Duodenogastric reflux and gastric stump carcinoma

Gastric stump carcinoma after gastric surgery for benign disease is now widely recognized as a distinct clinical entity. The stump carcinoma was often found to be localized to the anastomosis, known to be the site with severe duodenogastric reflux. For this reason, duodenogastric reflux, including the reflux of bile and pancreatic juice, after a Billroth II procedure for benign disease is frequently discussed as an important factor related to the development of stump carcinoma. Many experiments have implicated bile acids, the main component of the duodenal juice, in gastric carcinogenesis. In particular, rat models without the use of the carcinogen, N-methyl-N′-nitro-N-nitrosoguanidine (MNNG), showed adenocarcinoma in the remnant stomach that was related to the severity of duodenogastric reflux. However, human data are, inevitably, much less consistent. Whether the incidence of stump carcinoma is higher than that of gastric carcinoma in general is still controversial. Concerning the histogenesis of stump carcinoma after benign disease, a relationship between gastritis cystica polyposa (GCP) and gastric type adenocarcinoma has been suggested. Recently, the population at risk of gastric stump carcinoma for benign disease has been diminishing significantly, and the incidence of gastric stump carcinoma after surgery for malignant disease has been increasing. The influence of duodenogastric reflux in the gastric remnant after malignant disease may differ from its influence in the gastric remnant after benign disease. Further clinical study is needed to elucidate the pathogenetic factors involved in gastric stump carcinoma. Received: July 30, 2001 / Accepted: October 16, 2001     

Chemoprevention of glandular stomach carcinogenesis through duodenogastric reflux in rats by a COX-2 inhibitor

Duodenogastric reflux (DGR) causes glandular stomach carcinogenesis in rats without carcinogens. We aimed to investigate how this carcinogenesis might be prevented by a selective COX-2 inhibitor, meloxicam. A series of 188 Fisher 344 rats underwent a surgical DGR procedure and were divided into 2 groups. One group was given commercial chow (control group), and the other an experimental chow containing meloxicam [0.3 mg/kg bw/day] (meloxicam group). The animals were sequentially sacrificed at weeks 20, 30, 40, 50 and 60 after surgery. The stomachs were removed and examined for the presence of carcinoma, incidence of reflux-induced morphologic changes, COX-2 expression and its activity. Adenocarcinoma in the glandular stomach developed in 7 of 21 animals (33%) in the control group at week 60, but none of 20 (0%) in the meloxicam group (p < 0.01). Moreover, reflux-induced gastritis was definitely alleviated in the meloxicam group compared with the control group. COX-2 immunoreactivity was predominantly detected in stromal cells such as macrophages and fibroblasts. Compared with nonsurgical rats, RNA expression of COX-2 in the mucosa increased, reaching peak at an early phase of week 20 in both groups (p < 0.005). Expression of microsomal prostaglandin E synthase-1 was lower in the meloxicam group than in the control group. PGE(2) production was significantly suppressed throughout the experiment in the meloxicam group compared with the control group (p < 0.01). Gastric carcinogenesis via duodenal reflux was mediated by the COX-2 pathway in rats. Administration of meloxicam prevented this carcinogenesis by suppressing the inflammatory process.     

Clinical Manifestations and Role of Proton Pump Inhibitors in the Management of Laryngopharyngeal Reflux

Laryngopharyngeal reflux (LPR) refers to the backflow of stomach contents into the throat that is into the hypopharynx. LPR is different from classical Gastroesophageal reflux disease (GERD) in many ways. Proton pump inhibitors have become the treatment of choice even though conflicting results exists in their response. Treatment requires acid suppression to be as complete as possible and treatment failure is not uncommon. In this article we present here our prospective study of 50 patients diagnosed as a case of LPR on the basis of reflux finding score and reflux symptom index. We tried to evaluate the role of PPI in LPR management by observing the effect of PPI on reflux finding score (RFS) and reflux symptom index (RFI) during the follow up period of 16 weeks.     

A selective cyclooxygenase‐2 inhibitor prevents inflammation‐related squamous cell carcinogenesis of the forestomach via duodenogastric reflux in rats

BACKGROUND:

Duodenal reflux causes inflammation‐related squamous cell carcinogenesis in the forestomach of rats without any carcinogens. The aim of this study was to investigate the efficacy of a selective cyclooxygenase (COX)‐2 inhibitor, meloxicam, in preventing this carcinogenesis.

