血清学指标联合筛查对胃癌诊断的临床意义

目的用统计学和生物信息学找到胃癌早期诊断的生物标志,建立诊断模型。方法回顾性分析解放军总医院2009年至2010年消化科的住院患者179例,根据胃镜检查结果分为胃癌组（139例）和不典型增生组（40例）。用统计学的多参数法分析胃癌和不典型增生患者的血清学参数。用SPSS18.0统计学软件分析两组血清肿瘤标志物、细胞因子以及常规生化指标的差异,建立分类模型。结果在所有的血清学指标中,两组有20项有差异（P〈0.05）,其中12项具有显著差异（P〈0.01）。单一指标的诊断准确率均较低,IL-6和CEA的诊断水平最高,曲线下面积（AUC）分别为0.824和0.721。Logistic回归分析显示,CEA、CA72-4、IL-6、IMA、SOD和ApoA1在胃癌的鉴别诊断中有重要的统计学意义,分类预测准确度达85.3%。结论用统计学软件对大量数据进行挖掘,为胃癌的早期诊断提供了有前景的研究方向。CEA、CA72-4、IL-6、IMA、SOD和ApoA1在胃癌和不典型增生的鉴别诊断中有着重要的意义。     

<Emphasis Type="Italic">Helicobacter pylori</Emphasis> infection and gastric cancer

Helicobacter pylori infection has an association with histological gastritis, gastric atrophy, gastric cancer, and mucosa-associated lymphoid tissue (MALT) lymphoma in the stomach. Gastric cancer occurs in only a minority of infected individuals, however. Such clinical diversities are caused by variations of H. pylori pathogenicity, host susceptibility, environmental factors, and interactions of these factors. By three prospective epidemiological studies, the International Agency for Research on Cancer, World Health Organization (IARC/WHO) concluded in 1994 that H. pylori had a causal linkage to gastric carcinogenesis and is a definite carcinogen in humans. In addition, the Mongolian gerbil model with or without low-dose chemical carcinogens demonstrated that H. pylori infection could develop into gastric cancer. The experimental studies have elucidated that virulence factors of H. pylori have an interaction with gastric epithelial cell signaling related to carcinogenesis. The cag pathogenicity island (cagPAI) is a major virulence gene cluster and codes the type IV secretion machinery system, forming a cylinder-like structure. The CagA protein is translocated into target cells via this secretion system and induces a hummingbird morphology, growth factor-like effect. The other gene products are probably translocated into target cells and accelerate cellular proliferation and apoptosis. Understanding the molecular mechanism of the interaction between H. pylori and gastric epithelial cells will provide us with a new strategy for effective prevention of the development of gastric cancer induced by H. pylori infection.     

Comparison of serum trefoil factor 3 with the pepsinogen test for the screening of diffuse-type gastric cancer

Emerging data show that serum trefoil factor 3 (TFF3) alone and combined with the serum pepsinogen (PG) test can increase the diagnostic yield of gastric cancer. We aimed to evaluate the diagnostic value of serum TFF3 for the screening of gastric cancer in Korean patients, especially for the screening of the diffuse type of gastric cancer, and compared TFF3 to the serum PG test. We enrolled 25 healthy controls and 79 subjects with gastric cancer who underwent endoscopic resection or surgery from June 2006 to June 2015. Data about age, sex, histological type according to the Lauren classification, stage of gastric cancer, and status of H. pylori were collected. Serum levels of PG I and PG II were measured by the latex-enhanced turbidimetric immunoassay, and serum TFF3 levels were measured by enzyme-linked immunosorbent assay. The optimal cutoff value of serum TFF3 was ≥8.9 ng/mL to diagnose gastric cancer, with 73.4 % sensitivity and 92.0 % specificity, which were higher than those of the serum PG I/II ratio, with 69.6 % sensitivity and 68.0 % specificity. The optimal sensitivity and specificity of serum TFF3 for the diagnosis of diffuse-type gastric cancer were 68.0 and 92.0 %, respectively, which were lower than those for the diagnosis of intestinal-type gastric cancer (75.6 and 100 %, respectively). Serum TFF3 is a more stable and useful marker than the serum PG test for the screening of gastric cancer in Korean patients. Serum TFF3 showed good diagnostic power in detecting both intestinal- and diffuse-type gastric cancer although it showed decreased power in diffuse type.     

Histologic types and possible initial stages in early gastric carcinoma.

