Mouse models for gastric cancer: Matching models to biological questions

Gastric cancer is the third leading cause of cancer‐related mortality worldwide. This is in part due to the asymptomatic nature of the disease, which often results in late‐stage diagnosis, at which point there are limited treatment options. Even when treated successfully, gastric cancer patients have a high risk of tumor recurrence and acquired drug resistance. It is vital to gain a better understanding of the molecular mechanisms underlying gastric cancer pathogenesis to facilitate the design of new‐targeted therapies that may improve patient survival. A number of chemically and genetically engineered mouse models of gastric cancer have provided significant insight into the contribution of genetic and environmental factors to disease onset and progression. This review outlines the strengths and limitations of current mouse models of gastric cancer and their relevance to the pre‐clinical development of new therapeutics.     

Prevalence and prognosis of gastric cancer detected by screening in a large Japanese population: data from a single institute over 30 years

BACKGROUND AND AIM: In Japan, screening examination with photofluorography is widely performed to reduce the mortality due to gastric cancer. The possibility of a future decline in gastric cancer cases and changes in its characteristics is suggested. The aim of this study was to examine the usefulness of direct radiology as a general health screening technique and the historical changes of gastric cancer in Japan. METHODS: This study involved 936 patients with gastric cancer whose carcinomas were detected by direct radiology as part of a general health screening at the Aichi Prefectural Center for Health Care from 1970 to 2000. We studied the prevalence of gastric carcinoma, its prognosis, differences between the two histological types of carcinoma and historical changes. RESULTS: The age-adjusted cancer detection rate slightly decreased. Comparing two histological types, diffuse-type carcinoma cases relatively increased. Intestinal-type carcinomas increased in the lower portion of the stomach, whereas diffuse-type increased in the upper portion. The 5-year survival rate was 92.7% for intestinal-type carcinoma and 84.8% for diffuse-type. Diffuse-type carcinomas were further progressed than intestinal-type when detected by direct radiology; however, detection of diffuse-type improved, so the percentage of early gastric cancer of diffuse type significantly increased, and the survival rate significantly improved, from 70.4% to 90.5%. CONCLUSION: The prevalence of gastric cancer has been decreasing, but the proportion of diffuse-type carcinoma localized in the upper portion of the stomach has been increasing in Japan.     

Serum screening for detection of high-risk group for early-stage diffuse type gastric cancer in Japanese

Background and Aim: Serum screening systems are beneficial for gastric cancer mass surveys; however, the marker for diffuse type gastric cancer (DGC) is not defined. We attempted to define the high‐risk group for DGC by using serum markers of anti‐Helicobacter pylori antibody and pepsinogens (PG). Methods: Forty‐two patients in the early stage of DGC and 511 controls were enrolled. Fasting serum samples were collected, and anti‐H. pylori antibody and PG were evaluated. The risk for DGC was calculated. Results: The prevalence of DGC was higher in H. pylori‐positive patients (odds ratio [OR] = 4.3 in men, 9.6 in women). DGC prevalence was significantly higher in the PG1+ group in women (OR = 10.7); however, it was lower in the PG3+ group in both men and women. Patients with PG II ≥ 30 revealed a significantly higher risk for DGC. By combining factors, higher OR (OR = 12.5 in men, 42.7 in women) were obtained when we defined the risk group as H. pylori‐positive, PG‐negative, and having PG II ≥ 30. Conclusion: The risk group for DGC can be defined by evaluating ordinary serum gastritis markers.     

A morphologic study of gastric carcinoma in southern India

A detailed histologic and histochemical analysis of resected specimens of stomach showed that in southern India the intestinal type of gastric carcinoma was the most prevalent. This suggests that this region is a high risk area for gastric carcinoma. A minority of patients (16%) were below 40 years of age but the prevalence of chronic gastritis or intestinal metaplasia was not higher in this age group. Possible factors contributing to the aetiology are discussed.     

