits. The risk of non-cardiac gastric cancer development during surveillance was re-analyzed based on serum pepsinogen, sex, age, body mass index (BMI), alcohol, and smoking habit.
Results: A total of 6158 subjects with 37 non-cardiac gastric cancer development (male/female = 4259/1899, mean age = 49.0, mean follow-up period = 4.79 years) were entered into analysis. In a multivariate analysis, old age (by 10 years; (odds ratio) OR, 2.8; p  < .001), alcohol (weekly; OR, 2.4; p  = .03), smoking (current; OR, 5.6; p  = .006 and past; OR, 3.9; p  = .04), and pepsinogen status ("atrophic"; OR, 6.2; p  < .001) were independent risk factors, whereas BMI was not. The annual incidence of gastric cancer was 1.2% in the older subjects aged ≥ 60 years with "atrophic" pepsinogen status. Moreover, it was as high as 2.9% when they had both alcohol and current smoking habits.
Conclusions: Old age, alcohol, and smoking habits additionally promoted the risk for gastric cancer in subjects with gastric atrophy.     

微小RNA与胃癌的关系

微小RNA（microRNA、miRNA）与胃癌的发生发展可通过调控其靶基因参与的信号传导通路,影响胃癌的发生、侵袭和转移等过程,发挥着类似于癌基因或抑癌基因的作用。目前,已发现多种microR—NA与胃癌关系密切,包括通过调节周期蛋白依赖性蛋白激酶（Cdk）表达影响胃癌细胞增殖的miR-106b-93～25家族、miR-222—221家族和抑制高迁移率族蛋白A2（HMGA2）基因表达抑制胃癌细胞转移的miR-129和let-一7miRNA家族等。另有研究表明,miR-d21和miR-31检测阳性率显著高于血清CEA,可能成为新的胃癌肿瘤标志物。miR-15b和miR-16与胃癌多药耐药的关系也说明microRNA可能成为胃癌治疗新的靶点。     

PRR11在胃癌中的表达及其与预后的关系

检测PRR11蛋白在胃癌中的表达,分析其表达异常与胃癌临床指标及预后间的关系。用Western免疫印迹比较胃癌和正常组织中PRR11的表达。构建含167例胃癌的组织芯片,用免疫组化法检测PI汛11蛋白在胃癌组织中的表达,统计学分析其与肿瘤大小、肿瘤侵袭、组织分化、淋巴结转移、TNM分期及胃癌患者总生存期之间的关系。PRR11在胃癌组织中的表达高于癌旁组织,在胃癌中的表达率为50．9％（85／167）,而在癌旁黏膜中不表达或微弱表达。PRR11的表达与胃壁侵袭、淋巴结转移、疾病分期和组织分化呈正相关（P〈0．05）。单因素生存分析表明,PRRll蛋白阳性表达患者较阴性患者生存期短（45个月VS81个月,P〈0．001）。多因素生存分析也表明,PRR11蛋白阳性表达患者生存期短于阴性患者（95％CI：0．347～0．865,P=0．01）。高表达PRR11与胃癌的发生、进展及预后密切相关,是判断胃癌患者预后的重要指标之一。     

Genome Sequences of Three Helicobacter pylori Strains Isolated from Atrophic Gastritis and Gastric Ulcer Patients in China

Helicobacter pylori is a bacterial pathogen which can lead to several human gastric diseases. Here we describe the genome sequences of three strains isolated from atrophic gastritis and gastric ulcers patients in China. The data will permit genomic characterization of traits that may contribute to various gastric diseases.     

胃癌前病变及胃癌的血清学生物标志物研究进展

胃癌是死亡率极高的恶性肿瘤.胃癌的早期诊断有助于发现并选择合适的治疗方案以降低其死亡率.近年来随着分子生物学技术的发展,血清学标志物以其创伤小,痛苦少而成了研究的重点.由于胃癌通常由一系列癌前疾病发展而来,因此与胃癌前病变各个阶段相关的血清学生物标志物的检测对于胃部肿瘤的早期诊断同样具有重要的临床意义.本文综述了目前胃癌前病变阶段及胃癌诊断相关的血清学生物标记物研究的最新进展.这些血清学标志物对于病情估计以及胃癌的早期诊断、组织分型及判断预后等都具有重要意义.     

Identification of miRNAs Expression Profile in Gastric Cancer Using Self-Organizing Maps (SOM)

In this paper, an unsupervised artificial neural network was implemented to identify the patters of specific signatures. The networkwas based on the differential expression of miRNAs (under or over expression) found in healthy or cancerous gastric tissues.Among the tissues analyzes, the neural network evaluated 514 miRNAs of gastric tissue that exhibited significant differentialexpression. The result suggested a specific expression signature nine miRNAs (hsa-mir-21, hsa-mir-29a, hsa-mir-29c, hsa-mir-148a,hsa-mir-141, hsa-let-7b, hsa-mir-31, hsa-mir-451, and hsa-mir-192), all with significant values (p-value < 0.01 and fold change > 5) thatclustered the samples into two groups: healthy tissue and gastric cancer tissue. The results obtained “in silico” must be validated ina molecular biology laboratory; if confirmed, this method may be used in the future as a risk marker for gastric cancerdevelopment.     