Among 2003 gastric specimens from 301 patients, diagnosis for carcinoma was made in 45 cases. Examination of resection preparations revealed 36 cases of deep invasive stomach carcinoma and 9 cases of early gastric cancer confined to mucosa and/or submucosa. Carcinomatous proliferations limited to mucosa or submucosa are classified in three histologic types: intestinal (adeno), mucocellular (signet ring cell), and anaplastic (solid) type of early gastric cancer. Mixed types have been found combining the first and the second, or the second and the third type. One case presented a mixture of all three types. Possible precursor or initial stages of all three types were found in further 31 biopsies. Some of them were glandular lesions in superficial parts of the mucosa; this kind has been described previously as possible preneoplastic stage of the intestinal type of early gastric cancer. "Signet ring cell drippings" from lower parts of tubule necks were recorded as an initial form of the signet ring cell type. The process is interpreted as detaching of isolated signet ring cells from a gland neck zone in progressing atypical transformation. An early neoplastic stage of the anaplastic (solid) type of early gastric cancer is identified in the "gland neck dysplasia" located exclusively in the antrum between surface mucosa and antrum glands. This lesion appears rich in cells and stretched like a broad ribbon. Early gastric cancer of this third type will arise in the very same location. Conclusions from formal histogenesis suggest that the signet ring cell type and the anaplastic (solid) type of early gastric cancer might start in the lower part of tubule necks. In consequence, the neck region of gastric glands could be the critical field of malignant transformation in the gastric mucosa. Long-term follow-up studies will be needed to verify these observations and their interpretation.     

Gastric Cancer Screening in Common Variable Immunodeficiency

Individuals with common variable immunodeficiency (CVID) have an increased risk of gastric cancer, and gastrointestinal lymphoma, yet screening for premalignant gastric lesions is rarely offered routinely to these patients. Proposed screening protocols are not widely accepted and are based on gastric cancer risk factors that are not applicable to all CVID patients. Fifty-two CVID patients were recruited for screening gastroscopy irrespective of symptoms or blood results and were compared to 40 controls presenting for gastroscopy for other clinical indications. Overall, 34% of CVID patients had intestinal metaplasia (IM), atrophic gastritis or moderate to severe non-atrophic gastritis, which can increase the risk of gastric cancer, compared to 7.5% of controls (p <?0.01). Focal nodular lymphoid hyperplasia, a precursor lesion for gastrointestinal lymphoma, was seen in eight CVID patients (16%), one of whom was diagnosed with gastrointestinal lymphoma on the same endoscopy. High-risk gastric pathology was associated with increased time since diagnosis of CVID, smoking, Helicobacter pylori, a low-serum pepsinogen I concentration, and diarrhea, but not pepsinogen I/II ratio, iron studies, vitamin B12 levels or upper gastrointestinal symptoms. There was a lower rate of detection of IM when fewer biopsies were taken, and IM and gastric atrophy were rarely predicted by the endoscopist macroscopically, highlighting the need for standardized biopsy protocols. The prevalence of premalignant gastric lesions in patients with CVID highlights the need for routine gastric screening. We propose a novel gastric screening protocol to detect early premalignant lesions and reduce the risk of gastric cancer and gastric lymphoma in these patients.     

Gastric intestinal metaplasia: subtypes and natural history

BACKGROUND: It has been suggested that the subtyping of intestinal metaplasia in the stomach is useful in stratifying patients with regard to risk of developing gastric cancer. AIM: To determine whether subtyping intestinal metaplasia provided useful information regarding the natural history of intestinal metaplasia. METHODS: The study used large cup gastric biopsy specimens from predetermined locations (gastric mapping). Follow up biopsies were obtained at one, two, and/or nine years. Biopsies with intestinal metaplasia were stained with high iron diamine/Alcian blue (HID/AB) to determine whether they expressed neutral mucins, sialomucins, or sulphomucins. RESULTS: Seventy nine patients with intestinal metaplasia were studied and characterised with regard to the most advanced subtype of intestinal metaplasia. The most severe type of intestinal metaplasia was type II in 33 patients and type III in 34 patients. Helicobacter pylori was cured in 67 patients. Follow up showed that changes in type of metaplasia (apparent regression or progression) occurred in both directions and were independent of H pylori status. For example, biopsy sites with "loss" of metaplasia at a follow up visit might have it "reappear" at a subsequent visit. During follow up, no patient developed gastric dysplasia or died from gastric cancer. CONCLUSION: HID subtyping did not provide useful information to the clinician or the pathologist. The data are consistent with the notion that the pattern, extent, and severity of atrophy with/without intestinal metaplasia is a far more important predictor of increased cancer risk than intestinal metaplasia subtype.     