METHODS:

A series of 188 rats underwent a surgical duodenogastric reflux procedure and were divided into 2 groups. One group was given commercial chow (control group), and the other was given experimental chow containing meloxicam (0.3 mg/kg body weight/day) (meloxicam group). The animals were sequentially sacrificed at Weeks 20, 30, 40, 50, and 60 after surgery. The forestomach was examined for the presence of carcinoma, the incidence of reflux‐related morphological changes, COX‐2 expression, and its activity.

RESULTS:

At Week 60, squamous cell carcinoma developed in 8 of 21 animals (38%) in the control group, but none of 20 (0%) in the meloxicam group (P < .05). In addition, basal cell dysplasia developed in 19 of 21 (90%) animals in the control group, but only 4 of 20 (20%) in the meloxicam group (P < .01). COX‐2 immunoreactivity was predominantly detected in macrophages in the epithelial stroma. Compared with nonsurgical rats, RNA expression of COX‐2 in the epithelium was up‐regulated, reaching peak at an early stage of Week 20 in both groups (P < .005). The expression of microsomal prostaglandin E synthase‐1 was lower in the meloxicam group than in the control group. PGE₂ production was significantly suppressed throughout the experiment in the meloxicam group compared with the control group (P < .005).

CONCLUSIONS:

Meloxicam was effective in preventing reflux‐induced squamous cell carcinogenesis via an inflamed squamous epithelium. Cancer 2009. © 2009 American Cancer Society.     

Duodenogastric Reflux Increases the Penetration of N-3H-Methyl-N-nitro-N-nitrosoguanidine into the Antral Mucosa of Rats: A Possible Role for Mucosal Erosions and Increased Cell Proliferation in Gastric Carcinogenesis

Duodenogastric reflux is a risk factor for gastric carcinogenesis, but the pathogenesis is not fully understood. We studied the risk of N-methyl-N-nitro-N-nitrosoguanidine (MNNG)-induced carcinogenesis in the antrum of rats with duodenogastric reflux. Duodenal fluid was directed into the stomach through the pylorus (pyloric reflux group) or through a gastrojejunostomy (jejunal reflux group). After twenty-four weeks, 5-bromo-2-deoxyuridine (BrdU) was injected intravenously and the stomach was exposed to N-³H-methyl-N-nitro-N-nitrosoguanidine (³H-MNNG). The antral mucosa was examined with immunohistochemistry and autoradiography for identification of proliferating cells (BrdU labelled) and cells at risk of MNNG-induced carcinogenesis (³H-MNNG and BrdU-labelled cells). Duodenogastric reflux increased the number of double-labelled cells in the antral mucosa from 4.8±0.6 per mm in the control group to 11.3±1.9 in the jejunal reflux group (P<0.05) and 12.7±0.9 in the pyloric reflux group (P<0.05). Mucosal erosions were observed in 15 of 28 annuals with pyloric reflux and the number of double-labelled cells in the erosion area (4.3±0.7) was higher than in the same area of animals without erosion (1.4±0.5) (P<0.05). Duodenogastric reflux increased the cell proliferation and significantly changed the distance between the surface epithelial lining and the proliferating cells when compared to the controls. These results indicate that duodenogastric reflux increases the penetration of ³H-MNNG into the antrum mucosa of rats. Increased cell proliferation and erosions increase the number of cells at risk of an initiation process from a penetrating gastric carcinogen.     