血清OPN、HE4和CA125检测对卵巢癌的临床意义

目的：探讨联合检测血清OPN、HE4和CA125对卵巢癌的临床意义。方法：选择2010年6月-2012年7月西安市中心医院妇科及陕西省肿瘤医院妇瘤科收治的35例卵巢癌患者、73例卵巢良性肿瘤患者及40例同期体检的健康妇女为研究对象,应用ELISA法检测患者手术前后血清OPN、HE4水平,电化学发光法检测患者手术前后血清CA125水平,计算3种肿瘤标志物单项以及联合检测在卵巢癌诊断中的敏感性及特异性。结果：（1）卵巢癌患者术前血清OPN、HE4和CA125水平分别为94.6±61.06ng/mL、412.3±278.62 pmol/mL和398.64±220.91 U/mL,与卵巢良性肿瘤组及正常对照组比较差异有统计学意义（P〈0.05）;（2）卵巢癌患者手术前与术后1月血清OPN、HE4和CA125水平比较,差异均有统计学意义（P〈0.05）;（3）血清OPN、HE4和CA125水平联合检测诊断卵巢癌的敏感性（94.3%）显著高于血清OPN、HE4和CA125单项指标检测（分别为37.1%、71.4%和77.1%）,联合检测与单项指标检测比较差异均有统计学意义（P〈0.05）,而血清OPN、HE4和CA125联合检测诊断卵巢癌的特异性（78.8%）稍低于血清OPN、HE4和CA125单项指标检测（分别为87.6%、100%和80.5%）,联合检测与单项指标检测的特异性比较差异无统计学意义（P〉0.05）。血清HE4单项指标检测的特异性高达100%。结论：联合检测卵巢癌患者血清OPN、HE4和CA125水平可作为诊断和评估卵巢癌预后的参考指标。     

NDRG—1基因表达的影响因素

恶性肿瘤细胞迁移是一个非常重要的临床问题,也是导致癌症患者死亡的主要原因之一。N—myc下游调节基因1（NDRG—J）是近年发现的与细胞分化相关的基因,在阻止肿瘤细胞入侵和迁移,尤其是抑制肿瘤组织生长的过程中扮演着非常重要的角色。该基因可以被多种分化调节剂诱导表达。我们就影响其表达的几个典型因素做简要综述。     

Factors Influencing Patient Pathways for Receipt of Cancer Care at an NCI-Designated Comprehensive Cancer Center

Background

Within the field of oncology, increasing access to high quality care has been identified as a priority to reduce cancer disparities. Previous research reveals that the facilities where patients receive their cancer care have implications for cancer outcomes. However, there is little understanding of how patients decide where to seek cancer care. This study examined the factors that shape patients’ pathways to seek their cancer care at a National Cancer Institute-designated comprehensive cancer center (NCI-CCC), and differences in these factors by race, income and education.

Methods

In-depth interviews and survey questionnaires were administered to a random sample of 124 patients at one NCI-CCC in the Northeast US. In-depth interview data was first analyzed qualitatively to identify themes and patterns in patients’ pathways to receive their cancer care at an NCI-CCC. Logistic Regression was used to examine if these pathways varied by patient race, income, and education.

Results

Two themes emerged: following the recommendation of a physician and following advice from social network members. Quantitative data analysis shows that patient pathways to care at an NCI-CCC varied by education and income. Patients with lower income and education most commonly sought their cancer care at an NCI-CCC due to the recommendation of a physician. Patients with higher income and education most commonly cited referral by a specialist physician or the advice of a social network member. There were no statistically significant differences in pathways to care by race.

Conclusions

Our findings show that most patients relied on physician recommendations or advice from a social network member in deciding to seek their cancer care at an NCI-CCC. Due to the role of physicians in shaping patients’ pathways to the NCI-CCC, initiatives that strengthen partnerships between NCI-CCCs and community physicians who serve underserved communities may improve access to NCI-CCCs.     

跟骨强度指数与影响因素相关性分析

目的：探讨跟骨强度指数与其影响因素的相关性。方法：共入选1024例体检人员。（1）通过Achilles定量超声（QUS）系统测量左跟骨强度指数;（2）使用RGC-120型体重秤测量身高、体重并计算体重指数;（3）通过问卷调查收集体检人员年龄、膳食、运动、吸烟、饮酒等影响因素的相关资料;（4）将各影响因素与跟骨强度指数进行相关分析和多元逐步回归分析。结果：（1）直线相关分析结果显示,跟骨强度指数与身高、体重、体重指数、饮用牛奶年数、运动年数呈正相关（;2）多因素逐步回归分析显示,跟骨强度指数仅与体重指数、运动年数具有显著的回归效果。结论：体重指数与运动年数是跟骨强度指数的独立影响因素,对骨质疏松的诊断与预防具有重要的意义。     

Incidence,Predictive Factors,and Clinical Outcomes of Acute Kidney Injury after Gastric Surgery for Gastric Cancer

Background

Postoperative acute kidney injury (AKI), a serious surgical complication, is common after cardiac surgery; however, reports on AKI after noncardiac surgery are limited. We sought to determine the incidence and predictive factors of AKI after gastric surgery for gastric cancer and its effects on the clinical outcomes.