Gastrin Is an Essential Cofactor for Helicobacter-Associated Gastric Corpus Carcinogenesis in C57BL/6 Mice

We have previously described a synergistic interaction between hypergastrinemia and Helicobacter felis infection on gastric corpus carcinogenesis in FVB/N mice housed under specific-pathogen-free conditions. However, gastrin-deficient (GAS-KO) mice on a mixed C57BL/6/129Sv genetic background maintained in conventional housing were reported to develop spontaneous gastric antral tumors. Therefore, we investigated the role of gastrin in Helicobacter-associated gastric carcinogenesis in H. felis-infected mice on a uniform C57BL/6 background housed in specific-pathogen-free conditions. Hypergastrinemic transgenic (INS-GAS) mice, GAS-KO mice, and C57BL/6 wild-type mice were infected with H. felis for either 12 or 18 months. At 12 months postinfection, INS-GAS mice had mild corpus dysplasia, while B6 wild-type mice had either severe gastritis or metaplasia, and GAS-KO mice had only mild to moderate gastritis. At 18 months postinfection, both INS-GAS and B6 wild-type mice had both severe atrophic gastritis and corpus dysplasia, while GAS-KO mice had severe gastritis with mild gastric atrophy, but no corpus dysplasia. In contrast, both GAS-KO and B6 wild-type mice had mild to moderate antral dysplasia, while INS-GAS mice did not. H. felis antral colonization remained stable over time among the three groups of mice. These results point to a distinct effect of gastrin on carcinogenesis of both the gastric corpus and antrum, suggesting that gastrin is an essential cofactor for gastric corpus carcinogenesis in C57BL/6 mice.Gastric cancer remains the second leading cause of cancer-related mortality in the world, although its incidence and mortality rates have been decreasing in the United States over the past 70 years.^1,2,3 The risk of developing gastric adenocarcinoma is strongly associated with Helicobacter pylori infection, which is gradually disappearing from western societies. Despite the overall decline in gastric cancer prevalence, the treatment of stomach cancer remains a challenging clinical problem, since most patients who undergo surgical resection develop regional or distant recurrences and the overall 5-year survival rate for gastric cancer patients remains around 20% in western countries.³H. pylori, first identified in the gastric antrum of patients with active chronic gastritis and peptic ulcers,⁴ is now recognized as the major cause of gastric cancer, and has been classified as a group I carcinogen by World Health Organization.^5,6 H. pylori infection causes persistent chronic gastritis, which in susceptible individuals may progress to atrophy, intestinal metaplasia, dysplasia, and finally, intestinal-type gastric cancer. This sequence, commonly referred to as Correa’s cascade, is considered the primary histological pathway for the development of intestinal type of gastric cancer,⁷ and is both initiated and promoted by H. pylori infection.It has generally been recognized that H. pylori infection results in a mild (1.5- to 2-fold elevation) hypergastrinemia that occurs early on in the course of the infection in many individuals. Given the known properties of gastrin as a mucosal growth factor, hypergastrinemia was postulated to be a factor promoting the development of gastric cancer. Indeed, previous studies have suggested a possible association between hypergastrinemia, Helicobacter infection, and gastric cancer.^8,9,10,11,12 Therefore, to study the role of gastrin and the potential mechanisms involved in gastric carcinogenesis, we developed a mouse model of gastric cancer through the generation of insulin-gastrin (INS-GAS) transgenic mice that overexpressed human amidated gastrin. In the absence of Helicobacter infection, INS-GAS mice on an FVB/N genetic background exhibited mild hypergastrinemia in association with elevated gastric acid secretion and an increased parietal cell number at 1 to 3 months of age. With increasing age, the INS-GAS mice showed progressive loss of parietal cells and significant changes in the corpus, including hypochlorhydria, gastric atrophy, metaplasia, and dysplasia. At 20 months of age, INS-GAS mice developed invasive gastric cancer.⁹ The gastric cancer phenotype was accelerated by gastric Helicobacter spp. infection, and lesion severity was more profound in male INS-GAS mice.¹⁰ The cause of this gender-specific incidence was due in part to ovarian-dependent estrogen production, since H. pylori infected ovariectomized female INS-GAS mice also developed severe gastric neoplasia, and 17beta-estradiol treatment significantly suppressed this phenotype.¹²However, determining the role of gastrin in predisposing individuals to gastric cancer has not been straightforward. Some H. pylori-infected patients have lower levels of gastrin and acid secretion relative to non-infected healthy persons, and hypochlorhydria probably plays an important role in the carcinogenic process through altered bacterial colonization along with changes in nitrite levels.¹³ Gastrin-deficient mice on a mixed C57BL6/129Sv background developed spontaneous gastric antral tumors when maintained under conventional housing conditions at 12 months of age, while C57BL/6 wild-type and somatostatin-deficient mice did not develop tumors.¹⁴ The authors concluded that neoplastic transformation of the antrum does not require gastrin, and that gastrin may actually suppress the development of gastric antral tumors. In addition, there have been other genetic models reported, such as the gp130^757F/F mouse, which do not appear to be dependent on gastrin for tumor development.¹⁵ It has been difficult to reconcile these observations regarding the influence of gastrin on gastric cancer, given the different genetic backgrounds, housing conditions, and Helicobacter infection status. Thus, the purpose of this study is to examine the effect of gastrin in Helicobacter-associated gastric carcinogenesis using hypergastrinemic (INS-GAS) mice and gastrin deficient (GAS-KO) mice on a uniform C57BL/6 background and housed under SPF conditions.     