MMP2、TIMP2、bFGF在大鼠肺鳞癌癌变过程中的动态表达

目的 观察诱发大鼠肺鳞癌癌变过程中基质金属蛋白酶（MMP2）其及抑制剂（TIMP2）、碱性成纤维细胞生长因子（bFGF)的动态表达和DNA指数（DI）的变化，探讨上述指标与肺癌发生发展及侵袭转移的关系。方法 用3－甲基胆蒽（3－methylcholanthrene,MCA)及二乙基亚硝胺（diethylnitrosamine,DEN)在左肺叶支气管灌注诱发大鼠肺鳞状细胞癌。第15－270天分批处死动物，取左肺组织。应用免疫组织化学S－P法检测大鼠肺鳞癌癌变各阶段组织的MMP2、TIMP2、bFGF的蛋白表达，在Feulgen染色切片上测量DI值。结果 随大鼠肺鳞癌的发生发展，MMP2、bFGF的表达均逐渐增强，DI值也逐渐增高，但TIMP2的表达增强不明显。不典型增生、原位癌、早期浸润癌阶段，bFGF阳性系数差异有显著性（P＜0.05)，并且原位癌与有远处转移的浸润癌相比，bFGF蛋白表达有极显著性意义（P＜0.01)。原位癌与早期浸润癌相比MMP2表达（P＜0.05)，早期浸润癌与有远处转移的浸润癌之间MMP2表达（P＜0.05)。浸润癌与对照组相比TIMP2的表达（P＜0.01)。大鼠肺鳞癌癌变中TIMP2的表达与MMP2、bFGF的表达呈负相关（P＜0.05)。MMP2的表达与bFGF的表达呈正相关（P＜0.01)。MMP2和bFGF的表达与DNA异倍 体呈正相关（P＜0.01)，并且MMP2与大鼠肺鳞癌晚期发生转移相关。结论 新生血管形成是大鼠肺鳞癌发生发展的重要机制，基底膜（BM）的过度降解破坏是大鼠肺鳞癌侵袭转移的关键。bFGF与肿瘤血管生成、肿瘤的浸润扩散密切相关。MMPs/TIMPs之间的相互作用及平衡状态是恶性肿瘤侵袭转移分子生物学机制中的重要环节。     

幽门螺杆菌致胃癌相关因素研究进展

幽门螺杆菌已被世界卫生组织国际癌症研究机构列为胃癌的第一类致癌物.虽然全世界超过半数人口感染幽门螺杆菌,但最终发展为胃腺癌者仅占感染人群的1％～3％.近年来的观点认为,胃癌是一种感染性疾病,毒力因子、宿主遗传因素和环境因素共同影响着幽门螺杆菌的致胃癌作用.其中,毒力因子在致胃癌初始发生的相关免疫反应中起重要作用,宿主遗传因素可影响炎性反应的严重度并可能加重胃黏膜损伤,而环境因素则可能改变幽门螺杆菌感染的临床结局.本文就幽门螺杆菌致胃癌相关因素的最新研究进展进行综述.     

mTOR与胃癌

哺乳动物雷帕霉素靶蛋白（mTOR）是一种非典型的丝氨酸／苏氨酸蛋白激酶,属于磷脂酰肌醇激酶相关激酶（PIKK）蛋白家族成员。mTOR在肿瘤细胞生长、凋亡和肿瘤血管生成方面起着重要作用。目前以mTOR为靶点的分子靶向药物治疗已成为当前研究的热点。     

mTOR in gastric cancer

Mammalian target of rapamycin (mTOR) is an atypical serine / threonine protein kinase, and belongs to the phosphatidylinositol kinase related kinase ( PIKK) family. mTOR plays an important role in tumor cell growth, apoptosis and tumor angiogenesis. Molecular therapy targeted mTOR has become a hot research topiccurrently.     

Low-protein diet promotes sodium chloride-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine in Wistar rats.

Sodium chloride (NaCl) initiates and promotes experimental carcinogenesis in rats. We recently found that a high-protein diet attenuates NaCl-enhanced gastric carcinogenesis in Wistar rats. To investigate the effect of a purified low-protein diet on NaCl-enhanced gastric carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Wistar rats, rats were fed a purified diet with an equalized caloric content containing 1% or 2% NaCl and 25% casein (normal-protein diet) or 10% casein (low-protein diet) after oral treatment with MNNG for 25 weeks. In week 52, neither 1% nor 2% NaCl had a significant effect on gastric carcinogenesis in rats fed a normal-protein diet. However, oral administration of 2%, but not 1%, NaCl significantly increased the incidence of gastric cancers in rats fed a low-protein diet. Oral administration of 2% NaCl also significantly increased the bromodeoxyuridine (BrdU)-labeling index and the ornithine decarboxylase (ODC) activity and decreased apoptosis of gastric cancers in rats fed a low-protein diet. However, 2% NaCl had no significant effect on these three parameters in rats fed a normal-protein diet. These findings indicate that a low-protein diet enhances the effect of NaCl in gastric carcinogenesis and that this enhancement may be mediated by increased cell proliferation and reduced apoptosis of gastric cancers.     