Prevalence of subtypes of intestinal metaplasia in gastric antral mucosa

A prospective gastroscopic-bioptic study of 533 patients was performed to assess the prevalence and distribution of intestinal metaplasia (IM) and its subtypes in the antral mucosa of patients with various upper intestinal disorders and to assess whether the presence of certain IM subtypes might be of help in selecting patients for careful endoscopic-bioptic surveillance in the screening for gastric carcinoma. IM was found in 135 patients (25.3%). Its prevalence increased with age (P<0.001) and was strongly associated with intestinal-type carcinoma as compared to diffuse-type carcinoma (P<0.001), gastritis (P<0.001), and gastric ulcer (P<0.05). Type I IM was predominant (98.5%), whereas types II and III IM, respectively, were found in 77.8% and 15.6% of the patients with IM. No difference in the prevalence of type I and II IM was found among the various gastric disease states. Type III IM was strongly associated with intestinal-type carcinoma as compared to either benign lesions (P<0.01) or diffuse-type carcinoma. These results suggest that type III IM may play a special role in the histogenesis of intestinal-type carcinoma and suggest that the finding of this IM subtype in gastric biopsies may possibly be of help in identifying patients at greater risk of developing carcinoma.     

Role of intestinal metaplasia subtyping in the risk of gastric cancer in Korea

Background and Aim:  Gastric cancer is believed to develop by a multistage process. Intestinal metaplasia (IM) is regarded as a premalignant condition; it is classified into subtypes I, II and III. The aim of this study was to evaluate whether the subtypes of IM were associated with progression to gastric cancer.
Methods:  The study cohort consisted of 861 subjects, categorized as controls, gastric ulcers, dysplasia and cancer. The IM was scored histologically using the Sydney classification for the antrum and the body of the stomach. The biopsies were stained with high iron diamine and alcian blue (pH 2.5) (HID-AB2.5), and the IM was subtyped as I, II or III.
Results:  The proportion of IM subtypes I, II and III were 14.5%, 47.2% and 38.3% in the antrum, and 28.1%, 57.8% and 14.1% in the body of the stomach, respectively. These distributions did not show significant differences depending on disease or Helicobacter pylori positivity. In cases that were H. pylori -positive, the prevalence of IM subtype II in the cancer and dysplasia groups was higher than in the control group in the body of the stomach ( P  < 0.05). The proportion of IM subtype III in the antrum increased in proportion with age ( P  = 0.036).
Conclusions:  IM subtyping was not found to play a major role in the prediction of gastric cancer development in Korea. IM subtype III was associated with aging, and IM subtype II appeared to be related to gastric carcinogenesis in the presence of H. pylori infection.     

The role of endoscopy in the management of hereditary diffuse gastric cancer syndrome

Hereditary diffuse gastric cancer(HDGC) syndrome is an inherited cancer risk syndrome associated with path-ogenic germline CDH1 variants. Given the high risk for developing diffuse gastric cancer, CDH1 carriers are recommended to undergo prophylactic total gastrectomy for cancer risk reduction. Current guidelines recommend upper endoscopy in CDH1 carriers prior to surgery and then annually for individuals deferring prophylactic total gastrectomy.Management of individuals from HDGC families without CDH1 pathogenic variants remains less clear, and management of families with CDH1 pathogenic variants in the absence of a family history of gastric cancer is particularly problematic at present. Despite adherence to surveillance protocols, endoscopic detection of cancer foci in HDGC is suboptimal and imperfect for facilitating decision-making. Alternative endoscopic modalities, such as chromoendoscopy,endoscopic ultrasound, and other non-white light methods have been utilized,but are of limited utility to further improve cancer detection and risk stratification in HDGC. Herein, we review what is known and what remains unclear about endoscopic surveillance for HDGC, among individuals with and without germline CDH1 pathogenic variants. Ultimately, the use of endoscopy in the management of HDGC remains a challenging arena, but one in which further research to improve surveillance is crucial.     

Pedunculated gastric carcinoma demonstrating a gastric foveolar phenotype

We report a case of gastric cancer complicated with very well differentiated adenocarcinoma containing signet ring cells. An endoscopic examination revealed a pedunculated polyp in the fornix of the stomach. A surgical operation was performed and the pathological findings showed very well differentiated adenocarcinoma mimicking gastric foveolae with a poorly differentiated component containing signet ring cells. This is the first case of pedunculated gastric cancer complicated with very well differentiated adenocarcinoma containing signet ring cells and also demonstrating a gastric foveolar phenotype.     