Serum metabolic profiling of human gastric cancer based on gas chromatography/mass spectrometry

Research on molecular mechanisms of carcinogenesis plays an important role in diagnosing and treating gastric cancer. Metabolic profiling may offer the opportunity to understand the molecular mechanism of carcinogenesis and help to non-invasively identify the potential biomarkers for the early diagnosis of human gastric cancer. The aims of this study were to explore the underlying metabolic mechanisms of gastric cancer and to identify biomarkers associated with morbidity. Gas chromatography/mass spectrometry (GC/MS) was used to analyze the serum metabolites of 30 Chinese gastric cancer patients and 30 healthy controls. Diagnostic models for gastric cancer were constructed using orthogonal partial least squares discriminant analysis (OPLS-DA). Acquired metabolomic data were analyzed by the nonparametric Wilcoxon test to find serum metabolic biomarkers for gastric cancer. The OPLS-DA model showed adequate discrimination between cancer and non-cancer cohorts while the model failed to discriminate different pathological stages (I-IV) of gastric cancer patients. A total of 44 endogenous metabolites such as amino acids, organic acids, carbohydrates, fatty acids, and steroids were detected, of which 18 differential metabolites were identified with significant differences. A total of 13 variables were obtained for their greatest contribution in the discriminating OPLS-DA model [variable importance in the projection (VIP) value >1.0], among which 11 metabolites were identified using both VIP values (VIP >1) and the Wilcoxon test. These metabolites potentially revealed perturbations of glycolysis and of amino acid, fatty acid, cholesterol, and nucleotide metabolism of gastric cancer patients. These results suggest that gastric cancer serum metabolic profiling has great potential in detecting this disease and helping to understand its metabolic mechanisms.     

Proteomic Profiling of Paraffin-Embedded Samples Identifies Metaplasia-Specific and Early-Stage Gastric Cancer Biomarkers