Pathologic characteristics of gastric cancer in the elderly: a retrospective study of 994 surgical patients

Background The clinicopathologic features of gastric carcinoma in elderly people have been reported previously. The present study examined the patterns and distribution of gastric carcinomas in the elderly, especially in patients aged 85 and older.Methods A retrospective study of 994 consecutive Japanese patients aged 65 years or older was performed. In this group, a total of 1147 lesions were analyzed. Pathological findings in the very old group (older than 85 years; n = 126) were compared with those in younger groups (65–74 years [young-old group]; n = 356) and (75–84 years [middle-old group]; n = 512).Results While the male-to-female ratio significantly decreased with advancing age, the relative odds of gastric cancer in men were higher than those in women in all age groups. In the very old group, cancer of the lower third of the stomach tended to increase with advancing age, and accounted for 43.7% of cases. In the population overall, differentiated-type adenocarcinoma accounted for 89.6% in the early cancers and 50.3% in the advanced cancers. The proportion of cases involving differentiated-type carcinoma significantly increased with advancing age in early cancer and female advanced cancer cases, whereas no significant change was found in male advanced-cancer patients. In the very old group, lymph node metastasis was found in 5.4% of early cancers and 72.7% in advanced cancers. Multiple cancers significantly increased with advancing age (P < 0.05; 10.7% in the younger-old group, 12.7% in the middle-old group, and 19.0% in the very old group).Conclusion These results indicate that, in the very old group, gastric cancers showed a distal shift with predominantly differentiated-type carcinoma in the early stages and increased undifferentiated-type carcinomas in advanced stages. These results suggest increased histologic diversity with tumor growth. These findings have important implications for the screening and diagnosis of gastric cancer in the elderly.     

胃癌腹膜转移的相关基因

胃癌腹膜转移涉及黏附、降解、移动、血管生成等阶段,每一阶段均有多种基因的改变和各种生物学活性物质的参与.随着分子生物学的发展,参与转移的基因越来越多地作为早期诊断的肿瘤标记物或是分子治疗的靶点而被应用于基础实验和临床研究.     

恶性肿瘤pH依赖性生理性耐药及其对策

目前绝大多数的肿瘤耐药机制研究均集中于肿瘤细胞基因和蛋白水平,而对肿瘤组织微环境的关注则相对较少.恶性实体瘤实际上是一个类似于器官的异质性实体结构,肿瘤组织微环境中的理化因子,例如肿瘤局部pH值、血流、压力和氧供等,均会对药物的疗效产生重要的影响.上述现象被定义为“生理性耐药”,其不同于信号通路或蛋白表达改变所引起的耐药.本文将重点介绍肿瘤组织局部pH值变化引起的耐药,即pH依赖性生理性耐药(pH-induced physiological drug resistance,PIPDR)的产生及其临床意义.     

Proton Pump Inhibitor Use and the Efficacy of Chemotherapy in Metastatic Colorectal Cancer: A Post Hoc Analysis of a Randomized Phase III Trial (AXEPT)