Methods

We conducted a retrospective study of 4718 patients with normal renal function who underwent partial or total gastrectomy for gastric cancer between June 2002 and December 2011. Postoperative AKI was defined by serum creatinine change, as per the Kidney Disease Improving Global Outcomes guideline.

Results

Of the 4718 patients, 679 (14.4%) developed AKI. Length of hospital stay, intensive care unit admission rates, and in-hospital mortality rate (3.5% versus 0.2%) were significantly higher in patients with AKI than in those without. AKI was also associated with requirement of renal replacement therapy. Multivariate analysis revealed that male gender; hypertension; chronic obstructive pulmonary disease; hypoalbuminemia (<4 g/dl); use of diuretics, vasopressors, and contrast agents; and packed red blood cell transfusion were independent predictors for AKI after gastric surgery. Postoperative AKI and vasopressor use entailed a high risk of 3-month mortality after multiple adjustments.

Conclusions

AKI was common after gastric surgery for gastric cancer and associated with adverse outcomes. We identified several factors associated with postoperative AKI; recognition of these predictive factors may help reduce the incidence of AKI after gastric surgery. Furthermore, postoperative AKI in patients with gastric cancer is an important risk factor for short-term mortality.     

金黄色葡萄球菌特异性卵黄抗体的制备及其影响因素

目的:考察金黄色葡萄球菌特异性卵黄抗体制备过程中的影响因素.方法:以灭活的金黄色葡萄球菌为抗原,采用不同的浓度(108cfu/mL,109cfu/mL,1010cfu/mL)、在不同免疫佐剂(商品弗氏佐剂和自制弗氏佐剂)作用下,对不同日龄(120天和300天)的蛋鸡进行免疫.免疫后收集鸡蛋,蛋黄用6倍体积水稀释,采用ELISA法测定抗体效价.结果:抗原浓度为109cfu/mL所得抗体效价最高;免疫120日龄蛋鸡获得抗体效价高于免疫300日龄蛋鸡所得抗体效价;在抗原浓度和蛋鸡日龄相同的情况下,商品弗氏佐剂比自制具有更好的免疫增强作用.结论:特异性卵黄抗体制备受多种因素的影响,抗原浓度、蛋鸡日龄、佐剂质量均对卵黄中特异性抗体水平有影响.     

Serum and Gastric Luminal Epidermal Growth Factor in Helicobacter Pylori—Associated Gastritis and Peptic Ulcer Disease

Background Helicobacter pylori is the cause of chronic (type B) gastritis, duodenal ulceration (DU), and gastric ulceration (GU). Smoking is associated with delayed ulcer healing. Epidermal growth factor (EGF) is produced in the salivary and Brunner's glands of the upper gastrointestinal tract, inhibits gastri acid secretion, and is a powerful mitogen. Materials and Methods. We sought to determine gastric luminal EGF (GL-EGF) in smokers and patients with Hp-associated DU and the effect of Hp eradication. Our aim was to determine GL-EGF in patients with GU and the effect of ulcer healing and to measure serum EGF in patients with Hp gastritis with or without DU disease. Results. GL-EGF was reduced in smokers compared to control (p= .008). Subjects with HP gastritis had reduced GL-EGF compared to controls (p= .0002). There was no difference in GL-EGF between Hp-positive subjects who had DU and those with chronic gastritis alone. Eradication of Hp from those patients with DU had no effect on the low levels of GL-EGF. There was no difference between GL-EGF in Hp gastritis alone and in Hp-associated active GU. GL-EGF fell after ulcer healing (p= .04), a difference confirmed by analysis of paired samples from patients before and after ulcer healing (p= .03). There was no difference in serum EGF between controls and subjects with Hp infection. There was no difference in serum EGF in subjects with DU-associated and non-ulcer-associated gastritis. Conclusions. Subjects with Hp gastritis, or those who smoke, had low concentrations of GL-EGF regardless of whether DU was present. Eradication of Hp did not return the concentrations of GL-EGF to normal in DU subjects. Individuals with Hp gastritis and inactive GU had low levels of GL-EGF compared to non-ulcer Hp infection. The relative increase in GL-EGF that occurred with ulceration of the gastric mucosa may have resulted from the development of an ulcer-associated cell lineage. Serum EGF did not play a role in the pathogenesis of Hp gastritis or of associated DU ulcer disease.