Early diagnosis and curative resection are the predominant factors associated with increased survival in patients with gastric cancer. However, most gastric cancer cases are still diagnosed at later stages. Since most pathologic specimens are archived as FFPE samples, the ability to use them to generate expression profiles can greatly improve cancer biomarker discovery. We sought to uncover new biomarkers for stomach preneoplastic metaplasias and neoplastic lesions by generating proteome profiles using FFPE samples. We combined peptide isoelectric focusing and liquid chromatography–tandem mass spectrometry analysis to generate proteomic profiles from FFPE samples of intestinal-type gastric cancer, metaplasia, and normal mucosa. The expression patterns of selected proteins were analyzed by immunostaining first in single tissue sections from normal stomach, metaplasia, and gastric cancer and later in larger tissue array cohorts. We detected 60 proteins up-regulated and 87 proteins down-regulated during the progression from normal mucosa to metaplasia to gastric cancer. Two of the up-regulated proteins, LTF and DMBT1, were validated as specific markers for spasmolytic polypeptide–expressing metaplasia and intestinal metaplasia, respectively. In cancers, significantly lower levels of DMBT1 or LTF correlated with more advanced disease and worse prognosis. Thus, proteomic profiling using FFPE samples has led to the identification of two novel markers for stomach metaplasias and gastric cancer prognosis.Despite the general advances in endoscopic screening and therapies, gastric cancer 5-year survival rates remain extremely poor,¹ representing the second leading cause of cancer-related death worldwide. The major proximate cause of gastric cancer is chronic Helicobacter pylori infection, which leads to a chronic inflammatory response and subsequent oxyntic atrophy (loss of acid-secreting parietal cells). In the fundus and corpus of the atrophic stomach, two types of metaplasia have been described: intestinal metaplasia (IM), characterized by the presence of cells with intestinal and goblet cell morphologic features, and spasmolytic polypeptide–expressing metaplasia (SPEM), which shows morphologic characteristics of the deep antral glands and expresses trefoil factor 2 (TFF2), originally designated spasmolytic polypeptide.^2,3Both types of metaplasia are associated with intestinal-type gastric cancer^4,5 and are considered neoplastic precursors, although the mechanisms driving the progression from metaplasia to neoplasia remain unclear. Recent studies in mice have found that SPEM originates from the transdifferentiation of mature chief cells.⁶ Other studies in Mongolian gerbils indicate that after H. pylori–induced parietal cell loss, SPEM is the first metaplastic lesion to evolve, whereas IM develops in the setting of preexisting SPEM.^7,8 Recent pathologic examinations in humans have suggested that a similar relationship between SPEM and IM may exist in humans.^9,10Molecular profiling studies have identified a variety of potentially useful markers for gastric cancer.^11–14 However, owing to the high heterogeneity of gastric tumors, no definitive markers have been established. High levels of REG4 were detected in patients with gastric cancer with metastasis, and its expression was correlated with worse prognosis.^14,15 Other studies have noted that REG4 contributes to the resistance of gastric cancer to fluorouracil-based chemotherapy; in addition, patients with gastric cancer showed increased levels of serum REG4. However, despite a specificity of 99%, the diagnostic sensitivity was only 36%.^14,16 OLFM4 expression has been associated with intestinal-type gastric cancer. However, different proportions of OLFM4-positive tumors were observed in two independent studies (65%¹⁷ in contrast to 32%¹¹), and its prognostic value is still not clear.^11,18 Inclusion of the less heterogenous metaplastic lesions in the molecular profiling studies could allow a better understanding of the molecular alterations during gastric carcinogenesis and could lead to the development of early-stage gastric cancer biomarkers. Indeed, in a previous study, mRNA expression profiling of IM and SPEM identified several metaplasia and gastric cancer markers, including CDH17 and MUC13, as useful prognostic markers for stage I gastric cancer.¹¹ The combined loss of four metaplasia markers (CDH17, REG4, MUC13, and LGALS4) is an independent indicator of survival in undifferentiated or stage II/III gastric cancer.¹⁹Formalin-fixed, paraffin-embedded (FFPE) tissue samples are abundantly available in pathology archives, representing a valuable resource for biomarker discovery. Recent developments have facilitated the analysis of proteomic profiles from paraffin-embedded tissues with yields in the range of 90% of the peptides isolated from frozen tissue, showing good equivalence between the protein profiles from frozen and FFPE samples.^20,21 This innovation means that proteomic analysis can be performed on paraffin-embedded tissue samples with defined pathologic and histologic characteristics, allowing more specific analyses in better-characterized samples.In the present studies, we performed proteomic profiling using macrodissected FFPE samples from intestinal-type gastric cancer, stomach metaplasia, and normal mucosa. These studies identified a variety of proteins that are up-regulated in metaplasia and cancer. We identified lactotransferrin (LTF) as a novel specific marker for SPEM and deleted in malignant brain tumor 1 (DMBT1) as a marker for IM. In addition, we found that expression of either LTF or DMBT1 influences the survival of patients with gastric cancer.     

Gene therapy for gastric diseases

Gene therapy for gastric cancer and gastric ulcer is a rationalized strategy since various genes correlate with these diseases. Since gene expressions in non-target tissues/cells cause side effects, a selective gene delivery system targeted to the stomach and/or cancer must be developed. The route of vector transfer (direct injection, systemic, intraperitoneal, gastric serosal surface and oral administration) is an important issue which can determine efficacy and safety. Strategies for cancer gene therapy can be categorized as suicide gene therapy, growth inhibition and apoptosis induction, immunotherapy, anti-angiogenesis, and others. Combination of the target gene with other genes and/or strategies such as chemotherapy and virotherapy is promising. Candidates for treatment of gastric ulcer are vascular endothelial growth factor, angiopoietin-1, serum response factor, and cationic host defense peptide cathelicidin. In this review, we discuss stomach- and cancer-targeted gene transfer methods and summarize gene therapy trials for gastric cancer and gastric ulcer.     