BackgroundConcomitant use of proton pump inhibitors (PPIs) with capecitabine was suggested to be associated with poor outcomes in gastrointestinal cancers. We analyzed the differential impact of PPI use on capecitabine and fluorouracil using the data set from the AXEPT trial, a phase III randomized trial that demonstrated the noninferiority of mXELIRI (modified XELIRI: capecitabine plus irinotecan) to FOLFIRI (leucovorin, fluorouracil, and irinotecan), either with or without bevacizumab in patients with metastatic colorectal cancer.Patients and MethodsOut of the per‐protocol set (n = 620), patients with information on concomitant medications (n = 482) were included in this post hoc analysis. PPI use was defined as concomitant exposure of capecitabine and the use of any PPI for 20% or more of the study period. The treatment‐by‐PPI‐use interaction was examined after adjusting for stratification factors.ResultsOf the 482 patients, 49 (10.1%) used PPI. Among the PPI users, the mXELIRI group tended to have poorer overall survival compared with the FOLFIRI group. In contrast, among the nonusers, the overall survival of the mXELIRI group was significantly better than that of the FOLFIRI group. Similarly, a trend of worse progression‐free survival with mXELIRI compared with FOLFIRI was observed in PPI users but not in nonusers. Treatment‐by‐PPI‐use interaction was significant for overall survival and progression‐free survival.ConclusionThe significant interaction between PPI use and the type of fluoropyrimidine in terms of overall and progression‐free survival suggests that fluorouracil could be a more favorable option than capecitabine for patients with metastatic colorectal cancer using PPIs.Implications for PracticeThis study showed a significant interaction between the use of proton pump inhibitors (PPIs) and the type of fluoropyrimidines. This interaction mainly comes from the positive impact of PPIs in the survival outcomes in the fluorouracil arm rather than a negative impact of PPIs in the capecitabine arm. The possible drug‐drug interaction shown in this study suggests that fluorouracil, rather than capecitabine, could be a more appropriate choice of fluoropyrimidine for patients who are taking PPIs in the treatment of metastatic colorectal cancer.     

Proton pump inhibitors for the treatment of cancer in companion animals

The treatment of cancer presents a clinical challenge both in human and veterinary medicine. Chemotherapy protocols require the use of toxic drugs that are not always specific, do not selectively target cancerous cells thus resulting in many side effects. A recent therapeutic approach takes advantage of the altered acidity of the tumour microenvironment by using proton pump inhibitors (PPIs) to block the hydrogen transport out of the cell. The alteration of the extracellular pH kills tumour cells, reverses drug resistance, and reduces cancer metastasis. Human clinical trials have prompted to consider this as a viable and safe option for the treatment of cancer in companion animals. Preliminary animal studies suggest that the same positive outcome could be achievable. The purpose of this review is to support investigations into the use of PPIs for cancer treatment cancer in companion animals by considering the evidence available in both human and veterinary medicine.     

癌前病变Caspase-3表达下调与胃黏膜癌变的关联

目的观察Caspase-3蛋白在胃癌及其癌前病变组织中的表达,分析它与细胞凋亡和细胞增殖的关系,探讨Caspase-3蛋白在胃癌发生过程中的生物学意义及相关分子病理学机制。方法选取184例胃黏膜活检和手术切除组织标本,其中胃癌20例,慢性萎缩性胃炎6例,萎缩性胃炎伴肠上皮化生(简称肠上皮化生)31例,萎缩性胃炎伴不典型增生(简称不典型增生)114例;正常对照13 例。采用SABC法检测Caspase-3蛋白的表达;通过图像域值分析计算其阳性指数,分析其与细胞增殖(Ki67蛋白阳性指数)和凋亡(TUNEL指数)的相关关系。结果 Caspase-3蛋白在重度不典型增生组织中的阳性指数(29．8％±3．9％)显著低于轻度(58．3％±4．2％)和中度不典型增生(50．4％± 4．8％)及萎缩性胃炎(68．3％±3．3％)或肠上皮化生(70．9％±4．3％),差异有统计学意义(P<0．05); 而与胃癌(26．9％±3．0％)相比,差异无统计学意义(P>0．05)。Caspase-3蛋白表达与细胞凋亡呈显著正相关(r=0．94,P<0．05),Caspase-3蛋白阳性组细胞增殖指数(18．3％±2．2％)显著低于阴性组(48．9％±3．1％;P<0．05)。结论 Caspase-3蛋白在萎缩性胃炎、肠上皮化生和(或)轻中度不典型增生黏膜中表达上调,而在重度不典型增生及胃癌组织中表达下调,且这种变化与细胞凋亡呈显著正相关。Caspase-3失活或表达下调相关的细胞凋亡和增殖紊乱可能在胃黏膜损伤及癌变过程中起某种作用。     