Frequent loss of heterozygosity at 8p22 chromosomal region in diffuse type of gastric cancer

AIM： TO study the loss of heterozygosity （LOH） at 8p21-23 locus in diffuse gastric cancer.
METHODS： To evaluate the involvement of this region in gastric cancer, we used eight microsatellite markers covering two Mb of mentioned region, to perform a high-resolution analysis of allele loss in 42 cases of late diffuse gastric adenocarcinoma.
RESULTS： Six of these STS makers： D8S1149, D8S1645, D8S1643, D8S1508, D8S1591, and D8S1145 showed 36%, 28%, 37%, 41%, 44% and 53% LOH, respectively.
CONCLUSION： A critical region of loss, close to the NAT2 locus and relatively far from FEZ1 gene currently postulated as tumor suppressor gene in this region.     

The intestinal and diffuse types of gastric carcinoma in Maori and non-Maori patients in Auckland

Histologic specimens of gastric carcinoma from 128 Maori, Pacific Island Polynesian, and European patients in Auckland, New Zealand, were classified into intestinal or diffuse type. The ratio of intestinal to diffuse type (ID) was lowest (0.3) in the female Maori patients and highest (1.4) in the male Maori. The higher ID ratio reflects the increased risk of gastric carcinoma in the Maori men as compared with the other groups studied.     

A clinical and pathological study of diffuse type hepatocellular carcinoma

ABSTRACT— Six autopsy cases of the rare, diffuse type of hepatocellular carcinoma (HCC), as classified gross anatomically according to the strict definition, have been studied. The prominent clinical feature was the rapid deterioration of the patient's general condition, terminating in hepatic failure. The liver size enlarged quickly, at a perceptible speed, often accompanied by abdominal pain. Diagnosis of this particular type of HCC was difficult, and celiac angiography and scintiscan of the liver were only suggestive when considered together with other laboratory data. Hepatitis B surface antigen was positive in all three patients in whom it was tested. The entire liver was studded with minute, uniformly sized tumor nodules, evenly distributed throughout. Some of them were grossly indistinguishable from cirrhotic nodules. All livers had an underlying cirrhosis which was characterized by relatively small regenerative nodules with thin stromas. Large portal branches at the hilum contained tumor thrombi in all patients, except for one case in which left lobectomy was followed by intraportal dissemination. Histologically, all tumor nodules represented intrahepatic metastases via the portal vein system. Tumor cells were poorly differentiated. These findings suggest that the diffuse type of HCC most frequently, if not always, represents intrahepatic, widespread portal metastases which have occurred within a short period of time.     

Clinicopathological features of early gastric cancer with duodenal invasion

The incidence of early gastric cancer （EGC） with duodenal invasion is extremely low, although advanced gastric cancer that arises in the antrum occasionally invades the duodenum. We investigated the clinicopathological features of EGC with duodenal invasion and provided strategies for clinical management.A Medline search was performed using the keyword early gastric cancer＂ and ＂duodenal invasion＇： Additional articles were obtained from references within the papers identified by the Medline search. We revealed that EGC with duodenal invasion was of the superficial spreading type of tumor. Tumors 〉 60 mm in size invaded the duodenum more extensively, and the distance of duodenal invasion from the pyloric ring was further in the elevated type than in the depressed type of tumor.There was no significant difference between the length of duodenal invasion and the histological type of the tumor. Gastric cancer located adjacent to the pyloric ring, even if cancer invasion was confined to the mucosa or submucosa, was more likely to invade the duodenum.The present study reveals that the elevated type of EGC is associated with more extensive duodenal invasion when the tumor size is 〉 60 ram, thus highlighting the importance of identification of duodenal invasion in these cases. We also reveal that sufficient duodenal resection with a cancer-free distal surgical margin should be performed in cases of duodenal invasion.     