Gastric carcinoma promoted by alkaline reflux gastritis -- with special reference to bile and other surfactants as promoters of postoperative gastric cancer

For reasons that are not known, the incidence of stomach cancer is declining in most countries. In contrast, cancer of the gastric remnant after partial gastrectomy for peptic ulcer disease seems to be increasing. "Stump cancer" has been claimed to be a separate disease entity and has recently been mentioned as an iatrogenic cancer. Alkaline bile reflux, dietary surfactants and maybe the abuse of tobacco are postulated as promoting or initiating agents, in causing malignant transformation of the operated as well as non-operated stomach. Variations in gastric pH, microflora and emptying rate may be of importance in the carcinogenic process. The decline in cancer incidence in the non-operated stomach has mainly been restricted to the intestinal type of cancer. Thus, it is important to note that stump cancer often is of the diffuse type. Different target cells and/or modes of carcinogen exposure may be of etiological importance in these histologically and clinically separate neoplastic diseases.     

Gastric carcinoma with lymphoid stroma

Summary A total of 626 surgically resected gastric carcinomas were reviewed, and 24 cases (3.8%) of gastric carcinoma with lymphoid stroma were identified. The tumour cells were consistently arranged in an anastomosing trabecular or alveolar pattern and were densely infiltrated by lymphoid cells. The specimens were studied using mucin histochemistry and the indirect immunoperoxidase method to determine the histochemical properties of this form of gastric carcinoma. The tumour cells were consistently positive for concanavalin A paradoxical staining, class III and almost devoid of acidic mucins, features demonstrating preferential differentiation toward pyloric glands or pseudopyloric glands. Immunohistochemically, positive reactions for Leu M1 and lysozyme, marker substances of (pseudo)pyloric gland cells, were often observed. Carcinoembryonic antigen was positive in focal areas without (pseudo)pyloric glandular patterns. Secretory component was focally positive. HLA-DR was strongly expressed in most cancer cells and 17 tumours (71%) showed positivity for interleukin 1 (IL-1). The lymphoid stroma contained a high percentage of UCHL1-reactive T cells both within and around the cancer cell nests, while SL26-reactive B cells clustered in lymphoid follicles. A considerable number of T-lymphoid cells were also reactive for IL-1. A number of plasma cells with a predominance of IgG-type were distributed around the cancer cell nests. S-100 protein-positive dendritic cells were not identified. We speculate that the prominent lymphoid stroma including intraepithelial lymphocyte-like T cells with IL-1 receptors is possibly induced by IL-1 related mediators released from the HLA-DR-positive gastric cancer cells of the (pseudo)pyloric gland-type.     

Gastric mucosal calcinosis: clinicopathologic considerations

Generally, gastric mucosal calcinosis (GMC) is only rarely encountered in routine biopsies. GMC may be classified as dystrophic, metastatic, or idiopathic. Metastatic calcification represents the most frequently encountered subtype, and refers to the deposition of calcium salts on largely normal tissues in the setting of an abnormal serum biochemical environment (hypercalcemia, hyperphosphatemia, and/or an elevated CaxPO4 product). In contrast, dystrophic calcification implies calcification in inflammed, fibrotic, or otherwise altered tissue in the setting of a normal biochemical environment. The gastric mucosa, along with the kidneys and lungs, are preferential sites for metastatic calcification, a finding that has been attributed to the relative intracellular alkalinity at these sites. In addition to the wide variety of hypercalcemia and/or hyperphosphatemia-causing clinical conditions, GMC has also been associated with atrophic gastritis, hypervitaminosis A, organ transplantation, gastric neoplasia, uremia with eucalcemia/euphosphatemia, and the use of aluminum-containing antacids, citrate-containing blood products, isotretinoin, and sucralfate. Although GMC has rarely been associated with epigastric pain and/or dyspepsia, most come to clinical attention owing to their accumulation of bone-seeking radiopharmaceuticals or represent a postmortem finding. The precise significance or mechanistic basis for GMC remains to be elucidated. However, their presence in gastric biopsies should be reported, as they may serve as an indicator for generalized metastatic calcification, especially in organs where they may be fatal, such as the heart. Furthermore, some examples of systemic calcification are reversible with normalization of biochemical parameters, which highlights the need for pathologists to report this finding when encountered in a premortem gastric biopsy.     