榄香烯联合NP方案综合治疗晚期非小细胞肺癌的临床观察

目的观察榄香烯联合NP化疗方案、沙利度胺以及化疗前24 h口服质子泵抑制剂(PPI)综合治疗晚期非小细胞肺癌的疗效。方法将136例晚期非小细胞肺癌患者随机分为对照组和综合治疗组,各68例。综合治疗组给予长春瑞滨、顺铂化疗及口服沙利度胺、静脉滴注榄香烯注射液,化疗前24 h口服质子泵抑制剂(PPI)等治疗;对照组给予长春瑞滨、顺铂化疗。21天为1个周期,2~3个周期后评价疗效。结果综合治疗组有效率(CR+PR)为76.5%(52/68),明显高于对照组48.5%(33/68);综合治疗组1年、2年、3年生存率分别为88.2%、57.4%、33.8%,中位生存期为22个月;而对照组分别为60.3%、29.4%、13.2%,中位生存期为9个月。2组生存差异比较,有统计学意义(P<0.01)。KPS评分及体重变化综合治疗组明显好于对照组(P<0.01)。综合治疗组及对照组Ⅱ度及Ⅱ度以上胃肠道反应总发生率分别为16.2%(11/68)和47.1%(32/68),2组间差异有统计学意义(P<0.01)。结论榄香烯联合NP化疗方案、沙利度胺以及化疗前24 h口服质子泵抑制剂(PPI)综合治疗晚期非小细胞肺癌能明显提高患者近期治疗有效率和生存率,降低肿瘤耐药,提高化疗药物的疗效,增强机体免疫力,提高生存质量。     

特异性环氧合酶抑制剂和抗癌药联用对胃癌细胞增殖的影响

目的观察特异性环氧合酶抑制剂(SCI)罗非昔布和塞来昔布与抗癌药联用对胃癌细胞增殖的影响。方法0.1μmol/L罗非昔布、50μmol/L塞来昔布与不同浓度5-氟尿嘧啶(5-Fu)、顺铂(DDP)、鬼臼乙叉甙(VP-16)单用、联用48 h。四甲基偶氮唑盐(MTT)法检测各组抑制率,中效原理和金正均法评价SCI与常用抗癌药联用的效果。结果0.1μmol/L罗非昔布和50μmol/L塞来昔布单用对胃癌细胞增殖抑制率分别为42.63%±1.26%和50.67%±2.35%。1、10、100μg/ml抗癌药单用对胃癌细胞增殖抑制率,5-Fu分别为39.75%±3.14%、49.96%±2.08%和87.93%±3.66%;DDP分别为48.28%±2.08%、59.46%±1.69%和88.23%±4.81%;VP-16分别为29.23%±3.27%、49.34%±3.75%和79.24%±2.44%。罗非昔布和塞来昔布与不同浓度抗癌药联用抑制率均高于单用,具有协同作用。结论罗非昔布和塞来昔布与抗癌药联用后起协同作用,SCI可作为抗癌药的化疗增敏剂。     

Sporadic fundic gland polyps with dysplasia or carcinoma: Clinical and endoscopic characteristics

Fundic gland polyps (FGPs) are the most common gastric polyps and have been regarded as benign lesions with little malignant potential, except in the setting of familial adenomatous polyposis. However, in recent years, the prevalence of FGPs has been increasing along with the widespread and frequent use of proton pump inhibitors (PPIs). To date, several cases of FGPs with dysplasia or carcinoma (FGPD/CAs) have been reported. In this review, we evaluated the clinical and endoscopic characteristics of sporadic FGPD/CAs. Majority of the patients with sporadic FGPD/CAs were middle-aged women receiving PPI therapy and without Helicobacter pylori (H. pylori) infection. Majority of the sporadic FGPD/ CAs occurred in the body of the stomach and were sessile and small with a mean size of 5.4 mm. The sporadic FGPs with carcinoma showed redness, irregular surface structure, depression, or erosion during white light observation and irregular microvessels on the lesion surface during magnifying narrow-band imaging. In addition, sporadic FGPs, even with dysplasia, are likely to progress to cancer slowly. Therefore, frequent endoscopy is not required for patients with sporadic FGPs. However, histopathological evaluation is necessary if endoscopic findings different from ordinary FGPs are observed, regardless of their size. In the future, the prevalence of FGPs is expected to further increase along with the widespread and frequent use of PPIs and decreasing infection rate of H. pylori. Currently, it is unclear whether FGPD/CAs will also increase in the same way as FGPs. However, the trends of these lesions warrant further attention in the future.