肠型胃腺癌及不典型增生组织中血管活性肠肽mRNA表达的研究

目的　血管活性肠肽 (VIP)与肿瘤关系密切 ,VIP可促进和 /或抑制一些肿瘤生长 ,而且一些肿瘤细胞有VIP的自分泌调节作用。VIP对胃癌生长的影响 ,胃癌细胞是否分泌VIP及存在VIP自分泌调节作用尚有争议。研究肠型胃腺癌及不典型增生组织中VIPmRNA的表达情况 ,试图探讨VIP在胃腺癌发生发展中的作用。方法　通过RT PCR方法 ,检测 1 5例正常胃窦黏膜、1 6例不典型增生胃黏膜及 2 0例肠型胃腺癌组织中VIPmRNA的表达量 ,通过与恒定表达的β actin(内参照 )mRNA表达量比较 ,计算出VIPmRNA与 β actinmRNA表达量的积分光密度比值 (V/B) ,以V/B值反映各组织中VIPmRNA表达量的高低。结果　肠型胃腺癌组织中V/B值明显高于不典型增生胃黏膜及正常胃窦黏膜 ,其V/B值分别为 :1 .452 2± 0 .32 82 ,0 .962 3± 0 .2 2 5 0 ,0 .951 3± 0 .2 66 9,差异有非常显著性 (P<0 .0 1 )。正常胃窦黏膜与不典型增生胃黏膜中 ,V/B值的差异无显著性 (P >0 .0 5)。结论　肠型胃腺癌组织VIPmRNA表达量明显高于不典型增生胃黏膜 ;VIP可能在肠型胃腺癌的发生发展中起重要的作用。     

胃黏膜肠上皮化生内镜诊断和分级的研究进展

胃黏膜肠上皮化生（gastric intestinal metaplasia,GIM）是一种癌前组织病理学改变,其临床意义在于对胃癌发生风险的提示,有着大面积肠上皮化生背景的胃黏膜具有较高的癌变风险;另外,不完全型GIM与肠型胃癌相关。因此,GIM的内镜下监测对及时发现和管理早期胃癌具有重要意义。可操作的GIM胃癌风险评估分级提供了较好地针对肠上皮化生的胃黏膜癌变风险评估,但每次评估需要标准的活检,增加了损伤风险,GIM内镜分级在此背景下被提出,但其应用受内镜诊断GIM的准确性和临床使用的便捷性所制约。笔者分析了各类内镜下诊断技术对GIM的诊断效果,结合人工智能辅助识别GIM面积,综述EGGIM评分的可行性。     

Decreased incidences of intestinal and diffuse types of gastric carcinoma in Finland during a 20-year period

The incidence of gastric carcinoma (GCA) has decreased throughout the world. This decrease is attributed to a decline in incidence of the intestinal type of GCA (IGCA), whereas the diffuse (DGCA) type of GCA is considered to be endemic in nature and more stable in incidence. In the present study we have estimated how much the incidences of IGCA and DGCA have decreased in percentage in Finland from 1952-61 to 1972-81. Our calculations are based on the Finnish Cancer Registry data of new GCA cases, on population statistics in Finland, and on the percentage distribution of GCA subtypes in three consecutive samples of GCA patients collected in the time periods 1952-61 (reference series) and 1972-81 (two separate samples: series A and B). The samples totaled 1837 GCA cases. We calculated that the incidence of IGCA had decreased from 1952-61 to 1972-81 by 62-71% (reference series versus series A - reference series versus series B) among men and by 69-70% among women. Correspondingly, the incidence of DGCA was calculated to have decreased by 30-39% among men and 37-42% among women. We conclude that not only has the incidence of IGCA decreased in percentage approximately twice as much as the incidence of DGCA but DGCA has also distinctly decreased in incidence in Finland from 1952-61 to 1972-81.     

Intestinal metaplasia and gastric carcinoma: A histological study of 198 gastrectomy specimens

One hundred and ninety-eight consecutive gastrectomy specimens (78 gastric carcinomas, 120 benign lesions) were reviewed and examined to study the relation between intestinal metaplasia (IM) and gastric carcinomas (GC). IM was classified as complete (type I) and incomplete (types II and III) depending on the types of mucin secreted. Only type III IM was found to be significantly associated with GC ( P = 0.0005) when GC was treated as a group in contrast to non-neoplastic lesions. On subdivsion into different types of GC, such association was only found in the intestinal type but not the diffuse type. The significance of the association between type III IM and the intestinal type GC is discussed. In addition, dysplasia was significantly associated with GC and not with benign lesions ( P < 0.005).