A study of the antiulcer mechanisms of propanolol in rats

Although propranolol has been shown to protect against enthanol and stress ulceration, the antiulcer mechanisms are still unclear. The present study examined the antiulcer mechanisms of propranolol in three different types of ulceration induced respectively by ethanol (60%), indomethacin (30 mg/kg) and stress (cold-restraint). Propranolol pretreatment in the highest dose (10 mg/kg) given either intraperitoneally (i.p.) or orally (p.o.) prevented gastric mucosal damage in these three ulcer models. The three doses of the drug (2.5, 5 or 10 mg/kg) dose-dependently decreased systemic blood pressure which was accompanied by a reduction of gastric mucosal blood flow. These findings suggest that the protection was unrelated to an improvement of local circulation in the stomach. However, propranolol preserved the mucus levels in the three types of ulcer models. The -adrenoceptor blocker also increased the basal gastric mucosal potential difference. These findings indicate that propranolol strengthens the mucosal barrier by the preservation of mucosal mucus and enhancement of the mucosal integrity in the stomach.accepted by R. O. Day     

Elevated alpha1-acid glycoprotein in gastric cancer patients inhibits the anticancer effects of paclitaxel,effects restored by co-administration of erythromycin

Paclitaxel (PTX) which easily elutes into ascites is widely used to treat gastric cancer patients with peritoneal carcinomatosis (PC), but clinical outcomes are suboptimal. Increased concentrations of α1-acid glycoprotein (AGP), an important drug-binding protein, have been reported in the plasma and ascites of cancer patients. This study sought to clarify whether AGP binds to PTX and alters its anticancer effects. AGP concentrations were measured in the serum and ascites of gastric cancer patients with PC and in the serum of healthy volunteers. The in vitro effects of AGP and AGP plus erythromycin (EM) on PTX were evaluated by MTT assays in the gastric cancer cell lines. We also measured AGP concentrations in the ascites of PC model mice and examined the effects of EM plus PTX on PC. The mean AGP concentrations in the serum and ascites of gastric cancer patients with PC were 1524 and 834 μg/mL, respectively, higher than the mean AGP concentration of 650 μg/mL observed in the sera of healthy volunteers. AGP > 400 μg/mL significantly suppressed the cell growth inhibitory effect of PTX in vitro, but the co-administration of EM restored it. Elevated AGP concentrations were observed in the ascites of PC model mice. Administration of PTX alone did not markedly diminish PC, whereas co-administration of PTX and EM significantly reduced PC (p = 0.011). AGP is an important regulatory factor modulating the anticancer activity of intraperitoneal PTX. The co-administration of PTX and EM may be effective in treating gastric cancer patients with PC.     

Assessment of a HER2 scoring system for gastric cancer: results from a validation study

Aims:  Human epidermal growth factor receptor 2 (HER2) overexpression/amplification is implicated in the development of various solid tumour types. Validated methods and scoring systems for evaluating HER2 status exist in breast cancer, but not in gastric cancer. The aim was to establish a HER2 scoring system for gastric cancer to identify suitable patients for enrolment in a trial of trastuzumab (Herceptin^®) in advanced metastatic gastric cancer.
Methods and results:  Formalin-fixed paraffin-embedded gastric cancer samples were tested for HER2 status using the fluorescence in situ hybridization (FISH) pharmDx™ kit (Dako Denmark A/S). Immunohistochemistry (IHC) was performed using the HercepTest™ (Dako). Concordance between FISH and IHC was 93.5% in 168 evaluable samples. Eleven samples were scored as FISH+ but IHC− or equivocal.
Conclusions:  IHC/FISH discrepancies were attributed to basolateral membranous immunoreactivity of glandular cells resulting in incomplete membranous reactivity and/or a higher rate of tumour heterogeneity in gastric cancer compared with breast cancer. With modifications to the IHC scoring system, the HercepTest™ is considered valid for the identification of HER2+ gastric tumours for this clinical trial. Correlation of HER2 scores with clinical outcomes will be needed to determine which patients might benefit from trastuzumab therapy.     

Two patients with metastasis of cancer to other neoplasm: A thyroid carcinoma metastatic to a lung carcinoma and a gastric carcinoma metastatic to a thyroid adenoma

Two patients with rare cancer-to-neopiasm metastasis are presented. One patient was a 69-year-old woman who had undergone gastrectomy for gastric cancer 10 months previously and died of generalized metastases. An autopsy revealed generalized metastases of the gastric carcinoma, together with a cystic, hemorrhagic thyroid tumor measuring 2.0 cm in diameter. Histologically, the thyroid tumor was an oxyphilic adenoma with multiple metastatic foci of gastric adenocarcinoma. Because no metastasis was found in the background thyroid tissue, this metastasis might have developed specifically and not by chance, most likely due to the rich vascularity and good circulation of the thyroid adenoma. The other patient was an 82-year-old man who had undergone total thyroidectomy for thyroid cancer 6 years previously. An abnormal lung shadow was found on a chest radiograph during postoperative follow-up. Transbronchial biopsy of the lung tumor revealed a squamous-cell carcinoma. The resected lung tumor measured 2.7 cm in diameter, with small foci of metastatic papillary carcinoma of the thyroid gland and multiple small metastases in the background lung tissue, indicating that the metastases to lung cancer had occurred by chance. Metastasis of cancer to other neoplasms is discussed, and a review of the literature is presented.     

Inactivation of the E-cadherin gene in sporadic diffuse-type gastric cancer.

Loss of the cell adhesion molecule E-cadherin has been observed in a variety of human carcinomas, and germline E-cadherin mutations have been found in several familial cases of diffuse gastric cancer. We sought to determine the prevalence and nature of E-cadherin alterations in "sporadic" gastric carcinomas. We performed comprehensive sequencing of the coding region, loss of heterozygosity (LOH) analysis, and immunohistochemical protein expression determination on 40 sporadic gastric adenocarcinomas. In total, 7 of 25 diffuse-type cancers harbored genetic alterations in the E-cadherin gene. Novel mutations predicted to significantly compromise protein function were found within 4 of these cancers, 2 of which harbored alterations resulting in biallelic inactivation of the gene product. Three diffuse cancers failed to amplify Exon 8 of E-cadherin, suggesting the presence of a homozygous abnormality. Notably, one germline E-cadherin mutation was also identified within these "sporadic" diffuse cancers. Significant gene mutations were not found in the 14 intestinal-type or histologically mixed cancer. Immunohistochemistry revealed aberrant or negative protein expression in seven diffuse-type tumors, four of which correlated with the genetic alterations. Both diffuse and intestinal-type tumors exhibited low rates of LOH, suggesting that allelic loss at the locus is not a common mechanism for E-cadherin inactivation during gastric tumorigenesis. Our observations suggest that inactivation of the E-cadherin gene occurs only in a subset of diffuse-type gastric cancers, as the majority of cases did not contain genetic alterations or identifiable protein abnormalities. Germline E-cadherin alterations, although rare, may underlie some diffuse gastric cancer cases that have important biologic and practical implications     

Circulating free plasma tumor DNA in patients with advanced gastric cancer receiving systemic chemotherapy

Background

Advanced gastric cancers are usually associated with incurable conditions for which systemic treatments are indicated. Recent studies suggest that circulating cell-free plasma DNA of tumour origin (tDNA) is a promising non-invasive biomarker that can be used to predict the prognosis and monitor the efficacy of systemic treatments in patients with certain types of cancer. We conducted a pilot study to analyse the potential role of tDNA as a biomarker in patients with advanced gastric cancer.

Methods

We included 30 patients with locally advanced unresectable or metastatic gastric cancer. We obtained samples (10?mL of total blood) from each patient every 3 months and performed concomitant CT until disease progression or death. Total cell-free circulating DNA (cfDNA) samples were measured using GeneQuant RNA/DNA Calculator-Amersham Pharmacia Biotech (Biochrom) Ltd. The cfDNA was used to evaluate the ALU DNA sequences 247 and 115. The level of tDNA was calculated from the ratio of the expression of ALU DNA sequences and the concentration of total cell-free DNA. We utilized the RECIST criteria 1.1 to evaluate the tumour response.

Results

Patients with advanced gastric cancer had significantly higher concentrations of cfDNA compared with normal controls (p =?0.00015), which allowed us to conclude that the cfDNA in the patients originated from the tumour. We did not find any significant correlation between the level of tDNA and OS or tumour response. However, after the first cycles of chemotherapy (at 3 months), we observed that patients with lower tDNA levels had significantly longer DFS compared with those with higher levels (Cox Regression p =?0.0228).

Conclusions

At 3 months after the beginning of chemotherapy, the tDNA levels are correlated with DFS in patients with advanced gastric cancer who receive systemic chemotherapy. tDNA may be a specific, non-invasive and cost effective new biomarker for these patients.